Cholesterol catalyses Aβ42 aggregation through a heterogeneous nucleation pathway in the presence of lipid membranes

NASA Astrophysics Data System (ADS)

Habchi, Johnny; Chia, Sean; Galvagnion, Céline; Michaels, Thomas C. T.; Bellaiche, Mathias M. J.; Ruggeri, Francesco Simone; Sanguanini, Michele; Idini, Ilaria; Kumita, Janet R.; Sparr, Emma; Linse, Sara; Dobson, Christopher M.; Knowles, Tuomas P. J.; Vendruscolo, Michele

2018-06-01

Alzheimer's disease is a neurodegenerative disorder associated with the aberrant aggregation of the amyloid-β peptide. Although increasing evidence implicates cholesterol in the pathogenesis of Alzheimer's disease, the detailed mechanistic link between this lipid molecule and the disease process remains to be fully established. To address this problem, we adopt a kinetics-based strategy that reveals a specific catalytic role of cholesterol in the aggregation of Aβ42 (the 42-residue form of the amyloid-β peptide). More specifically, we demonstrate that lipid membranes containing cholesterol promote Aβ42 aggregation by enhancing its primary nucleation rate by up to 20-fold through a heterogeneous nucleation pathway. We further show that this process occurs as a result of cooperativity in the interaction of multiple cholesterol molecules with Aβ42. These results identify a specific microscopic pathway by which cholesterol dramatically enhances the onset of Aβ42 aggregation, thereby helping rationalize the link between Alzheimer's disease and the impairment of cholesterol homeostasis.

Processing of Mass/Count Information in Alzheimer's Disease and Mild Cognitive Impairment

ERIC Educational Resources Information Center

Taler, Vanessa; Jarema, Gonia

2004-01-01

This study examines the processing of a specific linguistic distinction, the mass/count distinction, in patients suffering from Alzheimer's disease (AD) and mild cognitive impairment (MCI). Fourteen AD and 10 MCI subjects were tested using a sentence grammaticality judgement task where grammaticality violations were caused by determiner--noun…

Molecular property diagnostic suite (MPDS): Development of disease-specific open source web portals for drug discovery.

PubMed

Nagamani, S; Gaur, A S; Tanneeru, K; Muneeswaran, G; Madugula, S S; Consortium, Mpds; Druzhilovskiy, D; Poroikov, V V; Sastry, G N

2017-11-01

Molecular property diagnostic suite (MPDS) is a Galaxy-based open source drug discovery and development platform. MPDS web portals are designed for several diseases, such as tuberculosis, diabetes mellitus, and other metabolic disorders, specifically aimed to evaluate and estimate the drug-likeness of a given molecule. MPDS consists of three modules, namely data libraries, data processing, and data analysis tools which are configured and interconnected to assist drug discovery for specific diseases. The data library module encompasses vast information on chemical space, wherein the MPDS compound library comprises 110.31 million unique molecules generated from public domain databases. Every molecule is assigned with a unique ID and card, which provides complete information for the molecule. Some of the modules in the MPDS are specific to the diseases, while others are non-specific. Importantly, a suitably altered protocol can be effectively generated for another disease-specific MPDS web portal by modifying some of the modules. Thus, the MPDS suite of web portals shows great promise to emerge as disease-specific portals of great value, integrating chemoinformatics, bioinformatics, molecular modelling, and structure- and analogue-based drug discovery approaches.

Mutant mice: experimental organisms as materialised models in biomedicine.

PubMed

Huber, Lara; Keuck, Lara K

2013-09-01

Animal models have received particular attention as key examples of material models. In this paper, we argue that the specificities of establishing animal models-acknowledging their status as living beings and as epistemological tools-necessitate a more complex account of animal models as materialised models. This becomes particularly evident in animal-based models of diseases that only occur in humans: in these cases, the representational relation between animal model and human patient needs to be generated and validated. The first part of this paper presents an account of how disease-specific animal models are established by drawing on the example of transgenic mice models for Alzheimer's disease. We will introduce an account of validation that involves a three-fold process including (1) from human being to experimental organism; (2) from experimental organism to animal model; and (3) from animal model to human patient. This process draws upon clinical relevance as much as scientific practices and results in disease-specific, yet incomplete, animal models. The second part of this paper argues that the incompleteness of models can be described in terms of multi-level abstractions. We qualify this notion by pointing to different experimental techniques and targets of modelling, which give rise to a plurality of models for a specific disease. Copyright © 2013 Elsevier Ltd. All rights reserved.

Specificity and disease in the ubiquitin system

PubMed Central

Chaugule, Viduth K.; Walden, Helen

2016-01-01

Post-translational modification (PTM) of proteins by ubiquitination is an essential cellular regulatory process. Such regulation drives the cell cycle and cell division, signalling and secretory pathways, DNA replication and repair processes and protein quality control and degradation pathways. A huge range of ubiquitin signals can be generated depending on the specificity and catalytic activity of the enzymes required for attachment of ubiquitin to a given target. As a consequence of its importance to eukaryotic life, dysfunction in the ubiquitin system leads to many disease states, including cancers and neurodegeneration. This review takes a retrospective look at our progress in understanding the molecular mechanisms that govern the specificity of ubiquitin conjugation. PMID:26862208

Novel insights into an old disease: recent developments in scabies mite biology.

PubMed

Holt, Deborah C; Fischer, Katja

2013-04-01

Scabies is a serious disease of both humans and other animals caused by infestation of the skin with the ectoparasitic mite Sarcoptes scabiei. Our current understanding of scabies mite biology and disease processes is far outweighed by the significant, worldwide impact of the disease. This review summarizes the recent data which furthers our knowledge of mite biology, host specificity and parasite host evasion mechanisms. Recent data concords with the previous work demonstrating limited gene flow between different host-associated populations of scabies mites. This evidence of the host specificity of scabies mites has important implications for disease control programmes. Other studies have begun to decipher the molecular basis of the complex host-parasite interactions underlying scabies infestations. Scabies mites have developed complex mechanisms to interfere with the host defence processes that may also enhance the survival of the associated skin microbiome, consistent with the epidemiological evidence. Recently developed natural host models of scabies are valuable tools to further study the disease processes and to trial novel therapeutic agents. Although significant progress has been made, further research is needed to understand the biology, host-parasite interactions and pathogenesis of this ubiquitous parasite.

Muscle-Specific Mis-Splicing and Heart Disease Exemplified by RBM20.

PubMed

Rexiati, Maimaiti; Sun, Mingming; Guo, Wei

2018-01-05

Alternative splicing is an essential post-transcriptional process to generate multiple functional RNAs or proteins from a single transcript. Progress in RNA biology has led to a better understanding of muscle-specific RNA splicing in heart disease. The recent discovery of the muscle-specific splicing factor RNA-binding motif 20 (RBM20) not only provided great insights into the general alternative splicing mechanism but also demonstrated molecular mechanism of how this splicing factor is associated with dilated cardiomyopathy. Here, we review our current knowledge of muscle-specific splicing factors and heart disease, with an emphasis on RBM20 and its targets, RBM20-dependent alternative splicing mechanism, RBM20 disease origin in induced Pluripotent Stem Cells (iPSCs), and RBM20 mutations in dilated cardiomyopathy. In the end, we will discuss the multifunctional role of RBM20 and manipulation of RBM20 as a potential therapeutic target for heart disease.

Genetics Home Reference: Erdheim-Chester disease

MedlinePlus

... are slightly more likely to develop the disease, accounting for about 60 percent of cases. Related Information ... the growth and division (proliferation) of cells, the process by which cells mature to carry out specific ...

Goal-setting in clinical medicine.

PubMed

Bradley, E H; Bogardus, S T; Tinetti, M E; Inouye, S K

1999-07-01

The process of setting goals for medical care in the context of chronic disease has received little attention in the medical literature, despite the importance of goal-setting in the achievement of desired outcomes. Using qualitative research methods, this paper develops a theory of goal-setting in the care of patients with dementia. The theory posits several propositions. First, goals are generated from embedded values but are distinct from values. Goals vary based on specific circumstances and alternatives whereas values are person-specific and relatively stable in the face of changing circumstances. Second, goals are hierarchical in nature, with complex mappings between general and specific goals. Third, there are a number of factors that modify the goal-setting process, by affecting the generation of goals from values or the translation of general goals to specific goals. Modifying factors related to individuals include their degree of risk-taking, perceived self-efficacy, and acceptance of the disease. Disease factors that modify the goal-setting process include the urgency and irreversibility of the medical condition. Pertinent characteristics of the patient-family-clinician interaction include the level of participation, control, and trust among patients, family members, and clinicians. The research suggests that the goal-setting process in clinical medicine is complex, and the potential for disagreements regarding goals substantial. The nature of the goal-setting process suggests that explicit discussion of goals for care may be necessary to promote effective patient-family-clinician communication and adequate care planning.

Specific deficit of colour-colour short-term memory binding in sporadic and familial Alzheimer's disease.

PubMed

Parra, Mario A; Sala, Sergio Della; Abrahams, Sharon; Logie, Robert H; Méndez, Luis Guillermo; Lopera, Francisco

2011-06-01

Short-term memory binding of visual features which are processed across different dimensions (shape-colour) is impaired in sporadic Alzheimer's disease, familial Alzheimer's disease, and in asymptomatic carriers of familial Alzheimer's disease. This study investigated whether Alzheimer's disease also impacts on within-dimension binding processes. The study specifically explored whether visual short-term memory binding of features of the same type (colour-colour) is sensitive to Alzheimer's disease. We used a neuropsychological battery and a short-term memory binding task to assess patients with sporadic Alzheimer's disease (Experiment 1), familial Alzheimer's disease (Experiment 2) due to the mutation E280A of the Presenilin-1 gene and asymptomatic carriers of the mutation. The binding task assessed change detection within arrays of unicoloured objects (Colour Only) or bicoloured objects the colours of which had to be remembered separately (Unbound Colours) or together (Bound Colours). Performance on the Bound Colours condition (1) explained the largest proportion of variance between patients (sporadic and familial Alzheimer's disease), (2) combined more sensitivity and specificity for the disease than other more traditional neuropsychological tasks, (3) identified asymptomatic carriers of the mutation even when traditional neuropsychological measures and other measures of short-term memory did not and, (4) contrary to shape-colour binding, correlated with measures of hippocampal functions. Colour-colour binding and shape-colour binding both appear to be sensitive to AD even though they seem to rely on different brain mechanisms. Copyright © 2011 Elsevier Ltd. All rights reserved.

Predictive Models for Tomato Spotted Wilt Virus Spread Dynamics, Considering Frankliniella occidentalis Specific Life Processes as Influenced by the Virus

PubMed Central

Ogada, Pamella Akoth; Moualeu, Dany Pascal; Poehling, Hans-Michael

2016-01-01

Several models have been studied on predictive epidemics of arthropod vectored plant viruses in an attempt to bring understanding to the complex but specific relationship between the three cornered pathosystem (virus, vector and host plant), as well as their interactions with the environment. A large body of studies mainly focuses on weather based models as management tool for monitoring pests and diseases, with very few incorporating the contribution of vector’s life processes in the disease dynamics, which is an essential aspect when mitigating virus incidences in a crop stand. In this study, we hypothesized that the multiplication and spread of tomato spotted wilt virus (TSWV) in a crop stand is strongly related to its influences on Frankliniella occidentalis preferential behavior and life expectancy. Model dynamics of important aspects in disease development within TSWV-F. occidentalis-host plant interactions were developed, focusing on F. occidentalis’ life processes as influenced by TSWV. The results show that the influence of TSWV on F. occidentalis preferential behaviour leads to an estimated increase in relative acquisition rate of the virus, and up to 33% increase in transmission rate to healthy plants. Also, increased life expectancy; which relates to improved fitness, is dependent on the virus induced preferential behaviour, consequently promoting multiplication and spread of the virus in a crop stand. The development of vector–based models could further help in elucidating the role of tri-trophic interactions in agricultural disease systems. Use of the model to examine the components of the disease process could also boost our understanding on how specific epidemiological characteristics interact to cause diseases in crops. With this level of understanding we can efficiently develop more precise control strategies for the virus and the vector. PMID:27159134

Predictive Models for Tomato Spotted Wilt Virus Spread Dynamics, Considering Frankliniella occidentalis Specific Life Processes as Influenced by the Virus.

PubMed

Ogada, Pamella Akoth; Moualeu, Dany Pascal; Poehling, Hans-Michael

2016-01-01

Several models have been studied on predictive epidemics of arthropod vectored plant viruses in an attempt to bring understanding to the complex but specific relationship between the three cornered pathosystem (virus, vector and host plant), as well as their interactions with the environment. A large body of studies mainly focuses on weather based models as management tool for monitoring pests and diseases, with very few incorporating the contribution of vector's life processes in the disease dynamics, which is an essential aspect when mitigating virus incidences in a crop stand. In this study, we hypothesized that the multiplication and spread of tomato spotted wilt virus (TSWV) in a crop stand is strongly related to its influences on Frankliniella occidentalis preferential behavior and life expectancy. Model dynamics of important aspects in disease development within TSWV-F. occidentalis-host plant interactions were developed, focusing on F. occidentalis' life processes as influenced by TSWV. The results show that the influence of TSWV on F. occidentalis preferential behaviour leads to an estimated increase in relative acquisition rate of the virus, and up to 33% increase in transmission rate to healthy plants. Also, increased life expectancy; which relates to improved fitness, is dependent on the virus induced preferential behaviour, consequently promoting multiplication and spread of the virus in a crop stand. The development of vector-based models could further help in elucidating the role of tri-trophic interactions in agricultural disease systems. Use of the model to examine the components of the disease process could also boost our understanding on how specific epidemiological characteristics interact to cause diseases in crops. With this level of understanding we can efficiently develop more precise control strategies for the virus and the vector.

The roles of protein expression in synaptic plasticity and memory consolidation

PubMed Central

Rosenberg, Tali; Gal-Ben-Ari, Shunit; Dieterich, Daniela C.; Kreutz, Michael R.; Ziv, Noam E.; Gundelfinger, Eckart D.; Rosenblum, Kobi

2014-01-01

The amount and availability of proteins are regulated by their synthesis, degradation, and transport. These processes can specifically, locally, and temporally regulate a protein or a population of proteins, thus affecting numerous biological processes in health and disease states. Accordingly, malfunction in the processes of protein turnover and localization underlies different neuronal diseases. However, as early as a century ago, it was recognized that there is a specific need for normal macromolecular synthesis in a specific fragment of the learning process, memory consolidation, which takes place minutes to hours following acquisition. Memory consolidation is the process by which fragile short-term memory is converted into stable long-term memory. It is accepted today that synaptic plasticity is a cellular mechanism of learning and memory processes. Interestingly, similar molecular mechanisms subserve both memory and synaptic plasticity consolidation. In this review, we survey the current view on the connection between memory consolidation processes and proteostasis, i.e., maintaining the protein contents at the neuron and the synapse. In addition, we describe the technical obstacles and possible new methods to determine neuronal proteostasis of synaptic function and better explain the process of memory and synaptic plasticity consolidation. PMID:25429258

MR imaging of spinal infection.

PubMed

Tins, Bernhard J; Cassar-Pullicino, Victor N

2004-09-01

Magnetic resonance (MR) imaging plays a pivotal role in the diagnosis and management of spinal infection, enjoying a high sensitivity and specificity. A thorough understanding of spinal anatomy and the physicochemical pathological processes associated with infection is a desirable prerequisite allowing accurate interpretation of the disease process. Apart from confirmation of the disease, MR imaging is also best suited to excluding multifocal spinal involvement and the detection/exclusion of complications. It plays an essential role in the decision-making process concerning conservative versus surgical treatment and is also the best imaging method to monitor the effect of treatment. The MR features of infection confidently exclude tumor, degeneration, and so forth as the underlying process; differentiate pyogenic from granulomatous infections in most cases; and can suggest the rarer specific infective organisms. Copyright 2004 Thieme Medical Publishers, Inc.

Capturing structured, pulmonary disease-specific data elements in electronic health records.

PubMed

Gronkiewicz, Cynthia; Diamond, Edward J; French, Kim D; Christodouleas, John; Gabriel, Peter E

2015-04-01

Electronic health records (EHRs) have the potential to improve health-care quality by allowing providers to make better decisions at the point of care based on electronically aggregated data and by facilitating clinical research. These goals are easier to achieve when key, disease-specific clinical information is documented as structured data elements (SDEs) that computers can understand and process, rather than as free-text/natural-language narrative. This article reviews the benefits of capturing disease-specific SDEs. It highlights several design and implementation considerations, including the impact on efficiency and expressivity of clinical documentation and the importance of adhering to data standards when available. Pulmonary disease-specific examples of collection instruments are provided from two commonly used commercial EHRs. Future developments that can leverage SDEs to improve clinical quality and research are discussed.

Pathway mapping and development of disease-specific biomarkers: protein-based network biomarkers

PubMed Central

Chen, Hao; Zhu, Zhitu; Zhu, Yichun; Wang, Jian; Mei, Yunqing; Cheng, Yunfeng

2015-01-01

It is known that a disease is rarely a consequence of an abnormality of a single gene, but reflects the interactions of various processes in a complex network. Annotated molecular networks offer new opportunities to understand diseases within a systems biology framework and provide an excellent substrate for network-based identification of biomarkers. The network biomarkers and dynamic network biomarkers (DNBs) represent new types of biomarkers with protein–protein or gene–gene interactions that can be monitored and evaluated at different stages and time-points during development of disease. Clinical bioinformatics as a new way to combine clinical measurements and signs with human tissue-generated bioinformatics is crucial to translate biomarkers into clinical application, validate the disease specificity, and understand the role of biomarkers in clinical settings. In this article, the recent advances and developments on network biomarkers and DNBs are comprehensively reviewed. How network biomarkers help a better understanding of molecular mechanism of diseases, the advantages and constraints of network biomarkers for clinical application, clinical bioinformatics as a bridge to the development of diseases-specific, stage-specific, severity-specific and therapy predictive biomarkers, and the potentials of network biomarkers are also discussed. PMID:25560835

Diagnosis of Periodontal Diseases: Building a Bridge from Today's Methods to Tomorrow's Technology.

ERIC Educational Resources Information Center

Jeffcoat, Marjorie K.

1994-01-01

A discussion of advancements in diagnosis of periodontal diseases looks first at the screening process, reviews specific periodontal diseases and their clinical signs and symptoms, and explains both traditional and newly developed diagnostic tests. A framework for understanding the tests' clinical usefulness is also presented. (MSE)

Tests of Dorsolateral Frontal Function Correlate with Objective Tests of Postural Stability in Early to Moderate Stage Parkinson’s Disease

PubMed Central

Nocera, Joe R.; Price, Catherine; Fernandez, Hubert H.; Amano, Shinichi; Vallabhajosula, Srikant; Okun, Michael S.; Hwynn, Nelson; Hass, Chris J.

2010-01-01

A substantial number of individuals with Parkinson’s disease who display impaired postural stability experience accelerated cognitive decline and an increased prevalence of dementia. To date, studies suggest that this relationship, believed to be due to involvement of nondopaminergic circuitry, occurs later in the disease process. Research has yet to adequately investigate this cognitive-posturomotor relationship especially when examining earlier disease states. To gain greater understanding of the relationship between postural stability and cognitive function/dysfunction we evaluated a more stringent, objective measure of postural stability (center of pressure displacement), and also more specific measures of cognition in twenty-two patients with early to moderate stage Parkinson’s disease. The magnitude of the center of pressure displacement in this cohort was negatively correlated with performance on tests known to activate dorsolateral frontal regions. Additionally, the postural stability item of the UPDRS exhibited poor correlation with the more objective measure of center of pressure displacement and all specific measures of cognition. These results may serve as rationale for a more thorough evaluation of postural stability and cognition especially in individuals with mild Parkinson’s disease. Greater understanding of the relationship between motor and cognitive processes in Parkinson’s disease will be critical for understanding the disease process and its potential therapeutic possibilities. PMID:20829093

Quality improvement tools for chronic disease care--more effective processes are less likely to be implemented in developing countries.

PubMed

Hashim, Muhammad Jawad; Prinsloo, Adrianna; Mirza, Deen M

2013-01-01

Chronic disease services may be improved if care management processes (CMPs), such as disease-specific flowsheets and chronic disease registries, are used. The newly industrialized Gulf state health service has underdeveloped primary care but higher diabetes prevalence. This paper's aim is to investigate care management processes in United Arab Emirates (UAE) primary care clinics to explore these issues. A cross-sectional survey using self-administered questionnaires given to family physicians and nurses attending a UAE University workshop was used to collect data. All 38 participants completed the questionnaire: 68 per cent were women and 81 per cent physicians. Care management processes in use included: medical records, 76 per cent; clinical guidelines, 74 per cent; chronic disease care rooms, 74 per cent; disease-specific flowsheets, 61 per cent; medical record audits, 57 per cent; chronic disease nurse-educators, 58 per cent; electronic medical records (EMR), 34 per cent; and incentive plans based on clinical performance, 21 per cent. Only 62 per cent and 48 per cent reported that flowsheets and problem lists, respectively, were completed by physicians. Responses to the open-ended question included using traditional quality improvement (QI) approaches such as continuing education and staff meetings, but not proactive systems such as disease registries and self-management. The study used a small, non-random sample and the survey instrument's psychometric properties were not collected. Chronic disease care CMPs are present in UAE clinics but use is limited. Quality improvement should include disease registries, reminder-tracking systems, patient self-management support and quality incentives. This report highlights the lag regarding adopting more effective CMPs in developing countries.

Patient-Specific Pluripotent Stem Cells in Neurological Diseases

PubMed Central

Durnaoglu, Serpen; Genc, Sermin; Genc, Kursad

2011-01-01

Many human neurological diseases are not currently curable and result in devastating neurologic sequelae. The increasing availability of induced pluripotent stem cells (iPSCs) derived from adult human somatic cells provides new prospects for cellreplacement strategies and disease-related basic research in a broad spectrum of human neurologic diseases. Patient-specific iPSC-based modeling of neurogenetic and neurodegenerative diseases is an emerging efficient tool for in vitro modeling to understand disease and to screen for genes and drugs that modify the disease process. With the exponential increase in iPSC research in recent years, human iPSCs have been successfully derived with different technologies and from various cell types. Although there remain a great deal to learn about patient-specific iPSC safety, the reprogramming mechanisms, better ways to direct a specific reprogramming, ideal cell source for cellular grafts, and the mechanisms by which transplanted stem cells lead to an enhanced functional recovery and structural reorganization, the discovery of the therapeutic potential of iPSCs offers new opportunities for the treatment of incurable neurologic diseases. However, iPSC-based therapeutic strategies need to be thoroughly evaluated in preclinical animal models of neurological diseases before they can be applied in a clinical setting. PMID:21776279

Sensible use of antisense: how to use oligonucleotides as research tools.

PubMed

Myers, K J; Dean, N M

2000-01-01

In the past decade, there has been a vast increase in the amount of gene sequence information that has the potential to revolutionize the way diseases are both categorized and treated. Old diagnoses, largely anatomical or descriptive in nature, are likely to be superceded by the molecular characterization of the disease. The recognition that certain genes drive key disease processes will also enable the rational design of gene-specific therapeutics. Antisense oligonucleotides represent a technology that should play multiple roles in this process.

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis.

PubMed

Taroni, Jaclyn N; Greene, Casey S; Martyanov, Viktor; Wood, Tammara A; Christmann, Romy B; Farber, Harrison W; Lafyatis, Robert A; Denton, Christopher P; Hinchcliff, Monique E; Pioli, Patricia A; Mahoney, J Matthew; Whitfield, Michael L

2017-03-23

Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology. We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test. We identified a common pathogenic gene expression signature-an immune-fibrotic axis-indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an "inflammatory" SSc gene expression signature. Our results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases.

Computational multiscale modeling in protein--ligand docking.

PubMed

Taufer, Michela; Armen, Roger; Chen, Jianhan; Teller, Patricia; Brooks, Charles

2009-01-01

In biological systems, the binding of small molecule ligands to proteins is a crucial process for almost every aspect of biochemistry and molecular biology. Enzymes are proteins that function by catalyzing specific biochemical reactions that convert reactants into products. Complex organisms are typically composed of cells in which thousands of enzymes participate in complex and interconnected biochemical pathways. Some enzymes serve as sequential steps in specific pathways (such as energy metabolism), while others function to regulate entire pathways and cellular functions [1]. Small molecule ligands can be designed to bind to a specific enzyme and inhibit the biochemical reaction. Inhibiting the activity of key enzymes may result in the entire biochemical pathways being turned on or off [2], [3]. Many small molecule drugs marketed today function in this generic way as enzyme inhibitors. If research identifies a specific enzyme as being crucial to the progress of disease, then this enzyme may be targeted with an inhibitor, which may slow down or reverse the progress of disease. In this way, enzymes are targeted from specific pathogens (e.g., virus, bacteria, fungi) for infectious diseases [4], [5], and human enzymes are targeted for noninfectious diseases such as cardiovascular disease, cancer, diabetes, and neurodegenerative diseases [6].

Immunogenetic mechanisms for the coexistence of organ-specific and systemic autoimmune diseases.

PubMed

Fridkis-Hareli, Masha

2008-02-15

Organ-specific autoimmune diseases affect particular targets in the body, whereas systemic diseases engage multiple organs. Both types of autoimmune diseases may coexist in the same patient, either sequentially or concurrently, sustained by the presence of autoantibodies directed against the corresponding autoantigens. Multiple factors, including those of immunological, genetic, endocrine and environmental origin, contribute to the above condition. Due to association of certain autoimmune disorders with HLA alleles, it has been intriguing to examine the immunogenetic basis for autoantigen presentation leading to the production of two or more autoantibodies, each distinctive of an organ-specific or systemic disease. This communication offers the explanation for shared autoimmunity as illustrated by organ-specific blistering diseases and the connective tissue disorders of systemic nature. Several hypothetical mechanisms implicating HLA determinants, autoantigenic peptides, T cells, and B cells have been proposed to elucidate the process by which two autoimmune diseases are induced in the same individual. One of these scenarios, based on the assumption that the patient carries two disease-susceptible HLA genes, arises when a single T cell epitope of each autoantigen recognizes its HLA protein, leading to the generation of two types of autoreactive B cells, which produce autoantibodies. Another mechanism functioning whilst an epitope derived from either autoantigen binds each of the HLA determinants, resulting in the induction of both diseases by cross-presentation. Finally, two discrete epitopes originating from the same autoantigen may interact with each of the HLA specificities, eliciting the production of both types of autoantibodies. Despite the lack of immediate or unequivocal experimental evidence supporting the present hypothesis, several approaches may secure a better understanding of shared autoimmunity. Among these are animal models expressing the transgenes of human disease-associated HLA determinants and T or B cell receptors, as well as in vitro binding studies employing purified HLA proteins, synthetic peptides, and cellular assays with antigen-presenting cells and patient's lymphocytes. Indisputably, a bioinformatics-based search for peptide motifs and the modeling of the conformation of bound autoantigenic peptides associated with their respective HLA alleles will reveal some of these important processes. The elucidation of HLA-restricted immune recognition mechanisms prompting the production of two or more disease-specific autoantibodies holds significant clinical ramifications and implications for the development of more effective treatment protocols.

A process-model based approach to prospective memory impairment in Parkinson's disease.

PubMed

Kliegel, Matthias; Altgassen, Mareike; Hering, Alexandra; Rose, Nathan S

2011-07-01

The present review discusses the current state of research on the clinical neuropsychology of prospective memory in Parkinson's disease. To do so the paper is divided in two sections. In the first section, we briefly outline key features of the (partly implicit) rationale underlying the available literature on the clinical neuropsychology of prospective memory. Here, we present a conceptual model that guides our approach to the clinical neuropsychology of prospective memory in general and to the effects of Parkinson's disease on prospective memory in particular. In the second section, we use this model to guide our review of the available literature and suggest some open issues and future directions motivated by previous findings and the proposed conceptual model. The review suggests that certain phases of the prospective memory process (intention formation und initiation) are particularly impaired by Parkinson's disease. In addition, it is argued that prospective memory may be preserved when tasks involve specific features (e.g., focal cues) that reduce the need for strategic monitoring processes. In terms of suggestions for future directions, it is noted that intervention studies are needed which target the specific phases of the prospective memory process that are impaired in Parkinson's disease, such as planning interventions. Moreover, it is proposed that prospective memory deficits in Parkinson's disease should be explored in the context of a general impairment in the ability to form an intention and plan or coordinate an appropriate series of actions. Copyright © 2011 Elsevier Ltd. All rights reserved.

