Modeling human gastrointestinal inflammatory diseases using microphysiological culture systems.

Science.gov (United States)

Hartman, Kira G; Bortner, James D; Falk, Gary W; Ginsberg, Gregory G; Jhala, Nirag; Yu, Jian; Martín, Martín G; Rustgi, Anil K; Lynch, John P

2014-09-01

Gastrointestinal illnesses are a significant health burden for the US population, with 40 million office visits each year for gastrointestinal complaints and nearly 250,000 deaths. Acute and chronic inflammations are a common element of many gastrointestinal diseases. Inflammatory processes may be initiated by a chemical injury (acid reflux in the esophagus), an infectious agent (Helicobacter pylori infection in the stomach), autoimmune processes (graft versus host disease after bone marrow transplantation), or idiopathic (as in the case of inflammatory bowel diseases). Inflammation in these settings can contribute to acute complaints (pain, bleeding, obstruction, and diarrhea) as well as chronic sequelae including strictures and cancer. Research into the pathophysiology of these conditions has been limited by the availability of primary human tissues or appropriate animal models that attempt to physiologically model the human disease. With the many recent advances in tissue engineering and primary human cell culture systems, it is conceivable that these approaches can be adapted to develop novel human ex vivo systems that incorporate many human cell types to recapitulate in vivo growth and differentiation in inflammatory microphysiological environments. Such an advance in technology would improve our understanding of human disease progression and enhance our ability to test for disease prevention strategies and novel therapeutics. We will review current models for the inflammatory and immunological aspects of Barrett's esophagus, acute graft versus host disease, and inflammatory bowel disease and explore recent advances in culture methodologies that make these novel microphysiological research systems possible. © 2014 by the Society for Experimental Biology and Medicine.

Primatology. Human diseases threaten great apes.

Science.gov (United States)

Ferber, D

2000-08-25

Researchers are uncovering disturbing evidence that scientists and tourists are infecting wild primates with human pathogens. In response, ape specialists, including the American Society of Primatologists, are now calling for stricter health standards for researchers and tourists. They are also urging researchers to learn how to diagnose disease in their study animals.

Epidemiological studies on Johne’s disease in ruminants and Crohn’s disease in humans in Egypt

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A. Fawzy

2013-12-01

Full Text Available The correlation between Johne’s disease (JD and Crohn’s disease (CD in Egypt was investigated. A total of 371 human and 435 animal sera were collected from the same Egyptian governorates that had a known history of paratuberculosis infection and were subjected to screening for paratuberculosis using ELISA to assess the human/animal risk at a single time point. Five CD patients and five JD clinically infected dairy cattle were also included. Out of 435 animal serum samples, 196 (45.2% were MAP-ELISA positive. Twenty three (6.1% out of 371 human serum samples were MAP-ELISA positive, while 37 (9.9% were positive for anti-Saccharomyces cerevisiae antibodies (ASCA ELISAs. There was a very poor agreement between human MAP and ASCA ELISAs (0.036 by kappa statistics. The prevalence of MAP antibodies among humans is clearly lower than in animals. In conclusion there is an increase in Johne’s disease incidence in animals and a very weak relationship between MAP and Crohn’s disease in humans in Egypt.

[Oral microbiota: a promising predictor of human oral and systemic diseases].

Science.gov (United States)

Xin, Xu; Junzhi, He; Xuedong, Zhou

2015-12-01

A human oral microbiota is the ecological community of commensal, symbiotic, and pathogenic microorganisms found in human oral cavity. Oral microbiota exists mostly in the form of a biofilm and maintains a dynamic ecological equilibrium with the host body. However, the disturbance of this ecological balance inevitably causes oral infectious diseases, such as dental caries, apical periodontitis, periodontal diseases, pericoronitis, and craniofacial bone osteomyelitis. Oral microbiota is also correlated with many systemic diseases, including cancer, diabetes mellitus, rheumatoid arthritis, cardiovascular diseases, and preterm birth. Hence, oral microbiota has been considered as a potential biomarker of human diseases. The "Human Microbiome Project" and other metagenomic projects worldwide have advanced our knowledge of the human oral microbiota. The integration of these metadata has been the frontier of oral microbiology to improve clinical translation. By reviewing recent progress on studies involving oral microbiota-related oral and systemic diseases, we aimed to propose the essential role of oral microbiota in the prediction of the onset, progression, and prognosis of oral and systemic diseases. An oral microbiota-based prediction model helps develop a new paradigm of personalized medicine and benefits the human health in the post-metagenomics era.

Positions of human dwellings affect few tropical diseases near ...

African Journals Online (AJOL)

user

Some factors that possibly affect tropical disease distribution was investigated in about 500 randomize human dwellings. The studied factors include wild animals, domestic animals, wild plants, cultivated plants, nature of soil, nature of water, positions of human dwellings, nature of building material and position of animal ...

Drosophila tools and assays for the study of human diseases

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Berrak Ugur

2016-03-01

Full Text Available Many of the internal organ systems of Drosophila melanogaster are functionally analogous to those in vertebrates, including humans. Although humans and flies differ greatly in terms of their gross morphological and cellular features, many of the molecular mechanisms that govern development and drive cellular and physiological processes are conserved between both organisms. The morphological differences are deceiving and have led researchers to undervalue the study of invertebrate organs in unraveling pathogenic mechanisms of diseases. In this review and accompanying poster, we highlight the physiological and molecular parallels between fly and human organs that validate the use of Drosophila to study the molecular pathogenesis underlying human diseases. We discuss assays that have been developed in flies to study the function of specific genes in the central nervous system, heart, liver and kidney, and provide examples of the use of these assays to address questions related to human diseases. These assays provide us with simple yet powerful tools to study the pathogenic mechanisms associated with human disease-causing genes.

Multinational corporations and infectious disease: Embracing human rights management techniques.

Science.gov (United States)

Salcito, Kendyl; Singer, Burton H; Weiss, Mitchell G; Winkler, Mirko S; Krieger, Gary R; Wielga, Mark; Utzinger, Jürg

2014-01-01

Global health institutions have called for governments, international organisations and health practitioners to employ a human rights-based approach to infectious diseases. The motivation for a human rights approach is clear: poverty and inequality create conditions for infectious diseases to thrive, and the diseases, in turn, interact with social-ecological systems to promulgate poverty, inequity and indignity. Governments and intergovernmental organisations should be concerned with the control and elimination of these diseases, as widespread infections delay economic growth and contribute to higher healthcare costs and slower processes for realising universal human rights. These social determinants and economic outcomes associated with infectious diseases should interest multinational companies, partly because they have bearing on corporate productivity and, increasingly, because new global norms impose on companies a responsibility to respect human rights, including the right to health. We reviewed historical and recent developments at the interface of infectious diseases, human rights and multinational corporations. Our investigation was supplemented with field-level insights at corporate capital projects that were developed in areas of high endemicity of infectious diseases, which embraced rights-based disease control strategies. Experience and literature provide a longstanding business case and an emerging social responsibility case for corporations to apply a human rights approach to health programmes at global operations. Indeed, in an increasingly globalised and interconnected world, multinational corporations have an interest, and an important role to play, in advancing rights-based control strategies for infectious diseases. There are new opportunities for governments and international health agencies to enlist corporate business actors in disease control and elimination strategies. Guidance offered by the United Nations in 2011 that is widely embraced

A model for Huanglongbing spread between citrus plants including delay times and human intervention

Science.gov (United States)

Vilamiu, Raphael G. d'A.; Ternes, Sonia; Braga, Guilherme A.; Laranjeira, Francisco F.

2012-09-01

The objective of this work was to present a compartmental deterministic mathematical model for representing the dynamics of HLB disease in a citrus orchard, including delay in the disease's incubation phase in the plants, and a delay period on the nymphal stage of Diaphorina citri, the most important HLB insect vector in Brazil. Numerical simulations were performed to assess the possible impacts of human detection efficiency of symptomatic plants, as well as the influence of a long incubation period of HLB in the plant.

Single-Domain Antibodies As Therapeutics against Human Viral Diseases

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Yanling Wu

2017-12-01

Full Text Available In full-size formats, monoclonal antibodies have been highly successful as therapeutics against cancer and immune diseases. However, their large size leads to inaccessibility of some epitopes and relatively high production costs. As an alternative, single-domain antibodies (sdAbs offer special advantages compared to full-size antibodies, including smaller size, larger number of accessible epitopes, relatively low production costs and improved robustness. Currently, sdAbs are being developed against a number of viruses, including human immunodeficiency virus-1 (HIV-1, influenza viruses, hepatitis C virus (HCV, respiratory syncytial virus (RSV, and enteric viruses. Although sdAbs are very potent inhibitors of viral infections, no sdAbs have been approved for clinical use against virial infection or any other diseases. In this review, we discuss the current state of research on sdAbs against viruses and their potential as therapeutics against human viral diseases.

Tumor cell anaplasia and multinucleation are predictors of disease recurrence in oropharyngeal squamous cell carcinoma, including among just the human papillomavirus-related cancers.

Science.gov (United States)

Lewis, James S; Scantlebury, Juliette B; Luo, Jingqin; Thorstad, Wade L

2012-07-01

Oropharyngeal squamous cell carcinoma (SCC) is frequently related to high risk human papillomavirus. This tumor expresses p16, frequently has a nonkeratinizing morphology, and has improved outcomes. Despite having a good prognosis, tumors can have focal or diffuse nuclear anaplasia or multinucleation, the significance of which is unknown. From a database of 270 oropharyngeal SCCs with known histologic typing (using our established system) and p16 immunohistochemistry, all surgically resected cases (149) were reviewed. Anaplasia was defined as any × 40 field with ≥ 3 tumor nuclei with diameters ≥ 5 lymphocyte nuclei (~25 μm), and multinucleation was defined as any × 40 field with ≥ 3 tumor cells with multiple nuclei. p16 was positive in 128 cases (85.9%), 64 cases (43.0%) showed anaplasia, and 71 (47.7%) showed multinucleation. Anaplasia and multinucleation were highly related (Panaplasia or multinucleation had worse overall, disease-specific, and disease-free survival (Panaplasia and multinucleation both predicted worse disease-specific survival (hazard ratio 9.9, P=0.04; and hazard ratio 11.9, P=0.02, respectively) independent of the other variables. In summary, among surgically resectable oropharyngeal SCC (including among just the p16-positive cohort), tumor cell anaplasia and multinucleation independently correlated with disease recurrence and poorer survival.

Human gene therapy and imaging in neurological diseases

International Nuclear Information System (INIS)

Jacobs, Andreas H.; Winkler, Alexandra; Castro, Maria G.; Lowenstein, Pedro

2005-01-01

Molecular imaging aims to assess non-invasively disease-specific biological and molecular processes in animal models and humans in vivo. Apart from precise anatomical localisation and quantification, the most intriguing advantage of such imaging is the opportunity it provides to investigate the time course (dynamics) of disease-specific molecular events in the intact organism. Further, molecular imaging can be used to address basic scientific questions, e.g. transcriptional regulation, signal transduction or protein/protein interaction, and will be essential in developing treatment strategies based on gene therapy. Most importantly, molecular imaging is a key technology in translational research, helping to develop experimental protocols which may later be applied to human patients. Over the past 20 years, imaging based on positron emission tomography (PET) and magnetic resonance imaging (MRI) has been employed for the assessment and ''phenotyping'' of various neurological diseases, including cerebral ischaemia, neurodegeneration and brain gliomas. While in the past neuro-anatomical studies had to be performed post mortem, molecular imaging has ushered in the era of in vivo functional neuro-anatomy by allowing neuroscience to image structure, function, metabolism and molecular processes of the central nervous system in vivo in both health and disease. Recently, PET and MRI have been successfully utilised together in the non-invasive assessment of gene transfer and gene therapy in humans. To assess the efficiency of gene transfer, the same markers are being used in animals and humans, and have been applied for phenotyping human disease. Here, we review the imaging hallmarks of focal and disseminated neurological diseases, such as cerebral ischaemia, neurodegeneration and glioblastoma multiforme, as well as the attempts to translate gene therapy's experimental knowledge into clinical applications and the way in which this process is being promoted through the use of

Chronic Inflammatory Periodontal Disease in Patients with Human Immunodeficiency Virus.

OpenAIRE

Vania López Rodríguez; Emilio Carpio Muñoz; Vicente Fardales Macías; Iralys Benítez Guzmán

2009-01-01

Background: The Chronic Inflammatory Periodontal Disease is related with multiple risk factors. Those patients with human immunodeficiency virus have higher risk of presenting this disease and it is usually more serious in these cases. Objective: To describe the prevalence of Chronic Inflammatory Periodontal Disease in patients with HIV. Methods: Descriptive, observational, cross-sectional study including patients with HIV in Sancti Spiritus province. The occurrence of the disease was determi...

HUMAN PAPILLOMA VIRUS. PREVENTION OF HPV-ASSOCIATED DISEASES

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F. C. Shakhtakhtinskaya

2015-01-01

Full Text Available High prevalence of sexually transmitted diseases among the population attracts attention of specialists in all countries due to frequent development of complications resulting in reproductive dysfunction. The article presents one of the urgent issues of modern medicine — papillomavirus infection, which is the most common sexually transmitted disease. 70–80% of the sexually active persons contract human papilloma virus at one point. HPV induces a broad range of oncological reproductive diseases, including cervical, vulvar, vaginal and anal cancer and anogenital condylomae, which are observed both in men and women. The only reliable method of preventing papillomavirus infection is vaccination. The authors present new data on the use of the quadrivalent vaccine, including a new immunization pattern for 9–14-years-old girls.

Viral diseases and human evolution

Directory of Open Access Journals (Sweden)

Leal Élcio de Souza

2000-01-01

Full Text Available The interaction of man with viral agents was possibly a key factor shaping human evolution, culture and civilization from its outset. Evidence of the effect of disease, since the early stages of human speciation, through pre-historical times to the present suggest that the types of viruses associated with man changed in time. As human populations progressed technologically, they grew in numbers and density. As a consequence different viruses found suitable conditions to thrive and establish long-lasting associations with man. Although not all viral agents cause disease and some may in fact be considered beneficial, the present situation of overpopulation, poverty and ecological inbalance may have devastating effets on human progress. Recently emerged diseases causing massive pandemics (eg., HIV-1 and HCV, dengue, etc. are becoming formidable challenges, which may have a direct impact on the fate of our species.

The consequences of human actions on risks for infectious diseases: a review

OpenAIRE

Lindahl, Johanna F.; Grace, Delia

2015-01-01

The human population is growing, requiring more space for food production, and needing more animals to feed it. Emerging infectious diseases are increasing, causing losses in both human and animal lives, as well as large costs to society. Many factors are contributing to disease emergence, including climate change, globalization and urbanization, and most of these factors are to some extent caused by humans. Pathogens may be more or less prone to emergence in themselves, and rapidly mutating ...

Combinations of chromosome transfer and genome editing for the development of cell/animal models of human disease and humanized animal models.

Science.gov (United States)

Uno, Narumi; Abe, Satoshi; Oshimura, Mitsuo; Kazuki, Yasuhiro

2018-02-01

Chromosome transfer technology, including chromosome modification, enables the introduction of Mb-sized or multiple genes to desired cells or animals. This technology has allowed innovative developments to be made for models of human disease and humanized animals, including Down syndrome model mice and humanized transchromosomic (Tc) immunoglobulin mice. Genome editing techniques are developing rapidly, and permit modifications such as gene knockout and knockin to be performed in various cell lines and animals. This review summarizes chromosome transfer-related technologies and the combined technologies of chromosome transfer and genome editing mainly for the production of cell/animal models of human disease and humanized animal models. Specifically, these include: (1) chromosome modification with genome editing in Chinese hamster ovary cells and mouse A9 cells for efficient transfer to desired cell types; (2) single-nucleotide polymorphism modification in humanized Tc mice with genome editing; and (3) generation of a disease model of Down syndrome-associated hematopoiesis abnormalities by the transfer of human chromosome 21 to normal human embryonic stem cells and the induction of mutation(s) in the endogenous gene(s) with genome editing. These combinations of chromosome transfer and genome editing open up new avenues for drug development and therapy as well as for basic research.

Wildlife disease prevalence in human-modified landscapes.

Science.gov (United States)

Brearley, Grant; Rhodes, Jonathan; Bradley, Adrian; Baxter, Greg; Seabrook, Leonie; Lunney, Daniel; Liu, Yan; McAlpine, Clive

2013-05-01

Human-induced landscape change associated with habitat loss and fragmentation places wildlife populations at risk. One issue in these landscapes is a change in the prevalence of disease which may result in increased mortality and reduced fecundity. Our understanding of the influence of habitat loss and fragmentation on the prevalence of wildlife diseases is still in its infancy. What is evident is that changes in disease prevalence as a result of human-induced landscape modification are highly variable. The importance of infectious diseases for the conservation of wildlife will increase as the amount and quality of suitable habitat decreases due to human land-use pressures. We review the experimental and observational literature of the influence of human-induced landscape change on wildlife disease prevalence, and discuss disease transmission types and host responses as mechanisms that are likely to determine the extent of change in disease prevalence. It is likely that transmission dynamics will be the key process in determining a pathogen's impact on a host population, while the host response may ultimately determine the extent of disease prevalence. Finally, we conceptualize mechanisms and identify future research directions to increase our understanding of the relationship between human-modified landscapes and wildlife disease prevalence. This review highlights that there are rarely consistent relationships between wildlife diseases and human-modified landscapes. In addition, variation is evident between transmission types and landscape types, with the greatest positive influence on disease prevalence being in urban landscapes and directly transmitted disease systems. While we have a limited understanding of the potential influence of habitat loss and fragmentation on wildlife disease, there are a number of important areas to address in future research, particularly to account for the variability in increased and decreased disease prevalence. Previous studies

Mutations that Cause Human Disease: A Computational/Experimental Approach

Energy Technology Data Exchange (ETDEWEB)

Beernink, P; Barsky, D; Pesavento, B

2006-01-11

International genome sequencing projects have produced billions of nucleotides (letters) of DNA sequence data, including the complete genome sequences of 74 organisms. These genome sequences have created many new scientific opportunities, including the ability to identify sequence variations among individuals within a species. These genetic differences, which are known as single nucleotide polymorphisms (SNPs), are particularly important in understanding the genetic basis for disease susceptibility. Since the report of the complete human genome sequence, over two million human SNPs have been identified, including a large-scale comparison of an entire chromosome from twenty individuals. Of the protein coding SNPs (cSNPs), approximately half leads to a single amino acid change in the encoded protein (non-synonymous coding SNPs). Most of these changes are functionally silent, while the remainder negatively impact the protein and sometimes cause human disease. To date, over 550 SNPs have been found to cause single locus (monogenic) diseases and many others have been associated with polygenic diseases. SNPs have been linked to specific human diseases, including late-onset Parkinson disease, autism, rheumatoid arthritis and cancer. The ability to predict accurately the effects of these SNPs on protein function would represent a major advance toward understanding these diseases. To date several attempts have been made toward predicting the effects of such mutations. The most successful of these is a computational approach called ''Sorting Intolerant From Tolerant'' (SIFT). This method uses sequence conservation among many similar proteins to predict which residues in a protein are functionally important. However, this method suffers from several limitations. First, a query sequence must have a sufficient number of relatives to infer sequence conservation. Second, this method does not make use of or provide any information on protein structure, which

Molecular clocks and the human condition: approaching their characterization in human physiology and disease.

Science.gov (United States)

Fitzgerald, G A; Yang, G; Paschos, G K; Liang, X; Skarke, C

2015-09-01

Molecular clockworks knit together diverse biological networks and compelling evidence from model systems infers their importance in metabolism, immunological and cardiovascular function. Despite this and the diurnal variation in many aspects of human physiology and the phenotypic expression of disease, our understanding of the role and importance of clock function and dysfunction in humans is modest. There are tantalizing hints of connection across the translational divide and some correlative evidence of gene variation and human disease but most of what we know derives from forced desynchrony protocols in controlled environments. We now have the ability to monitor quantitatively ex vivo or in vivo the genome, metabolome, proteome and microbiome of humans in the wild. Combining this capability, with the power of mobile telephony and the evolution of remote sensing, affords a new opportunity for deep phenotyping, including the characterization of diurnal behaviour and the assessment of the impact of the clock on approved drug function. © 2015 John Wiley & Sons Ltd.

Human diseases associated with defective DNA repair

International Nuclear Information System (INIS)

Friedberg, E.C.; Ehmann, U.K.; Williams, J.I.

1979-01-01

The observations on xeroderma pigmentosum (XP) cells in culture were the first indications of defective DNA repair in association with human disease. Since then, a wealth of information on DNA repair in XP, and to a lesser extent in other diseases, has accumulated in the literature. Rather than clarifying the understanding of DNA repair mechanisms in normal cells and of defective DNA repair in human disease, the literature suggests an extraordinary complexity of both of the phenomena. In this review a number of discrete human diseases are considered separately. An attempt was made to systematically describe the pertinent clinical features and cellular and biochemical defects in these diseases, with an emphasis on defects in DNA metabolism, particularly DNA repair. Wherever possible observations have been correlated and unifying hypotheses presented concerning the nature of the basic defect(s) in these diseases. Discussions of the following diseases are presented: XP, ataxia telangiectasia; Fanconi's anemia; Hutchinson-Gilford progeria syndrome; Bloom's syndrome, Cockayne's syndrome; Down's syndrome; retinoblastoma; chronic lymphocytic leukemia; and other miscellaneous human diseases with possble DNA repair defects

PHD fingers in human diseases: Disorders arising from misinterpreting epigenetic marks

Energy Technology Data Exchange (ETDEWEB)

Baker, Lindsey A. [Rockefeller University, Laboratory of Chromatin Biology and Epigenetics, 1230 York Avenue, Box 78, New York, NY 10065 (United States); Allis, C. David [Rockefeller University, Laboratory of Chromatin Biology and Epigenetics, 1230 York Avenue, Box 78, New York, NY 10065 (United States)], E-mail: alliscd@rockefeller.edu; Wang, Gang G. [Rockefeller University, Laboratory of Chromatin Biology and Epigenetics, 1230 York Avenue, Box 78, New York, NY 10065 (United States)], E-mail: gwang@rockefeller.edu

2008-12-01

Histone covalent modifications regulate many, if not all, DNA-templated processes, including gene expression and DNA damage response. The biological consequences of histone modifications are mediated partially by evolutionarily conserved 'reader/effector' modules that bind to histone marks in a modification- and context-specific fashion and subsequently enact chromatin changes or recruit other proteins to do so. Recently, the Plant Homeodomain (PHD) finger has emerged as a class of specialized 'reader' modules that, in some instances, recognize the methylation status of histone lysine residues, such as histone H3 lysine 4 (H3K4). While mutations in catalytic enzymes that mediate the addition or removal of histone modifications (i.e., 'writers' and 'erasers') are already known to be involved in various human diseases, mutations in the modification-specific 'reader' proteins are only beginning to be recognized as contributing to human diseases. For instance, point mutations, deletions or chromosomal translocations that target PHD fingers encoded by many genes (such as recombination activating gene 2 (RAG2), Inhibitor of Growth (ING), nuclear receptor-binding SET domain-containing 1 (NSD1) and Alpha Thalassaemia and Mental Retardation Syndrome, X-linked (ATRX)) have been associated with a wide range of human pathologies including immunological disorders, cancers, and neurological diseases. In this review, we will discuss the structural features of PHD fingers as well as the diseases for which direct mutation or dysregulation of the PHD finger has been reported. We propose that misinterpretation of the epigenetic marks may serve as a general mechanism for human diseases of this category. Determining the regulatory roles of histone covalent modifications in the context of human disease will allow for a more thorough understanding of normal and pathological development, and may provide innovative therapeutic strategies

PHD fingers in human diseases: Disorders arising from misinterpreting epigenetic marks

International Nuclear Information System (INIS)

Baker, Lindsey A.; Allis, C. David; Wang, Gang G.

2008-01-01

Histone covalent modifications regulate many, if not all, DNA-templated processes, including gene expression and DNA damage response. The biological consequences of histone modifications are mediated partially by evolutionarily conserved 'reader/effector' modules that bind to histone marks in a modification- and context-specific fashion and subsequently enact chromatin changes or recruit other proteins to do so. Recently, the Plant Homeodomain (PHD) finger has emerged as a class of specialized 'reader' modules that, in some instances, recognize the methylation status of histone lysine residues, such as histone H3 lysine 4 (H3K4). While mutations in catalytic enzymes that mediate the addition or removal of histone modifications (i.e., 'writers' and 'erasers') are already known to be involved in various human diseases, mutations in the modification-specific 'reader' proteins are only beginning to be recognized as contributing to human diseases. For instance, point mutations, deletions or chromosomal translocations that target PHD fingers encoded by many genes (such as recombination activating gene 2 (RAG2), Inhibitor of Growth (ING), nuclear receptor-binding SET domain-containing 1 (NSD1) and Alpha Thalassaemia and Mental Retardation Syndrome, X-linked (ATRX)) have been associated with a wide range of human pathologies including immunological disorders, cancers, and neurological diseases. In this review, we will discuss the structural features of PHD fingers as well as the diseases for which direct mutation or dysregulation of the PHD finger has been reported. We propose that misinterpretation of the epigenetic marks may serve as a general mechanism for human diseases of this category. Determining the regulatory roles of histone covalent modifications in the context of human disease will allow for a more thorough understanding of normal and pathological development, and may provide innovative therapeutic strategies wherein 'chromatin readers' stand as potential drug

Borna disease virus and its role in the pathology of animals and humans

Directory of Open Access Journals (Sweden)

A. O. Mikheev

2017-12-01

Full Text Available Infectious diseases that are caused by numerous pathogenic microorganisms – bacteria, viruses, protozoa or fungi – can be transmitted from patients or carriers to healthy people or animals. A large group of infectious disease is caused by pathogens of animal infections – zoonoses. The issue of zoonoses is of great significance in human pathology and requires comprehensive study. This is of particular relevance to Ukraine, as the question of prevalence, level within the population and threats to human life and health from zoonoses, though highly important, has remained insufficiently studied. Information about many of these pathogens is absent in the existing scientific literature accessible in Ukraine – both veterinary and medical. This applies, in particular, to a causative agent of viral zoonoses the Borna disease virus or Bornavirus. For this purpose, an analysis of the literature concerning the role of the Bornavirus in the pathology of animals and humans was conducted. It is well known that a large number of pathogens of animal infections (zoonoses, including viral, pose a potential threat to human health. Among these potential threats is the Borna disease virus belonging to the family of Bornaviridae, order Mononegavirales. This order includes representatives of deadly human diseases like rabies (family Rhabdoviridae, Ebola virus (family Filoviridae and Nipah virus (family Paramyxoviridae. Borna virus disease affects mainly mammals, but can infect birds and even reptiles (Aspid bornavirus. It is established that Bornaviruses have a wide range of natural hosts (horses, sheeps, cats, bats and various birds, including domestic animals, which poses a potential threat to human health. This is evidenced by numerous, although contradictory, research into the role of the Borna disease virus in human pathologies such as schizophrenia, depression, prolonged fatigue syndrome, multiple sclerosis and others. Analysis of the literature clearly

Infectious prion diseases in humans: cannibalism, iatrogenicity and zoonoses.

Science.gov (United States)

Haïk, Stéphane; Brandel, Jean-Philippe

2014-08-01

In contrast with other neurodegenerative disorders associated to protein misfolding, human prion diseases include infectious forms (also called transmitted forms) such as kuru, iatrogenic Creutzfeldt-Jakob disease and variant Creutzfeldt-Jakob disease. The transmissible agent is thought to be solely composed of the abnormal isoform (PrP(Sc)) of the host-encoded prion protein that accumulated in the central nervous system of affected individuals. Compared to its normal counterpart, PrP(Sc) is β-sheet enriched and aggregated and its propagation is based on an autocatalytic conversion process. Increasing evidence supports the view that conformational variations of PrP(Sc) encoded the biological properties of the various prion strains that have been isolated by transmission studies in experimental models. Infectious forms of human prion diseases played a pivotal role in the emergence of the prion concept and in the characterization of the very unconventional properties of prions. They provide a unique model to understand how prion strains are selected and propagate in humans. Here, we review and discuss how genetic factors interplay with strain properties and route of transmission to influence disease susceptibility, incubation period and phenotypic expression in the light of the kuru epidemics due to ritual endocannibalism, the various series iatrogenic diseases secondary to extractive growth hormone treatment or dura mater graft and the epidemics of variant Creutzfeldt-Jakob disease linked to dietary exposure to the agent of bovine spongiform encephalopathy. Copyright © 2014 Elsevier B.V. All rights reserved.

Under the lash: Demodex mites in human diseases.

Science.gov (United States)

Lacey, Noreen; Kavanagh, Kevin; Tseng, Scheffer C G

2009-08-01

Demodex mites, class Arachnida and subclass Acarina, are elongated mites with clear cephalothorax and abdomens, the former with four pairs of legs. There are more than 100 species of Demodex mite, many of which are obligatory commensals of the pilosebaceous unit of mammals including cats, dogs, sheep, cattle, pigs, goats, deer, bats, hamsters, rats and mice. Among them, Demodex canis, which is found ubiquitously in dogs, is the most documented and investigated. In excessive numbers D. canis causes the inflammatory disease termed demodicosis (demodectic mange, follicular mange or red mange), which is more common in purebred dogs and has a hereditary predisposition in breeding kennels1. Two distinct Demodex species have been confirmed as the most common ectoparasite in man. The larger Demodex folliculorum, about 0.3-0.4 mm long, is primarily found as a cluster in the hair follicle (Figure 1a), while the smaller Demodex brevis, about 0.2-0.3 mm long with a spindle shape and stubby legs, resides solitarily in the sebaceous gland (Figure 1b). These two species are also ubiquitously found in all human races without gender preference. The pathogenic role of Demodex mites in veterinary medicine is not as greatly disputed as in human diseases. In this article, we review the key literature and our joint research experience regarding the pathogenic potential of these two mites in causing inflammatory diseases of human skin and eye. We hope that the evidence summarized herein will invite readers to take a different look at the life of Demodex mites in several common human diseases.

Modelling Neurodegenerative Diseases Using Human Pluripotent Stem Cells

DEFF Research Database (Denmark)

Hall, Vanessa Jane

2016-01-01

Neurodegenerative diseases are being modelled in-vitro using human patient-specific, induced pluripotent stem cells and transgenic embryonic stem cells to determine more about disease mechanisms, as well as to discover new treatments for patients. Current research in modelling Alzheimer’s disease......, frontotemporal dementia and Parkinson’s disease using pluripotent stem cells is described, along with the advent of gene-editing, which has been the complimentary tool for the field. Current methods used to model these diseases are predominantly dependent on 2D cell culture methods. Outcomes reveal that only...... that includes studying more complex 3D cell cultures, as well as accelerating aging of the neurons, may help to yield stronger phenotypes in the cultured cells. Thus, the use and application of pluripotent stem cells for modelling disease have already shown to be a powerful approach for discovering more about...

HSC extrinsic sex-related and intrinsic autoimmune disease-related human B-cell variation is recapitulated in humanized mice.

Science.gov (United States)

Borsotti, Chiara; Danzl, Nichole M; Nauman, Grace; Hölzl, Markus A; French, Clare; Chavez, Estefania; Khosravi-Maharlooei, Mohsen; Glauzy, Salome; Delmotte, Fabien R; Meffre, Eric; Savage, David G; Campbell, Sean R; Goland, Robin; Greenberg, Ellen; Bi, Jing; Satwani, Prakash; Yang, Suxiao; Bathon, Joan; Winchester, Robert; Sykes, Megan

2017-10-24

B cells play a major role in antigen presentation and antibody production in the development of autoimmune diseases, and some of these diseases disproportionally occur in females. Moreover, immune responses tend to be stronger in female vs male humans and mice. Because it is challenging to distinguish intrinsic from extrinsic influences on human immune responses, we used a personalized immune (PI) humanized mouse model, in which immune systems were generated de novo from adult human hematopoietic stem cells (HSCs) in immunodeficient mice. We assessed the effect of recipient sex and of donor autoimmune diseases (type 1 diabetes [T1D] and rheumatoid arthritis [RA]) on human B-cell development in PI mice. We observed that human B-cell levels were increased in female recipients regardless of the source of human HSCs or the strain of immunodeficient recipient mice. Moreover, mice injected with T1D- or RA-derived HSCs displayed B-cell abnormalities compared with healthy control HSC-derived mice, including altered B-cell levels, increased proportions of mature B cells and reduced CD19 expression. Our study revealed an HSC-extrinsic effect of recipient sex on human B-cell reconstitution. Moreover, the PI humanized mouse model revealed HSC-intrinsic defects in central B-cell tolerance that recapitulated those in patients with autoimmune diseases. These results demonstrate the utility of humanized mouse models as a tool to better understand human immune cell development and regulation.

Are human endogenous retroviruses triggers of autoimmune diseases?

DEFF Research Database (Denmark)

Nexø, Bjørn A; Villesen, Palle; Nissen, Kari K

2016-01-01

factors. Viruses including human endogenous retroviruses have long been linked to the occurrence of autoimmunity, but never proven to be causative factors. Endogenous viruses are retroviral sequences embedded in the host germline DNA and transmitted vertically through successive generations in a Mendelian...... manner. In this study by means of genetic epidemiology, we have searched for the involvement of endogenous retroviruses in three selected autoimmune diseases: multiple sclerosis, type 1 diabetes mellitus, and rheumatoid arthritis. We found that at least one human endogenous retroviral locus...

Linking environmental nutrient enrichment and disease emergence in humans and wildlife

Science.gov (United States)

Johnson, Pieter T. J.; Townsend, Alan R.; Cleveland, Cory C.; Glibert, Patricia M.; Howarth, Robert W.; McKenzie, Valerie J.; Rejmankova, Eliska; Ward, Mary H.

2009-01-01

Worldwide increases in the numbers of human and wildlife diseases present ecologists with the challenge of understanding how large-scale environmental changes affect host-parasite interactions. One of the most profound changes to Earth’s ecosystems is the alteration of global nutrient cycles, including those of phosphorus (P) and especially nitrogen (N). Alongside the obvious direct benefits of nutrient application for food production, growing evidence suggests that anthropogenic inputs of N and P can indirectly affect the abundance of infectious and noninfectious pathogens, sometimes leading to epidemic conditions. However, the mechanisms underpinning observed correlations, and how such patterns vary with disease type, have long remained conjectural. Here, we discuss recent experimental advances in this area to critically evaluate the relationship between environmental nutrient enrichment and disease. Given the inter-related nature of human and wildlife disease emergence, we include a broad range of human and wildlife examples from terrestrial, marine and freshwater ecosystems. We examine the consequences of nutrient pollution on directly transmitted, vector-borne, complex life cycle, and noninfectious pathogens, including West Nile virus, malaria, harmful algal blooms, coral reef diseases and amphibian malformations. Our synthetic examination suggests that the effects of environmental nutrient enrichment on disease are complex and multifaceted, varying with the type of pathogen, host species and condition, attributes of the ecosystem and the degree of enrichment; some pathogens increase in abundance whereas others decline or disappear. Nevertheless, available evidence indicates that ecological changes associated with nutrient enrichment often exacerbate infection and disease caused by generalist parasites with direct or simple life cycles. Observed mechanisms include changes in host/vector density, host distribution, infection resistance, pathogen virulence or

Mobile technologies for disease surveillance in humans and animals.

Science.gov (United States)

Mwabukusi, Mpoki; Karimuribo, Esron D; Rweyemamu, Mark M; Beda, Eric

2014-04-23

A paper-based disease reporting system has been associated with a number of challenges. These include difficulties to submit hard copies of the disease surveillance forms because of poor road infrastructure, weather conditions or challenging terrain, particularly in the developing countries. The system demands re-entry of the data at data processing and analysis points, thus making it prone to introduction of errors during this process. All these challenges contribute to delayed acquisition, processing and response to disease events occurring in remote hard to reach areas. Our study piloted the use of mobile phones in order to transmit near to real-time data from remote districts in Tanzania (Ngorongoro and Ngara), Burundi (Muyinga) and Zambia (Kazungula and Sesheke). Two technologies namely, digital and short messaging services were used to capture and transmit disease event data in the animal and human health sectors in the study areas based on a server-client model. Smart phones running the Android operating system (minimum required version: Android 1.6), and which supported open source application, Epicollect, as well as the Open Data Kit application, were used in the study. These phones allowed collection of geo-tagged data, with the opportunity of including static and moving images related to disease events. The project supported routine disease surveillance systems in the ministries responsible for animal and human health in Burundi, Tanzania and Zambia, as well as data collection for researchers at the Sokoine University of Agriculture, Tanzania. During the project implementation period between 2011 and 2013, a total number of 1651 diseases event-related forms were submitted, which allowed reporters to include GPS coordinates and photographs related to the events captured. It was concluded that the new technology-based surveillance system is useful in providing near to real-time data, with potential for enhancing timely response in rural remote areas of

Proteins aggregation and human diseases

International Nuclear Information System (INIS)

Hu, Chin-Kun

2015-01-01

Many human diseases and the death of most supercentenarians are related to protein aggregation. Neurodegenerative diseases include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), frontotemporallobar degeneration, etc. Such diseases are due to progressive loss of structure or function of neurons caused by protein aggregation. For example, AD is considered to be related to aggregation of Aβ40 (peptide with 40 amino acids) and Aβ42 (peptide with 42 amino acids) and HD is considered to be related to aggregation of polyQ (polyglutamine) peptides. In this paper, we briefly review our recent discovery of key factors for protein aggregation. We used a lattice model to study the aggregation rates of proteins and found that the probability for a protein sequence to appear in the conformation of the aggregated state can be used to determine the temperature at which proteins can aggregate most quickly. We used molecular dynamics and simple models of polymer chains to study relaxation and aggregation of proteins under various conditions and found that when the bending-angle dependent and torsion-angle dependent interactions are zero or very small, then protein chains tend to aggregate at lower temperatures. All atom models were used to identify a key peptide chain for the aggregation of insulin chains and to find that two polyQ chains prefer anti-parallel conformation. It is pointed out that in many cases, protein aggregation does not result from protein mis-folding. A potential drug from Chinese medicine was found for Alzheimer's disease. (paper)

Proteins aggregation and human diseases

Science.gov (United States)

Hu, Chin-Kun

2015-04-01

Many human diseases and the death of most supercentenarians are related to protein aggregation. Neurodegenerative diseases include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), frontotemporallobar degeneration, etc. Such diseases are due to progressive loss of structure or function of neurons caused by protein aggregation. For example, AD is considered to be related to aggregation of Aβ40 (peptide with 40 amino acids) and Aβ42 (peptide with 42 amino acids) and HD is considered to be related to aggregation of polyQ (polyglutamine) peptides. In this paper, we briefly review our recent discovery of key factors for protein aggregation. We used a lattice model to study the aggregation rates of proteins and found that the probability for a protein sequence to appear in the conformation of the aggregated state can be used to determine the temperature at which proteins can aggregate most quickly. We used molecular dynamics and simple models of polymer chains to study relaxation and aggregation of proteins under various conditions and found that when the bending-angle dependent and torsion-angle dependent interactions are zero or very small, then protein chains tend to aggregate at lower temperatures. All atom models were used to identify a key peptide chain for the aggregation of insulin chains and to find that two polyQ chains prefer anti-parallel conformation. It is pointed out that in many cases, protein aggregation does not result from protein mis-folding. A potential drug from Chinese medicine was found for Alzheimer's disease.

The role of chemerin in human disease

Directory of Open Access Journals (Sweden)

Magdalena Stojek

2017-02-01

Full Text Available Adipose tissue is not merely a storage depot of triacylglycerols but also a major endocrine organ. Its cells, including adipocytes, synthesize and secrete a range of biologically active molecules termed adipokines. Adipokines that display the properties of cytokines are often called adipocytokines. In recent years there has been increasing interest in a new adipokine called chemerin. Chemerin is a protein synthesized mostly by the adipose tissue and the liver as inactive pre-pro-chemerin. After the intracellular hydrolytic cutting off of the 20-amino-acid N-terminal polypeptide, it is secreted into the bloodstream as inactive pro-chemerin. Biologically active chemerin is then derived from pro-chemerin after cleavage of the C-terminal fragment by serum proteases involved in inflammation, coagulation and fibrinolysis. Proteolytic cleavage leads to formation of several chemerin-derived peptides, both biologically active (often with opposing functions and inactive.Within the last decade, there has been a growing number of publications regarding the role of chemerin in human disease. It seems to be implicated in the inflammatory response, metabolic syndrome, cardiovascular disease and alimentary tract disorders. The article presents the most recent information on the role of chemerin in human disease, and specifically alimentary tract disorders. The available evidence suggests that chemerin is an important link between adipose tissue mass, metabolic processes, the immune system and inflammation, and therefore plays a major role in human pathophysiology.

Annotating the human genome with Disease Ontology

Science.gov (United States)

Osborne, John D; Flatow, Jared; Holko, Michelle; Lin, Simon M; Kibbe, Warren A; Zhu, Lihua (Julie); Danila, Maria I; Feng, Gang; Chisholm, Rex L

2009-01-01

Background The human genome has been extensively annotated with Gene Ontology for biological functions, but minimally computationally annotated for diseases. Results We used the Unified Medical Language System (UMLS) MetaMap Transfer tool (MMTx) to discover gene-disease relationships from the GeneRIF database. We utilized a comprehensive subset of UMLS, which is disease-focused and structured as a directed acyclic graph (the Disease Ontology), to filter and interpret results from MMTx. The results were validated against the Homayouni gene collection using recall and precision measurements. We compared our results with the widely used Online Mendelian Inheritance in Man (OMIM) annotations. Conclusion The validation data set suggests a 91% recall rate and 97% precision rate of disease annotation using GeneRIF, in contrast with a 22% recall and 98% precision using OMIM. Our thesaurus-based approach allows for comparisons to be made between disease containing databases and allows for increased accuracy in disease identification through synonym matching. The much higher recall rate of our approach demonstrates that annotating human genome with Disease Ontology and GeneRIF for diseases dramatically increases the coverage of the disease annotation of human genome. PMID:19594883

Dissecting the role of AMP-activated protein kinase in human diseases

Institute of Scientific and Technical Information of China (English)

Jin Li; Liping Zhong; Fengzhong Wang; Haibo Zhu

2017-01-01

AMP-activated protein kinase (AMPK),known as a sensor and a master of cellular energy balance,integrates various regulatory signals including anabolic and catabolic metabolic processes.Accompanying the application of genetic methods and a plethora of AMPK agonists,rapid progress has identified AMPK as an attractive therapeutic target for several human diseases,such as cancer,type 2 diabetes,atherosclerosis,myocardial ischemia/reperfusion injury and neurodegenerative disease.The role of AMPK in metabolic and energetic modulation both at the intracellular and whole body levels has been reviewed elsewhere.In the present review,we summarize and update the paradoxical role of AMPK implicated in the diseases mentioned above and put forward the challenge encountered.Thus it will be expected to provide important clues for exploring rational methods of intervention in human diseases.

Trends in population-based studies of human genetics in infectious diseases.

Science.gov (United States)

Rowell, Jessica L; Dowling, Nicole F; Yu, Wei; Yesupriya, Ajay; Zhang, Lyna; Gwinn, Marta

2012-01-01

Pathogen genetics is already a mainstay of public health investigation and control efforts; now advances in technology make it possible to investigate the role of human genetic variation in the epidemiology of infectious diseases. To describe trends in this field, we analyzed articles that were published from 2001 through 2010 and indexed by the HuGE Navigator, a curated online database of PubMed abstracts in human genome epidemiology. We extracted the principal findings from all meta-analyses and genome-wide association studies (GWAS) with an infectious disease-related outcome. Finally, we compared the representation of diseases in HuGE Navigator with their contributions to morbidity worldwide. We identified 3,730 articles on infectious diseases, including 27 meta-analyses and 23 GWAS. The number published each year increased from 148 in 2001 to 543 in 2010 but remained a small fraction (about 7%) of all studies in human genome epidemiology. Most articles were by authors from developed countries, but the percentage by authors from resource-limited countries increased from 9% to 25% during the period studied. The most commonly studied diseases were HIV/AIDS, tuberculosis, hepatitis B infection, hepatitis C infection, sepsis, and malaria. As genomic research methods become more affordable and accessible, population-based research on infectious diseases will be able to examine the role of variation in human as well as pathogen genomes. This approach offers new opportunities for understanding infectious disease susceptibility, severity, treatment, control, and prevention.

A 3D human neural cell culture system for modeling Alzheimer’s disease

Science.gov (United States)

Kim, Young Hye; Choi, Se Hoon; D’Avanzo, Carla; Hebisch, Matthias; Sliwinski, Christopher; Bylykbashi, Enjana; Washicosky, Kevin J.; Klee, Justin B.; Brüstle, Oliver; Tanzi, Rudolph E.; Kim, Doo Yeon

2015-01-01

Stem cell technologies have facilitated the development of human cellular disease models that can be used to study pathogenesis and test therapeutic candidates. These models hold promise for complex neurological diseases such as Alzheimer’s disease (AD) because existing animal models have been unable to fully recapitulate all aspects of pathology. We recently reported the characterization of a novel three-dimensional (3D) culture system that exhibits key events in AD pathogenesis, including extracellular aggregation of β-amyloid and accumulation of hyperphosphorylated tau. Here we provide instructions for the generation and analysis of 3D human neural cell cultures, including the production of genetically modified human neural progenitor cells (hNPCs) with familial AD mutations, the differentiation of the hNPCs in a 3D matrix, and the analysis of AD pathogenesis. The 3D culture generation takes 1–2 days. The aggregation of β-amyloid is observed after 6-weeks of differentiation followed by robust tau pathology after 10–14 weeks. PMID:26068894

Molecular mechanisms of acrolein toxicity: relevance to human disease.

Science.gov (United States)

Moghe, Akshata; Ghare, Smita; Lamoreau, Bryan; Mohammad, Mohammad; Barve, Shirish; McClain, Craig; Joshi-Barve, Swati

2015-02-01

Acrolein, a highly reactive unsaturated aldehyde, is a ubiquitous environmental pollutant and its potential as a serious environmental health threat is beginning to be recognized. Humans are exposed to acrolein per oral (food and water), respiratory (cigarette smoke, automobile exhaust, and biocide use) and dermal routes, in addition to endogenous generation (metabolism and lipid peroxidation). Acrolein has been suggested to play a role in several disease states including spinal cord injury, multiple sclerosis, Alzheimer's disease, cardiovascular disease, diabetes mellitus, and neuro-, hepato-, and nephro-toxicity. On the cellular level, acrolein exposure has diverse toxic effects, including DNA and protein adduction, oxidative stress, mitochondrial disruption, membrane damage, endoplasmic reticulum stress, and immune dysfunction. This review addresses our current understanding of each pathogenic mechanism of acrolein toxicity, with emphasis on the known and anticipated contribution to clinical disease, and potential therapies. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Molecular Mechanism of Adult Neurogenesis and its Association with Human Brain Diseases

Directory of Open Access Journals (Sweden)

He Liu

2016-01-01

Full Text Available Recent advances in neuroscience challenge the old dogma that neurogenesis occurs only during embryonic development. Mounting evidence suggests that functional neurogenesis occurs throughout adulthood. This review article discusses molecular factors that affect adult neurogenesis, including morphogens, growth factors, neurotransmitters, transcription factors, and epigenetic factors. Furthermore, we summarize and compare current evidence of associations between adult neurogenesis and human brain diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and brain tumors.

Endangered species: mitochondrial DNA loss as a mechanism of human disease.

Science.gov (United States)

Herrera, Alan; Garcia, Iraselia; Gaytan, Norma; Jones, Edith; Maldonado, Alicia; Gilkerson, Robert

2015-06-01

Human mitochondrial DNA (mtDNA) is a small maternally inherited DNA, typically present in hundreds of copies in a single human cell. Thus, despite its small size, the mitochondrial genome plays a crucial role in the metabolic homeostasis of the cell. Our understanding of mtDNA genotype-phenotype relationships is derived largely from studies of the classical mitochondrial neuromuscular diseases, in which mutations of mtDNA lead to compromised mitochondrial bioenergetic function, with devastating pathological consequences. Emerging research suggests that loss, rather than mutation, of mtDNA plays a major role across a range of prevalent human diseases, including diabetes mellitus, cardiovascular disease, and aging. Here, we examine the 'rules' of mitochondrial genetics and function, the clinical settings in which loss of mtDNA is an emerging pathogenic mechanism, and explore mtDNA damage and its consequences for the organellar network and cell at large. As extranuclear genetic material arrayed throughout the cell to support metabolism, mtDNA is increasingly implicated in a host of disease conditions, opening a range of exciting questions regarding mtDNA and its role in cellular homeostasis.

Transfer RNA and human disease

Directory of Open Access Journals (Sweden)

Jamie A Abbott

2014-06-01

Full Text Available Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA genes are hotspots for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase, mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers, and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing. Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

Transfer RNA and human disease.

Science.gov (United States)

Abbott, Jamie A; Francklyn, Christopher S; Robey-Bond, Susan M

2014-01-01

Pathological mutations in tRNA genes and tRNA processing enzymes are numerous and result in very complicated clinical phenotypes. Mitochondrial tRNA (mt-tRNA) genes are "hotspots" for pathological mutations and over 200 mt-tRNA mutations have been linked to various disease states. Often these mutations prevent tRNA aminoacylation. Disrupting this primary function affects protein synthesis and the expression, folding, and function of oxidative phosphorylation enzymes. Mitochondrial tRNA mutations manifest in a wide panoply of diseases related to cellular energetics, including COX deficiency (cytochrome C oxidase), mitochondrial myopathy, MERRF (Myoclonic Epilepsy with Ragged Red Fibers), and MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes). Diseases caused by mt-tRNA mutations can also affect very specific tissue types, as in the case of neurosensory non-syndromic hearing loss and pigmentary retinopathy, diabetes mellitus, and hypertrophic cardiomyopathy. Importantly, mitochondrial heteroplasmy plays a role in disease severity and age of onset as well. Not surprisingly, mutations in enzymes that modify cytoplasmic and mitochondrial tRNAs are also linked to a diverse range of clinical phenotypes. In addition to compromised aminoacylation of the tRNAs, mutated modifying enzymes can also impact tRNA expression and abundance, tRNA modifications, tRNA folding, and even tRNA maturation (e.g., splicing). Some of these pathological mutations in tRNAs and processing enzymes are likely to affect non-canonical tRNA functions, and contribute to the diseases without significantly impacting on translation. This chapter will review recent literature on the relation of mitochondrial and cytoplasmic tRNA, and enzymes that process tRNAs, to human disease. We explore the mechanisms involved in the clinical presentation of these various diseases with an emphasis on neurological disease.

Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease

OpenAIRE

Specht, Andrew; Fiske, Laurie; Erger, Kirsten; Cossette, Travis; Verstegen, John; Campbell-Thompson, Martha; Struck, Maggie B.; Lee, Young Mok; Chou, Janice Y.; Byrne, Barry J.; Correia, Catherine E.; Mah, Cathryn S.; Weinstein, David A.; Conlon, Thomas J.

2011-01-01

A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size,...

A Novel Human Body Area Network for Brain Diseases Analysis.

Science.gov (United States)

Lin, Kai; Xu, Tianlang

2016-10-01

Development of wireless sensor and mobile communication technology provide an unprecedented opportunity for realizing smart and interactive healthcare systems. Designing such systems aims to remotely monitor the health and diagnose the diseases for users. In this paper, we design a novel human body area network for brain diseases analysis, which is named BABDA. Considering the brain is one of the most complex organs in the human body, the BABDA system provides four function modules to ensure the high quality of the analysis result, which includes initial data collection, data correction, data transmission and comprehensive data analysis. The performance evaluation conducted in a realistic environment with several criteria shows the availability and practicability of the BABDA system.

Mobile technologies for disease surveillance in humans and animals

Directory of Open Access Journals (Sweden)

Mpoki Mwabukusi

2014-04-01

Full Text Available A paper-based disease reporting system has been associated with a number of challenges. These include difficulties to submit hard copies of the disease surveillance forms because of poor road infrastructure, weather conditions or challenging terrain, particularly in the developing countries. The system demands re-entry of the data at data processing and analysis points, thus making it prone to introduction of errors during this process. All these challenges contribute to delayed acquisition, processing and response to disease events occurring in remote hard to reach areas. Our study piloted the use of mobile phones in order to transmit near to real-time data from remote districts in Tanzania (Ngorongoro and Ngara, Burundi (Muyinga and Zambia (Kazungula and Sesheke. Two technologies namely, digital and short messaging services were used to capture and transmit disease event data in the animal and human health sectors in the study areas based on a server–client model. Smart phones running the Android operating system (minimum required version: Android 1.6, and which supported open source application, Epicollect, as well as the Open Data Kit application, were used in the study. These phones allowed collection of geo-tagged data, with the opportunity of including static and moving images related to disease events. The project supported routine disease surveillance systems in the ministries responsible for animal and human health in Burundi, Tanzania and Zambia, as well as data collection for researchers at the Sokoine University of Agriculture, Tanzania. During the project implementation period between 2011 and 2013, a total number of 1651 diseases event-related forms were submitted, which allowed reporters to include GPS coordinates and photographs related to the events captured. It was concluded that the new technology-based surveillance system is useful in providing near to real-time data, with potential for enhancing

Mice, humans and haplotypes--the hunt for disease genes in SLE.

Science.gov (United States)

Rigby, R J; Fernando, M M A; Vyse, T J

2006-09-01

Defining the polymorphisms that contribute to the development of complex genetic disease traits is a challenging, although increasingly tractable problem. Historically, the technical difficulties in conducting association studies across the entire human genome are such that murine models have been used to generate candidate genes for analysis in human complex diseases, such as SLE. In this article we discuss the advantages and disadvantages of this approach and specifically address some assumptions made in the transition from studying one species to another, using lupus as an example. These issues include differences in genetic structure and genetic organisation which are a reflection on the population history. Clearly there are major differences in the histories of the human population and inbred laboratory strains of mice. Both human and murine genomes do exhibit structure at the genetic level. That is to say, they comprise haplotypes which are genomic regions that carry runs of polymorphisms that are not independently inherited. Haplotypes therefore reduce the number of combinations of the polymorphisms in the DNA in that region and facilitate the identification of disease susceptibility genes in both mice and humans. There are now novel means of generating candidate genes in SLE using mutagenesis (with ENU) in mice and identifying mice that generate antinuclear autoimmunity. In addition, murine models still provide a valuable means of exploring the functional consequences of genetic variation. However, advances in technology are such that human geneticists can now screen large fractions of the human genome for disease associations using microchip technologies that provide information on upwards of 100,000 different polymorphisms. These approaches are aimed at identifying haplotypes that carry disease susceptibility mutations and rely less on the generation of candidate genes.

Atypical memory B cells in human chronic infectious diseases: An interim report.

Science.gov (United States)

Portugal, Silvia; Obeng-Adjei, Nyamekye; Moir, Susan; Crompton, Peter D; Pierce, Susan K

2017-11-01

Immunological memory is a remarkable phenomenon in which survival of an initial infection by a pathogen leads to life-long protection from disease upon subsequent exposure to that same pathogen. For many infectious diseases, long-lived protective humoral immunity is induced after only a single infection in a process that depends on the generation of memory B cells (MBCs) and long-lived plasma cells. However, over the past decade it has become increasingly evident that many chronic human infectious diseases to which immunity is not readily established, including HIV-AIDS, malaria and TB, are associated with fundamental alterations in the composition and functionality of MBC compartments. A common feature of these diseases appears to be a large expansion of what have been termed exhausted B cells, tissue-like memory B cells or atypical memory B cells (aMBCs) that, for simplicity's sake, we refer to here as aMBCs. It has been suggested that chronic immune activation and inflammation drive the expansion of aMBCs and that in some way aMBCs contribute to deficiencies in the acquisition of immunity in chronic infectious diseases. Although aMBCs are heterogeneous both within individuals and between diseases, they have several features in common including low expression of the cell surface markers that define classical MBCs in humans including CD21 and CD27 and high expression of genes not usually expressed by classical MBCs including T-bet, CD11c and a variety of inhibitory receptors, notably members of the FcRL family. Another distinguishing feature is their greatly diminished ability to be stimulated through their B cell receptors to proliferate, secrete cytokines or produce antibodies. In this review, we describe our current understanding of the phenotypic markers of aMBCs, their specificity in relation to the disease-causing pathogen, their functionality, the drivers of their expansion in chronic infections and their life span. We briefly summarize the features of a

Influenza as a human disease

Indian Academy of Sciences (India)

First page Back Continue Last page Graphics. Influenza as a human disease. Commonly perceived as a mild disease, affects every one, sometimes a couple of times in a year. Globally, seasonal influenza epidemics result in about three to five million yearly cases of severe illness and about 250,000 to 500,000 yearly ...

Drosophila as a Model for Human Diseases-Focus on Innate Immunity in Barrier Epithelia.

Science.gov (United States)

Bergman, P; Seyedoleslami Esfahani, S; Engström, Y

2017-01-01

Epithelial immunity protects the host from harmful microbial invaders but also controls the beneficial microbiota on epithelial surfaces. When this delicate balance between pathogen and symbiont is disturbed, clinical disease often occurs, such as in inflammatory bowel disease, cystic fibrosis, or atopic dermatitis, which all can be in part linked to impairment of barrier epithelia. Many innate immune receptors, signaling pathways, and effector molecules are evolutionarily conserved between human and Drosophila. This review describes the current knowledge on Drosophila as a model for human diseases, with a special focus on innate immune-related disorders of the gut, lung, and skin. The discovery of antimicrobial peptides, the crucial role of Toll and Toll-like receptors, and the evolutionary conservation of signaling to the immune systems of both human and Drosophila are described in a historical perspective. Similarities and differences between human and Drosophila are discussed; current knowledge on receptors, signaling pathways, and effectors are reviewed, including antimicrobial peptides, reactive oxygen species, as well as autophagy. We also give examples of human diseases for which Drosophila appears to be a useful model. In addition, the limitations of the Drosophila model are mentioned. Finally, we propose areas for future research, which include using the Drosophila model for drug screening, as a validation tool for novel genetic mutations in humans and for exploratory research of microbiota-host interactions, with relevance for infection, wound healing, and cancer. © 2017 Elsevier Inc. All rights reserved.

Palaeopathology and genes: investigating the genetics of infectious diseases in excavated human skeletal remains and mummies from past populations.

Science.gov (United States)

Anastasiou, Evilena; Mitchell, Piers D

2013-10-01

The aim of this paper is to review the use of genetics in palaeomicrobiology, and to highlight the importance of understanding past diseases. Palaeomicrobiology is the study of disease pathogens in skeletal and mummified remains from archaeological contexts. It has revolutionarised our understanding of health in the past by enabling a deeper knowledge of the origins and evolution of many diseases that have shaped us as a species. Bacterial diseases explored include tuberculosis, leprosy, bubonic plague, typhoid, syphilis, endemic and epidemic typhus, trench fever, and Helicobacter pylori. Viral diseases discussed include influenza, hepatitis B, human papilloma virus (HPV), human T-cell lymphotrophic virus (HTLV-1) and human immunodeficiency virus (HIV). Parasitic diseases investigated include malaria, leishmaniasis, Chagas' disease, roundworm, whipworm, pinworm, Chinese liver fluke, fleas and lice. Through a better understanding of disease origins and their evolution, we can place into context how many infectious diseases are changing over time, and so help us estimate how they may change in the future. Copyright © 2013 Elsevier B.V. All rights reserved.

Defining the Human Macula Transcriptome and Candidate Retinal Disease Genes UsingEyeSAGE

Science.gov (United States)

Rickman, Catherine Bowes; Ebright, Jessica N.; Zavodni, Zachary J.; Yu, Ling; Wang, Tianyuan; Daiger, Stephen P.; Wistow, Graeme; Boon, Kathy; Hauser, Michael A.

2009-01-01

Purpose To develop large-scale, high-throughput annotation of the human macula transcriptome and to identify and prioritize candidate genes for inherited retinal dystrophies, based on ocular-expression profiles using serial analysis of gene expression (SAGE). Methods Two human retina and two retinal pigment epithelium (RPE)/choroid SAGE libraries made from matched macula or midperipheral retina and adjacent RPE/choroid of morphologically normal 28- to 66-year-old donors and a human central retina longSAGE library made from 41- to 66-year-old donors were generated. Their transcription profiles were entered into a relational database, EyeSAGE, including microarray expression profiles of retina and publicly available normal human tissue SAGE libraries. EyeSAGE was used to identify retina- and RPE-specific and -associated genes, and candidate genes for retina and RPE disease loci. Differential and/or cell-type specific expression was validated by quantitative and single-cell RT-PCR. Results Cone photoreceptor-associated gene expression was elevated in the macula transcription profiles. Analysis of the longSAGE retina tags enhanced tag-to-gene mapping and revealed alternatively spliced genes. Analysis of candidate gene expression tables for the identified Bardet-Biedl syndrome disease gene (BBS5) in the BBS5 disease region table yielded BBS5 as the top candidate. Compelling candidates for inherited retina diseases were identified. Conclusions The EyeSAGE database, combining three different gene-profiling platforms including the authors’ multidonor-derived retina/RPE SAGE libraries and existing single-donor retina/RPE libraries, is a powerful resource for definition of the retina and RPE transcriptomes. It can be used to identify retina-specific genes, including alternatively spliced transcripts and to prioritize candidate genes within mapped retinal disease regions. PMID:16723438

in Human Liver Diseases

Directory of Open Access Journals (Sweden)

Minoru Fujimoto

2010-01-01

Full Text Available Toll-like receptor (TLR signaling pathways are strictly coordinated by several mechanisms to regulate adequate innate immune responses. Recent lines of evidence indicate that the suppressor of cytokine signaling (SOCS family proteins, originally identified as negative-feedback regulators in cytokine signaling, are involved in the regulation of TLR-mediated immune responses. SOCS1, a member of SOCS family, is strongly induced upon TLR stimulation. Cells lacking SOCS1 are hyperresponsive to TLR stimulation. Thus, SOCS1 is an important regulator for both cytokine and TLR-induced responses. As an immune organ, the liver contains various types of immune cells such as T cells, NK cells, NKT cells, and Kupffer cells and is continuously challenged with gut-derived bacterial and dietary antigens. SOCS1 may be implicated in pathophysiology of the liver. The studies using SOCS1-deficient mice revealed that endogenous SOCS1 is critical for the prevention of liver diseases such as hepatitis, cirrhosis, and cancers. Recent studies on humans suggest that SOCS1 is involved in the development of various liver disorders in humans. Thus, SOCS1 and other SOCS proteins are potential targets for the therapy of human liver diseases.

Genome-scale metabolic models applied to human health and disease.

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Cook, Daniel J; Nielsen, Jens

2017-11-01

Advances in genome sequencing, high throughput measurement of gene and protein expression levels, data accessibility, and computational power have allowed genome-scale metabolic models (GEMs) to become a useful tool for understanding metabolic alterations associated with many different diseases. Despite the proven utility of GEMs, researchers confront multiple challenges in the use of GEMs, their application to human health and disease, and their construction and simulation in an organ-specific and disease-specific manner. Several approaches that researchers are taking to address these challenges include using proteomic and transcriptomic-informed methods to build GEMs for individual organs, diseases, and patients and using constraints on model behavior during simulation to match observed metabolic fluxes. We review the challenges facing researchers in the use of GEMs, review the approaches used to address these challenges, and describe advances that are on the horizon and could lead to a better understanding of human metabolism. WIREs Syst Biol Med 2017, 9:e1393. doi: 10.1002/wsbm.1393 For further resources related to this article, please visit the WIREs website. © 2017 Wiley Periodicals, Inc.

Genome editing of human pluripotent stem cells to generate human cellular disease models

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Kiran Musunuru

2013-07-01

Full Text Available Disease modeling with human pluripotent stem cells has come into the public spotlight with the awarding of the Nobel Prize in Physiology or Medicine for 2012 to Drs John Gurdon and Shinya Yamanaka for the discovery that mature cells can be reprogrammed to become pluripotent. This discovery has opened the door for the generation of pluripotent stem cells from individuals with disease and the differentiation of these cells into somatic cell types for the study of disease pathophysiology. The emergence of genome-editing technology over the past few years has made it feasible to generate and investigate human cellular disease models with even greater speed and efficiency. Here, recent technological advances in genome editing, and its utility in human biology and disease studies, are reviewed.

Mitochondrial Fusion Proteins and Human Diseases

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Michela Ranieri

2013-01-01

Full Text Available Mitochondria are highly dynamic, complex organelles that continuously alter their shape, ranging between two opposite processes, fission and fusion, in response to several stimuli and the metabolic demands of the cell. Alterations in mitochondrial dynamics due to mutations in proteins involved in the fusion-fission machinery represent an important pathogenic mechanism of human diseases. The most relevant proteins involved in the mitochondrial fusion process are three GTPase dynamin-like proteins: mitofusin 1 (MFN1 and 2 (MFN2, located in the outer mitochondrial membrane, and optic atrophy protein 1 (OPA1, in the inner membrane. An expanding number of degenerative disorders are associated with mutations in the genes encoding MFN2 and OPA1, including Charcot-Marie-Tooth disease type 2A and autosomal dominant optic atrophy. While these disorders can still be considered rare, defective mitochondrial dynamics seem to play a significant role in the molecular and cellular pathogenesis of more common neurodegenerative diseases, for example, Alzheimer’s and Parkinson’s diseases. This review provides an overview of the basic molecular mechanisms involved in mitochondrial fusion and focuses on the alteration in mitochondrial DNA amount resulting from impairment of mitochondrial dynamics. We also review the literature describing the main disorders associated with the disruption of mitochondrial fusion.

Exploring the potential relevance of human-specific genes to complex disease

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Cooper David N

2011-01-01

Full Text Available Abstract Although human disease genes generally tend to be evolutionarily more ancient than non-disease genes, complex disease genes appear to be represented more frequently than Mendelian disease genes among genes of more recent evolutionary origin. It is therefore proposed that the analysis of human-specific genes might provide new insights into the genetics of complex disease. Cross-comparison with the Human Gene Mutation Database (http://www.hgmd.org revealed a number of examples of disease-causing and disease-associated mutations in putatively human-specific genes. A sizeable proportion of these were missense polymorphisms associated with complex disease. Since both human-specific genes and genes associated with complex disease have often experienced particularly rapid rates of evolutionary change, either due to weaker purifying selection or positive selection, it is proposed that a significant number of human-specific genes may play a role in complex disease.

A description of human hydatid disease in Tasmania in the post-eradication era.

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O'Hern, Jennifer A; Cooley, Louise

2013-07-22

To describe human hydatid disease in Tasmania since 1996, the 2013 that the state was declared provisionally hydatid-free. Individuals with a new diagnosis or history of hydatid disease between January 1996 and July 2012 were identified through a number of sources including public health notifications, discharge coding from Tasmanian public hospitals, and the Royal Hobart Hospital pathology laboratory information system. Individuals were included if they fulfilled the case definition. Details regarding their diagnosis, management and risk factors were obtained by interview, review of medical notes, or both. The information was collected and analysed over a 3-month period from 30 July 2012 to 30 October 2012. Patient demographics, site of infection, details of hydatid disease management and outcomes, time and place of likely hydatid acquisition, and public health notification. Fifty-one patients were identified, of whom 41 met the case definition. Twenty-five represented new diagnoses between 1996 and 2012. Median age was 71 2013s (range, 44-99 2013s). There were 21 women and 20 men. Thirty-eight patients had hepatic disease, five of whom had at least one other site involved. Four had extra-abdominal disease. Twenty-nine patients could be assessed for possible time and place of hydatid acquisition and all had significant risk factors for hydatid acquisition before 1980. Ten of the 25 patients diagnosed between 1996 and 2012 had been notified to the Tasmanian Department of Health and Human Services. We found no evidence of transmission of hydatid disease to humans following the provisional declaration of eradication of hydatid disease.

Lipidomics of human brain aging and Alzheimer's disease pathology.

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Naudí, Alba; Cabré, Rosanna; Jové, Mariona; Ayala, Victoria; Gonzalo, Hugo; Portero-Otín, Manuel; Ferrer, Isidre; Pamplona, Reinald

2015-01-01

Lipids stimulated and favored the evolution of the brain. Adult human brain contains a large amount of lipids, and the largest diversity of lipid classes and lipid molecular species. Lipidomics is defined as "the full characterization of lipid molecular species and of their biological roles with respect to expression of proteins involved in lipid metabolism and function, including gene regulation." Therefore, the study of brain lipidomics can help to unravel the diversity and to disclose the specificity of these lipid traits and its alterations in neural (neurons and glial) cells, groups of neural cells, brain, and fluids such as cerebrospinal fluid and plasma, thus helping to uncover potential biomarkers of human brain aging and Alzheimer disease. This review will discuss the lipid composition of the adult human brain. We first consider a brief approach to lipid definition, classification, and tools for analysis from the new point of view that has emerged with lipidomics, and then turn to the lipid profiles in human brain and how lipids affect brain function. Finally, we focus on the current status of lipidomics findings in human brain aging and Alzheimer's disease pathology. Neurolipidomics will increase knowledge about physiological and pathological functions of brain cells and will place the concept of selective neuronal vulnerability in a lipid context. © 2015 Elsevier Inc. All rights reserved.

Can Neglected Tropical Diseases Compromise Human Wellbeing in Sex-, Age-, and Trait-Specific Ways?

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David C Geary

2016-04-01

Full Text Available Traits that facilitate competition for reproductive resources or that influence mate choice have evolved to signal resilience to infectious disease and other stressors. As a result, the dynamics of competition and choice can, in theory, be used to generate predictions about sex-, age-, and trait-specific vulnerabilities for any sexually reproducing species, including humans. These dynamics and associated vulnerabilities are reviewed for nonhuman species, focusing on traits that are compromised by exposure to parasites. Using the same approach, sex-, age-, and trait-specific vulnerabilities to parasitic disease are illustrated for children's and adolescent's physical growth and fitness. Suggestions are then provided for widening the assessment of human vulnerabilities to include age-appropriate measures of behavioral (e.g., children's play and cognitive (e.g., language fluency traits. These are traits that are likely to be compromised by infection in age- and sex-specific ways. Inclusion of these types of measures in studies of neglected tropic diseases has the potential to provide a more nuanced understanding of how these diseases undermine human wellbeing and may provide a useful means to study the efficacy of associated treatments.

Implications of prion adaptation and evolution paradigm for human neurodegenerative diseases.

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Kabir, M Enamul; Safar, Jiri G

2014-01-01

There is a growing body of evidence indicating that number of human neurodegenerative diseases, including Alzheimer disease, Parkinson disease, fronto-temporal dementias, and amyotrophic lateral sclerosis, propagate in the brain via prion-like intercellular induction of protein misfolding. Prions cause lethal neurodegenerative diseases in humans, the most prevalent being sporadic Creutzfeldt-Jakob disease (sCJD); they self-replicate and spread by converting the cellular form of prion protein (PrP(C)) to a misfolded pathogenic conformer (PrP(Sc)). The extensive phenotypic heterogeneity of human prion diseases is determined by polymorphisms in the prion protein gene, and by prion strain-specific conformation of PrP(Sc). Remarkably, even though informative nucleic acid is absent, prions may undergo rapid adaptation and evolution in cloned cells and upon crossing the species barrier. In the course of our investigation of this process, we isolated distinct populations of PrP(Sc) particles that frequently co-exist in sCJD. The human prion particles replicate independently and undergo competitive selection of those with lower initial conformational stability. Exposed to mutant substrate, the winning PrP(Sc) conformers are subject to further evolution by natural selection of the subpopulation with the highest replication rate due to the lowest stability. Thus, the evolution and adaptation of human prions is enabled by a dynamic collection of distinct populations of particles, whose evolution is governed by the selection of progressively less stable, faster replicating PrP(Sc) conformers. This fundamental biological mechanism may explain the drug resistance that some prions gained after exposure to compounds targeting PrP(Sc). Whether the phenotypic heterogeneity of other neurodegenerative diseases caused by protein misfolding is determined by the spectrum of misfolded conformers (strains) remains to be established. However, the prospect that these conformers may evolve and

IgY antibodies in human nutrition for disease prevention.

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Müller, Sandra; Schubert, Andreas; Zajac, Julia; Dyck, Terry; Oelkrug, Christopher

2015-10-20

Oral administration of preformed specific antibodies is an attractive approach against infections of the digestive system in humans and animals in times of increasing antibiotic resistances. Previous studies showed a positive effect of egg yolk IgY antibodies on bacterial intoxications in animals and humans. Immunization of chickens with specific antigens offers the possibility to create various forms of antibodies. Research shows that orally applied IgY's isolated from egg yolks can passively cure or prevent diseases of the digestive system. The use of these alternative therapeutic drugs provides further advantages: (1) The production of IgY's is a non-invasive alternative to current methods; (2) The keeping of chickens is inexpensive; (3) The animals are easy to handle; (4) It avoids repetitive bleeding of laboratory animals; (5) It is also very cost effective regarding the high IgY concentration within the egg yolk. Novel targets of these antigen specific antibodies are Helicobacter pylori and also molecules involved in signaling pathways in gastric cancer. Furthermore, also dental caries causing bacteria like Streptococcus mutans or opportunistic Pseudomonas aeruginosa in cystic fibrosis patients are possible targets. Therefore, IgY's included in food for human consumption may be able to prevent or cure human diseases.

Impacts of environment on human diseases: a web service for the human exposome

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Karssenberg, Derek; Vaartjes, Ilonca; Kamphuis, Carlijn; Strak, Maciek; Schmitz, Oliver; Soenario, Ivan; de Jong, Kor

2017-04-01

The exposome is the totality of human environmental exposures from conception onwards. Identifying the contribution of the exposome to human diseases and health is a key issue in health research. Examples include the effect of air pollution exposure on cardiovascular diseases, the impact of disease vectors (mosquitos) and surface hydrology exposure on malaria, and the effect of fast food restaurant exposure on obesity. Essential to health research is to disentangle the effects of the exposome and genome on health. Ultimately this requires quantifying the totality of all human exposures, for each individual in the studied human population. This poses a massive challenge to geoscientists, as environmental data are required at a high spatial and temporal resolution, with a large spatial and temporal coverage representing the area inhabited by the population studied and the time span representing several decades. Then, these data need to be combined with space-time paths of individuals to calculate personal exposures for each individual in the population. The Global and Geo Health Data Centre is taking this challenge by providing a web service capable of enriching population data with exposome information. Our web service can generate environmental information either from archived national (up to 5 m spatial and 1 h temporal resolution) and global environmental information or generated on the fly using environmental models running as microservices. On top of these environmental data services runs an individual exposure service enabling health researchers to select different spatial and temporal aggregation methods and to upload space-time paths of individuals. These are then enriched with personal exposures and eventually returned to the user. We illustrate the service in an example of individual exposures to air pollutants calculated from hyper resolution air pollution data and various approaches to estimate space-time paths of individuals.

[Bartonellosis. II. Other Bartonella responsible for human diseases].

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Piémont, Y; Heller, R

1999-01-01

In addition to Bartonella henselae, five other Bartonella species were involved in human pathology. As for B. henselae, ectoparasites seem to be responsible for the transmission of most or all these bacterial species. B. bacilliformis is responsible for Carrion's disease that occurs in some valleys of Colombia, Ecuador and Peru. This disease is transmitted by biting of infected sandflies. The bacterial reservoir is constituted by humans only. That disease occurs either as an acute form with severe infectious hemolytic anemia (or Oroya fever), or as benign cutaneous tumors, also called verruga peruana. Healthy blood carriers of the bacterium exist. Trench fever was described during the First World War. This non-lethal disease is constituted of recurrent febrile attacks associated particularly with osseous pains. The causative agent of the disease is B. quintana, transmitted by the body louse. Humans seem to be the reservoir of that bacterium. In some patients, B. quintana can be responsible for endocarditis, bacillary angiomatosis and chronic or recurrent bacteremia. Other human infections due to Bartonella sp. have been described: B. vinsonii, isolated from blood of small rodents, and B. elizabethae, the reservoir of which is currently unknown, can be responsible for endocardites. B. clarridgeiae (isolated from blood of 5% of pet cats and 17% of stray cats) may be responsible for human cat scratch disease. All these bartonelloses are diagnosed by non-standard blood culture or by in vitro DNA amplification or by serological testing. Their treatment requires tetracyclines or chloramphenicol or macrolides.

Monkey-based research on human disease: the implications of genetic differences.

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Bailey, Jarrod

2014-11-01

Assertions that the use of monkeys to investigate human diseases is valid scientifically are frequently based on a reported 90-93% genetic similarity between the species. Critical analyses of the relevance of monkey studies to human biology, however, indicate that this genetic similarity does not result in sufficient physiological similarity for monkeys to constitute good models for research, and that monkey data do not translate well to progress in clinical practice for humans. Salient examples include the failure of new drugs in clinical trials, the highly different infectivity and pathology of SIV/HIV, and poor extrapolation of research on Alzheimer's disease, Parkinson's disease and stroke. The major molecular differences underlying these inter-species phenotypic disparities have been revealed by comparative genomics and molecular biology - there are key differences in all aspects of gene expression and protein function, from chromosome and chromatin structure to post-translational modification. The collective effects of these differences are striking, extensive and widespread, and they show that the superficial similarity between human and monkey genetic sequences is of little benefit for biomedical research. The extrapolation of biomedical data from monkeys to humans is therefore highly unreliable, and the use of monkeys must be considered of questionable value, particularly given the breadth and potential of alternative methods of enquiry that are currently available to scientists. 2014 FRAME.

Emerging role of mitophagy in human diseases and physiology.

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Um, Jee-Hyun; Yun, Jeanho

2017-06-01

Mitophagy is a process of selective removal of damaged or unnecessary mitochondria using autophagic machinery. Mitophagy plays an essential role in maintaining mitochondrial quality control and homeostasis. Mitochondrial dysfunctions and defective mitophagy in neurodegenerative diseases, cancer, and metabolic diseases indicate a close link between human disease and mitophagy. Furthermore, recent studies showing the involvement of mitophagy in differentiation and development, suggest that mitophagy may play a more active role in controlling cellular functions. A better understanding of mitophagy will provide insights about human disease and offer novel chance for treatment. This review mainly focuses on the recent implications for mitophagy in human diseases and normal physiology. [BMB Reports 2017; 50(6): 299-307].

Entomologic index for human risk of Lyme disease.

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Mather, T N; Nicholson, M C; Donnelly, E F; Matyas, B T

1996-12-01

An entomologic index based on density estimates of Lyme disease spirochete-infected nymphal deer ticks (lxodes scapularis) was developed to assess human risk of Lyme disease. The authors used a standardized protocol to determine tick density and infection in numerous forested sites in six Rhode Island towns. An entomologic risk index calculated for each town was compared with the number of human Lyme disease cases reported to the Rhode Island State Health Department for the same year. A strong positive relation between entomologic risk index and the Lyme disease case rate for each town suggested that the entomologic index was predictive of Lyme disease risk.

Genetic Variation and Adaptation in Africa: Implications for Human Evolution and Disease

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Gomez, Felicia; Hirbo, Jibril; Tishkoff, Sarah A.

2014-01-01

Because modern humans originated in Africa and have adapted to diverse environments, African populations have high levels of genetic and phenotypic diversity. Thus, genomic studies of diverse African ethnic groups are essential for understanding human evolutionary history and how this leads to differential disease risk in all humans. Comparative studies of genetic diversity within and between African ethnic groups creates an opportunity to reconstruct some of the earliest events in human population history and are useful for identifying patterns of genetic variation that have been influenced by recent natural selection. Here we describe what is currently known about genetic variation and evolutionary history of diverse African ethnic groups. We also describe examples of recent natural selection in African genomes and how these data are informative for understanding the frequency of many genetic traits, including those that cause disease susceptibility in African populations and populations of recent African descent. PMID:24984772

Role of Lactobacillus reuteri in Human Health and Diseases

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Qinghui Mu

2018-04-01

Full Text Available Lactobacillus reuteri (L. reuteri is a well-studied probiotic bacterium that can colonize a large number of mammals. In humans, L. reuteri is found in different body sites, including the gastrointestinal tract, urinary tract, skin, and breast milk. The abundance of L. reuteri varies among different individuals. Several beneficial effects of L. reuteri have been noted. First, L. reuteri can produce antimicrobial molecules, such as organic acids, ethanol, and reuterin. Due to its antimicrobial activity, L. reuteri is able to inhibit the colonization of pathogenic microbes and remodel the commensal microbiota composition in the host. Second, L. reuteri can benefit the host immune system. For instance, some L. reuteri strains can reduce the production of pro-inflammatory cytokines while promoting regulatory T cell development and function. Third, bearing the ability to strengthen the intestinal barrier, the colonization of L. reuteri may decrease the microbial translocation from the gut lumen to the tissues. Microbial translocation across the intestinal epithelium has been hypothesized as an initiator of inflammation. Therefore, inflammatory diseases, including those located in the gut as well as in remote tissues, may be ameliorated by increasing the colonization of L. reuteri. Notably, the decrease in the abundance of L. reuteri in humans in the past decades is correlated with an increase in the incidences of inflammatory diseases over the same period of time. Direct supplementation or prebiotic modulation of L. reuteri may be an attractive preventive and/or therapeutic avenue against inflammatory diseases.

Finding aroma clues in the human breath to diagnose diseases

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A. Dan Wilson

2016-01-01

History of human odor analysis in disease diagnosis The use of the sense of smell as an indicator of human disease probably originated with Hippocrates (circa 400 BC). Early medical practitioners recognized that the presence of human diseases changed the odors released from the body and breath. Physicians once relied heavily on their sense of smell to provide useful...

[New-generation high-throughput technologies based 'omics' research strategy in human disease].

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Yang, Xu; Jiao, Rui; Yang, Lin; Wu, Li-Ping; Li, Ying-Rui; Wang, Jun

2011-08-01

In recent years, new-generation high-throughput technologies, including next-generation sequencing technology and mass spectrometry method, have been widely applied in solving biological problems, especially in human diseases field. This data driven, large-scale and industrialized research model enables the omnidirectional and multi-level study of human diseases from the perspectives of genomics, transcriptomics and proteomics levels, etc. In this paper, the latest development of the high-throughput technologies that applied in DNA, RNA, epigenomics, metagenomics including proteomics and some applications in translational medicine are reviewed. At genomics level, exome sequencing has been the hot spot of the recent research. However, the predominance of whole genome resequencing in detecting large structural variants within the whole genome level is coming to stand out as the drop of sequencing cost, which also makes it possible for personalized genome based medicine application. At trancriptomics level, e.g., small RNA sequencing can be used to detect known and predict unknown miRNA. Those small RNA could not only be the biomarkers for disease diagnosis and prognosis, but also show the potential of disease treatment. At proteomics level, e.g., target proteomics can be used to detect the possible disease-related protein or peptides, which can be useful index for clinical staging and typing. Furthermore, the application and development of trans-omics study in disease research are briefly introduced. By applying bioinformatics technologies for integrating multi-omics data, the mechanism, diagnosis and therapy of the disease are likely to be systemically explained and realized, so as to provide powerful tools for disease diagnosis and therapies.

The human microbiota: the role of microbial communities in health and disease

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Luz Elena Botero Palacio

2016-01-01

Full Text Available During the last decade, there has been increasing awareness of the massive number of microorganisms, collectively known as the human microbiota, that are associated with humans. This microbiota outnumbers the host cells by approximately a factor of ten and contains a large repertoire of microbial genome-encoded metabolic processes. The diverse human microbiota and its associated metabolic potential can provide the host with novel functions that can influence host health and disease status in ways that still need to be analyzed. The microbiota varies with age, with features that depend on the body site, host lifestyle and health status. The challenge is therefore to identify and characterize these microbial communities and use this information to learn how they function and how they can influence the host in terms of health and well-being. Here we provide an overview of some of the recent studies involving the human microbiota and about how these communities might affect host health and disease. A special emphasis is given to studies related to tuberculosis, a disease that claims over one million lives each year worldwide and still represents a challenge for control in many countries, including Colombia.

Bacterial Urease and its Role in Long-Lasting Human Diseases

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Konieczna, Iwona; Żarnowiec, Paulina; Kwinkowski, Marek; Kolesińska, Beata; Frączyk, Justyna; Kamiński, Zbigniew; Kaca, Wiesław

2012-01-01

Urease is a virulence factor found in various pathogenic bacteria. It is essential in colonization of a host organism and in maintenance of bacterial cells in tissues. Due to its enzymatic activity, urease has a toxic effect on human cells. The presence of ureolytic activity is an important marker of a number of bacterial infections. Urease is also an immunogenic protein and is recognized by antibodies present in human sera. The presence of such antibodies is connected with progress of several long-lasting diseases, like rheumatoid arthritis, atherosclerosis or urinary tract infections. In bacterial ureases, motives with a sequence and/or structure similar to human proteins may occur. This phenomenon, known as molecular mimicry, leads to the appearance of autoantibodies, which take part in host molecules destruction. Detection of antibodies-binding motives (epitopes) in bacterial proteins is a complex process. However, organic chemistry tools, such as synthetic peptide libraries, are helpful in both, epitope mapping as well as in serologic investigations. In this review, we present a synthetic report on a molecular organization of bacterial ureases - genetic as well as structural. We characterize methods used in detecting urease and ureolytic activity, including techniques applied in disease diagnostic processes and in chemical synthesis of urease epitopes. The review also provides a summary of knowledge about a toxic effect of bacterial ureases on human body and about occurrence of anti-urease antibodies in long-lasting diseases. PMID:23305365

Human heart disease : lessons from human pluripotent stem cell-derived cardiomyocytes

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Giacomelli, E.; Mummery, C.L.; Bellin, M.

2017-01-01

Technical advances in generating and phenotyping cardiomyocytes from human pluripotent stem cells (hPSC-CMs) are now driving their wider acceptance as in vitro models to understand human heart disease and discover therapeutic targets that may lead to new compounds for clinical use. Current

Immunomodulatory activity of interleukin-27 in human chronic periapical diseases.

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Li, Juan; Wang, Rong; Huang, Shi-Guang

2017-01-01

This study aims to observe expression of IL-27 on different cells in periapical tissues of different types of human chronic periapical diseases. Periapical tissue specimens of 60 donors, including healthy control (n=20), periapical granuloma group (n=20) and radicular cysts group (n=20), were fixed in 10% buffered formalin, stained with hematoxylin and eosin for histopathology. Then specimens were stained with double- immuno-fluorescence assay for identification of IL-27-tryptase (mast cells, MCs), IL-27-CD14 (mononuclear phagocyte cells, MPs) and IL-27-CD31 (endothelial cells, ECs) double-positive cells in periapical tissues. The results indicated that compared with healthy control, the densities (cells/mm 2 ) of IL-27-tryptase, IL-27-CD14 and IL-27-CD31 double-positive cells were significantly increased in human chronic periapical diseases (periapical granuloma group and radicular cysts group) ( P cysts group was significantly higher than those in periapical granuloma group ( P periapical granuloma group had no significant difference with those in radicular cysts group ( P =0.170 and 0.138, respectively). IL-27-CD14 double positive cells density achieved to peak among three cell groups in radicular cysts groups. In conclusion, IL-27 expressed in MCs, MPs and ECs of human chronic periapical diseases with different degrees. IL-27-tryptase double-positive cells may participate in pathogenic mechanism of chronic periapical diseases, especially for formation of fibrous in periapical cysts. IL-27-CD14 and IL-27-CD31 double-positive cells may participate in immunologic response to resist periapical infection, and they may play an dual role in pathogenesis and localization of periapical diseases.

An Emerging Tick-Borne Disease of Humans Is Caused by a Subset of Strains with Conserved Genome Structure

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Barbet, Anthony F.; Al-Khedery, Basima; Stuen, Snorre; Granquist, Erik G.; Felsheim, Roderick F.; Munderloh, Ulrike G.

2013-01-01

The prevalence of tick-borne diseases is increasing worldwide. One such emerging disease is human anaplasmosis. The causative organism, Anaplasma phagocytophilum, is known to infect multiple animal species and cause human fatalities in the U.S., Europe and Asia. Although long known to infect ruminants, it is unclear why there are increasing numbers of human infections. We analyzed the genome sequences of strains infecting humans, animals and ticks from diverse geographic locations. Despite extensive variability amongst these strains, those infecting humans had conserved genome structure including the pfam01617 superfamily that encodes the major, neutralization-sensitive, surface antigen. These data provide potential targets to identify human-infective strains and have significance for understanding the selective pressures that lead to emergence of disease in new species. PMID:25437207

CRISPR/Cas9 for Human Genome Engineering and Disease Research.

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Xiong, Xin; Chen, Meng; Lim, Wendell A; Zhao, Dehua; Qi, Lei S

2016-08-31

The clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system, a versatile RNA-guided DNA targeting platform, has been revolutionizing our ability to modify, manipulate, and visualize the human genome, which greatly advances both biological research and therapeutics development. Here, we review the current development of CRISPR/Cas9 technologies for gene editing, transcription regulation, genome imaging, and epigenetic modification. We discuss the broad application of this system to the study of functional genomics, especially genome-wide genetic screening, and to therapeutics development, including establishing disease models, correcting defective genetic mutations, and treating diseases.

Being human: The role of pluripotent stem cells in regenerative medicine and humanizing Alzheimer's disease models.

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Sproul, Andrew A

2015-01-01

Human pluripotent stem cells (PSCs) have the capacity to revolutionize medicine by allowing the generation of functional cell types such as neurons for cell replacement therapy. However, the more immediate impact of PSCs on treatment of Alzheimer's disease (AD) will be through improved human AD model systems for mechanistic studies and therapeutic screening. This review will first briefly discuss different types of PSCs and genome-editing techniques that can be used to modify PSCs for disease modeling or for personalized medicine. This will be followed by a more in depth analysis of current AD iPSC models and a discussion of the need for more complex multicellular models, including cell types such as microglia. It will finish with a discussion on current clinical trials using PSC-derived cells and the long-term potential of such strategies for treating AD. Copyright © 2015 Elsevier Ltd. All rights reserved.

Skin Diseases: Cross-section of human skin

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Skip Navigation Bar Home Current Issue Past Issues Skin Diseases Cross-section of human skin Past Issues / Fall 2008 Table of Contents For ... Logical Images, Inc. I n the areas of skin health and skin diseases, the NIH's National Institute ...

Proteomics analyses for the global proteins in the brain tissues of different human prion diseases.

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Shi, Qi; Chen, Li-Na; Zhang, Bao-Yun; Xiao, Kang; Zhou, Wei; Chen, Cao; Zhang, Xiao-Mei; Tian, Chan; Gao, Chen; Wang, Jing; Han, Jun; Dong, Xiao-Ping

2015-04-01

Proteomics changes of brain tissues have been described in different neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. However, the brain proteomics of human prion disease remains less understood. In the study, the proteomics patterns of cortex and cerebellum of brain tissues of sporadic Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD were analyzed with isobaric tags for relative and absolute quantitation combined with multidimensional liquid chromatography and MS analysis, with the brains from three normal individuals as controls. Global protein profiling, significant pathway, and functional categories were analyzed. In total, 2287 proteins were identified with quantitative information both in cortex and cerebellum regions. Cerebellum tissues appeared to contain more up- and down-regulated proteins (727 proteins) than cortex regions (312 proteins) of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD. Viral myocarditis, Parkinson's disease, Alzheimer's disease, lysosome, oxidative phosphorylation, protein export, and drug metabolism-cytochrome P450 were the most commonly affected pathways of the three kinds of diseases. Almost coincident biological functions were identified in the brain tissues of the three diseases. In all, data here demonstrate that the brain tissues of Creutzfeldt-Jakob disease, fatal familial insomnia, and G114V genetic CJD have obvious proteomics changes at their terminal stages, which show the similarities not only among human prion diseases but also with other neurodegeneration diseases. This is the first study to provide a reference proteome map for human prion diseases and will be helpful for future studies focused on potential biomarkers for the diagnosis and therapy of human prion diseases. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

From animal models to human disease: a genetic approach for personalized medicine in ALS.

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Picher-Martel, Vincent; Valdmanis, Paul N; Gould, Peter V; Julien, Jean-Pierre; Dupré, Nicolas

2016-07-11

Amyotrophic Lateral Sclerosis (ALS) is the most frequent motor neuron disease in adults. Classical ALS is characterized by the death of upper and lower motor neurons leading to progressive paralysis. Approximately 10 % of ALS patients have familial form of the disease. Numerous different gene mutations have been found in familial cases of ALS, such as mutations in superoxide dismutase 1 (SOD1), TAR DNA-binding protein 43 (TDP-43), fused in sarcoma (FUS), C9ORF72, ubiquilin-2 (UBQLN2), optineurin (OPTN) and others. Multiple animal models were generated to mimic the disease and to test future treatments. However, no animal model fully replicates the spectrum of phenotypes in the human disease and it is difficult to assess how a therapeutic effect in disease models can predict efficacy in humans. Importantly, the genetic and phenotypic heterogeneity of ALS leads to a variety of responses to similar treatment regimens. From this has emerged the concept of personalized medicine (PM), which is a medical scheme that combines study of genetic, environmental and clinical diagnostic testing, including biomarkers, to individualized patient care. In this perspective, we used subgroups of specific ALS-linked gene mutations to go through existing animal models and to provide a comprehensive profile of the differences and similarities between animal models of disease and human disease. Finally, we reviewed application of biomarkers and gene therapies relevant in personalized medicine approach. For instance, this includes viral delivering of antisense oligonucleotide and small interfering RNA in SOD1, TDP-43 and C9orf72 mice models. Promising gene therapies raised possibilities for treating differently the major mutations in familial ALS cases.

Human glia can both induce and rescue aspects of disease phenotype in Huntington disease

DEFF Research Database (Denmark)

Benraiss, Abdellatif; Wang, Su; Herrlinger, Stephanie

2016-01-01

The causal contribution of glial pathology to Huntington disease (HD) has not been heavily explored. To define the contribution of glia to HD, we established human HD glial chimeras by neonatally engrafting immunodeficient mice with mutant huntingtin (mHTT)-expressing human glial progenitor cells...... chimeras are hyperexcitable. Conversely, normal glia can ameliorate disease phenotype in transgenic HD mice, as striatal transplantation of normal glia rescues aspects of electrophysiological and behavioural phenotype, restores interstitial potassium homeostasis, slows disease progression and extends...

Natural selection and infectious disease in human populations

Science.gov (United States)

Karlsson, Elinor K.; Kwiatkowski, Dominic P.; Sabeti, Pardis C.

2015-01-01

The ancient biological 'arms race' between microbial pathogens and humans has shaped genetic variation in modern populations, and this has important implications for the growing field of medical genomics. As humans migrated throughout the world, populations encountered distinct pathogens, and natural selection increased the prevalence of alleles that are advantageous in the new ecosystems in both host and pathogens. This ancient history now influences human infectious disease susceptibility and microbiome homeostasis, and contributes to common diseases that show geographical disparities, such as autoimmune and metabolic disorders. Using new high-throughput technologies, analytical methods and expanding public data resources, the investigation of natural selection is leading to new insights into the function and dysfunction of human biology. PMID:24776769

Human inherited diseases with altered mechanisms for DNA repair and mutagenesis

Energy Technology Data Exchange (ETDEWEB)

Cleaver, J.E.

1977-01-01

A variety of human diseases involving clinical symptoms of increased cancer risk, and disorders of the central nervous system, and of hematopoietic, immunological, ocular, and cutaneous tissues and embryological development have defects in biochemical pathways for excision repair of damaged DNA. Excision repair has multiple branches by which damaged nucleotides, bases, and cross-links are excised and requires cofactors that control the access of repair enzymes to damage in DNA in chromatin. Diseases in which repair defects are a consistent feature of their biochemistry include xeroderma pigmentosum, ataxia telangiectasia and Fanconi's anemia.

Glycogen storage disease type Ia in canines: a model for human metabolic and genetic liver disease.

Science.gov (United States)

Specht, Andrew; Fiske, Laurie; Erger, Kirsten; Cossette, Travis; Verstegen, John; Campbell-Thompson, Martha; Struck, Maggie B; Lee, Young Mok; Chou, Janice Y; Byrne, Barry J; Correia, Catherine E; Mah, Cathryn S; Weinstein, David A; Conlon, Thomas J

2011-01-01

A canine model of Glycogen storage disease type Ia (GSDIa) is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including "lactic acidosis", larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.

Glycogen Storage Disease Type Ia in Canines: A Model for Human Metabolic and Genetic Liver Disease

Directory of Open Access Journals (Sweden)

Andrew Specht

2011-01-01

Full Text Available A canine model of Glycogen storage disease type Ia (GSDIa is described. Affected dogs are homozygous for a previously described M121I mutation resulting in a deficiency of glucose-6-phosphatase-α. Metabolic, clinicopathologic, pathologic, and clinical manifestations of GSDIa observed in this model are described and compared to those observed in humans. The canine model shows more complete recapitulation of the clinical manifestations seen in humans including “lactic acidosis”, larger size, and longer lifespan compared to other animal models. Use of this model in preclinical trials of gene therapy is described and briefly compared to the murine model. Although the canine model offers a number of advantages for evaluating potential therapies for GSDIa, there are also some significant challenges involved in its use. Despite these challenges, the canine model of GSDIa should continue to provide valuable information about the potential for generating curative therapies for GSDIa as well as other genetic hepatic diseases.

Quantifying human-environment interactions using videography in the context of infectious disease transmission.

Science.gov (United States)

Julian, Timothy R; Bustos, Carla; Kwong, Laura H; Badilla, Alejandro D; Lee, Julia; Bischel, Heather N; Canales, Robert A

2018-05-08

Quantitative data on human-environment interactions are needed to fully understand infectious disease transmission processes and conduct accurate risk assessments. Interaction events occur during an individual's movement through, and contact with, the environment, and can be quantified using diverse methodologies. Methods that utilize videography, coupled with specialized software, can provide a permanent record of events, collect detailed interactions in high resolution, be reviewed for accuracy, capture events difficult to observe in real-time, and gather multiple concurrent phenomena. In the accompanying video, the use of specialized software to capture humanenvironment interactions for human exposure and disease transmission is highlighted. Use of videography, combined with specialized software, allows for the collection of accurate quantitative representations of human-environment interactions in high resolution. Two specialized programs include the Virtual Timing Device for the Personal Computer, which collects sequential microlevel activity time series of contact events and interactions, and LiveTrak, which is optimized to facilitate annotation of events in real-time. Opportunities to annotate behaviors at high resolution using these tools are promising, permitting detailed records that can be summarized to gain information on infectious disease transmission and incorporated into more complex models of human exposure and risk.

Impacts of Gut Bacteria on Human Health and Diseases

Science.gov (United States)

Zhang, Yu-Jie; Li, Sha; Gan, Ren-You; Zhou, Tong; Xu, Dong-Ping; Li, Hua-Bin

2015-01-01

Gut bacteria are an important component of the microbiota ecosystem in the human gut, which is colonized by 1014 microbes, ten times more than the human cells. Gut bacteria play an important role in human health, such as supplying essential nutrients, synthesizing vitamin K, aiding in the digestion of cellulose, and promoting angiogenesis and enteric nerve function. However, they can also be potentially harmful due to the change of their composition when the gut ecosystem undergoes abnormal changes in the light of the use of antibiotics, illness, stress, aging, bad dietary habits, and lifestyle. Dysbiosis of the gut bacteria communities can cause many chronic diseases, such as inflammatory bowel disease, obesity, cancer, and autism. This review summarizes and discusses the roles and potential mechanisms of gut bacteria in human health and diseases. PMID:25849657

Human microbiomes and their roles in dysbiosis, common diseases, and novel therapeutic approaches.

Science.gov (United States)

Belizário, José E; Napolitano, Mauro

2015-01-01

The human body is the residence of a large number of commensal (non-pathogenic) and pathogenic microbial species that have co-evolved with the human genome, adaptive immune system, and diet. With recent advances in DNA-based technologies, we initiated the exploration of bacterial gene functions and their role in human health. The main goal of the human microbiome project is to characterize the abundance, diversity and functionality of the genes present in all microorganisms that permanently live in different sites of the human body. The gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. Microbe gene-products exert pivotal functions via the regulation of food digestion and immune system development. Studies are confirming that manipulation of non-pathogenic bacterial strains in the host can stimulate the recovery of the immune response to pathogenic bacteria causing diseases. Different approaches, including the use of nutraceutics (prebiotics and probiotics) as well as phages engineered with CRISPR/Cas systems and quorum sensing systems have been developed as new therapies for controlling dysbiosis (alterations in microbial community) and common diseases (e.g., diabetes and obesity). The designing and production of pharmaceuticals based on our own body's microbiome is an emerging field and is rapidly growing to be fully explored in the near future. This review provides an outlook on recent findings on the human microbiomes, their impact on health and diseases, and on the development of targeted therapies.

HUMAN MICROBIOMES AND THEIR ROLES IN DYSBIOSIS, COMMON DISEASES AND NOVEL THERAPEUTIC APPROACHES

Directory of Open Access Journals (Sweden)

Jose Ernesto Belizario

2015-10-01

Full Text Available The human body is the residence of a large number of commensal (non-pathogenic and pathogenic microbial species that have co-evolved with the human genome, adaptive immune system and diet. With recent advances in DNA-based technologies, we initiated the exploration of bacterial gene functions and their role in human health. The main goal of the human microbiome project is to characterize the abundance, diversity and functionality of the genes present in all microorganisms that permanently live in different sites of the human body. The gut microbiota expresses over 3.3 million bacterial genes, while the human genome expresses only 20 thousand genes. Microbe gene-products exert pivotal functions via the regulation of food digestion and immune system development. Studies are confirming that manipulation of non-pathogenic bacterial strains in the host can stimulate the recovery of the immune response to pathogenic bacteria causing diseases. Different approaches, including the use of nutraceutics (prebiotics and probiotics as well as phages engineered with CRISPR/cas systems and quorum sensing systems have been developed as new therapies for controlling dysbiosis (alterations in microbial community and common diseases (e.g. diabetes and obesity. The designing and production of pharmaceuticals based on our own body’s microbiome is an emerging field and is rapidly growing to be fully explored in the near future. This review provides an outlook on recent findings on the human microbiomes, their impact on health and diseases, and on the development of targeted therapies.

Emerging arboviral human diseases in Southern Europe.

Science.gov (United States)

Papa, Anna

2017-08-01

Southern Europe is characterized by unique landscape and climate which attract tourists, but also arthropod vectors, some of them carrying pathogens. Among several arboviral diseases that emerged in the region during the last decade, West Nile fever accounted for high number of human cases and fatalities, while Crimean-Congo hemorrhagic fever expanded its geographic distribution, and is considered as a real threat for Europe. Viruses evolve rapidly and acquire mutations making themselves stronger and naive populations more vulnerable. In an effort to tackle efficiently the emerging arboviral diseases, preparedness and strategic surveillance are needed for the early detection of the pathogen and containment and mitigation of probable outbreaks. In this review, the main human arboviral diseases that emerged in Southern Europe are described. © 2017 Wiley Periodicals, Inc.

Best Practices for Preventing Vector-Borne Diseases in Dogs and Humans.

Science.gov (United States)

Dantas-Torres, Filipe; Otranto, Domenico

2016-01-01

Vector-borne diseases constitute a diversified group of illnesses, which are caused by a multitude of pathogens transmitted by arthropod vectors, such as mosquitoes, fleas, ticks, and sand flies. Proper management of these diseases is important from both human and veterinary medicine standpoints, given that many of these pathogens are transmissible to humans and dogs, which often live in close contact. In this review, we summarize the most important vector-borne diseases of dogs and humans and the best practices for their prevention. The control of these diseases would ultimately improve animal and human health and wellbeing, particularly in developing countries in the tropics, where the risk of these diseases is high and access to health care is poor. Copyright © 2015 Elsevier Ltd. All rights reserved.

Molecular Pathology of Human Prion Diseases

Directory of Open Access Journals (Sweden)

2009-03-01

Full Text Available Prion diseases are fatal neurodegenerative conditions in humans and animals. In this review, we summarize the molecular background of phenotypic variability, relation of prion protein (PrP to other proteins associated with neurodegenerative diseases, and pathogenesis of neuronal vulnerability. PrP exists in different forms that may be present in both diseased and non-diseased brain, however, abundant disease-associated PrP together with tissue pathology characterizes prion diseases and associates with transmissibility. Prion diseases have different etiological background with distinct pathogenesis and phenotype. Mutations of the prion protein gene are associated with genetic forms. The codon 129 polymorphism in combination with the Western blot pattern of PrP after proteinase K digestion serves as a basis for molecular subtyping of sporadic Creutzfeldt-Jakob disease. Tissue damage may result from several parallel, interacting or subsequent pathways that involve cellular systems associated with synapses, protein processing, oxidative stress, autophagy, and apoptosis.