Specific Inhibition of β-Secretase Processing of the Alzheimer Disease Amyloid Precursor Protein.

PubMed

Ben Halima, Saoussen; Mishra, Sabyashachi; Raja, K Muruga Poopathi; Willem, Michael; Baici, Antonio; Simons, Kai; Brüstle, Oliver; Koch, Philipp; Haass, Christian; Caflisch, Amedeo; Rajendran, Lawrence

2016-03-08

Development of disease-modifying therapeutics is urgently needed for treating Alzheimer disease (AD). AD is characterized by toxic β-amyloid (Aβ) peptides produced by β- and γ-secretase-mediated cleavage of the amyloid precursor protein (APP). β-secretase inhibitors reduce Aβ levels, but mechanism-based side effects arise because they also inhibit β-cleavage of non-amyloid substrates like Neuregulin. We report that β-secretase has a higher affinity for Neuregulin than it does for APP. Kinetic studies demonstrate that the affinities and catalytic efficiencies of β-secretase are higher toward non-amyloid substrates than toward APP. We show that non-amyloid substrates are processed by β-secretase in an endocytosis-independent manner. Exploiting this compartmentalization of substrates, we specifically target the endosomal β-secretase by an endosomally targeted β-secretase inhibitor, which blocked cleavage of APP but not non-amyloid substrates in many cell systems, including induced pluripotent stem cell (iPSC)-derived neurons. β-secretase inhibitors can be designed to specifically inhibit the Alzheimer process, enhancing their potential as AD therapeutics without undesired side effects. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Correlation of proteome-wide changes with social immunity behaviors provides insight into resistance to the parasitic mite, Varroa destructor, in the honey bee (Apis mellifera)

PubMed Central

2012-01-01

Background Disease is a major factor driving the evolution of many organisms. In honey bees, selection for social behavioral responses is the primary adaptive process facilitating disease resistance. One such process, hygienic behavior, enables bees to resist multiple diseases, including the damaging parasitic mite Varroa destructor. The genetic elements and biochemical factors that drive the expression of these adaptations are currently unknown. Proteomics provides a tool to identify proteins that control behavioral processes, and these proteins can be used as biomarkers to aid identification of disease tolerant colonies. Results We sampled a large cohort of commercial queen lineages, recording overall mite infestation, hygiene, and the specific hygienic response to V. destructor. We performed proteome-wide correlation analyses in larval integument and adult antennae, identifying several proteins highly predictive of behavior and reduced hive infestation. In the larva, response to wounding was identified as a key adaptive process leading to reduced infestation, and chitin biosynthesis and immune responses appear to represent important disease resistant adaptations. The speed of hygienic behavior may be underpinned by changes in the antenna proteome, and chemosensory and neurological processes could also provide specificity for detection of V. destructor in antennae. Conclusions Our results provide, for the first time, some insight into how complex behavioural adaptations manifest in the proteome of honey bees. The most important biochemical correlations provide clues as to the underlying molecular mechanisms of social and innate immunity of honey bees. Such changes are indicative of potential divergence in processes controlling the hive-worker maturation. PMID:23021491

Correlation of proteome-wide changes with social immunity behaviors provides insight into resistance to the parasitic mite, Varroa destructor, in the honey bee (Apis mellifera).

PubMed

Parker, Robert; Guarna, M Marta; Melathopoulos, Andony P; Moon, Kyung-Mee; White, Rick; Huxter, Elizabeth; Pernal, Stephen F; Foster, Leonard J

2012-06-29

Disease is a major factor driving the evolution of many organisms. In honey bees, selection for social behavioral responses is the primary adaptive process facilitating disease resistance. One such process, hygienic behavior, enables bees to resist multiple diseases, including the damaging parasitic mite Varroa destructor. The genetic elements and biochemical factors that drive the expression of these adaptations are currently unknown. Proteomics provides a tool to identify proteins that control behavioral processes, and these proteins can be used as biomarkers to aid identification of disease tolerant colonies. We sampled a large cohort of commercial queen lineages, recording overall mite infestation, hygiene, and the specific hygienic response to V. destructor. We performed proteome-wide correlation analyses in larval integument and adult antennae, identifying several proteins highly predictive of behavior and reduced hive infestation. In the larva, response to wounding was identified as a key adaptive process leading to reduced infestation, and chitin biosynthesis and immune responses appear to represent important disease resistant adaptations. The speed of hygienic behavior may be underpinned by changes in the antenna proteome, and chemosensory and neurological processes could also provide specificity for detection of V. destructor in antennae. Our results provide, for the first time, some insight into how complex behavioural adaptations manifest in the proteome of honey bees. The most important biochemical correlations provide clues as to the underlying molecular mechanisms of social and innate immunity of honey bees. Such changes are indicative of potential divergence in processes controlling the hive-worker maturation.

NIH Research: “The public wants diseases cured...” | NIH MedlinePlus the Magazine

MedlinePlus

... allergies, or a specific research focus; in my case, mast cells, which cause allergic reactions. We look at the mechanisms of disease; how asthma develops, for example. It is a slow and painstaking process. But ...

[Comparative research into sensitivity and specificity of immune-enzyme analysis with chemiluminescence and colorimetric detection for detecting antigens and antibodies to avian influenza viruses and newcastle disease].

PubMed

Vitkova, O N; Kapustina, T P; Mikhailova, V V; Safonov, G A; Vlasova, N N; Belousova, R V

2015-01-01

The goal of this work was to demonstrate the results of the development of the enzyme-linked immunosorbent tests with chemiluminescence detection and colorimetric detection of specific viral antigens and antibodies for identifying the avian influenza and the Newcastle disease viruses: high sensitivity and specificity of the immuno- chemiluminescence assay, which are 10-50 times higher than those of the ELISA colorimetric method. The high effectiveness of the results and the automation of the process of laboratory testing (using a luminometer) allow these methods to be recommended for including in primary screening tests for these infectious diseases.

The regulated secretory pathway and human disease: insights from gene variants and single nucleotide polymorphisms.

PubMed

Lin, Wei-Jye; Salton, Stephen R

2013-01-01

The regulated secretory pathway provides critical control of peptide, growth factor, and hormone release from neuroendocrine and endocrine cells, and neurons, maintaining physiological homeostasis. Propeptides and prohormones are packaged into dense core granules (DCGs), where they frequently undergo tissue-specific processing as the DCG matures. Proteins of the granin family are DCG components, and although their function is not fully understood, data suggest they are involved in DCG formation and regulated protein/peptide secretion, in addition to their role as precursors of bioactive peptides. Association of gene variation, including single nucleotide polymorphisms (SNPs), with neuropsychiatric, endocrine, and metabolic diseases, has implicated specific secreted proteins and peptides in disease pathogenesis. For example, a SNP at position 196 (G/A) of the human brain-derived neurotrophic factor gene dysregulates protein processing and secretion and leads to cognitive impairment. This suggests more generally that variants identified in genes encoding secreted growth factors, peptides, hormones, and proteins involved in DCG biogenesis, protein processing, and the secretory apparatus, could provide insight into the process of regulated secretion as well as disorders that result when it is impaired.

The Regulated Secretory Pathway and Human Disease: Insights from Gene Variants and Single Nucleotide Polymorphisms

PubMed Central

Lin, Wei-Jye; Salton, Stephen R.

2013-01-01

The regulated secretory pathway provides critical control of peptide, growth factor, and hormone release from neuroendocrine and endocrine cells, and neurons, maintaining physiological homeostasis. Propeptides and prohormones are packaged into dense core granules (DCGs), where they frequently undergo tissue-specific processing as the DCG matures. Proteins of the granin family are DCG components, and although their function is not fully understood, data suggest they are involved in DCG formation and regulated protein/peptide secretion, in addition to their role as precursors of bioactive peptides. Association of gene variation, including single nucleotide polymorphisms (SNPs), with neuropsychiatric, endocrine, and metabolic diseases, has implicated specific secreted proteins and peptides in disease pathogenesis. For example, a SNP at position 196 (G/A) of the human brain-derived neurotrophic factor gene dysregulates protein processing and secretion and leads to cognitive impairment. This suggests more generally that variants identified in genes encoding secreted growth factors, peptides, hormones, and proteins involved in DCG biogenesis, protein processing, and the secretory apparatus, could provide insight into the process of regulated secretion as well as disorders that result when it is impaired. PMID:23964269

Understanding Gulf War Illness: An Integrative Modeling Approach

DTIC Science & Technology

2016-10-01

Southeastern University, 3301 College Avenue, Fort Lauderdale, FL 33314 Centers for Disease Control, NIOSH, 1095 Willowdale Road, Morgantown, WV 26505...SUPPLEMENTARY NOTES 14. ABSTRACT The goal of the GWI consortium is to develop a better understanding of GWI and identify specific disease targets to...find treatments that will address the cause of the disease . The consortium will integrate our clinical understanding of the disease process with

An Energy efficient application specific integrated circuit for electrocardiogram feature detection and its potential for ambulatory cardiovascular disease detection

PubMed Central

Bhaumik, Basabi

2016-01-01

A novel algorithm based on forward search is developed for real-time electrocardiogram (ECG) signal processing and implemented in application specific integrated circuit (ASIC) for QRS complex related cardiovascular disease diagnosis. The authors have evaluated their algorithm using MIT-BIH database and achieve sensitivity of 99.86% and specificity of 99.93% for QRS complex peak detection. In this Letter, Physionet PTB diagnostic ECG database is used for QRS complex related disease detection. An ASIC for cardiovascular disease detection is fabricated using 130-nm CMOS high-speed process technology. The area of the ASIC is 0.5 mm2. The power dissipation is 1.73 μW at the operating frequency of 1 kHz with a supply voltage of 0.6 V. The output from the ASIC is fed to their Android application that generates diagnostic report and can be sent to a cardiologist through email. Their ASIC result shows average failed detection rate of 0.16% for six leads data of 290 patients in PTB diagnostic ECG database. They also have implemented a low-leakage version of their ASIC. The ASIC dissipates only 45 pJ with a supply voltage of 0.9 V. Their proposed ASIC is most suitable for energy efficient telemetry cardiovascular disease detection system. PMID:27284458

An Energy efficient application specific integrated circuit for electrocardiogram feature detection and its potential for ambulatory cardiovascular disease detection.

PubMed

Jain, Sanjeev Kumar; Bhaumik, Basabi

2016-03-01

A novel algorithm based on forward search is developed for real-time electrocardiogram (ECG) signal processing and implemented in application specific integrated circuit (ASIC) for QRS complex related cardiovascular disease diagnosis. The authors have evaluated their algorithm using MIT-BIH database and achieve sensitivity of 99.86% and specificity of 99.93% for QRS complex peak detection. In this Letter, Physionet PTB diagnostic ECG database is used for QRS complex related disease detection. An ASIC for cardiovascular disease detection is fabricated using 130-nm CMOS high-speed process technology. The area of the ASIC is 0.5 mm(2). The power dissipation is 1.73 μW at the operating frequency of 1 kHz with a supply voltage of 0.6 V. The output from the ASIC is fed to their Android application that generates diagnostic report and can be sent to a cardiologist through email. Their ASIC result shows average failed detection rate of 0.16% for six leads data of 290 patients in PTB diagnostic ECG database. They also have implemented a low-leakage version of their ASIC. The ASIC dissipates only 45 pJ with a supply voltage of 0.9 V. Their proposed ASIC is most suitable for energy efficient telemetry cardiovascular disease detection system.

Growth Hormone Resistance—Special Focus on Inflammatory Bowel Disease

PubMed Central

Soendergaard, Christoffer; Young, Jonathan A.; Kopchick, John J.

2017-01-01

Growth hormone (GH) plays major anabolic and catabolic roles in the body and is important for regulating several aspects of growth. During an inflammatory process, cells may develop a state of GH resistance during which their response to GH stimulation is limited. In this review, we will emphasize specific mechanisms governing the formation of GH resistance in the active phase of inflammatory bowel disease. The specific molecular effects mediated through individual inflammatory mediators and processes will be highlighted to provide an overview of the transcriptional, translational and post-translational inflammation-mediated impacts on the GH receptor (GHR) along with the impacts on GH-induced intracellular signaling. We also will review GH’s effects on mucosal healing and immune cells in the context of experimental colitis, human inflammatory bowel disease and in patients with short bowel syndrome. PMID:28486400

The role of the striatum in rule application: the model of Huntington's disease at early stage.

PubMed

Teichmann, Marc; Dupoux, Emmanuel; Kouider, Sid; Brugières, Pierre; Boissé, Marie-Françoise; Baudic, Sophie; Cesaro, Pierre; Peschanski, Marc; Bachoud-Lévi, Anne-Catherine

2005-05-01

The role of the basal ganglia, and more specifically of the striatum, in language is still debated. Recent studies have proposed that linguistic abilities involve two distinct types of processes: the retrieving of stored information, implicating temporal lobe areas, and the application of combinatorial rules, implicating fronto-striatal circuits. Studies of patients with focal lesions and neurodegenerative diseases have suggested a role for the striatum in morphological rule application, but functional imaging studies found that the left caudate was involved in syntactic processing and not morphological processing. In the present study, we tested the view that the basal ganglia are involved in rule application and not in lexical retrieving in a model of striatal dysfunction, namely Huntington's disease at early stages. We assessed the rule-lexicon dichotomy in the linguistic domain with morphology (conjugation of non-verbs and verbs) and syntax (sentence comprehension) and in a non-linguistic domain with arithmetic operations (subtraction and multiplication). Thirty Huntington's disease patients (15 at stage I and 15 at stage II) and 20 controls matched for their age and cultural level were included in this study. Huntington's disease patients were also assessed using the Unified Huntington's Disease Rating Scale (UHDRS) and MRI. We found that early Huntington's disease patients were impaired in rule application in the linguistic and non-linguistic domains (morphology, syntax and subtraction), whereas they were broadly spared with lexical processing. The pattern of performance was similar in patients at stage I and stage II, except that stage II patients were more impaired in all tasks assessing rules and had in addition a very slight impairment in the lexical condition of conjugation. Finally, syntactic rule abilities correlated with all markers of the disease evolution including bicaudate ratio and performance in executive function, whereas there was no correlation with arithmetic and morphological abilities. Together, this suggests that the striatum is involved in rule processing more than in lexical processing and that it extends to linguistic and non-linguistic domains. These results are discussed in terms of domain-specific versus domain-general processes of rule application.

Thrombospondin in colorectal disease.

PubMed

Behzad; Abdalla; Gardy; Battrick; Kumar; Haboubi

2000-05-01

To assess the presence of thrombospondin (TSP) in normal and colonic disease and correlate its presence to survival in colorectal cancers. A specific antibody was used to stain paraffin-embedded sections of human colorectal disease (103 carcinomas, 10 inflammatory bowel disease (IBD), 10 diverticulosis and 10 normal). The stained sections were viewed by light microscopy and the degree of staining was quantified using computer-assisted image analysis system. Seventy-three percent of carcinomas, 30% of IBD and 80% of the diverticulosis specimens stained for TSP. None of the 'normal' specimens examined showed any staining. No significant correlation could be detected between TSP expression and survival in colorectal cancer patients. The presence of TSP in the colon is not specific and merely indicates the presence of a disease process.

The road to JCAHO disease-specific care certification: a step-by-step process log.

PubMed

Morrison, Kathy

2005-01-01

In 2002, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) implemented Disease-Specific Care (DSC) certification. This is a voluntary program in which organizations have their disease management program evaluated by this regulatory agency. Some of the DSC categories are stroke, heart failure, acute MI, diabetes, and pneumonia. The criteria for any disease management program certification are: compliance with consensus-based national standards, effective use of established clinical practice guidelines to manage and optimize care, and an organized approach to performance measurement and improvement activities. Successful accomplishment of DSC certification defines organizations as Centers of Excellence in management of that particular disease. This article will review general guidelines for DSC certification with an emphasis on Primary Stroke Center certification.

Classic and new animal models of Parkinson's disease.

PubMed

Blesa, Javier; Phani, Sudarshan; Jackson-Lewis, Vernice; Przedborski, Serge

2012-01-01

Neurological disorders can be modeled in animals so as to recreate specific pathogenic events and behavioral outcomes. Parkinson's Disease (PD) is the second most common neurodegenerative disease of an aging population, and although there have been several significant findings about the PD disease process, much of this process still remains a mystery. Breakthroughs in the last two decades using animal models have offered insights into the understanding of the PD disease process, its etiology, pathology, and molecular mechanisms. Furthermore, while cellular models have helped to identify specific events, animal models, both toxic and genetic, have replicated almost all of the hallmarks of PD and are useful for testing new neuroprotective or neurorestorative strategies. Moreover, significant advances in the modeling of additional PD features have come to light in both classic and newer models. In this review, we try to provide an updated summary of the main characteristics of these models as well as the strengths and weaknesses of what we believe to be the most popular PD animal models. These models include those produced by 6-hydroxydopamine (6-OHDA), 1-methyl-1,2,3,6-tetrahydropiridine (MPTP), rotenone, and paraquat, as well as several genetic models like those related to alpha-synuclein, PINK1, Parkin and LRRK2 alterations.

Retrieval of radiology reports citing critical findings with disease-specific customization.

PubMed

Lacson, Ronilda; Sugarbaker, Nathanael; Prevedello, Luciano M; Ivan, Ip; Mar, Wendy; Andriole, Katherine P; Khorasani, Ramin

2012-01-01

Communication of critical results from diagnostic procedures between caregivers is a Joint Commission national patient safety goal. Evaluating critical result communication often requires manual analysis of voluminous data, especially when reviewing unstructured textual results of radiologic findings. Information retrieval (IR) tools can facilitate this process by enabling automated retrieval of radiology reports that cite critical imaging findings. However, IR tools that have been developed for one disease or imaging modality often need substantial reconfiguration before they can be utilized for another disease entity. THIS PAPER: 1) describes the process of customizing two Natural Language Processing (NLP) and Information Retrieval/Extraction applications - an open-source toolkit, A Nearly New Information Extraction system (ANNIE); and an application developed in-house, Information for Searching Content with an Ontology-Utilizing Toolkit (iSCOUT) - to illustrate the varying levels of customization required for different disease entities and; 2) evaluates each application's performance in identifying and retrieving radiology reports citing critical imaging findings for three distinct diseases, pulmonary nodule, pneumothorax, and pulmonary embolus. Both applications can be utilized for retrieval. iSCOUT and ANNIE had precision values between 0.90-0.98 and recall values between 0.79 and 0.94. ANNIE had consistently higher precision but required more customization. Understanding the customizations involved in utilizing NLP applications for various diseases will enable users to select the most suitable tool for specific tasks.

Retrieval of Radiology Reports Citing Critical Findings with Disease-Specific Customization

PubMed Central

Lacson, Ronilda; Sugarbaker, Nathanael; Prevedello, Luciano M; Ivan, IP; Mar, Wendy; Andriole, Katherine P; Khorasani, Ramin

2012-01-01

Background: Communication of critical results from diagnostic procedures between caregivers is a Joint Commission national patient safety goal. Evaluating critical result communication often requires manual analysis of voluminous data, especially when reviewing unstructured textual results of radiologic findings. Information retrieval (IR) tools can facilitate this process by enabling automated retrieval of radiology reports that cite critical imaging findings. However, IR tools that have been developed for one disease or imaging modality often need substantial reconfiguration before they can be utilized for another disease entity. Purpose: This paper: 1) describes the process of customizing two Natural Language Processing (NLP) and Information Retrieval/Extraction applications – an open-source toolkit, A Nearly New Information Extraction system (ANNIE); and an application developed in-house, Information for Searching Content with an Ontology-Utilizing Toolkit (iSCOUT) – to illustrate the varying levels of customization required for different disease entities and; 2) evaluates each application’s performance in identifying and retrieving radiology reports citing critical imaging findings for three distinct diseases, pulmonary nodule, pneumothorax, and pulmonary embolus. Results: Both applications can be utilized for retrieval. iSCOUT and ANNIE had precision values between 0.90-0.98 and recall values between 0.79 and 0.94. ANNIE had consistently higher precision but required more customization. Conclusion: Understanding the customizations involved in utilizing NLP applications for various diseases will enable users to select the most suitable tool for specific tasks. PMID:22934127

Primary Respiratory Chain Disease Causes Tissue-Specific Dysregulation of the Global Transcriptome and Nutrient-Sensing Signaling Network

PubMed Central

Zhang, Zhe; Tsukikawa, Mai; Peng, Min; Polyak, Erzsebet; Nakamaru-Ogiso, Eiko; Ostrovsky, Julian; McCormack, Shana; Place, Emily; Clarke, Colleen; Reiner, Gail; McCormick, Elizabeth; Rappaport, Eric; Haas, Richard; Baur, Joseph A.; Falk, Marni J.

2013-01-01

Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure. Global transcriptional and post-transcriptional dysregulation was also found to occur in a highly tissue-specific fashion. In particular, RC disease muscle had decreased transcription of cytosolic ribosomal proteins suggestive of reduced anabolic processes, increased transcription of mitochondrial ribosomal proteins, shorter 5′-UTRs that likely improve translational efficiency, and stabilization of 3′-UTRs containing AU-rich elements. RC disease fibroblasts showed a strikingly similar pattern of global transcriptome dysregulation in a reverse direction. In parallel with these transcriptional effects, RC disease dysregulated the integrated nutrient-sensing signaling network involving FOXO, PPAR, sirtuins, AMPK, and mTORC1, which collectively sense nutrient availability and regulate cellular growth. Altered activities of central nodes in the nutrient-sensing signaling network were validated by phosphokinase immunoblot analysis in RC inhibited cells. Remarkably, treating RC mutant fibroblasts with nicotinic acid to enhance sirtuin and PPAR activity also normalized mTORC1 and AMPK signaling, restored NADH/NAD+ redox balance, and improved cellular respiratory capacity. These data specifically highlight a common pathogenesis extending across different molecular and biochemical etiologies of individual RC disorders that involves global transcriptome modifications. We further identify the integrated nutrient-sensing signaling network as a common cellular response that mediates, and may be amenable to targeted therapies for, tissue-specific sequelae of primary mitochondrial RC disease. PMID:23894440

Improving the quality of transition and transfer of care in young adults with congenital heart disease.

PubMed

Everitt, Ian K; Gerardin, Jennifer F; Rodriguez, Fred H; Book, Wendy M

2017-05-01

The transition and transfer from pediatric to adult care is becoming increasingly important as improvements in the diagnosis and management of congenital heart disease allow patients to live longer. Transition is a complex and continuous process that requires careful planning. Inadequate transition has adverse effects on patients, their families and healthcare delivery systems. Currently, significant gaps exist in patient care as adolescents transfer to adult care and there are little data to drive the informed management of transition and transfer of care in adolescent congenital heart disease patients. Appropriate congenital heart disease care has been shown to decrease mortality in the adult population. This paper reviews the transition and transfer of care processes and outlines current congenital heart disease specific guidelines in the United States and compares these recommendations to Canadian and European guidelines. It then reviews perceived and real barriers to successful transition and identifies predictors of success during transfer to adult congenital heart disease care. Lastly, it explores how disease-specific markers of outcomes and quality indicators are being utilized to guide transition and transfer of care in other chronic childhood illnesses, and identifies existing knowledge gaps and structural impediments to improving the management of transition and transfer among congenital heart disease patients. © 2017 Wiley Periodicals, Inc.

Common variants associated with plasma triglycerides and risk for coronary artery disease

USDA-ARS?s Scientific Manuscript database

Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common va...

Connexins, pannexins and their channels in fibroproliferative diseases

PubMed Central

Willebrords, Joost; Da Silva, Tereza Cristina; Maes, Michaël; Pereira, Isabel Veloso Alves; Crespo-Yanguas, Sara; Hernandez-Blazquez, Francisco Javier; Dagli, Maria Lúcia Zaidan; Vinken, Mathieu

2017-01-01

Cellular and molecular mechanisms of wound healing, tissue repair and fibrogenesis are established in different organs and are essential for the maintenance of function and tissue integrity after cell injury. These mechanisms are also involved in a plethora of fibroproliferative diseases or organ-specific fibrotic disorders, all of which are associated with the excessive deposition of extracellular matrix components. Fibroblasts, which are key cells in tissue repair and fibrogenesis, rely on communicative cellular networks to ensure efficient control of these processes and to prevent abnormal accumulation of extracellular matrix into the tissue. Despite the significant impact on human health, and thus the epidemiologic relevance, there is still no effective treatment for most fibrosis-related diseases. This paper provides an overview of current concepts and mechanisms involved in the participation of cellular communication via connexin-based pores as well as pannexin-based channels in the processes of tissue repair and fibrogenesis in chronic diseases. Understanding these mechanisms may contribute to the development of new therapeutic strategies to clinically manage fibroproliferative diseases and organ-specific fibrotic disorders. PMID:26914707

Using multiple decrement models to estimate risk and morbidity from specific AIDS illnesses. Multicenter AIDS Cohort Study (MACS).

PubMed

Hoover, D R; Peng, Y; Saah, A J; Detels, R R; Day, R S; Phair, J P

A simple non-parametric approach is developed to simultaneously estimate net incidence and morbidity time from specific AIDS illnesses in populations at high risk for death from these illnesses and other causes. The disease-death process has four-stages that can be recast as two sandwiching three-state multiple decrement processes. Non-parametric estimation of net incidence and morbidity time with error bounds are achieved from these sandwiching models through modification of methods from Aalen and Greenwood, and bootstrapping. An application to immunosuppressed HIV-1 infected homosexual men reveals that cytomegalovirus disease, Kaposi's sarcoma and Pneumocystis pneumonia are likely to occur and cause significant morbidity time.

Annotating Cancer Variants and Anti-Cancer Therapeutics in Reactome

PubMed Central

Milacic, Marija; Haw, Robin; Rothfels, Karen; Wu, Guanming; Croft, David; Hermjakob, Henning; D’Eustachio, Peter; Stein, Lincoln

2012-01-01

Reactome describes biological pathways as chemical reactions that closely mirror the actual physical interactions that occur in the cell. Recent extensions of our data model accommodate the annotation of cancer and other disease processes. First, we have extended our class of protein modifications to accommodate annotation of changes in amino acid sequence and the formation of fusion proteins to describe the proteins involved in disease processes. Second, we have added a disease attribute to reaction, pathway, and physical entity classes that uses disease ontology terms. To support the graphical representation of “cancer” pathways, we have adapted our Pathway Browser to display disease variants and events in a way that allows comparison with the wild type pathway, and shows connections between perturbations in cancer and other biological pathways. The curation of pathways associated with cancer, coupled with our efforts to create other disease-specific pathways, will interoperate with our existing pathway and network analysis tools. Using the Epidermal Growth Factor Receptor (EGFR) signaling pathway as an example, we show how Reactome annotates and presents the altered biological behavior of EGFR variants due to their altered kinase and ligand-binding properties, and the mode of action and specificity of anti-cancer therapeutics. PMID:24213504

Management of upper extremity dysfunction in people with Parkinson disease and Huntington disease: facilitating outcomes across the disease lifespan.