Follicular Helper CD4+ T Cells in Human Neuroautoimmune Diseases and Their Animal Models

Directory of Open Access Journals (Sweden)

Xueli Fan

2015-01-01

Full Text Available Follicular helper CD4+ T (TFH cells play a fundamental role in humoral immunity deriving from their ability to provide help for germinal center (GC formation, B cell differentiation into plasma cells and memory cells, and antibody production in secondary lymphoid tissues. TFH cells can be identified by a combination of markers, including the chemokine receptor CXCR5, costimulatory molecules ICOS and PD-1, transcription repressor Bcl-6, and cytokine IL-21. It is difficult and impossible to get access to secondary lymphoid tissues in humans, so studies are usually performed with human peripheral blood samples as circulating counterparts of tissue TFH cells. A balance of TFH cell generation and function is critical for protective antibody response, whereas overactivation of TFH cells or overexpression of TFH-associated molecules may result in autoimmune diseases. Emerging data have shown that TFH cells and TFH-associated molecules may be involved in the pathogenesis of neuroautoimmune diseases including multiple sclerosis (MS, neuromyelitis optica (NMO/neuromyelitis optica spectrum disorders (NMOSD, and myasthenia gravis (MG. This review summarizes the features of TFH cells, including their development, function, and roles as well as TFH-associated molecules in neuroautoimmune diseases and their animal models.

Human health improvement in Sub-Saharan Africa through integrated management of arthropod transmitted diseases and natural resources

Directory of Open Access Journals (Sweden)

Baumgärtner Johann

2001-01-01

Full Text Available A concept of an ecosystem approach to human health improvement in Sub-Saharan Africa is presented here. Three factors mainly affect the physical condition of the human body: the abiotic environment, vector-transmitted diseases, and natural resources. Our concept relies on ecological principles embedded in a social context and identifies three sets of subsystems for study and management: human disease subsystems, natural resource subsystems, and decision-support subsystems. To control human diseases and to secure food from resource subsystems including livestock or crops, integrated preventive approaches are preferred over exclusively curative and sectorial approaches. Environmental sustainability - the basis for managing matter and water flows - contributes to a healthy human environment and constitutes the basis for social sustainability. For planning and implementation of the human health improvement scheme, participatory decision-support subsystems adapted to the local conditions need to be designed through institutional arrangements. The applicability of this scheme is demonstrated in urban and rural Ethiopia.

Human health improvement in Sub-Saharan Africa through integrated management of arthropod transmitted diseases and natural resources

Directory of Open Access Journals (Sweden)

Johann Baumgärtner

Full Text Available A concept of an ecosystem approach to human health improvement in Sub-Saharan Africa is presented here. Three factors mainly affect the physical condition of the human body: the abiotic environment, vector-transmitted diseases, and natural resources. Our concept relies on ecological principles embedded in a social context and identifies three sets of subsystems for study and management: human disease subsystems, natural resource subsystems, and decision-support subsystems. To control human diseases and to secure food from resource subsystems including livestock or crops, integrated preventive approaches are preferred over exclusively curative and sectorial approaches. Environmental sustainability - the basis for managing matter and water flows - contributes to a healthy human environment and constitutes the basis for social sustainability. For planning and implementation of the human health improvement scheme, participatory decision-support subsystems adapted to the local conditions need to be designed through institutional arrangements. The applicability of this scheme is demonstrated in urban and rural Ethiopia.

Human health improvement in Sub-Saharan Africa through integrated management of arthropod transmitted diseases and natural resources.

Science.gov (United States)

Baumgärtner, J; Bieri, M; Buffoni, G; Gilioli, G; Gopalan, H; Greiling, J; Tikubet, G; Van Schayk, I

2001-01-01

A concept of an ecosystem approach to human health improvement in Sub-Saharan Africa is presented here. Three factors mainly affect the physical condition of the human body: the abiotic environment, vector-transmitted diseases, and natural resources. Our concept relies on ecological principles embedded in a social context and identifies three sets of subsystems for study and management: human disease subsystems, natural resource subsystems, and decision-support subsystems. To control human diseases and to secure food from resource subsystems including livestock or crops, integrated preventive approaches are preferred over exclusively curative and sectorial approaches. Environmental sustainability - the basis for managing matter and water flows - contributes to a healthy human environment and constitutes the basis for social sustainability. For planning and implementation of the human health improvement scheme, participatory decision-support subsystems adapted to the local conditions need to be designed through institutional arrangements. The applicability of this scheme is demonstrated in urban and rural Ethiopia.

Chronic Obstructive Pulmonary Disease (COPD) Includes: Chronic Bronchitis and Emphysema

Science.gov (United States)

... Submit Button NCHS Home Chronic Obstructive Pulmonary Disease (COPD) Includes: Chronic Bronchitis and Emphysema Recommend on Facebook ... Percent of visits to office-based physicians with COPD indicated on the medical record: 3.2% Source: ...

Profiles of microbial fatty acids in the human metabolome are disease-specific

Directory of Open Access Journals (Sweden)

Zhanna A Ktsoyan

2011-01-01

Full Text Available The human gastrointestinal tract is inhabited by a diverse and dense symbiotic microbiota, the composition of which is the result of host-microbe co-evolution and co-adaptation. This tight integration creates intense crosstalk and signalling between the host and microbiota at the cellular and metabolic levels. In many genetic or infectious diseases the balance between host and microbiota may be compromised resulting in erroneous communication. Consequently, the composition of the human metabolome, which includes the gut metabolome, may be different in health and disease states in terms of microbial products and metabolites entering systemic circulation. To test this hypothesis, we measured the level of hydroxy, branched, cyclopropyl and unsaturated fatty acids, aldehydes, and phenyl derivatives in blood of patients with a hereditary autoinflammatory disorder, familial Mediterranean fever (FMF, and in patients with peptic ulceration (PU resulting from Helicobacter pylori infection. Discriminant function analysis of a data matrix consisting of 94 cases as statistical units (37 FMF patients, 14 PU patients, and 43 healthy controls and the concentration of 35 microbial products in the blood as statistical variables revealed a high accuracy of the proposed model (all cases were correctly classified. This suggests that the profile of microbial products and metabolites in the human metabolome is specific for a given disease and may potentially serve as a biomarker for disease.

Human genetics of infectious diseases: between proof of principle and paradigm.

Science.gov (United States)

Alcaïs, Alexandre; Abel, Laurent; Casanova, Jean-Laurent

2009-09-01

The observation that only a fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. As we discuss here, human predisposition to infectious diseases seems to cover a continuous spectrum from monogenic to polygenic inheritance. Although many studies have provided proof of principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. However, in the future, studies in human genetics are likely to establish a new paradigm for infectious diseases.

Human anthrax as a re-emerging disease.

Science.gov (United States)

Doganay, Mehmet; Demiraslan, Hayati

2015-01-01

Anthrax is primarily a disease of herbivores and the etiological agent is B. anthracis which is a gram-positive, aerobic, spore-forming, and rod shaped bacterium. Bacillus anthracis spores are highly resistant to heat, pressure, ultraviolet and ionizing radiation, chemical agents and disinfectants. For these reasons, B. anthracis spores are an attractive choice as biological agents for the use of bioweapon and/or bioterrorism. Soil is the main reservoir for the infectious agent. The disease most commonly affects wild and domestic mammals. Human are secondarily infected by contact with infected animals and contaminated animal products or directly expose to B. anthracis spores. Anthrax occurs worldwide. This infection is still endemic or hyperendemic in both animals and humans in some part of areas of the world; particularly in Middle East, West Africa, Central Asia, some part of India, South America. However, some countries are claiming free of anthrax, and anthrax has become a re-emerging disease in western countries with the intentional outbreak. Currently, anthrax is classified according to its setting as (1) naturally occurring anthrax, (2) bioterrorism-related anthrax. Vast majority of human anthrax are occurring as naturally occurring anthrax in the world. It is also a threaten disease for western countries. The aim of this paper is to review the relevant patents, short historical perspective, microbiological and epidemiological features, clinical presentations and treatment.

Human endogenous retroviruses in neurologic disease.

Science.gov (United States)

Christensen, Tove

2016-01-01

Endogenous retroviruses are pathogenic - in other species than the human. Disease associations for Human Endogenous RetroViruses (HERVs) are emerging, but so far an unequivocal pathogenetic cause-effect relationship has not been established. A role for HERVs has been proposed in neurological and neuropsychiatric diseases as diverse as multiple sclerosis (MS) and schizophrenia (SCZ). Particularly for MS, many aspects of the activation and involvement of specific HERV families (HERV-H/F and HERV-W/MSRV) have been reported, both for cells in the circulation and in the central nervous system. Notably envelope genes and their gene products (Envs) appear strongly associated with the disease. For SCZ, for ALS, and for HIV-associated dementia (HAD), indications are accumulating for involvement of the HERV-K family, and also HERV-H/F and/or HERV-W. Activation is reasonably a prerequisite for causality as most HERV sequences remain quiescent in non-pathological conditions, so the importance of regulatory pathways and epigenetics involved in regulating HERV activation, derepression, and also involvement of retroviral restriction factors, is emerging. HERV-directed antiretrovirals have potential as novel therapeutic paradigms in neurologic disease, particularly in MS. The possible protective or ameliorative effects of antiretroviral therapy in MS are substantiated by reports that treatment of HIV infection may be associated with a significantly decreased risk of MS. Further studies of HERVs, their role in neurologic diseases, and their potential as therapeutic targets are essential. © 2016 APMIS. Published by John Wiley & Sons Ltd.

Drosophila melanogaster Models of Metal-Related Human Diseases and Metal Toxicity.

Science.gov (United States)

Calap-Quintana, Pablo; González-Fernández, Javier; Sebastiá-Ortega, Noelia; Llorens, José Vicente; Moltó, María Dolores

2017-07-06

Iron, copper and zinc are transition metals essential for life because they are required in a multitude of biological processes. Organisms have evolved to acquire metals from nutrition and to maintain adequate levels of each metal to avoid damaging effects associated with its deficiency, excess or misplacement. Interestingly, the main components of metal homeostatic pathways are conserved, with many orthologues of the human metal-related genes having been identified and characterized in Drosophila melanogaster . Drosophila has gained appreciation as a useful model for studying human diseases, including those caused by mutations in pathways controlling cellular metal homeostasis. Flies have many advantages in the laboratory, such as a short life cycle, easy handling and inexpensive maintenance. Furthermore, they can be raised in a large number. In addition, flies are greatly appreciated because they offer a considerable number of genetic tools to address some of the unresolved questions concerning disease pathology, which in turn could contribute to our understanding of the metal metabolism and homeostasis. This review recapitulates the metabolism of the principal transition metals, namely iron, zinc and copper, in Drosophila and the utility of this organism as an experimental model to explore the role of metal dyshomeostasis in different human diseases. Finally, a summary of the contribution of Drosophila as a model for testing metal toxicity is provided.

Quantifying human-environment interactions using videography in the context of infectious disease transmission

Directory of Open Access Journals (Sweden)

Timothy R. Julian

2018-05-01

Full Text Available Quantitative data on human-environment interactions are needed to fully understand infectious disease transmission processes and conduct accurate risk assessments. Interaction events occur during an individual’s movement through, and contact with, the environment, and can be quantified using diverse methodologies. Methods that utilize videography, coupled with specialized software, can provide a permanent record of events, collect detailed interactions in high resolution, be reviewed for accuracy, capture events difficult to observe in real-time, and gather multiple concurrent phenomena. In the accompanying video, the use of specialized software to capture humanenvironment interactions for human exposure and disease transmission is highlighted. Use of videography, combined with specialized software, allows for the collection of accurate quantitative representations of human-environment interactions in high resolution. Two specialized programs include the Virtual Timing Device for the Personal Computer, which collects sequential microlevel activity time series of contact events and interactions, and LiveTrak, which is optimized to facilitate annotation of events in real-time. Opportunities to annotate behaviors at high resolution using these tools are promising, permitting detailed records that can be summarized to gain information on infectious disease transmission and incorporated into more complex models of human exposure and risk.

Human hereditary diseases associated with elevated frequency of chromosome aberrations

International Nuclear Information System (INIS)

Ejima, Yosuke

1988-01-01

Human recessive diseases collectively known as chromosome breakage syndromes include Fanconi's anemia, Bloom's syndrome and ataxia telangiectasia. Cells from these patients show chromosome instabilities both spontaneously and following treatments with radiations or certain chemicals, where defects in DNA metabolisms are supposed to be involved. Cells from patients with ataxia telangiectasia are hypersensitive to ionizing radiations, though DNA replication is less affected than in normal cells. Chromatid-type as well as chromosom-type aberrations are induced in cells irradiated in G 0 or G 1 phases. These unusual responses to radiations may provide clues for understanding the link between DNA replicative response and cellular radiosensitivity. Alterations in cellular radiosensitivity or spontaneous chromosome instabilities are observed in some patients with congenital chromosome anomalies or dominant diseases, where underlying defects may be different from those in recessive diseases. (author)

Human hereditary diseases associated with elevated frequency of chromosome aberrations

Energy Technology Data Exchange (ETDEWEB)

Ejima, Yosuke; Ikushima, Takaji (ed.)

1988-07-01

Human recessive diseases collectively known as chromosome breakage syndromes include Fanconi's anemia, Bloom's syndrome and ataxia telangiectasia. Cells from these patients show chromosome instabilities both spontaneously and following treatments with radiations or certain chemicals, where defects in DNA metabolisms are supposed to be involved. Cells from patients with ataxia telangiectasia are hypersensitive to ionizing radiations, though DNA replication is less affected than in normal cells. Chromatid-type as well as chromosom-type aberrations are induced in cells irradiated in G/sub 0/ or G/sub 1/ phases. These unusual responses to radiations may provide clues for understanding the link between DNA replicative response and cellular radiosensitivity. Alterations in cellular radiosensitivity or spontaneous chromosome instabilities are observed in some patients with congenital chromosome anomalies or dominant diseases, where underlying defects may be different from those in recessive diseases.

Animal models for human genetic diseases

African Journals Online (AJOL)

Sharif Sons

The study of human genetic diseases can be greatly aided by animal models because of their similarity .... and gene targeting in embryonic stem cells) has been a powerful tool in .... endonucleases that are designed to make a doublestrand.

RNA FISH for detecting expanded repeats in human diseases.

Science.gov (United States)

Urbanek, Martyna O; Krzyzosiak, Wlodzimierz J

2016-04-01

RNA fluorescence in situ hybridization (FISH) is a widely used technique for detecting transcripts in fixed cells and tissues. Many variants of RNA FISH have been proposed to increase signal strength, resolution and target specificity. The current variants of this technique facilitate the detection of the subcellular localization of transcripts at a single molecule level. Among the applications of RNA FISH are studies on nuclear RNA foci in diseases resulting from the expansion of tri-, tetra-, penta- and hexanucleotide repeats present in different single genes. The partial or complete retention of mutant transcripts forming RNA aggregates within the nucleoplasm has been shown in multiple cellular disease models and in the tissues of patients affected with these atypical mutations. Relevant diseases include, among others, myotonic dystrophy type 1 (DM1) with CUG repeats, Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3) with CAG repeats, fragile X-associated tremor/ataxia syndrome (FXTAS) with CGG repeats, myotonic dystrophy type 2 (DM2) with CCUG repeats, amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) with GGGGCC repeats and spinocerebellar ataxia type 32 (SCA32) with GGCCUG. In this article, we summarize the results obtained with FISH to examine RNA nuclear inclusions. We provide a detailed protocol for detecting RNAs containing expanded CAG and CUG repeats in different cellular models, including fibroblasts, lymphoblasts, induced pluripotent stem cells and murine and human neuronal progenitors. We also present the results of the first single-molecule FISH application in a cellular model of polyglutamine disease. Copyright © 2015 Elsevier Inc. All rights reserved.

Genetic human prion disease modelled in PrP transgenic Drosophila.

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Thackray, Alana M; Cardova, Alzbeta; Wolf, Hanna; Pradl, Lydia; Vorberg, Ina; Jackson, Walker S; Bujdoso, Raymond

2017-09-20

Inherited human prion diseases, such as fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD), are associated with autosomal dominant mutations in the human prion protein gene PRNP and accumulation of PrP Sc , an abnormal isomer of the normal host protein PrP C , in the brain of affected individuals. PrP Sc is the principal component of the transmissible neurotoxic prion agent. It is important to identify molecular pathways and cellular processes that regulate prion formation and prion-induced neurotoxicity. This will allow identification of possible therapeutic interventions for individuals with, or at risk from, genetic human prion disease. Increasingly, Drosophila has been used to model human neurodegenerative disease. An important unanswered question is whether genetic prion disease with concomitant spontaneous prion formation can be modelled in Drosophila We have used pUAST/PhiC31-mediated site-directed mutagenesis to generate Drosophila transgenic for murine or hamster PrP (prion protein) that carry single-codon mutations associated with genetic human prion disease. Mouse or hamster PrP harbouring an FFI (D178N) or fCJD (E200K) mutation showed mild Proteinase K resistance when expressed in Drosophila Adult Drosophila transgenic for FFI or fCJD variants of mouse or hamster PrP displayed a spontaneous decline in locomotor ability that increased in severity as the flies aged. Significantly, this mutant PrP-mediated neurotoxic fly phenotype was transferable to recipient Drosophila that expressed the wild-type form of the transgene. Collectively, our novel data are indicative of the spontaneous formation of a PrP-dependent neurotoxic phenotype in FFI- or CJD-PrP transgenic Drosophila and show that inherited human prion disease can be modelled in this invertebrate host. © 2017 The Author(s).

Human Environmental Disease Network: A computational model to assess toxicology of contaminants.

Science.gov (United States)

Taboureau, Olivier; Audouze, Karine

2017-01-01

During the past decades, many epidemiological, toxicological and biological studies have been performed to assess the role of environmental chemicals as potential toxicants associated with diverse human disorders. However, the relationships between diseases based on chemical exposure rarely have been studied by computational biology. We developed a human environmental disease network (EDN) to explore and suggest novel disease-disease and chemical-disease relationships. The presented scored EDN model is built upon the integration of systems biology and chemical toxicology using information on chemical contaminants and their disease relationships reported in the TDDB database. The resulting human EDN takes into consideration the level of evidence of the toxicant-disease relationships, allowing inclusion of some degrees of significance in the disease-disease associations. Such a network can be used to identify uncharacterized connections between diseases. Examples are discussed for type 2 diabetes (T2D). Additionally, this computational model allows confirmation of already known links between chemicals and diseases (e.g., between bisphenol A and behavioral disorders) and also reveals unexpected associations between chemicals and diseases (e.g., between chlordane and olfactory alteration), thus predicting which chemicals may be risk factors to human health. The proposed human EDN model allows exploration of common biological mechanisms of diseases associated with chemical exposure, helping us to gain insight into disease etiology and comorbidity. This computational approach is an alternative to animal testing supporting the 3R concept.

Roentgenosemiotics and diagnosis of human diseases

International Nuclear Information System (INIS)

Mikhajlov, A.N.

1989-01-01

Modern concepts concerning roentgenologic semiotics, diagnosis of almost all the human diseases as well as the features of roentgenologic examintion of organs and systems are described. Roentgenologic symptoms and syndroms are systematized and standardized by anatomy branches. 48 refs

The humankind genome: from genetic diversity to the origin of human diseases.

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Belizário, Jose E

2013-12-01

Genome-wide association studies have failed to establish common variant risk for the majority of common human diseases. The underlying reasons for this failure are explained by recent studies of resequencing and comparison of over 1200 human genomes and 10 000 exomes, together with the delineation of DNA methylation patterns (epigenome) and full characterization of coding and noncoding RNAs (transcriptome) being transcribed. These studies have provided the most comprehensive catalogues of functional elements and genetic variants that are now available for global integrative analysis and experimental validation in prospective cohort studies. With these datasets, researchers will have unparalleled opportunities for the alignment, mining, and testing of hypotheses for the roles of specific genetic variants, including copy number variations, single nucleotide polymorphisms, and indels as the cause of specific phenotypes and diseases. Through the use of next-generation sequencing technologies for genotyping and standardized ontological annotation to systematically analyze the effects of genomic variation on humans and model organism phenotypes, we will be able to find candidate genes and new clues for disease's etiology and treatment. This article describes essential concepts in genetics and genomic technologies as well as the emerging computational framework to comprehensively search websites and platforms available for the analysis and interpretation of genomic data.

S5-4: Formal Modeling of Affordance in Human-Included Systems

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Namhun Kim

2012-10-01

Full Text Available In spite of it being necessary for humans to consider modeling, analysis, and control of human-included systems, it has been considered a challenging problem because of the critical role of humans in complex systems and of humans' capability of executing unanticipated actions–both beneficial and detrimental ones. Thus, to provide systematic approaches to modeling human actions as a part of system behaviors, a formal modeling framework for human-involved systems in which humans play a controlling role based on their perceptual information is presented. The theory of affordance provides definitions of human actions and their associated properties; Finite State Automata (FSA based modeling is capable of mapping nondeterministic humans into computable components in the system representation. In this talk, we investigate the role of perception in human actions in the system operation and examine the representation of perceptual elements in affordance-based modeling formalism. The proposed framework is expected to capture the natural ways in which humans participate in the system as part of its operation. A human-machine cooperative manufacturing system control example and a human agent simulation example will be introduced for the illustrative purposes at the end of the presentation.

Significance of functional disease-causal/susceptible variants identified by whole-genome analyses for the understanding of human diseases.

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Hitomi, Yuki; Tokunaga, Katsushi

2017-01-01

Human genome variation may cause differences in traits and disease risks. Disease-causal/susceptible genes and variants for both common and rare diseases can be detected by comprehensive whole-genome analyses, such as whole-genome sequencing (WGS), using next-generation sequencing (NGS) technology and genome-wide association studies (GWAS). Here, in addition to the application of an NGS as a whole-genome analysis method, we summarize approaches for the identification of functional disease-causal/susceptible variants from abundant genetic variants in the human genome and methods for evaluating their functional effects in human diseases, using an NGS and in silico and in vitro functional analyses. We also discuss the clinical applications of the functional disease causal/susceptible variants to personalized medicine.

Genetic engineering in nonhuman primates for human disease modeling.

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Sato, Kenya; Sasaki, Erika

2018-02-01

Nonhuman primate (NHP) experimental models have contributed greatly to human health research by assessing the safety and efficacy of newly developed drugs, due to their physiological and anatomical similarities to humans. To generate NHP disease models, drug-inducible methods, and surgical treatment methods have been employed. Recent developments in genetic and developmental engineering in NHPs offer new options for producing genetically modified disease models. Moreover, in recent years, genome-editing technology has emerged to further promote this trend and the generation of disease model NHPs has entered a new era. In this review, we summarize the generation of conventional disease model NHPs and discuss new solutions to the problem of mosaicism in genome-editing technology.

Modeling human diseases: an education in interactions and interdisciplinary approaches

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Leonard Zon

2016-06-01

Full Text Available Traditionally, most investigators in the biomedical arena exploit one model system in the course of their careers. Occasionally, an investigator will switch models. The selection of a suitable model system is a crucial step in research design. Factors to consider include the accuracy of the model as a reflection of the human disease under investigation, the numbers of animals needed and ease of husbandry, its physiology and developmental biology, and the ability to apply genetics and harness the model for drug discovery. In my lab, we have primarily used the zebrafish but combined it with other animal models and provided a framework for others to consider the application of developmental biology for therapeutic discovery. Our interdisciplinary approach has led to many insights into human diseases and to the advancement of candidate drugs to clinical trials. Here, I draw on my experiences to highlight the importance of combining multiple models, establishing infrastructure and genetic tools, forming collaborations, and interfacing with the medical community for successful translation of basic findings to the clinic.

Animal models of human respiratory syncytial virus disease

NARCIS (Netherlands)

Bem, Reinout A.; Domachowske, Joseph B.; Rosenberg, Helene F.

2011-01-01

Infection with the human pneumovirus pathogen, respiratory syncytial virus (hRSV), causes a wide spectrum of respiratory disease, notably among infants and the elderly. Laboratory animal studies permit detailed experimental modeling of hRSV disease and are therefore indispensable in the search for

Alzheimer’s disease is not “brain aging”: neuropathological, genetic, and epidemiological human studies

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Head, Elizabeth; Schmitt, Frederick A.; Davis, Paulina R.; Neltner, Janna H.; Jicha, Gregory A.; Abner, Erin L.; Smith, Charles D.; Van Eldik, Linda J.; Kryscio, Richard J.; Scheff, Stephen W.

2011-01-01

Human studies are reviewed concerning whether “aging”-related mechanisms contribute to Alzheimer’s disease (AD) pathogenesis. AD is defined by specific neuropathology: neuritic amyloid plaques and neocortical neurofibrillary tangles. AD pathology is driven by genetic factors related not to aging per se, but instead to the amyloid precursor protein (APP). In contrast to genes involved in APP-related mechanisms, there is no firm connection between genes implicated in human “accelerated aging” diseases (progerias) and AD. The epidemiology of AD in advanced age is highly relevant but deceptively challenging to address given the low autopsy rates in most countries. In extreme old age, brain diseases other than AD approximate AD prevalence while the impact of AD pathology appears to peak by age 95 and decline thereafter. Many distinct brain diseases other than AD afflict older human brains and contribute to cognitive impairment. Additional prevalent pathologies include cerebrovascular disease and hippocampal sclerosis, both high-morbidity brain diseases that appear to peak in incidence later than AD chronologically. Because of these common brain diseases of extreme old age, the epidemiology differs between clinical “dementia” and the subset of dementia cases with AD pathology. Additional aging-associated mechanisms for cognitive decline such as diabetes and synapse loss have been linked to AD and these hypotheses are discussed. Criteria are proposed to define an “aging-linked” disease, and AD fails all of these criteria. In conclusion, it may be most fruitful to focus attention on specific pathways involved in AD rather than attributing it to an inevitable consequence of aging. PMID:21516511

Modeling human disease using organotypic cultures

DEFF Research Database (Denmark)

Schweiger, Pawel J; Jensen, Kim B

2016-01-01

animal models and in vitro cell culture systems. However, it has been exceedingly difficult to model disease at the tissue level. Since recently, the gap between cell line studies and in vivo modeling has been narrowing thanks to progress in biomaterials and stem cell research. Development of reliable 3D...... culture systems has enabled a rapid expansion of sophisticated in vitro models. Here we focus on some of the latest advances and future perspectives in 3D organoids for human disease modeling....

Proteome analysis of human substantia nigra in Parkinson's disease

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Werner Cornelius J

2008-02-01

Full Text Available Abstract Background Parkinson's disease (PD is the most common neurodegenerative disorder involving the motor system. Although not being the only region involved in PD, affection of the substantia nigra and its projections is responsible for some of the most debilitating features of the disease. To further advance a comprehensive understanding of nigral pathology, we conducted a tissue based comparative proteome study of healthy and diseased human substantia nigra. Results The gross number of differentially regulated proteins in PD was 221. In total, we identified 37 proteins, of which 16 were differentially expressed. Identified differential proteins comprised elements of iron metabolism (H-ferritin and glutathione-related redox metabolism (GST M3, GST P1, GST O1, including novel redox proteins (SH3BGRL. Additionally, many glial or related proteins were found to be differentially regulated in PD (GFAP, GMFB, galectin-1, sorcin, as well as proteins belonging to metabolic pathways sparsely described in PD, such as adenosyl homocysteinase (methylation, aldehyde dehydrogenase 1 and cellular retinol-binding protein 1 (aldehyde metabolism. Further differentially regulated proteins included annexin V, beta-tubulin cofactor A, coactosin-like protein and V-type ATPase subunit 1. Proteins that were similarly expressed in healthy or diseased substantia nigra comprised housekeeping proteins such as COX5A, Rho GDI alpha, actin gamma 1, creatin-kinase B, lactate dehydrogenase B, disulfide isomerase ER-60, Rab GDI beta, methyl glyoxalase 1 (AGE metabolism and glutamine synthetase. Interestingly, also DJ-1 and UCH-L1 were expressed similarly. Furthermore, proteins believed to serve as internal standards were found to be expressed in a constant manner, such as 14-3-3 epsilon and hCRMP-2, thus lending further validity to our results. Conclusion Using an approach encompassing high sensitivity and high resolution, we show that alterations of SN in PD include many

Disease modeling using human induced pluripotent stem cells: lessons from the liver.

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Gieseck, Richard L; Colquhoun, Jennifer; Hannan, Nicholas R F

2015-01-01

Human pluripotent stem cells (hPSCs) have the capacity to differentiate into any of the hundreds of distinct cell types that comprise the human body. This unique characteristic has resulted in considerable interest in the field of regenerative medicine, given the potential for these cells to be used to protect, repair, or replace diseased, injured, and aged cells within the human body. In addition to their potential in therapeutics, hPSCs can be used to study the earliest stages of human development and to provide a platform for both drug screening and disease modeling using human cells. Recently, the description of human induced pluripotent stem cells (hIPSCs) has allowed the field of disease modeling to become far more accessible and physiologically relevant, as pluripotent cells can be generated from patients of any genetic background. Disease models derived from hIPSCs that manifest cellular disease phenotypes have been established to study several monogenic diseases; furthermore, hIPSCs can be used for phenotype-based drug screens to investigate complex diseases for which the underlying genetic mechanism is unknown. As a result, the use of stem cells as research tools has seen an unprecedented growth within the last decade as researchers look for in vitro disease models which closely mimic in vivo responses in humans. Here, we discuss the beginnings of hPSCs, starting with isolation of human embryonic stem cells, moving into the development and optimization of hIPSC technology, and ending with the application of hIPSCs towards disease modeling and drug screening applications, with specific examples highlighting the modeling of inherited metabolic disorders of the liver. This article is part of a Special Issue entitled Linking transcription to physiology in lipodomics. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

Integrated metagenomics/metaproteomics reveals human host-microbiota signatures of Crohn's disease.

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Alison R Erickson

Full Text Available Crohn's disease (CD is an inflammatory bowel disease of complex etiology, although dysbiosis of the gut microbiota has been implicated in chronic immune-mediated inflammation associated with CD. Here we combined shotgun metagenomic and metaproteomic approaches to identify potential functional signatures of CD in stool samples from six twin pairs that were either healthy, or that had CD in the ileum (ICD or colon (CCD. Integration of these omics approaches revealed several genes, proteins, and pathways that primarily differentiated ICD from healthy subjects, including depletion of many proteins in ICD. In addition, the ICD phenotype was associated with alterations in bacterial carbohydrate metabolism, bacterial-host interactions, as well as human host-secreted enzymes. This eco-systems biology approach underscores the link between the gut microbiota and functional alterations in the pathophysiology of Crohn's disease and aids in identification of novel diagnostic targets and disease specific biomarkers.

Integrated Metagenomics/Metaproteomics Reveals Human Host-Microbiota Signatures of Crohn's Disease

Science.gov (United States)

Darzi, Youssef; Mongodin, Emmanuel F.; Pan, Chongle; Shah, Manesh; Halfvarson, Jonas; Tysk, Curt; Henrissat, Bernard; Raes, Jeroen; Verberkmoes, Nathan C.; Jansson, Janet K.

2012-01-01

Crohn's disease (CD) is an inflammatory bowel disease of complex etiology, although dysbiosis of the gut microbiota has been implicated in chronic immune-mediated inflammation associated with CD. Here we combined shotgun metagenomic and metaproteomic approaches to identify potential functional signatures of CD in stool samples from six twin pairs that were either healthy, or that had CD in the ileum (ICD) or colon (CCD). Integration of these omics approaches revealed several genes, proteins, and pathways that primarily differentiated ICD from healthy subjects, including depletion of many proteins in ICD. In addition, the ICD phenotype was associated with alterations in bacterial carbohydrate metabolism, bacterial-host interactions, as well as human host-secreted enzymes. This eco-systems biology approach underscores the link between the gut microbiota and functional alterations in the pathophysiology of Crohn's disease and aids in identification of novel diagnostic targets and disease specific biomarkers. PMID:23209564

A murine model of human myeloma bone disease

NARCIS (Netherlands)

Garrett, I.R.; Dallas, S.; Radl, J.; Mundy, G.R.

1997-01-01

Myeloma causes a devastating and unique form of osteolytic bone disease. Although osteoclast activation is responsible for bone destruction, the precise mechanisms by which myeloma cells increase osteoclast activity have not been defined. An animal model of human myeloma bone disease mould help in

Molecular biology of human muscle disease

Energy Technology Data Exchange (ETDEWEB)

Dunne, P.W.; Epstein, H.F. (Baylor Coll. of Medicine, Houston, TX (United States))

1991-01-01

The molecular revolution that is transforming the entire biomedical field has had far-reaching impact in its application to inherited human muscle disease. The gene for Duchenne muscular dystrophy was one of the first cloned without knowledge of the defective protein product. This success was based upon the availability of key chromosomal aberrations that provided molecular landmarks for the disease locus. Subsequent discoveries regarding the mode of expression for this gene, the structure and localization of its protein product dystrophin, and molecular diagnosis of affected and carrier individuals constitute a paradigm for investigation of human genetics. Finding the gene for myotonic muscular dystrophy is requiring the brute force approach of cloning several million bases of DNA, identifying expressed sequences, and characterizing candidate genes. The gene that causes hypertrophic cardiomyopathy has been found serendipitously to be one of the genetic markers on chromosome 14, the {beta} myosin heavy chain.

Multifractal Detrended Fluctuation Analysis of Human gait Diseases

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Srimonti eDutta

2013-10-01

Full Text Available IIn this paper multifractal detrended fluctuation analysis is used to study the human gait time series for normal and diseased sets. It is observed that long range correlation is primarily responsible for the origin of multifractality. The study reveals that the degree of multifractality is more for normal set compared to diseased set. However the method fails to distinguish between the two diseased sets.

Human genome-microbiome interaction: metagenomics frontiers for the aetiopathology of autoimmune diseases.

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Gundogdu, Aycan; Nalbantoglu, Ufuk

2017-04-01

A short while ago, the human genome and microbiome were analysed simultaneously for the first time as a multi-omic approach. The analyses of heterogeneous population cohorts showed that microbiome components were associated with human genome variations. In-depth analysis of these results reveals that the majority of those relationships are between immune pathways and autoimmune disease-associated microbiome components. Thus, it can be hypothesized that autoimmunity may be associated with homeostatic disequilibrium of the human-microbiome interactome. Further analysis of human genome-human microbiome relationships in disease contexts with tailored systems biology approaches may yield insights into disease pathogenesis and prognosis.

A framework for annotating human genome in disease context.

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Xu, Wei; Wang, Huisong; Cheng, Wenqing; Fu, Dong; Xia, Tian; Kibbe, Warren A; Lin, Simon M

2012-01-01

Identification of gene-disease association is crucial to understanding disease mechanism. A rapid increase in biomedical literatures, led by advances of genome-scale technologies, poses challenge for manually-curated-based annotation databases to characterize gene-disease associations effectively and timely. We propose an automatic method-The Disease Ontology Annotation Framework (DOAF) to provide a comprehensive annotation of the human genome using the computable Disease Ontology (DO), the NCBO Annotator service and NCBI Gene Reference Into Function (GeneRIF). DOAF can keep the resulting knowledgebase current by periodically executing automatic pipeline to re-annotate the human genome using the latest DO and GeneRIF releases at any frequency such as daily or monthly. Further, DOAF provides a computable and programmable environment which enables large-scale and integrative analysis by working with external analytic software or online service platforms. A user-friendly web interface (doa.nubic.northwestern.edu) is implemented to allow users to efficiently query, download, and view disease annotations and the underlying evidences.

Developmental Immunotoxicity, Perinatal Programming, and Noncommunicable Diseases: Focus on Human Studies

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Dietert, Rodney R.

2014-01-01

Developmental immunotoxicity (DIT) is a term given to encompass the environmentally induced disruption of normal immune development resulting in adverse outcomes. A myriad of chemical, physical, and psychological factors can all contribute to DIT. As a core component of the developmental origins of adult disease, DIT is interlinked with three important concepts surrounding health risks across a lifetime: (1) the Barker Hypothesis, which connects prenatal development to later-life diseases, (2) the hygiene hypothesis, which connects newborns and infants to risk of later-life diseases and, (3) fetal programming and epigenetic alterations, which may exert effects both in later life and across future generations. This review of DIT considers: (1) the history and context of DIT research, (2) the fundamental features of DIT, (3) the emerging role of DIT in risk of noncommunicable diseases (NCDs) and (4) the range of risk factors that have been investigated through human research. The emphasis on the human DIT-related literature is significant since most prior reviews of DIT have largely focused on animal research and considerations of specific categories of risk factors (e.g., heavy metals). Risk factors considered in this review include air pollution, aluminum, antibiotics, arsenic, bisphenol A, ethanol, lead (Pb), maternal smoking and environmental tobacco smoke, paracetamol (acetaminophen), pesticides, polychlorinated biphenyls, and polyfluorinated compounds. PMID:26556429

Three-dimensional genome architecture influences partner selection for chromosomal translocations in human disease.

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Jesse M Engreitz

Full Text Available Chromosomal translocations are frequent features of cancer genomes that contribute to disease progression. These rearrangements result from formation and illegitimate repair of DNA double-strand breaks (DSBs, a process that requires spatial colocalization of chromosomal breakpoints. The "contact first" hypothesis suggests that translocation partners colocalize in the nuclei of normal cells, prior to rearrangement. It is unclear, however, the extent to which spatial interactions based on three-dimensional genome architecture contribute to chromosomal rearrangements in human disease. Here we intersect Hi-C maps of three-dimensional chromosome conformation with collections of 1,533 chromosomal translocations from cancer and germline genomes. We show that many translocation-prone pairs of regions genome-wide, including the cancer translocation partners BCR-ABL and MYC-IGH, display elevated Hi-C contact frequencies in normal human cells. Considering tissue specificity, we find that translocation breakpoints reported in human hematologic malignancies have higher Hi-C contact frequencies in lymphoid cells than those reported in sarcomas and epithelial tumors. However, translocations from multiple tissue types show significant correlation with Hi-C contact frequencies, suggesting that both tissue-specific and universal features of chromatin structure contribute to chromosomal alterations. Our results demonstrate that three-dimensional genome architecture shapes the landscape of rearrangements directly observed in human disease and establish Hi-C as a key method for dissecting these effects.

Differential overexpression of SERPINA3 in human prion diseases.

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Vanni, S; Moda, F; Zattoni, M; Bistaffa, E; De Cecco, E; Rossi, M; Giaccone, G; Tagliavini, F; Haïk, S; Deslys, J P; Zanusso, G; Ironside, J W; Ferrer, I; Kovacs, G G; Legname, G

2017-11-15

Prion diseases are fatal neurodegenerative disorders with sporadic, genetic or acquired etiologies. The molecular alterations leading to the onset and the spreading of these diseases are still unknown. In a previous work we identified a five-gene signature able to distinguish intracranially BSE-infected macaques from healthy ones, with SERPINA3 showing the most prominent dysregulation. We analyzed 128 suitable frontal cortex samples, from prion-affected patients (variant Creutzfeldt-Jakob disease (vCJD) n = 20, iatrogenic CJD (iCJD) n = 11, sporadic CJD (sCJD) n = 23, familial CJD (gCJD) n = 17, fatal familial insomnia (FFI) n = 9, Gerstmann-Sträussler-Scheinker syndrome (GSS)) n = 4), patients with Alzheimer disease (AD, n = 14) and age-matched controls (n = 30). Real Time-quantitative PCR was performed for SERPINA3 transcript, and ACTB, RPL19, GAPDH and B2M were used as reference genes. We report SERPINA3 to be strongly up-regulated in the brain of all human prion diseases, with only a mild up-regulation in AD. We show that this striking up-regulation, both at the mRNA and at the protein level, is present in all types of human prion diseases analyzed, although to a different extent for each specific disorder. Our data suggest that SERPINA3 may be involved in the pathogenesis and the progression of prion diseases, representing a valid tool for distinguishing different forms of these disorders in humans.

Does biodiversity protect humans against infectious disease? Reply

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Wood, Chelsea L.; Lafferty, Kevin D.; DeLeo, Giulio; Young, Hillary S.; Hudson, Peter J.; Kuris, Armand M.

2016-01-01

The dilution effect is the sort of idea that everyone wants to be true. If nature protects humans against infectious disease, imagine the implications: nature's value could be tallied in terms of human suffering avoided. This makes a potent argument for conservation, convincing even to those who would otherwise be disinclined to support conservation initiatives. The appeal of the dilution effect has been recognized by others: “the desire to make the case for conservation has led to broad claims regarding the benefits of nature conservation for human health” (Bauch et al. 2015). Randolph and Dobson (2012) were among the first to critique these claims, making the case that promotion of conservation to reduce Lyme disease risk, although well intentioned, was flawed. Along with Randolph and Dobson's critique, there have been several calls for a more nuanced scientific assessment of the relationship between biodiversity and disease transmission (Dunn 2010, Salkeld et al. 2013, Wood and Lafferty 2013, Young et al. 2013). In response, supporters of the dilution effect have instead increased the scope of their generalizations with review papers, press releases, and, like Levi et al. (2015), letters. These responses have been successful; it is not uncommon to read papers that repeat the assertion that biodiversity generally interferes with disease transmission and that conservation will therefore generally benefit human health. Here, we explain how Levi et al. (2015) and other, similar commentaries use selective interpretation and shifting definitions to argue for the generality of the dilution effect hypothesis.

Leveraging human-centered design in chronic disease prevention.

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Matheson, Gordon O; Pacione, Chris; Shultz, Rebecca K; Klügl, Martin

2015-04-01

Bridging the knowing-doing gap in the prevention of chronic disease requires deep appreciation and understanding of the complexities inherent in behavioral change. Strategies that have relied exclusively on the implementation of evidence-based data have not yielded the desired progress. The tools of human-centered design, used in conjunction with evidence-based data, hold much promise in providing an optimal approach for advancing disease prevention efforts. Directing the focus toward wide-scale education and application of human-centered design techniques among healthcare professionals will rapidly multiply their effective ability to bring the kind of substantial results in disease prevention that have eluded the healthcare industry for decades. This, in turn, would increase the likelihood of prevention by design. Copyright © 2015 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.

The potential usefulness of human leukocyte antigen typing for celiac disease screening: a systematic review and meta-analysis

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Alicia Díaz-Redondo

2015-07-01

Full Text Available Background and aim: The presence of specific human leukocyte antigen-DQ2 and DQ8 seems to be necessary for celiac disease development, but the real contribution of its typing for screening is still uncertain. We aim to conduct a systematic review and meta-analysis of the diagnostic performance of human leukocyte antigen typing tests for celiac disease screening. Methods: Systematic review of published studies assessing accuracy of human leukocyte antigen DQ2 and DQ8 typing for the detection of celiac disease were selected. MEDLINE and EMBASE were searched from 1st January 2004 until 31st December 2013. Two independent researchers carried out selection and classification of studies, data extraction and analysis. Meta-analysis combining sensitivities, specificities and likelihood ratios of HLA-DQ2 and DQ8 for the diagnosis of celiac disease were carried out. Results: 6 studies including 1303 individuals were finally evaluated. Pooled sensitivity was 98% (95% confidence interval: 97-99. Overall specificity was 45% (95% confidence interval: 41-48. Regarding specificity, studies were heterogeneous and a subgroup analysis was done according to the type of population included. Overall negative likelihood ratio was 0.05 (0.03-0.09. Conclusions: Due to its great sensitivity and low negative likelihood ratio, human leukocyte antigen-DQ2/DQ8 typing would be an appropriate test for ruling out celiac disease in the general population suffering related symptoms, and even more in at risk population.

Human Embryonic Stem Cell Therapy in Crohn's Disease: A Case Report.

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Shroff, Geeta

2016-02-29

Crohn's disease is a chronic inflammatory disease of the intestines, mainly the colon and ileum, related with ulcers and fistulae. It is estimated to affect 565,000 people in the United States. Currently available therapies, such as antibiotics, thiopurines, and anti-tumor necrosis factor-alpha agents, are only observed to reduce the complications associated with Crohn's disease and to improve quality of life, but cannot cure the disease. Stem cell therapy appears to have certain advantages over conventional therapies. Our study aimed to evaluate the efficacy of human embryonic stem cell therapy in a patient with Crohn's disease. A 21-year-old male with chief complaints of intolerance to specific foods, abdominal pain, and diarrhea underwent human embryonic stem cell therapy for two months. After undergoing human embryonic stem cell therapy, the patient showed symptomatic relief. He had no complaints of back pain, abdominal pain, or diarrhea and had improved digestion. The patient had no signs and symptoms of skin infection, and had improved limb stamina, strength, and endurance. The condition of patient was stable after the therapy. Human embryonic stem cell therapy might serve as a new optimistic treatment approach for Crohn's disease.

Human genome-microbiome interaction: metagenomics frontiers for the aetiopathology of autoimmune diseases

Science.gov (United States)

Nalbantoglu, Ufuk

2017-01-01

A short while ago, the human genome and microbiome were analysed simultaneously for the first time as a multi-omic approach. The analyses of heterogeneous population cohorts showed that microbiome components were associated with human genome variations. In-depth analysis of these results reveals that the majority of those relationships are between immune pathways and autoimmune disease-associated microbiome components. Thus, it can be hypothesized that autoimmunity may be associated with homeostatic disequilibrium of the human-microbiome interactome. Further analysis of human genome–human microbiome relationships in disease contexts with tailored systems biology approaches may yield insights into disease pathogenesis and prognosis. PMID:28785422

[Leprosy, a pillar of human genetics of infectious diseases].

Science.gov (United States)

Gaschignard, J; Scurr, E; Alcaïs, A

2013-06-01

Despite a natural reservoir of Mycobacterium leprae limited to humans and free availability of an effective antibiotic treatment, more than 200,000 people develop leprosy each year. This disease remains a major cause of disability and social stigma worldwide. The cause of this constant incidence is currently unknown and indicates that important aspects of the complex relationship between the pathogen and its human host remain to be discovered. An important contribution of host genetics to susceptibility to leprosy has long been suggested to account for the considerable variability between individuals sustainably exposed to M. leprae. Given the inability to cultivate M. leprae in vitro and in the absence of relevant animal model, genetic epidemiology is the main strategy used to identify the genes and, consequently, the immunological pathways involved in protective immunity to M. leprae. Recent genome-wide studies have identified new pathophysiological pathways which importance is only beginning to be understood. In addition, the prism of human genetics placed leprosy at the crossroads of other common diseases such as Crohn's disease, asthma or myocardial infarction. Therefore, novel lights on the pathogenesis of many common diseases could eventually emerge from the detailed understanding of a disease of the shadows. Copyright © 2013 Elsevier Masson SAS. All rights reserved.

Disease-specific induced pluripotent stem cells: a platform for human disease modeling and drug discovery.

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Jang, Jiho; Yoo, Jeong-Eun; Lee, Jeong-Ah; Lee, Dongjin R; Kim, Ji Young; Huh, Yong Jun; Kim, Dae-Sung; Park, Chul-Yong; Hwang, Dong-Youn; Kim, Han-Soo; Kang, Hoon-Chul; Kim, Dong-Wook

2012-03-31

The generation of disease-specific induced pluripotent stem cell (iPSC) lines from patients with incurable diseases is a promising approach for studying disease mechanisms and drug screening. Such innovation enables to obtain autologous cell sources in regenerative medicine. Herein, we report the generation and characterization of iPSCs from fibroblasts of patients with sporadic or familial diseases, including Parkinson's disease (PD), Alzheimer's disease (AD), juvenile-onset, type I diabetes mellitus (JDM), and Duchenne type muscular dystrophy (DMD), as well as from normal human fibroblasts (WT). As an example to modeling disease using disease-specific iPSCs, we also discuss the previously established childhood cerebral adrenoleukodystrophy (CCALD)- and adrenomyeloneuropathy (AMN)-iPSCs by our group. Through DNA fingerprinting analysis, the origins of generated disease-specific iPSC lines were identified. Each iPSC line exhibited an intense alkaline phosphatase activity, expression of pluripotent markers, and the potential to differentiate into all three embryonic germ layers: the ectoderm, endoderm, and mesoderm. Expression of endogenous pluripotent markers and downregulation of retrovirus-delivered transgenes [OCT4 (POU5F1), SOX2, KLF4, and c-MYC] were observed in the generated iPSCs. Collectively, our results demonstrated that disease-specific iPSC lines characteristically resembled hESC lines. Furthermore, we were able to differentiate PD-iPSCs, one of the disease-specific-iPSC lines we generated, into dopaminergic (DA) neurons, the cell type mostly affected by PD. These PD-specific DA neurons along with other examples of cell models derived from disease-specific iPSCs would provide a powerful platform for examining the pathophysiology of relevant diseases at the cellular and molecular levels and for developing new drugs and therapeutic regimens.

Polyamines: Bio-Molecules with Diverse Functions in Plant and Human Health and Disease

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Avtar K. Handa

2018-02-01

Full Text Available Biogenic amines—polyamines (PAs, particularly putrescine, spermidine and spermine are ubiquitous in all living cells. Their indispensable roles in many biochemical and physiological processes are becoming commonly known, including promoters of plant life and differential roles in human health and disease. PAs positively impact cellular functions in plants—exemplified by increasing longevity, reviving physiological memory, enhancing carbon and nitrogen resource allocation/signaling, as well as in plant development and responses to extreme environments. Thus, one or more PAs are commonly found in genomic and metabolomics studies using plants, particulary during different abiotic stresses. In humans, a general decline in PA levels with aging occurs parallel with some human health disorders. Also, high PA dose is detrimental to patients suffering from cancer, aging, innate immunity and cognitive impairment during Alzheimer and Parkinson diseases. A dichotomy exists in that while PAs may increase longevity and reduce some age-associated cardiovascular diseases, in disease conditions involving higher cellular proliferation, their intake has negative consequences. Thus, it is essential that PA levels be rigorously quantified in edible plant sources as well as in dietary meats. Such a database can be a guide for medical experts in order to recommend which foods/meats a patient may consume and which ones to avoid. Accordingly, designing both high and low polyamine diets for human consumption are in vogue, particularly in medical conditions where PA intake may be detrimental, for instance, cancer patients. In this review, literature data has been collated for the levels of the three main PAs, putrescine, spermidine and spermine, in different edible sources—vegetables, fruits, cereals, nuts, meat, sea food, cheese, milk, and eggs. Based on our analysis of vast literature, the effects of PAs in human/animal health fall into two broad, Yang and Yin

Polyamines: Bio-Molecules with diverse functions in plant and human health and disease

Science.gov (United States)

Handa, Avtar K.; Fatima, Tahira; Mattoo, Autar K.

2018-02-01

Biogenic amines – polyamines (PAs), particularly putrescine, spermidine and spermine (and thermospermine) are ubiquitous in all living cells. Their indispensable roles in many biochemical and physiological processes are becoming commonly known, including promoters of plant life and differential roles in human health and disease. PAs positively impact cellular functions in plants – exemplified by increasing longevity, reviving physiological memory, enhancing carbon and nitrogen resource allocation/signaling, as well as in plant development and responses to extreme environments. Thus, one or more PAs are commonly found in genomic and metabolomics studies using plants, particulary during different abiotic stresses. In humans, a general decline in PA levels with aging occurs parallel with some human health disorders. Also, high PA dose is detrimental to patients suffering from cancer, aging, innate immunity and cognitive impairment during Alzheimer and Parkinson diseases. A dichotomy exists in that while PAs may increase longevity and reduce some age-associated cardiovascular diseases, in disease conditions involving higher cellular proliferation, their intake has negative consequences. Thus, it is essential that PA levels be rigorously quantified in edible plant sources as well as in dietary meats. Such a database can be a guide for medical experts in order to recommend which foods/meats a patient may consume and which ones to avoid. Accordingly, designing both high and low polyamine diets for human consumption are in vogue, particularly in medical conditions where PA intake may be detrimental, for instance, cancer patients. In this review, literature data has been collated for the levels of the three main PAs, putrescine, spermidine and spermine, in different edible sources - vegetables, fruits, cereals, nuts, meat, sea food, cheese, milk and eggs. Based on our analysis of vast literature, the effects of PAs in human/animal health fall into two broad, Yang and

Attributing the human disease burden of foodborne infections to specific sources.

NARCIS (Netherlands)

Pires, S.M.; Evers, E.G.; van Pelt, W.; Ayers, T.; Scallan, E.; Angulo, F.J.; Havelaar, A.H.; Hald, T.