PubMed

Quinn, Lori; Busse, Monica; Dal Bello-Haas, Vanina

2013-01-01

Parkinson Disease (PD) and Huntington Disease (HD) are degenerative neurological diseases, which can result in impairments and activity limitations affecting the upper extremities from early in the disease process. The progressive nature of these diseases poses unique challenges for therapists aiming to effectively maximize physical functioning and minimize participation restrictions in these patient groups. Research is underway in both diseases to develop effective disease-modifying agents and pharmacological interventions, as well as mobility-focused rehabilitation protocols. Rehabilitation, and in particular task-specific interventions, has the potential to influence the upper extremity functional abilities of patients with these degenerative conditions. However to date, investigations of interventions specifically addressing upper extremity function have been limited in both PD, and in particular HD. In this paper, we provide an update of the known pathological features of PD and HD as they relate to upper extremity function. We further review the available literature on the use of outcome measures, and the clinical management of upper extremity function in both conditions. Due to the currently limited evidence base in both diseases, we recommend utilization of a clinical management framework specific for degenerative conditions that can serve as a guideline for disease management. Copyright © 2013. Published by Elsevier Inc.

Harnessing RNA interference to develop neonatal therapies: from Nobel Prize winning discovery to proof of concept clinical trials.

PubMed

DeVincenzo, John P

2009-10-01

A revolution in the understanding of RNA biological processing and control is leading to revolutionary new concepts in human therapeutics. It has become increasingly clear that the so called "non-coding RNA" exerts specific and profound functional control on regulation of protein production and indeed controls the expression of all genes. Harnessing this naturally-occurring RNA-mediated regulation of protein production has immense human therapeutic potential. These processes are collectively known as RNA interference (RNAi). RNAi is a recently discovered, naturally-occurring intracellular process that regulates gene expression through the silencing of specific mRNAs. Methods of harnessing this natural pathway are being developed that allow the catalytic degradation of targeted mRNAs using specifically designed complementary small inhibitory RNAs (siRNA). siRNAs are being chemically modified to acquire drug-like properties. Numerous recent high profile publications have provided proofs of concept that RNA interference may be useful therapeutically. Much of the design of these siRNAs can be accomplished bioinformatically, thus potentially expediting drug discovery and opening new avenues of therapy for many uncommon, orphan, or emerging diseases. This makes this approach very attractive for developing therapies targeting orphan diseases including neonatal diseases. Theoretically, any disease that can be ameliorated through knockdown of any endogenous or exogenous protein is a potential therapeutic target for RNAi-based therapeutics. Lung diseases are particularly attractive targets for RNAi therapeutics since the affected cells' location increases their accessibility to topical administration of siRNA, for example by aerosol. Respiratory viral infections and chronic lung disease are examples of such diseases. RNAi therapeutics have been shown to be active against RSV, parainfluenza and human metapneumoviruses in vitro and in vivo resulting in profound antiviral effects. The first proof of concept test of efficacy of an RNAi-based therapeutic in man has been initiated. A discussion of the science behind RNA interference is followed by a presentation of the potential practical issues in applying this technology to neonatal respiratory viral diseases. RNAi may offer new strategies for the treatment of a variety of orphan diseases including neonatal diseases, RSV infections, and other respiratory viruses.

Leveraging Small Aquarium Fishes to Advance Understanding of Environmentally Influenced Human Disorders and Diseases

EPA Science Inventory

Small aquarium fishes provide a model organism that recapitulates the development, physiology and specific disease processes present in humans without the many limitations of rodent-based models currently in use. Fish models offer advantages in cost, rapid life-cycles, and extern...

[Rheumatoid arthritis as a connective tissue disease].

PubMed

Targońska-Stępniak, Bożena

2018-01-01

The available data indicate that seropositive rheumatoid arthritis (RA) develops as a result of systemic, autoimmune reaction directed against a range of "self" peptides/proteins that have undergone specific forms of post-translational modification. The development and progress of autoimmunity may be triggered by non-specific, local inflammatory processes outside the joints, for example in the oral or respiratory mucous membrane. The disease occurs in genetically susceptible individuals under the influence of environmental risk factors that promote autoimmunity and consequently the inflammatory process. Smoking is particularly linked with RA pathogenesis. Synovitis of multiple, symmetrical, peripheral joints is the most typical feature of RA which results in irreversible damage to joints structure and as a consequence in disability of patients. However, the inflammatory process in the course of RA has a systemic, constitutional nature. Therefore, extra-articular symptoms with internal organ involvement may occur additionally to synovitis, what is an unfavorable prognostic factor. Extra-articular manifestations of RA are associated with the high disease activity both inflammatory and immunological. They occur in patients with severe form of the disease and contribute to a significant lifespan reduction. This is usually associated with progressive atherosclerosis and cardiovascular complications. The systemic inhibition of an abnormal immune system activity is the mainstay of the effective RA treatment. The currently used disease modifying antirheumatic drugs affect the activity and function of different constituents of the immune system, including B and T lymphocytes and the main pro-inflammatory cytokines, and contribute to autoimmune and inflammatory processes.

Atherosclerotic Cardiovascular Disease Beginning in Childhood

PubMed Central

2010-01-01

Although the clinical manifestations of cardiovascular disease (CVD), such as myocardial infarction, stroke, and peripheral vascular disease, appear from middle age, the process of atherosclerosis can begin early in childhood. The early stage and progression of atherosclerosis in youth are influenced by risk factors that include obesity, hypertension, dyslipidemia, and smoking, and by the presence of specific diseases, such as diabetes mellitus and Kawasaki disease (KD). The existing evidence indicates that primary prevention of atherosclerotic disease should begin in childhood. Identification of children at risk for atherosclerosis may allow early intervention to decrease the atherosclerotic process, thereby preventing or delaying CVD. This review will describe the origin and progression of atherosclerosis in childhood, and the identification and management of known risk factors for atherosclerotic CVD in children and young adults. PMID:20111646

Potential Role of microRNAs in Cardiovascular Disease: Are They up to Their Hype?

PubMed

Duggal, Bhanu; Gupta, Manveen K; Naga Prasad, Sathyamangla V

Cardiovascular diseases remain the foremost cause of mortality globally. As molecular medicine unravels the alterations in genomic expression and regulation of the underlying atherosclerotic process, it opens new vistas for discovering novel diagnostic biomarkers and therapeutics for limiting the disease process. miRNAs have emerged as powerful regulators of protein translation by regulating gene expression at the post-transcriptional level. Overexpression and under-expression of specific miRNAs are being evaluated as a novel approach to diagnosis and treatment of cardiovascular disease. This review sheds light on the current knowledge of the miRNA evaluated in cardiovascular disease. In this review we summarize the data, including the more recent data, regarding miRNAs in cardiovascular disease and their potential role in future in diagnostic and therapeutic strategies.

Quantitative phase-digital holographic microscopy: a new imaging modality to identify original cellular biomarkers of diseases

NASA Astrophysics Data System (ADS)

Marquet, P.; Rothenfusser, K.; Rappaz, B.; Depeursinge, C.; Jourdain, P.; Magistretti, P. J.

2016-03-01

Quantitative phase microscopy (QPM) has recently emerged as a powerful label-free technique in the field of living cell imaging allowing to non-invasively measure with a nanometric axial sensitivity cell structure and dynamics. Since the phase retardation of a light wave when transmitted through the observed cells, namely the quantitative phase signal (QPS), is sensitive to both cellular thickness and intracellular refractive index related to the cellular content, its accurate analysis allows to derive various cell parameters and monitor specific cell processes, which are very likely to identify new cell biomarkers. Specifically, quantitative phase-digital holographic microscopy (QP-DHM), thanks to its numerical flexibility facilitating parallelization and automation processes, represents an appealing imaging modality to both identify original cellular biomarkers of diseases as well to explore the underlying pathophysiological processes.

Language impairment in Alzheimer’s disease and benefits of acetylcholinesterase inhibitors

PubMed Central

Ferris, Steven H; Farlow, Martin

2013-01-01

Alzheimer’s disease is characterized by progressively worsening deficits in several cognitive domains, including language. Language impairment in Alzheimer’s disease primarily occurs because of decline in semantic and pragmatic levels of language processing. Given the centrality of language to cognitive function, a number of language-specific scales have been developed to assess language deficits throughout progression of the disease and to evaluate the effects of pharmacotherapy on language function. Trials of acetylcholinesterase inhibitors, used for the treatment of clinical symptoms of Alzheimer’s disease, have generally focused on overall cognitive effects. However, in the current report, we review data indicating specific beneficial effects of acetylcholinesterase inhibitors on language abilities in patients with Alzheimer’s disease, with a particular focus on outcomes among patients in the moderate and severe disease stages, during which communication is at risk and preservation is particularly important. PMID:23946647

RNA Interference in Infectious Tropical Diseases

PubMed Central

Hong, Young S.

2008-01-01

Introduction of double-stranded RNA (dsRNA) into some cells or organisms results in degradation of its homologous mRNA, a process called RNA interference (RNAi). The dsRNAs are processed into short interfering RNAs (siRNAs) that subsequently bind to the RNA-induced silencing complex (RISC), causing degradation of target mRNAs. Because of this sequence-specific ability to silence target genes, RNAi has been extensively used to study gene functions and has the potential to control disease pathogens or vectors. With this promise of RNAi to control pathogens and vectors, this paper reviews the current status of RNAi in protozoans, animal parasitic helminths and disease-transmitting vectors, such as insects. Many pathogens and vectors cause severe parasitic diseases in tropical regions and it is difficult to control once the host has been invaded. Intracellularly, RNAi can be highly effective in impeding parasitic development and proliferation within the host. To fully realize its potential as a means to control tropical diseases, appropriate delivery methods for RNAi should be developed, and possible off-target effects should be minimized for specific gene suppression. RNAi can also be utilized to reduce vector competence to interfere with disease transmission, as genes critical for pathogenesis of tropical diseases are knockdowned via RNAi. PMID:18344671

Branching processes in disease epidemics

NASA Astrophysics Data System (ADS)

Singh, Sarabjeet

Branching processes have served as a model for chemical reactions, biological growth processes and contagion (of disease, information or fads). Through this connection, these seemingly different physical processes share some common universalities that can be elucidated by analyzing the underlying branching process. In this thesis, we focus on branching processes as a model for infectious diseases spreading between individuals belonging to different populations. The distinction between populations can arise from species separation (as in the case of diseases which jump across species) or spatial separation (as in the case of disease spreading between farms, cities, urban centers, etc). A prominent example of the former is zoonoses -- infectious diseases that spill from animals to humans -- whose specific examples include Nipah virus, monkeypox, HIV and avian influenza. A prominent example of the latter is infectious diseases of animals such as foot and mouth disease and bovine tuberculosis that spread between farms or cattle herds. Another example of the latter is infectious diseases of humans such as H1N1 that spread from one city to another through migration of infectious hosts. This thesis consists of three main chapters, an introduction and an appendix. The introduction gives a brief history of mathematics in modeling the spread of infectious diseases along with a detailed description of the most commonly used disease model -- the Susceptible-Infectious-Recovered (SIR) model. The introduction also describes how the stochastic formulation of the model reduces to a branching process in the limit of large population which is analyzed in detail. The second chapter describes a two species model of zoonoses with coupled SIR processes and proceeds into the calculation of statistics pertinent to cross species infection using multitype branching processes. The third chapter describes an SIR process driven by a Poisson process of infection spillovers. This is posed as a model of infectious diseases where a `reservoir' of infection exists that infects a susceptible host population at a constant rate. The final chapter of the thesis describes a general framework of modeling infectious diseases in a network of populations using multitype branching processes.

Pre-implementation guidelines for infectious disease point-of-care testing in medical institutions.

PubMed

van der Eijk, Annemiek A; Tintu, Andrei N; Hays, John P

2017-01-01

Infectious disease point-of-care test (ID-POCT) devices are becoming widely available, and in this respect, international quality standards and guidelines are available for consultation once ID-POCT has been implemented into medical institutions. However, specific guidelines for consultation during the initial pre-implementation decision-making process are currently lacking. Further, there exist pre-implementation issues specific to ID-POCT. Here we present pre-implementation guidelines for consultation when considering the implementation of ID-POCT in medical institutions.

Visual dysfunction in Parkinson’s disease

PubMed Central

Weil, Rimona S.; Schrag, Anette E.; Warren, Jason D.; Crutch, Sebastian J.; Lees, Andrew J.; Morris, Huw R.

2016-01-01

Patients with Parkinson’s disease have a number of specific visual disturbances. These include changes in colour vision and contrast sensitivity and difficulties with complex visual tasks such as mental rotation and emotion recognition. We review changes in visual function at each stage of visual processing from retinal deficits, including contrast sensitivity and colour vision deficits to higher cortical processing impairments such as object and motion processing and neglect. We consider changes in visual function in patients with common Parkinson’s disease-associated genetic mutations including GBA and LRRK2. We discuss the association between visual deficits and clinical features of Parkinson’s disease such as rapid eye movement sleep behavioural disorder and the postural instability and gait disorder phenotype. We review the link between abnormal visual function and visual hallucinations, considering current models for mechanisms of visual hallucinations. Finally, we discuss the role of visuo-perceptual testing as a biomarker of disease and predictor of dementia in Parkinson’s disease. PMID:27412389

Differential roles of NADPH oxidases in vascular physiology and pathophysiology

PubMed Central

Amanso, Angelica M.; Griendling, Kathy K.

2012-01-01

Reactive oxygen species (ROS) are produced by all vascular cells and regulate the major physiological functions of the vasculature. Production and removal of ROS are tightly controlled and occur in discrete subcellular locations, allowing for specific, compartmentalized signaling. Among the many sources of ROS in the vessel wall, NADPH oxidases are implicated in physiological functions such as control of vasomotor tone, regulation of extracellular matrix and phenotypic modulation of vascular smooth muscle cells. They are involved in the response to injury, whether as an oxygen sensor during hypoxia, as a regulator of protein processing, as an angiogenic stimulus, or as a mechanism of wound healing. These enzymes have also been linked to processes leading to disease development, including migration, proliferation, hypertrophy, apoptosis and autophagy. As a result, NADPH oxidases participate in atherogenesis, systemic and pulmonary hypertension and diabetic vascular disease. The role of ROS in each of these processes and diseases is complex, and a more full understanding of the sources, targets, cell-specific responses and counterbalancing mechanisms is critical for the rational development of future therapeutics. PMID:22202108

The specificity triad: notions of disease and therapeutic specificity in biomedical reasoning

PubMed Central

2014-01-01

Biomedicine is typically defined as the branch of medicine that is based on the principles of biology and biochemistry. A central tenet for biomedicine is the notion of disease and therapeutic specificity, i.e. the idea of tailored treatments for discrete disorders underpinned by specific pathologies. The present paper is concerned with how notions of disease and therapeutic specificity guide biomedical reasoning. To that end, the author proposes a model – the specificity triad – that draws on late philosopher and physician Ludwik Fleck’s concept of “style of thought” to offer a frame for investigating the intricate process through which links between disorders, mechanisms, and therapeutics are established by biomedicine. Next by applying the specificity triad model to scrutinize research efforts in two discrete areas of medicine—psychiatry and regenerative medicine—this paper seeks to stimulate pertinent discussions in and about biomedicine. These include discussions on the ambiguous epistemic status of psychiatry within contemporary biomedicine, as well as the relationship between developmental biology — historically relatively disjointed from biomedical enterprise — and the burgeoning field of regenerative medicine. PMID:25326797

Extracellular vesicles and their synthetic analogues in aging and age-associated brain diseases

PubMed Central

Smith, J. A.; Leonardi, T.; Huang, B.; Iraci, N.; Vega, B.; Pluchino, S.

2015-01-01

Multicellular organisms rely upon diverse and complex intercellular communications networks for a myriad of physiological processes. Disruption of these processes is implicated in the onset and propagation of disease and disorder, including the mechanisms of senescence at both cellular and organismal levels. In recent years, secreted extracellular vesicles (EVs) have been identified as a particularly novel vector by which cell-to-cell communications are enacted. EVs actively and specifically traffic bioactive proteins, nucleic acids, and metabolites between cells at local and systemic levels, modulating cellular responses in a bidirectional manner under both homeostatic and pathological conditions. EVs are being implicated not only in the generic aging process, but also as vehicles of pathology in a number of age-related diseases, including cancer and neurodegenerative and disease. Thus, circulating EVs—or specific EV cargoes—are being utilised as putative biomarkers of disease. On the other hand, EVs, as targeted intercellular shuttles of multipotent bioactive payloads, have demonstrated promising therapeutic properties, which can potentially be modulated and enhanced through cellular engineering. Furthermore, there is considerable interest in employing nanomedicinal approaches to mimic the putative therapeutic properties of EVs by employing synthetic analogues for targeted drug delivery. Herein we describe what is known about the origin and nature of EVs and subsequently review their putative roles in biology and medicine (including the use of synthetic EV analogues), with a particular focus on their role in aging and age-related brain diseases. PMID:24973266

Extracellular vesicles and their synthetic analogues in aging and age-associated brain diseases.

PubMed

Smith, J A; Leonardi, T; Huang, B; Iraci, N; Vega, B; Pluchino, S

2015-04-01

Multicellular organisms rely upon diverse and complex intercellular communications networks for a myriad of physiological processes. Disruption of these processes is implicated in the onset and propagation of disease and disorder, including the mechanisms of senescence at both cellular and organismal levels. In recent years, secreted extracellular vesicles (EVs) have been identified as a particularly novel vector by which cell-to-cell communications are enacted. EVs actively and specifically traffic bioactive proteins, nucleic acids, and metabolites between cells at local and systemic levels, modulating cellular responses in a bidirectional manner under both homeostatic and pathological conditions. EVs are being implicated not only in the generic aging process, but also as vehicles of pathology in a number of age-related diseases, including cancer and neurodegenerative and disease. Thus, circulating EVs-or specific EV cargoes-are being utilised as putative biomarkers of disease. On the other hand, EVs, as targeted intercellular shuttles of multipotent bioactive payloads, have demonstrated promising therapeutic properties, which can potentially be modulated and enhanced through cellular engineering. Furthermore, there is considerable interest in employing nanomedicinal approaches to mimic the putative therapeutic properties of EVs by employing synthetic analogues for targeted drug delivery. Herein we describe what is known about the origin and nature of EVs and subsequently review their putative roles in biology and medicine (including the use of synthetic EV analogues), with a particular focus on their role in aging and age-related brain diseases.

Integrated analysis of numerous heterogeneous gene expression profiles for detecting robust disease-specific biomarkers and proposing drug targets.

PubMed

Amar, David; Hait, Tom; Izraeli, Shai; Shamir, Ron

2015-09-18

Genome-wide expression profiling has revolutionized biomedical research; vast amounts of expression data from numerous studies of many diseases are now available. Making the best use of this resource in order to better understand disease processes and treatment remains an open challenge. In particular, disease biomarkers detected in case-control studies suffer from low reliability and are only weakly reproducible. Here, we present a systematic integrative analysis methodology to overcome these shortcomings. We assembled and manually curated more than 14,000 expression profiles spanning 48 diseases and 18 expression platforms. We show that when studying a particular disease, judicious utilization of profiles from other diseases and information on disease hierarchy improves classification quality, avoids overoptimistic evaluation of that quality, and enhances disease-specific biomarker discovery. This approach yielded specific biomarkers for 24 of the analyzed diseases. We demonstrate how to combine these biomarkers with large-scale interaction, mutation and drug target data, forming a highly valuable disease summary that suggests novel directions in disease understanding and drug repurposing. Our analysis also estimates the number of samples required to reach a desired level of biomarker stability. This methodology can greatly improve the exploitation of the mountain of expression profiles for better disease analysis. © The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.

Parietal cells-new perspectives in glomerular disease.

PubMed

Miesen, Laura; Steenbergen, Eric; Smeets, Bart

2017-07-01

In normal glomeruli, parietal epithelial cells (PECs) line the inside of Bowman's capsule and form an inconspicuous sheet of flat epithelial cells in continuity with the proximal tubular epithelial cells (PTECs) at the urinary pole and with the podocytes at the vascular pole. PECs, PTECs and podocytes have a common mesenchymal origin and are the result of divergent differentiation during embryogenesis. Podocytes and PTECs are highly differentiated cells with well-established functions pertaining to the maintenance of the filtration barrier and transport, respectively. For PECs, no specific function other than a structural one has been known until recently. Possible important functions for PECs in the fate of the glomerulus in glomerular disease have now become apparent: (1) PECs may be involved in the replacement of lost podocytes; (2) PECs form the basis of extracapillary proliferative lesions and subsequent sclerosis in glomerular disease. In addition to the acknowledgement that PECs are crucial in glomerular disease, knowledge has been gained regarding the molecular processes driving the phenotypic changes and behavior of PECs. Understanding these molecular processes is important for the development of specific therapeutic approaches aimed at either stimulation of the regenerative function of PECs or inhibition of the pro-sclerotic action of PECs. In this review, we discuss recent advances pertaining to the role of PECs in glomerular regeneration and disease and address the major molecular processes involved.

Mining the Immune Cell Proteome to Identify Ovarian Cancer-Specific Biomarkers

DTIC Science & Technology

2012-03-01

data and are in the process of identifying gene signatures that can be used as biomarkers for the identification of ovarian cancer-specific biomarkers...groups. The groups showed significant difference in age as well as gestational age, which is expected when considering the disease process . Isolation of...MUC4 in intracellular signaling.32 Oligosaccharides attached to the extracellular domains of mucins have also been shown to interact with different

Factors and processes modulating phenotypes in neuronopathic lysosomal storage diseases.

PubMed

Jakóbkiewicz-Banecka, Joanna; Gabig-Cimińska, Magdalena; Banecka-Majkutewicz, Zyta; Banecki, Bogdan; Węgrzyn, Alicja; Węgrzyn, Grzegorz

2014-03-01

Lysosomal storage diseases are inherited metabolic disorders caused by genetic defects causing deficiency of various lysosomal proteins, and resultant accumulation of non-degraded compounds. They are multisystemic diseases, and in most of them (>70%) severe brain dysfunctions are evident. However, expression of various phenotypes in particular diseases is extremely variable, from non-neuronopathic to severely neurodegenerative in the deficiency of the same enzyme. Although all lysosomal storage diseases are monogenic, clear genotype-phenotype correlations occur only in some cases. In this article, we present an overview on various factors and processes, both general and specific for certain disorders, that can significantly modulate expression of phenotypes in these diseases. On the basis of recent reports describing studies on both animal models and clinical data, we propose a hypothesis that efficiency of production of compounds that cannot be degraded due to enzyme deficiency might be especially important in modulation of phenotypes of patients suffering from lysosomal storage diseases.

A combined disease management and process modeling approach for assessing and improving care processes: a fall management case-study.

PubMed

Askari, Marjan; Westerhof, Richard; Eslami, Saied; Medlock, Stephanie; de Rooij, Sophia E; Abu-Hanna, Ameen

2013-10-01

To propose a combined disease management and process modeling approach for evaluating and improving care processes, and demonstrate its usability and usefulness in a real-world fall management case study. We identified essential disease management related concepts and mapped them into explicit questions meant to expose areas for improvement in the respective care processes. We applied the disease management oriented questions to a process model of a comprehensive real world fall prevention and treatment program covering primary and secondary care. We relied on interviews and observations to complete the process models, which were captured in UML activity diagrams. A preliminary evaluation of the usability of our approach by gauging the experience of the modeler and an external validator was conducted, and the usefulness of the method was evaluated by gathering feedback from stakeholders at an invitational conference of 75 attendees. The process model of the fall management program was organized around the clinical tasks of case finding, risk profiling, decision making, coordination and interventions. Applying the disease management questions to the process models exposed weaknesses in the process including: absence of program ownership, under-detection of falls in primary care, and lack of efficient communication among stakeholders due to missing awareness about other stakeholders' workflow. The modelers experienced the approach as usable and the attendees of the invitational conference found the analysis results to be valid. The proposed disease management view of process modeling was usable and useful for systematically identifying areas of improvement in a fall management program. Although specifically applied to fall management, we believe our case study is characteristic of various disease management settings, suggesting the wider applicability of the approach. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Conformational Transitions in Molecular Systems

NASA Astrophysics Data System (ADS)

Bachmann, M.; Janke, W.

2008-11-01

Proteins are the "work horses" in biological systems. In almost all functions specific proteins are involved. They control molecular transport processes, stabilize the cell structure, enzymatically catalyze chemical reactions; others act as molecular motors in the complex machinery of molecular synthetization processes. Due to their significance, misfolds and malfunctions of proteins typically entail disastrous diseases, such as Alzheimer's disease and bovine spongiform encephalopathy (BSE). Therefore, the understanding of the trinity of amino acid composition, geometric structure, and biological function is one of the most essential challenges for the natural sciences. Here, we glance at conformational transitions accompanying the structure formation in protein folding processes.

MicroRNAs in right ventricular remodelling.

PubMed

Batkai, Sandor; Bär, Christian; Thum, Thomas

2017-10-01

Right ventricular (RV) remodelling is a lesser understood process of the chronic, progressive transformation of the RV structure leading to reduced functional capacity and subsequent failure. Besides conditions concerning whole hearts, some pathology selectively affects the RV, leading to a distinct RV-specific clinical phenotype. MicroRNAs have been identified as key regulators of biological processes that drive the progression of chronic diseases. The role of microRNAs in diseases affecting the left ventricle has been studied for many years, however there is still limited information on microRNAs specific to diseases in the right ventricle. Here, we review recently described details on the expression, regulation, and function of microRNAs in the pathological remodelling of the right heart. Recently identified strategies using microRNAs as pharmacological targets or biomarkers will be highlighted. Increasing knowledge of pathogenic microRNAs will finally help improve our understanding of underlying distinct mechanisms and help utilize novel targets or biomarkers to develop treatments for patients suffering from right heart diseases. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Language Processing within the Striatum: Evidence from a PET Correlation Study in Huntington's Disease

ERIC Educational Resources Information Center

Teichmann, Marc; Gaura, Veronique; Demonet, Jean-Francois; Supiot, Frederic; Delliaux, Marie; Verny, Christophe; Renou, Pierre; Remy, Philippe; Bachoud-Levi, Anne-Catherine

2008-01-01

The role of sub-cortical structures in language processing, and more specifically of the striatum, remains controversial. In line with psycholinguistic models stating that language processing implies both the recovery of lexical information and the application of combinatorial rules, the striatum has been claimed to be involved either in the…

Common and specific signatures of gene expression and protein-protein interactions in autoimmune diseases.

PubMed

Tuller, T; Atar, S; Ruppin, E; Gurevich, M; Achiron, A

2013-03-01

The aim of this study is to understand intracellular regulatory mechanisms in peripheral blood mononuclear cells (PBMCs), which are either common to many autoimmune diseases or specific to some of them. We incorporated large-scale data such as protein-protein interactions, gene expression and demographical information of hundreds of patients and healthy subjects, related to six autoimmune diseases with available large-scale gene expression measurements: multiple sclerosis (MS), systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis (JRA), Crohn's disease (CD), ulcerative colitis (UC) and type 1 diabetes (T1D). These data were analyzed concurrently by statistical and systems biology approaches tailored for this purpose. We found that chemokines such as CXCL1-3, 5, 6 and the interleukin (IL) IL8 tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In addition, the anti-apoptotic gene BCL3, interferon-γ (IFNG), and the vitamin D receptor (VDR) gene physically interact with significantly many genes that tend to be differentially expressed in PBMCs of patients with the analyzed autoimmune diseases. In general, similar cellular processes tend to be differentially expressed in PBMC in the analyzed autoimmune diseases. Specifically, the cellular processes related to cell proliferation (for example, epidermal growth factor, platelet-derived growth factor, nuclear factor-κB, Wnt/β-catenin signaling, stress-activated protein kinase c-Jun NH2-terminal kinase), inflammatory response (for example, interleukins IL2 and IL6, the cytokine granulocyte-macrophage colony-stimulating factor and the B-cell receptor), general signaling cascades (for example, mitogen-activated protein kinase, extracellular signal-regulated kinase, p38 and TRK) and apoptosis are activated in most of the analyzed autoimmune diseases. However, our results suggest that in each of the analyzed diseases, apoptosis and chemotaxis are activated via different subsignaling pathways. Analyses of the expression levels of dozens of genes and the protein-protein interactions among them demonstrated that CD and UC have relatively similar gene expression signatures, whereas the gene expression signatures of T1D and JRA relatively differ from the signatures of the other autoimmune diseases. These diseases are the only ones activated via the Fcɛ pathway. The relevant genes and pathways reported in this study are discussed at length, and may be helpful in the diagnoses and understanding of autoimmunity and/or specific autoimmune diseases.