2009-01-01

Foodborne diseases are an important cause of human illness worldwide. Humans acquire these infections from a variety of sources and routes of transmission. Many efforts have been made in the last decades to prevent and control foodborne diseases, particularly foodborne zoonoses. However, information

Attributing the Human Disease Burden of Foodborne Infections to Specific Sources

DEFF Research Database (Denmark)

Pires, Sara Monteiro; Evers, Eric E.; Van Pely, Wilfrid

2009-01-01

Foodborne diseases are an important cause of human illness worldwide. Humans acquire these infections from a variety of sources and routes of transmission. Many efforts have been made in the last decades to prevent and control foodborne diseases, particularly foodborne zoonoses. However...

Experimental primates and non-human primate (NHP) models of human diseases in China: current status and progress.

Science.gov (United States)

Zhang, Xiao-Liang; Pang, Wei; Hu, Xin-Tian; Li, Jia-Li; Yao, Yong-Gang; Zheng, Yong-Tang

2014-11-18

Non-human primates (NHPs) are phylogenetically close to humans, with many similarities in terms of physiology, anatomy, immunology, as well as neurology, all of which make them excellent experimental models for biomedical research. Compared with developed countries in America and Europe, China has relatively rich primate resources and has continually aimed to develop NHPs resources. Currently, China is a leading producer and a major supplier of NHPs on the international market. However, there are some deficiencies in feeding and management that have hampered China's growth in NHP research and materials. Nonetheless, China has recently established a number of primate animal models for human diseases and achieved marked scientific progress on infectious diseases, cardiovascular diseases, endocrine diseases, reproductive diseases, neurological diseases, and ophthalmic diseases, etc. Advances in these fields via NHP models will undoubtedly further promote the development of China's life sciences and pharmaceutical industry, and enhance China's position as a leader in NHP research. This review covers the current status of NHPs in China and other areas, highlighting the latest developments in disease models using NHPs, as well as outlining basic problems and proposing effective countermeasures to better utilize NHP resources and further foster NHP research in China.

Mouse Chromosome Engineering for Modeling Human Disease

OpenAIRE

van der Weyden, Louise; Bradley, Allan

2006-01-01

Chromosomal rearrangements occur frequently in humans and can be disease-associated or phenotypically neutral. Recent technological advances have led to the discovery of copy-number changes previously undetected by cytogenetic techniques. To understand the genetic consequences of such genomic changes, these mutations need to be modeled in experimentally tractable systems. The mouse is an excellent organism for this analysis because of its biological and genetic similarity to humans, and the e...

Human genetics of infectious diseases: a unified theory

Science.gov (United States)

Casanova, Jean-Laurent; Abel, Laurent

2007-01-01

Since the early 1950s, the dominant paradigm in the human genetics of infectious diseases postulates that rare monogenic immunodeficiencies confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections are associated with the polygenic inheritance of multiple susceptibility genes (one infection, multiple genes). Recent studies, since 1996 in particular, have challenged this view. A newly recognised group of primary immunodeficiencies predisposing the individual to a principal or single type of infection is emerging. In parallel, several common infections have been shown to reflect the inheritance of one major susceptibility gene, at least in some populations. This novel causal relationship (one gene, one infection) blurs the distinction between patient-based Mendelian genetics and population-based complex genetics, and provides a unified conceptual frame for exploring the molecular genetic basis of infectious diseases in humans. PMID:17255931

Insect Peptides - Perspectives in Human Diseases Treatment.

Science.gov (United States)

Chowanski, Szymon; Adamski, Zbigniew; Lubawy, Jan; Marciniak, Pawel; Pacholska-Bogalska, Joanna; Slocinska, Malgorzata; Spochacz, Marta; Szymczak, Monika; Urbanski, Arkadiusz; Walkowiak-Nowicka, Karolina; Rosinski, Grzegorz

2017-01-01

Insects are the largest and the most widely distributed group of animals in the world. Their diversity is a source of incredible variety of different mechanisms of life processes regulation. There are many agents that regulate immunology, reproduction, growth and development or metabolism. Hence, it seems that insects may be a source of numerous substances useful in human diseases treatment. Especially important in the regulation of insect physiology are peptides, like neuropeptides, peptide hormones or antimicrobial peptides. There are two main aspects where they can be helpful, 1) Peptides isolated from insects may become potential drugs in therapy of different diseases, 2) A lot of insect peptide hormones show structural or functional homology to mammalian peptide hormones and the comparative studies may give a new look on human disorders. In our review we focused on three group of insect derived peptides: 1) immune-active peptides, 2) peptide hormones and 3) peptides present in venoms. In our review we try to show the considerable potential of insect peptides in searching for new solutions for mammalian diseases treatment. We summarise the knowledge about properties of insect peptides against different virulent agents, anti-inflammatory or anti-nociceptive properties as well as compare insect and mammalian/vertebrate peptide endocrine system to indicate usefulness of knowledge about insect peptide hormones in drug design. The field of possible using of insect delivered peptide to therapy of various human diseases is still not sufficiently explored. Undoubtedly, more attention should be paid to insects due to searching new drugs. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Human Embryonic Stem Cell Therapy in Crohn’s Disease: A Case Report

Science.gov (United States)

Shroff, Geeta

2016-01-01

Patient: Male, 21 Final Diagnosis: Crohn’s disease Symptoms: Intolerance to specific foods • abdominal pain and diarrhea Medication: Human embryonic stem cell therapy Clinical Procedure: Human embryonic stem cell transplantation Specialty: Gastroenterology Objective: Unusual or unexpected effect of treatment Background: Crohn’s disease is a chronic inflammatory disease of the intestines, mainly the colon and ileum, related with ulcers and fistulae. It is estimated to affect 565 000 people in the United States. Currently available therapies, such as antibiotics, thiopurines, and anti-tumor necrosis factor-alpha agents, are only observed to reduce the complications associated with Crohn’s disease and to improve quality of life, but cannot cure the disease. Stem cell therapy appears to have certain advantages over conventional therapies. Our study aimed to evaluate the efficacy of human embryonic stem cell therapy in a patient with Crohn’s disease. Case Report: A 21-year-old male with chief complaints of intolerance to specific foods, abdominal pain, and diarrhea underwent human embryonic stem cell therapy for two months. After undergoing human embryonic stem cell therapy, the patient showed symptomatic relief. He had no complaints of back pain, abdominal pain, or diarrhea and had improved digestion. The patient had no signs and symptoms of skin infection, and had improved limb stamina, strength, and endurance. The condition of patient was stable after the therapy. Conclusions: Human embryonic stem cell therapy might serve as a new optimistic treatment approach for Crohn’s disease. PMID:26923312

Modeling Human Neurological and Neurodegenerative Diseases: From Induced Pluripotent Stem Cells to Neuronal Differentiation and Its Applications in Neurotrauma.

Science.gov (United States)

Bahmad, Hisham; Hadadeh, Ola; Chamaa, Farah; Cheaito, Katia; Darwish, Batoul; Makkawi, Ahmad-Kareem; Abou-Kheir, Wassim

2017-01-01

With the help of several inducing factors, somatic cells can be reprogrammed to become induced pluripotent stem cell (iPSCs) lines. The success is in obtaining iPSCs almost identical to embryonic stem cells (ESCs), therefore various approaches have been tested and ultimately several ones have succeeded. The importance of these cells is in how they serve as models to unveil the molecular pathways and mechanisms underlying several human diseases, and also in its potential roles in the development of regenerative medicine. They further aid in the development of regenerative medicine, autologous cell therapy and drug or toxicity screening. Here, we provide a comprehensive overview of the recent development in the field of iPSCs research, specifically for modeling human neurological and neurodegenerative diseases, and its applications in neurotrauma. These are mainly characterized by progressive functional or structural neuronal loss rendering them extremely challenging to manage. Many of these diseases, including Parkinson's disease (PD), Huntington's disease (HD), Amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) have been explored in vitro . The main purpose is to generate patient-specific iPS cell lines from the somatic cells that carry mutations or genetic instabilities for the aim of studying their differentiation potential and behavior. This new technology will pave the way for future development in the field of stem cell research anticipating its use in clinical settings and in regenerative medicine in order to treat various human diseases, including neurological and neurodegenerative diseases.

Human genetics of infectious diseases: between proof of principle and paradigm

OpenAIRE

Alcaïs, Alexandre; Abel, Laurent; Casanova, Jean-Laurent

2009-01-01

The observation that only a fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. As we discuss here, human predisposition to infectious diseases seems to cover a continuous spectrum from monogenic to polygenic inheritance. Although many studies have provided proo...

[Diseases transmitted through water for human consumption].

Science.gov (United States)

Franco, E; Dentamaro, M

2003-01-01

The water for human consumption maintains a biological risk and can transmit diseases. The classical waterborne and the presently frequent diseases caused by protozoi Giardia and Cryptosporidium are considered and Arcobacter butzleri, a new waterborne pathogen, is described. Many measures have been adopted by institutions to ensure the quality of the drinking water. Managers and public health operators is working in order to verify the efficiency of more suitable indicators for its monitoring.

Autophagy as a Molecular Target of Flavonoids Underlying their Protective Effects in Human Disease.

Science.gov (United States)

Prieto-Domínguez, Nestor; Garcia-Mediavilla, Maria V; Sanchez-Campos, Sonia; Mauriz, Jose L; Gonzalez-Gallego, Javier

2018-01-01

Autophagy is a cellular pathway with the ability to maintain cell homeostasis through the elimination of damaged or useless cellular components, and its deregulation may initiate or aggravate different human diseases. Flavonoids, a group of plant metabolites, are able to modulate different molecular and cellular processes including autophagy. To review the effects of flavonoids on autophagy pathway in both invasive and noninvasive human diseases, focusing on the global outcomes in their progression. Moreover, the efficacy of the combination of flavonoids with drugs or other natural nontoxic compounds was also reviewed. A literature search was performed to identify and analyze peer-reviewed publications containing in vitro and in vivo studies focused on autophagy deregulation in different proliferative and non-proliferative pathologies and the potential protective effects of flavonoids. Analyzed publications indicated that imbalance between cell death and survival induced by changes in autophagy play an important role in the pathophysiology of a number of human diseases. The use of different flavonoids as autophagy modulators, alone or in combination with other molecules, might be a worthy strategy in the treatment of cancer, neurodegenerative disorders, cardiovascular diseases, hepatic diseases, leishmaniasis, influenza, gastric ulcers produced by Helicobacter pylori infection, diabetes, asthma, age-related macular degeneration or osteoporosis. Flavonoids could potentially constitute important adjuvant agents of conventional therapies in the treatment of autophagy deregulation-related diseases. Moreover, combined therapy may help to diminish the doses of those conventional treatments, leading to reduced drug-derivative side effects and to improved patients' survival. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Modeling Viral Infectious Diseases and Development of Antiviral Therapies Using Human Induced Pluripotent Stem Cell-Derived Systems.

Science.gov (United States)

Trevisan, Marta; Sinigaglia, Alessandro; Desole, Giovanna; Berto, Alessandro; Pacenti, Monia; Palù, Giorgio; Barzon, Luisa

2015-07-13

The recent biotechnology breakthrough of cell reprogramming and generation of induced pluripotent stem cells (iPSCs), which has revolutionized the approaches to study the mechanisms of human diseases and to test new drugs, can be exploited to generate patient-specific models for the investigation of host-pathogen interactions and to develop new antimicrobial and antiviral therapies. Applications of iPSC technology to the study of viral infections in humans have included in vitro modeling of viral infections of neural, liver, and cardiac cells; modeling of human genetic susceptibility to severe viral infectious diseases, such as encephalitis and severe influenza; genetic engineering and genome editing of patient-specific iPSC-derived cells to confer antiviral resistance.

Modeling Viral Infectious Diseases and Development of Antiviral Therapies Using Human Induced Pluripotent Stem Cell-Derived Systems

Directory of Open Access Journals (Sweden)

Marta Trevisan

2015-07-01

Full Text Available The recent biotechnology breakthrough of cell reprogramming and generation of induced pluripotent stem cells (iPSCs, which has revolutionized the approaches to study the mechanisms of human diseases and to test new drugs, can be exploited to generate patient-specific models for the investigation of host–pathogen interactions and to develop new antimicrobial and antiviral therapies. Applications of iPSC technology to the study of viral infections in humans have included in vitro modeling of viral infections of neural, liver, and cardiac cells; modeling of human genetic susceptibility to severe viral infectious diseases, such as encephalitis and severe influenza; genetic engineering and genome editing of patient-specific iPSC-derived cells to confer antiviral resistance.

Kalirin, a key player in synapse formation, is implicated in human diseases.

Science.gov (United States)

Mandela, Prashant; Ma, Xin-Ming

2012-01-01

Synapse formation is considered to be crucial for learning and memory. Understanding the underlying molecular mechanisms of synapse formation is a key to understanding learning and memory. Kalirin-7, a major isoform of Kalirin in adult rodent brain, is an essential component of mature excitatory synapses. Kalirin-7 interacts with multiple PDZ-domain-containing proteins including PSD95, spinophilin, and GluR1 through its PDZ-binding motif. In cultured hippocampal/cortical neurons, overexpression of Kalirin-7 increases spine density and spine size whereas reduction of endogenous Kalirin-7 expression decreases synapse number, and spine density. In Kalirin-7 knockout mice, spine length, synapse number, and postsynaptic density (PSD) size are decreased in hippocampal CA1 pyramidal neurons; these morphological alterations are accompanied by a deficiency in long-term potentiation (LTP) and a decreased spontaneous excitatory postsynaptic current (sEPSC) frequency. Human Kalirin-7, also known as Duo or Huntingtin-associated protein-interacting protein (HAPIP), is equivalent to rat Kalirin-7. Recent studies show that Kalirin is relevant to many human diseases such as Huntington's Disease, Alzheimer's Disease, ischemic stroke, schizophrenia, depression, and cocaine addiction. This paper summarizes our recent understanding of Kalirin function.

STRESS AS PREDISPOSING FACTOR OF SOME CHRONIC DISEASES INCLUDING PERIODONTAL DISEASE

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Dewi-Nurul M Dewi-Nurul

2006-04-01

Full Text Available Stress is hypothesized as a common pathway for several related chronic diseases of man. Psychosocial stress as modified by perceptions and coping by patients can lead to physical processes. Psychoneuroimmunologic (PNI studies have suggested that psychosocial stress can alter immune function and increase vulnerability to illnesses. The patients also have high sensitivity to periodontal disease (PD. This article describes the association of stress as a physiological response to diseases such as PD, rheumatoid arthritis (RA, and inflammatory bowel disease. The psychosocial stress can lead to physiological processes through 1 the hypothalamic-pituitary-adrenal (HPA axis leading to glucocortico-steroid secretion; 2 the autonomic nervous system, resulting in the release of catecholamine; or 3 the hypothalamic-pituitary-gonadal axis, resulting in the release of sex hormones. These processes may affect chronic diseases. It can be concluded that psychosocial stress in periodontal disease patients must be considered and social support must be provided in order to achieve an optimum periodontal therapy result.

Cracking the Code of Human Diseases Using Next-Generation Sequencing: Applications, Challenges, and Perspectives

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Vincenza Precone

2015-01-01

Full Text Available Next-generation sequencing (NGS technologies have greatly impacted on every field of molecular research mainly because they reduce costs and increase throughput of DNA sequencing. These features, together with the technology’s flexibility, have opened the way to a variety of applications including the study of the molecular basis of human diseases. Several analytical approaches have been developed to selectively enrich regions of interest from the whole genome in order to identify germinal and/or somatic sequence variants and to study DNA methylation. These approaches are now widely used in research, and they are already being used in routine molecular diagnostics. However, some issues are still controversial, namely, standardization of methods, data analysis and storage, and ethical aspects. Besides providing an overview of the NGS-based approaches most frequently used to study the molecular basis of human diseases at DNA level, we discuss the principal challenges and applications of NGS in the field of human genomics.

UK Iatrogenic Creutzfeldt-Jakob disease: investigating human prion transmission across genotypic barriers using human tissue-based and molecular approaches.

Science.gov (United States)

Ritchie, Diane L; Barria, Marcelo A; Peden, Alexander H; Yull, Helen M; Kirkpatrick, James; Adlard, Peter; Ironside, James W; Head, Mark W

2017-04-01

Creutzfeldt-Jakob disease (CJD) is the prototypic human prion disease that occurs most commonly in sporadic and genetic forms, but it is also transmissible and can be acquired through medical procedures, resulting in iatrogenic CJD (iCJD). The largest numbers of iCJD cases that have occurred worldwide have resulted from contaminated cadaveric pituitary-derived human growth hormone (hGH) and its use to treat primary and secondary growth hormone deficiency. We report a comprehensive, tissue-based and molecular genetic analysis of the largest series of UK hGH-iCJD cases reported to date, including in vitro kinetic molecular modelling of genotypic factors influencing prion transmission. The results show the interplay of prion strain and host genotype in governing the molecular, pathological and temporal characteristics of the UK hGH-iCJD epidemic and provide insights into the adaptive mechanisms involved when prions cross genotypic barriers. We conclude that all of the available evidence is consistent with the hypothesis that the UK hGH-iCJD epidemic resulted from transmission of the V2 human prion strain, which is associated with the second most common form of sporadic CJD.

Human prion diseases in the United States.

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Robert C Holman

Full Text Available BACKGROUND: Prion diseases are a family of rare, progressive, neurodegenerative disorders that affect humans and animals. The most common form of human prion disease, Creutzfeldt-Jakob disease (CJD, occurs worldwide. Variant CJD (vCJD, a recently emerged human prion disease, is a zoonotic foodborne disorder that occurs almost exclusively in countries with outbreaks of bovine spongiform encephalopathy. This study describes the occurrence and epidemiology of CJD and vCJD in the United States. METHODOLOGY/PRINCIPAL FINDINGS: Analysis of CJD and vCJD deaths using death certificates of US residents for 1979-2006, and those identified through other surveillance mechanisms during 1996-2008. Since CJD is invariably fatal and illness duration is usually less than one year, the CJD incidence is estimated as the death rate. During 1979 through 2006, an estimated 6,917 deaths with CJD as a cause of death were reported in the United States, an annual average of approximately 247 deaths (range 172-304 deaths. The average annual age-adjusted incidence for CJD was 0.97 per 1,000,000 persons. Most (61.8% of the CJD deaths occurred among persons >or=65 years of age for an average annual incidence of 4.8 per 1,000,000 persons in this population. Most deaths were among whites (94.6%; the age-adjusted incidence for whites was 2.7 times higher than that for blacks (1.04 and 0.40, respectively. Three patients who died since 2004 were reported with vCJD; epidemiologic evidence indicated that their infection was acquired outside of the United States. CONCLUSION/SIGNIFICANCE: Surveillance continues to show an annual CJD incidence rate of about 1 case per 1,000,000 persons and marked differences in CJD rates by age and race in the United States. Ongoing surveillance remains important for monitoring the stability of the CJD incidence rates, and detecting occurrences of vCJD and possibly other novel prion diseases in the United States.

Immunotherapy of Human Papilloma Virus Induced Disease

Science.gov (United States)

van der Burg, Sjoerd H

2012-01-01

Immunotherapy is the generic name for treatment modalities aiming to reinforce the immune system against diseases in which the immune system plays a role. The design of an optimal immunotherapeutic treatment against chronic viruses and associated diseases requires a detailed understanding of the interactions between the target virus and its host, in order to define the specific strategies that may have the best chance to deliver success at each stage of disease. Recently, a first series of successes was reported for the immunotherapy of Human Papilloma Virus (HPV)-induced premalignant diseases but there is definitely room for improvement. Here I discuss a number of topics that in my opinion require more study as the answers to these questions allows us to better understand the underlying mechanisms of disease and as such to tailor treatment. PMID:23341861

New variant of Creutzfeldt-Jakob (vCJD) disease and other human prion diseases under epidemiological surveillance in Brazil

OpenAIRE

Gattás, Vera Lúcia; Lima Neto, Antonio Silva; Dimech, George Santiago; Mancini, Denise; Cantarino, Ligia Maria; Marins, José Ricardo Pio; Luna, Expedito José Albuquerque

2007-01-01

Abstract To increase the timeliness of detection of human cases of the new variant of Creutzfeldt-Jakob disease (vCJD) and to reduce the risk of transmission, the Brazilian Ministry of Health has established and standardized rules and control measures. These include the definition of criteria for suspect cases, reporting, monitoring, and control measures for illness prevention and transmission. Guidelines to be used by the team of health care staff were published and distributed to health wor...

DEGAS: de novo discovery of dysregulated pathways in human diseases.

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Igor Ulitsky

Full Text Available BACKGROUND: Molecular studies of the human disease transcriptome typically involve a search for genes whose expression is significantly dysregulated in sick individuals compared to healthy controls. Recent studies have found that only a small number of the genes in human disease-related pathways show consistent dysregulation in sick individuals. However, those studies found that some pathway genes are affected in most sick individuals, but genes can differ among individuals. While a pathway is usually defined as a set of genes known to share a specific function, pathway boundaries are frequently difficult to assign, and methods that rely on such definition cannot discover novel pathways. Protein interaction networks can potentially be used to overcome these problems. METHODOLOGY/PRINCIPAL FINDINGS: We present DEGAS (DysrEgulated Gene set Analysis via Subnetworks, a method for identifying connected gene subnetworks significantly enriched for genes that are dysregulated in specimens of a disease. We applied DEGAS to seven human diseases and obtained statistically significant results that appear to home in on compact pathways enriched with hallmarks of the diseases. In Parkinson's disease, we provide novel evidence for involvement of mRNA splicing, cell proliferation, and the 14-3-3 complex in the disease progression. DEGAS is available as part of the MATISSE software package (http://acgt.cs.tau.ac.il/matisse. CONCLUSIONS/SIGNIFICANCE: The subnetworks identified by DEGAS can provide a signature of the disease potentially useful for diagnosis, pinpoint possible pathways affected by the disease, and suggest targets for drug intervention.

The DNA-damage response in human biology and disease

DEFF Research Database (Denmark)

Jackson, Stephen P; Bartek, Jiri

2009-01-01

, signal its presence and mediate its repair. Such responses, which have an impact on a wide range of cellular events, are biologically significant because they prevent diverse human diseases. Our improving understanding of DNA-damage responses is providing new avenues for disease management....

The impact of Fusarium mycotoxins on human and animal host susceptibility to infectious diseases.

Science.gov (United States)

Antonissen, Gunther; Martel, An; Pasmans, Frank; Ducatelle, Richard; Verbrugghe, Elin; Vandenbroucke, Virginie; Li, Shaoji; Haesebrouck, Freddy; Van Immerseel, Filip; Croubels, Siska

2014-01-28

Contamination of food and feed with mycotoxins is a worldwide problem. At present, acute mycotoxicosis caused by high doses is rare in humans and animals. Ingestion of low to moderate amounts of Fusarium mycotoxins is common and generally does not result in obvious intoxication. However, these low amounts may impair intestinal health, immune function and/or pathogen fitness, resulting in altered host pathogen interactions and thus a different outcome of infection. This review summarizes the current state of knowledge about the impact of Fusarium mycotoxin exposure on human and animal host susceptibility to infectious diseases. On the one hand, exposure to deoxynivalenol and other Fusarium mycotoxins generally exacerbates infections with parasites, bacteria and viruses across a wide range of animal host species. Well-known examples include coccidiosis in poultry, salmonellosis in pigs and mice, colibacillosis in pigs, necrotic enteritis in poultry, enteric septicemia of catfish, swine respiratory disease, aspergillosis in poultry and rabbits, reovirus infection in mice and Porcine Reproductive and Respiratory Syndrome Virus infection in pigs. However, on the other hand, T-2 toxin has been shown to markedly decrease the colonization capacity of Salmonella in the pig intestine. Although the impact of the exposure of humans to Fusarium toxins on infectious diseases is less well known, extrapolation from animal models suggests possible exacerbation of, for instance, colibacillosis and salmonellosis in humans, as well.

Including pathogen risk in life cycle assessment of wastewater management. 1. Estimating the burden of disease associated with pathogens.

Science.gov (United States)

Harder, Robin; Heimersson, Sara; Svanström, Magdalena; Peters, Gregory M

2014-08-19

The environmental performance of wastewater and sewage sludge management is commonly assessed using life cycle assessment (LCA), whereas pathogen risk is evaluated with quantitative microbial risk assessment (QMRA). This study explored the application of QMRA methodology with intent to include pathogen risk in LCA and facilitate a comparison with other potential impacts on human health considered in LCA. Pathogen risk was estimated for a model wastewater treatment system (WWTS) located in an industrialized country and consisting of primary, secondary, and tertiary wastewater treatment, anaerobic sludge digestion, and land application of sewage sludge. The estimation was based on eight previous QMRA studies as well as parameter values taken from the literature. A total pathogen risk (expressed as burden of disease) on the order of 0.2-9 disability-adjusted life years (DALY) per year of operation was estimated for the model WWTS serving 28,600 persons and for the pathogens and exposure pathways included in this study. The comparison of pathogen risk with other potential impacts on human health considered in LCA is detailed in part 2 of this article series.

Transcriptional profiling of human liver identifies sex-biased genes associated with polygenic dyslipidemia and coronary artery disease.

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Yijing Zhang

Full Text Available Sex-differences in human liver gene expression were characterized on a genome-wide scale using a large liver sample collection, allowing for detection of small expression differences with high statistical power. 1,249 sex-biased genes were identified, 70% showing higher expression in females. Chromosomal bias was apparent, with female-biased genes enriched on chrX and male-biased genes enriched on chrY and chr19, where 11 male-biased zinc-finger KRAB-repressor domain genes are distributed in six clusters. Top biological functions and diseases significantly enriched in sex-biased genes include transcription, chromatin organization and modification, sexual reproduction, lipid metabolism and cardiovascular disease. Notably, sex-biased genes are enriched at loci associated with polygenic dyslipidemia and coronary artery disease in genome-wide association studies. Moreover, of the 8 sex-biased genes at these loci, 4 have been directly linked to monogenic disorders of lipid metabolism and show an expression profile in females (elevated expression of ABCA1, APOA5 and LDLR; reduced expression of LIPC that is consistent with the lower female risk of coronary artery disease. Female-biased expression was also observed for CYP7A1, which is activated by drugs used to treat hypercholesterolemia. Several sex-biased drug-metabolizing enzyme genes were identified, including members of the CYP, UGT, GPX and ALDH families. Half of 879 mouse orthologs, including many genes of lipid metabolism and homeostasis, show growth hormone-regulated sex-biased expression in mouse liver, suggesting growth hormone might play a similar regulatory role in human liver. Finally, the evolutionary rate of protein coding regions for human-mouse orthologs, revealed by dN/dS ratio, is significantly higher for genes showing the same sex-bias in both species than for non-sex-biased genes. These findings establish that human hepatic sex differences are widespread and affect diverse cell

Herpesviruses dUTPases: A New Family of Pathogen-Associated Molecular Pattern (PAMP Proteins with Implications for Human Disease

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Marshall V. Williams

2016-12-01

Full Text Available The human herpesviruses are ubiquitous viruses and have a prevalence of over 90% in the adult population. Following a primary infection they establish latency and can be reactivated over a person’s lifetime. While it is well accepted that human herpesviruses are implicated in numerous diseases ranging from dermatological and autoimmune disease to cancer, the role of lytic proteins in the pathophysiology of herpesvirus-associated diseases remains largely understudies. Only recently have we begun to appreciate the importance of lytic proteins produced during reactivation of the virus, in particular the deoxyuridine triphosphate nucleotidohydrolases (dUTPase, as key modulators of the host innate and adaptive immune responses. In this review, we provide evidence from animal and human studies of the Epstein–Barr virus as a prototype, supporting the notion that herpesviruses dUTPases are a family of proteins with unique immunoregulatory functions that can alter the inflammatory microenvironment and thus exacerbate the immune pathology of herpesvirus-related diseases including myalgic encephalomyelitis/chronic fatigue syndrome, autoimmune diseases, and cancer.

Global and disease-associated genetic variation in the human Fanconi anemia gene family.

Science.gov (United States)

Rogers, Kai J; Fu, Wenqing; Akey, Joshua M; Monnat, Raymond J

2014-12-20

Fanconi anemia (FA) is a human recessive genetic disease resulting from inactivating mutations in any of 16 FANC (Fanconi) genes. Individuals with FA are at high risk of developmental abnormalities, early bone marrow failure and leukemia. These are followed in the second and subsequent decades by a very high risk of carcinomas of the head and neck and anogenital region, and a small continuing risk of leukemia. In order to characterize base pair-level disease-associated (DA) and population genetic variation in FANC genes and the segregation of this variation in the human population, we identified 2948 unique FANC gene variants including 493 FA DA variants across 57,240 potential base pair variation sites in the 16 FANC genes. We then analyzed the segregation of this variation in the 7578 subjects included in the Exome Sequencing Project (ESP) and the 1000 Genomes Project (1KGP). There was a remarkably high frequency of FA DA variants in ESP/1KGP subjects: at least 1 FA DA variant was identified in 78.5% (5950 of 7578) individuals included in these two studies. Six widely used functional prediction algorithms correctly identified only a third of the known, DA FANC missense variants. We also identified FA DA variants that may be good candidates for different types of mutation-specific therapies. Our results demonstrate the power of direct DNA sequencing to detect, estimate the frequency of and follow the segregation of deleterious genetic variation in human populations. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

G protein-coupled receptor mutations and human genetic disease.

Science.gov (United States)

Thompson, Miles D; Hendy, Geoffrey N; Percy, Maire E; Bichet, Daniel G; Cole, David E C

2014-01-01

Genetic variations in G protein-coupled receptor genes (GPCRs) disrupt GPCR function in a wide variety of human genetic diseases. In vitro strategies and animal models have been used to identify the molecular pathologies underlying naturally occurring GPCR mutations. Inactive, overactive, or constitutively active receptors have been identified that result in pathology. These receptor variants may alter ligand binding, G protein coupling, receptor desensitization and receptor recycling. Receptor systems discussed include rhodopsin, thyrotropin, parathyroid hormone, melanocortin, follicle-stimulating hormone (FSH), luteinizing hormone, gonadotropin-releasing hormone (GNRHR), adrenocorticotropic hormone, vasopressin, endothelin-β, purinergic, and the G protein associated with asthma (GPRA or neuropeptide S receptor 1 (NPSR1)). The role of activating and inactivating calcium-sensing receptor (CaSR) mutations is discussed in detail with respect to familial hypocalciuric hypercalcemia (FHH) and autosomal dominant hypocalemia (ADH). The CASR mutations have been associated with epilepsy. Diseases caused by the genetic disruption of GPCR functions are discussed in the context of their potential to be selectively targeted by drugs that rescue altered receptors. Examples of drugs developed as a result of targeting GPCRs mutated in disease include: calcimimetics and calcilytics, therapeutics targeting melanocortin receptors in obesity, interventions that alter GNRHR loss from the cell surface in idiopathic hypogonadotropic hypogonadism and novel drugs that might rescue the P2RY12 receptor congenital bleeding phenotype. De-orphanization projects have identified novel disease-associated receptors, such as NPSR1 and GPR35. The identification of variants in these receptors provides genetic reagents useful in drug screens. Discussion of the variety of GPCRs that are disrupted in monogenic Mendelian disorders provides the basis for examining the significance of common

RAS signalling in energy metabolism and rare human diseases.

Science.gov (United States)

Dard, L; Bellance, N; Lacombe, D; Rossignol, R

2018-05-08

The RAS pathway is a highly conserved cascade of protein-protein interactions and phosphorylation that is at the heart of signalling networks that govern proliferation, differentiation and cell survival. Recent findings indicate that the RAS pathway plays a role in the regulation of energy metabolism via the control of mitochondrial form and function but little is known on the participation of this effect in RAS-related rare human genetic diseases. Germline mutations that hyperactivate the RAS pathway have been discovered and linked to human developmental disorders that are known as RASopathies. Individuals with RASopathies, which are estimated to affect approximately 1/1000 human birth, share many overlapping characteristics, including cardiac malformations, short stature, neurocognitive impairment, craniofacial dysmorphy, cutaneous, musculoskeletal, and ocular abnormalities, hypotonia and a predisposition to developing cancer. Since the identification of the first RASopathy, type 1 neurofibromatosis (NF1), which is caused by the inactivation of neurofibromin 1, several other syndromes have been associated with mutations in the core components of the RAS-MAPK pathway. These syndromes include Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), which was formerly called LEOPARD syndrome, Costello syndrome (CS), cardio-facio-cutaneous syndrome (CFC), Legius syndrome (LS) and capillary malformation-arteriovenous malformation syndrome (CM-AVM). Here, we review current knowledge about the bioenergetics of the RASopathies and discuss the molecular control of energy homeostasis and mitochondrial physiology by the RAS pathway. Copyright © 2018 Elsevier B.V. All rights reserved.

Diseases of Poverty and Lifestyle, Well-Being and Human Development

OpenAIRE

Singh, Ajai R.; Singh, Shakuntala A.

2008-01-01

The problems of the haves differ substantially from those of the have-nots. Individuals in developing societies have to fight mainly against infectious and communicable diseases, while in the developed world the battles are mainly against lifestyle diseases. Yet, at a very fundamental level, the problems are the same-the fight is against distress, disability, and premature death; against human exploitation and for human development and self-actualisation; against the callousness to critical c...

The expanding universe of cohesin functions: a new genome stability caretaker involved in human disease and cancer.

Science.gov (United States)

Mannini, Linda; Menga, Stefania; Musio, Antonio

2010-06-01

Cohesin is responsible for sister chromatid cohesion, ensuring the correct chromosome segregation. Beyond this role, cohesin and regulatory cohesin genes seem to play a role in preserving genome stability and gene transcription regulation. DNA damage is thought to be a major culprit for many human diseases, including cancer. Our present knowledge of the molecular basis underlying genome instability is extremely limited. Mutations in cohesin genes cause human diseases such as Cornelia de Lange syndrome and Roberts syndrome/SC phocomelia, and all the cell lines derived from affected patients show genome instability. Cohesin mutations have also been identified in colorectal cancer. Here, we will discuss the human disorders caused by alterations of cohesin function, with emphasis on the emerging role of cohesin as a genome stability caretaker.

Genetic Modification of the Lung Directed Toward Treatment of Human Disease.

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Sondhi, Dolan; Stiles, Katie M; De, Bishnu P; Crystal, Ronald G

2017-01-01

Genetic modification therapy is a promising therapeutic strategy for many diseases of the lung intractable to other treatments. Lung gene therapy has been the subject of numerous preclinical animal experiments and human clinical trials, for targets including genetic diseases such as cystic fibrosis and α1-antitrypsin deficiency, complex disorders such as asthma, allergy, and lung cancer, infections such as respiratory syncytial virus (RSV) and Pseudomonas, as well as pulmonary arterial hypertension, transplant rejection, and lung injury. A variety of viral and non-viral vectors have been employed to overcome the many physical barriers to gene transfer imposed by lung anatomy and natural defenses. Beyond the treatment of lung diseases, the lung has the potential to be used as a metabolic factory for generating proteins for delivery to the circulation for treatment of systemic diseases. Although much has been learned through a myriad of experiments about the development of genetic modification of the lung, more work is still needed to improve the delivery vehicles and to overcome challenges such as entry barriers, persistent expression, specific cell targeting, and circumventing host anti-vector responses.

The Human Phenotype Ontology: Semantic Unification of Common and Rare Disease

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Groza, Tudor; Köhler, Sebastian; Moldenhauer, Dawid; Vasilevsky, Nicole; Baynam, Gareth; Zemojtel, Tomasz; Schriml, Lynn Marie; Kibbe, Warren Alden; Schofield, Paul N.; Beck, Tim; Vasant, Drashtti; Brookes, Anthony J.; Zankl, Andreas; Washington, Nicole L.; Mungall, Christopher J.; Lewis, Suzanna E.; Haendel, Melissa A.; Parkinson, Helen; Robinson, Peter N.

2015-01-01

The Human Phenotype Ontology (HPO) is widely used in the rare disease community for differential diagnostics, phenotype-driven analysis of next-generation sequence-variation data, and translational research, but a comparable resource has not been available for common disease. Here, we have developed a concept-recognition procedure that analyzes the frequencies of HPO disease annotations as identified in over five million PubMed abstracts by employing an iterative procedure to optimize precision and recall of the identified terms. We derived disease models for 3,145 common human diseases comprising a total of 132,006 HPO annotations. The HPO now comprises over 250,000 phenotypic annotations for over 10,000 rare and common diseases and can be used for examining the phenotypic overlap among common diseases that share risk alleles, as well as between Mendelian diseases and common diseases linked by genomic location. The annotations, as well as the HPO itself, are freely available. PMID:26119816

Low seroprevalence of human Lyme disease near a focus of high entomologic risk.

Science.gov (United States)

Rand, P W; Lacombe, E H; Smith, R P; Gensheimer, K; Dennis, D T

1996-08-01

To investigate a low rate of reported human Lyme disease adjacent to an area where the vector tick had become well established, we performed human and canine serosurveys and gathered data on environmental factors related to the risk of transmission. In March 1993, we obtained serum samples and conducted questionnaires that included information on outdoor activities, lot size, and frequency of deer sightings from 272 individuals living within a 5-km strip extending 12 km inland from a study site in south coastal Maine where collections revealed an abundant population of deer ticks. Serologic analysis was done using a flagellin-based enzyme-linked immunosorbent assay (ELISA) followed by Western immunoblot of positive and equivocal samples. Sera from 71 unvaccinated dogs within the study area were also analyzed for anti-Borrelia antibodies by ELISA. Human seropositivity was limited to two individuals living within 1.2 km of the coast. The frequency of daily deer sightings decreased sharply outside this area. Canine seropositivity, 100% within the first 0.8 km, decreased to 2% beyond 1.5 km. Canine serology appears to correlate with the entomologic indicators of the risk of Lyme disease transmission. Possible explanations for the low human seroprevalence are offered.

Possible roles of transglutaminases in molecular mechanisms responsible for human neurodegenerative diseases

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Nicola Gaetano Gatta

2016-11-01

Full Text Available Transglutaminases are a family of Ca2+-dependent enzymes which catalyze post-translational modifications of proteins. The main activity of these enzymes is the cross-linking of glutaminyl residues of a protein/peptide substrate to lysyl residues of a protein/peptide co-substrate. In addition to lysyl residues, other second nucleophilic co-substrates may include monoamines or polyamines (to form mono- or bi-substituted/crosslinked adducts or –OH groups (to form ester linkages. In absence of co-substrates, the nucleophile may be water, resulting in the net deamidation of the glutaminyl residue. Transglutaminase activity has been suggested to be involved in molecular mechanisms responsible for both physiological or pathological processes. In particular, transglutaminase activity has been shown to be responsible for human autoimmune diseases, Celiac Disease is just one of them. Interestingly, neurodegenerative diseases, such as Alzheimer’s Disease, Parkinson’s Disease, supranuclear palsy, Huntington’s Disease and other polyglutamine diseases, are characterized in part by aberrant cerebral transglutaminase activity and by increased cross-linked proteins in affected brains. This review describes the possible molecular mechanisms by which these enzymes could be responsible for such diseases and the possible use of transglutaminase inhibitors for patients with diseases characterized by aberrant transglutaminase activity.

Prioritizing Zoonotic Diseases: Differences in Perspectives Between Human and Animal Health Professionals in North America.

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Ng, V; Sargeant, J M

2016-05-01

Zoonoses pose a significant burden of illness in North America. Zoonoses represent an additional threat to public health because the natural reservoirs are often animals, particularly wildlife, thus eluding control efforts such as quarantine, vaccination and social distancing. As there are limited resources available, it is necessary to prioritize diseases in order to allocate resources to those posing the greatest public health threat. Many studies have attempted to prioritize zoonoses, but challenges exist. This study uses a quantitative approach, conjoint analysis (CA), to overcome some limitations of traditional disease prioritization exercises. We used CA to conduct a zoonoses prioritization study involving a range of human and animal health professionals across North America; these included epidemiologists, public health practitioners, research scientists, physicians, veterinarians, laboratory technicians and nurses. A total of 699 human health professionals (HHP) and 585 animal health professionals (AHP) participated in this study. We used CA to prioritize 62 zoonotic diseases using 21 criteria. Our findings suggest CA can be used to produce reasonable criteria scores for disease prioritization. The fitted models were satisfactory for both groups with a slightly better fit for AHP compared to HHP (84.4% certainty fit versus 83.6%). Human-related criteria were more influential for HHP in their decision to prioritize zoonoses, while animal-related criteria were more influential for AHP resulting in different disease priority lists. While the differences were not statistically significant, a difference of one or two ranks could be considered important for some individuals. A potential solution to address the varying opinions is discussed. The scientific framework for disease prioritization presented can be revised on a regular basis by updating disease criteria to reflect diseases as they evolve over time; such a framework is of value allowing diseases of

Non-Human Primates Harbor Diverse Mammalian and Avian Astroviruses Including Those Associated with Human Infections.

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Erik A Karlsson

Full Text Available Astroviruses (AstVs are positive sense, single-stranded RNA viruses transmitted to a wide range of hosts via the fecal-oral route. The number of AstV-infected animal hosts has rapidly expanded in recent years with many more likely to be discovered because of the advances in viral surveillance and next generation sequencing. Yet no study to date has identified human AstV genotypes in animals, although diverse AstV genotypes similar to animal-origin viruses have been found in children with diarrhea and in one instance of encephalitis. Here we provide important new evidence that non-human primates (NHP can harbor a wide variety of mammalian and avian AstV genotypes, including those only associated with human infection. Serological analyses confirmed that >25% of the NHP tested had antibodies to human AstVs. Further, we identified a recombinant AstV with parental relationships to known human AstVs. Phylogenetic analysis suggests AstVs in NHP are on average evolutionarily much closer to AstVs from other animals than are AstVs from bats, a frequently proposed reservoir. Our studies not only demonstrate that human astroviruses can be detected in NHP but also suggest that NHP are unique in their ability to support diverse AstV genotypes, further challenging the paradigm that astrovirus infection is species-specific.

Human genetics of infectious diseases: a unified theory

OpenAIRE

Casanova, Jean-Laurent; Abel, Laurent

2007-01-01

Since the early 1950s, the dominant paradigm in the human genetics of infectious diseases postulates that rare monogenic immunodeficiencies confer vulnerability to multiple infectious diseases (one gene, multiple infections), whereas common infections are associated with the polygenic inheritance of multiple susceptibility genes (one infection, multiple genes). Recent studies, since 1996 in particular, have challenged this view. A newly recognised group of primary immunodeficiencies predispos...

Human drivers of ecological and evolutionary dynamics in emerging and disappearing infectious disease systems.

Science.gov (United States)

Rogalski, Mary A; Gowler, Camden D; Shaw, Clara L; Hufbauer, Ruth A; Duffy, Meghan A

2017-01-19

Humans have contributed to the increased frequency and severity of emerging infectious diseases, which pose a significant threat to wild and domestic species, as well as human health. This review examines major pathways by which humans influence parasitism by altering (co)evolutionary interactions between hosts and parasites on ecological timescales. There is still much to learn about these interactions, but a few well-studied cases show that humans influence disease emergence every step of the way. Human actions significantly increase dispersal of host, parasite and vector species, enabling greater frequency of infection in naive host populations and host switches. Very dense host populations resulting from urbanization and agriculture can drive the evolution of more virulent parasites and, in some cases, more resistant host populations. Human activities that reduce host genetic diversity or impose abiotic stress can impair the ability of hosts to adapt to disease threats. Further, evolutionary responses of hosts and parasites can thwart disease management and biocontrol efforts. Finally, in rare cases, humans influence evolution by eradicating an infectious disease. If we hope to fully understand the factors driving disease emergence and potentially control these epidemics we must consider the widespread influence of humans on host and parasite evolutionary trajectories.This article is part of the themed issue 'Human influences on evolution, and the ecological and societal consequences'. © 2016 The Author(s).

Human Retrotransposon Insertion Polymorphisms Are Associated with Health and Disease via Gene Regulatory Phenotypes

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Lu Wang

2017-08-01

Full Text Available The human genome hosts several active families of transposable elements (TEs, including the Alu, LINE-1, and SVA retrotransposons that are mobilized via reverse transcription of RNA intermediates. We evaluated how insertion polymorphisms generated by human retrotransposon activity may be related to common health and disease phenotypes that have been previously interrogated through genome-wide association studies (GWAS. To address this question, we performed a genome-wide screen for retrotransposon polymorphism disease associations that are linked to TE induced gene regulatory changes. Our screen first identified polymorphic retrotransposon insertions found in linkage disequilibrium (LD with single nucleotide polymorphisms that were previously associated with common complex diseases by GWAS. We further narrowed this set of candidate disease associated retrotransposon polymorphisms by identifying insertions that are located within tissue-specific enhancer elements. We then performed expression quantitative trait loci analysis on the remaining set of candidates in order to identify polymorphic retrotransposon insertions that are associated with gene expression changes in B-cells of the human immune system. This progressive and stringent screen yielded a list of six retrotransposon insertions as the strongest candidates for TE polymorphisms that lead to disease via enhancer-mediated changes in gene regulation. For example, we found an SVA insertion within a cell-type specific enhancer located in the second intron of the B4GALT1 gene. B4GALT1 encodes a glycosyltransferase that functions in the glycosylation of the Immunoglobulin G (IgG antibody in such a way as to convert its activity from pro- to anti-inflammatory. The disruption of the B4GALT1 enhancer by the SVA insertion is associated with down-regulation of the gene in B-cells, which would serve to keep the IgG molecule in a pro-inflammatory state. Consistent with this idea, the B4GALT1 enhancer

Changing Patterns of Emerging Zoonotic Diseases in Wildlife, Domestic Animals, and Humans Linked to Biodiversity Loss and Globalization.

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Aguirre, A Alonso

2017-12-15

The fundamental human threats to biodiversity including habitat destruction, globalization, and species loss have led to ecosystem disruptions altering infectious disease transmission patterns, the accumulation of toxic pollutants, and the invasion of alien species and pathogens. To top it all, the profound role of climate change on many ecological processes has affected the inability of many species to adapt to these relatively rapid changes. This special issue, "Zoonotic Disease Ecology: Effects on Humans, Domestic Animals and Wildlife," explores the complex interactions of emerging infectious diseases across taxa linked to many of these anthropogenic and environmental drivers. Selected emerging zoonoses including RNA viruses, Rift Valley fever, trypanosomiasis, Hanta virus infection, and other vector-borne diseases are discussed in detail. Also, coprophagous beetles are proposed as important vectors in the transmission and maintenance of infectious pathogens. An overview of the impacts of climate change in emerging disease ecology within the context of Brazil as a case study is provided. Animal Care and Use Committee requirements were investigated, concluding that ecology journals have low rates of explicit statements regarding the welfare and wellbing of wildlife during experimental studies. Most of the solutions to protect biodiversity and predicting and preventing the next epidemic in humans originating from wildlife are oriented towards the developed world and are less useful for biodiverse, low-income economies. We need the development of regional policies to address these issues at the local level.

Genetic deletion of amphiregulin restores the normal skin phenotype in a mouse model of the human skin disease tylosis

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Vishnu Hosur

2017-08-01

Full Text Available In humans, gain-of-function (GOF mutations in RHBDF2 cause the skin disease tylosis. We generated a mouse model of human tylosis and show that GOF mutations in RHBDF2 cause tylosis by enhancing the amount of amphiregulin (AREG secretion. Furthermore, we show that genetic disruption of AREG ameliorates skin pathology in mice carrying the human tylosis disease mutation. Collectively, our data suggest that RHBDF2 plays a critical role in regulating EGFR signaling and its downstream events, including development of tylosis, by facilitating enhanced secretion of AREG. Thus, targeting AREG could have therapeutic benefit in the treatment of tylosis.

Biodiversity loss, emerging infectious diseases and impact on human and crops

International Nuclear Information System (INIS)

Shinwari, Z.K.; Gilani, S.A.; Khan, A.L.

2012-01-01

We are losing biodiversity through several factors ranging from global warming, climatic change, unsustainable use of natural resources, human settlements, demand for food, medicine etc. Consequently, the biodiversity losses are causing emergence of infectious diseases (EIDs) which are making them more virulent than the past. Both biodiversity loss and emergence of diseases significantly impact the human derived benefits in-terms of economy and food. Ecological stability, productivity and food-web interactions are indirectly correlated with biodiversity and any change in these will cause losses in biodiversity that would certainly influence the human derived benefits and crops. The current article reviews the biodiversity losses and emerging infectious diseases at various levels reported by recent literature which will help in current status of EIDs and future recommendations. (author)

Harnessing what lies within: Programming immunity with biocompatible devices to treat human disease

Science.gov (United States)

Roberts, Reid Austin

Advances in our mechanistic insight of cellular function and how this relates to host physiology have revealed a world which is intimately connected at the macro and micro level. Our increasing understanding of biology exemplifies this, where cells respond to environmental cues through interconnected networks of proteins which function as receptors and adaptors to elicit gene expression changes that drive appropriate cellular programs for a given stimulus. Consequently, our deeper molecular appreciation of host homeostasis implicates aberrations of these pathways in nearly all major human disease categories, including those of infectious, metabolic, neurologic, oncogenic, and autoimmune etiology. We have come to recognize the mammalian immune system as a common network hub among all these varied pathologies. As such, the major goal of this dissertation is to identify a platform to program immune responses in mammals so that we may enhance our ability to treat disease and improve health in the 21st century. Using advances in materials science, in particular a recently developed particle fabrication technology termed Particle Replication in Non-wetting Templates (PRINT), our studies systematically assess the murine and human immune response to precisely fabricated nano- and microscale particles composed of biodegradable and biocompatible materials. We then build on these findings and present particle design parameters to program a number of clinically attractive immune responses by targeting endogenous cellular signaling pathways. These include control of particle uptake through surface modification, design parameters that modulate the magnitude and kinetics of biological signaling dynamics that can be used to exacerbate or dampen inflammatory responses, as well as particle designs which may be of use in treating allergies and autoimmune disorders. In total, this dissertation provides evidence that rational design of biocompatible nano- and microparticles is a viable

Regenerative Medicine, Disease Modelling, and Drug Discovery in Human Pluripotent Stem Cell-Derived Kidney Tissue

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Navin Gupta

2017-08-01

Full Text Available The multitude of research clarifying critical factors in embryonic organ development has been instrumental in human stem cell research. Mammalian organogenesis serves as the archetype for directed differentiation protocols, subdividing the process into a series of distinct intermediate stages that can be chemically induced and monitored for the expression of stage-specific markers. Significant advances over the past few years include established directed differentiation protocols of human embryonic stem cells and human induced pluripotent stem cells (hiPSC into human kidney organoids in vitro. Human kidney tissue in vitro simulates the in vivo response when subjected to nephrotoxins, providing a novel screening platform during drug discovery to facilitate identification of lead candidates, reduce developmental expenditures, and reduce future rates of drug-induced acute kidney injury. Patient-derived hiPSC, which bear naturally occurring DNA mutations, may allow for modelling of human genetic diseases to enable determination of pathological mechanisms and screening for novel therapeutics. In addition, recent advances in genome editing with clustered regularly interspaced short palindromic repeats (CRISPR/Cas9 enable the generation of specific mutations to study genetic disease, with non-mutated lines serving as an ideal isogenic control. The growing population of patients with end-stage kidney disease is a worldwide healthcare problem, with high morbidity and mortality rates, that warrants the discovery of novel forms of renal replacement therapy. Coupling the outlined advances in hiPSC research with innovative bioengineering techniques, such as decellularised kidney and three-dimensional printed scaffolds, may contribute to the development of bioengineered transplantable human kidney tissue as a means of renal replacement therapy.

The Impact of Evolutionary Driving Forces on Human Complex Diseases: A Population Genetics Approach

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Amr T. M. Saeb

2016-01-01

Full Text Available Investigating the molecular evolution of human genome has paved the way to understand genetic adaptation of humans to the environmental changes and corresponding complex diseases. In this review, we discussed the historical origin of genetic diversity among human populations, the evolutionary driving forces that can affect genetic diversity among populations, and the effects of human movement into new environments and gene flow on population genetic diversity. Furthermore, we presented the role of natural selection on genetic diversity and complex diseases. Then we reviewed the disadvantageous consequences of historical selection events in modern time and their relation to the development of complex diseases. In addition, we discussed the effect of consanguinity on the incidence of complex diseases in human populations. Finally, we presented the latest information about the role of ancient genes acquired from interbreeding with ancient hominids in the development of complex diseases.

Animal models for human genetic diseases | Sharif | African Journal ...

African Journals Online (AJOL)

The study of human genetic diseases can be greatly aided by animal models because of their similarity to humans in terms of genetics. In addition to understand diverse aspects of basic biology, model organisms are extensively used in applied research in agriculture, industry, and also in medicine, where they are used to ...

Evolutionary constraint and disease associations of post-translational modification sites in human genomes.

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Jüri Reimand

2015-01-01

Full Text Available Interpreting the impact of human genome variation on phenotype is challenging. The functional effect of protein-coding variants is often predicted using sequence conservation and population frequency data, however other factors are likely relevant. We hypothesized that variants in protein post-translational modification (PTM sites contribute to phenotype variation and disease. We analyzed fraction of rare variants and non-synonymous to synonymous variant ratio (Ka/Ks in 7,500 human genomes and found a significant negative selection signal in PTM regions independent of six factors, including conservation, codon usage, and GC-content, that is widely distributed across tissue-specific genes and function classes. PTM regions are also enriched in known disease mutations, suggesting that PTM variation is more likely deleterious. PTM constraint also affects flanking sequence around modified residues and increases around clustered sites, indicating presence of functionally important short linear motifs. Using target site motifs of 124 kinases, we predict that at least ∼180,000 motif-breaker amino acid residues that disrupt PTM sites when substituted, and highlight kinase motifs that show specific negative selection and enrichment of disease mutations. We provide this dataset with corresponding hypothesized mechanisms as a community resource. As an example of our integrative approach, we propose that PTPN11 variants in Noonan syndrome aberrantly activate the protein by disrupting an uncharacterized cluster of phosphorylation sites. Further, as PTMs are molecular switches that are modulated by drugs, we study mutated binding sites of PTM enzymes in disease genes and define a drug-disease network containing 413 novel predicted disease-gene links.

The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease.

Science.gov (United States)

Eppig, Janan T; Blake, Judith A; Bult, Carol J; Kadin, James A; Richardson, Joel E

2015-01-01

The Mouse Genome Database (MGD, http://www.informatics.jax.org) serves the international biomedical research community as the central resource for integrated genomic, genetic and biological data on the laboratory mouse. To facilitate use of mouse as a model in translational studies, MGD maintains a core of high-quality curated data and integrates experimentally and computationally generated data sets. MGD maintains a unified catalog of genes and genome features, including functional RNAs, QTL and phenotypic loci. MGD curates and provides functional and phenotype annotations for mouse genes using the Gene Ontology and Mammalian Phenotype Ontology. MGD integrates phenotype data and associates mouse genotypes to human diseases, providing critical mouse-human relationships and access to repositories holding mouse models. MGD is the authoritative source of nomenclature for genes, genome features, alleles and strains following guidelines of the International Committee on Standardized Genetic Nomenclature for Mice. A new addition to MGD, the Human-Mouse: Disease Connection, allows users to explore gene-phenotype-disease relationships between human and mouse. MGD has also updated search paradigms for phenotypic allele attributes, incorporated incidental mutation data, added a module for display and exploration of genes and microRNA interactions and adopted the JBrowse genome browser. MGD resources are freely available to the scientific community. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Functional modules, mutational load and human genetic disease.

Science.gov (United States)

Zaghloul, Norann A; Katsanis, Nicholas

2010-04-01

The ability to generate a massive amount of sequencing and genotyping data is transforming the study of human genetic disorders. Driven by such innovation, it is likely that whole exome and whole-genome resequencing will replace regionally focused approaches for gene discovery and clinical testing in the next few years. However, this opportunity brings a significant interpretative challenge to assigning function and phenotypic variance to common and rare alleles. Understanding the effect of individual mutations in the context of the remaining genomic variation represents a major challenge to our interpretation of disease. Here, we discuss the challenges of assigning mutation functionality and, drawing from the examples of ciliopathies as well as cohesinopathies and channelopathies, discuss possibilities for the functional modularization of the human genome. Functional modularization in addition to the development of physiologically relevant assays to test allele functionality will accelerate our understanding of disease architecture and enable the use of genome-wide sequence data for disease diagnosis and phenotypic prediction in individuals. Copyright 2010 Elsevier Ltd. All rights reserved.

Annotating Diseases Using Human Phenotype Ontology Improves Prediction of Disease-Associated Long Non-coding RNAs.

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Le, Duc-Hau; Dao, Lan T M

2018-05-23

Recently, many long non-coding RNAs (lncRNAs) have been identified and their biological function has been characterized; however, our understanding of their underlying molecular mechanisms related to disease is still limited. To overcome the limitation in experimentally identifying disease-lncRNA associations, computational methods have been proposed as a powerful tool to predict such associations. These methods are usually based on the similarities between diseases or lncRNAs since it was reported that similar diseases are associated with functionally similar lncRNAs. Therefore, prediction performance is highly dependent on how well the similarities can be captured. Previous studies have calculated the similarity between two diseases by mapping exactly each disease to a single Disease Ontology (DO) term, and then use a semantic similarity measure to calculate the similarity between them. However, the problem of this approach is that a disease can be described by more than one DO terms. Until now, there is no annotation database of DO terms for diseases except for genes. In contrast, Human Phenotype Ontology (HPO) is designed to fully annotate human disease phenotypes. Therefore, in this study, we constructed disease similarity networks/matrices using HPO instead of DO. Then, we used these networks/matrices as inputs of two representative machine learning-based and network-based ranking algorithms, that is, regularized least square and heterogeneous graph-based inference, respectively. The results showed that the prediction performance of the two algorithms on HPO-based is better than that on DO-based networks/matrices. In addition, our method can predict 11 novel cancer-associated lncRNAs, which are supported by literature evidence. Copyright © 2018 Elsevier Ltd. All rights reserved.

Modelling the influence of human behaviour on the spread of infectious diseases: a review.

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Funk, Sebastian; Salathé, Marcel; Jansen, Vincent A A

2010-09-06

Human behaviour plays an important role in the spread of infectious diseases, and understanding the influence of behaviour on the spread of diseases can be key to improving control efforts. While behavioural responses to the spread of a disease have often been reported anecdotally, there has been relatively little systematic investigation into how behavioural changes can affect disease dynamics. Mathematical models for the spread of infectious diseases are an important tool for investigating and quantifying such effects, not least because the spread of a disease among humans is not amenable to direct experimental study. Here, we review recent efforts to incorporate human behaviour into disease models, and propose that such models can be broadly classified according to the type and source of information which individuals are assumed to base their behaviour on, and according to the assumed effects of such behaviour. We highlight recent advances as well as gaps in our understanding of the interplay between infectious disease dynamics and human behaviour, and suggest what kind of data taking efforts would be helpful in filling these gaps.

Receptors for sensory neuropeptides in human inflammatory diseases: Implications for the effector role of sensory neurons

International Nuclear Information System (INIS)

Mantyh, P.W.; Catton, M.D.; Boehmer, C.G.; Welton, M.L.; Passaro, E.P. Jr.; Maggio, J.E.; Vigna, S.R.

1989-01-01

Glutamate and several neuropeptides are synthesized and released by subpopulations of primary afferent neurons. These sensory neurons play a role in regulating the inflammatory and immune responses in peripheral tissues. Using quantitative receptor autoradiography we have explored what changes occur in the location and concentration of receptor binding sites for sensory neurotransmitters in the colon in two human inflammatory diseases, ulcerative colitis and Crohn's disease. The sensory neurotransmitter receptors examined included bombesin, calcitonin gene related peptide-alpha, cholecystokinin, galanin, glutamate, somatostatin, neurokinin A (substance K), substance P, and vasoactive intestinal polypeptide. Of the nine receptor binding sites examined only substance P binding sites associated with arterioles, venules and lymph nodules were dramatically up-regulated in the inflamed tissue. These data suggest that substance P is involved in regulating the inflammatory and immune responses in human inflammatory diseases and indicate a specificity of efferent action for each sensory neurotransmitter in peripheral tissues

The Human Proteome Organization Chromosome 6 Consortium: integrating chromosome-centric and biology/disease driven strategies.

Science.gov (United States)

Borchers, C H; Kast, J; Foster, L J; Siu, K W M; Overall, C M; Binkowski, T A; Hildebrand, W H; Scherer, A; Mansoor, M; Keown, P A

2014-04-04

The Human Proteome Project (HPP) is designed to generate a comprehensive map of the protein-based molecular architecture of the human body, to provide a resource to help elucidate biological and molecular function, and to advance diagnosis and treatment of diseases. Within this framework, the chromosome-based HPP (C-HPP) has allocated responsibility for mapping individual chromosomes by country or region, while the biology/disease HPP (B/D-HPP) coordinates these teams in cross-functional disease-based groups. Chromosome 6 (Ch6) provides an excellent model for integration of these two tasks. This metacentric chromosome has a complement of 1002-1034 genes that code for known, novel or putative proteins. Ch6 is functionally associated with more than 120 major human diseases, many with high population prevalence, devastating clinical impact and profound societal consequences. The unique combination of genomic, proteomic, metabolomic, phenomic and health services data being drawn together within the Ch6 program has enormous potential to advance personalized medicine by promoting robust biomarkers, subunit vaccines and new drug targets. The strong liaison between the clinical and laboratory teams, and the structured framework for technology transfer and health policy decisions within Canada will increase the speed and efficacy of this transition, and the value of this translational research. Canada has been selected to play a leading role in the international Human Proteome Project, the global counterpart of the Human Genome Project designed to understand the structure and function of the human proteome in health and disease. Canada will lead an international team focusing on chromosome 6, which is functionally associated with more than 120 major human diseases, including immune and inflammatory disorders affecting the brain, skeletal system, heart and blood vessels, lungs, kidney, liver, gastrointestinal tract and endocrine system. Many of these chronic and persistent

Consequences of evolution: is rhinosinusitis, like otitis media, a unique disease of humans?

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Bluestone, Charles D; Pagano, Anthony S; Swarts, J Douglas; Laitman, Jeffrey T

2012-12-01

We hypothesize that if otitis media is most likely primarily a human disease due to consequences of evolution, rhinosinusitis may also be limited to humans for similar reasons. If otitis media, with its associated hearing loss, occurred in animals in the wild, they probably would have been culled out by predation. Similarly, if rhinosinusitis occurred regularly in animals, they likely would have suffered from severely decreased olfactory abilities, crucial for predator avoidance, and presumably would likewise have been selected against evolutionarily. Thus, both otitis media and rhinosinusitis-common conditions particularly in infants and young children-appear to be essentially human conditions. Their manifestation in our species is likely due to our unique evolutionary trajectory and may be a consequence of adaptations, including adaptations to bipedalism and speech, loss of prognathism, and immunologic and environmental factors.

[Genetics and susceptibility to human papillomaviruses: epidermodysplasia verruciformis, a disease model].

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Orth, Gérard

2010-06-01

The outcomes of infection by human papillomaviruses (HPV), both oncogenic and non oncogenic, show major interindividual variability The underlying genetic factors and mechanisms are poorly known, but their complexity is illustrated by epidermodysplasia verruciformis (EV), a rare autosomal recessive genodermatosis associated with a high risk of non melanoma skin cancer. This model disease is characterized by abnormal susceptibility to widespread betapapillomaviruses, including HPV-5, a virus associated with EV cancers. Most cases of EV are caused by a mutation that inactivates either of two related genes, EVER1 and EVER2. This inactivation likely compensates for the absence of a viral gene (E5 or E8) essential for HPV pathogenicity. Proteins E5 and E8 interfere with the interaction between EVER proteins and ZnT1, a zinc transporter EV is thus likely to represent a primary defect of intrinsic (constitutive) immunity or innate immunity to betapapillomaviruses, involving modulation of zinc homeostasis upon keratinocyte infection. It remains to be established which cellular genes are involved in intrinsic, innate or acquired immune responses to other human papillomaviruses, including oncogenic genital types.

Credit scores, cardiovascular disease risk, and human capital.

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Israel, Salomon; Caspi, Avshalom; Belsky, Daniel W; Harrington, HonaLee; Hogan, Sean; Houts, Renate; Ramrakha, Sandhya; Sanders, Seth; Poulton, Richie; Moffitt, Terrie E

2014-12-02

Credit scores are the most widely used instruments to assess whether or not a person is a financial risk. Credit scoring has been so successful that it has expanded beyond lending and into our everyday lives, even to inform how insurers evaluate our health. The pervasive application of credit scoring has outpaced knowledge about why credit scores are such useful indicators of individual behavior. Here we test if the same factors that lead to poor credit scores also lead to poor health. Following the Dunedin (New Zealand) Longitudinal Study cohort of 1,037 study members, we examined the association between credit scores and cardiovascular disease risk and the underlying factors that account for this association. We find that credit scores are negatively correlated with cardiovascular disease risk. Variation in household income was not sufficient to account for this association. Rather, individual differences in human capital factors—educational attainment, cognitive ability, and self-control—predicted both credit scores and cardiovascular disease risk and accounted for ∼45% of the correlation between credit scores and cardiovascular disease risk. Tracing human capital factors back to their childhood antecedents revealed that the characteristic attitudes, behaviors, and competencies children develop in their first decade of life account for a significant portion (∼22%) of the link between credit scores and cardiovascular disease risk at midlife. We discuss the implications of these findings for policy debates about data privacy, financial literacy, and early childhood interventions.

Human pluripotent stem cell models of cardiac disease: from mechanisms to therapies

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Karina O. Brandão

2017-09-01

Full Text Available It is now a decade since human induced pluripotent stem cells (hiPSCs were first described. The reprogramming of adult somatic cells to a pluripotent state has become a robust technology that has revolutionised our ability to study human diseases. Crucially, these cells capture all the genetic aspects of the patient from which they were derived. Combined with advances in generating the different cell types present in the human heart, this has opened up new avenues to study cardiac disease in humans and investigate novel therapeutic approaches to treat these pathologies. Here, we provide an overview of the current state of the field regarding the generation of cardiomyocytes from human pluripotent stem cells and methods to assess them functionally, an essential requirement when investigating disease and therapeutic outcomes. We critically evaluate whether treatments suggested by these in vitro models could be translated to clinical practice. Finally, we consider current shortcomings of these models and propose methods by which they could be further improved.

Exhaustive Genome-Wide Search for SNP-SNP Interactions Across 10 Human Diseases

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William Murk

2016-07-01

Full Text Available The identification of statistical SNP-SNP interactions may help explain the genetic etiology of many human diseases, but exhaustive genome-wide searches for these interactions have been difficult, due to a lack of power in most datasets. We aimed to use data from the Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA study to search for SNP-SNP interactions associated with 10 common diseases. FastEpistasis and BOOST were used to evaluate all pairwise interactions among approximately N = 300,000 single nucleotide polymorphisms (SNPs with minor allele frequency (MAF ≥ 0.15, for the dichotomous outcomes of allergic rhinitis, asthma, cardiac disease, depression, dermatophytosis, type 2 diabetes, dyslipidemia, hemorrhoids, hypertensive disease, and osteoarthritis. A total of N = 45,171 subjects were included after quality control steps were applied. These data were divided into discovery and replication subsets; the discovery subset had > 80% power, under selected models, to detect genome-wide significant interactions (P < 10−12. Interactions were also evaluated for enrichment in particular SNP features, including functionality, prior disease relevancy, and marginal effects. No interaction in any disease was significant in both the discovery and replication subsets. Enrichment analysis suggested that, for some outcomes, interactions involving SNPs with marginal effects were more likely to be nominally replicated, compared to interactions without marginal effects. If SNP-SNP interactions play a role in the etiology of the studied conditions, they likely have weak effect sizes, involve lower-frequency variants, and/or involve complex models of interaction that are not captured well by the methods that were utilized.

Human endogenous retroviruses and multiple sclerosis: innocent bystanders or disease determinants?

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Antony, Joseph M; Deslauriers, Andre M; Bhat, Rakesh K; Ellestad, Kristofer K; Power, Christopher

2011-02-01

Human endogenous retroviruses (HERVs) constitute 5-8% of human genomic DNA and are replication incompetent despite expression of individual HERV genes from different chromosomal loci depending on the specific tissue. Several HERV genes have been detected as transcripts and proteins in the central nervous system, frequently in the context of neuroinflammation. The HERV-W family has received substantial attention in large part because of associations with diverse syndromes including multiple sclerosis (MS) and several psychiatric disorders. A HERV-W-related retroelement, multiple sclerosis retrovirus (MSRV), has been reported in MS patients to be both a biomarker as well as an effector of aberrant immune responses. HERV-H and HERV-K have also been implicated in MS and other neurological diseases but await delineation of their contributions to disease. The HERV-W envelope-encoded glycosylated protein, syncytin-1, is encoded by chromosome 7q21 and exhibits increased glial expression within MS lesions. Overexpression of syncytin-1 in glia induces endoplasmic reticulum stress leading to neuroinflammation and the induction of free radicals, which damage proximate cells. Syncytin-1's receptor, ASCT1 is a neutral amino acid transporter expressed on glia and is suppressed in white matter of MS patients. Of interest, antioxidants ameliorate syncytin-1's neuropathogenic effects raising the possibility of using these agents as therapeutics for neuroinflammatory diseases. Given the multiple insertion sites of HERV genes as complete and incomplete open reading frames, together with their differing capacity to be expressed and the complexities of individual HERVs as both disease markers and bioactive effectors, HERV biology is a compelling area for understanding neuropathogenic mechanisms and developing new therapeutic strategies. 2010 Elsevier B.V. All rights reserved.

The nuclear envelopathies and human diseases

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Jeang Kuan-Teh

2009-10-01

Full Text Available Abstract The nuclear envelope (NE consists of two membrane layers that segregate the nuclear from the cytoplasmic contents. Recent progress in our understanding of nuclear-lamina associated diseases has revealed intriguing connections between the envelope components and nuclear processes. Here, we review the functions of the nuclear envelope in chromosome organization, gene expression, DNA repair and cell cycle progression, and correlate deficiencies in envelope function with human pathologies.

[Unconventional disease agents--a danger for humans and animals?].

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Kaaden, O R

1994-02-01

The occurrence of bovine spongiform encephalopathy (BSE) in Great Britain in 1985/86, has focused again the public concern as well as scientific interest to the Scrapie disease of sheep and goat known more than 150 years. The agents of scrapie and BSE are characterized by unusual biological and physical-chemical properties, especially their high tenacity. Therefore, they are also designated "unconventional agents of viruses". Different theories have been proposed about their infectious characteristics--especially because of the apparent or real missing of an agent-specific nucleic acid--which are named Virinos, Prions or Nemavirus. The broad host range of Scrapie respective BSE, which includes domestic and wild ruminants, Suidae, Felidae, Mustelidae, small rodents, birds and non-primates, has created some concern since there might be an aetiological correlation between the transmissible spongiform encephalopathies of man (Creutzfeld-Jakob- and Gerstmann-Sträussler-Scheinker-Disease) and that of animals. Although at present neither epidemiological nor molecular biological evidence whatsoever was proved, the hypothesis cannot be completely disproved. The probability of infection through digestive tract seems to be rather unlikely but special precautions should be taken as far as production, investigation and application of human medicine drugs of animal origin. Furthermore, research about the aetiology of "unconventional agents" and pathogenesis of resulting diseases is necessary and should be intensified in Germany. Finally, only an early intra vitam-Diagnose and in vitro detection can avoid an further spread of this new category of diseases.

Enhanced vulnerability of human proteins towards disease-associated inactivation through divergent evolution.

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Medina-Carmona, Encarnación; Fuchs, Julian E; Gavira, Jose A; Mesa-Torres, Noel; Neira, Jose L; Salido, Eduardo; Palomino-Morales, Rogelio; Burgos, Miguel; Timson, David J; Pey, Angel L

2017-09-15

Human proteins are vulnerable towards disease-associated single amino acid replacements affecting protein stability and function. Interestingly, a few studies have shown that consensus amino acids from mammals or vertebrates can enhance protein stability when incorporated into human proteins. Here, we investigate yet unexplored relationships between the high vulnerability of human proteins towards disease-associated inactivation and recent evolutionary site-specific divergence of stabilizing amino acids. Using phylogenetic, structural and experimental analyses, we show that divergence from the consensus amino acids at several sites during mammalian evolution has caused local protein destabilization in two human proteins linked to disease: cancer-associated NQO1 and alanine:glyoxylate aminotransferase, mutated in primary hyperoxaluria type I. We demonstrate that a single consensus mutation (H80R) acts as a disease suppressor on the most common cancer-associated polymorphism in NQO1 (P187S). The H80R mutation reactivates P187S by enhancing FAD binding affinity through local and dynamic stabilization of its binding site. Furthermore, we show how a second suppressor mutation (E247Q) cooperates with H80R in protecting the P187S polymorphism towards inactivation through long-range allosteric communication within the structural ensemble of the protein. Our results support that recent divergence of consensus amino acids may have occurred with neutral effects on many functional and regulatory traits of wild-type human proteins. However, divergence at certain sites may have increased the propensity of some human proteins towards inactivation due to disease-associated mutations and polymorphisms. Consensus mutations also emerge as a potential strategy to identify structural hot-spots in proteins as targets for pharmacological rescue in loss-of-function genetic diseases. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please

Human infectious disease burdens decrease with urbanization but not with biodiversity.

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Wood, Chelsea L; McInturff, Alex; Young, Hillary S; Kim, DoHyung; Lafferty, Kevin D

2017-06-05

Infectious disease burdens vary from country to country and year to year due to ecological and economic drivers. Recently, Murray et al. (Murray CJ et al 2012 Lancet 380 , 2197-2223. (doi:10.1016/S0140-6736(12)61689-4)) estimated country-level morbidity and mortality associated with a variety of factors, including infectious diseases, for the years 1990 and 2010. Unlike other databases that report disease prevalence or count outbreaks per country, Murray et al. report health impacts in per-person disability-adjusted life years (DALYs), allowing comparison across diseases with lethal and sublethal health effects. We investigated the spatial and temporal relationships between DALYs lost to infectious disease and potential demographic, economic, environmental and biotic drivers, for the 60 intermediate-sized countries where data were available and comparable. Most drivers had unique associations with each disease. For example, temperature was positively associated with some diseases and negatively associated with others, perhaps due to differences in disease agent thermal optima, transmission modes and host species identities. Biodiverse countries tended to have high disease burdens, consistent with the expectation that high diversity of potential hosts should support high disease transmission. Contrary to the dilution effect hypothesis, increases in biodiversity over time were not correlated with improvements in human health, and increases in forestation over time were actually associated with increased disease burden. Urbanization and wealth were associated with lower burdens for many diseases, a pattern that could arise from increased access to sanitation and healthcare in cities and increased investment in healthcare. The importance of urbanization and wealth helps to explain why most infectious diseases have become less burdensome over the past three decades, and points to possible levers for further progress in improving global public health.This article is part

Global burden of human brucellosis: a systematic review of disease frequency.

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Anna S Dean

Full Text Available BACKGROUND: This report presents a systematic review of scientific literature published between 1990-2010 relating to the frequency of human brucellosis, commissioned by WHO. The objectives were to identify high quality disease incidence data to complement existing knowledge of the global disease burden and, ultimately, to contribute towards the calculation of a Disability-Adjusted Life Years (DALY estimate for brucellosis. METHODS/PRINCIPAL FINDINGS: Thirty three databases were searched, identifying 2,385 articles relating to human brucellosis. Based on strict screening criteria, 60 studies were selected for quality assessment, of which only 29 were of sufficient quality for data analysis. Data were only available from 15 countries in the regions of Northern Africa and Middle East, Western Europe, Central and South America, Sub-Saharan Africa, and Central Asia. Half of the studies presented incidence data, six of which were longitudinal prospective studies, and half presented seroprevalence data which were converted to incidence rates. Brucellosis incidence varied widely between, and within, countries. Although study biases cannot be ruled out, demographic, occupational, and socioeconomic factors likely play a role. Aggregated data at national or regional levels do not capture these complexities of disease dynamics and, consequently, at-risk populations or areas may be overlooked. In many brucellosis-endemic countries, health systems are weak and passively-acquired official data underestimate the true disease burden. CONCLUSIONS: High quality research is essential for an accurate assessment of disease burden, particularly in Eastern Europe, the Asia-Pacific, Central and South America and Africa where data are lacking. Providing formal epidemiological and statistical training to researchers is essential for improving study quality. An integrated approach to disease surveillance involving both human health and veterinary services would allow a

Systematic review of brucellosis in Kenya: disease frequency in humans and animals and risk factors for human infection.

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Njeru, J; Wareth, G; Melzer, F; Henning, K; Pletz, M W; Heller, R; Neubauer, H

2016-08-22

Brucellosis is a debilitating zoonotic disease affecting humans and animals. A comprehensive, evidence-based assessment of literature and officially available data on animal and human brucellosis for Kenya are missing. The aim of the current review is to provide frequency estimates of brucellosis in humans, animals and risk factors for human infection, and help to understand the current situation in Kenya. A total of accessible 36 national and international publications on brucellosis from 1916 to 2016 were reviewed to estimate the frequency of brucellosis in humans and animals, and strength of associations between potential risk factors and seropositivity in humans in Kenya. The conducted studies revealed only few and fragmented evidence of the disease spatial and temporal distribution in an epidemiological context. Bacteriological evidence revealed the presence of Brucella (B.) abortus and B. melitensis in cattle and human patients, whilst B. suis was isolated from wild rodents only. Similar evidence for Brucella spp infection in small ruminants and other animal species is unavailable. The early and most recent serological studies revealed that animal brucellosis is widespread in all animal production systems. The animal infection pressure in these systems has remained strong due to mixing of large numbers of animals from different geographical regions, movement of livestock in search of pasture, communal sharing of grazing land, and the concentration of animals around water points. Human cases are more likely seen in groups occupationally or domestically exposed to livestock or practicing risky social-cultural activities such as consumption of raw blood and dairy products, and slaughtering of animals within the homesteads. Many brucellosis patients are misdiagnosed and probably mistreated due to lack of reliable laboratory diagnostic support resulting to adverse health outcomes of the patients and routine disease underreporting. We found no studies of disease

Using therapeutic cloning to fight human disease: a conundrum or reality?

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Hall, Vanessa J; Stojkovic, Petra; Stojkovic, Miodrag

2006-07-01

The development and transplantation of autologous cells derived from nuclear transfer embryonic stem cell (NT-ESC) lines to treat patients suffering from disease has been termed therapeutic cloning. Human NT is still a developing field, with further research required to improve somatic cell NT and human embryonic stem cell differentiation to deliver safe and effective cell replacement therapies. Furthermore, the implications of transferring mitochondrial heteroplasmic cells, which may harbor aberrant epigenetic gene expression profiles, are of concern. The production of human NT-ESC lines also remains plagued by ethical dilemmas, societal concerns, and controversies. Recently, a number of alternate therapeutic strategies have been proposed to circumvent the moral implications surrounding human nuclear transfer. It will be critical to overcome these biological, legislative, and moral restraints to maximize the potential of this therapeutic strategy and to alleviate human disease.

Analogs of human genetic skin disease in domesticated animals

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Justin Finch, MD

2017-09-01

The genetic skin diseases we will review are pigmentary mosaicism, piebaldism, albinism, Griscelli syndrome, ectodermal dysplasias, Waardenburg syndrome, and mucinosis in both humans and domesticated animals.

A genome-wide scan reveals important roles of DNA methylation in human longevity by regulating age-related disease genes.

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Fu-Hui Xiao

Full Text Available It is recognized that genetic factors contribute to human longevity. Besides the hypothesis of existence of longevity genes, another suggests that a lower frequency of risk alleles decreases the incidence of age-related diseases in the long-lived people. However, the latter finds no support from recent genetic studies. Considering the crucial role of epigenetic modification in gene regulation, we then hypothesize that suppressing disease-related genes in longevity individuals is likely achieved by epigenetic modification, e.g. DNA methylation. To test this hypothesis, we investigated the genome-wide methylation profile in 4 Chinese female centenarians and 4 middle-aged controls using methyl-DNA immunoprecipitation sequencing. 626 differentially methylated regions (DMRs were observed between both groups. Interestingly, genes with these DMRs were enriched in age-related diseases, including type-2 diabetes, cardiovascular disease, stroke and Alzheimer's disease. This pattern remains rather stable after including methylomes of two white individuals. Further analyses suggest that the observed DMRs likely have functional roles in regulating disease-associated gene expressions, with some genes [e.g. caspase 3 (CASP3] being down-regulated whereas the others [i.e. interleukin 1 receptor, type 2 (IL1R2] up-regulated. Therefore, our study suggests that suppressing the disease-related genes via epigenetic modification is an important contributor to human longevity.

A study on the air pollution related human diseases in Thiruvananthapuram City, Kerala

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Bency, K.T.; Jansy, J.; Thakappan, B.; Kumar, B.; Sreelekha, T.T.; Hareendran, N.K.; Nair, P.K.K.; Krishnan Nair, M. [National Inst. of Environmental Health, Thiruvananthapuram, Kerala (India). Regional Cancer Centre

2005-07-01

This paper contains the results of a study that examined the impacts of air pollution on human health in Thiruvananthapuram City, India. The study compared health impacts arising from air pollution in three different zones including residential, commercial, and industrial. The paper presents the findings from the study according to each of these zones and presents conclusions.The study found that each zone had its individual environmental problems which were characterized by specific diseases. In the residential zone, there was a prevalence of diseases such as breast cancer and cardiac-related problems as well as dietary problems linked to obesity. In the industrial zone, respiratory illnesses related to air pollution were prevalent. Cardiac and vector-borne diseases, related to environmental hazards like waste water stagnation, dust and solid waste problem, were high in the commercial zone. 14 refs., 3 figs.

Early-life experiences and the development of adult diseases with a focus on mental illness: The Human Birth Theory.

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Maccari, Stefania; Polese, Daniela; Reynaert, Marie-Line; Amici, Tiziana; Morley-Fletcher, Sara; Fagioli, Francesca

2017-02-07

In mammals, early adverse experiences, including mother-pup interactions, shape the response of an individual to chronic stress or to stress-related diseases during adult life. This has led to the elaboration of the theory of the developmental origins of health and disease, in particular adult diseases such as cardiovascular and metabolic disorders. In addition, in humans, as stated by Massimo Fagioli's Human Birth Theory, birth is healthy and equal for all individuals, so that mental illness develop exclusively in the postnatal period because of the quality of the relationship in the first year of life. Thus, this review focuses on the importance of programming during the early developmental period on the manifestation of adult diseases in both animal models and humans. Considering the obvious differences between animals and humans we cannot systematically move from animal models to humans. Consequently, in the first part of this review, we will discuss how animal models can be used to dissect the influence of adverse events occurring during the prenatal and postnatal periods on the developmental trajectories of the offspring, and in the second part, we will discuss the role of postnatal critical periods on the development of mental diseases in humans. Epigenetic mechanisms that cause reversible modifications in gene expression, driving the development of a pathological phenotype in response to a negative early postnatal environment, may lie at the core of this programming, thereby providing potential new therapeutic targets. The concept of the Human Birth Theory leads to a comprehension of the mental illness as a pathology of the human relationship immediately after birth and during the first year of life. Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.

Reverse engineering human neurodegenerative disease using pluripotent stem cell technology.

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Liu, Ying; Deng, Wenbin

2016-05-01

With the technology of reprogramming somatic cells by introducing defined transcription factors that enables the generation of "induced pluripotent stem cells (iPSCs)" with pluripotency comparable to that of embryonic stem cells (ESCs), it has become possible to use this technology to produce various cells and tissues that have been difficult to obtain from living bodies. This advancement is bringing forth rapid progress in iPSC-based disease modeling, drug screening, and regenerative medicine. More and more studies have demonstrated that phenotypes of adult-onset neurodegenerative disorders could be rather faithfully recapitulated in iPSC-derived neural cell cultures. Moreover, despite the adult-onset nature of the diseases, pathogenic phenotypes and cellular abnormalities often exist in early developmental stages, providing new "windows of opportunity" for understanding mechanisms underlying neurodegenerative disorders and for discovering new medicines. The cell reprogramming technology enables a reverse engineering approach for modeling the cellular degenerative phenotypes of a wide range of human disorders. An excellent example is the study of the human neurodegenerative disease amyotrophic lateral sclerosis (ALS) using iPSCs. ALS is a progressive neurodegenerative disease characterized by the loss of upper and lower motor neurons (MNs), culminating in muscle wasting and death from respiratory failure. The iPSC approach provides innovative cell culture platforms to serve as ALS patient-derived model systems. Researchers have converted iPSCs derived from ALS patients into MNs and various types of glial cells, all of which are involved in ALS, to study the disease. The iPSC technology could be used to determine the role of specific genetic factors to track down what's wrong in the neurodegenerative disease process in the "disease-in-a-dish" model. Meanwhile, parallel experiments of targeting the same specific genes in human ESCs could also be performed to control

New variant of Creutzfeldt-Jakob (vCJD disease and other human prion diseases under epidemiological surveillance in Brazil

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Vera Lúcia Gattás

Full Text Available Abstract To increase the timeliness of detection of human cases of the new variant of Creutzfeldt-Jakob disease (vCJD and to reduce the risk of transmission, the Brazilian Ministry of Health has established and standardized rules and control measures. These include the definition of criteria for suspect cases, reporting, monitoring, and control measures for illness prevention and transmission. Guidelines to be used by the team of health care staff were published and distributed to health workers. A detailed proposal for a simplified system of surveillance for prion diseases was developed and mandatory reporting introduced. Additional effort is necessary to increase vCJD case detection, thus making it necessary to establish a partnership with health care services for best identification of suspected cases and dissemination of information to all involved in the service dealing with vCJD investigation.

The Burden of Human Papillomavirus Infections and Related Diseases in Sub-Saharan Africa

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De Vuyst, Hugo; Alemany, Laia; Lacey, Charles; Chibwesha, Carla J.; Sahasrabuddhe, Vikrant; Banura, Cecily; Denny, Lynette; Parham, Groesbeck P.

2014-01-01

Despite the scarcity of high quality cancer registries and lack of reliable mortality data, it is clear that human papillomavirus (HPV)-associated diseases, particularly cervical cancer, are major causes of morbidity and mortality in sub-Saharan Africa (SSA). Cervical cancer incidence rates in SSA are the highest in the world and the disease is the most common cause of cancer death among women in the region. The high incidence of cervical cancer is a consequence of the inability of most countries to either initiate or sustain cervical cancer prevention services. In addition, it appears that the prevalence of HPV in women with normal cytology is higher than in more developed areas of the world, at an average of 24%. There is, however, significant regional variation in SSA, with the highest incidence of HPV infection and cervical cancer found in Eastern and Western Africa. It is expected that, due to aging and growth of the population, but also to lack of access to appropriate prevention services and the concomitant human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) epidemic, cervical cancer incidence and mortality rates in SSA will rise over the next 20 years. HPV16 and 18 are the most common genotypes in cervical cancer in SSA, although other carcinogenic HPV types, such as HPV45 and 35, are also relatively more frequent compared with other world regions. Data on other HPV-related anogenital cancers including those of the vulva, vagina, anus, and penis, are limited. Genital warts are common and associated with HPV types 6 and 11. HIV infection increases incidence and prevalence of all HPV-associated diseases. Sociocultural determinants of HPV-related disease, as well as the impact of forces that result in social destabilization, demand further study. Strategies to reduce the excessive burden of HPV-related diseases in SSA include age-appropriate prophylactic HPV vaccination, cervical cancer prevention services for women of the reproductive

Can the silkworm (Bombyx mori) be used as a human disease model?

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Tabunoki, Hiroko; Bono, Hidemasa; Ito, Katsuhiko; Yokoyama, Takeshi

2016-02-01

Bombyx mori (silkworm) is the most famous lepidopteran in Japan. B. mori has long been used in the silk industry and also as a model insect for agricultural research. In recent years, B. mori has attracted interest in its potential for use in pathological analysis of model animals. For example, the human macular carotenoid transporter was discovered using information of B. mori carotenoid transporter derived from yellow-cocoon strain. The B. mori carotenoid transport system is useful in human studies. To develop a human disease model, we characterized the human homologs of B. mori, and by constructing KAIKO functional annotation pipeline, and to analyze gene expression profile of a unique B. mori mutant strain using microarray analysis. As a result, we identified a novel molecular network involved in Parkinson's disease. Here we describe the potential use of a spontaneous mutant silkworm strain as a human disease model. We also summarize recent progress in the application of genomic information for annotation of human homologs in B. mori. The B. mori mutant will provide a clue to pathological mechanisms, and the findings will be helpful for the development of therapies and for medical drug discovery.

The emerging paradigm of network medicine in the study of human disease.

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Chan, Stephen Y; Loscalzo, Joseph

2012-07-20

The molecular pathways that govern human disease consist of molecular circuits that coalesce into complex, overlapping networks. These network pathways are presumably regulated in a coordinated fashion, but such regulation has been difficult to decipher using only reductionistic principles. The emerging paradigm of "network medicine" proposes to utilize insights garnered from network topology (eg, the static position of molecules in relation to their neighbors) as well as network dynamics (eg, the unique flux of information through the network) to understand better the pathogenic behavior of complex molecular interconnections that traditional methods fail to recognize. As methodologies evolve, network medicine has the potential to capture the molecular complexity of human disease while offering computational methods to discern how such complexity controls disease manifestations, prognosis, and therapy. This review introduces the fundamental concepts of network medicine and explores the feasibility and potential impact of network-based methods for predicting individual manifestations of human disease and designing rational therapies. Wherever possible, we emphasize the application of these principles to cardiovascular disease.

Research priorities for Chagas disease, human African trypanosomiasis and leishmaniasis.

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2012-01-01

This report provides a review and analysis of the research landscape for three diseases - Chagas disease, human African trypanosomiasis and leishmaniasis - that disproportionately afflict poor and remote populations with limited access to health services. It represents the work of the disease reference group on Chagas Disease, Human African Trypanosomiasis and Leishmaniasis (DRG3) which was established to identify key research priorities through review of research evidence and input from stakeholders' consultations. The diseases, which are caused by related protozoan parasites, are described in terms of their epidemiology and diseases burden, clinical forms and pathogenesis, HIV coinfection, diagnosis, drugs and drug resistance, vaccines, vector control, and health-care interventions. Priority areas for research are identified based on criteria such as public health relevance, benefit and impact on poor populations and equity, and feasibility. The priorities are found in the areas of diagnostics, drugs, vector control, asymptomatic infection, economic analysis of treatment and vector control methods, and in some specific issues such as surveillance methods or transmission-blocking vaccines for particular diseases. This report will be useful to researchers, policy and decision-makers, funding bodies, implementation organizations, and civil society. This is one of ten disease and thematic reference group reports that have come out of the TDR Think Tank, all of which have contributed to the development of the Global Report for Research on Infectious Diseases of Poverty, available at: www.who.int/tdr/stewardship/global_report/en/index.html.

Linking human diseases to animal models using ontology-based phenotype annotation.

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Nicole L Washington

2009-11-01

Full Text Available Scientists and clinicians who study genetic alterations and disease have traditionally described phenotypes in natural language. The considerable variation in these free-text descriptions has posed a hindrance to the important task of identifying candidate genes and models for human diseases and indicates the need for a computationally tractable method to mine data resources for mutant phenotypes. In this study, we tested the hypothesis that ontological annotation of disease phenotypes will facilitate the discovery of new genotype-phenotype relationships within and across species. To describe phenotypes using ontologies, we used an Entity-Quality (EQ methodology, wherein the affected entity (E and how it is affected (Q are recorded using terms from a variety of ontologies. Using this EQ method, we annotated the phenotypes of 11 gene-linked human diseases described in Online Mendelian Inheritance in Man (OMIM. These human annotations were loaded into our Ontology-Based Database (OBD along with other ontology-based phenotype descriptions of mutants from various model organism databases. Phenotypes recorded with this EQ method can be computationally compared based on the hierarchy of terms in the ontologies and the frequency of annotation. We utilized four similarity metrics to compare phenotypes and developed an ontology of homologous and analogous anatomical structures to compare phenotypes between species. Using these tools, we demonstrate that we can identify, through the similarity of the recorded phenotypes, other alleles of the same gene, other members of a signaling pathway, and orthologous genes and pathway members across species. We conclude that EQ-based annotation of phenotypes, in conjunction with a cross-species ontology, and a variety of similarity metrics can identify biologically meaningful similarities between genes by comparing phenotypes alone. This annotation and search method provides a novel and efficient means to identify

A unified pathogenesis for kidney diseases, including genetic diseases and cancers, by the protein-homeostasis-system hypothesis.

Science.gov (United States)

Lee, Kyung-Yil

2017-06-01

Every cell of an organism is separated and protected by a cell membrane. It is proposed that harmony between intercellular communication and the health of an organism is controlled by a system, designated the protein-homeostasis-system (PHS). Kidneys consist of a variety of types of renal cells, each with its own characteristic cell-receptor interactions and producing characteristic proteins. A functional union of these renal cells can be determined by various renal function tests, and harmonious intercellular communication is essential for the healthy state of the host. Injury to a kind of renal cells can impair renal function and induce an imbalance in total body health. Every acute or chronic renal disease has unknown etiologic substances that are responsible for renal cell injury at the molecular level. The immune/repair system of the host should control the etiologic substances acting against renal cells; if this system fails, the disease progresses to end stage renal disease. Each renal disease has its characteristic pathologic lesions where immune cells and immune proteins, such as immunoglobulins and complements, are infiltrated. These immune cells and immune proteins may control the etiologic substances involved in renal pathologic lesions. Also, genetic renal diseases and cancers may originate from a protein deficiency or malfunctioning protein under the PHS. A unified pathogenesis for renal diseases, including acute glomerulonephritis, idiopathic nephrotic syndrome, immunoglobulin A nephropathy, genetic renal diseases such as Alport syndrome, and malignancies such as Wilms tumor and renal cell carcinoma, is proposed using the PHS hypothesis.

Diseases of the abdomen including the pelvis

International Nuclear Information System (INIS)

Kido, C.; Tanaka, H.

1983-01-01

This book discusses the following diseases: fatty liver; cystic disease of the liver; liver abscess; liver cirrhosis; hepatic hemangioma; cholelithiasis; primary liver cancer; cholangioma; cancer of the common bile duct; pancreatic cyst; pancreatic calculi; chronic pancreatitis; pancreatic pseudocyst; chronic pancreatitis: pancreatic fatty degeneration; cancer of the pancreas; nonfunctioning kidney: chalk kidney; polycystic kidney; perirenal calcified abscess; renal infarct; cancer of the renal pelvis; adrenal pheochromocytoma; adenoma of the adrenal cortex; leiomyosarcoma of the stomach; malignant mesothelioma; intraperitoneal abscess; perityphlic abscess; retroperitoneal reticulum cell sarcoma; and retroperitoneal cyst

Recapitulation of spinal motor neuron-specific disease phenotypes in a human cell model of spinal muscular atrophy

Institute of Scientific and Technical Information of China (English)

Zhi-Bo Wang; Xiaoqing Zhang; Xue-Jun Li

2013-01-01

Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease.Here,we developed a closely representative cell model of SMA by knocking down the disease-determining gene,survival motor neuron (SMN),in human embryonic stem cells (hESCs).Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons.Notably,the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated.Furthermore,these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-A7 (lacking exon 7)knockdown,and were specific to spinal motor neurons.Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes,including specific axonal defects and motor neuron loss.Finally,knockdown of SMNFL led to excessive mitochondrial oxidative stress in human motor neuron progenitors.The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine,a potent antioxidant,which prevented disease-related apoptosis and subsequent motor neuron death.Thus,we report here the successful establishment of an hESC-based SMA model,which exhibits disease gene isoform specificity,cell type specificity,and phenotype reversibility.Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA.

Melatonin and human mitochondrial diseases

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Reza Sharafati-Chaleshtori

2017-01-01

Full Text Available Mitochondrial dysfunction is one of the main causative factors in a wide variety of complications such as neurodegenerative disorders, ischemia/reperfusion, aging process, and septic shock. Decrease in respiratory complex activity, increase in free radical production, increase in mitochondrial synthase activity, increase in nitric oxide production, and impair in electron transport system and/or mitochondrial permeability are considered as the main factors responsible for mitochondrial dysfunction. Melatonin, the pineal gland hormone, is selectively taken up by mitochondria and acts as a powerful antioxidant, regulating the mitochondrial bioenergetic function. Melatonin increases the permeability of membranes and is the stimulator of antioxidant enzymes including superoxide dismutase, glutathione peroxidase, glutathione reductase, and catalase. It also acts as an inhibitor of lipoxygenase. Melatonin can cause resistance to oxidation damage by fixing the microsomal membranes. Melatonin has been shown to retard aging and inhibit neurodegenerative disorders, ischemia/reperfusion, septic shock, diabetes, cancer, and other complications related to oxidative stress. The purpose of the current study, other than introducing melatonin, was to present the recent findings on clinical effects in diseases related to mitochondrial dysfunction including diabetes, cancer, gastrointestinal diseases, and diseases related to brain function.

Human endogenous retroviruses and chosen disease parameters in morphea

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Dańczak-Pazdrowska, Aleksandra; Szramka-Pawlak, Beata; Żaba, Ryszard; Osmola-Mańkowska, Agnieszka; Silny, Wojciech

2017-01-01

Introduction Morphea (localized scleroderma) is a relatively rare disease characterized by excessive skin fibrosis. Human endogenous retroviruses (HERV) are largely distributed within the human genome with hundreds of thousands of elements. The HERV have been widely studied in autoimmune disorders, yet hardly ever assessed in diseases with a good prognosis such as morphea. Aim In this study we focus on the possible relations between the expression of chosen HERV and factors influencing the pathomechanism of the disease, such as age, sex, titres of anti-nuclear antibodies, as well as duration, activity, and severity of the disease (LoSSI index). Material and methods Real-time polymerase chain reaction (PCR) targeting six HERV sequences of interest were performed on samples derived from peripheral blood mononuclear cells (PBMC) and skin biopsies. Results In PBMC we found a statistically significant negative correlation between HERV-W env expression and LoSSI index (p = 0.01). Additionally, HERV-W env was downregulated in patients with the active form of morphea. In all other cases we found no correlation whatsoever nor statistically significant differences below the p = 0.05 threshold. Conclusions Morphea seems to be an autoimmune disease where the impact of HERV is not so apparent. It seems that probing many patients for the expression of just a few sequences is not as effective as previously expected. For initial studies of HERV in other diseases we recommend high throughput techniques such as HERV-dedicated DNA microarrays or massive parallel sequencing. PMID:28261031

Human endogenous retroviruses and chosen disease parameters in morphea

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Michał J. Kowalczyk

2017-02-01

Full Text Available Introduction: Morphea (localized scleroderma is a relatively rare disease characterized by excessive skin fibrosis. Human endogenous retroviruses (HERV are largely distributed within the human genome with hundreds of thousands of elements. The HERV have been widely studied in autoimmune disorders, yet hardly ever assessed in diseases with a good prognosis such as morphea. Aim: In this study we focus on the possible relations between the expression of chosen HERV and factors influencing the pathomechanism of the disease, such as age, sex, titres of anti-nuclear antibodies, as well as duration, activity, and severity of the disease (LoSSI index. Material and methods: Real-time polymerase chain reaction (PCR targeting six HERV sequences of interest were performed on samples derived from peripheral blood mononuclear cells (PBMC and skin biopsies. Results: In PBMC we found a statistically significant negative correlation between HERV-W env expression and LoSSI index (p = 0.01. Additionally, HERV-W env was downregulated in patients with the active form of morphea. In all other cases we found no correlation whatsoever nor statistically significant differences below the p = 0.05 threshold. Conclusions : Morphea seems to be an autoimmune disease where the impact of HERV is not so apparent. It seems that probing many patients for the expression of just a few sequences is not as effective as previously expected. For initial studies of HERV in other diseases we recommend high throughput techniques such as HERV-dedicated DNA microarrays or massive parallel sequencing.

Increased diacylglycerols characterize hepatic lipid changes in progression of human nonalcoholic fatty liver disease; comparison to a murine model.

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Gorden, D Lee; Ivanova, Pavlina T; Myers, David S; McIntyre, J Oliver; VanSaun, Michael N; Wright, J Kelly; Matrisian, Lynn M; Brown, H Alex

2011-01-01

The spectrum of nonalcoholic fatty liver disease (NAFLD) includes steatosis, nonalcoholic steatohepatitis (NASH), and progression to cirrhosis. While differences in liver lipids between disease states have been reported, precise composition of phospholipids and diacylglycerols (DAG) at a lipid species level has not been previously described. The goal of this study was to characterize changes in lipid species through progression of human NAFLD using advanced lipidomic technology and compare this with a murine model of early and advanced NAFLD. Utilizing mass spectrometry lipidomics, over 250 phospholipid and diacylglycerol species (DAGs) were identified in normal and diseased human and murine liver extracts. Significant differences between phospholipid composition of normal and diseased livers were demonstrated, notably among DAG species, consistent with previous reports that DAG transferases are involved in the progression of NAFLD and liver fibrosis. In addition, a novel phospholipid species (ether linked phosphatidylinositol) was identified in human cirrhotic liver extracts. Using parallel lipidomics analysis of murine and human liver tissues it was determined that mice maintained on a high-fat diet provide a reproducible model of NAFLD in regards to specificity of lipid species in the liver. These studies demonstrated that novel lipid species may serve as markers of advanced liver disease and importantly, marked increases in DAG species are a hallmark of NAFLD. Elevated DAGs may contribute to altered triglyceride, phosphatidylcholine (PC), and phosphatidylethanolamine (PE) levels characteristic of the disease and specific DAG species might be important lipid signaling molecules in the progression of NAFLD.

Human care system for heart-rate and human-movement trajectory in home and its application to detect mental disease

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Hata, Yutaka; Kanazawa, Seigo; Endo, Maki; Tsuchiya, Naoki; Nakajima, Hiroshi

2012-06-01

This paper proposes a heart rate monitoring system for detecting autonomic nervous system by the heart rate variability using an air pressure sensor to diagnose mental disease. Moreover, we propose a human behavior monitoring system for detecting the human trajectory in home by an infrared camera. In day and night times, the human behavior monitoring system detects the human movement in home. The heart rate monitoring system detects the heart rate in bed in night time. The air pressure sensor consists of a rubber tube, cushion cover and pressure sensor, and it detects the heart rate by setting it to bed. It unconstraintly detects the RR-intervals; thereby the autonomic nervous system can be assessed. The autonomic nervous system analysis can examine the mental disease. While, the human behavior monitoring system obtains distance distribution image by an infrared camera. It classifies adult, child and the other object from distance distribution obtained by the camera, and records their trajectories. This behavior, i.e., trajectory in home, strongly corresponds to cognitive disorders. Thus, the total system can detect mental disease and cognitive disorders by uncontacted sensors to human body.

Traditional and Modern Uses of Natural Honey in Human Diseases: A Review

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Tahereh Eteraf-Oskouei

2013-06-01

Full Text Available   Honey is a by-product of flower nectar and the upper aero-digestive tract of the honey bee, which is concentrated through a dehydration process inside the bee hive. Honey has a very complex chemical composition that varies depending on the botanical source. It has been used both as food and medicine since ancient times. Human use of honey is traced to some 8000 years ago as depicted by Stone Age paintings. In addition to important role of natural honey in the traditional medicine, during the past few decades, it was subjected to laboratory and clinical investigations by several research groups and it has found a place in modern medicine. Honey has been reported to have an inhibitory effect on around 60 species of bacteria, some species of fungi and viruses. Antioxidant capacity of honey is important in many disease conditions and is due to a wide range of compounds including phenolics, peptides, organic acids, enzymes, and Maillard reaction products. Honey has also been used in some gastrointestinal, cardiovascular, inflammatory and neoplastic states. This review covers the composition, physico-chemical properties and the most important uses of natural honey in human diseases.

Bowen's Disease Associated With Two Human Papilloma Virus Types.

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Eftekhari, Hojat; Gharaei Nejad, Kaveh; Azimi, Seyyede Zeinab; Rafiei, Rana; Mesbah, Alireza

2017-09-01

Bowen's disease (BD) is an epidermal in-situ squamous cell carcinoma (SCC). Most Human Papilloma Viruses (HPV)-positive lesions in Bowen's disease are localized to the genital region or distal extremities (periungual sites) in which HPV type-16 is frequently detected. Patient was a 64-year-old construction worker for whom we detected 2 erythematous psoriasiform reticular scaly plaques on peri-umbilical and medial knee. Biopsy established the diagnosis of Bowen's disease and polymerase chain reaction assay showed HPV-6, -18 co-infection. Patient was referred for surgical excision.

Estimating the global burden of thalassogenic diseases: human infectious diseases caused by wastewater pollution of the marine environment.