Specific Disruption of Hippocampal Mossy Fiber Synapses in a Mouse Model of Familial Alzheimer's Disease

PubMed Central

Wilke, Scott A.; Raam, Tara; Antonios, Joseph K.; Bushong, Eric A.; Koo, Edward H.; Ellisman, Mark H.; Ghosh, Anirvan

2014-01-01

The earliest stages of Alzheimer's disease (AD) are characterized by deficits in memory and cognition indicating hippocampal pathology. While it is now recognized that synapse dysfunction precedes the hallmark pathological findings of AD, it is unclear if specific hippocampal synapses are particularly vulnerable. Since the mossy fiber (MF) synapse between dentate gyrus (DG) and CA3 regions underlies critical functions disrupted in AD, we utilized serial block-face electron microscopy (SBEM) to analyze MF microcircuitry in a mouse model of familial Alzheimer's disease (FAD). FAD mutant MF terminal complexes were severely disrupted compared to control – they were smaller, contacted fewer postsynaptic spines and had greater numbers of presynaptic filopodial processes. Multi-headed CA3 dendritic spines in the FAD mutant condition were reduced in complexity and had significantly smaller sites of synaptic contact. Significantly, there was no change in the volume of classical dendritic spines at neighboring inputs to CA3 neurons suggesting input-specific defects in the early course of AD related pathology. These data indicate a specific vulnerability of the DG-CA3 network in AD pathogenesis and demonstrate the utility of SBEM to assess circuit specific alterations in mouse models of human disease. PMID:24454724

Inhibition of c-Jun N-terminal kinase activation reverses Alzheimer disease phenotypes in APPswe/PS1dE9 mice.

PubMed

Zhou, Qiong; Wang, Man; Du, Ying; Zhang, Wei; Bai, Miao; Zhang, Zhuo; Li, Zhuyi; Miao, Jianting

2015-04-01

Growing evidence indicates that the activation of c-Jun N-terminal kinase (JNK) is implicated in the multiple major pathological features of Alzheimer disease (AD). However, whether specific inhibition of JNK activation could prevent disease progression in adult transgenic AD models at moderate stage remains unknown. Here we first investigated the potential disease-modifying therapeutic effect of systemic administration of SP600125, a small-molecule JNK-specific inhibitor, in middle-aged APPswe/PS1dE9 mice. Using behavioral, histological, and biochemical methods, outcomes of SP600125 treatment on neuropathology and cognitive deficits were studied in APPswe/PS1dE9 mice. Compared with vehicle-treated APPswe/PS1dE9 mice, chronic treatment of SP600125 for 12 weeks potently inhibited JNK activation, which resulted in a marked improvement of behavioral measures of cognitive deficits and a dramatic reduction in amyloid plaque burden, β-amyloid production, tau hyperphosphorylation, inflammatory responses, and synaptic loss in these transgenic animals. In particular, we found that SP600125 treatment strongly promoted nonamyloidogenic amyloid precursor protein (APP) processing and inhibited amyloidogenic APP processing via regulating APP-cleavage secretase expression (ie, ADAM10, BACE1, and PS1) in APPswe/PS1dE9 mice. Our findings demonstrate that chronic SP600125 treatment is powerfully effective in slowing down disease progression by markedly reducing multiple pathological features and ameliorating cognitive deficits associated with AD. This study highlights the concept that active JNK actually contributes to the development of the disease, and provides critical preclinical evidence that specific inhibition of JNK activation by SP600125 treatment may be a novel promising disease-modifying therapeutic strategy for the treatment of AD. © 2015 American Neurological Association.

Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis.

PubMed

Hamada, Tsuyoshi; Keum, NaNa; Nishihara, Reiko; Ogino, Shuji

2017-03-01

Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on "the unique disease principle," the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine.

Molecular pathological epidemiology: new developing frontiers of big data science to study etiologies and pathogenesis

PubMed Central

Hamada, Tsuyoshi; Keum, NaNa; Nishihara, Reiko; Ogino, Shuji

2016-01-01

Molecular pathological epidemiology (MPE) is an integrative field that utilizes molecular pathology to incorporate interpersonal heterogeneity of a disease process into epidemiology. In each individual, the development and progression of a disease are determined by a unique combination of exogenous and endogenous factors, resulting in different molecular and pathological subtypes of the disease. Based on “the unique disease principle,” the primary aim of MPE is to uncover an interactive relationship between a specific environmental exposure and disease subtypes in determining disease incidence and mortality. This MPE approach can provide etiologic and pathogenic insights, potentially contributing to precision medicine for personalized prevention and treatment. Although breast, prostate, lung, and colorectal cancers have been among the most commonly studied diseases, the MPE approach can be used to study any disease. In addition to molecular features, host immune status and microbiome profile likely affect a disease process, and thus serve as informative biomarkers. As such, further integration of several disciplines into MPE has been achieved (e.g., pharmaco-MPE, immuno-MPE, and microbial MPE), to provide novel insights into underlying etiologic mechanisms. With the advent of high-throughput sequencing technologies, available genomic and epigenomic data have expanded dramatically. The MPE approach can also provide a specific risk estimate for each disease subgroup, thereby enhancing the impact of genome-wide association studies on public health. In this article, we present recent progress of MPE, and discuss the importance of accounting for the disease heterogeneity in the era of big-data health science and precision medicine. PMID:27738762

Alterations in the Ubiquitin Proteasome System in Persistent but Not Reversible Proteinuric Diseases

PubMed Central

Beeken, Maire; Lindenmeyer, Maja T.; Blattner, Simone M.; Radón, Victoria; Oh, Jun; Meyer, Tobias N.; Hildebrand, Diana; Schlüter, Hartmut; Reinicke, Anna T.; Knop, Jan-Hendrik; Vivekanandan-Giri, Anuradha; Münster, Silvia; Sachs, Marlies; Wiech, Thorsten; Pennathur, Subramaniam; Cohen, Clemens D.; Kretzler, Matthias; Stahl, Rolf A.K.

2014-01-01

Podocytes are the key cells affected in nephrotic glomerular kidney diseases, and they respond uniformly to injury with cytoskeletal rearrangement. In nephrotic diseases, such as membranous nephropathy and FSGS, persistent injury often leads to irreversible structural damage, whereas in minimal change disease, structural alterations are mostly transient. The factors leading to persistent podocyte injury are currently unknown. Proteolysis is an irreversible process and could trigger persistent podocyte injury through degradation of podocyte-specific proteins. We, therefore, analyzed the expression and functional consequence of the two most prominent proteolytic systems, the ubiquitin proteasome system (UPS) and the autophagosomal/lysosomal system, in persistent and transient podocyte injuries. We show that differential upregulation of both proteolytic systems occurs in persistent human and rodent podocyte injury. The expression of specific UPS proteins in podocytes differentiated children with minimal change disease from children with FSGS and correlated with poor clinical outcome. Degradation of the podocyte-specific protein α-actinin-4 by the UPS depended on oxidative modification in membranous nephropathy. Notably, the UPS was overwhelmed in podocytes during experimental glomerular disease, resulting in abnormal protein accumulation and compensatory upregulation of the autophagosomal/lysosomal system. Accordingly, inhibition of both proteolytic systems enhanced proteinuria in persistent nephrotic disease. This study identifies altered proteolysis as a feature of persistent podocyte injury. In the future, specific UPS proteins may serve as new biomarkers or therapeutic targets in persistent nephrotic syndrome. PMID:24722446

Central Pain Processing in Early-Stage Parkinson's Disease: A Laser Pain fMRI Study

PubMed Central

Petschow, Christine; Scheef, Lukas; Paus, Sebastian; Zimmermann, Nadine; Schild, Hans H.; Klockgether, Thomas; Boecker, Henning

2016-01-01

Background & Objective Pain is a common non-motor symptom in Parkinson’s disease. As dopaminergic dysfunction is suggested to affect intrinsic nociceptive processing, this study was designed to characterize laser-induced pain processing in early-stage Parkinson’s disease patients in the dopaminergic OFF state, using a multimodal experimental approach at behavioral, autonomic, imaging levels. Methods 13 right-handed early-stage Parkinson’s disease patients without cognitive or sensory impairment were investigated OFF medication, along with 13 age-matched healthy control subjects. Measurements included warmth perception thresholds, heat pain thresholds, and central pain processing with event-related functional magnetic resonance imaging (erfMRI) during laser-induced pain stimulation at lower (E = 440 mJ) and higher (E = 640 mJ) target energies. Additionally, electrodermal activity was characterized during delivery of 60 randomized pain stimuli ranging from 440 mJ to 640 mJ, along with evaluation of subjective pain ratings on a visual analogue scale. Results No significant differences in warmth perception thresholds, heat pain thresholds, electrodermal activity and subjective pain ratings were found between Parkinson’s disease patients and controls, and erfMRI revealed a generally comparable activation pattern induced by laser-pain stimuli in brain areas belonging to the central pain matrix. However, relatively reduced deactivation was found in Parkinson’s disease patients in posterior regions of the default mode network, notably the precuneus and the posterior cingulate cortex. Conclusion Our data during pain processing extend previous findings suggesting default mode network dysfunction in Parkinson’s disease. On the other hand, they argue against a genuine pain-specific processing abnormality in early-stage Parkinson’s disease. Future studies are now required using similar multimodal experimental designs to examine pain processing in more advanced stages of Parkinson’s disease. PMID:27776130

Lung capillary injury and repair in left heart disease: a new target for therapy?

PubMed

Azarbar, Sayena; Dupuis, Jocelyn

2014-07-01

The lungs are the primary organs affected in LHD (left heart disease). Increased left atrial pressure leads to pulmonary alveolar-capillary stress failure, resulting in cycles of alveolar wall injury and repair. The reparative process causes the proliferation of MYFs (myofibroblasts) with fibrosis and extracellular matrix deposition, resulting in thickening of the alveolar wall. Although the resultant reduction in vascular permeability is initially protective against pulmonary oedema, the process becomes maladaptive causing a restrictive lung syndrome with impaired gas exchange. This pathological process may also contribute to PH (pulmonary hypertension) due to LHD. Few clinical trials have specifically evaluated lung structural remodelling and the effect of related therapies in LHD. Currently approved treatment for chronic HF (heart failure) may have direct beneficial effects on lung structural remodelling. In the future, novel therapies specifically targeting the remodelling processes may potentially be utilized. In the present review, we summarize data supporting the clinical importance and pathophysiological mechanisms of lung structural remodelling in LHD and propose that this pathophysiological process should be explored further in pre-clinical studies and future therapeutic trials.

[Fibrous tissue(s): a key for lesion characterization in digestive diseases].

PubMed

Régent, D; Laurent, V; Antunes, L; Debelle, L; Cannard, L; Leclerc, Jc; Beot, S

2002-02-01

Fibrosis is one of the hallmarks of inflammatory and repair processes in pathology. Various exogenous and endogenous stimuli, including tumor development, can induce inflammatory reactions. During the post-equilibrium phase after IV injection of non specific contrast media, CT and/or MR allow the study of these inflammatory answers to tumoral or infectious processes. Delayed enhancement of collagenic fibrous tissue during the late post-equilibrium phase is an essential complementary data in the characterization of many liver lesions: cirrhosis, cholangiocarcinoma, focal nodular hyperplasia, fibrous metastasis. but also for the differential diagnosis of pancreatic diseases (groove pancreatitis vs ductal adenocarcinoma) or of gastro-intestinal diseases (gastric adenocarcinoma vs lymphoma, mechanical complication vs inflammatory bouts of ileal Crohn's disease).

Advances of Molecular Imaging for Monitoring the Anatomical and Functional Architecture of the Olfactory System.

PubMed

Zhang, Xintong; Bi, Anyao; Gao, Quansheng; Zhang, Shuai; Huang, Kunzhu; Liu, Zhiguo; Gao, Tang; Zeng, Wenbin

2016-01-20

The olfactory system of organisms serves as a genetically and anatomically model for studying how sensory input can be translated into behavior output. Some neurologic diseases are considered to be related to olfactory disturbance, especially Alzheimer's disease, Parkinson's disease, multiple sclerosis, and so forth. However, it is still unclear how the olfactory system affects disease generation processes and olfaction delivery processes. Molecular imaging, a modern multidisciplinary technology, can provide valid tools for the early detection and characterization of diseases, evaluation of treatment, and study of biological processes in living subjects, since molecular imaging applies specific molecular probes as a novel approach to produce special data to study biological processes in cellular and subcellular levels. Recently, molecular imaging plays a key role in studying the activation of olfactory system, thus it could help to prevent or delay some diseases. Herein, we present a comprehensive review on the research progress of the imaging probes for visualizing olfactory system, which is classified on different imaging modalities, including PET, MRI, and optical imaging. Additionally, the probes' design, sensing mechanism, and biological application are discussed. Finally, we provide an outlook for future studies in this field.

Autophagy and its implication in human oral diseases.

PubMed

Tan, Ya-Qin; Zhang, Jing; Zhou, Gang

2017-02-01

Macroautophagy/autophagy is a conserved lysosomal degradation process essential for cell physiology and human health. By regulating apoptosis, inflammation, pathogen clearance, immune response and other cellular processes, autophagy acts as a modulator of pathogenesis and is a potential therapeutic target in diverse diseases. With regard to oral disease, autophagy can be problematic either when it is activated or impaired, because this process is involved in diverse functions, depending on the specific disease and its level of progression. In particular, activated autophagy functions as a cytoprotective mechanism under environmental stress conditions, which regulates tumor growth and mediates resistance to anticancer treatment in established tumors. During infections and inflammation, activated autophagy selectively delivers microbial antigens to the immune systems, and is therefore connected to the elimination of intracellular pathogens. Impaired autophagy contributes to oxidative stress, genomic instability, chronic tissue damage, inflammation and tumorigenesis, and is involved in aberrant bacterial clearance and immune priming. Hence, substantial progress in the study of autophagy provides new insights into the pathogenesis of oral diseases. This review outlines the mechanisms of autophagy, and highlights the emerging roles of this process in oral cancer, periapical lesions, periodontal diseases, and oral candidiasis.

Autophagy and its implication in human oral diseases

PubMed Central

Tan, Ya-Qin; Zhang, Jing; Zhou, Gang

2017-01-01

ABSTRACT Macroautophagy/autophagy is a conserved lysosomal degradation process essential for cell physiology and human health. By regulating apoptosis, inflammation, pathogen clearance, immune response and other cellular processes, autophagy acts as a modulator of pathogenesis and is a potential therapeutic target in diverse diseases. With regard to oral disease, autophagy can be problematic either when it is activated or impaired, because this process is involved in diverse functions, depending on the specific disease and its level of progression. In particular, activated autophagy functions as a cytoprotective mechanism under environmental stress conditions, which regulates tumor growth and mediates resistance to anticancer treatment in established tumors. During infections and inflammation, activated autophagy selectively delivers microbial antigens to the immune systems, and is therefore connected to the elimination of intracellular pathogens. Impaired autophagy contributes to oxidative stress, genomic instability, chronic tissue damage, inflammation and tumorigenesis, and is involved in aberrant bacterial clearance and immune priming. Hence, substantial progress in the study of autophagy provides new insights into the pathogenesis of oral diseases. This review outlines the mechanisms of autophagy, and highlights the emerging roles of this process in oral cancer, periapical lesions, periodontal diseases, and oral candidiasis. PMID:27764582

From Pathways to Targets: Understanding the Mechanisms behind Polyglutamine Disease

PubMed Central

Weber, Jonasz Jeremiasz; Sowa, Anna Sergeevna

2014-01-01

The history of polyglutamine diseases dates back approximately 20 years to the discovery of a polyglutamine repeat in the androgen receptor of SBMA followed by the identification of similar expansion mutations in Huntington's disease, SCA1, DRPLA, and the other spinocerebellar ataxias. This common molecular feature of polyglutamine diseases suggests shared mechanisms in disease pathology and neurodegeneration of disease specific brain regions. In this review, we discuss the main pathogenic pathways including proteolytic processing, nuclear shuttling and aggregation, mitochondrial dysfunction, and clearance of misfolded polyglutamine proteins and point out possible targets for treatment. PMID:25309920

Quantitative Stratification of Diffuse Parenchymal Lung Diseases

PubMed Central

Raghunath, Sushravya; Rajagopalan, Srinivasan; Karwoski, Ronald A.; Maldonado, Fabien; Peikert, Tobias; Moua, Teng; Ryu, Jay H.; Bartholmai, Brian J.; Robb, Richard A.

2014-01-01

Diffuse parenchymal lung diseases (DPLDs) are characterized by widespread pathological changes within the pulmonary tissue that impair the elasticity and gas exchange properties of the lungs. Clinical-radiological diagnosis of these diseases remains challenging and their clinical course is characterized by variable disease progression. These challenges have hindered the introduction of robust objective biomarkers for patient-specific prediction based on specific phenotypes in clinical practice for patients with DPLD. Therefore, strategies facilitating individualized clinical management, staging and identification of specific phenotypes linked to clinical disease outcomes or therapeutic responses are urgently needed. A classification schema consistently reflecting the radiological, clinical (lung function and clinical outcomes) and pathological features of a disease represents a critical need in modern pulmonary medicine. Herein, we report a quantitative stratification paradigm to identify subsets of DPLD patients with characteristic radiologic patterns in an unsupervised manner and demonstrate significant correlation of these self-organized disease groups with clinically accepted surrogate endpoints. The proposed consistent and reproducible technique could potentially transform diagnostic staging, clinical management and prognostication of DPLD patients as well as facilitate patient selection for clinical trials beyond the ability of current radiological tools. In addition, the sequential quantitative stratification of the type and extent of parenchymal process may allow standardized and objective monitoring of disease, early assessment of treatment response and mortality prediction for DPLD patients. PMID:24676019

Mapping the “What” and “Where” Visual Cortices and Their Atrophy in Alzheimer's Disease: Combined Activation Likelihood Estimation with Voxel-Based Morphometry

PubMed Central

Deng, Yanjia; Shi, Lin; Lei, Yi; Liang, Peipeng; Li, Kuncheng; Chu, Winnie C. W.; Wang, Defeng

2016-01-01

The human cortical regions for processing high-level visual (HLV) functions of different categories remain ambiguous, especially in terms of their conjunctions and specifications. Moreover, the neurobiology of declined HLV functions in patients with Alzheimer's disease (AD) has not been fully investigated. This study provides a functionally sorted overview of HLV cortices for processing “what” and “where” visual perceptions and it investigates their atrophy in AD and MCI patients. Based upon activation likelihood estimation (ALE), brain regions responsible for processing five categories of visual perceptions included in “what” and “where” visions (i.e., object, face, word, motion, and spatial visions) were analyzed, and subsequent contrast analyses were performed to show regions with conjunctive and specific activations for processing these visual functions. Next, based on the resulting ALE maps, the atrophy of HLV cortices in AD and MCI patients was evaluated using voxel-based morphometry. Our ALE results showed brain regions for processing visual perception across the five categories, as well as areas of conjunction and specification. Our comparisons of gray matter (GM) volume demonstrated atrophy of three “where” visual cortices in late MCI group and extensive atrophy of HLV cortices (25 regions in both “what” and “where” visual cortices) in AD group. In addition, the GM volume of atrophied visual cortices in AD and MCI subjects was found to be correlated to the deterioration of overall cognitive status and to the cognitive performances related to memory, execution, and object recognition functions. In summary, these findings may add to our understanding of HLV network organization and of the evolution of visual perceptual dysfunction in AD as the disease progresses. PMID:27445770

Isolation of Precursor Cells from Waste Solid Fat Tissue

NASA Technical Reports Server (NTRS)

Byerly, Diane; Sognier, Marguerite A.

2009-01-01

A process for isolating tissue-specific progenitor cells exploits solid fat tissue obtained as waste from such elective surgical procedures as abdominoplasties (tummy tucks) and breast reductions. Until now, a painful and risky process of aspiration of bone marrow has been used to obtain a limited number of tissue- specific progenitor cells. The present process yields more tissue-specific progenitor cells and involves much less pain and risk for the patient. This process includes separation of fat from skin, mincing of the fat into small pieces, and forcing a fat saline mixture through a sieve. The mixture is then digested with collagenase type I in an incubator. After centrifugation tissue-specific progenitor cells are recovered and placed in a tissue-culture medium in flasks or Petri dishes. The tissue-specific progenitor cells can be used for such purposes as (1) generating three-dimensional tissue equivalent models for studying bone loss and muscle atrophy (among other deficiencies) and, ultimately, (2) generating replacements for tissues lost by the fat donor because of injury or disease.

Healthy aging: The ultimate preventative medicine.

PubMed

Kaeberlein, Matt; Rabinovitch, Peter S; Martin, George M

2015-12-04

Age is the greatest risk factor for nearly every major cause of mortality in developed nations. Despite this, most biomedical research focuses on individual disease processes without much consideration for the relationships between aging and disease. Recent discoveries in the field of geroscience, which aims to explain biological mechanisms of aging, have provided insights into molecular processes that underlie biological aging and, perhaps more importantly, potential interventions to delay aging and promote healthy longevity. Here we describe some of these advances, along with efforts to move geroscience from the bench to the clinic. We also propose that greater emphasis should be placed on research into basic aging processes, because interventions that slow aging will have a greater effect on quality of life compared with disease-specific approaches. Copyright © 2015, American Association for the Advancement of Science.

[Practical guidelines for genetic testing in cardiovascular diseases].

PubMed

Reinhard, W; Trenkwalder, T; Schunkert, H

2017-08-01

In the last decade, genetic testing for cardiovascular disorders has become more and more relevant. Progress in molecular genetics has led to new opportunities for diagnostics, improved risk prediction and could lead to novel therapeutic approaches. Genetic diagnostic testing is relevant for both confirming a diagnosis as well as deciding on therapeutic consequences, if applicable. Furthermore, predictive testing in family members for specific cardiovascular diseases is now a standard procedure in holistic patient management. The process of genetic testing as well as documentation requirements and discussion of test results with patients are subject to legal regulations. These regulations might be confusing for clinical practitioners/cardiologists. The aim of this article is to provide a clinical framework for genetic testing. First, we explain the legal and ethical background. Second, we illustrate the process of genetic testing step by step and present updates on remuneration. Finally, we discuss the significance of genetic testing and specific disease indications in cardiology.

A survey of basic reproductive ratios in vector-borne disease transmission modeling

NASA Astrophysics Data System (ADS)

Soewono, E.; Aldila, D.

2015-03-01

Vector-borne diseases are commonly known in tropical and subtropical countries. These diseases have contributed to more than 10% of world infectious disease cases. Among the vectors responsible for transmitting the diseases are mosquitoes, ticks, fleas, flies, bugs and worms. Several of the diseases are known to contribute to the increasing threat to human health such as malaria, dengue, filariasis, chikungunya, west nile fever, yellow fever, encephalistis, and anthrax. It is necessary to understand the real process of infection, factors which contribute to the complication of the transmission in order to come up with a good and sound mathematical model. Although it is not easy to simulate the real transmission process of the infection, we could say that almost all models have been developed from the already long known Host-Vector model. It constitutes the main transmission processes i.e. birth, death, infection and recovery. From this simple model, the basic concepts of Disease Free and Endemic Equilibria and Basic Reproductive Ratio can be well explained and understood. Theoretical, modeling, control and treatment aspects of disease transmission problems have then been developed for various related diseases. General construction as well as specific forms of basic reproductive ratios for vector-borne diseases are discusses here.

The role of egocentric and allocentric abilities in Alzheimer's disease: a systematic review.

PubMed

Serino, Silvia; Cipresso, Pietro; Morganti, Francesca; Riva, Giuseppe

2014-07-01

A great effort has been made to identify crucial cognitive markers that can be used to characterize the cognitive profile of Alzheimer's disease (AD). Because topographical disorientation is one of the earliest clinical manifestation of AD, an increasing number of studies have investigated the spatial deficits in this clinical population. In this systematic review, we specifically focused on experimental studies investigating allocentric and egocentric deficits to understand which spatial cognitive processes are differentially impaired in the different stages of the disease. First, our results highlighted that spatial deficits appear in the earliest stages of the disease. Second, a need for a more ecological assessment of spatial functions will be presented. Third, our analysis suggested that a prevalence of allocentric impairment exists. Specifically, two selected studies underlined that a more specific impairment is found in the translation between the egocentric and allocentric representations. In this perspective, the implications for future research and neurorehabilitative interventions will be discussed. Copyright © 2014 Elsevier B.V. All rights reserved.

Unusual causes of abdominal pain: sickle cell anemia.

PubMed

Ahmed, Shahid; Shahid, Rabia K; Russo, Linda A

2005-04-01

Sickle cell disease is characterized by chronic hemolytic anemia and vaso-occlusive painful crises. The vascular occlusion in sickle cell disease is a complex process and accounts for the majority of the clinical manifestation of the disease. Abdominal pain is an important component of vaso-occlusive painful crises. It often represents a substantial diagnostic challenge in this population of patients. These episodes are often attributed to micro-vessel occlusion and infarcts of mesentery and abdominal viscera. Abdominal pain due to sickle cell vaso-occlusive crisis is often indistinguishable from an acute intra-abdominal disease process such as acute cholecystitis, acute pancreatitis, hepatic infarction, ischemic colitis and acute appendicitis. In the majority of cases, however, no specific cause is identified and spontaneous resolution occurs. This chapter will focus on etiologies, pathophysiology and management of abdominal pain in patients with sickle cell disease.

Development of a quality-of-life instrument for autoimmune bullous disease: the Autoimmune Bullous Disease Quality of Life questionnaire.

PubMed

Sebaratnam, Deshan F; Hanna, Anna Marie; Chee, Shien-ning; Frew, John W; Venugopal, Supriya S; Daniel, Benjamin S; Martin, Linda K; Rhodes, Lesley M; Tan, Jeremy Choon Kai; Wang, Charles Qian; Welsh, Belinda; Nijsten, Tamar; Murrell, Dédée F

2013-10-01

Quality-of-life (QOL) evaluation is an increasingly important outcome measure in dermatology, with disease-specific QOL instruments being the most sensitive to changes in disease status. To develop a QOL instrument specific to autoimmune bullous disease (AIBD). A comprehensive item generation process was used to build a 45-item pilot Autoimmune Bullous Disease Quality of Life (ABQOL) questionnaire, distributed to 70 patients with AIBD. Experts in bullous disease refined the pilot ABQOL before factor analysis was performed to yield the final ABQOL questionnaire of 17 questions. We evaluated validity and reliability across a range of indices. Australian dermatology outpatient clinics and private dermatology practices. PATIENTS AND EXPOSURE: Patients with a histological diagnosis of AIBD. The development of an AIBD-specific QOL instrument. Face and content validity were established through the comprehensive patient interview process and expert review. In terms of convergent validity, the ABQOL was found to have a moderate correlation with scores on the Dermatology Life Quality Index (R = 0.63) and the General Health subscale of the 36-Item Short Form Health Survey (R = 0.69; P = .009) and low correlation with the Pemphigus Disease Area Index (R = 0.42) and Autoimmune Bullous Disease Skin Disorder Intensity Score (R = 0.48). In terms of discriminant validity, the ABQOL was found to be more sensitive than the Dermatology Life Quality Index (P = .02). The ABQOL was also found to be a reliable instrument evaluated by internal consistency (Cronbach α coefficient, 0.84) and test-retest reliability (mean percentage variation, 0.92). The ABQOL has been shown to be a valid and reliable instrument that may serve as an end point in clinical trials. Future work should include incorporating patient weighting on questions to further increase content validity and translation of the measure to other languages. anzctr.org.au Identifier: ACTRN12612000750886.

Avian cardiology.

PubMed

Strunk, Anneliese; Wilson, G Heather

2003-01-01

The field of avian cardiology is continually expanding. Although a great deal of the current knowledge base has been derived from poultry data, research and clinical reports involving companion avian species have been published. This article will present avian cardiovascular anatomy and physiology, history and physical examination considerations in the avian cardiac disease patient, specific diagnostic tools, cardiovascular disease processes, and current therapeutic modalities.