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Shuval, Hillel

2003-06-01

This paper presents a preliminary attempt at obtaining an order-of-magnitude estimate of the global burden of disease (GBD) of human infectious diseases associated with swimming/bathing in coastal waters polluted by wastewater, and eating raw or lightly steamed filter-feeding shellfish harvested from such waters. Such diseases will be termed thalassogenic--caused by the sea. Until recently these human health effects have been viewed primarily as local phenomena, not generally included in the world agenda of marine scientists dealing with global marine pollution problems. The massive global scale of the problem can be visualized when one considers that the wastewater and human body wastes of a significant portion of the world's population who reside along the coastline or in the vicinity of the sea are discharged daily, directly or indirectly, into the marine coastal waters, much of it with little or no treatment. Every cubic metre of raw domestic wastewater discharged into the sea can carry millions of infectious doses of pathogenic microorganisms. It is estimated that globally, foreign and local tourists together spend some 2 billion man-days annually at coastal recreational resorts and many are often exposed there to coastal waters polluted by wastewater. Annually some 800 million meals of potentially contaminated filter-feeding shellfish/bivalves and other sea foods, harvested in polluted waters are consumed, much of it raw or lightly steamed. A number of scientific studies have shown that swimmers swallow significant amounts of polluted seawater and can become ill with gastrointestinal and respiratory diseases from the pathogens they ingest. Based on risk assessments from the World Health Organization (WHO) and academic research sources the present study has made an estimate that globally, each year, there are in excess of 120 million cases of gastrointestinal disease and in excess of 50 million cases of more severe respiratory diseases caused by swimming and

Gene expression patterns associated with neurological disease in human HIV infection.

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Pietro Paolo Sanna

Full Text Available The pathogenesis and nosology of HIV-associated neurological disease (HAND remain incompletely understood. Here, to provide new insight into the molecular events leading to neurocognitive impairments (NCI in HIV infection, we analyzed pathway dysregulations in gene expression profiles of HIV-infected patients with or without NCI and HIV encephalitis (HIVE and control subjects. The Gene Set Enrichment Analysis (GSEA algorithm was used for pathway analyses in conjunction with the Molecular Signatures Database collection of canonical pathways (MSigDb. We analyzed pathway dysregulations in gene expression profiles of patients from the National NeuroAIDS Tissue Consortium (NNTC, which consists of samples from 3 different brain regions, including white matter, basal ganglia and frontal cortex of HIV-infected and control patients. While HIVE is characterized by widespread, uncontrolled inflammation and tissue damage, substantial gene expression evidence of induction of interferon (IFN, cytokines and tissue injury is apparent in all brain regions studied, even in the absence of NCI. Various degrees of white matter changes were present in all HIV-infected subjects and were the primary manifestation in patients with NCI in the absence of HIVE. In particular, NCI in patients without HIVE in the NNTC sample is associated with white matter expression of chemokines, cytokines and β-defensins, without significant activation of IFN. Altogether, the results identified distinct pathways differentially regulated over the course of neurological disease in HIV infection and provide a new perspective on the dynamics of pathogenic processes in the course of HIV neurological disease in humans. These results also demonstrate the power of the systems biology analyses and indicate that the establishment of larger human gene expression profile datasets will have the potential to provide novel mechanistic insight into the pathogenesis of neurological disease in HIV

Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

KAUST Repository

Hoehndorf, Robert

2015-06-08

Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

Analysis of the human diseasome using phenotype similarity between common, genetic, and infectious diseases

Science.gov (United States)

Hoehndorf, Robert; Schofield, Paul N.; Gkoutos, Georgios V.

2015-06-01

Phenotypes are the observable characteristics of an organism arising from its response to the environment. Phenotypes associated with engineered and natural genetic variation are widely recorded using phenotype ontologies in model organisms, as are signs and symptoms of human Mendelian diseases in databases such as OMIM and Orphanet. Exploiting these resources, several computational methods have been developed for integration and analysis of phenotype data to identify the genetic etiology of diseases or suggest plausible interventions. A similar resource would be highly useful not only for rare and Mendelian diseases, but also for common, complex and infectious diseases. We apply a semantic text-mining approach to identify the phenotypes (signs and symptoms) associated with over 6,000 diseases. We evaluate our text-mined phenotypes by demonstrating that they can correctly identify known disease-associated genes in mice and humans with high accuracy. Using a phenotypic similarity measure, we generate a human disease network in which diseases that have similar signs and symptoms cluster together, and we use this network to identify closely related diseases based on common etiological, anatomical as well as physiological underpinnings.

A neutralizing human monoclonal antibody protects against lethal disease in a new ferret model of acute nipah virus infection.

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Katharine N Bossart

2009-10-01

Full Text Available Nipah virus is a broadly tropic and highly pathogenic zoonotic paramyxovirus in the genus Henipavirus whose natural reservoirs are several species of Pteropus fruit bats. Nipah virus has repeatedly caused outbreaks over the past decade associated with a severe and often fatal disease in humans and animals. Here, a new ferret model of Nipah virus pathogenesis is described where both respiratory and neurological disease are present in infected animals. Severe disease occurs with viral doses as low as 500 TCID(50 within 6 to 10 days following infection. The underlying pathology seen in the ferret closely resembles that seen in Nipah virus infected humans, characterized as a widespread multisystemic vasculitis, with virus replicating in highly vascular tissues including lung, spleen and brain, with recoverable virus from a variety of tissues. Using this ferret model a cross-reactive neutralizing human monoclonal antibody, m102.4, targeting the henipavirus G glycoprotein was evaluated in vivo as a potential therapeutic agent. All ferrets that received m102.4 ten hours following a high dose oral-nasal Nipah virus challenge were protected from disease while all controls died. This study is the first successful post-exposure passive antibody therapy for Nipah virus using a human monoclonal antibody.

Systematic review of brucellosis in Kenya: disease frequency in humans and animals and risk factors for human infection

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J. Njeru

2016-08-01

Full Text Available Abstract Background Brucellosis is a debilitating zoonotic disease affecting humans and animals. A comprehensive, evidence-based assessment of literature and officially available data on animal and human brucellosis for Kenya are missing. The aim of the current review is to provide frequency estimates of brucellosis in humans, animals and risk factors for human infection, and help to understand the current situation in Kenya. Methods A total of accessible 36 national and international publications on brucellosis from 1916 to 2016 were reviewed to estimate the frequency of brucellosis in humans and animals, and strength of associations between potential risk factors and seropositivity in humans in Kenya. Results The conducted studies revealed only few and fragmented evidence of the disease spatial and temporal distribution in an epidemiological context. Bacteriological evidence revealed the presence of Brucella (B. abortus and B. melitensis in cattle and human patients, whilst B. suis was isolated from wild rodents only. Similar evidence for Brucella spp infection in small ruminants and other animal species is unavailable. The early and most recent serological studies revealed that animal brucellosis is widespread in all animal production systems. The animal infection pressure in these systems has remained strong due to mixing of large numbers of animals from different geographical regions, movement of livestock in search of pasture, communal sharing of grazing land, and the concentration of animals around water points. Human cases are more likely seen in groups occupationally or domestically exposed to livestock or practicing risky social-cultural activities such as consumption of raw blood and dairy products, and slaughtering of animals within the homesteads. Many brucellosis patients are misdiagnosed and probably mistreated due to lack of reliable laboratory diagnostic support resulting to adverse health outcomes of the patients and routine

Mosquitoes as vectors of human disease in South Africa | Jupp ...

African Journals Online (AJOL)

While malaria is the most important mosquito-borne disease in South Africa, there are also several mosquito-borne viruses that also cause human disease. The most significant are chikungunya, West Nile, Sindbis and Rift Valley fever viruses. In this review these are compared with malaria, mainly in regard to their ecology ...

Human Genome Sequencing in Health and Disease

Science.gov (United States)

Gonzaga-Jauregui, Claudia; Lupski, James R.; Gibbs, Richard A.

2013-01-01

Following the “finished,” euchromatic, haploid human reference genome sequence, the rapid development of novel, faster, and cheaper sequencing technologies is making possible the era of personalized human genomics. Personal diploid human genome sequences have been generated, and each has contributed to our better understanding of variation in the human genome. We have consequently begun to appreciate the vastness of individual genetic variation from single nucleotide to structural variants. Translation of genome-scale variation into medically useful information is, however, in its infancy. This review summarizes the initial steps undertaken in clinical implementation of personal genome information, and describes the application of whole-genome and exome sequencing to identify the cause of genetic diseases and to suggest adjuvant therapies. Better analysis tools and a deeper understanding of the biology of our genome are necessary in order to decipher, interpret, and optimize clinical utility of what the variation in the human genome can teach us. Personal genome sequencing may eventually become an instrument of common medical practice, providing information that assists in the formulation of a differential diagnosis. We outline herein some of the remaining challenges. PMID:22248320

Comparative Transcriptomic Profiling and Gene Expression for Myxomatous Mitral Valve Disease in the Dog and Human

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Greg R. Markby

2017-07-01

Full Text Available Myxomatous mitral valve disease is the single most important mitral valve disease in both dogs and humans. In the case of the dog it is ubiquitous, such that all aged dogs will have some evidence of the disease, and for humans it is known as Barlow’s disease and affects up to 3% of the population, with an expected increase in prevalence as the population ages. Disease in the two species show many similarities and while both have the classic myxomatous degeneration only in humans is there extensive fibrosis. This dual pathology of the human disease markedly affects the valve transcriptome and the difference between the dog and human is dominated by changes in genes associated with fibrosis. This review will briefly examine the comparative valve pathology and then, in more detail, the transcriptomic profiling and gene expression reported so far for both species.

The Spanish biology/disease initiative within the human proteome project: Application to rheumatic diseases.

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Ruiz-Romero, Cristina; Calamia, Valentina; Albar, Juan Pablo; Casal, José Ignacio; Corrales, Fernando J; Fernández-Puente, Patricia; Gil, Concha; Mateos, Jesús; Vivanco, Fernando; Blanco, Francisco J

2015-09-08

The Spanish Chromosome 16 consortium is integrated in the global initiative Human Proteome Project, which aims to develop an entire map of the proteins encoded following a gene-centric strategy (C-HPP) in order to make progress in the understanding of human biology in health and disease (B/D-HPP). Chromosome 16 contains many genes encoding proteins involved in the development of a broad range of diseases, which have a significant impact on the health care system. The Spanish HPP consortium has developed a B/D platform with five programs focused on selected medical areas: cancer, obesity, cardiovascular, infectious and rheumatic diseases. Each of these areas has a clinical leader associated to a proteomic investigator with the responsibility to get a comprehensive understanding of the proteins encoded by Chromosome 16 genes. Proteomics strategies have enabled great advances in the area of rheumatic diseases, particularly in osteoarthritis, with studies performed on joint cells, tissues and fluids. In this manuscript we describe how the Spanish HPP-16 consortium has developed a B/D platform with five programs focused on selected medical areas: cancer, obesity, cardiovascular, infectious and rheumatic diseases. Each of these areas has a clinical leader associated to a proteomic investigator with the responsibility to get a comprehensive understanding of the proteins encoded by Chromosome 16 genes. We show how the Proteomic strategy has enabled great advances in the area of rheumatic diseases, particularly in osteoarthritis, with studies performed on joint cells, tissues and fluids. This article is part of a Special Issue entitled: HUPO 2014. Copyright © 2015 Elsevier B.V. All rights reserved.

Linking adult hippocampal neurogenesis with human physiology and disease.

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Bowers, Megan; Jessberger, Sebastian

2016-07-01

We here review the existing evidence linking adult hippocampal neurogenesis and human brain function in physiology and disease. Furthermore, we aim to point out where evidence is missing, highlight current promising avenues of investigation, and suggest future tools and approaches to foster the link between life-long neurogenesis and human brain function. Developmental Dynamics 245:702-709, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Human Gut Microbiota: Toward an Ecology of Disease

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Selber-Hnatiw, Susannah; Rukundo, Belise; Ahmadi, Masoumeh; Akoubi, Hayfa; Al-Bizri, Hend; Aliu, Adelekan F.; Ambeaghen, Tanyi U.; Avetisyan, Lilit; Bahar, Irmak; Baird, Alexandra; Begum, Fatema; Ben Soussan, Hélène; Blondeau-Éthier, Virginie; Bordaries, Roxane; Bramwell, Helene; Briggs, Alicia; Bui, Richard; Carnevale, Matthew; Chancharoen, Marisa; Chevassus, Talia; Choi, Jin H.; Coulombe, Karyne; Couvrette, Florence; D'Abreau, Samantha; Davies, Meghan; Desbiens, Marie-Pier; Di Maulo, Tamara; Di Paolo, Sean-Anthony; Do Ponte, Sabrina; dos Santos Ribeiro, Priscyla; Dubuc-Kanary, Laure-Anne; Duncan, Paola K.; Dupuis, Frédérique; El-Nounou, Sara; Eyangos, Christina N.; Ferguson, Natasha K.; Flores-Chinchilla, Nancy R.; Fotakis, Tanya; Gado Oumarou H D, Mariam; Georgiev, Metodi; Ghiassy, Seyedehnazanin; Glibetic, Natalija; Grégoire Bouchard, Julien; Hassan, Tazkia; Huseen, Iman; Ibuna Quilatan, Marlon-Francis; Iozzo, Tania; Islam, Safina; Jaunky, Dilan B.; Jeyasegaram, Aniththa; Johnston, Marc-André; Kahler, Matthew R.; Kaler, Kiranpreet; Kamani, Cedric; Karimian Rad, Hessam; Konidis, Elisavet; Konieczny, Filip; Kurianowicz, Sandra; Lamothe, Philippe; Legros, Karina; Leroux, Sebastien; Li, Jun; Lozano Rodriguez, Monica E.; Luponio-Yoffe, Sean; Maalouf, Yara; Mantha, Jessica; McCormick, Melissa; Mondragon, Pamela; Narayana, Thivaedee; Neretin, Elizaveta; Nguyen, Thi T. T.; Niu, Ian; Nkemazem, Romeo B.; O'Donovan, Martin; Oueis, Matthew; Paquette, Stevens; Patel, Nehal; Pecsi, Emily; Peters, Jackie; Pettorelli, Annie; Poirier, Cassandra; Pompa, Victoria R.; Rajen, Harshvardhan; Ralph, Reginald-Olivier; Rosales-Vasquez, Josué; Rubinshtein, Daria; Sakr, Surya; Sebai, Mohammad S.; Serravalle, Lisa; Sidibe, Fily; Sinnathurai, Ahnjana; Soho, Dominique; Sundarakrishnan, Adithi; Svistkova, Veronika; Ugbeye, Tsolaye E.; Vasconcelos, Megan S.; Vincelli, Michael; Voitovich, Olga; Vrabel, Pamela; Wang, Lu; Wasfi, Maryse; Zha, Cong Y.; Gamberi, Chiara

2017-01-01

Composed of trillions of individual microbes, the human gut microbiota has adapted to the uniquely diverse environments found in the human intestine. Quickly responding to the variances in the ingested food, the microbiota interacts with the host via reciprocal biochemical signaling to coordinate the exchange of nutrients and proper immune function. Host and microbiota function as a unit which guards its balance against invasion by potential pathogens and which undergoes natural selection. Disturbance of the microbiota composition, or dysbiosis, is often associated with human disease, indicating that, while there seems to be no unique optimal composition of the gut microbiota, a balanced community is crucial for human health. Emerging knowledge of the ecology of the microbiota-host synergy will have an impact on how we implement antibiotic treatment in therapeutics and prophylaxis and how we will consider alternative strategies of global remodeling of the microbiota such as fecal transplants. Here we examine the microbiota-human host relationship from the perspective of the microbial community dynamics. PMID:28769880

Interconnectivity of human cellular metabolism and disease prevalence

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Lee, Deok-Sun

2010-12-01

Fluctuations of metabolic reaction fluxes may cause abnormal concentrations of toxic or essential metabolites, possibly leading to metabolic diseases. The mutual binding of enzymatic proteins and ones involving common metabolites enforces distinct coupled reactions, by which local perturbations may spread through the cellular network. Such network effects at the molecular interaction level in human cellular metabolism can reappear in the patterns of disease occurrence. Here we construct the enzyme-reaction network and the metabolite-reaction network, capturing the flux coupling of metabolic reactions caused by the interacting enzymes and the shared metabolites, respectively. Diseases potentially caused by the failure of individual metabolic reactions can be identified by using the known disease-gene association, which allows us to derive the probability of an inactivated reaction causing diseases from the disease records at the population level. We find that the greater the number of proteins that catalyze a reaction, the higher the mean prevalence of its associated diseases. Moreover, the number of connected reactions and the mean size of the avalanches in the networks constructed are also shown to be positively correlated with the disease prevalence. These findings illuminate the impact of the cellular network topology on disease development, suggesting that the global organization of the molecular interaction network should be understood to assist in disease diagnosis, treatment, and drug discovery.

Towards a general framework for including noise impacts in LCA

NARCIS (Netherlands)

Cucurachi, Stefano; Heijungs, Reinout; Ohlau, Katrin

Purpose Several damages have been associated with the exposure of human beings to noise. These include auditory effects, i.e., hearing impairment, but also non-auditory physiological ones such as hypertension and ischemic heart disease, or psychological ones such as annoyance, depression, sleep

X-ray diffraction evidence for myelin disorder in brain from humans with Alzheimer's disease.

Science.gov (United States)

Chia, L S; Thompson, J E; Moscarello, M A

1984-09-05

Wide-angle X-ray diffraction studies revealed that the lipid phase transition temperature of myelin from brain tissue of humans with Alzheimer's disease was about 12 degrees C lower than that of normal age-matched controls, indicating differences in the physical organization of the myelin lipid bilayer. Elevated levels of malondialdehyde and conjugated diene were found in brain tissue from humans with Alzheimer's disease, indicating an increased amount of lipid peroxidation over the controls. An increase in myelin disorder and in lipid peroxidation can both be correlated with aging in human brain, but the changes in myelin from humans with Alzheimer's disease are more pronounced than in normal aging. These changes might represent severe or accelerated aging.

Plebotomine Vectors of Human Disease.

Science.gov (United States)

1984-12-30

incriminated as vectors of Leishmania mexicana among rodents and/or humans from Mexico to the Amazon Basin. Specimens referable to L. olmeca olmeca...in the format similar to that given for the species group baityi included in this report. Additional phlebotomines from Tanzania, Brazil, Peru and...species group baityi included in this report. Additional phlebotomines from Tanzania, Brazil, Peru and Venezuela were slide-mounted and added to the

Evaluation of Potential Infectivity of Alzheimer and Parkinson Disease Proteins in Recipients of Cadaver-Derived Human Growth Hormone

Science.gov (United States)

Irwin, David J.; Abrams, Joseph Y.; Schonberger, Lawrence B.; Leschek, Ellen Werber; Mills, James L.; Lee, Virginia M.-Y.; Trojanowski, John Q.

2013-01-01

Importance Growing evidence of cell-to-cell transmission of neurodegenerative disease (ND)–associated proteins (NDAPs) (ie, tau, Aβ, and α-synuclein) suggests possible similarities in the infectious prion protein (PrPsc) in spongiform encephalopathies. There are limited data on the potential human-to-human transmission of NDAPs associated with Alzheimer disease (AD) and other non-PrPsc ND. Objective To examine evidence for human-to-human transmission of AD, Parkinson disease (PD), and related NDAPs in cadaveric human growth hormone (c-hGH) recipients. Design We conducted a detailed immunohistochemical analysis of pathological NDAPs other than PrPsc in human pituitary glands. We also searched for ND in recipients of pituitary-derived c-hGH by reviewing the National Hormone and Pituitary Program (NHPP) cohort database and medical literature. Setting University-based academic center and agencies of the US Department of Health and Human Services. Participants Thirty-four routine autopsy subjects (10 non-ND controls and 24 patients with ND) and a US cohort of c-hGH recipients in the NHPP. Main Outcome Measures Detectable NDAPs in human pituitary sections and death certificate reports of non-PrPsc ND in the NHPP database. Results We found mild amounts of pathological tau, Aβ, and α-synuclein deposits in the adeno/neurohypophysis of patients with ND and control patients. No cases of AD or PD were identified, and 3 deaths attributed to amyotrophic lateral sclerosis (ALS) were found among US NHPP c-hGH recipients, including 2 of the 796 decedents in the originally confirmed NHPP c-hGH cohort database. Conclusions and Relevance Despite the likely frequent exposure of c-hGH recipients to NDAPs, and their markedly elevated risk of PrPsc-related disease, this population of NHPP c-hGH recipients does not appear to be at increased risk of AD or PD. We discovered 3 ALS cases of unclear significance among US c-hGH recipients despite the absence of pathological deposits of ALS

The genus Malassezia and human disease

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Inamadar A

2003-07-01

Full Text Available Sabouraud's Pityrosporum is now recognized as Malassezia. With taxonomic revision of the genus, newer species have been included. The role of this member of the normal human skin flora in different cutaneous and systemic disorders is becoming clearer. The immunological responses it induces in the human body are conflicting and their relevance to clinical features is yet to be explored.

Cross-pollination of research findings, although uncommon, may accelerate discovery of human disease genes

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Duda Marlena

2012-11-01

Full Text Available Abstract Background Technological leaps in genome sequencing have resulted in a surge in discovery of human disease genes. These discoveries have led to increased clarity on the molecular pathology of disease and have also demonstrated considerable overlap in the genetic roots of human diseases. In light of this large genetic overlap, we tested whether cross-disease research approaches lead to faster, more impactful discoveries. Methods We leveraged several gene-disease association databases to calculate a Mutual Citation Score (MCS for 10,853 pairs of genetically related diseases to measure the frequency of cross-citation between research fields. To assess the importance of cooperative research, we computed an Individual Disease Cooperation Score (ICS and the average publication rate for each disease. Results For all disease pairs with one gene in common, we found that the degree of genetic overlap was a poor predictor of cooperation (r2=0.3198 and that the vast majority of disease pairs (89.56% never cited previous discoveries of the same gene in a different disease, irrespective of the level of genetic similarity between the diseases. A fraction (0.25% of the pairs demonstrated cross-citation in greater than 5% of their published genetic discoveries and 0.037% cross-referenced discoveries more than 10% of the time. We found strong positive correlations between ICS and publication rate (r2=0.7931, and an even stronger correlation between the publication rate and the number of cross-referenced diseases (r2=0.8585. These results suggested that cross-disease research may have the potential to yield novel discoveries at a faster pace than singular disease research. Conclusions Our findings suggest that the frequency of cross-disease study is low despite the high level of genetic similarity among many human diseases, and that collaborative methods may accelerate and increase the impact of new genetic discoveries. Until we have a better

Human prion diseases: surgical lessons learned from iatrogenic prion transmission.

Science.gov (United States)

Bonda, David J; Manjila, Sunil; Mehndiratta, Prachi; Khan, Fahd; Miller, Benjamin R; Onwuzulike, Kaine; Puoti, Gianfranco; Cohen, Mark L; Schonberger, Lawrence B; Cali, Ignazio

2016-07-01

The human prion diseases, or transmissible spongiform encephalopathies, have captivated our imaginations since their discovery in the Fore linguistic group in Papua New Guinea in the 1950s. The mysterious and poorly understood "infectious protein" has become somewhat of a household name in many regions across the globe. From bovine spongiform encephalopathy (BSE), commonly identified as mad cow disease, to endocannibalism, media outlets have capitalized on these devastatingly fatal neurological conditions. Interestingly, since their discovery, there have been more than 492 incidents of iatrogenic transmission of prion diseases, largely resulting from prion-contaminated growth hormone and dura mater grafts. Although fewer than 9 cases of probable iatrogenic neurosurgical cases of Creutzfeldt-Jakob disease (CJD) have been reported worldwide, the likelihood of some missed cases and the potential for prion transmission by neurosurgery create considerable concern. Laboratory studies indicate that standard decontamination and sterilization procedures may be insufficient to completely remove infectivity from prion-contaminated instruments. In this unfortunate event, the instruments may transmit the prion disease to others. Much caution therefore should be taken in the absence of strong evidence against the presence of a prion disease in a neurosurgical patient. While the Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO) have devised risk assessment and decontamination protocols for the prevention of iatrogenic transmission of the prion diseases, incidents of possible exposure to prions have unfortunately occurred in the United States. In this article, the authors outline the historical discoveries that led from kuru to the identification and isolation of the pathological prion proteins in addition to providing a brief description of human prion diseases and iatrogenic forms of CJD, a brief history of prion disease nosocomial transmission

Transplantation of Human Embryonic Stem Cells in Patients with Multiple Sclerosis and Lyme Disease

OpenAIRE

Shroff, Geeta

2016-01-01

Case series Patient: Male, 42 ? Female, 30 Final Diagnosis: Human embryonic stem cells showed good therapeutic potential for treatment of multiple sclerosis with lyme disease Symptoms: Fatigue ? weakness in limbs Medication: ? Clinical Procedure: Human embryonic stem cells transplantation Specialty: Transplantology Objective: Rare disease Background: Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease in which the myelin sheath of nerve cells is damaged. It can cause dela...

Simian virus 40 infection in humans and association with human diseases: results and hypotheses

International Nuclear Information System (INIS)

Barbanti-Brodano, Giuseppe; Sabbioni, Silvia; Martini, Fernanda; Negrini, Massimo; Corallini, Alfredo; Tognon, Mauro

2004-01-01

Simian virus 40 (SV40) is a monkey virus that was introduced in the human population by contaminated poliovaccines, produced in SV40-infected monkey cells, between 1955 and 1963. Epidemiological evidence now suggests that SV40 may be contagiously transmitted in humans by horizontal infection, independent of the earlier administration of SV40-contaminated poliovaccines. This evidence includes detection of SV40 DNA sequences in human tissues and of SV40 antibodies in human sera, as well as rescue of infectious SV40 from a human tumor. Detection of SV40 DNA sequences in blood and sperm and of SV40 virions in sewage points to the hematic, sexual, and orofecal routes as means of virus transmission in humans. The site of latent infection in humans is not known, but the presence of SV40 in urine suggests the kidney as a possible site of latency, as it occurs in the natural monkey host. SV40 in humans is associated with inflammatory kidney diseases and with specific tumor types: mesothelioma, lymphoma, brain, and bone. These human tumors correspond to the neoplasms that are induced by SV40 experimental inoculation in rodents and by generation of transgenic mice with the SV40 early region gene directed by its own early promoter-enhancer. The mechanisms of SV40 tumorigenesis in humans are related to the properties of the two viral oncoproteins, the large T antigen (Tag) and the small t antigen (tag). Tag acts mainly by blocking the functions of p53 and RB tumor suppressor proteins, as well as by inducing chromosomal aberrations in the host cell. These chromosome alterations may hit genes important in oncogenesis and generate genetic instability in tumor cells. The clastogenic activity of Tag, which fixes the chromosome damage in the infected cells, may explain the low viral load in SV40-positive human tumors and the observation that Tag is expressed only in a fraction of tumor cells. 'Hit and run' seems the most plausible mechanism to support this situation. The small tag

A knowledge based approach to matching human neurodegenerative disease and animal models

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Maryann E Martone

2013-05-01

Full Text Available Neurodegenerative diseases present a wide and complex range of biological and clinical features. Animal models are key to translational research, yet typically only exhibit a subset of disease features rather than being precise replicas of the disease. Consequently, connecting animal to human conditions using direct data-mining strategies has proven challenging, particularly for diseases of the nervous system, with its complicated anatomy and physiology. To address this challenge we have explored the use of ontologies to create formal descriptions of structural phenotypes across scales that are machine processable and amenable to logical inference. As proof of concept, we built a Neurodegenerative Disease Phenotype Ontology and an associated Phenotype Knowledge Base using an entity-quality model that incorporates descriptions for both human disease phenotypes and those of animal models. Entities are drawn from community ontologies made available through the Neuroscience Information Framework and qualities are drawn from the Phenotype and Trait Ontology. We generated ~1200 structured phenotype statements describing structural alterations at the subcellular, cellular and gross anatomical levels observed in 11 human neurodegenerative conditions and associated animal models. PhenoSim, an open source tool for comparing phenotypes, was used to issue a series of competency questions to compare individual phenotypes among organisms and to determine which animal models recapitulate phenotypic aspects of the human disease in aggregate. Overall, the system was able to use relationships within the ontology to bridge phenotypes across scales, returning non-trivial matches based on common subsumers that were meaningful to a neuroscientist with an advanced knowledge of neuroanatomy. The system can be used both to compare individual phenotypes and also phenotypes in aggregate. This proof of concept suggests that expressing complex phenotypes using formal

Human Parvoviruses

Science.gov (United States)

Söderlund-Venermo, Maria; Young, Neal S.

2016-01-01

SUMMARY Parvovirus B19 (B19V) and human bocavirus 1 (HBoV1), members of the large Parvoviridae family, are human pathogens responsible for a variety of diseases. For B19V in particular, host features determine disease manifestations. These viruses are prevalent worldwide and are culturable in vitro, and serological and molecular assays are available but require careful interpretation of results. Additional human parvoviruses, including HBoV2 to -4, human parvovirus 4 (PARV4), and human bufavirus (BuV) are also reviewed. The full spectrum of parvovirus disease in humans has yet to be established. Candidate recombinant B19V vaccines have been developed but may not be commercially feasible. We review relevant features of the molecular and cellular biology of these viruses, and the human immune response that they elicit, which have allowed a deep understanding of pathophysiology. PMID:27806994

The human prion diseases. A review with special emphasis on new variant CJD and comments on surveillance.

LENUS (Irish Health Repository)

Keohane, C

2012-02-03

The transmissible spongiform encephalopathies or prion diseases represent a new group of diseases with unique clinical and neuropathological features, the transmission of which is both genetic and infectious. The responsible agent is unconventional and appears to be largely composed of a glycoprotein, the prion protein PrP. This is normally present on different cells. In prion diseases, it becomes converted to the pathogenic form PrPres which is resistant to proteinase and accumulates within the brain and this process is accompanied by the development of spongiform change, gliosis and neuronal loss. The human prion diseases include Kuru a progressive cerebellar degeneration with late dementia affecting Fore tribes in New-Guinea, now almost extinct, regarded as being related to cannibalism. Creutzfeldt-Jakob disease is the more frequent human prion disease. Its incidence is approximately one case per million per year. Four variants are now recognized: sporadic, familial, iatrogenic and the new variant. The latter represents a distinct clinico-pathological entity. It is now widely accepted that it is due to the same agent responsible for Bovine Spongiform Encephalopathy in cattle. Gerstmann-Straussler-Scheinker disease is a very rare inherited disorder due to a number of different mutations in the PRP gene, characterized by abundant deposits of plaque PrPres in the cerebral grey matter. Fatal familial insomnia is another inherited disorder due to a mutation at codon 178 of the PRP gene associated with methionine on codon 129 of the mutant allele. The main neuropathological change is neuronal loss in the thalamus with little or no spongiosis and usually no PrPres deposition. Following the emergence of new variant CJD in 1996, surveillance of all forms of prion diseases has been now been actively introduced in many European nations in order to determine the true incidence and geographic distribution of these rare disorders in humans.

The commensal microbiota and the development of human disease - an introduction.

Science.gov (United States)

Marsh, Philip D

2015-01-01

Humans have co-evolved with microorganisms, and both exist in a symbiotic or mutualistic relationship. We are colonised by a diverse, resident microbiota, which develop into structurally and functionally organised biofilms. The resident microorganisms gain a secure, warm, nutritious habitat from the host and, in return, contribute to the development of many important host functions. The resident microbiota of each habitat is natural and provides important benefits for the host including immunological priming, down-regulation of excessive pro-inflammatory responses, regulation of gastrointestinal and cardiovascular systems, and prevention of colonisation by exogenous microbes. The biological properties of each habitat determine which microorganisms can colonise and grow, and dictate which will be major or minor components of the resident microbiota of a site. This results in different surfaces having distinct but characteristic microbiotas. This relationship between the resident microbiota and the host is dynamic and, on occasions, this symbiotic relationship breaks down due to, for example, changes in lifestyle, immune status or following broad spectrum antibiotic therapy. This 'dysbiosis' can result in previously minor components of the microbiota out-competing the normally dominant and beneficial bacteria, thereby increasing the risk of disease. Such perturbations have been associated with a number of clinical disorders such as obesity, allergy, and a variety of inflammatory diseases, including periodontal diseases. A better understanding of the delicate balance between the host and its resident microbiota could lead to novel approaches to the promotion of health and the prevention of dysbiosis.

Cross-species analysis of genetically engineered mouse models of MAPK-driven colorectal cancer identifies hallmarks of the human disease

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Peter J. Belmont

2014-06-01

Full Text Available Effective treatment options for advanced colorectal cancer (CRC are limited, survival rates are poor and this disease continues to be a leading cause of cancer-related deaths worldwide. Despite being a highly heterogeneous disease, a large subset of individuals with sporadic CRC typically harbor relatively few established ‘driver’ lesions. Here, we describe a collection of genetically engineered mouse models (GEMMs of sporadic CRC that combine lesions frequently altered in human patients, including well-characterized tumor suppressors and activators of MAPK signaling. Primary tumors from these models were profiled, and individual GEMM tumors segregated into groups based on their genotypes. Unique allelic and genotypic expression signatures were generated from these GEMMs and applied to clinically annotated human CRC patient samples. We provide evidence that a Kras signature derived from these GEMMs is capable of distinguishing human tumors harboring KRAS mutation, and tracks with poor prognosis in two independent human patient cohorts. Furthermore, the analysis of a panel of human CRC cell lines suggests that high expression of the GEMM Kras signature correlates with sensitivity to targeted pathway inhibitors. Together, these findings implicate GEMMs as powerful preclinical tools with the capacity to recapitulate relevant human disease biology, and support the use of genetic signatures generated in these models to facilitate future drug discovery and validation efforts.

The suggestion of common cause of disease, characteristics of human body, and medical treatment

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Byung-Jun Cho

2011-06-01

Full Text Available Objectives & Methods: This suggestion was attempted to be elevated the recognition of common characteristics in disease. So, we performed to analyze the correlation of common cause of disease, characteristics of human body, and medical treatment. And the results are as follows. Results: 1. The cause of disease is consist of genetic factor, aging, habit, food of not good in health, weather, environment, deficit of the physical activity, stress and so on. 2. Generally, human has common and individual weakness. Individual weakness is appeared similar to the occurrence of volcano and lapse. 3. The correlation of disease and medical treatments is possible to explain using the quotation of the law of motion made by Isaac Newton, the great physicist. 4. When the process of the medical treatment was not progressed, the prognosis is determined by the correlation of the homeostasis(H' in human body and the homeostasis(H of disease. 5. The prognosis of disease is determined by the relationship between the energy of disease(F and medical treatment(F'. 6. The exact diagnosis is possible to predict the treatment sequence, and the facts that homeostasis in human body and disease, relationship between the energy of disease(F and medical treatment(F', action and reaction are important to determine the prognosis. 7. The careful observation of improving response and worsening action of disease becomes available for exact prognosis. Conclusion: The above described contents may be useful in clinical studies, and the concrete clinical reports about this will be made afterward.

Role of Vitamin D in human Diseases and Disorders – An Overview

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Priyanshee Gohil

2014-06-01

Full Text Available Vitamin D is a fat soluble vitamin and generated in human skin by ultraviolet (UV light. Today, vitamin D is considered to be a steroidal hormone and plays a central role in bone mineralization and calcium homeostasis. The active form of the vitamin D is 1, 25-dihydroxyvitamin D [1, 25-dihydroxycholecalciferol (DHCC] which mediatesproliferation, differentiation and various functions at the cellular level through Vitamin D receptors (VDR.Therefore, compromised vitamin D status is likely to be involved in progression or pathogenesis of various disorders. This assumption is consistent with findings from epidemiological studies that a compromised vitamin D status in humans increases the risk of autoimmune diseases, such as inflammatory bowel disease, rheumatoid arthritis, systemic lupus erythematosus (SLE, multiple sclerosis and type I diabetes mellitus. However, diseases like cancer, cardiovascular disorders and bone disorders are yet not focused. Thus the role of vitamin D in pathogenesis of various diseases is complex and controversial. This review briefly summarizes the role of vitamin D in development and progression of different human disorders.

Serological prevalence of human parvovirus B19 in diseases or disordersrelated to different human body systems.

Science.gov (United States)

Aktaş, Osman; Aydin, Hakan; Uslu, Hakan

2016-02-17

Human parvovirus B19 is a pathogen that affects different parts of the body. We planned this study because of the lack of data on B19 seroprevalence based on different body-system diseases. The prevalence of parvovirus B19 antibodies was investigated retrospectively in 1239 patients by review of medical records from 2009-2012, according to their diseases classified under general titles in compliance with the International Classification of Diseases (ICD-10). Parvovirus B19-specific antibodies were detected by quantitative enzyme immunoassays. The positivity rate was 27.8% for only IgG, 8.5% for only IgM, and 2.6% for both IgG and IgM. The highest positivity for IgG alone was found in musculoskeletal system and connective tissue diseases (55.9%), while the highest positivity for IgM was found in neoplasms (16.4%). The highest positivity for IgG was seen in rheumatoid arthritis (72.2%) and pregnancy (52.6%), and the highest positivity for total IgM was found in upper respiratory tract disease (21.0%) and hepatic failure (17.1%). Parvovirus B19 seroprevalence was relatively low in northeastern Anatolia compared to most serological studies conducted in other regions. We think that this study has provided the first wide-ranging information on the seroprevalence of B19 in diseases and disorders of the major human body systems.

BIOLOGY OF HUMAN MALARIA PLASMODIA INCLUDING PLASMODIUM KNOWLESI

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Spinello Antinori

2012-03-01

Full Text Available Malaria is a vector-borne infection caused by unicellular parasite of the genus Plasmodium. Plasmodia are obligate intracellular parasites that in humans after a clinically silent replication phase in the liver are able to infect and replicate within the erythrocytes. Four species (P.falciparum, P.malariae, P.ovale and P.vivax are traditionally recognized as responsible of natural infection in human beings but the recent upsurge of P.knowlesi malaria in South-East Asia has led clinicians to consider it as the fifth human malaria parasite. Recent studies in wild-living apes in Africa have revealed that P.falciparum, the most deadly form of human malaria, is not only human-host restricted as previously believed and its phylogenetic lineage is much more complex with new species identified in gorilla, bonobo and chimpanzee. Although less impressive, new data on biology of P.malariae, P.ovale and P.vivax are also emerging and will be briefly discussed in this review.

Interconnectivity of human cellular metabolism and disease prevalence

International Nuclear Information System (INIS)

Lee, Deok-Sun

2010-01-01

Fluctuations of metabolic reaction fluxes may cause abnormal concentrations of toxic or essential metabolites, possibly leading to metabolic diseases. The mutual binding of enzymatic proteins and ones involving common metabolites enforces distinct coupled reactions, by which local perturbations may spread through the cellular network. Such network effects at the molecular interaction level in human cellular metabolism can reappear in the patterns of disease occurrence. Here we construct the enzyme-reaction network and the metabolite-reaction network, capturing the flux coupling of metabolic reactions caused by the interacting enzymes and the shared metabolites, respectively. Diseases potentially caused by the failure of individual metabolic reactions can be identified by using the known disease–gene association, which allows us to derive the probability of an inactivated reaction causing diseases from the disease records at the population level. We find that the greater the number of proteins that catalyze a reaction, the higher the mean prevalence of its associated diseases. Moreover, the number of connected reactions and the mean size of the avalanches in the networks constructed are also shown to be positively correlated with the disease prevalence. These findings illuminate the impact of the cellular network topology on disease development, suggesting that the global organization of the molecular interaction network should be understood to assist in disease diagnosis, treatment, and drug discovery

Comprehensive Control of Human Papillomavirus Infections and Related Diseases

Science.gov (United States)

Bosch, F. Xavier; Broker, Thomas R.; Forman, David; Moscicki, Anna-Barbara; Gillison, Maura L.; Doorbar, John; Stern, Peter L.; Stanley, Margaret; Arbyn, Marc; Poljak, Mario; Cuzick, Jack; Castle, Philip E.; Schiller, John T.; Markowitz, Lauri E.; Fisher, William A.; Canfell, Karen; Denny, Lynette A.; Franco, Eduardo L.; Steben, Marc; Kane, Mark A.; Schiffman, Mark; Meijer, Chris J.L.M.; Sankaranarayanan, Rengaswamy; Castellsagué, Xavier; Kim, Jane J.; Brotons, Maria; Alemany, Laia; Albero, Ginesa; Diaz, Mireia; de Sanjosé, Silvia

2014-01-01

Infection with human papillomavirus (HPV) is recognized as one of the major causes of infection-related cancer worldwide, as well as the causal factor in other diseases. Strong evidence for a causal etiology with HPV has been stated by the International Agency for Research on Cancer for cancers of the cervix uteri, penis, vulva, vagina, anus and oropharynx (including base of the tongue and tonsils). Of the estimated 12.7 million new cancers occurring in 2008 worldwide, 4.8% were attributable to HPV infection, with substantially higher incidence and mortality rates seen in developing versus developed countries. In recent years, we have gained tremendous knowledge about HPVs and their interactions with host cells, tissues and the immune system; have validated and implemented strategies for safe and efficacious prophylactic vaccination against HPV infections; have developed increasingly sensitive and specific molecular diagnostic tools for HPV detection for use in cervical cancer screening; and have substantially increased global awareness of HPV and its many associated diseases in women, men, and children. While these achievements exemplify the success of biomedical research in generating important public health interventions, they also generate new and daunting challenges: costs of HPV prevention and medical care, the implementation of what is technically possible, socio-political resistance to prevention opportunities, and the very wide ranges of national economic capabilities and health care systems. Gains and challenges faced in the quest for comprehensive control of HPV infection and HPV-related cancers and other disease are summarized in this review. The information presented may be viewed in terms of a reframed paradigm of prevention of cervical cancer and other HPV-related diseases that will include strategic combinations of at least four major components: 1) routine introduction of HPV vaccines to women in all countries, 2) extension and simplification of

Validation of celiac disease diagnoses recorded in the Danish National Patient Register using duodenal biopsies, celiac disease-specific antibodies, and human leukocyte-antigen genotypes

DEFF Research Database (Denmark)

Dydensborg Sander, Stine; Størdal, Ketil; Plato Hansen, Tine

2016-01-01

PURPOSE: The purpose of this study was to validate the celiac disease diagnoses recorded in the Danish National Patient Register. To validate the diagnoses, we used information on duodenal biopsies from a national register of pathology reports (the Patobank) and information on celiac disease......-specific antibodies and human leukocyte antigen (HLA) genotypes obtained from patient medical records. PATIENTS AND METHODS: We included all the children who were born from 1995 to 2012 and who were registered as having celiac disease in the Danish National Patient Register. We reviewed all the pathology reports...... on duodenal biopsies in the Patobank and the information in the medical records on celiac disease-specific antibodies (ie, anti-tissue transglutaminase 2 IgA and IgG, endomysial antibodies IgA, and anti-deamidated gliadin peptide IgG) and HLA genotypes. RESULTS: We identified 2,247 children who were...

Limits to human enhancement: nature, disease, therapy or betterment?

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Hofmann, Bjørn

2017-10-10

New technologies facilitate the enhancement of a wide range of human dispositions, capacities, or abilities. While it is argued that we need to set limits to human enhancement, it is unclear where we should find resources to set such limits. Traditional routes for setting limits, such as referring to nature, the therapy-enhancement distinction, and the health-disease distinction, turn out to have some shortcomings. However, upon closer scrutiny the concept of enhancement is based on vague conceptions of what is to be enhanced. Explaining why it is better to become older, stronger, and more intelligent presupposes a clear conception of goodness, which is seldom provided. In particular, the qualitative better is frequently confused with the quantitative more. We may therefore not need "external" measures for setting its limits - they are available in the concept of enhancement itself. While there may be shortcomings in traditional sources of limit setting to human enhancement, such as nature, therapy, and disease, such approaches may not be necessary. The specification-of-betterment problem inherent in the conception of human enhancement itself provides means to restrict its unwarranted proliferation. We only need to demand clear, sustainable, obtainable goals for enhancement that are based on evidence, and not on lofty speculations, hypes, analogies, or weak associations. Human enhancements that specify what will become better, and provide adequate evidence, are good and should be pursued. Others should not be accepted.

Chronic wasting disease prions are not transmissible to transgenic mice overexpressing human prion protein.

Science.gov (United States)

Sandberg, Malin K; Al-Doujaily, Huda; Sigurdson, Christina J; Glatzel, Markus; O'Malley, Catherine; Powell, Caroline; Asante, Emmanuel A; Linehan, Jacqueline M; Brandner, Sebastian; Wadsworth, Jonathan D F; Collinge, John

2010-10-01

Chronic wasting disease (CWD) is a prion disease that affects free-ranging and captive cervids, including mule deer, white-tailed deer, Rocky Mountain elk and moose. CWD-infected cervids have been reported in 14 USA states, two Canadian provinces and in South Korea. The possibility of a zoonotic transmission of CWD prions via diet is of particular concern in North America where hunting of cervids is a popular sport. To investigate the potential public health risks posed by CWD prions, we have investigated whether intracerebral inoculation of brain and spinal cord from CWD-infected mule deer transmits prion infection to transgenic mice overexpressing human prion protein with methionine or valine at polymorphic residue 129. These transgenic mice have been utilized in extensive transmission studies of human and animal prion disease and are susceptible to BSE and vCJD prions, allowing comparison with CWD. Here, we show that these mice proved entirely resistant to infection with mule deer CWD prions arguing that the transmission barrier associated with this prion strain/host combination is greater than that observed with classical BSE prions. However, it is possible that CWD may be caused by multiple prion strains. Further studies will be required to evaluate the transmission properties of distinct cervid prion strains as they are characterized.

The role of human endogenous retroviruses in the pathogenesis of autoimmune diseases.

Science.gov (United States)

Brodziak, Andrzej; Ziółko, Ewa; Muc-Wierzgoń, Małgorzata; Nowakowska-Zajdel, Ewa; Kokot, Teresa; Klakla, Katarzyna

2012-06-01

This paper presents a new, recently formulated theory, which concerns the etiopathological process of autoimmune diseases. This theory takes into account the existence in the human genome, since approximately 40 million years, of so-called human endogenous retroviruses (HERVs), which are transmitted to descendants "vertically" by the germ cells. It was recently established that these generally silent sequences perform some physiological roles, but occasionally become active and influence the development of some chronic diseases like diabetes, some neoplasms, chronic diseases of the nervous system (eg, sclerosis multiplex), schizophrenia and autoimmune diseases. We present a short synopsis of immunological processes involved in the pathogenesis of autoimmune diseases, such as molecular mimicry, epitope spreading and activation of the superantigen. We then focus on experimental findings related to systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and some diseases of hepar and otorhinal tissues. We conclude the outline of this new model of the development of chronic diseases and indicate the conclusions important for the teaching of the basis of pathology.

Computational study of ‘HUB’ microRNA in human cardiac diseases

Science.gov (United States)

Krishnan, Remya; Nair, Achuthsankar S.; Dhar, Pawan K.

2017-01-01

MicroRNAs (miRNAs) are small non-coding RNAs ~22 nucleotides long that do not encode for proteins but have been reported to influence gene expression in normal and abnormal health conditions. Though a large body of scientific literature on miRNAs exists, their network level profile linking molecules with their corresponding phenotypes, is less explored. Here, we studied a network of 191 human miRNAs reported to play a role in 30 human cardiac diseases. Our aim was to study miRNA network properties like hubness and preferred associations, using data mining, network graph theory and statistical analysis. A total of 16 miRNAs were found to have a disease node connectivity of >5 edges (i.e., they were linked to more than 5 diseases) and were considered hubs in the miRNAcardiac disease network. Alternatively, when diseases were considered as hubs, >10 of miRNAs showed up on each ‘disease hub node’. Of all the miRNAs associated with diseases, 19 miRNAs (19/24= 79.1% of upregulated events) were found to be upregulated in atherosclerosis. The data suggest micro RNAs as early stage biological markers in cardiac conditions with potential towards microRNA based therapeutics. PMID:28479745

The Association between Gene-Environment Interactions and Diseases Involving the Human GST Superfamily with SNP Variants

Directory of Open Access Journals (Sweden)

Antoinesha L. Hollman

2016-03-01

Full Text Available Exposure to environmental hazards has been associated with diseases in humans. The identification of single nucleotide polymorphisms (SNPs in human populations exposed to different environmental hazards, is vital for detecting the genetic risks of some important human diseases. Several studies in this field have been conducted on glutathione S-transferases (GSTs, a phase II detoxification superfamily, to investigate its role in the occurrence of diseases. Human GSTs consist of cytosolic and microsomal superfamilies that are further divided into subfamilies. Based on scientific search engines and a review of the literature, we have found a large amount of published articles on human GST super- and subfamilies that have greatly assisted in our efforts to examine their role in health and disease. Because of its polymorphic variations in relation to environmental hazards such as air pollutants, cigarette smoke, pesticides, heavy metals, carcinogens, pharmaceutical drugs, and xenobiotics, GST is considered as a significant biomarker. This review examines the studies on gene-environment interactions related to various diseases with respect to single nucleotide polymorphisms (SNPs found in the GST superfamily. Overall, it can be concluded that interactions between GST genes and environmental factors play an important role in human diseases.

Effects of antibiotics on human microbiota and subsequent disease.

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Keeney, Kristie M; Yurist-Doutsch, Sophie; Arrieta, Marie-Claire; Finlay, B Brett

2014-01-01

Although antibiotics have significantly improved human health and life expectancy, their disruption of the existing microbiota has been linked to significant side effects such as antibiotic-associated diarrhea, pseudomembranous colitis, and increased susceptibility to subsequent disease. By using antibiotics to break colonization resistance against Clostridium, Salmonella, and Citrobacter species, researchers are now exploring mechanisms for microbiota-mediated modulation against pathogenic infection, revealing potential roles for different phyla and family members as well as microbiota-liberated sugars, hormones, and short-chain fatty acids in regulating pathogenicity. Furthermore, connections are now being made between microbiota dysbiosis and a variety of different diseases such as rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, atopy, and obesity. Future advances in the rapidly developing field of microbial bioinformatics will enable researchers to further characterize the mechanisms of microbiota modulation of disease and potentially identify novel therapeutics against disease.

Human Gut-Derived Commensal Bacteria Suppress CNS Inflammatory and Demyelinating Disease.

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Mangalam, Ashutosh; Shahi, Shailesh K; Luckey, David; Karau, Melissa; Marietta, Eric; Luo, Ningling; Choung, Rok Seon; Ju, Josephine; Sompallae, Ramakrishna; Gibson-Corley, Katherine; Patel, Robin; Rodriguez, Moses; David, Chella; Taneja, Veena; Murray, Joseph

2017-08-08

The human gut is colonized by a large number of microorganisms (∼10 13 bacteria) that support various physiologic functions. A perturbation in the healthy gut microbiome might lead to the development of inflammatory diseases, such as multiple sclerosis (MS). Therefore, gut commensals might provide promising therapeutic options for treating MS and other diseases. We report the identification of human gut-derived commensal bacteria, Prevotella histicola, which can suppress experimental autoimmune encephalomyelitis (EAE) in a human leukocyte antigen (HLA) class II transgenic mouse model. P. histicola suppresses disease through the modulation of systemic immune responses. P. histicola challenge led to a decrease in pro-inflammatory Th1 and Th17 cells and an increase in the frequencies of CD4 + FoxP3 + regulatory T cells, tolerogenic dendritic cells, and suppressive macrophages. Our study provides evidence that the administration of gut commensals may regulate a systemic immune response and may, therefore, have a possible role in treatment strategies for MS. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Direct Lineage Reprogramming Reveals Disease-Specific Phenotypes of Motor Neurons from Human ALS Patients

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Meng-Lu Liu

2016-01-01

Full Text Available Subtype-specific neurons obtained from adult humans will be critical to modeling neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS. Here, we show that adult human skin fibroblasts can be directly and efficiently converted into highly pure motor neurons without passing through an induced pluripotent stem cell stage. These adult human induced motor neurons (hiMNs exhibit the cytological and electrophysiological features of spinal motor neurons and form functional neuromuscular junctions (NMJs with skeletal muscles. Importantly, hiMNs converted from ALS patient fibroblasts show disease-specific degeneration manifested through poor survival, soma shrinkage, hypoactivity, and an inability to form NMJs. A chemical screen revealed that the degenerative features of ALS hiMNs can be remarkably rescued by the small molecule kenpaullone. Taken together, our results define a direct and efficient strategy to obtain disease-relevant neuronal subtypes from adult human patients and reveal their promising value in disease modeling and drug identification.

Short-term Evaluation of a Comprehensive Education Program Including Inhaler Training and Disease Management on Chronic Obstructive Pulmonary Disease.

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Yoo, Kwang Ha; Chung, Wou Young; Park, Joo Hun; Hwang, Sung Chul; Kim, Tae Eun; Oh, Min Jung; Kang, Dae Ryong; Rhee, Chin Kook; Yoon, Hyoung Kyu; Kim, Tae Hyung; Kim, Deog Kyeom; Park, Yong Bum; Kim, Sang Ha; Yum, Ho Kee

2017-10-01

Proper education regarding inhaler usage and optimal management of chronic obstructive pulmonary disease (COPD) is essential for effectively treating patients with COPD. This study was conducted to evaluate the effects of a comprehensive education program including inhaler training and COPD management. We enlisted 127 patients with COPD on an outpatient basis at 43 private clinics in Korea. The patients were educated on inhaler usage and disease management for three visits across 2 weeks. Physicians and patients were administered a COPD assessment test (CAT) and questionnaires about the correct usage of inhalers and management of COPD before commencement of this program and after their third visit. The outcomes of 127 COPD patients were analyzed. CAT scores (19.6±12.5 vs. 15.1±12.3) improved significantly after this program (pmanagement and the correct technique for using inhalers than those who did not have improved CAT scores (peducation program including inhaler training and COPD management at a primary care setting improved CAT scores and led to patients' better understanding of COPD management. Copyright©2017. The Korean Academy of Tuberculosis and Respiratory Diseases

Mitochondrial Damage-Associated Molecular Patterns: From Inflammatory Signaling to Human Diseases

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Serge Grazioli

2018-05-01

Full Text Available Over the recent years, much has been unraveled about the pro-inflammatory properties of various mitochondrial molecules once they are leaving the mitochondrial compartment. On entering the cytoplasm or the extracellular space, mitochondrial DAMPs (also known as mitochondrial alarmins can become pro-inflammatory and initiate innate and adaptive immune responses by activating cell surface and intracellular receptors. Current evidence indicates that uncontrolled and excessive release of mitochondrial DAMPs is associated with severity, has prognosis value in human diseases, and contributes to the dysregulated process observed in numerous inflammatory and autoimmune conditions, as well as in ischemic heart disease and cancer. Herein, we review that the expanding research field of mitochondrial DAMPs in innate immune responses and the current knowledge on the association between mitochondrial DAMPs and human diseases.

Use of genome editing tools in human stem cell-based disease modeling and precision medicine.

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Wei, Yu-da; Li, Shuang; Liu, Gai-gai; Zhang, Yong-xian; Ding, Qiu-rong

2015-10-01

Precision medicine emerges as a new approach that takes into account individual variability. The successful conduct of precision medicine requires the use of precise disease models. Human pluripotent stem cells (hPSCs), as well as adult stem cells, can be differentiated into a variety of human somatic cell types that can be used for research and drug screening. The development of genome editing technology over the past few years, especially the CRISPR/Cas system, has made it feasible to precisely and efficiently edit the genetic background. Therefore, disease modeling by using a combination of human stem cells and genome editing technology has offered a new platform to generate " personalized " disease models, which allow the study of the contribution of individual genetic variabilities to disease progression and the development of precise treatments. In this review, recent advances in the use of genome editing in human stem cells and the generation of stem cell models for rare diseases and cancers are discussed.

Human Gut Microbiota: Toward an Ecology of Disease

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Susannah Selber-Hnatiw

2017-07-01

Full Text Available Composed of trillions of individual microbes, the human gut microbiota has adapted to the uniquely diverse environments found in the human intestine. Quickly responding to the variances in the ingested food, the microbiota interacts with the host via reciprocal biochemical signaling to coordinate the exchange of nutrients and proper immune function. Host and microbiota function as a unit which guards its balance against invasion by potential pathogens and which undergoes natural selection. Disturbance of the microbiota composition, or dysbiosis, is often associated with human disease, indicating that, while there seems to be no unique optimal composition of the gut microbiota, a balanced community is crucial for human health. Emerging knowledge of the ecology of the microbiota-host synergy will have an impact on how we implement antibiotic treatment in therapeutics and prophylaxis and how we will consider alternative strategies of global remodeling of the microbiota such as fecal transplants. Here we examine the microbiota-human host relationship from the perspective of the microbial community dynamics.

Isolation of primary human hepatocytes from normal and diseased liver tissue: a one hundred liver experience.

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Ricky H Bhogal

2011-03-01

Full Text Available Successful and consistent isolation of primary human hepatocytes remains a challenge for both cell-based therapeutics/transplantation and laboratory research. Several centres around the world have extensive experience in the isolation of human hepatocytes from non-diseased livers obtained from donor liver surplus to surgical requirement or at hepatic resection for tumours. These livers are an important but limited source of cells for therapy or research. The capacity to isolate cells from diseased liver tissue removed at transplantation would substantially increase availability of cells for research. However no studies comparing the outcome of human hepatocytes isolation from diseased and non-diseased livers presently exist. Here we report our experience isolating human hepatocytes from organ donors, non-diseased resected liver and cirrhotic tissue. We report the cell yields and functional qualities of cells isolated from the different types of liver and demonstrate that a single rigorous protocol allows the routine harvest of good quality primary hepatocytes from the most commonly accessible human liver tissue samples.

Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease

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Machado, Mariana Verdelho; Michelotti, Gregory Alexander; Xie, Guanhua; de Almeida, Thiago Pereira; Boursier, Jerome; Bohnic, Brittany; Guy, Cynthia D.; Diehl, Anna Mae

2015-01-01

Background and aims Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet. Methods Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared. Results The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation. Conclusion Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH. PMID:26017539

Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease.

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Mariana Verdelho Machado

Full Text Available Non-alcoholic steatohepatitis (NASH, the potentially progressive form of nonalcoholic fatty liver disease (NAFLD, is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD diet and Western diet.Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose for 16 weeks. Liver pathology and metabolic profile were compared.The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation.Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH.

Transcriptome Profiling in Human Diseases: New Advances and Perspectives.

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Casamassimi, Amelia; Federico, Antonio; Rienzo, Monica; Esposito, Sabrina; Ciccodicola, Alfredo

2017-07-29

In the last decades, transcriptome profiling has been one of the most utilized approaches to investigate human diseases at the molecular level. Through expression studies, many molecular biomarkers and therapeutic targets have been found for several human pathologies. This number is continuously increasing thanks to total RNA sequencing. Indeed, this new technology has completely revolutionized transcriptome analysis allowing the quantification of gene expression levels and allele-specific expression in a single experiment, as well as to identify novel genes, splice isoforms, fusion transcripts, and to investigate the world of non-coding RNA at an unprecedented level. RNA sequencing has also been employed in important projects, like ENCODE (Encyclopedia of the regulatory elements) and TCGA (The Cancer Genome Atlas), to provide a snapshot of the transcriptome of dozens of cell lines and thousands of primary tumor specimens. Moreover, these studies have also paved the way to the development of data integration approaches in order to facilitate management and analysis of data and to identify novel disease markers and molecular targets to use in the clinics. In this scenario, several ongoing clinical trials utilize transcriptome profiling through RNA sequencing strategies as an important instrument in the diagnosis of numerous human pathologies.

Human prion diseases in The Netherlands : clinico-pathological, genetic and molecular aspects

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Jansen, C.

2011-01-01

Prion diseases, or transmissible spongiform encephalopathies (TSEs), are invariably fatal neurodegenerative disorders that can be sporadic, inherited or acquired by infection. In humans, TSEs comprise three major groups showing a wide phenotypic heterogeneity: Creutzfeldt-Jakob disease (CJD),

The contribution of human/non-human animal chimeras to stem cell research

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Sonya Levine

2017-10-01

Full Text Available Chimeric animals are made up of cells from two separate zygotes. Human/non-human animal chimeras have been used for a number of research purposes, including human disease modeling. Pluripotent stem cell (PSC research has relied upon the chimera approach to examine the developmental potential of stem cells, to determine the efficacy of cell replacement therapies, and to establish a means of producing human organs. Based on ethical issues, this work has faced pushback from various sources including funding agencies. We discuss here the essential role these studies have played, from gaining a better understanding of human biology to providing a stepping stone to human disease treatments. We also consider the major ethical issues, as well as the current status of support for this work in the United States.

Imaging neuroreceptors in the human brain in health and disease

International Nuclear Information System (INIS)

Wagner, H.N. Jr.; Dannals, R.F.; Frost, J.J.

1985-01-01

For nearly a century it has been known that chemical activity accompanies mental activity, but only recently has it been possible to begin to examine its exact nature. Positron-emitting radioactive tracers have made it possible to study the chemistry of the human brain in health and disease, using chiefly cyclotron-produced radionuclides, carbon-11, fluorine-18 and oxygen-15. It is now well established that measurable increases in regional cerebral blood flow, and glucose and oxygen metabolism accompany the mental functions of perception, cognition, emotion and motion. On 25 May 1983 the first imaging of a neuroreceptor in the human brain was accomplished with carbon-11 N-methyl spiperone, a ligand that binds preferentially to dopamine-2 receptors, 80% of which are located in the caudate nucleus and putamen. Quantitative imaging of serotonin-2, opiate, benzodiazapine and muscarinic cholinergic receptors has subsequently been accomplished. In studies of normal men and women, it has been found that dopamine and serotonin receptor activity decreases dramatically with age, such a decrease being more pronounced in men than in women and greater in the case of dopamine-2 receptors than in serotonin-2 receptors. Preliminary studies of patients with neuropsychiatric disorders suggest that dopamine-2 receptor activity is diminished in the caudate nucleus of patients with Huntington's disease. Positron tomography permits a quantitative assay of picomolar quantities of neuroreceptors within the living human brain. Studies of patients with Parkinson's disease, Alzheimer's disease, depression, anxiety, schizophrenia, acute and chronic pain states and drug addiction are now in progress. (author)

A critical review of the postulated role of the non-essential amino acid, β-N-methylamino-L-alanine, in neurodegenerative disease in humans

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Chernoff, Neil; Hill, D. J.; Diggs, D. L.; Faison, B. D.; Francis, B. M.; Lang, J. R.; Larue, M. M.; Le, T.-T.; Loftin, Keith A.; Lugo, J. N.; Schmid, J. E.; Winnik, W. W.

2017-01-01

The compound BMAA (β-N-methylamino-L-alanine) has been postulated to play a significant role in four serious neurological human diseases: Amyotrophic Lateral Sclerosis/Parkinsonism Dementia Complex (ALS/PDC) found on Guam, and ALS, Parkinsonism, and dementia that occur globally. ALS/PDC with symptoms of all three diseases first came to the attention of the scientific community during and after World War II. It was initially associated with cycad flour used for food because BMAA is a product of symbiotic cycad root-dwelling cyanobacteria. Human consumption of flying foxes that fed on cycad seeds was later suggested as a source of BMAA on Guam and a cause of ALS/PDC. Subsequently, the hypothesis was expanded to include a causative role for BMAA in other neurodegenerative diseases including Alzheimer’s disease (AD) through exposures attributed to proximity to freshwaters and/or consumption of seafood due to its purported production by most species of cyanobacteria. The hypothesis that BMAA is the critical factor in the genesis of these neurodegenerative diseases received considerable attention in the medical, scientific, and public arenas. This review examines the history of ALS/PDC and the BMAA-human disease hypotheses; similarities and differences between ALS/PDC and the other diseases with similar symptomologies; the relationship of ALS/PDC to other similar diseases, studies of BMAA-mediated effects in lab animals, inconsistencies and data gaps in the hypothesis; and other compounds and agents that were suggested as the cause of ALS/PDC on Guam. The review concludes that the hypothesis of a causal BMAA neurodegenerative disease relationship is not supported by existing data.

Perturbation of the Human Microbiome as a Contributor to Inflammatory Bowel Disease

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Bayan Missaghi

2014-06-01

Full Text Available The human microbiome consist of the composite genome of native flora that have evolved with humanity over millennia and which contains 150-fold more genes than the human genome. A “healthy” microbiome plays an important role in the maintenance of health and prevention of illness, inclusive of autoimmune disease such as inflammatory bowel disease (IBD. IBD is a prevalent spectrum of disorders, most notably defined by Crohn’s disease (CD and ulcerative colitis (UC, which are associated with considerable suffering, morbidity, and cost. This review presents an outline of the loss of a normal microbiome as an etiology of immune dysregulation and IBD pathogenesis initiation. We, furthermore, summarize the knowledge on the role of a healthy microbiome in terms of its diversity and important functional elements and, lastly, conclude with some of the therapeutic interventions and modalities that are now being explored as potential applications of microbiome-host interactions.

Human BK Polyomavirus—The Potential for Head and Neck Malignancy and Disease

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Raquel Burger-Calderon

2015-07-01

Full Text Available Members of the human Polyomaviridae family are ubiquitous and pathogenic among immune-compromised individuals. While only Merkel cell polyomavirus (MCPyV has conclusively been linked to human cancer, all members of the polyomavirus (PyV family encode the oncoprotein T antigen and may be potentially carcinogenic. Studies focusing on PyV pathogenesis in humans have become more abundant as the number of PyV family members and the list of associated diseases has expanded. BK polyomavirus (BKPyV in particular has emerged as a new opportunistic pathogen among HIV positive individuals, carrying harmful implications. Increasing evidence links BKPyV to HIV-associated salivary gland disease (HIVSGD. HIVSGD is associated with elevated risk of lymphoma formation and its prevalence has increased among HIV/AIDS patients. Determining the relationship between BKPyV, disease and tumorigenesis among immunosuppressed individuals is necessary and will allow for expanding effective anti-viral treatment and prevention options in the future.

Spatio-temporal epidemiology of human West Nile virus disease in South Dakota.

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Wimberly, Michael C; Giacomo, Paolla; Kightlinger, Lon; Hildreth, Michael B

2013-10-29

Despite a cold temperate climate and low human population density, the Northern Great Plains has become a persistent hot spot for human West Nile virus (WNV) disease in North America. Understanding the spatial and temporal patterns of WNV can provide insights into the epidemiological and ecological factors that influence disease emergence and persistence. We analyzed the 1,962 cases of human WNV disease that occurred in South Dakota from 2002-2012 to identify the geographic distribution, seasonal cycles, and interannual variability of disease risk. The geographic and seasonal patterns of WNV have changed since the invasion and initial epidemic in 2002-2003, with cases shifting toward the eastern portion of South Dakota and occurring earlier in the transmission season in more recent years. WNV cases were temporally autocorrelated at lags of up to six weeks and early season cumulative case numbers were correlated with seasonal totals, indicating the possibility of using these data for short-term early detection of outbreaks. Epidemiological data are likely to be most effective for early warning of WNV virus outbreaks if they are integrated with entomological surveillance and environmental monitoring to leverage the strengths and minimize the weaknesses of each information source.

Amniotic Fluid Stem Cells: A Novel Source for Modeling of Human Genetic Diseases

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Ivana Antonucci

2016-04-01

Full Text Available In recent years, great interest has been devoted to the use of Induced Pluripotent Stem cells (iPS for modeling of human genetic diseases, due to the possibility of reprogramming somatic cells of affected patients into pluripotent cells, enabling differentiation into several cell types, and allowing investigations into the molecular mechanisms of the disease. However, the protocol of iPS generation still suffers from technical limitations, showing low efficiency, being expensive and time consuming. Amniotic Fluid Stem cells (AFS represent a potential alternative novel source of stem cells for modeling of human genetic diseases. In fact, by means of prenatal diagnosis, a number of fetuses affected by chromosomal or Mendelian diseases can be identified, and the amniotic fluid collected for genetic testing can be used, after diagnosis, for the isolation, culture and differentiation of AFS cells. This can provide a useful stem cell model for the investigation of the molecular basis of the diagnosed disease without the necessity of producing iPS, since AFS cells show some features of pluripotency and are able to differentiate in cells derived from all three germ layers “in vitro”. In this article, we describe the potential benefits provided by using AFS cells in the modeling of human genetic diseases.

A cocktail of humanized anti-pertussis toxin antibodies limits disease in murine and baboon models of whooping cough.

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Nguyen, Annalee W; Wagner, Ellen K; Laber, Joshua R; Goodfield, Laura L; Smallridge, William E; Harvill, Eric T; Papin, James F; Wolf, Roman F; Padlan, Eduardo A; Bristol, Andy; Kaleko, Michael; Maynard, Jennifer A

2015-12-02

Despite widespread vaccination, pertussis rates are rising in industrialized countries and remain high worldwide. With no specific therapeutics to treat disease, pertussis continues to cause considerable infant morbidity and mortality. The pertussis toxin is a major contributor to disease, responsible for local and systemic effects including leukocytosis and immunosuppression. We humanized two murine monoclonal antibodies that neutralize pertussis toxin and expressed them as human immunoglobulin G1 molecules with no loss of affinity or in vitro neutralization activity. When administered prophylactically to mice as a binary cocktail, antibody treatment completely mitigated the Bordetella pertussis-induced rise in white blood cell counts and decreased bacterial colonization. When administered therapeutically to baboons, antibody-treated, but not untreated control animals, experienced a blunted rise in white blood cell counts and accelerated bacterial clearance rates. These preliminary findings support further investigation into the use of these antibodies to treat human neonatal pertussis in conjunction with antibiotics and supportive care. Copyright © 2015, American Association for the Advancement of Science.

[Spontaneous models of human diseases in dogs: ichthyoses as an example].

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André, Catherine; Grall, Anaïs; Guaguere, Éric; Thomas, Anne; Galibert, Francis

2013-06-01

Ichthyoses encompass a heterogeneous group of genodermatoses characterized by abnormal desquamation over the entire body due to defects of the terminal differentiation of keratinocytes and desquamation, which occur in the upper layer of the epidermis. Even though in humans more than 40 genes have already been identified, the genetic causes of several forms remain unknown and are difficult to identify in Humans. Strikingly, several purebred dogs are also affected by specific forms of ichthyoses. In the Golden retriever dog breed, an autosomal recessive form of ichthyosis, resembling human autosomal recessive congenital ichthyoses, has recently been diagnosed with a high incidence. We first characterized the disease occurring in the golden retriever breed and collected cases and controls. A genome-wide association study on 40 unrelated Golden retriever dogs, using the canine 49.000 SNPs (single nucleotide polymorphisms) array (Affymetrix v2), followed by statistical analyses and candidate gene sequencing, allowed to identify the causal mutation in the lipase coding PNPLA1 gene (patatin-like phospholipase domain-containing protein). Screening for alterations in the human ortholog gene in 10 autosomal recessive congenital ichthyoses families, for which no genetic cause has been identified thus far, allowed to identify two recessive mutations in the PNPLA1 protein in two families. This collaborative work between "human" and "canine" geneticists, practicians, histopathologists, biochemists and electron microscopy experts not only allowed to identify, in humans, an eighth gene for autosomal recessive congenital ichthyoses, but also allowed to highlight the function of this as-yet-unknown skin specific lipase in the lipid metabolism of the skin barrier. For veterinary medicine and breeding practices, a genetic test has been developed. These findings illustrate the importance of the discovery of relevant human orthologous canine genetic diseases, whose causes can be tracked

Information to prevent human exposure to disease agents associated with wildlife—U.S. Geological Survey circulars on zoonotic disease

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Meteyer, Carol U.; Moede Rogall, Gail

2018-03-05

The U.S. Geological Survey in collaboration with the U.S. Fish and Wildlife Service and others have published reports with information about geographic distribution, specific pathogens, disease ecology, and strategies to avoid exposure and infection for a selection of zoonotic diseases. Zoonotic diseases are diseases that can be passed from animals to humans, such as rabies and plague. This summary factsheet highlights the reports on plague, bat rabies, and raccoon roundworm with links to all seven zoonotic diseases covered in this series.

Lung Disease Including Asthma and Adult Vaccination

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... can make it hard to breathe. Certain vaccinepreventable diseases can also increase swelling of your airways and lungs. The combination of the two can lead to pneumonia and other serious respiratory illnesses. Vaccines are one of the safest ways ...

Human Chagas Disease and Migration in the Context of Globalization: Some Particular Aspects

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João Carlos Pinto Dias

2013-01-01

Full Text Available Human Chagas disease originated in Latin America, being spread around the world in relation with multiple bioecological, sociocultural, and political factors. The process of the disease production and dispersion is discussed, emphasizing the human migration and correlated aspects, in the context of globalization. Positive and negative consequences concern the future of this trypanosomiasis, mainly in terms of the ecologic and sociopolitical characteristics of the endemic and nonendemic countries.

The disease burden of human cystic echinococcosis based on HDRs from 2001 to 2014 in Italy.

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Toni Piseddu

2017-07-01

Full Text Available Cystic echinococcosis (CE is an important neglected zoonotic parasitic infection belonging to the subgroup of seven Neglected Zoonotic Disease (NZDs included in the World Health Organization's official list of 18 Neglected Tropical Diseases (NTDs. CE causes serious global human health concerns and leads to significant economic losses arising from the costs of medical treatment, morbidity, life impairments and fatality rates in human cases. Moreover, CE is endemic in several Italian Regions. The aim of this study is to perform a detailed analysis of the economic burden of hospitalization and treatment costs and to estimate the Disability Adjusted Life Years (DALYs of CE in Italy.In the period from 2001 to 2014, the direct costs of 21,050 Hospital Discharge Records (HDRs belonging to 12,619 patients with at least one CE-related diagnosis codes were analyzed in order to quantify the economic burden of CE. CE cases average per annum are 901 (min-max = 480-1,583. Direct costs include expenses for hospitalizations, medical and surgical treatment incurred by public and private hospitals and were computed on an individual basis according to Italian Health Ministry legislation. Moreover, we estimated the DALYs for each patient. The Italian financial burden of CE is around € 53 million; the national average economic burden per annum is around € 4 million; the DALYs of the population from 2001 to 2014 are 223.35 annually and 5.26 DALYs per 105 inhabitants.In Italy, human CE is responsible for significant economic losses in the public health sector. In humans, costs associated with CE have been shown to have a great impact on affected individuals, their families and the community as a whole. This study could be used as a tool to prioritize and make decisions with regard to a surveillance system for this largely preventable yet neglected disease. It demonstrates the need of implementing a CE control program aimed at preventing the considerable economic

Vaccination via Chloroplast Genetics: Affordable Protein Drugs for the Prevention and Treatment of Inherited or Infectious Human Diseases.

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Daniell, Henry; Chan, Hui-Ting; Pasoreck, Elise K

2016-11-23

Plastid-made biopharmaceuticals treat major metabolic or genetic disorders, including Alzheimer's, diabetes, hypertension, hemophilia, and retinopathy. Booster vaccines made in chloroplasts prevent global infectious diseases, such as tuberculosis, malaria, cholera, and polio, and biological threats, such as anthrax and plague. Recent advances in this field include commercial-scale production of human therapeutic proteins in FDA-approved cGMP facilities, development of tags to deliver protein drugs to targeted human cells or tissues, methods to deliver precise doses, and long-term stability of protein drugs at ambient temperature, maintaining their efficacy. Codon optimization utilizing valuable information from sequenced chloroplast genomes enhanced expression of eukaryotic human or viral genes in chloroplasts and offered unique insights into translation in chloroplasts. Support from major biopharmaceutical companies, development of hydroponic production systems, and evaluation by regulatory agencies, including the CDC, FDA, and USDA, augur well for advancing this novel concept to the clinic and revolutionizing affordable healthcare.

Outcomes of surgically treated human papillomavirus-related oropharyngeal squamous cell carcinoma with N3 disease.

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Zenga, Joseph; Haughey, Bruce H; Jackson, Ryan S; Adkins, Douglas R; Aranake-Chrisinger, John; Bhatt, Neel; Gay, Hiram A; Kallogjeri, Dorina; Martin, Eliot J; Moore, Eric J; Paniello, Randal C; Rich, Jason T; Thorstad, Wade L; Nussenbaum, Brian

2017-09-01

To evaluate outcomes for patients with pathological N3 (pN3) neck disease from human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) and determine variables predictive of survival. Retrospective case series with chart review. This study was conducted between 1998 and 2013 and included patients with HPV-related OPSCC treated with surgery with or without adjuvant therapy and who had pN3 nodal disease. The primary outcome was disease-specific survival (DSS). Secondary outcomes included overall survival (OS), disease-free survival (DFS), adverse events, and gastrostomy tube rates. Thirty-nine patients were included, of whom 36 (90%) underwent adjuvant therapy. Median follow-up was 39 months (range, 2-147 months). Mean age was 56 years, and 87% were male. Seventeen patients (44%) underwent selective neck dissection, whereas six (15%) underwent radical (n = 2) or extended radical (n = 4) neck dissection. Ninety-two percent had extracapsular extension. Five-year Kaplan-Meier estimated DSS, OS, and DFS were 89% (95% confidence interval [CI]: 79%-99%), 87% (95% CI: 75%-99%), and 84% (95% CI: 72%-96%), respectively. The disease recurrence rate was 10% (5% regional, 5% distant metastasis). Patients with less than 5 pathologically positive lymph nodes (P = .041) had improved DFS. Patients with HPV-related OPSCC and pN3 nodal disease treated with surgery and adjuvant therapy have very favorable long-term survival and regional control. Patients with five or more pathologically positive lymph nodes may be at higher risk for recurrence. 4. Laryngoscope, 127:2033-2037, 2017. © 2016 The American Laryngological, Rhinological and Otological Society, Inc.

Human inflammatory bowel disease does not associate with Lawsonia intracellularis infection

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Giese Thomas

2006-09-01

Full Text Available Abstract Background There is increasing evidence that bacterial infection of the intestinal mucosa may contribute to the pathogenesis of inflammatory bowel diseases (IBD. In pigs, an obligate intracellular bacterium, Lawsonia intracellularis (LI, was shown to cause proliferative enteropathy (PE of which some forms display histological and clinical similarities to human IBD. Since LI-similar Desulfovibrio spp. may infect human cells, we hypothesized that LI might be associated with the development of human IBD. Results In human intestinal tissue samples, PCR using LLG, 50SL27, LSA and strictly LI-specific 16SII primers, yielded either no amplicons or products with weak homology to human genomic sequences. Sequencing of these amplicons revealed no specificity for LI. However, amplification of DNA with less specific 16SI primers resulted in products bearing homology to certain Streptococcus species. These 16SI-amplified products were present in healthy and diseased specimens, without obvious prevalence. Conclusion LI is not associated with the pathogenesis of UC or CD. Whether an immunologic response to commensal bacteria such as streptococci may contribute to the chronic inflammatory condition in IBD, remained to be determined.

Pulmonary disease in patients with human immunodeficiency virus infection

DEFF Research Database (Denmark)

Lundgren, J D; Orholm, Marianne; Lundgren, B

1989-01-01

cause pulmonary disease alone or in combination. Bilateral interstitial infiltrates are the most frequent chest x-ray abnormality and are most frequently caused by infection with Pneumocystis carinii. Cytomegalovirus, Mycobacterium tuberculosis, nonspecific interstitial pneumonitis and pulmonary Kaposi......Pulmonary disease is the most important cause of morbidity and mortality in patients infected with human immunodeficiency virus (HIV). All parts of the hospital system are expected to be involved in the diagnosis and treatment of HIV infected patients in the coming years. Many different processes......'s sarcoma are the most important parts of the differential diagnosis. An aggressive approach to the diagnosis of pulmonary disease in this patient population is indicated in order to provide optimal care and assess new therapies....

Human health and the water environment: using the DPSEEA framework to identify the driving forces of disease.

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Gentry-Shields, Jennifer; Bartram, Jamie

2014-01-15

There is a growing awareness of global forces that threaten human health via the water environment. A better understanding of the dynamic between human health and the water environment would enable prediction of the significant driving forces and effective strategies for coping with or preventing them. This report details the use of the Driving Force-Pressure-State-Exposure-Effect-Action (DPSEEA) framework to explore the linkage between water-related diseases and their significant driving forces. The DPSEEA frameworks indicate that a select group of driving forces, including population growth, agriculture, infrastructure (dams and irrigation), and climate change, is at the root cause of key global disease burdens. Construction of the DPSEEA frameworks also allows for the evaluation of public health interventions. Sanitation was found to be a widely applicable and effective intervention, targeting the driver/pressure linkage of most of the water-related diseases examined. Ultimately, the DPSEEA frameworks offer a platform for constituents in both the health and environmental fields to collaborate and commit to a common goal targeting the same driving forces. © 2013.

Automation Diagnosis of Skin Disease in Humans using Dempster-Shafer Method

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Khairina, Dyna Marisa; Hatta, Heliza Rahmania; Rustam; Maharani, Septya

2018-02-01

Skin disease is an infectious disease that is common in people of all ages. Disorders of the skin often occur because there are factors, among others, are climate, environment, shelter, unhealthy living habits, allergies and others. Skin diseases in Indonesia are mostly caused by bacterial, fungal, parasitic, and allergies. The objective of the research is to diagnose skin diseases in humans by using the method of making decision tree then performing the search by forward chaining and calculating the probability value of Dempster-Shafer method. The results of research in the form of an automated system that can resemble an expert in diagnosing skin disease accurately and can help in overcoming the problem of skin diseases.

A simple method for assessment of human anti-Neu5Gc antibodies applied to Kawasaki disease.

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Vered Padler-Karavani

Full Text Available N-glycolylneuraminic acid (Neu5Gc is an immunogenic sugar of dietary origin that metabolically incorporates into diverse native glycoconjugates in humans. Anti-Neu5Gc antibodies are detected in all human sera, though with variable levels and epitope-recognition profiles. These antibodies likely play a role in several inflammation-mediated pathologies including cardiovascular diseases and cancer. In cancer, they have dualistic and opposing roles, either stimulating or repressing disease, as a function of their dose, and some of these antibodies serve as carcinoma biomarkers. Thus, anti-Neu5Gc antibodies may signify risk of inflammation-mediated diseases, and changes in their levels could potentially be used to monitor disease progression and/or response to therapy. Currently, it is difficult to determine levels of anti-Neu5Gc antibodies in individual human samples because these antibodies recognize multiple Neu5Gc-epitopes. Here we describe a simple and specific method for detection and overall estimation of human anti-Neu5Gc antibodies. We exploit the difference between two mouse models that differ only by Neu5Gc-presence (wild-type or Neu5Gc-absence (Cmah(-/- knockout. We characterize mouse serum from both strains by HPLC, lectin and mass-spectrometry analysis and show the target Neu5Gc-epitopes. We then use Cmah(-/- knockout sera to inhibit all non-Neu5Gc-reactivity followed by binding to wild-type sera to detect overall anti-Neu5Gc response in a single assay. We applied this methodology to characterize and quantify anti-Neu5Gc IgG and IgA in sera of patients with Kawasaki disease (KD at various stages compared to controls. KD is an acute childhood febrile disease characterized by inflammation of coronary arteries that untreated may lead to coronary artery aneurysms with risk of thrombosis and myocardial infarction. This estimated response is comparable to the average of detailed anti-Neu5Gc IgG profile analyzed by a sialoglycan microarray

Economic Burden of Human Papillomavirus-Related Diseases in Italy

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Baio, Gianluca; Capone, Alessandro; Marcellusi, Andrea; Mennini, Francesco Saverio; Favato, Giampiero

2012-01-01

Introduction Human papilloma virus (HPV) genotypes 6, 11, 16, and 18 impose a substantial burden of direct costs on the Italian National Health Service that has never been quantified fully. The main objective of the present study was to address this gap: (1) by estimating the total direct medical costs associated with nine major HPV-related diseases, namely invasive cervical cancer, cervical dysplasia, cancer of the vulva, vagina, anus, penis, and head and neck, anogenital warts, and recurrent respiratory papillomatosis, and (2) by providing an aggregate measure of the total economic burden attributable to HPV 6, 11, 16, and 18 infection. Methods For each of the nine conditions, we used available Italian secondary data to estimate the lifetime cost per case, the number of incident cases of each disease, the total economic burden, and the relative prevalence of HPV types 6, 11, 16, and 18, in order to estimate the aggregate fraction of the total economic burden attributable to HPV infection. Results The total direct costs (expressed in 2011 Euro) associated with the annual incident cases of the nine HPV-related conditions included in the analysis were estimated to be €528.6 million, with a plausible range of €480.1–686.2 million. The fraction attributable to HPV 6, 11, 16, and 18 was €291.0 (range €274.5–315.7 million), accounting for approximately 55% of the total annual burden of HPV-related disease in Italy. Conclusions The results provided a plausible estimate of the significant economic burden imposed by the most prevalent HPV-related diseases on the Italian welfare system. The fraction of the total direct lifetime costs attributable to HPV 6, 11, 16, and 18 infections, and the economic burden of noncervical HPV-related diseases carried by men, were found to be cost drivers relevant to the making of informed decisions about future investments in programmes of HPV prevention. PMID:23185412

The contribution of human/non-human animal chimeras to stem cell research.

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Levine, Sonya; Grabel, Laura

2017-10-01

Chimeric animals are made up of cells from two separate zygotes. Human/non-human animal chimeras have been used for a number of research purposes, including human disease modeling. Pluripotent stem cell (PSC) research has relied upon the chimera approach to examine the developmental potential of stem cells, to determine the efficacy of cell replacement therapies, and to establish a means of producing human organs. Based on ethical issues, this work has faced pushback from various sources including funding agencies. We discuss here the essential role these studies have played, from gaining a better understanding of human biology to providing a stepping stone to human disease treatments. We also consider the major ethical issues, as well as the current status of support for this work in the United States. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Genome and Epigenome Editing in Mechanistic Studies of Human Aging and Aging-Related Disease.

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Lau, Cia-Hin; Suh, Yousin

2017-01-01

The recent advent of genome and epigenome editing technologies has provided a new paradigm in which the landscape of the human genome and epigenome can be precisely manipulated in their native context. Genome and epigenome editing technologies can be applied to many aspects of aging research and offer the potential to develop novel therapeutics against age-related diseases. Here, we discuss the latest technological advances in the CRISPR-based genome and epigenome editing toolbox, and provide insight into how these synthetic biology tools could facilitate aging research by establishing in vitro cell and in vivo animal models to dissect genetic and epigenetic mechanisms underlying aging and age-related diseases. We discuss recent developments in the field with the aims to precisely modulate gene expression and dynamic epigenetic landscapes in a spatial and temporal manner in cellular and animal models, by complementing the CRISPR-based editing capability with conditional genetic manipulation tools including chemically inducible expression systems, optogenetics, logic gate genetic circuits, tissue-specific promoters, and the serotype-specific adeno-associated virus. We also discuss how the combined use of genome and epigenome editing tools permits investigators to uncover novel molecular pathways involved in the pathophysiology and etiology conferred by risk variants associated with aging and aging-related disease. A better understanding of the genetic and epigenetic regulatory mechanisms underlying human aging and age-related disease will significantly contribute to the developments of new therapeutic interventions for extending health span and life span, ultimately improving the quality of life in the elderly populations. © 2016 S. Karger AG, Basel.

Transgenic mice expressing human glucocerebrosidase variants: utility for the study of Gaucher disease.

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Sanders, Angela; Hemmelgarn, Harmony; Melrose, Heather L; Hein, Leanne; Fuller, Maria; Clarke, Lorne A

2013-08-01

Gaucher disease is an autosomal recessively inherited storage disorder caused by deficiency of the lysosomal hydrolase, acid β-glucosidase. The disease manifestations seen in Gaucher patients are highly heterogeneous as is the responsiveness to therapy. The elucidation of the precise factors responsible for this heterogeneity has been challenging as the development of clinically relevant animal models of Gaucher disease has been problematic. Although numerous murine models for Gaucher disease have been described each has limitations in their specific utility. We describe here, transgenic murine models of Gaucher disease that will be particularly useful for the study of pharmacological chaperones. We have produced stable transgenic mouse strains that individually express wild type, N370S and L444P containing human acid β-glucosidase and show that each of these transgenic lines rescues the lethal phenotype characteristic of acid β-glucosidase null mice. Both the N370S and L444P transgenic models show early and progressive elevations of tissue sphingolipids with L444P mice developing progressive splenic Gaucher cell infiltration. We demonstrate the potential utility of these new transgenic models for the study of Gaucher disease pathogenesis. In addition, since these mice produce only human enzyme, they are particularly relevant for the study of pharmacological chaperones that are specifically targeted to human acid β-glucosidase and the common mutations underlying Gaucher disease. Copyright © 2013 Elsevier Inc. All rights reserved.

Contributions of neurotropic human herpesviruses herpes simplex virus 1 and human herpesvirus 6 to neurodegenerative disease pathology

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Jessica M Hogestyn

2018-01-01

Full Text Available Human herpesviruses (HVs have developed ingenious mechanisms that enable them to traverse the defenses of the central nervous system (CNS. The ability of HVs to enter a state of latency, a defining characteristic of this viral family, allows them to persist in the human host indefinitely. As such, HVs represent the most frequently detected pathogens in the brain. Under constant immune pressure, these infections are largely asymptomatic in healthy hosts. However, many neurotropic HVs have been directly connected with CNS pathology in the context of other stressors and genetic risk factors. In this review, we discuss the potential mechanisms by which neurotropic HVs contribute to neurodegenerative disease (NDD pathology by highlighting two prominent members of the HV family, herpes simplex virus 1 (HSV-1 and human herpesvirus 6 (HHV-6. We (i introduce the infectious pathways and replicative cycles of HSV-1 and HHV-6 and then (ii review the clinical evidence supporting associations between these viruses and the NDDs Alzheimer's disease (AD and multiple sclerosis (MS, respectively. We then (iii highlight and discuss potential mechanisms by which these viruses exert negative effects on neurons and glia. Finally, we (iv discuss how these viruses could interact with other disease-modifying factors to contribute to the initiation and/or progression of NDDs.

Transcriptome Profiling in Human Diseases: New Advances and Perspectives

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Amelia Casamassimi

2017-07-01

Full Text Available In the last decades, transcriptome profiling has been one of the most utilized approaches to investigate human diseases at the molecular level. Through expression studies, many molecular biomarkers and therapeutic targets have been found for several human pathologies. This number is continuously increasing thanks to total RNA sequencing. Indeed, this new technology has completely revolutionized transcriptome analysis allowing the quantification of gene expression levels and allele-specific expression in a single experiment, as well as to identify novel genes, splice isoforms, fusion transcripts, and to investigate the world of non-coding RNA at an unprecedented level. RNA sequencing has also been employed in important projects, like ENCODE (Encyclopedia of the regulatory elements and TCGA (The Cancer Genome Atlas, to provide a snapshot of the transcriptome of dozens of cell lines and thousands of primary tumor specimens. Moreover, these studies have also paved the way to the development of data integration approaches in order to facilitate management and analysis of data and to identify novel disease markers and molecular targets to use in the clinics. In this scenario, several ongoing clinical trials utilize transcriptome profiling through RNA sequencing strategies as an important instrument in the diagnosis of numerous human pathologies.

Evaluating Human T-Cell Therapy of Cytomegalovirus Organ Disease in HLA-Transgenic Mice.

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Simone Thomas

2015-07-01

Full Text Available Reactivation of human cytomegalovirus (HCMV can cause severe disease in recipients of hematopoietic stem cell transplantation. Although preclinical research in murine models as well as clinical trials have provided 'proof of concept' for infection control by pre-emptive CD8 T-cell immunotherapy, there exists no predictive model to experimentally evaluate parameters that determine antiviral efficacy of human T cells in terms of virus control in functional organs, prevention of organ disease, and host survival benefit. We here introduce a novel mouse model for testing HCMV epitope-specific human T cells. The HCMV UL83/pp65-derived NLV-peptide was presented by transgenic HLA-A2.1 in the context of a lethal infection of NOD/SCID/IL-2rg-/- mice with a chimeric murine CMV, mCMV-NLV. Scenarios of HCMV-seropositive and -seronegative human T-cell donors were modeled by testing peptide-restimulated and T-cell receptor-transduced human T cells, respectively. Upon transfer, the T cells infiltrated host tissues in an epitope-specific manner, confining the infection to nodular inflammatory foci. This resulted in a significant reduction of viral load, diminished organ pathology, and prolonged survival. The model has thus proven its potential for a preclinical testing of the protective antiviral efficacy of HCMV epitope-specific human T cells in the evaluation of new approaches to an immunotherapy of CMV disease.

Disease induction by human microbial pathogens in plant-model systems: potential, problems and prospects.

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van Baarlen, Peter; van Belkum, Alex; Thomma, Bart P H J

2007-02-01

Relatively simple eukaryotic model organisms such as the genetic model weed plant Arabidopsis thaliana possess an innate immune system that shares important similarities with its mammalian counterpart. In fact, some human pathogens infect Arabidopsis and cause overt disease with human symptomology. In such cases, decisive elements of the plant's immune system are likely to be targeted by the same microbial factors that are necessary for causing disease in humans. These similarities can be exploited to identify elementary microbial pathogenicity factors and their corresponding targets in a green host. This circumvents important cost aspects that often frustrate studies in humans or animal models and, in addition, results in facile ethical clearance.

"Bird biting" mosquitoes and human disease: a review of the role of Culex pipiens complex mosquitoes in epidemiology.

Science.gov (United States)

Farajollahi, Ary; Fonseca, Dina M; Kramer, Laura D; Marm Kilpatrick, A

2011-10-01

The transmission of vector-borne pathogens is greatly influenced by the ecology of their vector, which is in turn shaped by genetic ancestry, the environment, and the hosts that are fed on. One group of vectors, the mosquitoes in the Culex pipiens complex, play key roles in the transmission of a range of pathogens including several viruses such as West Nile and St. Louis encephalitis viruses, avian malaria (Plasmodium spp.), and filarial worms. The Cx. pipiens complex includes Culex pipiens pipiens with two forms, pipiens and molestus, Culex pipiens pallens, Culex quinquefasciatus, Culex australicus, and Culex globocoxitus. While several members of the complex have limited geographic distributions, Cx. pipienspipiens and Cx. quinquefasciatus are found in all known urban and sub-urban temperate and tropical regions, respectively, across the world, where they are often principal disease vectors. In addition, hybrids are common in areas of overlap. Although gaps in our knowledge still remain, the advent of genetic tools has greatly enhanced our understanding of the history of speciation, domestication, dispersal, and hybridization. We review the taxonomy, genetics, evolution, behavior, and ecology of members of the Cx. pipiens complex and their role in the transmission of medically important pathogens. The adaptation of Cx. pipiens complex mosquitoes to human-altered environments led to their global distribution through dispersal via humans and, combined with their mixed feeding patterns on birds and mammals (including humans), increased the transmission of several avian pathogens to humans. We highlight several unanswered questions that will increase our ability to control diseases transmitted by these mosquitoes. Copyright © 2011 Elsevier B.V. All rights reserved.

Inner-ear circulation in humans is disrupted by extracranial venous outflow strictures: Implications for Ménière’s disease

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Eleuterio F. Toro

2018-02-01

Full Text Available Ménière’s disease (MD is a pathology of the inner ear, the symptoms of which include tinnitus, vertigo attacks, fluctuating hearing loss, and nausea. Neither cause nor cure are currently known, though animal experiments suggest that disruption of the inner ear circulation, including venous hypertension and endolymphatic hydrops, to be hallmarks of the disease. Recent evidence for humans suggests a potential link to strictures in the extracranial venous outflow routes. The purpose of the present work is to demonstrate that the inner-ear circulation in humans is disrupted by extracranial venous outflow stricture and to discuss the implications of this finding for MD. The hypothesis linking extracranial venous outflow strictures to the altered dynamics of central nervous system (CNS fluid compartments is investigated theoretically via a global, closed-loop, multiscale mathematical model for the entire human circulation, interacting with the brain parenchyma and cerebrospinal fluid (CSF. The fluid dynamics model for the full human body includes submodels for the heart, pulmonary circulation, arterial system, microvasculature, venous system and the CSF, with a specially refined description of the inner ear vasculature. We demonstrate that extracranial venous outflow strictures disrupt inner ear circulation, and more generally, alter the dynamics of fluid compartments in the whole CNS. Specifically, as compared to a healthy control, the computational results from our model show that subjects with extracranial outflow venous strictures exhibit: altered inner ear circulation, redirection of flow to collaterals, increased intracranial venous pressure and increased intracranial pressure. Our findings are consistent with recent clinical evidence in humans that links extracranial outflow venous strictures to MD, aid the mechanistic understanding of the underlying features of the disease and lend support to recently proposed biophysically motivated

Metabolomics in plants and humans: applications in the prevention and diagnosis of diseases.

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Gomez-Casati, Diego F; Zanor, Maria I; Busi, María V

2013-01-01

In the recent years, there has been an increase in the number of metabolomic approaches used, in parallel with proteomic and functional genomic studies. The wide variety of chemical types of metabolites available has also accelerated the use of different techniques in the investigation of the metabolome. At present, metabolomics is applied to investigate several human diseases, to improve their diagnosis and prevention, and to design better therapeutic strategies. In addition, metabolomic studies are also being carried out in areas such as toxicology and pharmacology, crop breeding, and plant biotechnology. In this review, we emphasize the use and application of metabolomics in human diseases and plant research to improve human health.

High-resolution, label-free two-photon imaging of diseased human corneas

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Batista, Ana; Breunig, Hans Georg; König, Aisada; Schindele, Andreas; Hager, Tobias; Seitz, Berthold; König, Karsten

2018-03-01

The diagnosis of corneal diseases may be improved by monitoring the metabolism of cells and the structural organization of the stroma using two-photon imaging (TPI). We used TPI to assess the differences between nonpathological (NP) human corneas and corneas diagnosed with either keratoconus, Acanthamoeba keratitis, or stromal corneal scars. Images were acquired using a custom-built five-dimensional laser-scanning microscope with a broadband sub-15 femtosecond near-infrared pulsed excitation laser and a 16-channel photomultiplier tube detector in combination with a time-correlated single photon counting module. Morphological alterations of epithelial cells were observed for all pathologies. Moreover, diseased corneas showed alterations to the cells' metabolism that were revealed using the NAD(P)H free to protein-bound ratios. The mean autofluorescence lifetime of the stroma and the organization of the collagen fibers were also significantly altered due to the pathologies. We demonstrate that TPI can be used to distinguish between NP and diseased human corneas, based not only on alterations of the cells' morphology, which can also be evaluated using current clinical devices, but on additional morphological and functional features such as the organization of the stroma and the cells' metabolism. Therefore, TPI could become an efficient tool for diagnosing corneal diseases and better understanding the biological processes of the diseases.

Family Aggregation of Human T-Lymphotropic Virus 1-Associated Diseases: a Systematic Review

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Carolina Alvarez

2016-10-01

Full Text Available Human T-lymphotropic virus 1 (HTLV-1 is a retrovirus that produces a persistent infection. Two transmission routes (from mother to child and via sexual intercourse favor familial clustering of HTLV-1. It is yet unknown why most HTLV-1 carriers remain asymptomatic while about 10% of them develop complications. HTLV-1 associated diseases were originally described as sporadic entities, but familial presentations have been reported. To explore what is known about family aggregation of HTLV-1-associated diseases we undertook a systematic review. We aimed at answering whether, when and where family aggregation of HTLV-1-associated diseases was reported, which relatives were affected and which hypotheses were proposed to explain aggregation. We searched MEDLINE, abstract books of HTLV conferences and reference lists of selected papers. Search terms used referred to HTLV-1 infection, and HTLV-1-associated diseases, and family studies. HTLV-1-associated diseases considered are adult T-cell leukemia/lymphoma (ATLL, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP, HTLV-1-associated uveitis, and infective dermatitis. Seventy-four records reported HTLV-1-associated diseases in more than one member of the same family and were included. Most reports came from HTLV-1-endemic countries, mainly Japan (n=30 and Brazil (n=10. These reports described a total of 270 families in which more than one relative had HTLV-1-associated diseases. In most families, different family members suffered from the same disease (n=221. The diseases most frequently reported were ATLL (114 families and HAM/TSP (101 families. Most families (n=142 included two to four affected individuals. The proportion of ATLL patients with family history of ATLL ranged from 2% to 26%. The proportion of HAM/TSP patients with family history of HAM/TSP ranged from 1% to 48%. The predominant cluster types for ATLL were clusters of siblings and parent-child pairs and for HAM/TSP, an

Human pathogen shown to cause disease in the threatened eklhorn coral Acropora palmata.

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Kathryn Patterson Sutherland

Full Text Available Coral reefs are in severe decline. Infections by the human pathogen Serratia marcescens have contributed to precipitous losses in the common Caribbean elkhorn coral, Acropora palmata, culminating in its listing under the United States Endangered Species Act. During a 2003 outbreak of this coral disease, called acroporid serratiosis (APS, a unique strain of the pathogen, Serratia marcescens strain PDR60, was identified from diseased A. palmata, human wastewater, the non-host coral Siderastrea siderea and the corallivorous snail Coralliophila abbreviata. In order to examine humans as a source and other marine invertebrates as vectors and/or reservoirs of the APS pathogen, challenge experiments were conducted with A. palmata maintained in closed aquaria to determine infectivity of strain PDR60 from reef and wastewater sources. Strain PDR60 from wastewater and diseased A. palmata caused disease signs in elkhorn coral in as little as four and five days, respectively, demonstrating that wastewater is a definitive source of APS and identifying human strain PDR60 as a coral pathogen through fulfillment of Koch's postulates. A. palmata inoculated with strain PDR60 from C. abbreviata showed limited virulence, with one of three inoculated fragments developing APS signs within 13 days. Strain PDR60 from non-host coral S. siderea showed a delayed pathogenic effect, with disease signs developing within an average of 20 days. These results suggest that C. abbreviata and non-host corals may function as reservoirs or vectors of the APS pathogen. Our results provide the first example of a marine "reverse zoonosis" involving the transmission of a human pathogen (S. marcescens to a marine invertebrate (A. palmata. These findings underscore the interaction between public health practices and environmental health indices such as coral reef survival.

Human pathogen shown to cause disease in the threatened eklhorn coral Acropora palmata.

Science.gov (United States)

Sutherland, Kathryn Patterson; Shaban, Sameera; Joyner, Jessica L; Porter, James W; Lipp, Erin K

2011-01-01

Coral reefs are in severe decline. Infections by the human pathogen Serratia marcescens have contributed to precipitous losses in the common Caribbean elkhorn coral, Acropora palmata, culminating in its listing under the United States Endangered Species Act. During a 2003 outbreak of this coral disease, called acroporid serratiosis (APS), a unique strain of the pathogen, Serratia marcescens strain PDR60, was identified from diseased A. palmata, human wastewater, the non-host coral Siderastrea siderea and the corallivorous snail Coralliophila abbreviata. In order to examine humans as a source and other marine invertebrates as vectors and/or reservoirs of the APS pathogen, challenge experiments were conducted with A. palmata maintained in closed aquaria to determine infectivity of strain PDR60 from reef and wastewater sources. Strain PDR60 from wastewater and diseased A. palmata caused disease signs in elkhorn coral in as little as four and five days, respectively, demonstrating that wastewater is a definitive source of APS and identifying human strain PDR60 as a coral pathogen through fulfillment of Koch's postulates. A. palmata inoculated with strain PDR60 from C. abbreviata showed limited virulence, with one of three inoculated fragments developing APS signs within 13 days. Strain PDR60 from non-host coral S. siderea showed a delayed pathogenic effect, with disease signs developing within an average of 20 days. These results suggest that C. abbreviata and non-host corals may function as reservoirs or vectors of the APS pathogen. Our results provide the first example of a marine "reverse zoonosis" involving the transmission of a human pathogen (S. marcescens) to a marine invertebrate (A. palmata). These findings underscore the interaction between public health practices and environmental health indices such as coral reef survival.

Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease): a clinicoradiological profile of three cases including two with skeletal disease

International Nuclear Information System (INIS)

Gupta, Priya; Babyn, Paul

2008-01-01

Originally described as sinus histiocytosis with massive lymphadenopathy, Rosai-Dorfman disease (RDD) is a rare histiocytic proliferative disorder with a distinctive microscopic appearance. A rare entity, RDD is often under-diagnosed because of a low index of suspicion by both radiologist and pathologist. Through this article, we wish to apprise radiologists of the spectrum of disease that can be encountered in this disorder. RDD can mimic other common childhood skeletal diseases including benign Langerhans cell histiocytosis and lymphoma. The clinical and radiological manifestations of RDD vary depending upon organ involvement, and its imaging features are often confused with those of other disorders. RDD should be considered in the differential diagnosis of unifocal and multifocal skeletal involvement caused by granulomatous diseases, infections, pseudogranulomatous lesions and malignancy. As long-term outcome is usually good, a conservative approach is justified in most cases. Contrasted with its typical appearance, presenting with bilateral symmetrical cervical adenopathy (as shown in one patient), we also report extranodal involvement of bone in two patients. Extranodal disease occurs along with concomitant nodal disease in about 43% of patients. In 23% of patients, isolated extranodal RDD can be seen, most commonly in the head and neck. In two of our patients, we observed extranodal involvement with skeletal involvement away from the head and neck not associated with lymphadenopathy. Skeletal involvement in RDD without lymphadenopathy is rare, occurring only in 2% of all the patients reported to date. (orig.)