An Integrated Framework for Process-Driven Model Construction in Disease Ecology and Animal Health

PubMed Central

Mancy, Rebecca; Brock, Patrick M.; Kao, Rowland R.

2017-01-01

Process models that focus on explicitly representing biological mechanisms are increasingly important in disease ecology and animal health research. However, the large number of process modelling approaches makes it difficult to decide which is most appropriate for a given disease system and research question. Here, we discuss different motivations for using process models and present an integrated conceptual analysis that can be used to guide the construction of infectious disease process models and comparisons between them. Our presentation complements existing work by clarifying the major differences between modelling approaches and their relationship with the biological characteristics of the epidemiological system. We first discuss distinct motivations for using process models in epidemiological research, identifying the key steps in model design and use associated with each. We then present a conceptual framework for guiding model construction and comparison, organised according to key aspects of epidemiological systems. Specifically, we discuss the number and type of disease states, whether to focus on individual hosts (e.g., cows) or groups of hosts (e.g., herds or farms), how space or host connectivity affect disease transmission, whether demographic and epidemiological processes are periodic or can occur at any time, and the extent to which stochasticity is important. We use foot-and-mouth disease and bovine tuberculosis in cattle to illustrate our discussion and support explanations of cases in which different models are used to address similar problems. The framework should help those constructing models to structure their approach to modelling decisions and facilitate comparisons between models in the literature. PMID:29021983

An Integrated Framework for Process-Driven Model Construction in Disease Ecology and Animal Health.

PubMed

Mancy, Rebecca; Brock, Patrick M; Kao, Rowland R

2017-01-01

Process models that focus on explicitly representing biological mechanisms are increasingly important in disease ecology and animal health research. However, the large number of process modelling approaches makes it difficult to decide which is most appropriate for a given disease system and research question. Here, we discuss different motivations for using process models and present an integrated conceptual analysis that can be used to guide the construction of infectious disease process models and comparisons between them. Our presentation complements existing work by clarifying the major differences between modelling approaches and their relationship with the biological characteristics of the epidemiological system. We first discuss distinct motivations for using process models in epidemiological research, identifying the key steps in model design and use associated with each. We then present a conceptual framework for guiding model construction and comparison, organised according to key aspects of epidemiological systems. Specifically, we discuss the number and type of disease states, whether to focus on individual hosts (e.g., cows) or groups of hosts (e.g., herds or farms), how space or host connectivity affect disease transmission, whether demographic and epidemiological processes are periodic or can occur at any time, and the extent to which stochasticity is important. We use foot-and-mouth disease and bovine tuberculosis in cattle to illustrate our discussion and support explanations of cases in which different models are used to address similar problems. The framework should help those constructing models to structure their approach to modelling decisions and facilitate comparisons between models in the literature.

Protease-mediated drug delivery

NASA Astrophysics Data System (ADS)

Dickson, Eva F.; Goyan, Rebecca L.; Kennedy, James C.; Mackay, M.; Mendes, M. A. K.; Pottier, Roy H.

2003-12-01

Drugs used in disease treatment can cause damage to both malignant and normal tissue. This toxicity limits the maximum therapeutic dose. Drug targeting is of high interest to increase the therapeutic efficacy of the drug without increasing systemic toxicity. Certain tissue abnormalities, disease processes, cancers, and infections are characterized by high levels of activity of specific extracellular and/or intracellular proteases. Abnormally high activity levels of specific proteases are present at sites of physical or chemical trauma, blood clots, malignant tumors, rheumatoid arthritis, inflammatory bowel disease, gingival disease, glomerulonerphritis, and acute pancreatitis. Abnormal protease activity is suspected in development of liver thrombosis, pulmonary emphysema, atherosclerosis, and muscular dystrophy. Inactiviating disease-associated proteases by the administration of appropriate protease inhibitors has had limited success. Instead, one could use such proteases to target drugs to treat the condition. Protease mediated drug delivery offers such a possibility. Solubilizing groups are attached to insoluble drugs via a polypeptide chain which is specifically cleavable by certian proteases. When the solubilized drug enounters the protease, the solubilizing moieties are cleaved, and the drug precipitates at the disease location. Thus, a smaller systemic dosage could result in a therapeutic drug concentration at the treatment site with less systemic toxicity.

Interrelationship of canonical and non-canonical Wnt signalling pathways in chronic metabolic diseases.

PubMed

Ackers, Ian; Malgor, Ramiro

2018-01-01

Chronic diseases account for approximately 45% of all deaths in developed countries and are particularly prevalent in countries with the most sophisticated and robust public health systems. Chronic metabolic diseases, specifically lifestyle-related diseases pertaining to diet and exercise, continue to be difficult to treat clinically. The most prevalent of these chronic metabolic diseases include obesity, diabetes, non-alcoholic fatty liver disease, chronic kidney disease and cardiovascular disease and will be the focus of this review. Wnt proteins are highly conserved glycoproteins best known for their role in development and homeostasis of tissues. Given the importance of Wnt signalling in homeostasis, aberrant Wnt signalling likely regulates metabolic processes and may contribute to the development of chronic metabolic diseases. Expression of Wnt proteins and dysfunctional Wnt signalling has been reported in multiple chronic diseases. It is interesting to speculate about an interrelationship between the Wnt signalling pathways as a potential pathological mechanism in chronic metabolic diseases. The aim of this review is to summarize reported findings on the contrasting roles of Wnt signalling in lifestyle-related chronic metabolic diseases; specifically, the contribution of Wnt signalling to lipid accumulation, fibrosis and chronic low-grade inflammation.

Degos' disease: a distinctive pattern of disease, chiefly of lupus erythematosus, and not a specific disease per se.

PubMed

Ball, Elizabeth; Newburger, Amy; Ackerman, A Bernard

2003-08-01

Degos' disease, known confusingly as malignant strophic papularis, is an uncommon condition of unknown cause characterized by distinctive infarctive lesions in the skin, gastrointestinal tract, and central nervous system; the lesions at the two latter sites often result in death. We deem Degos' disease to be analogous to lupus erythematosus in the sense that each is fundamentally a systemic pathologic process involving several organs, among them the skin, but, moreover, we regard Degos' disease, in most instances, to be an actual manifestation of lupus erythematosus. Histopathologically, the findings in sections of tissue of skin lesions of Degos' disease are indistinguishable from those of one expression of cutaneous lupus erythematosus; immunopathologically, some patients with morphologic findings stereotypical of Degos' disease display signs characteristic of lupus erythematosus. For these reasons, we consider Degos' disease to be a distinctive pattern of disease, rather than a specific disease per se, just as are erythema multiforme, erythema nodosum, leukocytoclastic vasculitis, Sweet's syndrome, and pyoderma gangrenosum, to name but five of scores of them. The singular pattern that is designated Degos' disease usually is an expression of lupus erythematosus, but, episodically, of conditions like dermatomyositis and rheumatoid arthritis.

Facial feedback and autonomic responsiveness reflect impaired emotional processing in Parkinson's Disease.

PubMed

Balconi, Michela; Pala, Francesca; Manenti, Rosa; Brambilla, Michela; Cobelli, Chiara; Rosini, Sandra; Benussi, Alberto; Padovani, Alessandro; Borroni, Barbara; Cotelli, Maria

2016-08-11

Emotional deficits are part of the non-motor features of Parkinson's disease but few attention has been paid to specific aspects such as subjective emotional experience and autonomic responses. This study aimed to investigate the mechanisms of emotional recognition in Parkinson's Disease (PD) using the following levels: explicit evaluation of emotions (Self-Assessment Manikin) and implicit reactivity (Skin Conductance Response; electromyographic measure of facial feedback of the zygomaticus and corrugator muscles). 20 PD Patients and 34 healthy controls were required to observe and evaluate affective pictures during physiological parameters recording. In PD, the appraisal process on both valence and arousal features of emotional cues were preserved, but we found significant impairment in autonomic responses. Specifically, in comparison to healthy controls, PD patients revealed lower Skin Conductance Response values to negative and high arousing emotional stimuli. In addition, the electromyographic measures showed defective responses exclusively limited to negative and high arousing emotional category: PD did not show increasing of corrugator activity in response to negative emotions as happened in heathy controls. PD subjects inadequately respond to the emotional categories which were considered more "salient": they had preserved appraisal process, but impaired automatic ability to distinguish between different emotional contexts.

Strategic Protein Target Analysis for Developing Drugs to Stop Dental Caries

PubMed Central

Horst, J.A.; Pieper, U.; Sali, A.; Zhan, L.; Chopra, G.; Samudrala, R.; Featherstone, J.D.B.

2012-01-01

Dental caries is the most common disease to cause irreversible damage in humans. Several therapeutic agents are available to treat or prevent dental caries, but none besides fluoride has significantly influenced the disease burden globally. Etiologic mechanisms of the mutans group streptococci and specific Lactobacillus species have been characterized to various degrees of detail, from identification of physiologic processes to specific proteins. Here, we analyze the entire Streptococcus mutans proteome for potential drug targets by investigating their uniqueness with respect to non-cariogenic dental plaque bacteria, quality of protein structure models, and the likelihood of finding a drug for the active site. Our results suggest specific targets for rational drug discovery, including 15 known virulence factors, 16 proteins for which crystallographic structures are available, and 84 previously uncharacterized proteins, with various levels of similarity to homologs in dental plaque bacteria. This analysis provides a map to streamline the process of clinical development of effective multispecies pharmacologic interventions for dental caries. PMID:22899687

Recent advances in the diagnosis and treatment of niemann-pick disease type C in children: a guide to early diagnosis for the general pediatrician.

PubMed

Alobaidy, Hanna

2015-01-01

Niemann-Pick disease (NP-C) is a lysosomal storage disease in which impaired intracellular lipid transport leads to accumulation of cholesterol and glycosphingolipids in various neurovisceral tissues. It is an autosomal recessive disorder, caused by mutations in the NPC1 or NPC2 genes. The clinical spectrum is grouped by the age of onset and onset of neurological manifestation: pre/perinatal; early infantile; late infantile; and juvenile periods. The NP-C Suspicion Index (SI) screening tool was developed to identify suspected patients with this disease. It is especially good at recognizing the disease in patients older than four years of age. Biochemical tests involving genetic markers and Filipin staining of skin fibroblast are being employed to assist diagnosis. Therapy is mostly supportive and since 2009, the first specific therapy approved for use was Miglustat (Zavesca) aimed at stabilizing the rate of progression of neurological manifestation. The prognosis correlates with age at onset of neurological signs; patients with early onset form progress faster. The NP-C disease has heterogeneous neurovisceral manifestations. A SI is a screening tool that helps in diagnostic process. Filipin staining test is a specific biomarker diagnostic test. Miglustat is the first disease-specific therapy.

The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels

PubMed Central

Salazar, Dominique A.; Butler, Victoria J.; Argouarch, Andrea R.; Hsu, Tsung-Yuan; Mason, Amanda; Nakamura, Ayumi; McCurdy, Helen; Cox, David; Ng, Rachel; Pan, Gloria; Seeley, William W.; Miller, Bruce L.

2015-01-01

Mutations in the human progranulin gene resulting in protein haploinsufficiency cause frontotemporal lobar degeneration with TDP-43 inclusions. Although progress has been made in understanding the normal functions of progranulin and TDP-43, the molecular interactions between these proteins remain unclear. Progranulin is proteolytically processed into granulins, but the role of granulins in the pathogenesis of neurodegenerative disease is unknown. We used a Caenorhabditis elegans model of neuronal TDP-43 proteinopathy to specifically interrogate the contribution of granulins to the neurodegenerative process. Complete loss of the progranulin gene did not worsen TDP-43 toxicity, whereas progranulin heterozygosity did. Interestingly, expression of individual granulins alone had little effect on behavior. In contrast, when granulins were coexpressed with TDP-43, they exacerbated its toxicity in a variety of behaviors including motor coordination. These same granulins increased TDP-43 levels via a post-translational mechanism. We further found that in human neurodegenerative disease subjects, granulin fragments accumulated specifically in diseased regions of brain. To our knowledge, this is the first demonstration of a toxic role for granulin fragments in a neurodegenerative disease model. These studies suggest that presence of cleaved granulins, rather than or in addition to loss of full-length progranulin, may contribute to disease in TDP-43 proteinopathies. PMID:26109656

Combining functionalised nanoparticles and SERS for the detection of DNA relating to disease.

PubMed

Graham, Duncan; Stevenson, Ross; Thompson, David G; Barrett, Lee; Dalton, Colette; Faulds, Karen

2011-01-01

DNA functionalised nanoparticle probes offer new opportunities in analyte detection. Ultrasensitive, molecularly specific targeting of analytes is possible through the use of metallic nanoparticles and their ability to generate a surface enhanced Raman scattering (SERS) response. This is leading to a new range of diagnostic clinical probes based on SERS detection. Our approaches have shown how such probes can detect specific DNA sequences by using a biomolecular recognition event to 'turn on' a SERS response through a controlled assembly process of the DNA functionalised nanoparticles. Further, we have prepared DNA aptamer functionalised SERS probes and demonstrated how introduction of a protein target can change the aggregation state of the nanoparticles in a dose-dependant manner. These approaches are being used as methods to detect biomolecules that indicate a specific disease being present with a view to improving disease management.

Detection of magnetically enhanced cancer tumors using SQUID magnetometry: A feasibility study

NASA Astrophysics Data System (ADS)

Kenning, G. G.; Rodriguez, R.; Zotev, V. S.; Moslemi, A.; Wilson, S.; Hawel, L.; Byus, C.; Kovach, J. S.

2005-01-01

Nanoparticles bound to various biological molecules and pharmacological agents can be administered systemically, to humans without apparent toxicity. This opens an era in the targeting of specific tissues and disease processes for noninvasive imaging and treatment. An important class of particles used predominantly for magnetic resonance imaging is based on iron-oxide ferrites. We performed computer simulations using experimentally determined values for concentrations of superparamagnetic particles achievable in specific tissues of the mouse in vivo and concentrations of particles linked to monoclonal antibodies specific to antigens of two human cancer cell lines in vitro. An instrument to target distance of 12cm, into the body, was selected as relevant to our goal of developing a rapid inexpensive method of scanning the body for occult disease. The simulations demonstrate the potential feasibility of superconducting quantum interference device magnetometry to detect induced magnetic fields in focal concentrations of superparamagnetic particles targeted, in vivo, to sites of disease.

Framing the inborn aging process and longevity science.

PubMed

Farrelly, Colin

2010-06-01

The medical sciences are currently dominated by the "disease-model" approach to health extension, an approach that prioritizes the study of pathological mechanisms with the goal of discovering treatment modalities for specific diseases. This approach has marginalized research on the aging process itself, research that could lead to an intervention that retards aging, thus conferring health dividends that would far exceed what could be expected by eliminating any specific disease of aging. This paper offers a diagnosis of how this sub-optimal approach to health extension arose and some general prescriptions concerning how progress could be made in terms of adopting a more rational approach to health extension. Drawing on empirical findings from psychology and economics, "prospect theory" is applied to the challenges of "framing" the inborn aging process given the cognitive capacities of real (rather than rational) decision-makers under conditions of risk and uncertainty. Prospect theory reveals that preferences are in fact dependent on whether particular outcomes of a choice are regarded as "a loss" or "a gain", relative to a reference point (or "aspiration level for survival"). And this has significant consequences for the way biogerontologists ought to characterise the central aspirations of the field (i.e. to prevent disease versus extend lifespan). Furthermore, it reveals the importance of shifting the existing reference point of the medical sciences to one that is shaped by the findings of evolutionary biology and biodemography.

Inflammatory cells implicated in neoplasia development in idiopathic inflammatory bowel disease.

PubMed

Hashash, Jana G; Hartman, Douglas J

2017-11-10

The inflammatory mechanisms that lead to the clinical symptoms that are grouped under the term inflammatory bowel disease have not been fully characterized. Although a specific mechanism has not been identified, inflammatory bowel disease is believed to be related to an inability by the immune system to shut active inflammation within the intestine. Many contributing factors have been implicated in the disease process. Based on population studies, patients with inflammatory bowel disease have an increased risk for neoplastic development. Although no specific immune cell has been implicated in neoplastic development within this patient population, several immune cells have been implicated as possible etiologies in inflammatory bowel disease. In this review, we will review the clinical evidence about the risk for neoplastic development in inflammatory bowel disease and the current clinical guidelines to survey this patient population. We will also review the pathologic assessment of inflammation within this patient population as well the underlying immune cells and cytokines that have been implicated in the etiology of inflammatory bowel disease. Copyright © 2017 Elsevier Inc. All rights reserved.

Identification of common coexpression modules based on quantitative network comparison.

PubMed

Jo, Yousang; Kim, Sanghyeon; Lee, Doheon

2018-06-13

Finding common molecular interactions from different samples is essential work to understanding diseases and other biological processes. Coexpression networks and their modules directly reflect sample-specific interactions among genes. Therefore, identification of common coexpression network or modules may reveal the molecular mechanism of complex disease or the relationship between biological processes. However, there has been no quantitative network comparison method for coexpression networks and we examined previous methods for other networks that cannot be applied to coexpression network. Therefore, we aimed to propose quantitative comparison methods for coexpression networks and to find common biological mechanisms between Huntington's disease and brain aging by the new method. We proposed two similarity measures for quantitative comparison of coexpression networks. Then, we performed experiments using known coexpression networks. We showed the validity of two measures and evaluated threshold values for similar coexpression network pairs from experiments. Using these similarity measures and thresholds, we quantitatively measured the similarity between disease-specific and aging-related coexpression modules and found similar Huntington's disease-aging coexpression module pairs. We identified similar Huntington's disease-aging coexpression module pairs and found that these modules are related to brain development, cell death, and immune response. It suggests that up-regulated cell signalling related cell death and immune/ inflammation response may be the common molecular mechanisms in the pathophysiology of HD and normal brain aging in the frontal cortex.

Challenges to understanding spatial patterns of disease: philosophical alternatives to logical positivism.

PubMed

Mayer, J D

1992-08-01

Most studies of disease distribution, in medical geography and other related disciplines, have been empirical in nature and rooted in the assumptions of logical positivism. However, some of the more newly articulated philosophies of the social sciences, and of social theory, have much to add in the understanding of the processes and mechanisms underlying disease distribution. This paper represents a plea for creative synthesis between logical positivism and realism or structuration, and uses specific examples to suggest how disease distribution, as a surface phenomenon, can be explained using deeper analysis.

Critical Insights into Cardiovascular Disease from Basic Research on the Oxidation of Phospholipids: the γ-Hydroxyalkenal Phospholipid Hypothesis

PubMed Central

Salomon, Robert G.; Gu, Xiaodong

2011-01-01

Basic research, exploring the hypothesis that γ-hydroxyalkenal phospholipids are generated in vivo through oxidative cleavage of polyunsaturated phospholipids, is delivering a bonanza of molecular mechanistic insights into cardiovascular disease. Rather than targeting a specific pathology, these studies were predicated on the presumption that a fundamental understanding of lipid oxidation is likely to provide critical insights into disease processes. This investigational approach – from the chemistry of biomolecules to disease phenotype – that complements the more common opposite paradigm, is proving remarkably productive. PMID:21870852

Inferring infection hazard in wildlife populations by linking data across individual and population scales.

PubMed

Pepin, Kim M; Kay, Shannon L; Golas, Ben D; Shriner, Susan S; Gilbert, Amy T; Miller, Ryan S; Graham, Andrea L; Riley, Steven; Cross, Paul C; Samuel, Michael D; Hooten, Mevin B; Hoeting, Jennifer A; Lloyd-Smith, James O; Webb, Colleen T; Buhnerkempe, Michael G

2017-03-01

Our ability to infer unobservable disease-dynamic processes such as force of infection (infection hazard for susceptible hosts) has transformed our understanding of disease transmission mechanisms and capacity to predict disease dynamics. Conventional methods for inferring FOI estimate a time-averaged value and are based on population-level processes. Because many pathogens exhibit epidemic cycling and FOI is the result of processes acting across the scales of individuals and populations, a flexible framework that extends to epidemic dynamics and links within-host processes to FOI is needed. Specifically, within-host antibody kinetics in wildlife hosts can be short-lived and produce patterns that are repeatable across individuals, suggesting individual-level antibody concentrations could be used to infer time since infection and hence FOI. Using simulations and case studies (influenza A in lesser snow geese and Yersinia pestis in coyotes), we argue that with careful experimental and surveillance design, the population-level FOI signal can be recovered from individual-level antibody kinetics, despite substantial individual-level variation. In addition to improving inference, the cross-scale quantitative antibody approach we describe can reveal insights into drivers of individual-based variation in disease response, and the role of poorly understood processes such as secondary infections, in population-level dynamics of disease. © 2017 John Wiley & Sons Ltd/CNRS.

Inferring infection hazard in wildlife populations by linking data across individual and population scales

USGS Publications Warehouse

Pepin, Kim M.; Kay, Shannon L.; Golas, Ben D.; Shriner, Susan A.; Gilbert, Amy T.; Miller, Ryan S.; Graham, Andrea L.; Riley, Steven; Cross, Paul C.; Samuel, Michael D.; Hooten, Mevin B.; Hoeting, Jennifer A.; Lloyd-Smith, James O.; Webb, Colleen T.; Buhnerkempe, Michael G.

2017-01-01

Our ability to infer unobservable disease-dynamic processes such as force of infection (infection hazard for susceptible hosts) has transformed our understanding of disease transmission mechanisms and capacity to predict disease dynamics. Conventional methods for inferring FOI estimate a time-averaged value and are based on population-level processes. Because many pathogens exhibit epidemic cycling and FOI is the result of processes acting across the scales of individuals and populations, a flexible framework that extends to epidemic dynamics and links within-host processes to FOI is needed. Specifically, within-host antibody kinetics in wildlife hosts can be short-lived and produce patterns that are repeatable across individuals, suggesting individual-level antibody concentrations could be used to infer time since infection and hence FOI. Using simulations and case studies (influenza A in lesser snow geese and Yersinia pestis in coyotes), we argue that with careful experimental and surveillance design, the population-level FOI signal can be recovered from individual-level antibody kinetics, despite substantial individual-level variation. In addition to improving inference, the cross-scale quantitative antibody approach we describe can reveal insights into drivers of individual-based variation in disease response, and the role of poorly understood processes such as secondary infections, in population-level dynamics of disease.

HttQ111/+ Huntington's Disease Knock-in Mice Exhibit Brain Region-Specific Morphological Changes and Synaptic Dysfunction.

PubMed

Kovalenko, Marina; Milnerwood, Austen; Giordano, James; St Claire, Jason; Guide, Jolene R; Stromberg, Mary; Gillis, Tammy; Sapp, Ellen; DiFiglia, Marian; MacDonald, Marcy E; Carroll, Jeffrey B; Lee, Jong-Min; Tappan, Susan; Raymond, Lynn; Wheeler, Vanessa C

2018-01-01

Successful disease-modifying therapy for Huntington's disease (HD) will require therapeutic intervention early in the pathogenic process. Achieving this goal requires identifying phenotypes that are proximal to the HTT CAG repeat expansion. To use Htt CAG knock-in mice, precise genetic replicas of the HTT mutation in patients, as models to study proximal disease events. Using cohorts of B6J.HttQ111/+ mice from 2 to 18 months of age, we analyzed pathological markers, including immunohistochemistry, brain regional volumes and cortical thickness, CAG instability, electron microscopy of striatal synapses, and acute slice electrophysiology to record glutamatergic transmission at striatal synapses. We also incorporated a diet perturbation paradigm for some of these analyses. B6J.HttQ111/+ mice did not exhibit significant neurodegeneration or gliosis but revealed decreased striatal DARPP-32 as well as subtle but regional-specific changes in brain volumes and cortical thickness that parallel those in HD patients. Ultrastructural analyses of the striatum showed reduced synapse density, increased postsynaptic density thickness and increased synaptic cleft width. Acute slice electrophysiology showed alterations in spontaneous AMPA receptor-mediated postsynaptic currents, evoked NMDA receptor-mediated excitatory postsynaptic currents, and elevated extrasynaptic NMDA currents. Diet influenced cortical thickness, but did not impact somatic CAG expansion, nor did it show any significant interaction with genotype on immunohistochemical, brain volume or cortical thickness measures. These data show that a single HttQ111 allele is sufficient to elicit brain region-specific morphological changes and early neuronal dysfunction, highlighting an insidious disease process already apparent in the first few months of life.

Processing postmortem specimens with C18-carboxypropylbetaine and analysis by PCR to develop an antemortem test for Mycobacterium avium infections in ducks.

PubMed

Thornton, C G; Cranfield, M R; MacLellan, K M; Brink, T L; Strandberg, J D; Carlin, E A; Torrelles, J B; Maslow, J N; Hasson, J L; Heyl, D M; Sarro, S J; Chatterjee, D; Passen, S

1999-03-01

Mycobacterium avium is the causative agent of the avian mycobacteriosis commonly known as avian tuberculosis (ATB). This infection causes disseminated disease, is difficult to diagnose, and is of serious concern because it causes significant mortality in birds. A new method was developed for processing specimens for an antemortem screening test for ATB. This novel method uses the zwitterionic detergent C18-carboxypropylbetaine (CB-18). Blood, bone marrow, bursa, and fecal specimens from 28 ducks and swabs of 20 lesions were processed with CB-18 for analysis by smear, culture, and polymerase chain reaction (PCR). Postmortem examination confirmed nine of these birds as either positive or highly suspect for disseminated disease. The sensitivities of smear, culture, and PCR, relative to postmortem analysis and independent of specimen type, were 44.4%, 88.9%, and 100%, respectively, and the specificities were 84.2%, 57.9%, and 15.8%, respectively. Reductions in specificity were due primarily to results among fecal specimens. However, these results were clustered among a subset of birds, suggesting that these tests actually identified birds in early stages of the disease. Restriction fragment length polymorphism mapping identified one strain of M. avium (serotype 1) that was isolated from lesions, bursa, bone marrow, blood, and feces of all but three of the culture-positive birds. In birds with confirmed disease, blood had the lowest sensitivity and the highest specificity by all diagnostic methods. Swabs of lesions provided the highest sensitivity by smear and culture (33.3% and 77.8%, respectively), whereas fecal specimens had the highest sensitivity by PCR (77.8%). The results of this study indicate that processing fecal specimens with CB-18, followed by PCR analysis, may provide a valuable first step for monitoring the presence of ATB in birds.

The development and implementation of the Chronic Care Management Programme in Counties Manukau.

PubMed

Wellingham, John; Tracey, Jocelyn; Rea, Harold; Gribben, Barry

2003-02-21

To develop an effective and efficient process for the seamless delivery of care for targeted patients with specific chronic diseases. To reduce inexplicable variation and maximise use of available resources by implementing evidence-based care processes. To develop a programme that is acceptable and applicable to the Counties Manukau region. A model for the management of people with chronic diseases was developed. Model components and potential interventions were piloted. For each disease project, a return on investment was calculated and external evaluation was undertaken. The initial model was subsequently modified and individual disease projects aligned to it. The final Chronic Care Management model, agreed in September 2001, described a single common process. Key components were the targeting of high risk patients, organisation of cost effective interventions into a system of care, and an integrated care server acting as a data warehouse with a rules engine, providing flags and reminders. Return on investment analysis suggested potential savings for each disease component from $277 to $980 per person per annum. For selected chronic diseases, introduction of an integrated chronic care management programme, based on internationally accepted best practice processes and interventions can make significant savings, reducing morbidity and improving the efficiency of health delivery in the Counties Manukau region.

Evidence of semantic processing impairments in behavioural variant frontotemporal dementia and Parkinson's disease.