Sexually Transmitted Diseases (STDs)

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... caused by bacteria, viruses, or parasites. Examples include gonorrhea, genital herpes, human papillomavirus infection, HIV/AIDS, chlamydia, ... genomic sequencing of pathogens responsible for trichomoniasis, chlamydia, gonorrhea, and human genital ulcer disease (chancroid). The sequencing ...

How to become a top model: impact of animal experimentation on human Salmonella disease research.

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Tsolis, Renée M; Xavier, Mariana N; Santos, Renato L; Bäumler, Andreas J

2011-05-01

Salmonella serotypes are a major cause of human morbidity and mortality worldwide. Over the past decades, a series of animal models have been developed to advance vaccine development, provide insights into immunity to infection, and study the pathogenesis of human Salmonella disease. The successive introduction of new animal models, each suited to interrogate previously neglected aspects of Salmonella disease, has ushered in important conceptual advances that continue to have a strong and sustained influence on the ideas driving research on Salmonella serotypes. This article reviews important milestones in the use of animal models to study human Salmonella disease and identify research needs to guide future work.

Lipid metabolism in peroxisomes in relation to human disease

NARCIS (Netherlands)

Wanders, R. J.; Tager, J. M.

1998-01-01

Peroxisomes were long believed to play only a minor role in cellular metabolism but it is now clear that they catalyze a number of important functions. The importance of peroxisomes in humans is stressed by the existence of a group of genetic diseases in man in which one or more peroxisomal

Modeling human diseases with induced pluripotent stem cells: from 2D to 3D and beyond.

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Liu, Chun; Oikonomopoulos, Angelos; Sayed, Nazish; Wu, Joseph C

2018-03-08

The advent of human induced pluripotent stem cells (iPSCs) presents unprecedented opportunities to model human diseases. Differentiated cells derived from iPSCs in two-dimensional (2D) monolayers have proven to be a relatively simple tool for exploring disease pathogenesis and underlying mechanisms. In this Spotlight article, we discuss the progress and limitations of the current 2D iPSC disease-modeling platform, as well as recent advancements in the development of human iPSC models that mimic in vivo tissues and organs at the three-dimensional (3D) level. Recent bioengineering approaches have begun to combine different 3D organoid types into a single '4D multi-organ system'. We summarize the advantages of this approach and speculate on the future role of 4D multi-organ systems in human disease modeling. © 2018. Published by The Company of Biologists Ltd.

The disease related deaths due to differentiated thyroid carcinomas treated multidisciplinary, including radioiodine

International Nuclear Information System (INIS)

Stefanovic, Lj.; Kermeci, K.; Malesevic, M.; Mihailovic, J.; Srbovan, D.; Popadic, S.

2002-01-01

Aim: To analyse the disease related deaths of differentiated thyroid carcinoma (DTC) patients treated multidisciplinary, including radioiodine. Patients and Methods: 364 DTC patients were treated from 1977 to the end of 2000. All patients were operated, treated by radioiodine and by hormonal therapy, external radiotherapy was applied in 22 and chemotherapy in 6 of them. 54 treated patients were lost from the follow-up. The course of disease and outcomes are known in 310 patients, among them 53 patients died. The disease related deaths occurred in 33 (10.6%) patients. Results: Between 33 patients whose deaths were in relation with DTC the disease progression was the cause of deaths in 30 (9.7% of treated) patients (the locoregional disease in 10, distant metastases /M1/ in 17, locoregional disease + M1 in 3 patients). From the late complications of treatment died 3 (1%) patients (all of them were in complete remission to the deaths). The mean survival of these 33 patients from the diagnosis to the end of the life was 6.9 years, median 5.1 years, range 2 months to 23.9 years. The five years survived 54.6% of them, 10 years 21.2% and more than 20 years 3%. M1 had 72.7% of patients (lung and/or bone M1 were present in 91.7% of them), N1 had 69.7% and in 30.3% local tumor was T4. In relation to all treated patients died 14.6% men compared to 9% women (p<0.05), 15.7% of patients 45 years old or older compared to 4.4% of younger then 45 years (p<0.001) and 21.3% of patients with follicular type of DTC compared to 7.3% with papillary type (p<0.001). From all patients without radioiodine accumulation in tumor tissue died 60%. Conclusion: The DTC related deaths were the consequence of M1 and less frequently the result of locoregional disease (T4 and/or N1) in about 1/10 of all treated patients. The deaths as result of the late complications of treatment were exceptional. The deaths were significantly more frequent between males, patients 45 years old or older and patients

Prevalence of Hookworm infection and Strongyloidiasis in Cats and Potential Risk Factor of Human Diseases

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Sedionoto, Blego; Anamnart, Witthaya

2018-02-01

Hookworm infection and Stronyloidiasis are public health problem in the worldwide which both of them could infective in human by penetrated on skin and they have potential risk from Gastrointestinal zoonotic helminths of pets, including cats. We investigated the prevalence soil transmitted helminths infection in human and cats used modified Formal-Ether Concentration and agar plate culture. Fecal samples of 23 cats and human from Naitung and Subua Villages (area study 1), and fecal samples of 15 cats and 17 humans from Thasala Beach villages (area study 2) were collected. Result of study in area study 1 showed prevalence of infection in human was not hookworm and strongyloidiasis but 10% humans have infected Ascaris and Tricuris, and in cats have infected by hookworm 75.2% and S. strercoralis 8.5%, toxocara 13%, spirometra 13% and overall prevalence 82.5%. In area study 2 showed in human has infected by Trichuris 100% and S. stercoralis 29.4% and in cats have infected by hookworm 100% and S. strercoralis 40%, toxocora 20%, and spirometra 20%. Helminth infection found in both humans in two areas study are S. strercoralis. Hookworms were the most common helminth in cats but did not connection with infection in human, while S. strercoralis was helminth infection in cats which has potential zoonotic disease to human.

Role of intestinal microbiota and metabolites on gut homeostasis and human diseases.

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Lin, Lan; Zhang, Jianqiong

2017-01-06

A vast diversity of microbes colonizes in the human gastrointestinal tract, referred to intestinal microbiota. Microbiota and products thereof are indispensable for shaping the development and function of host innate immune system, thereby exerting multifaceted impacts in gut health. This paper reviews the effects on immunity of gut microbe-derived nucleic acids, and gut microbial metabolites, as well as the involvement of commensals in the gut homeostasis. We focus on the recent findings with an intention to illuminate the mechanisms by which the microbiota and products thereof are interacting with host immunity, as well as to scrutinize imbalanced gut microbiota (dysbiosis) which lead to autoimmune disorders including inflammatory bowel disease (IBD), Type 1 diabetes (T1D) and systemic immune syndromes such as rheumatoid arthritis (RA). In addition to their well-recognized benefits in the gut such as occupation of ecological niches and competition with pathogens, commensal bacteria have been shown to strengthen the gut barrier and to exert immunomodulatory actions within the gut and beyond. It has been realized that impaired intestinal microbiota not only contribute to gut diseases but also are inextricably linked to metabolic disorders and even brain dysfunction. A better understanding of the mutual interactions of the microbiota and host immune system, would shed light on our endeavors of disease prevention and broaden the path to our discovery of immune intervention targets for disease treatment.

Extreme weather events and infectious disease outbreaks.

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McMichael, Anthony J

2015-01-01

Human-driven climatic changes will fundamentally influence patterns of human health, including infectious disease clusters and epidemics following extreme weather events. Extreme weather events are projected to increase further with the advance of human-driven climate change. Both recent and historical experiences indicate that infectious disease outbreaks very often follow extreme weather events, as microbes, vectors and reservoir animal hosts exploit the disrupted social and environmental conditions of extreme weather events. This review article examines infectious disease risks associated with extreme weather events; it draws on recent experiences including Hurricane Katrina in 2005 and the 2010 Pakistan mega-floods, and historical examples from previous centuries of epidemics and 'pestilence' associated with extreme weather disasters and climatic changes. A fuller understanding of climatic change, the precursors and triggers of extreme weather events and health consequences is needed in order to anticipate and respond to the infectious disease risks associated with human-driven climate change. Post-event risks to human health can be constrained, nonetheless, by reducing background rates of persistent infection, preparatory action such as coordinated disease surveillance and vaccination coverage, and strengthened disaster response. In the face of changing climate and weather conditions, it is critically important to think in ecological terms about the determinants of health, disease and death in human populations.

Gamma-ray excision repair in normal and diseased human cells

International Nuclear Information System (INIS)

Cerutti, P.A.; Remsen, J.F.

1976-01-01

Radiation products of the 5,6-dihydroxy-dihydrothymine type (t') are efficiently removed from the DNA during postirradiation incubation of bacterial and mammalian cells. In this chapter we describe the t'-excision system contained in normal human cells, in human carcinoma HeLa S-3 cells, and in skin fibroblasts from xeroderma pigmentosum (XP) and Fanconi's anemia (FA) patients. The latter diseases are characterized among other symptoms by a genetically increased susceptibility for the development of cancer

Global Considerations in Human Immunodeficiency Virus-Associated Respiratory Disease.

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Rylance, Jamie; Meghji, Jamilah; Miller, Robert F; Ferrand, Rashida A

2016-04-01

Respiratory tract infection, particularly tuberculosis, is a major cause of mortality among human immunodeficiency virus (HIV)-infected individuals. Antiretroviral therapy (ART) has resulted in a dramatic increase in survival, although coverage of HIV treatment remains low in many parts of the world. There is a concurrent growing burden of chronic noninfectious respiratory disease as a result of increased survival. Many risk factors associated with the development of respiratory disease, such as cigarette smoking and intravenous drug use, are overrepresented among people living with HIV. In addition, there is emerging evidence that HIV infection may directly cause or accelerate the course of chronic lung disease. This review summarizes the clinical spectrum and epidemiology of respiratory tract infections and noninfectious pulmonary pathologies, and factors that explain the global variation in HIV-associated respiratory disease. The potential for enhancing diagnoses of noninfective chronic conditions through the use of clinical algorithms is discussed. We also consider issues in assessment and management of HIV-related respiratory disease in view of the increasing global scale up of ART. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Multiple factors interact to produce responses resembling spectrum of human disease in Campylobacter jejuni infected C57BL/6 IL-10-/- mice

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Wolf John E

2009-03-01

Full Text Available Abstract Background Campylobacter jejuni infection produces a spectrum of clinical presentations in humans – including asymptomatic carriage, watery diarrhea, and bloody diarrhea – and has been epidemiologically associated with subsequent autoimmune neuropathies. This microorganism is genetically variable and possesses genetic mechanisms that may contribute to variability in nature. However, relationships between genetic variation in the pathogen and variation in disease manifestation in the host are not understood. We took a comparative experimental approach to explore differences among different C. jejuni strains and studied the effect of diet on disease manifestation in an interleukin-10 deficient mouse model. Results In the comparative study, C57BL/6 interleukin-10-/- mice were infected with seven genetically distinct C. jejuni strains. Four strains colonized the mice and caused disease; one colonized with no disease; two did not colonize. A DNA:DNA microarray comparison of the strain that colonized mice without disease to C. jejuni 11168 that caused disease revealed that putative virulence determinants, including loci encoding surface structures known to be involved in C. jejuni pathogenesis, differed from or were absent in the strain that did not cause disease. In the experimental study, the five colonizing strains were passaged four times in mice. For three strains, serial passage produced increased incidence and degree of pathology and decreased time to develop pathology; disease shifted from watery to bloody diarrhea. Mice kept on an ~6% fat diet or switched from an ~12% fat diet to an ~6% fat diet just before infection with a non-adapted strain also exhibited increased incidence and severity of disease and decreased time to develop disease, although the effects of diet were only statistically significant in one experiment. Conclusion C. jejuni strain genetic background and adaptation of the strain to the host by serial passage

ADAR RNA editing in human disease; more to it than meets the I.

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Gallo, Angela; Vukic, Dragana; Michalík, David; O'Connell, Mary A; Keegan, Liam P

2017-09-01

We review the structures and functions of ADARs and their involvements in human diseases. ADAR1 is widely expressed, particularly in the myeloid component of the blood system, and plays a prominent role in promiscuous editing of long dsRNA. Missense mutations that change ADAR1 residues and reduce RNA editing activity cause Aicardi-Goutières Syndrome, a childhood encephalitis and interferonopathy that mimics viral infection and resembles an extreme form of Systemic Lupus Erythmatosus (SLE). In Adar1 mouse mutant models aberrant interferon expression is prevented by eliminating interferon activation signaling from cytoplasmic dsRNA sensors, indicating that unedited cytoplasmic dsRNA drives the immune induction. On the other hand, upregulation of ADAR1 with widespread promiscuous RNA editing is a prominent feature of many cancers and particular site-specific RNA editing events are also affected. ADAR2 is most highly expressed in brain and is primarily required for site-specific editing of CNS transcripts; recent findings indicate that ADAR2 editing is regulated by neuronal excitation for synaptic scaling of glutamate receptors. ADAR2 is also linked to the circadian clock and to sleep. Mutations in ADAR2 could contribute to excitability syndromes such as epilepsy, to seizures, to diseases involving neuronal plasticity defects, such as autism and Fragile-X Syndrome, to neurodegenerations such as ALS, or to astrocytomas or glioblastomas in which reduced ADAR2 activity is required for oncogenic cell behavior. The range of human disease associated with ADAR1 mutations may extend further to include other inflammatory conditions while ADAR2 mutations may affect psychiatric conditions.

1st International Symposium on Stress-Associated RNA Granules in Human Disease and Viral Infection

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Bruce W. Banfield

2014-09-01

Full Text Available In recent years, important linkages have been made between RNA granules and human disease processes. On June 8-10 of this year, we hosted a new symposium, dubbed the 1st International Symposium on Stress-Associated RNA Granules in Human Disease and Viral Infection. This symposium brought together experts from diverse research disciplines ranging from cancer and neuroscience to infectious disease. This report summarizes speaker presentations and highlights current challenges in the field.

Barcoding heat shock proteins to human diseases: looking beyond the heat shock response.

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Kakkar, Vaishali; Meister-Broekema, Melanie; Minoia, Melania; Carra, Serena; Kampinga, Harm H

2014-04-01

There are numerous human diseases that are associated with protein misfolding and the formation of toxic protein aggregates. Activating the heat shock response (HSR)--and thus generally restoring the disturbed protein homeostasis associated with such diseases--has often been suggested as a therapeutic strategy. However, most data on activating the HSR or its downstream targets in mouse models of diseases associated with aggregate formation have been rather disappointing. The human chaperonome consists of many more heat shock proteins (HSPs) that are not regulated by the HSR, however, and researchers are now focusing on these as potential therapeutic targets. In this Review, we summarize the existing literature on a set of aggregation diseases and propose that each of them can be characterized or 'barcoded' by a different set of HSPs that can rescue specific types of aggregation. Some of these 'non-canonical' HSPs have demonstrated effectiveness in vivo, in mouse models of protein-aggregation disease. Interestingly, several of these HSPs also cause diseases when mutated--so-called chaperonopathies--which are also discussed in this Review.

DRUMS: a human disease related unique gene mutation search engine.

Science.gov (United States)

Li, Zuofeng; Liu, Xingnan; Wen, Jingran; Xu, Ye; Zhao, Xin; Li, Xuan; Liu, Lei; Zhang, Xiaoyan

2011-10-01

With the completion of the human genome project and the development of new methods for gene variant detection, the integration of mutation data and its phenotypic consequences has become more important than ever. Among all available resources, locus-specific databases (LSDBs) curate one or more specific genes' mutation data along with high-quality phenotypes. Although some genotype-phenotype data from LSDB have been integrated into central databases little effort has been made to integrate all these data by a search engine approach. In this work, we have developed disease related unique gene mutation search engine (DRUMS), a search engine for human disease related unique gene mutation as a convenient tool for biologists or physicians to retrieve gene variant and related phenotype information. Gene variant and phenotype information were stored in a gene-centred relational database. Moreover, the relationships between mutations and diseases were indexed by the uniform resource identifier from LSDB, or another central database. By querying DRUMS, users can access the most popular mutation databases under one interface. DRUMS could be treated as a domain specific search engine. By using web crawling, indexing, and searching technologies, it provides a competitively efficient interface for searching and retrieving mutation data and their relationships to diseases. The present system is freely accessible at http://www.scbit.org/glif/new/drums/index.html. © 2011 Wiley-Liss, Inc.

Structure-based assessment of disease-related mutations in human voltage-gated sodium channels

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Weiyun Huang

2017-02-01

Full Text Available ABSTRACT Voltage-gated sodium (Nav channels are essential for the rapid upstroke of action potentials and the propagation of electrical signals in nerves and muscles. Defects of Nav channels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Nav channels, with Nav1.1 and Nav1.5 each harboring more than 400 mutations. Nav channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Nav channels are required to understand their function and disease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium (Cav channel Cav1.1 provides a template for homology-based structural modeling of the evolutionarily related Nav channels. In this Resource article, we summarized all the reported disease-related mutations in human Nav channels, generated a homologous model of human Nav1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Nav channels, the analysis presented here serves as the base framework for mechanistic investigation of Nav channelopathies and for potential structure-based drug discovery.

Structure-based assessment of disease-related mutations in human voltage-gated sodium channels.

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Huang, Weiyun; Liu, Minhao; Yan, S Frank; Yan, Nieng

2017-06-01

Voltage-gated sodium (Na v ) channels are essential for the rapid upstroke of action potentials and the propagation of electrical signals in nerves and muscles. Defects of Na v channels are associated with a variety of channelopathies. More than 1000 disease-related mutations have been identified in Na v channels, with Na v 1.1 and Na v 1.5 each harboring more than 400 mutations. Na v channels represent major targets for a wide array of neurotoxins and drugs. Atomic structures of Na v channels are required to understand their function and disease mechanisms. The recently determined atomic structure of the rabbit voltage-gated calcium (Ca v ) channel Ca v 1.1 provides a template for homology-based structural modeling of the evolutionarily related Na v channels. In this Resource article, we summarized all the reported disease-related mutations in human Na v channels, generated a homologous model of human Na v 1.7, and structurally mapped disease-associated mutations. Before the determination of structures of human Na v channels, the analysis presented here serves as the base framework for mechanistic investigation of Na v channelopathies and for potential structure-based drug discovery.

Use of rodents as models of human diseases

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Thierry F Vandamme

2014-01-01

Full Text Available Advances in molecular biology have significantly increased the understanding of the biology of different diseases. However, these discoveries have not yet been fully translated into improved treatments for patients with diseases such as cancers. One of the factors limiting the translation of knowledge from preclinical studies to the clinic has been the limitations of in vivo diseases models. In this brief review, we will discuss the advantages and disadvantages of rodent models that have been developed to simulate human pathologies, focusing in models that employ xenografts and genetic modification. Within the framework of genetically engineered mouse (GEM models, we will review some of the current genetic strategies for modeling diseases in the mouse and the preclinical studies that have already been undertaken. We will also discuss how recent improvements in imaging technologies may increase the information derived from using these GEMs during early assessments of potential therapeutic pathways. Furthermore, it is interesting to note that one of the values of using a mouse model is the very rapid turnover rate of the animal, going through the process of birth to death in a very short timeframe relative to that of larger mammalian species.

Emerging zoonotic viral diseases.

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Wang, L-F; Crameri, G

2014-08-01

Zoonotic diseases are infectious diseases that are naturally transmitted from vertebrate animals to humans and vice versa. They are caused by all types of pathogenic agents, including bacteria, parasites, fungi, viruses and prions. Although they have been recognised for many centuries, their impact on public health has increased in the last few decades due to a combination of the success in reducing the spread of human infectious diseases through vaccination and effective therapies and the emergence of novel zoonotic diseases. It is being increasingly recognised that a One Health approach at the human-animal-ecosystem interface is needed for effective investigation, prevention and control of any emerging zoonotic disease. Here, the authors will review the drivers for emergence, highlight some of the high-impact emerging zoonotic diseases of the last two decades and provide examples of novel One Health approaches for disease investigation, prevention and control. Although this review focuses on emerging zoonotic viral diseases, the authors consider that the discussions presented in this paper will be equally applicable to emerging zoonotic diseases of other pathogen types.

Psoriasiform skin disease in transgenic pigs with high-copy ectopic expression of human integrins α2 and β1

DEFF Research Database (Denmark)

Staunstrup, Nicklas Heine; Stenderup, Karin; Mortensen, Sidsel

2017-01-01

Psoriasis is a complex human-specific disease characterized by perturbed keratinocyte proliferation and a pro-inflammatory environment in the skin. Porcine skin architecture and immunity are very similar to that in humans, rendering the pig a suitable animal model for studying the biology...... and β1 in suprabasal epidermal layers. Integrin-transgenic minipigs born into the project displayed skin phenotypes that correlated with the number of inserted transgenes. Molecular analyses were in good concordance with histological observations of psoriatic hallmarks, including hypogranulosis and T...

Operationalising factors that explain the emergence of infectious diseases: a case study of the human campylobacteriosis epidemic.

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Norval J C Strachan

Full Text Available A framework of general factors for infectious disease emergence was made operational for Campylobacter utilising explanatory variables including time series and risk factor data. These variables were generated using a combination of empirical epidemiology, case-case and case-control studies, time series analysis, and microbial sub-typing (source attribution, diversity, genetic distance to unravel the changing/emerging aetiology of human campylobacteriosis. The study focused on Scotland between 1990-2012 where there was a 75% increase in reported cases that included >300% increase in the elderly and 50% decrease in young children. During this period there were three phases 1990-2000 a 75% rise and a 20% fall to 2006, followed by a 19% resurgence. The rise coincided with expansions in the poultry industry, consumption of chicken, and a shift from rural to urban cases. The post-2000 fall occurred across all groups apart from the elderly and coincided with a drop of the prevalence of Campylobacter in chicken and a higher proportion of rural cases. The increase in the elderly was associated with uptake of proton pump inhibitors. During the resurgence the increase was predominantly in adults and the elderly, again there was increasing use of PPIs and high prevalences in chicken and ruminants. Cases associated with foreign travel during the study also increased from 9% to a peak of 16% in 2006 before falling to an estimated 10% in 2011, predominantly in adults and older children. During all three periods source attribution, genetic distance, and diversity measurements placed human isolates most similar to those in chickens. A combination of emergence factors generic for infectious diseases were responsible for the Campylobacter epidemic. It was possible to use these to obtain a putative explanation for the changes in human disease and the potential to make an informed view of how incidence rates may change in the future.

Wildlife Trade and Human Health in Lao PDR: An Assessment of the Zoonotic Disease Risk in Markets.

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Zoe F Greatorex

Full Text Available Although the majority of emerging infectious diseases can be linked to wildlife sources, most pathogen spillover events to people could likely be avoided if transmission was better understood and practices adjusted to mitigate risk. Wildlife trade can facilitate zoonotic disease transmission and represents a threat to human health and economies in Asia, highlighted by the 2003 SARS coronavirus outbreak, where a Chinese wildlife market facilitated pathogen transmission. Additionally, wildlife trade poses a serious threat to biodiversity. Therefore, the combined impacts of Asian wildlife trade, sometimes termed bush meat trade, on public health and biodiversity need assessing. From 2010 to 2013, observational data were collected in Lao PDR from markets selling wildlife, including information on volume, form, species and price of wildlife; market biosafety and visitor origin. The potential for traded wildlife to host zoonotic diseases that pose a serious threat to human health was then evaluated at seven markets identified as having high volumes of trade. At the seven markets, during 21 observational surveys, 1,937 alive or fresh dead mammals (approximately 1,009 kg were observed for sale, including mammals from 12 taxonomic families previously documented to be capable of hosting 36 zoonotic pathogens. In these seven markets, the combination of high wildlife volumes, high risk taxa for zoonoses and poor biosafety increases the potential for pathogen presence and transmission. To examine the potential conservation impact of trade in markets, we assessed the status of 33,752 animals observed during 375 visits to 93 markets, under the Lao PDR Wildlife and Aquatic Law. We observed 6,452 animals listed by Lao PDR as near extinct or threatened with extinction. The combined risks of wildlife trade in Lao PDR to human health and biodiversity highlight the need for a multi-sector approach to effectively protect public health, economic interests and

Wildlife Trade and Human Health in Lao PDR: An Assessment of the Zoonotic Disease Risk in Markets

Science.gov (United States)

Singhalath, Sinpakone; Silithammavong, Soubanh; Khammavong, Kongsy; Fine, Amanda E.; Weisman, Wendy; Douangngeun, Bounlom; Theppangna, Watthana; Keatts, Lucy; Gilbert, Martin; Karesh, William B.; Hansel, Troy; Zimicki, Susan; O’Rourke, Kathleen; Joly, Damien O.; Mazet, Jonna A. K.

2016-01-01

Although the majority of emerging infectious diseases can be linked to wildlife sources, most pathogen spillover events to people could likely be avoided if transmission was better understood and practices adjusted to mitigate risk. Wildlife trade can facilitate zoonotic disease transmission and represents a threat to human health and economies in Asia, highlighted by the 2003 SARS coronavirus outbreak, where a Chinese wildlife market facilitated pathogen transmission. Additionally, wildlife trade poses a serious threat to biodiversity. Therefore, the combined impacts of Asian wildlife trade, sometimes termed bush meat trade, on public health and biodiversity need assessing. From 2010 to 2013, observational data were collected in Lao PDR from markets selling wildlife, including information on volume, form, species and price of wildlife; market biosafety and visitor origin. The potential for traded wildlife to host zoonotic diseases that pose a serious threat to human health was then evaluated at seven markets identified as having high volumes of trade. At the seven markets, during 21 observational surveys, 1,937 alive or fresh dead mammals (approximately 1,009 kg) were observed for sale, including mammals from 12 taxonomic families previously documented to be capable of hosting 36 zoonotic pathogens. In these seven markets, the combination of high wildlife volumes, high risk taxa for zoonoses and poor biosafety increases the potential for pathogen presence and transmission. To examine the potential conservation impact of trade in markets, we assessed the status of 33,752 animals observed during 375 visits to 93 markets, under the Lao PDR Wildlife and Aquatic Law. We observed 6,452 animals listed by Lao PDR as near extinct or threatened with extinction. The combined risks of wildlife trade in Lao PDR to human health and biodiversity highlight the need for a multi-sector approach to effectively protect public health, economic interests and biodiversity. PMID:27008628

Decrease in Hurst exponent of human gait with aging and neurodegenerative diseases

International Nuclear Information System (INIS)

Zhauang Jianjun; Ning Xinbao; Yang Xiaodong; Huo Chengyu; Hou Fengzhen

2008-01-01

In this paper the decrease in the Hurst exponent of human gait with aging and neurodegenerative diseases was observed by using an improved rescaled range (R/S) analysis method. It indicates that the long-range correlations of gait rhythm from young healthy people are stronger than those from the healthy elderly and the diseased. The result further implies that fractal dynamics in human gait will be altered due to weakening or impairment of neural control on locomotion resulting from aging and neurodegenerative diseases. Due to analysing short-term data sequences rather than long datasets required by most nonlinear methods, the algorithm has the characteristics of simplicity and sensitivity, most importantly, fast calculation as well as powerful anti-noise capacities. These findings have implications for modelling locomotor control and also for quantifying gait dynamics in varying physiologic and pathologic states

Dog as a model in studies on human hereditary diseases and their gene therapy.

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Switonski, Marek

2014-03-01

During the last 15 years spectacular progress has been achieved in knowledge on the dog genome organization and the molecular background of hereditary diseases in this species. A majority of canine genetic diseases have their counterparts in humans and thus dogs are considered as a very important large animal model in human biomedicine. Among canine monogenic diseases with known causative gene mutations there are two large groups classified as retinal dystrophies and lysosomal storage diseases. Specific types of these diseases are usually diagnosed in a single or several breeds. A well known disorder, restricted to a single breed, is congenital stationary night blindness described in Briards. This disease is a counterpart of Leber amaurosis in children. On the other hand, one of the most common monogenic human diseases (Duchenne muscular dystrophy), has its canine counterparts in several breeds (e.g., the Golden retriever, Beagle and German short-haired pointer). For some of the canine diseases gene therapy strategy was successfully applied, e.g., for congenital stationary night blindness, rod-cone dystrophy and muccopolysaccharydoses type I, IIIB and VII. Since phenotypic variability between the breeds is exceptionally high, the dog is an interesting model to study the molecular background of congenital malformations (e.g., dwarfism and osteoporosis imperfecta). Also disorders of sexual development (DSD), especially testicular or ovotesticular DSD (78,XX; SRY-negative), which is widely distributed across dozens of breeds, are of particular interest. Studies on the genetic background of canine cancers, a major health problem in this species, are also quite advanced. On the other hand, genetic studies on canine counterparts of major human complex diseases (e.g., obesity, the metabolic syndrome and diabetes mellitus) are still in their infancy. Copyright © 2014 Society for Biology of Reproduction & the Institute of Animal Reproduction and Food Research of Polish

Diseases of poverty and lifestyle, well-being and human development.

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Singh, Ajai R; Singh, Shakuntala A

2008-01-01

The problems of the haves differ substantially from those of the have-nots. Individuals in developing societies have to fight mainly against infectious and communicable diseases, while in the developed world the battles are mainly against lifestyle diseases. Yet, at a very fundamental level, the problems are the same-the fight is against distress, disability, and premature death; against human exploitation and for human development and self-actualisation; against the callousness to critical concerns in regimes and scientific power centres.While there has been great progress in the treatment of individual diseases, human pathology continues to increase. Sicknesses are not decreasing in number, they are only changing in type.The primary diseases of poverty like TB, malaria, and HIV/AIDS-and the often co-morbid and ubiquitous malnutrition-take their toll on helpless populations in developing countries. Poverty is not just income deprivation but capability deprivation and optimism deprivation as well.While life expectancy may have increased in the haves, and infant and maternal mortality reduced, these gains have not necessarily ensured that well-being results. There are ever-multiplying numbers of individuals whose well-being is compromised due to lifestyle diseases. These diseases are the result of faulty lifestyles and the consequent crippling stress. But it serves no one's purpose to understand them as such. So, the prescription pad continues to prevail over lifestyle-change counselling or research.The struggle to achieve well-being and positive health, to ensure longevity, to combat lifestyle stress and professional burnout, and to reduce psychosomatic ailments continues unabated, with hardly an end in sight.WE THUS REALISE THAT MORBIDITY, DISABILITY, AND DEATH ASSAIL ALL THREE SOCIETIES: the ones with infectious diseases, the ones with diseases of poverty, and the ones with lifestyle diseases. If it is bacteria in their various forms that are the culprit in

The commensal microbiota and the development of human disease – an introduction

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Philip D. Marsh

2015-09-01

Full Text Available Humans have co-evolved with microorganisms, and both exist in a symbiotic or mutualistic relationship. We are colonised by a diverse, resident microbiota, which develop into structurally and functionally organised biofilms. The resident microorganisms gain a secure, warm, nutritious habitat from the host and, in return, contribute to the development of many important host functions. The resident microbiota of each habitat is natural and provides important benefits for the host including immunological priming, down-regulation of excessive pro-inflammatory responses, regulation of gastrointestinal and cardiovascular systems, and prevention of colonisation by exogenous microbes. The biological properties of each habitat determine which microorganisms can colonise and grow, and dictate which will be major or minor components of the resident microbiota of a site. This results in different surfaces having distinct but characteristic microbiotas. This relationship between the resident microbiota and the host is dynamic and, on occasions, this symbiotic relationship breaks down due to, for example, changes in lifestyle, immune status or following broad spectrum antibiotic therapy. This ‘dysbiosis’ can result in previously minor components of the microbiota out-competing the normally dominant and beneficial bacteria, thereby increasing the risk of disease. Such perturbations have been associated with a number of clinical disorders such as obesity, allergy, and a variety of inflammatory diseases, including periodontal diseases. A better understanding of the delicate balance between the host and its resident microbiota could lead to novel approaches to the promotion of health and the prevention of dysbiosis.

Human papillomavirus infection and cervical lesions in rheumatic diseases: a systematic review.

Directory of Open Access Journals (Sweden)

Ana Raposo

2016-07-01

Full Text Available An association between immune-mediated diseases and cervical pre-malignant and malignant lesions is described, having the human papillomavirus (HPV infection a causal role. Related studies have been generally focused on systemic lupus erythematosus (SLE patients, but relatively to other diseases, such as rheumatoid arthritis (RA, Sjögren's syndrome (SS and systemic sclerosis (SSc, data has not been systematically evaluated. We conducted a systematic review analysis of the literature in PubMed, including articles published until March of 2015, in patients with RA, SS, SLE and SSc, to evaluate the frequency of HPV infection, cervical dysplasia and cervical cancer, and associated factors, with particular interest on the role of glucocorticoids and immunosuppressive treatment. Moreover, safety and efficacy of HPV vaccines in these patients was investigated. Of 476 articles identified, 27 were finally included. The studies showed an increased prevalence of cervical dysplasia and cancer, with the HPV infection being an important associated factor, in particular in SLE patients. The data relatively to other rheumatic diseases was very scarse, but an increased prevalence of smear abnormalities was also found in RA. Patients exposed to glucocorticoids and to long-term immunosuppression, particularly cyclophosphamide, have increased risk of presenting more pre-malignant lesions than the general population. The available vaccines seem to be generally safe and immunogenic in the short- period evaluation, but long-term follow-up is required to evaluate the impact of the vaccine in the protection against HPV infection and occurrence of high-grade cervical lesions.

Regulatory Role of Small Nucleolar RNAs in Human Diseases

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Grigory A. Stepanov

2015-01-01

Full Text Available Small nucleolar RNAs (snoRNAs are appreciable players in gene expression regulation in human cells. The canonical function of box C/D and box H/ACA snoRNAs is posttranscriptional modification of ribosomal RNAs (rRNAs, namely, 2′-O-methylation and pseudouridylation, respectively. A series of independent studies demonstrated that snoRNAs, as well as other noncoding RNAs, serve as the source of various short regulatory RNAs. Some snoRNAs and their fragments can also participate in the regulation of alternative splicing and posttranscriptional modification of mRNA. Alterations in snoRNA expression in human cells can affect numerous vital cellular processes. SnoRNA level in human cells, blood serum, and plasma presents a promising target for diagnostics and treatment of human pathologies. Here we discuss the relation between snoRNAs and oncological, neurodegenerative, and viral diseases and also describe changes in snoRNA level in response to artificial stress and some drugs.

[Detection of human parvovirus B19, human bocavirus and human parvovirus 4 infections in blood samples among 95 patients with liver disease in Nanjing by nested PCR].

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Tong, Rui; Zhou, Wei-Min; Liu, Xi-Jun; Wang, Yue; Lou, Yong-Liang; Tan, Wen-Jie

2013-04-01

To analyze the infection of human parvovirus B19, human bocavirus (HBoV) and human parvovirus 4 (PARV4) in blood samples among patients with liver disease in Nanjing by molecular detection. Nested PCR assays were designed and validated to detect B19, HBoV and PARV4, respectively. The assays were used to screen three parvoviruses in blood samples from 95 patients with different liver disease in Nanjing. The parvovirus infection was analyzed statistically. The detection limits were 10 copies of genomic DNA equivalents per reaction for each assays and the good specificity were observed. The frequency of B19 and HBoV were 2/95 (2.1%) and 9/95 (9.5%) in blood samples respectively. No PARV4 was detected. HBoV was detected in 3/5 patients with drug-induced hepatitis. Both B19 and HBoV infection were detected in blood from patients with liver disease.

Gray wolf exposure to emerging vector-borne diseases in Wisconsin with comparison to domestic dogs and humans

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Jara, Rocio F.; Wydeven, Adrian P.; Samuel, Michael D.

2016-01-01

World-wide concern over emerging vector-borne diseases has increased in recent years for both animal and human health. In the United Sates, concern about vector-borne diseases in canines has focused on Lyme disease, anaplasmosis, ehrlichiosis, and heartworm which infect domestic and wild canids. Of these diseases, Lyme and anaplasmosis are also frequently diagnosed in humans. Gray wolves (Canis lupus) recolonized Wisconsin in the 1970s, and we evaluated their temporal and geographic patterns of exposure to these four vector-borne diseases in Wisconsin as the population expanded between 1985 and 2011. A high proportion of the Wisconsin wolves were exposed to the agents that cause Lyme (65.6%) and anaplasma (47.7%), and a smaller proportion to ehrlichiosis (5.7%) and infected with heartworm (9.2%). Wolf exposure to tick borne diseases was consistently higher in older animals. Wolf exposure was markedly higher than domestic dog (Canis familiaris) exposure for all 4 disease agents during 2001–2013. We found a cluster of wolf exposure to Borrelia burgdorferi in northwestern Wisconsin, which overlaps human and domestic dog clusters for the same pathogen. In addition, wolf exposure to Lyme disease in Wisconsin has increased, corresponding with the increasing human incidence of Lyme disease in a similar time period. Despite generally high prevalence of exposure none of these diseases appear to have slowed the growth of the Wisconsin wolf population.

Analysis of indel variations in the human disease-associated genes ...

Indian Academy of Sciences (India)

Keywords. insertion–deletion variations; haematological disease; tumours; human genetics. Journal of Genetics ... domly selected healthy Korean individuals using a blood genomic DNA ... Bioinformatics annotation and 3-D protein structure analysis. In this study ..... 2009 A genome-wide meta-analysis identifies. Journal of ...

Tight junctions and human diseases.

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Sawada, Norimasa; Murata, Masaki; Kikuchi, Keisuke; Osanai, Makoto; Tobioka, Hirotoshi; Kojima, Takashi; Chiba, Hideki

2003-09-01

Tight junctions are intercellular junctions adjacent to the apical end of the lateral membrane surface. They have two functions, the barrier (or gate) function and the fence function. The barrier function of tight junctions regulates the passage of ions, water, and various macromolecules, even of cancer cells, through paracellular spaces. The barrier function is thus relevant to edema, jaundice, diarrhea, and blood-borne metastasis. On the other hand, the fence function maintains cell polarity. In other words, tight junctions work as a fence to prevent intermixing of molecules in the apical membrane with those in the lateral membrane. This function is deeply involved in cancer cell biology, in terms of loss of cell polarity. Of the proteins comprising tight junctions, integral membrane proteins occludin, claudins, and JAMs have been recently discovered. Of these molecules, claudins are exclusively responsible for the formation of tight-junction strands and are connected with the actin cytoskeleton mediated by ZO-1. Thus, both functions of tight junctions are dependent on the integrity of the actin cytoskeleton as well as ATP. Mutations in the claudin14 and the claudin16 genes result in hereditary deafness and hereditary hypomagnesemia, respectively. Some pathogenic bacteria and viruses target and affect the tight-junction function, leading to diseases. In this review, the relationship between tight junctions and human diseases is summarized.

Possible pathophysiological roles of transglutaminase-catalyzed reactions in the pathogenesis of human neurodegenerative diseases

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Enrica Serretiello

2015-09-01

Full Text Available Transglutaminases (TG, E.C. 2.3.2.13 are related and ubiquitous enzymes that catalyze the cross linking of a glutaminyl residue of a protein/peptide substrate to a lysyl residue of a protein/peptide co-substrate. These enzymes are also capable of catalyzing other post-translational reactions important for cell life. The distribution and the physiological roles of human TGs have been widely studied in numerous cell types and tissues and recently their roles in several diseases have begun to be identified. It has been hypothesized that transglutaminase activity is directly involved in the pathogenetic mechanisms responsible for several human diseases. In particular, tissue TG (tTG, TG2, a member of the TG enzyme family, has been recently shown to be involved in the molecular mechanisms responsible for a very widespread human pathology, Celiac Disease (CD, one of the most common food intolerances described in the western population. The main food agent that provokes the strong and diffuse clinical symptoms has been known for several years to be gliadin, a protein present in a very large number of human foods derived from vegetables. Recently, some biochemical and immunological aspects of this very common disease have been clarified, and “tissue” transglutaminase, a multifunctional and ubiquitous enzyme, has been identified as one of the major factors. The aim of this review is to summarize the most recent findings concerning the relationships between the biochemical properties of the transglutaminase activity and the basic molecular mechanisms responsible for some human diseases, with particular reference to neuropsychiatric disorders. Possible molecular links between CD and neuropsychiatric disorders, and the use of transglutaminase inhibitors are also discussed.

Selective reactivation of human herpesvirus 6 in patients with autoimmune connective tissue diseases.

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Broccolo, Francesco; Drago, Francesco; Cassina, Giulia; Fava, Andrea; Fusetti, Lisa; Matteoli, Barbara; Ceccherini-Nelli, Luca; Sabbadini, Maria Grazia; Lusso, Paolo; Parodi, Aurora; Malnati, Mauro S

2013-11-01

Viral infections have been associated with autoimmune connective tissue diseases. To evaluate whether active infection by Epstein-Barr virus (EBV), cytomegalovirus (CMV), human herpesvirus (HHV)-6, -7, -8, as well as parvovirus B19 (B19V) occur in patients with autoimmune connective tissue diseases, viral DNA loads were assessed in paired samples of serum and peripheral blood mononuclear cells (PBMCs) of 115 patients affected by different disorders, including systemic sclerosis, systemic, and discoid lupus erythematosus, rheumatoid arthritis, and dermatomyositis. Two additional groups, patients affected by inflammatory diseases (n=51) and healthy subjects (n=58) were studied as controls. The titers of anti-HHV-6 and anti-EBV antibodies were also evaluated. Cell-free HHV-6 serum viremia was detected in a significantly higher proportion of connective tissue diseases patients compared to controls (Preactivation and the active disease state was found only for lupus erythematosus (P=0.021). By contrast, the rate of cell-free EBV viremia was similar in patients and controls groups. Cell-free CMV, HHV-8, and B19V viremia was not detected in any subject. Anti-HHV-6 and anti-EBV early antigen IgG titers were both significantly higher in autoimmune diseases patients as compared to healthy controls, although they were not associated with the presence of viremia. EBV, HHV-6, -7 prevalence and viral load in PBMCs of patients with connective tissue diseases and controls were similar. These data suggest that HHV-6 may act as a pathogenic factor predisposing patients to the development of autoimmune connective tissue diseases or, conversely, that these disorders may predispose patients to HHV-6 reactivation. © 2013 Wiley Periodicals, Inc.

Hepatic cholesterol ester hydrolase in human liver disease.

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Simon, J B; Poon, R W

1978-09-01

Human liver contains an acid cholesterol ester hydrolase (CEH) of presumed lysosomal origin, but its significance is unknown. We developed a modified CEH radioassay suitable for needle biopsy specimens and measured hepatic activity of this enzyme in 69 patients undergoing percutaneous liver biopsy. Histologically normal livers hydrolyzed 5.80 +/- 0.78 SEM mumoles of cholesterol ester per hr per g of liver protein (n, 10). Values were similar in alcoholic liver disease (n, 17), obstructive jaundice (n, 9), and miscellaneous hepatic disorders (n, 21). In contrast, mean hepatic CEH activity was more than 3-fold elevated in 12 patients with acute hepatitis, 21.05 +/- 2.45 SEM mumoles per hr per g of protein (P less than 0.01). In 2 patients studied serially, CEH returned to normal as hepatitis resolved. CEH activity in all patients paralleled SGOT levels (r, 0.84; P less than 0.01). There was no correlation with serum levels of free or esterified cholesterol nor with serum activity of lecithin-cholesterol acyltransferase, the enzyme responsible for cholesterol esterification in plasma. These studies confirm the presence of CEH activity in human liver and show markedly increased activity in acute hepatitis. The pathogenesis and clinical significance of altered hepatic CEH activity in liver disease require further study.

The role of phospholipid oxidation products in inflammatory and autoimmune diseases: evidence from animal models and in humans.

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Leitinger, Norbert

2008-01-01

Since the discovery of oxidized phospholipids (OxPL) and their implication as modulators of inflammation in cardiovascular disease, roles for these lipid oxidation products have been suggested in many other disease settings. Lipid oxidation products accumulate in inflamed and oxidatively damaged tissue, where they are derived from oxidative modification of lipoproteins, but also from membranes of cells undergoing apoptosis. Thus, increased oxidative stress as well as decreased clearance of apoptotic cells has been implied to contribute to accumulation of OxPL in chronically inflamed tissues.A central role for OxPL in disease states associated with dyslipedemia, including atherosclerosis, diabetes and its complications, metabolic syndrome, and renal insufficiency, as well as general prothrombotic states, has been proposed. In addition, in organs which are constantly exposed to oxidative stress, including lung, skin, and eyes, increased levels of OxPL are suggested to contribute to inflammatory conditions. Moreover, accumulation of OxPL causes general immunmodulation and may lead to autoimmune diseases. Evidence is accumulating that OxPL play a role in lupus erythematosus, antiphospholipid syndrome, and rheumatoid arthritis. Last but not least, a role for OxPL in neurological disorders including multiple sclerosis (MS), Alzheimer's and Parkinson's disease has been suggested.This chapter will summarize recent findings obtained in animal models and from studies in humans that indicate that formation of OxPL represents a general mechanism that may play a major role in chronic inflammatory and autoimmune diseases.

The human oral metaproteome reveals potential biomarkers for caries disease

DEFF Research Database (Denmark)

Belda-Ferre, Pedro; Williamson, James; Simón-Soro, Áurea

2015-01-01

metabolism and immune response. We applied multivariate analysis in order to find the minimum set of proteins that better allows discrimination of healthy and caries-affected dental plaque samples, detecting seven bacterial and five human protein functions that allow determining the health status......Tooth decay is considered the most prevalent human disease worldwide. We present the first metaproteomic study of the oral biofilm, using different mass spectrometry approaches that have allowed us to quantify individual peptides in healthy and caries-bearing individuals. A total of 7771 bacterial...... and 853 human proteins were identified in 17 individuals, which provide the first available protein repertoire of human dental plaque. Actinomyces and Coryneybacterium represent a large proportion of the protein activity followed by Rothia and Streptococcus. Those four genera account for 60-90% of total...

Control of human parasitic diseases: Context and overview.

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Molyneux, David H

2006-01-01

The control of parasitic diseases of humans has been undertaken since the aetiology and natural history of the infections was recognized and the deleterious effects on human health and well-being appreciated by policy makers, medical practitioners and public health specialists. However, while some parasitic infections such as malaria have proved difficult to control, as defined by a sustained reduction in incidence, others, particularly helminth infections can be effectively controlled. The different approaches to control from diagnosis, to treatment and cure of the clinically sick patient, to control the transmission within the community by preventative chemotherapy and vector control are outlined. The concepts of eradication, elimination and control are defined and examples of success summarized. Overviews of the health policy and financing environment in which programmes to control or eliminate parasitic diseases are positioned and the development of public-private partnerships as vehicles for product development or access to drugs for parasite disease control are discussed. Failure to sustain control of parasites may be due to development of drug resistance or the failure to implement proven strategies as a result of decreased resources within the health system, decentralization of health management through health-sector reform and the lack of financial and human resources in settings where per capita government expenditure on health may be less than $US 5 per year. However, success has been achieved in several large-scale programmes through sustained national government investment and/or committed donor support. It is also widely accepted that the level of investment in drug development for the parasitic diseases of poor populations is an unattractive option for pharmaceutical companies. The development of partnerships to specifically address this need provides some hope that the intractable problems of the treatment regimens for the trypanosomiases and

Barcoding heat shock proteins to human diseases : looking beyond the heat shock response

NARCIS (Netherlands)

Kakkar, Vaishali; Meister-Broekema, Melanie; Minoia, Melania; Carra, Serena; Kampinga, Harm H.

There are numerous human diseases that are associated with protein misfolding and the formation of toxic protein aggregates. Activating the heat shock response (HSR) - and thus generally restoring the disturbed protein homeostasis associated with such diseases - has often been suggested as a

The draft genome sequence of the ferret (Mustela putorius furo) facilitates study of human respiratory disease.

Science.gov (United States)

Peng, Xinxia; Alföldi, Jessica; Gori, Kevin; Eisfeld, Amie J; Tyler, Scott R; Tisoncik-Go, Jennifer; Brawand, David; Law, G Lynn; Skunca, Nives; Hatta, Masato; Gasper, David J; Kelly, Sara M; Chang, Jean; Thomas, Matthew J; Johnson, Jeremy; Berlin, Aaron M; Lara, Marcia; Russell, Pamela; Swofford, Ross; Turner-Maier, Jason; Young, Sarah; Hourlier, Thibaut; Aken, Bronwen; Searle, Steve; Sun, Xingshen; Yi, Yaling; Suresh, M; Tumpey, Terrence M; Siepel, Adam; Wisely, Samantha M; Dessimoz, Christophe; Kawaoka, Yoshihiro; Birren, Bruce W; Lindblad-Toh, Kerstin; Di Palma, Federica; Engelhardt, John F; Palermo, Robert E; Katze, Michael G

2014-12-01

The domestic ferret (Mustela putorius furo) is an important animal model for multiple human respiratory diseases. It is considered the 'gold standard' for modeling human influenza virus infection and transmission. Here we describe the 2.41 Gb draft genome assembly of the domestic ferret, constituting 2.28 Gb of sequence plus gaps. We annotated 19,910 protein-coding genes on this assembly using RNA-seq data from 21 ferret tissues. We characterized the ferret host response to two influenza virus infections by RNA-seq analysis of 42 ferret samples from influenza time-course data and showed distinct signatures in ferret trachea and lung tissues specific to 1918 or 2009 human pandemic influenza virus infections. Using microarray data from 16 ferret samples reflecting cystic fibrosis disease progression, we showed that transcriptional changes in the CFTR-knockout ferret lung reflect pathways of early disease that cannot be readily studied in human infants with cystic fibrosis disease.

Xeroderma pigmentosum and other diseases of human premature aging and DNA repair: Molecules to patients

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Niedernhofer, Laura J.; Bohr, Vilhelm A.; Sander, Miriam; Kraemer, Kenneth H.

2012-01-01

A workshop1 to share, consider and discuss the latest developments in understanding xeroderma pigmentosum and other human diseases caused by defects in nucleotide excision repair (NER) of DNA damage was held on September 21–24, 2010 in Virginia. It was attended by approximately 100 researchers and clinicians, as well as several patients and representatives of patient support groups. This was the third in a series of workshops with similar design and goals: to emphasize discussion and interaction among participants as well as open exchange of information and ideas. The participation of patients, their parents and physicians was an important feature of this and the preceding two workshops. Topics discussed included the natural history and clinical features of the diseases, clinical and laboratory diagnosis of these rare diseases, therapeutic strategies, mouse models of neurodegeneration, molecular analysis of accelerated aging, impact of transcriptional defects and mitochondrial dysfunction on neurodegeneration, and biochemical insights into mechanisms of NER and base excision repair. PMID:21708183

Role of Carbamylated Biomolecules in Human Diseases.

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Badar, Asim; Arif, Zarina; Alam, Khursheed

2018-04-01

Carbamylation (or carbamoylation) is a non-enzymatic modification of biomolecules mediated by cyanate, a dissociation product of urea. Proteins are more sensitive to carbamylation. Two major sites of carbamylation reaction are: N α -amino moiety of a protein N-terminus and the N ɛ -amino moiety of proteins' lysine residues. In kidney diseases, urea accumulates and the burden of carbamylation increases. This may lead to alteration in the structure and function of many important proteins relevant in maintenance of homeostasis. Carbamylated proteins namely, carbamylated-haemoglobin and carbamylated-low density lipoprotein (LDL) have been implicated in hypoxia and atherosclerosis, respectively. Furthermore, carbamylation of insulin, oxytocin, and erythropoietin have caused changes in the action of these hormones vis-à-vis the metabolic pathways they control. In this short review, authors have compiled the data on role of carbamylated proteins, enzymes, hormones, LDL, and so on, in human diseases. © 2018 IUBMB Life, 70(4):267-275, 2018. © 2018 International Union of Biochemistry and Molecular Biology.

Genetic variation in lipid desaturases and its impact on the development of human disease.

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