PubMed

Cousins, Katheryn A Q; Grossman, Murray

2017-12-01

Category-specific impairments caused by brain damage can provide important insights into how semantic concepts are organized in the brain. Recent research has demonstrated that disease to sensory and motor cortices can impair perceptual feature knowledge important to the representation of semantic concepts. This evidence supports the grounded cognition theory of semantics, the view that lexical knowledge is partially grounded in perceptual experience and that sensory and motor regions support semantic representations. Less well understood, however, is how heteromodal semantic hubs work to integrate and process semantic information. Although the majority of semantic research to date has focused on how sensory cortical areas are important for the representation of semantic features, new research explores how semantic memory is affected by neurodegeneration in regions important for semantic processing. Here, we review studies that demonstrate impairments to abstract noun knowledge in behavioural variant frontotemporal degeneration (bvFTD) and to action verb knowledge in Parkinson's disease, and discuss how these deficits relate to disease of the semantic selection network. Findings demonstrate that semantic selection processes are supported by the left inferior frontal gyrus (LIFG) and basal ganglia, and that disease to these regions in bvFTD and Parkinson's disease can lead to categorical impairments for abstract nouns and action verbs, respectively.

Detection of Practice Pattern Trends through Natural Language Processing of Clinical Narratives and Biomedical Literature

PubMed Central

Chen, Elizabeth S.; Stetson, Peter D.; Lussier, Yves A.; Markatou, Marianthi; Hripcsak, George; Friedman, Carol

2007-01-01

Clinical knowledge, best evidence, and practice patterns evolve over time. The ability to track these changes and study practice trends may be valuable for performance measurement and quality improvement efforts. The goal of this study was to assess the feasibility and validity of methods to generate and compare trends in biomedical literature and clinical narrative. We focused on the challenge of detecting trends in medication usage over time for two diseases: HIV/AIDS and asthma. Information about disease-specific medications in published randomized control trials and discharge summaries at New York-Presbyterian Hospital over a ten-year period were extracted using Natural Language Processing. This paper reports on the ability of our semi-automated process to discover disease-drug practice pattern trends and interpretation of findings across the biomedical and clinical text sources. PMID:18693810

Mechanisms of Protein Seeding in Neurodegenerative Diseases

PubMed Central

Walker, Lary C.; Diamond, Marc I.; Duff, Karen E.; Hyman, Bradley T.

2013-01-01

Most age-associated neurodegenerative diseases involve the aggregation of specific proteins within the nervous system. In Alzheimer’s disease, the insidious pathogenic process begins many years before the symptoms emerge, and the lesions that characterize the disease – senile plaques and neurofibrillary tangles – ramify systematically through the brain. We review evidence that the β-amyloid and tau proteins, which aggregate to form senile plaques and neurofibrillary tangles, respectively, are induced to misfold and self-assemble by a process of templated conformational change that amplifies a toxic species. Recent data also indicate that the spread of these lesions from one site to another is mediated by the cellular uptake, transport and release of endogenous seeds formed by the cognate proteins. This simple pathogenic principle suggests that the formation, trafficking and metabolism of pathogenic protein seeds are promising therapeutic targets for Alzheimer’s disease and other neurodegenerative disorders. PMID:23599928

Tooth formation - delayed or absent

MedlinePlus

... missing teeth they never developed. Cosmetic or orthodontic dentistry can correct this problem. Causes Specific diseases can ... process. In: Dean JA, ed. McDonald and Avery's Dentistry for the Child and Adolescent . 10th ed. St. ...

Second-Order Analysis of Semiparametric Recurrent Event Processes

PubMed Central

Guan, Yongtao

2011-01-01

Summary A typical recurrent event dataset consists of an often large number of recurrent event processes, each of which contains multiple event times observed from an individual during a followup period. Such data have become increasingly available in medical and epidemiological studies. In this paper, we introduce novel procedures to conduct second-order analysis for a flexible class of semiparametric recurrent event processes. Such an analysis can provide useful information regarding the dependence structure within each recurrent event process. Specifically, we will use the proposed procedures to test whether the individual recurrent event processes are all Poisson processes and to suggest sensible alternative models for them if they are not. We apply these procedures to a well-known recurrent event dataset on chronic granulomatous disease and an epidemiological dataset on Meningococcal disease cases in Merseyside, UK to illustrate their practical value. PMID:21361885

In vivo cell biology in zebrafish - providing insights into vertebrate development and disease.

PubMed

Vacaru, Ana M; Unlu, Gokhan; Spitzner, Marie; Mione, Marina; Knapik, Ela W; Sadler, Kirsten C

2014-02-01

Over the past decades, studies using zebrafish have significantly advanced our understanding of the cellular basis for development and human diseases. Zebrafish have rapidly developing transparent embryos that allow comprehensive imaging of embryogenesis combined with powerful genetic approaches. However, forward genetic screens in zebrafish have generated unanticipated findings that are mirrored by human genetic studies: disruption of genes implicated in basic cellular processes, such as protein secretion or cytoskeletal dynamics, causes discrete developmental or disease phenotypes. This is surprising because many processes that were assumed to be fundamental to the function and survival of all cell types appear instead to be regulated by cell-specific mechanisms. Such discoveries are facilitated by experiments in whole animals, where zebrafish provides an ideal model for visualization and manipulation of organelles and cellular processes in a live vertebrate. Here, we review well-characterized mutants and newly developed tools that underscore this notion. We focus on the secretory pathway and microtubule-based trafficking as illustrative examples of how studying cell biology in vivo using zebrafish has broadened our understanding of the role fundamental cellular processes play in embryogenesis and disease.

Inflammation in sickle cell disease.

PubMed

Conran, Nicola; Belcher, John D

2018-01-01

The primary β-globin gene mutation that causes sickle cell disease (SCD) has significant pathophysiological consequences that result in hemolytic events and the induction of the inflammatory processes that ultimately lead to vaso-occlusion. In addition to their role in the initiation of the acute painful vaso-occlusive episodes that are characteristic of SCD, inflammatory processes are also key components of many of the complications of the disease including autosplenectomy, acute chest syndrome, pulmonary hypertension, leg ulcers, nephropathy and stroke. We, herein, discuss the events that trigger inflammation in the disease, as well as the mechanisms, inflammatory molecules and cells that propagate these inflammatory processes. Given the central role that inflammation plays in SCD pathophysiology, many of the therapeutic approaches currently under pre-clinical and clinical development for the treatment of SCD endeavor to counter aspects or specific molecules of these inflammatory processes and it is possible that, in the future, we will see anti-inflammatory drugs being used either together with, or in place of, hydroxyurea in those SCD patients for whom hematopoietic stem cell transplants and evolving gene therapies are not a viable option.

Lupus erythematosus revisited.

PubMed

Kuhn, Annegret; Wenzel, Joerg; Bijl, Marc

2016-01-01

Lupus erythematosus (LE) is a multifactorial autoimmune disease with clinical manifestations of differing severity. The exact pathomechanisms and interactions resulting in the inflammatory and immunological processes of this heterogeneous disease remain elusive. Approaches in the understanding of the pathomechanisms revealed that the clinical expression of LE is predisposed by susceptibility genes and that various environmental factors are responsible for an abnormal immune response. Several studies demonstrated that ultraviolet (UV) light is one of the major factors in the pathogenesis of the disease. Standardized photoprovocation in patients with LE has been shown to be a safe and efficient model for evaluating the underlying pathomechanisms which lead to the production of autoantibodies and immune complexes. In particular, interferons were defined as important players in the early activation of the immune system and were observed to play a specific role in the immunological interface between the innate and the adaptive immune system. Abnormalities or disturbances in the different processes of cell death, such as apoptosis or necrosis, have also been recognized as crucial in the pathogenesis of LE. Although each process is different and characterized by unique features, the processes are interrelated and result in a complex disease.

Multi-compartmental modeling of SORLA’s influence on amyloidogenic processing in Alzheimer’s disease

PubMed Central

2012-01-01

Background Proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in formation of neurotoxic Aβ peptides, causative of neurodegeneration in Alzheimer’s disease (AD). Processing involves monomeric and dimeric forms of APP that traffic through distinct cellular compartments where the various secretases reside. Amyloidogenic processing is also influenced by modifiers such as sorting receptor-related protein (SORLA), an inhibitor of APP breakdown and major AD risk factor. Results In this study, we developed a multi-compartment model to simulate the complexity of APP processing in neurons and to accurately describe the effects of SORLA on these processes. Based on dose–response data, our study concludes that SORLA specifically impairs processing of APP dimers, the preferred secretase substrate. In addition, SORLA alters the dynamic behavior of β-secretase, the enzyme responsible for the initial step in the amyloidogenic processing cascade. Conclusions Our multi-compartment model represents a major conceptual advance over single-compartment models previously used to simulate APP processing; and it identified APP dimers and β-secretase as the two distinct targets of the inhibitory action of SORLA in Alzheimer’s disease. PMID:22727043

[Crohns disease and ulcerative colitis - current view on genetic determination, immunopathogenesis and biologic therapy].

PubMed

Buc, M

2017-01-01

Crohns disease (CD) and ulcerative colitis (UC) are chronic inflammatory disorders of the intestine, also called inflammatory bowel diseases (IBD), which are not caused by pathogenic microorganisms but result from non-specific inflammatory processes in the bowel. IBD are polygenic diseases, as evidenced by the genome-wide association studies (GWAS), which have discovered more than 200 genes or genetic regions to be associated with IBD. Some of them are specific for CD or UC; however, there are 110 overlapping genes. In the pathogenesis of CD, activation of adaptive immunity mediated by TH1, TH17, or TH1/TH17 cells is induced because of disturbances in the mechanisms of innate immunity and autophagocytosis. By comparison, the major events that trigger autoimmune processes in UC are an increased translocation of commensal bacteria into the submucosa because of loose inter-epithelial connections with subsequent activation of ILC2, TH9, TH2, and NKT cells. Knowledge of the pathogenesis of a disease enables an effective therapy, which is especially true for biological therapy. It is noteworthy that monoclonal antibodies directed against the major protagonists underlying both CD and UC have failed. It points to the complexity of immunopathologic processes that run in both diseases. One can suppose that a blockade of one inflammatory pathway is circumvented by an alternative pathway. TNF is the principal pro-inflammatory cytokine that plays a major role in CD and UC as well. It was therefore decided to treat IBD patients with anti-TNF monoclonal antibodies, infliximab or adalimumab. Approximately one half of the CD patients and one third of the UC patients respond to this treatment.

Language processing within the striatum: evidence from a PET correlation study in Huntington's disease.

PubMed

Teichmann, Marc; Gaura, Véronique; Démonet, Jean-François; Supiot, Frédéric; Delliaux, Marie; Verny, Christophe; Renou, Pierre; Remy, Philippe; Bachoud-Lévi, Anne-Catherine

2008-04-01

The role of sub-cortical structures in language processing, and more specifically of the striatum, remains controversial. In line with psycholinguistic models stating that language processing implies both the recovery of lexical information and the application of combinatorial rules, the striatum has been claimed to be involved either in the former component or in the latter. The present study reconciles these conflicting views by showing the striatum's involvement in both language processes, depending on distinct striatal sub-regions. Using PET scanning in a model of striatal disorders, namely Huntington's disease (HD), we correlated metabolic data of 31 early stage HD patients regarding different striatal sub-regions with behavioural scores on three rule/lexicon tasks drawn from word morphology, syntax and from a non-linguistic domain, namely arithmetic. Behavioural results reflected impairment on both processing aspects, while deficits predominated on rule application. Both correlated with the left striatum but involved distinct striatal sub-regions. We suggest that the left striatum encompasses linguistic and arithmetic circuits, which differ with respect to their anatomical and functional specification, comprising ventrally located regions dedicated to rule computations and more dorsal portions pertaining to lexical devices.

Super-enhancer-mediated RNA processing revealed by integrative microRNA network analysis

PubMed Central

Suzuki, Hiroshi I.; Young, Richard A; Sharp, Phillip A

2017-01-01

Summary Super-enhancers are an emerging sub-class of regulatory regions controlling cell identity and disease genes. However, their biological function and impact on miRNA networks are unclear. Here we report that super-enhancers drive the biogenesis of master miRNAs crucial for cell identity by enhancing both transcription and Drosha/DGCR8-mediated primary miRNA (pri-miRNA) processing. Super-enhancers, together with broad H3K4me3 domains, shape a tissue-specific and evolutionarily conserved atlas of miRNA expression and function. CRISPR/Cas9 genomics revealed that super-enhancer constituents act cooperatively and facilitate Drosha/DGCR8 recruitment and pri-miRNA processing to boost cell-specific miRNA production. The BET-bromodomain inhibitor JQ1 preferentially inhibits super-enhancer-directed cotranscriptional pri-miRNA processing. Furthermore, super-enhancers are characterized by pervasive interaction with DGCR8/Drosha and DGCR8/Drosha-regulated mRNA stability control, suggesting unique RNA regulation at super-enhancers. Finally, super-enhancers mark multiple miRNAs associated with cancer hallmarks. This study presents principles underlying miRNA biology in health and disease and a unrecognized higher-order property of super-enhancers in RNA processing beyond transcription. PMID:28283057

Mitochondria in lung disease

PubMed Central

Cloonan, Suzanne M.; Choi, Augustine M.K.

2016-01-01

Mitochondria are a distinguishing feature of eukaryotic cells. Best known for their critical function in energy production via oxidative phosphorylation (OXPHOS), mitochondria are essential for nutrient and oxygen sensing and for the regulation of critical cellular processes, including cell death and inflammation. Such diverse functional roles for organelles that were once thought to be simple may be attributed to their distinct heteroplasmic genome, exclusive maternal lineage of inheritance, and ability to generate signals to communicate with other cellular organelles. Mitochondria are now thought of as one of the cell’s most sophisticated and dynamic responsive sensing systems. Specific signatures of mitochondrial dysfunction that are associated with disease pathogenesis and/or progression are becoming increasingly important. In particular, the centrality of mitochondria in the pathological processes and clinical phenotypes associated with a range of lung diseases is emerging. Understanding the molecular mechanisms regulating the mitochondrial processes of lung cells will help to better define phenotypes and clinical manifestations associated with respiratory disease and to identify potential diagnostic and therapeutic targets. PMID:26928034

Disease management with ARIMA model in time series.

PubMed

Sato, Renato Cesar

2013-01-01

The evaluation of infectious and noninfectious disease management can be done through the use of a time series analysis. In this study, we expect to measure the results and prevent intervention effects on the disease. Clinical studies have benefited from the use of these techniques, particularly for the wide applicability of the ARIMA model. This study briefly presents the process of using the ARIMA model. This analytical tool offers a great contribution for researchers and healthcare managers in the evaluation of healthcare interventions in specific populations.

Epigenetics in asthma and other inflammatory lung diseases.

PubMed

Durham, Andrew; Chou, Pai-Chien; Kirkham, Paul; Adcock, Ian M

2010-08-01

Asthma is a chronic inflammatory disease of the airways. The causes of asthma and other inflammatory lung diseases are thought to be both environmental and heritable. Genetic studies do not adequately explain the heritability and susceptabilty to the disease, and recent evidence suggests that epigentic changes may underlie these processes. Epigenetics are heritable noncoding changes to DNA and can be influenced by environmental factors such as smoking and traffic pollution, which can cause genome-wide and gene-specific changes in DNA methylation. In addition, alterations in histone acetyltransferase/deacetylase activities can be observed in the cells of patients with lung diseases such as severe asthma and chronic obstructive pulmonary disease, and are often linked to smoking. Drugs such as glucocorticoids, which are used to control inflammation, are dependent on histone deacetylase activity, which may be important in patients with severe asthma and chronic obstructive pulmonary disease who do not respond well to glucocorticoid therapy. Future work targeting specific histone acetyltransferases/deacetylases or (de)methylases may prove to be effective future anti-inflammatory treatments for patients with treatment-unresponsive asthma.

Periodontal disease and rheumatoid arthritis: the evidence accumulates for complex pathobiologic interactions

PubMed Central

Bingham, Clifton O.; Moni, Malini

2015-01-01

Purpose of review This review was conducted to focus on the recent clinical and translational research related to the associations between periodontal disease and rheumatoid arthritis. Recent findings There is a growing interest in the associations between oral health and autoimmune and inflammatory diseases. A number of epidemiologic studies have described associations between rheumatoid arthritis and periodontal disease. Recent clinical studies continue to support these reports, and are increasingly linked with biological assessments to better understand the nature of these relationships. A number of recent studies have evaluated the periopathogenic roles of Porphyromonas gingivalis, the oral microbiome, and mechanisms of site-specific and substrate-specific citrullination. These are helping to further elucidate the interactions between these two inflammatory disease processes. Summary Studies of clinical oral health parameters, the gingival microenvironment, autoantibodies and biomarkers, and rheumatoid arthritis disease activity measures are providing a better understanding of the potential mechanisms responsible for rheumatoid arthritis and periodontal disease associations. The cumulative results and ongoing studies have the promise to identify novel mechanisms and interventional strategies to improve patient outcomes for both conditions. PMID:23455329

A dynamic spatio-temporal model for spatial data

USGS Publications Warehouse

Hefley, Trevor J.; Hooten, Mevin B.; Hanks, Ephraim M.; Russell, Robin; Walsh, Daniel P.

2017-01-01

Analyzing spatial data often requires modeling dependencies created by a dynamic spatio-temporal data generating process. In many applications, a generalized linear mixed model (GLMM) is used with a random effect to account for spatial dependence and to provide optimal spatial predictions. Location-specific covariates are often included as fixed effects in a GLMM and may be collinear with the spatial random effect, which can negatively affect inference. We propose a dynamic approach to account for spatial dependence that incorporates scientific knowledge of the spatio-temporal data generating process. Our approach relies on a dynamic spatio-temporal model that explicitly incorporates location-specific covariates. We illustrate our approach with a spatially varying ecological diffusion model implemented using a computationally efficient homogenization technique. We apply our model to understand individual-level and location-specific risk factors associated with chronic wasting disease in white-tailed deer from Wisconsin, USA and estimate the location the disease was first introduced. We compare our approach to several existing methods that are commonly used in spatial statistics. Our spatio-temporal approach resulted in a higher predictive accuracy when compared to methods based on optimal spatial prediction, obviated confounding among the spatially indexed covariates and the spatial random effect, and provided additional information that will be important for containing disease outbreaks.

Cultural Sensitivity and Challenges in Management of the Transgender Patient With ESRD in Transplantation.

PubMed

Hoch, Deborah Ann; Bulman, Maya; McMahon, Dorn W

2016-03-01

Transgender patients with end-stage renal disease (ESRD) present with specific challenges during the transplant evaluation, perioperative management, and postoperative phase of care. Demographic information, health-care records, chosen name, and gender identity along with documentation of specific health-care needs can become a challenge when gender assigned at birth is incongruent with the patients gender identity. Medical care involves addressing the end-organ disease as well as addressing those aspects of care specific to the transgender patient. This review article provides information on defining transgender, the impact of ESRD, and transgender in the transplant process and considerations in the throughout phases of care. Current recommendations for management of this unique population are provided. © 2016, NATCO.

Field Manual of Wildlife Diseases

USGS Publications Warehouse

Franson, J. Christian; Friend, Milton; Gibbs, Samantha E.J.; Wild, Margaret A.

2015-01-01

We begin this new manual with introductory contextual and historical background about the convergence of wildlife disease with wildlife management as a wildlife conservation concern (section A, chap. 1). The remainder of the publication is focused on pragmatic information and considerations for addressing various aspects of wildlife disease. Section B focuses on concepts associated with disease surveillance and response to outbreaks, and section C deals with specific techniques for disease surveillance and investigation. Section D, “Diseases of Wild Birds,” and others that follow will address diseases of concern in various species groups. Electronic links facilitate timely access to a wide variety of supplemental information and processes relevant to content in this new version of the “Field Manual of Wildlife Diseases.”

Region-specific protein misfolding cyclic amplification reproduces brain tropism of prion strains.

PubMed

Privat, Nicolas; Levavasseur, Etienne; Yildirim, Serfildan; Hannaoui, Samia; Brandel, Jean-Philippe; Laplanche, Jean-Louis; Béringue, Vincent; Seilhean, Danielle; Haïk, Stéphane

2017-10-06

Human prion diseases such as Creutzfeldt-Jakob disease are transmissible brain proteinopathies, characterized by the accumulation of a misfolded isoform of the host cellular prion protein (PrP) in the brain. According to the prion model, prions are defined as proteinaceous infectious particles composed solely of this abnormal isoform of PrP (PrP Sc ). Even in the absence of genetic material, various prion strains can be propagated in experimental models. They can be distinguished by the pattern of disease they produce and especially by the localization of PrP Sc deposits within the brain and the spongiform lesions they induce. The mechanisms involved in this strain-specific targeting of distinct brain regions still are a fundamental, unresolved question in prion research. To address this question, we exploited a prion conversion in vitro assay, protein misfolding cyclic amplification (PMCA), by using experimental scrapie and human prion strains as seeds and specific brain regions from mice and humans as substrates. We show here that region-specific PMCA in part reproduces the specific brain targeting observed in experimental, acquired, and sporadic Creutzfeldt-Jakob diseases. Furthermore, we provide evidence that, in addition to cellular prion protein, other region- and species-specific molecular factors influence the strain-dependent prion conversion process. This important step toward understanding prion strain propagation in the human brain may impact research on the molecular factors involved in protein misfolding and the development of ultrasensitive methods for diagnosing prion disease. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

Evaluation of a regional disease management programme for patients with asthma or chronic obstructive pulmonary disease.

PubMed

Steuten, Lotte; Vrijhoef, Bert; Van Merode, Frits; Wesseling, Geert-Jan; Spreeuwenberg, Cor

2006-12-01

To assess the impact of a population-based disease management programme for adult patients with asthma or chronic obstructive pulmonary disease (COPD) on process measures, intermediate outcomes, and endpoints of care. Quasi-experimental design with 12-month follow-up. Region of Maastricht (the Netherlands) including university hospital and 16 general practices. Nine hundred and seventy-five patients of whom 658 have asthma and 317 COPD. Disease management programme. Endpoints of care are respiratory health, health utility, patient satisfaction, and total health care costs related to asthma or COPD. Quality aspects of care, disease control, self-care behaviour, smoking status, disease-specific knowledge, and patients' satisfaction improved after implementation of the programme. Lung function was not affected by implementation of the programme. For COPD patients, a significant improvement in health utility was found. For patients with asthma, significant cost savings were measured. Organizing health care according to principles of disease management for adults with asthma or COPD is associated with significant improvements in several processes and outcomes of care, while costs of care do not exceed the existing budget.

Study for identification of beneficial uses of Space (BUS). Volume 2: Technical report. Book 1: Development and business analysis of space processed isoenzymes

NASA Technical Reports Server (NTRS)

1975-01-01

A separation method to provide reasonable yields of high specificity isoenzymes for the purpose of large scale, early clinical diagnosis of diseases and organic damage such as, myocardial infarction, hepatoma, muscular dystrophy, and infectous disorders is presented. Preliminary development plans are summarized. An analysis of required research and development and production resources is included. The costs of such resources and the potential profitability of a commercial space processing opportunity for electrophoretic separation of high specificity isoenzymes are reviewed.

The Impact of Traumatic Brain Injury on Later Life: Effects on Normal Aging and Neurodegenerative Diseases.

PubMed

Griesbach, Grace S; Masel, Brent E; Helvie, Richard E; Ashley, Mark J

2018-01-01

The acute and chronic effects of traumatic brain injury (TBI) have been widely described; however, there is limited knowledge on how a TBI sustained during early adulthood or mid-adulthood will influence aging. Epidemiological studies have explored whether TBI poses a risk for dementia and other neurodegenerative diseases associated with aging. We will discuss the influence of TBI and resulting medical comorbidities such as endocrine, sleep, and inflammatory disturbances on age-related gray and white matter changes and cognitive decline. Post mortem studies examining amyloid, tau, and other proteins will be discussed within the context of neurodegenerative diseases and chronic traumatic encephalopathy. The data support the suggestion that pathological changes triggered by an earlier TBI will have an influence on normal aging processes and will interact with neurodegenerative disease processes rather than the development of a specific disease, such as Alzheimer's or Parkinson's. Chronic neurophysiologic change after TBI may have detrimental effects on neurodegenerative disease.

Disease-specific health-related quality of life instruments for IgE-mediated food allergy.

PubMed

Salvilla, S A; Dubois, A E J; Flokstra-de Blok, B M J; Panesar, S S; Worth, A; Patel, S; Muraro, A; Halken, S; Hoffmann-Sommergruber, K; DunnGalvin, A; Hourihane, J O'B; Regent, L; de Jong, N W; Roberts, G; Sheikh, A

2014-07-01

This is one of seven interlinked systematic reviews undertaken on behalf of the European Academy of Allergy and Clinical Immunology as part of their Guidelines for Food Allergy and Anaphylaxis, which focuses on instruments developed for IgE-mediated food allergy. Disease-specific questionnaires are significantly more sensitive than generic ones in measuring the response to interventions or future treatments, as well as estimating the general burden of food allergy. The aim of this systematic review was therefore to identify which disease-specific, validated instruments can be employed to enable assessment of the impact of, and investigations and interventions for, IgE-mediated food allergy on health-related quality of life (HRQL). Using a sensitive search strategy, we searched seven electronic bibliographic databases to identify disease-specific quality of life (QOL) tools relating to IgE-mediated food allergy. From the 17 eligible studies, we identified seven disease-specific HRQL instruments, which were then subjected to detailed quality appraisal. This revealed that these instruments have undergone formal development and validation processes, and have robust psychometric properties, and therefore provide a robust means of establishing the impact of food allergy on QOL. Suitable instruments are now available for use in children, adolescents, parents/caregivers, and adults. Further work must continue to develop a clinical minimal important difference for food allergy and for making these instruments available in a wider range of European languages. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

The role of diagnostic laboratories in support of animal disease surveillance systems.

PubMed

Zepeda, C

2007-01-01

Diagnostic laboratories are an essential component of animal disease surveillance systems. To understand the occurrence of disease in populations, surveillance systems rely on random or targeted surveys using three approaches: clinical, serological and virological surveillance. Clinical surveillance is the basis for early detection of disease and is usually centered on the detection of syndromes and clinical findings requiring confirmation by diagnostic laboratories. Although most of the tests applied usually perform to an acceptable standard, several have not been properly validated in terms of their diagnostic sensitivity and specificity. Sensitivity and specificity estimates can vary according to local conditions and, ideally, should be determined by national laboratories where the tests are to be applied. The importance of sensitivity and specificity estimates in the design and interpretation of statistically based surveys and risk analysis is fundamental to establish appropriate disease control and prevention strategies. The World Organisation for Animal Health's (OIE) network of reference laboratories acts as centers of expertise for the diagnosis of OIE listed diseases and have a role in promoting the validation of OIE prescribed tests for international trade. This paper discusses the importance of the epidemiological evaluation of diagnostic tests and the role of the OIE Reference Laboratories and Collaborating Centres in this process.

Estrogen anti-inflammatory activity in brain: a therapeutic opportunity for menopause and neurodegenerative diseases

PubMed Central

Vegeto, Elisabetta; Benedusi, Valeria; Maggi, Adriana

2008-01-01

Recent studies highlight the prominent role played by estrogens in protecting the central nervous system (CNS) against the noxious consequences of a chronic inflammatory reaction. The neurodegenerative process of several CNS diseases, including Multiple Sclerosis, Alzheimer’s and Parkinson’s Diseases, is associated with the activation of microglia cells, which drive the resident inflammatory response. Chronically stimulated during neurodegeneration, microglia cells are thought to provide detrimental effects on surrounding neurons. The inhibitory activity of estrogens on neuroinflammation and specifically on microglia might thus be considered as a beneficial therapeutic opportunity for delaying the onset or progression of neurodegenerative diseases; in addition, understanding the peculiar activity of this female hormone on inflammatory signalling pathways will possibly lead to the development of selected anti-inflammatory molecules. This review summarises the evidence for the involvement of microglia in neuroinflammation and the anti-inflammatory activity played by estrogens specifically in microglia. PMID:18522863

Protein components of the microRNA pathway and human diseases

PubMed Central

Perron, Marjorie P.; Provost, Patrick

2010-01-01

Summary MicroRNAs (miRNAs) are key regulators of messenger RNA (mRNA) translation known to be involved in a wide variety of cellular processes. In fact, their individual importance is reflected in the diseases that may arise upon the loss, mutation or dysfunction of specific miRNAs. It has been appreciated only recently that diseases may also develop when the protein components of the miRNA machinery itself are affected. The core enzymes of the major protein complexes involved in miRNA biogenesis and function, such as the ribonucleases III (RNases III) Drosha and Dicer as well as Argonaute 2 (Ago2), appear to be essential. However, the accessory proteins of the miRNA pathway, such as the DiGeorge syndrome critical region gene 8 (DGCR8) protein, Exportin-5 (Exp-5), TAR RNA binding protein (TRBP) and Fragile X mental retardation protein (FMRP), are each related, in various ways, to specific genetic diseases. PMID:19301657

Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

PubMed

Abdelhak, Ahmed; Junker, Andreas; Brettschneider, Johannes; Kassubek, Jan; Ludolph, Albert C; Otto, Markus; Tumani, Hayrettin

2015-07-31

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs.

Brain-Specific Cytoskeletal Damage Markers in Cerebrospinal Fluid: Is There a Common Pattern between Amyotrophic Lateral Sclerosis and Primary Progressive Multiple Sclerosis?

PubMed Central

Abdelhak, Ahmed; Junker, Andreas; Brettschneider, Johannes; Kassubek, Jan; Ludolph, Albert C.; Otto, Markus; Tumani, Hayrettin

2015-01-01

Many neurodegenerative disorders share a common pathophysiological pathway involving axonal degeneration despite different etiological triggers. Analysis of cytoskeletal markers such as neurofilaments, protein tau and tubulin in cerebrospinal fluid (CSF) may be a useful approach to detect the process of axonal damage and its severity during disease course. In this article, we review the published literature regarding brain-specific CSF markers for cytoskeletal damage in primary progressive multiple sclerosis and amyotrophic lateral sclerosis in order to evaluate their utility as a biomarker for disease progression in conjunction with imaging and histological markers which might also be useful in other neurodegenerative diseases associated with affection of the upper motor neurons. A long-term benefit of such an approach could be facilitating early diagnostic and prognostic tools and assessment of treatment efficacy of disease modifying drugs. PMID:26263977

Specific detection of the cleavage activity of mycobacterial enzymes using a quantum dot based DNA nanosensor

NASA Astrophysics Data System (ADS)

Jepsen, Morten Leth; Harmsen, Charlotte; Godbole, Adwait Anand; Nagaraja, Valakunja; Knudsen, Birgitta R.; Ho, Yi-Ping

2015-12-01

We present a quantum dot based DNA nanosensor specifically targeting the cleavage step in the reaction cycle of the essential DNA-modifying enzyme, mycobacterial topoisomerase I. The design takes advantages of the unique photophysical properties of quantum dots to generate visible fluorescence recovery upon specific cleavage by mycobacterial topoisomerase I. This report, for the first time, demonstrates the possibility to quantify the cleavage activity of the mycobacterial enzyme without the pre-processing sample purification or post-processing signal amplification. The cleavage induced signal response has also proven reliable in biological matrices, such as whole cell extracts prepared from Escherichia coli and human Caco-2 cells. It is expected that the assay may contribute to the clinical diagnostics of bacterial diseases, as well as the evaluation of treatment outcomes.We present a quantum dot based DNA nanosensor specifically targeting the cleavage step in the reaction cycle of the essential DNA-modifying enzyme, mycobacterial topoisomerase I. The design takes advantages of the unique photophysical properties of quantum dots to generate visible fluorescence recovery upon specific cleavage by mycobacterial topoisomerase I. This report, for the first time, demonstrates the possibility to quantify the cleavage activity of the mycobacterial enzyme without the pre-processing sample purification or post-processing signal amplification. The cleavage induced signal response has also proven reliable in biological matrices, such as whole cell extracts prepared from Escherichia coli and human Caco-2 cells. It is expected that the assay may contribute to the clinical diagnostics of bacterial diseases, as well as the evaluation of treatment outcomes. Electronic supplementary information (ESI) available: Characterization of the QD-based DNA Nanosensor. See DOI: 10.1039/c5nr06326d

The Repeat Expansion Diseases: the dark side of DNA repair?

PubMed Central

Zhao, Xiao-Nan; Usdin, Karen

2015-01-01

DNA repair normally protects the genome against mutations that threaten genome integrity and thus cell viability. However, growing evidence suggests that in the case of the Repeat Expansion Diseases, disorders that result from an increase in the size of a disease-specific microsatellite, the disease-causing mutation is actually the result of aberrant DNA repair. A variety of proteins from different DNA repair pathways have thus far been implicated in this process. This review will summarize recent findings from patients and from mouse models of these diseases that shed light on how these pathways may interact to cause repeat expansion. PMID:26002199

Circulating microRNAs as novel biomarkers for bone diseases - Complex signatures for multifactorial diseases?

PubMed

Hackl, Matthias; Heilmeier, Ursula; Weilner, Sylvia; Grillari, Johannes

2016-09-05

Biomarkers are essential tools in clinical research and practice. Useful biomarkers must combine good measurability, validated association with biological processes or outcomes, and should support clinical decision making if used in clinical practice. Several types of validated biomarkers have been reported in the context of bone diseases. However, because these biomarkers face certain limitations there is an interest in the identification of novel biomarkers for bone diseases, specifically in those that are tightly linked to the disease pathology leading to increased fracture-risk. MicroRNAs (miRNAs) are the most abundant RNA species to be found in cell-free blood. Encapsulated within microvesicles or bound to proteins, circulating miRNAs are remarkably stable analytes that can be measured using gold-standard technologies such as quantitative polymerase-chain-reaction (qPCR). Nevertheless, the analysis of circulating miRNAs faces several pre-analytical as well as analytical challenges. From a biological view, there is accumulating evidence that miRNAs play essential roles in the regulation of various biological processes including bone homeostasis. Moreover, specific changes in miRNA transcription levels or miRNA secretory levels have been linked to the development and progression of certain bone diseases. Only recently, results from circulating miRNAs analysis in patients with osteopenia, osteoporosis and fragility fractures have been reported. By comparing these findings to studies on circulating miRNAs in cellular senescence and aging or muscle physiology and sarcopenia, several overlaps were observed. This suggests that signatures observed during osteoporosis might not be specific to the pathophysiology in bone, but rather integrate information from several tissue types. Despite these promising first data, more work remains to be done until circulating miRNAs can serve as established and robust diagnostic tools for bone diseases in clinical research, clinical routine and in personalized medicine. Copyright © 2015 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Matrix metalloproteinase inhibitors as investigative tools in the pathogenesis and management of vascular disease.

PubMed

Benjamin, Mina M; Khalil, Raouf A

2012-01-01

Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade various components of the extracellular matrix (ECM). MMPs could also regulate the activity of several non-ECM bioactive substrates and consequently affect different cellular functions. Members of the MMPs family include collagenases, gelatinases, stromelysins, matrilysins, membrane-type MMPs, and others. Pro-MMPs are cleaved into active MMPs, which in turn act on various substrates in the ECM and on the cell surface. MMPs play an important role in the regulation of numerous physiological processes including vascular remodeling and angiogenesis. MMPs may also be involved in vascular diseases such as hypertension, atherosclerosis, aortic aneurysm, and varicose veins. MMPs also play a role in the hemodynamic and vascular changes associated with pregnancy and preeclampsia. The role of MMPs is commonly assessed by measuring their gene expression, protein amount, and proteolytic activity using gel zymography. Because there are no specific activators of MMPs, MMP inhibitors are often used to investigate the role of MMPs in different physiologic processes and in the pathogenesis of specific diseases. MMP inhibitors include endogenous tissue inhibitors (TIMPs) and pharmacological inhibitors such as zinc chelators, doxycycline, and marimastat. MMP inhibitors have been evaluated as diagnostic and therapeutic tools in cancer, autoimmune disease, and cardiovascular disease. Although several MMP inhibitors have been synthesized and tested both experimentally and clinically, only one MMP inhibitor, i.e., doxycycline, is currently approved by the Food and Drug Administration. This is mainly due to the undesirable side effects of MMP inhibitors especially on the musculoskeletal system. While most experimental and clinical trials of MMP inhibitors have not demonstrated significant benefits, some trials still showed promising results. With the advent of new genetic and pharmacological tools, disease-specific MMP inhibitors with fewer undesirable effects are being developed and could be useful in the management of vascular disease.

Periodontal therapy.

PubMed

Niemiec, Brook A

2008-05-01

Periodontal disease is the most common disease in small animal patients. It not only creates severe localized infection, but it has been linked to numerous severe systemic maladies. Proper therapy of this disease process results in a significant increase in the overall health of the patient. The treatment of periodontal disease is currently evolving due to the acceptance of the specific plaque hypothesis of periodontal disease. These findings have led to the development of the "one-stage full-mouth disinfection" treatment as well as a vaccine against these organisms. However, the cornerstone of therapy is still meticulous plaque control. This control is achieved via a combination of regular dental prophylaxis and home care. With progressive disease, advanced periodontal surgery or extraction becomes necessary.

Studying the Brain in a Dish: 3D Cell Culture Models of Human Brain Development and Disease.

PubMed

Brown, Juliana; Quadrato, Giorgia; Arlotta, Paola

2018-01-01

The study of the cellular and molecular processes of the developing human brain has been hindered by access to suitable models of living human brain tissue. Recently developed 3D cell culture models offer the promise of studying fundamental brain processes in the context of human genetic background and species-specific developmental mechanisms. Here, we review the current state of 3D human brain organoid models and consider their potential to enable investigation of complex aspects of human brain development and the underpinning of human neurological disease. © 2018 Elsevier Inc. All rights reserved.

Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology.

PubMed

Ferreira, Manuel A; Vonk, Judith M; Baurecht, Hansjörg; Marenholz, Ingo; Tian, Chao; Hoffman, Joshua D; Helmer, Quinta; Tillander, Annika; Ullemar, Vilhelmina; van Dongen, Jenny; Lu, Yi; Rüschendorf, Franz; Esparza-Gordillo, Jorge; Medway, Chris W; Mountjoy, Edward; Burrows, Kimberley; Hummel, Oliver; Grosche, Sarah; Brumpton, Ben M; Witte, John S; Hottenga, Jouke-Jan; Willemsen, Gonneke; Zheng, Jie; Rodríguez, Elke; Hotze, Melanie; Franke, Andre; Revez, Joana A; Beesley, Jonathan; Matheson, Melanie C; Dharmage, Shyamali C; Bain, Lisa M; Fritsche, Lars G; Gabrielsen, Maiken E; Balliu, Brunilda; Nielsen, Jonas B; Zhou, Wei; Hveem, Kristian; Langhammer, Arnulf; Holmen, Oddgeir L; Løset, Mari; Abecasis, Gonçalo R; Willer, Cristen J; Arnold, Andreas; Homuth, Georg; Schmidt, Carsten O; Thompson, Philip J; Martin, Nicholas G; Duffy, David L; Novak, Natalija; Schulz, Holger; Karrasch, Stefan; Gieger, Christian; Strauch, Konstantin; Melles, Ronald B; Hinds, David A; Hübner, Norbert; Weidinger, Stephan; Magnusson, Patrik K E; Jansen, Rick; Jorgenson, Eric; Lee, Young-Ae; Boomsma, Dorret I; Almqvist, Catarina; Karlsson, Robert; Koppelman, Gerard H; Paternoster, Lavinia

2017-12-01

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals, partly because of a shared genetic origin. To identify shared risk variants, we performed a genome-wide association study (GWAS; n = 360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P < 3 × 10 -8 ), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes.

Shared genetic origin of asthma, hay fever and eczema elucidates allergic disease biology

PubMed Central

Esparza-Gordillo, Jorge; Medway, Chris W; Mountjoy, Edward; Burrows, Kimberley; Hummel, Oliver; Grosche, Sarah; Brumpton, Ben M; Witte, John S; Hottenga, Jouke-Jan; Willemsen, Gonneke; Zheng, Jie; Rodríguez, Elke; Hotze, Melanie; Franke, Andre; Revez, Joana A; Beesley, Jonathan; Matheson, Melanie C; Dharmage, Shyamali C; Bain, Lisa M; Fritsche, Lars G; Gabrielsen, Maiken E; Balliu, Brunilda; Nielsen, Jonas B; Zhou, Wei; Hveem, Kristian; Langhammer, Arnulf; Holmen, Oddgeir L; Løset, Mari; Abecasis, Gonçalo R; Willer, Cristen J; Arnold, Andreas; Homuth, Georg; Schmidt, Carsten O; Thompson, Philip J; Martin, Nicholas G; Duffy, David L; Novak, Natalija; Schulz, Holger; Karrasch, Stefan; Gieger, Christian; Strauch, Konstantin; Melles, Ronald B; Hinds, David A; Hübner, Norbert; Weidinger, Stephan; Magnusson, Patrik KE; Jansen, Rick; Jorgenson, Eric; Lee, Young-Ae; Boomsma, Dorret I; Almqvist, Catarina; Karlsson, Robert; Koppelman, Gerard H; Paternoster, Lavinia

2017-01-01

Asthma, hay fever (or allergic rhinitis) and eczema (or atopic dermatitis) often coexist in the same individuals1, partly because of a shared genetic origin2–4. To identify shared risk variants, we performed a genome-wide association study (GWAS, n=360,838) of a broad allergic disease phenotype that considers the presence of any one of these three diseases. We identified 136 independent risk variants (P<3x10-8), including 73 not previously reported, which implicate 132 nearby genes in allergic disease pathophysiology. Disease-specific effects were detected for only six variants, confirming that most represent shared risk factors. Tissue-specific heritability and biological process enrichment analyses suggest that shared risk variants influence lymphocyte-mediated immunity. Six target genes provide an opportunity for drug repositioning, while for 36 genes CpG methylation was found to influence transcription independently of genetic effects. Asthma, hay fever and eczema partly coexist because they share many genetic risk variants that dysregulate the expression of immune-related genes. PMID:29083406

Vitamin D deficiency: infertility and neurodevelopmental diseases (attention deficit hyperactivity disorder, autism, and schizophrenia).

PubMed

Berridge, Michael J

2018-02-01

The process of development depends on a number of signaling systems that regulates the progressive sequence of developmental events. Infertility and neurodevelopmental diseases, such as attention deficit hyperactivity disorder, autism spectrum disorders, and schizophrenia, are caused by specific alterations in these signaling processes. Calcium signaling plays a prominent role throughout development beginning at fertilization and continuing through early development, implantation, and organ differentiation such as heart and brain development. Vitamin D plays a major role in regulating these signaling processes that control development. There is an increase in infertility and an onset of neurodevelopmental diseases when vitamin D is deficient. The way in which vitamin D deficiency acts to alter development is a major feature of this review. One of the primary functions of vitamin D is to maintain the phenotypic stability of both the Ca 2+ and redox signaling pathways that play such a key role throughout development.

Prediction of human disease-associated phosphorylation sites with combined feature selection approach and support vector machine.

PubMed

Xu, Xiaoyi; Li, Ao; Wang, Minghui

2015-08-01

Phosphorylation is a crucial post-translational modification, which regulates almost all cellular processes in life. It has long been recognised that protein phosphorylation has close relationship with diseases, and therefore many researches are undertaken to predict phosphorylation sites for disease treatment and drug design. However, despite the success achieved by these approaches, no method focuses on disease-associated phosphorylation sites prediction. Herein, for the first time the authors propose a novel approach that is specially designed to identify associations between phosphorylation sites and human diseases. To take full advantage of local sequence information, a combined feature selection method-based support vector machine (CFS-SVM) that incorporates minimum-redundancy-maximum-relevance filtering process and forward feature selection process is developed. Performance evaluation shows that CFS-SVM is significantly better than the widely used classifiers including Bayesian decision theory, k nearest neighbour and random forest. With the extremely high specificity of 99%, CFS-SVM can still achieve a high sensitivity. Besides, tests on extra data confirm the effectiveness and general applicability of CFS-SVM approach on a variety of diseases. Finally, the analysis of selected features and corresponding kinases also help the understanding of the potential mechanism of disease-phosphorylation relationships and guide further experimental validations.

Specialized nursing practice for chronic disease management in the primary care setting: an evidence-based analysis.

PubMed

2013-01-01

In response to the increasing demand for better chronic disease management and improved health care efficiency in Ontario, nursing roles have expanded in the primary health care setting. To determine the effectiveness of specialized nurses who have a clinical role in patient care in optimizing chronic disease management among adults in the primary health care setting. A literature search was performed using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database. Results were limited to randomized controlled trials and systematic reviews and were divided into 2 models: Model 1 (nurse alone versus physician alone) and Model 2 (nurse and physician versus physician alone). Effectiveness was determined by comparable outcomes between groups in Model 1, or improved outcomes or efficiency in Model 2. Six studies were included. In Model 1, there were no significant differences in health resource use, disease-specific measures, quality of life, or patient satisfaction. In Model 2, there was a reduction in hospitalizations and improved management of blood pressure and lipids among patients with coronary artery disease. Among patients with diabetes, there was a reduction in hemoglobin A1c but no difference in other disease-specific measures. There was a trend toward improved process measures, including medication prescribing and clinical assessments. Results related to quality of life were inconsistent, but patient satisfaction with the nurse-physician team was improved. Overall, there were more and longer visits to the nurse, and physician workload did not change. There was heterogeneity across patient populations, and in the titles, roles, and scope of practice of the specialized nurses. Specialized nurses with an autonomous role in patient care had comparable outcomes to physicians alone (Model 1) based on moderate quality evidence, with consistent results among a subgroup analysis of patients with diabetes based on low quality evidence. Model 2 showed an overall improvement in appropriate process measures, disease-specific measures, and patient satisfaction based on low to moderate quality evidence. There was low quality evidence that nurses working under Model 2 may reduce hospitalizations for patients with coronary artery disease. The specific role of the nurse in supplementing or substituting physician care was unclear, making it difficult to determine the impact on efficiency. Nurses with additional skills, training, or scope of practice may help improve the primary care of patients with chronic diseases. This review found that specialized nurses working on their own could achieve health outcomes that were similar to those of doctors. It also found that specialized nurses who worked with doctors could reduce hospital visits and improve certain patient outcomes related to diabetes, coronary artery disease, or heart failure. Patients who had nurse-led care were more satisfied and tended to receive more tests and medications. It is unclear whether specialized nurses improve quality of life or doctor workload.

Second-order analysis of semiparametric recurrent event processes.

PubMed

Guan, Yongtao

2011-09-01

A typical recurrent event dataset consists of an often large number of recurrent event processes, each of which contains multiple event times observed from an individual during a follow-up period. Such data have become increasingly available in medical and epidemiological studies. In this article, we introduce novel procedures to conduct second-order analysis for a flexible class of semiparametric recurrent event processes. Such an analysis can provide useful information regarding the dependence structure within each recurrent event process. Specifically, we will use the proposed procedures to test whether the individual recurrent event processes are all Poisson processes and to suggest sensible alternative models for them if they are not. We apply these procedures to a well-known recurrent event dataset on chronic granulomatous disease and an epidemiological dataset on meningococcal disease cases in Merseyside, United Kingdom to illustrate their practical value. © 2011, The International Biometric Society.

Zika Virus: A Review of Management Considerations and Controversies at Six Months.

PubMed

Singer, Laura; Vest, Kelly G; Beadling, Charles W

2017-06-01

Zika virus continues to pose a significant global health threat. While the outbreak pattern may seemingly mirror those of other arboviruses, unique transmission characteristics and clinical outcomes warrant a different approach to traditional public health practices. Sexual transmission and virus-associated fetal and nonfetal neurologic disorders specifically challenge conventional methods of disease protection and prevention with regard to vector control, disease surveillance, and health risk communication. The protocols for outbreak and case limitation led by the World Health Organization (in accordance with Public Health Emergency of International Concern declaration) may be augmented by localized risk categorization and assignment for Zika and future emergent outbreaks. There is currently a great deal of "behind the scenes" discussion about modifications to the formal process described in the International Health Regulations. A scalable, adaptable, and flexible process is needed that can be customized to a specific threat. (Disaster Med Public Health Preparedness. 2017;11:279-284).

Fundamentals of nuclear medicine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Alazraki, N.P.; Mishkin, F.S.

1988-01-01

The book begins with basic science and statistics relevant to nuclear medicine, and specific organ systems are addressed in separate chapters. A section of the text also covers imaging of groups of disease processes (eg, trauma, cancer). The authors present a comparison between nuclear medicine techniques and other diagnostic imaging studies. A table is given which comments on sensitivities and specificities of common nuclear medicine studies. The sensitivities and specificities are categorized as very high, high, moderate, and so forth.

The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels.

PubMed

Salazar, Dominique A; Butler, Victoria J; Argouarch, Andrea R; Hsu, Tsung-Yuan; Mason, Amanda; Nakamura, Ayumi; McCurdy, Helen; Cox, David; Ng, Rachel; Pan, Gloria; Seeley, William W; Miller, Bruce L; Kao, Aimee W

2015-06-24

Mutations in the human progranulin gene resulting in protein haploinsufficiency cause frontotemporal lobar degeneration with TDP-43 inclusions. Although progress has been made in understanding the normal functions of progranulin and TDP-43, the molecular interactions between these proteins remain unclear. Progranulin is proteolytically processed into granulins, but the role of granulins in the pathogenesis of neurodegenerative disease is unknown. We used a Caenorhabditis elegans model of neuronal TDP-43 proteinopathy to specifically interrogate the contribution of granulins to the neurodegenerative process. Complete loss of the progranulin gene did not worsen TDP-43 toxicity, whereas progranulin heterozygosity did. Interestingly, expression of individual granulins alone had little effect on behavior. In contrast, when granulins were coexpressed with TDP-43, they exacerbated its toxicity in a variety of behaviors including motor coordination. These same granulins increased TDP-43 levels via a post-translational mechanism. We further found that in human neurodegenerative disease subjects, granulin fragments accumulated specifically in diseased regions of brain. To our knowledge, this is the first demonstration of a toxic role for granulin fragments in a neurodegenerative disease model. These studies suggest that presence of cleaved granulins, rather than or in addition to loss of full-length progranulin, may contribute to disease in TDP-43 proteinopathies. Copyright © 2015 the authors 0270-6474/15/359315-14$15.00/0.

Unsupervised method for automatic construction of a disease dictionary from a large free text collection.

PubMed

Xu, Rong; Supekar, Kaustubh; Morgan, Alex; Das, Amar; Garber, Alan

2008-11-06

Concept specific lexicons (e.g. diseases, drugs, anatomy) are a critical source of background knowledge for many medical language-processing systems. However, the rapid pace of biomedical research and the lack of constraints on usage ensure that such dictionaries are incomplete. Focusing on disease terminology, we have developed an automated, unsupervised, iterative pattern learning approach for constructing a comprehensive medical dictionary of disease terms from randomized clinical trial (RCT) abstracts, and we compared different ranking methods for automatically extracting con-textual patterns and concept terms. When used to identify disease concepts from 100 randomly chosen, manually annotated clinical abstracts, our disease dictionary shows significant performance improvement (F1 increased by 35-88%) over available, manually created disease terminologies.

Unsupervised Method for Automatic Construction of a Disease Dictionary from a Large Free Text Collection

PubMed Central

Xu, Rong; Supekar, Kaustubh; Morgan, Alex; Das, Amar; Garber, Alan

2008-01-01

Concept specific lexicons (e.g. diseases, drugs, anatomy) are a critical source of background knowledge for many medical language-processing systems. However, the rapid pace of biomedical research and the lack of constraints on usage ensure that such dictionaries are incomplete. Focusing on disease terminology, we have developed an automated, unsupervised, iterative pattern learning approach for constructing a comprehensive medical dictionary of disease terms from randomized clinical trial (RCT) abstracts, and we compared different ranking methods for automatically extracting contextual patterns and concept terms. When used to identify disease concepts from 100 randomly chosen, manually annotated clinical abstracts, our disease dictionary shows significant performance improvement (F1 increased by 35–88%) over available, manually created disease terminologies. PMID:18999169

Expression profiling of cardiovascular disease

PubMed Central

2004-01-01

Cardiovascular disease is the most important cause of morbidity and mortality in developed countries, causing twice as many deaths as cancer in the USA. The major cardiovascular diseases, including coronary artery disease (CAD), myocardial infarction (MI), congestive heart failure (CHF) and common congenital heart disease (CHD), are caused by multiple genetic and environmental factors, as well as the interactions between them. The underlying molecular pathogenic mechanisms for these disorders are still largely unknown, but gene expression may play a central role in the development and progression of cardiovascular disease. Microarrays are high-throughput genomic tools that allow the comparison of global expression changes in thousands of genes between normal and diseased cells/tissues. Microarrays have recently been applied to CAD/MI, CHF and CHD to profile changes in gene expression patterns in diseased and non-diseased patients. This same technology has also been used to characterise endothelial cells, vascular smooth muscle cells and inflammatory cells, with or without various treatments that mimic disease processes involved in CAD/MI. These studies have led to the identification of unique subsets of genes associated with specific diseases and disease processes. Ongoing microarray studies in the field will provide insights into the molecular mechanism of cardiovascular disease and may generate new diagnostic and therapeutic markers. PMID:15588496

Surgery of chronic pancreatitis: chronicle of confusion and despair.

PubMed

Modlin, Irvin M; Kidd, Mark; Hults, Christopher; Hinoue, Toshi

2002-11-01

The evolution of surgery for pancreatitic disease has been arduous owing to the technical difficulties of addressing the organ and the lack of understanding the mechanisms of the disease processes involving it. In particular, the tardy advance of surgery in the management of chronic pancreatitis exemplifies these problems. Because no specific target has been identified, mechanical intervention has for the most part reflected intuitive or creative attempts to address perceived pathologic issues such as sphincter disease, calculi, and fibrotic masses. The past and present remain a confusion of etiologies and diagnoses. Treatment remains for the most part a dramatically disappointing scenario, and both patients and their physicians are frustrated. Although the remarkable technologic progress exhibited by the odyssey of operative strategy from simple drainage, to ductal drainage, to the complex refinements of extensive resection is a testimonial to surgical skill and determination, it has been nullified to a large extent by the inability to address the initiating factors of the disease or alter those that engender progress of the pathology. It is not unreasonable to recognize that we are facing an enigmatic disease process generically classified as "chronic pancreatitis" for want of any more specific terminology. In the light of our current knowledge and experience, intervention should probably be modest in the extreme and limited to centers and individuals with expertise or who are involved in specific studies to determine the precise criteria and techniques necessary for optimum intervention. It is important that when charting such a course future surgeons involved in the management of chronic pancreatitis have an understanding of the historical evolution of the subject. As Theodor Billroth, the greatest of the surgical innovators remarked: "An awareness of the past is necessary to comprehend the present, and without it no consideration of the future is possible."

HttQ111/+ Huntington’s Disease Knock-in Mice Exhibit Brain Region-Specific Morphological Changes and Synaptic Dysfunction

PubMed Central

Kovalenko, Marina; Milnerwood, Austen; Giordano, James; St. Claire, Jason; Guide, Jolene R.; Stromberg, Mary; Gillis, Tammy; Sapp, Ellen; DiFiglia, Marian; MacDonald, Marcy E.; Carroll, Jeffrey B.; Lee, Jong-Min; Tappan, Susan; Raymond, Lynn; Wheeler, Vanessa C.

2018-01-01

Background: Successful disease-modifying therapy for Huntington’s disease (HD) will require therapeutic intervention early in the pathogenic process. Achieving this goal requires identifying phenotypes that are proximal to the HTT CAG repeat expansion. Objective: To use Htt CAG knock-in mice, precise genetic replicas of the HTT mutation in patients, as models to study proximal disease events. Methods: Using cohorts of B6J.HttQ111/+ mice from 2 to 18 months of age, we analyzed pathological markers, including immunohistochemistry, brain regional volumes and cortical thickness, CAG instability, electron microscopy of striatal synapses, and acute slice electrophysiology to record glutamatergic transmission at striatal synapses. We also incorporated a diet perturbation paradigm for some of these analyses. Results: B6J.HttQ111/+ mice did not exhibit significant neurodegeneration or gliosis but revealed decreased striatal DARPP-32 as well as subtle but regional-specific changes in brain volumes and cortical thickness that parallel those in HD patients. Ultrastructural analyses of the striatum showed reduced synapse density, increased postsynaptic density thickness and increased synaptic cleft width. Acute slice electrophysiology showed alterations in spontaneous AMPA receptor-mediated postsynaptic currents, evoked NMDA receptor-mediated excitatory postsynaptic currents, and elevated extrasynaptic NMDA currents. Diet influenced cortical thickness, but did not impact somatic CAG expansion, nor did it show any significant interaction with genotype on immunohistochemical, brain volume or cortical thickness measures. Conclusions: These data show that a single HttQ111 allele is sufficient to elicit brain region-specific morphological changes and early neuronal dysfunction, highlighting an insidious disease process already apparent in the first few months of life. PMID:29480209

Network-Based Identification and Prioritization of Key Regulators of Coronary Artery Disease Loci

PubMed Central

Zhao, Yuqi; Chen, Jing; Freudenberg, Johannes M.; Meng, Qingying; Rajpal, Deepak K.; Yang, Xia

2017-01-01

Objective Recent genome-wide association studies of coronary artery disease (CAD) have revealed 58 genome-wide significant and 148 suggestive genetic loci. However, the molecular mechanisms through which they contribute to CAD and the clinical implications of these findings remain largely unknown. We aim to retrieve gene subnetworks of the 206 CAD loci and identify and prioritize candidate regulators to better understand the biological mechanisms underlying the genetic associations. Approach and Results We devised a new integrative genomics approach that incorporated (1) candidate genes from the top CAD loci, (2) the complete genetic association results from the 1000 genomes-based CAD genome-wide association studies from the Coronary Artery Disease Genome Wide Replication and Meta-Analysis Plus the Coronary Artery Disease consortium, (3) tissue-specific gene regulatory networks that depict the potential relationship and interactions between genes, and (4) tissue-specific gene expression patterns between CAD patients and controls. The networks and top-ranked regulators according to these data-driven criteria were further queried against literature, experimental evidence, and drug information to evaluate their disease relevance and potential as drug targets. Our analysis uncovered several potential novel regulators of CAD such as LUM and STAT3, which possess properties suitable as drug targets. We also revealed molecular relations and potential mechanisms through which the top CAD loci operate. Furthermore, we found that multiple CAD-relevant biological processes such as extracellular matrix, inflammatory and immune pathways, complement and coagulation cascades, and lipid metabolism interact in the CAD networks. Conclusions Our data-driven integrative genomics framework unraveled tissue-specific relations among the candidate genes of the CAD genome-wide association studies loci and prioritized novel network regulatory genes orchestrating biological processes relevant to CAD. PMID:26966275

Semi-automated literature mining to identify putative biomarkers of disease from multiple biofluids

PubMed Central

2014-01-01

Background Computational methods for mining of biomedical literature can be useful in augmenting manual searches of the literature using keywords for disease-specific biomarker discovery from biofluids. In this work, we develop and apply a semi-automated literature mining method to mine abstracts obtained from PubMed to discover putative biomarkers of breast and lung cancers in specific biofluids. Methodology A positive set of abstracts was defined by the terms ‘breast cancer’ and ‘lung cancer’ in conjunction with 14 separate ‘biofluids’ (bile, blood, breastmilk, cerebrospinal fluid, mucus, plasma, saliva, semen, serum, synovial fluid, stool, sweat, tears, and urine), while a negative set of abstracts was defined by the terms ‘(biofluid) NOT breast cancer’ or ‘(biofluid) NOT lung cancer.’ More than 5.3 million total abstracts were obtained from PubMed and examined for biomarker-disease-biofluid associations (34,296 positive and 2,653,396 negative for breast cancer; 28,355 positive and 2,595,034 negative for lung cancer). Biological entities such as genes and proteins were tagged using ABNER, and processed using Python scripts to produce a list of putative biomarkers. Z-scores were calculated, ranked, and used to determine significance of putative biomarkers found. Manual verification of relevant abstracts was performed to assess our method’s performance. Results Biofluid-specific markers were identified from the literature, assigned relevance scores based on frequency of occurrence, and validated using known biomarker lists and/or databases for lung and breast cancer [NCBI’s On-line Mendelian Inheritance in Man (OMIM), Cancer Gene annotation server for cancer genomics (CAGE), NCBI’s Genes & Disease, NCI’s Early Detection Research Network (EDRN), and others]. The specificity of each marker for a given biofluid was calculated, and the performance of our semi-automated literature mining method assessed for breast and lung cancer. Conclusions We developed a semi-automated process for determining a list of putative biomarkers for breast and lung cancer. New knowledge is presented in the form of biomarker lists; ranked, newly discovered biomarker-disease-biofluid relationships; and biomarker specificity across biofluids. PMID:25379168

Celiac Disease and Nonceliac Gluten Sensitivity: A Review.

PubMed

Leonard, Maureen M; Sapone, Anna; Catassi, Carlo; Fasano, Alessio

2017-08-15

The prevalence of gluten-related disorders is rising, and increasing numbers of individuals are empirically trying a gluten-free diet for a variety of signs and symptoms. This review aims to present current evidence regarding screening, diagnosis, and treatment for celiac disease and nonceliac gluten sensitivity. Celiac disease is a gluten-induced immune-mediated enteropathy characterized by a specific genetic genotype (HLA-DQ2 and HLA-DQ8 genes) and autoantibodies (antitissue transglutaminase and antiendomysial). Although the inflammatory process specifically targets the intestinal mucosa, patients may present with gastrointestinal signs or symptoms, extraintestinal signs or symptoms, or both, suggesting that celiac disease is a systemic disease. Nonceliac gluten sensitivity is diagnosed in individuals who do not have celiac disease or wheat allergy but who have intestinal symptoms, extraintestinal symptoms, or both, related to ingestion of gluten-containing grains, with symptomatic improvement on their withdrawal. The clinical variability and the lack of validated biomarkers for nonceliac gluten sensitivity make establishing the prevalence, reaching a diagnosis, and further study of this condition difficult. Nevertheless, it is possible to differentiate specific gluten-related disorders from other conditions, based on currently available investigations and algorithms. Clinicians cannot distinguish between celiac disease and nonceliac gluten sensitivity by symptoms, as they are similar in both. Therefore, screening for celiac disease must occur before a gluten-free diet is implemented, since once a patient initiates a gluten-free diet, testing for celiac disease is no longer accurate. Celiac disease and nonceliac gluten sensitivity are common. Although both conditions are treated with a gluten-free diet, distinguishing between celiac disease and nonceliac gluten sensitivity is important for long-term therapy. Patients with celiac disease should be followed up closely for dietary adherence, nutritional deficiencies, and the development of possible comorbidities.

Androgen receptor (AR) pathophysiological roles in androgen-related diseases in skin, bone/muscle, metabolic syndrome and neuron/immune systems: lessons learned from mice lacking AR in specific cells

PubMed Central

Chang, Chawnshang; Yeh, Shuyuan; Lee, Soo Ok; Chang, Ta-min

2013-01-01

The androgen receptor (AR) is expressed ubiquitously and plays a variety of roles in a vast number of physiological and pathophysiological processes. Recent studies of AR knockout (ARKO) mouse models, particularly the cell type- or tissue-specific ARKO models, have uncovered many AR cell type- or tissue-specific pathophysiological roles in mice, which otherwise would not be delineated from conventional castration and androgen insensitivity syndrome studies. Thus, the AR in various specific cell types plays pivotal roles in production and maturation of immune cells, bone mineralization, and muscle growth. In metabolism, the ARs in brain, particularly in the hypothalamus, and the liver appear to participate in regulation of insulin sensitivity and glucose homeostasis. The AR also plays key roles in cutaneous wound healing and cardiovascular diseases, including atherosclerosis and abdominal aortic aneurysm. This article will discuss the results obtained from the total, cell type-, or tissue-specific ARKO models. The understanding of AR cell type- or tissue-specific physiological and pathophysiological roles using these in vivo mouse models will provide useful information in uncovering AR roles in humans and eventually help us to develop better therapies via targeting the AR or its downstream signaling molecules to combat androgen/AR-related diseases. PMID:24653668

Systems-level mechanisms of action of Panax ginseng: a network pharmacological approach.

PubMed

Park, Sa-Yoon; Park, Ji-Hun; Kim, Hyo-Su; Lee, Choong-Yeol; Lee, Hae-Jeung; Kang, Ki Sung; Kim, Chang-Eop

2018-01-01

Panax ginseng has been used since ancient times based on the traditional Asian medicine theory and clinical experiences, and currently, is one of the most popular herbs in the world. To date, most of the studies concerning P. ginseng have focused on specific mechanisms of action of individual constituents. However, in spite of many studies on the molecular mechanisms of P. ginseng , it still remains unclear how multiple active ingredients of P. ginseng interact with multiple targets simultaneously, giving the multidimensional effects on various conditions and diseases. In order to decipher the systems-level mechanism of multiple ingredients of P. ginseng , a novel approach is needed beyond conventional reductive analysis. We aim to review the systems-level mechanism of P. ginseng by adopting novel analytical framework-network pharmacology. Here, we constructed a compound-target network of P. ginseng using experimentally validated and machine learning-based prediction results. The targets of the network were analyzed in terms of related biological process, pathways, and diseases. The majority of targets were found to be related with primary metabolic process, signal transduction, nitrogen compound metabolic process, blood circulation, immune system process, cell-cell signaling, biosynthetic process, and neurological system process. In pathway enrichment analysis of targets, mainly the terms related with neural activity showed significant enrichment and formed a cluster. Finally, relative degrees analysis for the target-disease association of P. ginseng revealed several categories of related diseases, including respiratory, psychiatric, and cardiovascular diseases.

[Quality indicators for National Disease Management Guidelines using the example of the National Disease Management Guideline for "Chronic Heart Failure"].

PubMed

Nothacker, Monika Judith; Langer, Thomas; Weinbrenner, Susanne

2011-01-01

Together with an expert committee a structured approach to determining quality indicators for National Disease Management Guidelines has been developed. The key steps of this approach include: introducing guideline authors to the methodology at an early stage of the process of guideline development, pre-selecting recommendations of the guideline which are potentially measurable by means of quality indicators, assessing the potentially measurable quality indicators in written form using five criteria (including their importance for the health care system and clarity of definitions) and approving them in a formal consensus process. For lack of a database these quality indicators must be regarded as preliminary. For the National Disease Management Guideline "Chronic Heart Failure" nine rate-based indicators have been chosen. The indicators correspond to important strong recommendations (grade of recommendation: A) from the fields of diagnosis (two), general therapeutic strategy (two), specific treatment (three), clinical monitoring (one) and co-ordination of care (one). In a second step, the quality indicators have to be validated within a pilot project. The determination and assessment of the potential quality indicators have revealed room for improvement of guideline development. In particular, there is a need for more health care data and for specification of recommendations.

Structural variants of yeast prions show conformer-specific requirements for chaperone activity

PubMed Central

Stein, Kevin C.; True, Heather L.

2016-01-01

Summary Molecular chaperones monitor protein homeostasis and defend against the misfolding and aggregation of proteins that is associated with protein conformational disorders. In these diseases, a variety of different aggregate structures can form. These are called prion strains, or variants, in prion diseases, and cause variation in disease pathogenesis. Here, we use variants of the yeast prions [RNQ+] and [PSI+] to explore the interactions of chaperones with distinct aggregate structures. We found that prion variants show striking variation in their relationship with Hsp40s. Specifically, the yeast Hsp40 Sis1, and its human ortholog Hdj1, had differential capacities to process prion variants, suggesting that Hsp40 selectivity has likely changed through evolution. We further show that such selectivity involves different domains of Sis1, with some prion conformers having a greater dependence on particular Hsp40 domains. Moreover, [PSI+] variants were more sensitive to certain alterations in Hsp70 activity as compared to [RNQ+] variants. Collectively, our data indicate that distinct chaperone machinery is required, or has differential capacity, to process different aggregate structures. Elucidating the intricacies of chaperone-client interactions, and how these are altered by particular client structures, will be crucial to understanding how this system can go awry in disease and contribute to pathological variation. PMID:25060529

GWAS4D: multidimensional analysis of context-specific regulatory variant for human complex diseases and traits.

PubMed

Huang, Dandan; Yi, Xianfu; Zhang, Shijie; Zheng, Zhanye; Wang, Panwen; Xuan, Chenghao; Sham, Pak Chung; Wang, Junwen; Li, Mulin Jun

2018-05-16

Genome-wide association studies have generated over thousands of susceptibility loci for many human complex traits, and yet for most of these associations the true causal variants remain unknown. Tissue/cell type-specific prediction and prioritization of non-coding regulatory variants will facilitate the identification of causal variants and underlying pathogenic mechanisms for particular complex diseases and traits. By leveraging recent large-scale functional genomics/epigenomics data, we develop an intuitive web server, GWAS4D (http://mulinlab.tmu.edu.cn/gwas4d or http://mulinlab.org/gwas4d), that systematically evaluates GWAS signals and identifies context-specific regulatory variants. The updated web server includes six major features: (i) updates the regulatory variant prioritization method with our new algorithm; (ii) incorporates 127 tissue/cell type-specific epigenomes data; (iii) integrates motifs of 1480 transcriptional regulators from 13 public resources; (iv) uniformly processes Hi-C data and generates significant interactions at 5 kb resolution across 60 tissues/cell types; (v) adds comprehensive non-coding variant functional annotations; (vi) equips a highly interactive visualization function for SNP-target interaction. Using a GWAS fine-mapped set for 161 coronary artery disease risk loci, we demonstrate that GWAS4D is able to efficiently prioritize disease-causal regulatory variants.

Alignment of the Kübler-Ross grief cycle phases with the process of adaptation to type 1 diabetes mellitus.

PubMed

Isla Pera, Pilar; Moncho Vasallo, Joaquín; Guasch Andreu, Oscar; Torras Rabasa, Alberto

2008-02-01

To understand the process of adaptation to type 1 diabetes mellitus (DM1) and analyze its alignment with the grief cycle phases described by Kübler-Ross. We performed an ethnographic study through in-depth interviews with 20 patients, 10 relatives and 12 health professionals (6 physicians and 6 nurses). For the analysis, the Miles and Huberman qualitative data analysis model was used. Patients diagnosed with DM1 and their families face a loss of lifestyle and of the objects, real or imaginary, of their previous life. Patients and relatives experience emotional reactions that in some cases can be similar to the grief cycle phases described by Kübler-Ross for terminal diseases (denial, anger, bargaining, depression and acceptance). However, there are some differences depending on personal and psycho-social factors. Health professionals tend to relate low adherence to denial of the disease, but some patients feel threatened by the demands of treatment and control and their effects on their quality of life, and consciously choose not to follow recommendations. It is more realistic to talk about disease adaptation than acceptance, since the loss processes are ongoing and patients must reconstruct their identity according to their situation. The grief cycle also affects the family and may differ from that of the patient in its duration, intensity and assessment of problems. Adaptation is a complex process in which many variables intervene. There are observable differences among the mechanisms used by each specific individual. Healthcare professionals, and specifically nurses, should consider the multiple psycho-social dimensions of chronic disease. Copyright © 2008 Sociedad Española de Endocrinología y Nutrición. Published by Elsevier Espana. All rights reserved.

Electromagnetized gold nanoparticles mediate direct lineage reprogramming into induced dopamine neurons in vivo for Parkinson's disease therapy

NASA Astrophysics Data System (ADS)

Yoo, Junsang; Lee, Euiyeon; Kim, Hee Young; Youn, Dong-Ho; Jung, Junghyun; Kim, Hongwon; Chang, Yujung; Lee, Wonwoong; Shin, Jaein; Baek, Soonbong; Jang, Wonhee; Jun, Won; Kim, Soochan; Hong, Jongki; Park, Hi-Joon; Lengner, Christopher J.; Moh, Sang Hyun; Kwon, Youngeun; Kim, Jongpil

2017-10-01

Electromagnetic fields (EMF) are physical energy fields generated by electrically charged objects, and specific ranges of EMF can influence numerous biological processes, which include the control of cell fate and plasticity. In this study, we show that electromagnetized gold nanoparticles (AuNPs) in the presence of specific EMF conditions facilitate an efficient direct lineage reprogramming to induced dopamine neurons in vitro and in vivo. Remarkably, electromagnetic stimulation leads to a specific activation of the histone acetyltransferase Brd2, which results in histone H3K27 acetylation and a robust activation of neuron-specific genes. In vivo dopaminergic neuron reprogramming by EMF stimulation of AuNPs efficiently and non-invasively alleviated symptoms in mouse Parkinson's disease models. This study provides a proof of principle for EMF-based in vivo lineage conversion as a potentially viable and safe therapeutic strategy for the treatment of neurodegenerative disorders.

Deficient symbol processing in Alzheimer disease.

PubMed

Toepper, Max; Steuwe, Carolin; Beblo, Thomas; Bauer, Eva; Boedeker, Sebastian; Thomas, Christine; Markowitsch, Hans J; Driessen, Martin; Sammer, Gebhard

2014-01-01

Symbols and signs have been suggested to improve the orientation of patients suffering from Alzheimer disease (AD). However, there are hardly any studies that confirm whether AD patients benefit from signs or symbols and which symbol characteristics might improve or impede their symbol comprehension. To address these issues, 30 AD patients and 30 matched healthy controls performed a symbol processing task (SPT) with 4 different item categories. A repeated-measures analysis of variance was run to identify impact of different item categories on performance accuracy in both the experimental groups. Moreover, SPT scores were correlated with neuropsychological test scores in a broad range of other cognitive domains. Finally, diagnostic accuracy of the SPT was calculated by a receiver-operating characteristic curve analysis. Results revealed a global symbol processing dysfunction in AD that was associated with semantic memory and executive deficits. Moreover, AD patients showed a disproportional performance decline at SPT items with visual distraction. Finally, the SPT total score showed high sensitivity and specificity in differentiating between AD patients and healthy controls. The present findings suggest that specific symbol features impede symbol processing in AD and argue for a diagnostic benefit of the SPT in neuropsychological assessment.

Shining a Light on Task-Shifting Policy: Exploring opportunities for adaptability in non-communicable disease management programmes in Uganda.

PubMed

Katende, Godfrey; Donnelly, Mary

2016-05-01

In terms of disease burden, many low- and middle-income countries are currently experiencing a transition from infectious to chronic diseases. In Uganda, non-communicable diseases (NCDs) have increased significantly in recent years; this challenge is compounded by the healthcare worker shortage and the underfunded health system administration. Addressing the growing prevalence of NCDs requires evidence-based policies and strategies to reduce morbidity and mortality rates; however, the integration and evaluation of new policies and processes pose many challenges. Task-shifting is the process whereby specific tasks are transferred to health workers with less training and fewer qualifications. Successful implementation of a task-shifting policy requires appropriate skill training, clearly defined roles, adequate evaluation, an enhanced training capacity and sufficient health worker incentives. This article focuses on task-shifting policy as a potentially effective strategy to address the growing burden of NCDs on the Ugandan healthcare system.

Crk1/2-dependent signaling is necessary for podocyte foot process spreading in mouse models of glomerular disease

PubMed Central

George, Britta; Verma, Rakesh; Soofi, Abdulsalam A.; Garg, Puneet; Zhang, Jidong; Park, Tae-Ju; Giardino, Laura; Ryzhova, Larisa; Johnstone, Duncan B.; Wong, Hetty; Nihalani, Deepak; Salant, David J.; Hanks, Steven K.; Curran, Tom; Rastaldi, Maria Pia; Holzman, Lawrence B.

2012-01-01

The morphology of healthy podocyte foot processes is necessary for maintaining the characteristics of the kidney filtration barrier. In most forms of glomerular disease, abnormal filter barrier function results when podocytes undergo foot process spreading and retraction by remodeling their cytoskeletal architecture and intercellular junctions during a process known as effacement. The cell adhesion protein nephrin is necessary for establishing the morphology of the kidney podocyte in development by transducing from the specialized podocyte intercellular junction phosphorylation-mediated signals that regulate cytoskeletal dynamics. The present studies extend our understanding of nephrin function by showing that nephrin activation in cultured podocytes induced actin dynamics necessary for lamellipodial protrusion. This process required a PI3K-, Cas-, and Crk1/2-dependent signaling mechanism distinct from the previously described nephrin-Nck1/2 pathway necessary for assembly and polymerization of actin filaments. Our present findings also support the hypothesis that mechanisms governing lamellipodial protrusion in culture are similar to those used in vivo during foot process effacement in a subset of glomerular diseases. In mice, podocyte-specific deletion of Crk1/2 prevented foot process effacement in one model of podocyte injury and attenuated foot process effacement and associated proteinuria in a delayed fashion in a second model. In humans, focal adhesion kinase and Cas phosphorylation — markers of focal adhesion complex–mediated Crk-dependent signaling — was induced in minimal change disease and membranous nephropathy, but not focal segmental glomerulosclerosis. Together, these observations suggest that activation of a Cas-Crk1/2–dependent complex is necessary for foot process effacement observed in distinct subsets of human glomerular diseases. PMID:22251701

In vivo cell biology in zebrafish – providing insights into vertebrate development and disease

PubMed Central

Vacaru, Ana M.; Unlu, Gokhan; Spitzner, Marie; Mione, Marina; Knapik, Ela W.; Sadler, Kirsten C.

2014-01-01

ABSTRACT Over the past decades, studies using zebrafish have significantly advanced our understanding of the cellular basis for development and human diseases. Zebrafish have rapidly developing transparent embryos that allow comprehensive imaging of embryogenesis combined with powerful genetic approaches. However, forward genetic screens in zebrafish have generated unanticipated findings that are mirrored by human genetic studies: disruption of genes implicated in basic cellular processes, such as protein secretion or cytoskeletal dynamics, causes discrete developmental or disease phenotypes. This is surprising because many processes that were assumed to be fundamental to the function and survival of all cell types appear instead to be regulated by cell-specific mechanisms. Such discoveries are facilitated by experiments in whole animals, where zebrafish provides an ideal model for visualization and manipulation of organelles and cellular processes in a live vertebrate. Here, we review well-characterized mutants and newly developed tools that underscore this notion. We focus on the secretory pathway and microtubule-based trafficking as illustrative examples of how studying cell biology in vivo using zebrafish has broadened our understanding of the role fundamental cellular processes play in embryogenesis and disease. PMID:24481493

A Systematic Investigation into Aging Related Genes in Brain and Their Relationship with Alzheimer's Disease.

PubMed

Meng, Guofeng; Zhong, Xiaoyan; Mei, Hongkang

2016-01-01

Aging, as a complex biological process, is accompanied by the accumulation of functional loses at different levels, which makes age to be the biggest risk factor to many neurological diseases. Even following decades of investigation, the process of aging is still far from being fully understood, especially at a systematic level. In this study, we identified aging related genes in brain by collecting the ones with sustained and consistent gene expression or DNA methylation changes in the aging process. Functional analysis with Gene Ontology to these genes suggested transcriptional regulators to be the most affected genes in the aging process. Transcription regulation analysis found some transcription factors, especially Specificity Protein 1 (SP1), to play important roles in regulating aging related gene expression. Module-based functional analysis indicated these genes to be associated with many well-known aging related pathways, supporting the validity of our approach to select aging related genes. Finally, we investigated the roles of aging related genes on Alzheimer's Disease (AD). We found that aging and AD related genes both involved some common pathways, which provided a possible explanation why aging made the brain more vulnerable to Alzheimer's Disease.

Pancreas lineage allocation and specification are regulated by sphingosine-1-phosphate signalling.

PubMed

Serafimidis, Ioannis; Rodriguez-Aznar, Eva; Lesche, Mathias; Yoshioka, Kazuaki; Takuwa, Yoh; Dahl, Andreas; Pan, Duojia; Gavalas, Anthony

2017-03-01

During development, progenitor expansion, lineage allocation, and implementation of differentiation programs need to be tightly coordinated so that different cell types are generated in the correct numbers for appropriate tissue size and function. Pancreatic dysfunction results in some of the most debilitating and fatal diseases, including pancreatic cancer and diabetes. Several transcription factors regulating pancreas lineage specification have been identified, and Notch signalling has been implicated in lineage allocation, but it remains unclear how these processes are coordinated. Using a combination of genetic approaches, organotypic cultures of embryonic pancreata, and genomics, we found that sphingosine-1-phosphate (S1p), signalling through the G protein coupled receptor (GPCR) S1pr2, plays a key role in pancreas development linking lineage allocation and specification. S1pr2 signalling promotes progenitor survival as well as acinar and endocrine specification. S1pr2-mediated stabilisation of the yes-associated protein (YAP) is essential for endocrine specification, thus linking a regulator of progenitor growth with specification. YAP stabilisation and endocrine cell specification rely on Gαi subunits, revealing an unexpected specificity of selected GPCR intracellular signalling components. Finally, we found that S1pr2 signalling posttranscriptionally attenuates Notch signalling levels, thus regulating lineage allocation. Both S1pr2-mediated YAP stabilisation and Notch attenuation are necessary for the specification of the endocrine lineage. These findings identify S1p signalling as a novel key pathway coordinating cell survival, lineage allocation, and specification and linking these processes by regulating YAP levels and Notch signalling. Understanding lineage allocation and specification in the pancreas will shed light in the origins of pancreatic diseases and may suggest novel therapeutic approaches.

Pancreas lineage allocation and specification are regulated by sphingosine-1-phosphate signalling

PubMed Central

Serafimidis, Ioannis; Rodriguez-Aznar, Eva; Lesche, Mathias; Yoshioka, Kazuaki; Takuwa, Yoh; Dahl, Andreas; Pan, Duojia; Gavalas, Anthony

2017-01-01

During development, progenitor expansion, lineage allocation, and implementation of differentiation programs need to be tightly coordinated so that different cell types are generated in the correct numbers for appropriate tissue size and function. Pancreatic dysfunction results in some of the most debilitating and fatal diseases, including pancreatic cancer and diabetes. Several transcription factors regulating pancreas lineage specification have been identified, and Notch signalling has been implicated in lineage allocation, but it remains unclear how these processes are coordinated. Using a combination of genetic approaches, organotypic cultures of embryonic pancreata, and genomics, we found that sphingosine-1-phosphate (S1p), signalling through the G protein coupled receptor (GPCR) S1pr2, plays a key role in pancreas development linking lineage allocation and specification. S1pr2 signalling promotes progenitor survival as well as acinar and endocrine specification. S1pr2-mediated stabilisation of the yes-associated protein (YAP) is essential for endocrine specification, thus linking a regulator of progenitor growth with specification. YAP stabilisation and endocrine cell specification rely on Gαi subunits, revealing an unexpected specificity of selected GPCR intracellular signalling components. Finally, we found that S1pr2 signalling posttranscriptionally attenuates Notch signalling levels, thus regulating lineage allocation. Both S1pr2-mediated YAP stabilisation and Notch attenuation are necessary for the specification of the endocrine lineage. These findings identify S1p signalling as a novel key pathway coordinating cell survival, lineage allocation, and specification and linking these processes by regulating YAP levels and Notch signalling. Understanding lineage allocation and specification in the pancreas will shed light in the origins of pancreatic diseases and may suggest novel therapeutic approaches. PMID:28248965

An ERP study of vocal emotion processing in asymmetric Parkinson’s disease

PubMed Central

Garrido-Vásquez, Patricia; Pell, Marc D.; Paulmann, Silke; Strecker, Karl; Schwarz, Johannes; Kotz, Sonja A.

2013-01-01

Parkinson’s disease (PD) has been related to impaired processing of emotional speech intonation (emotional prosody). One distinctive feature of idiopathic PD is motor symptom asymmetry, with striatal dysfunction being strongest in the hemisphere contralateral to the most affected body side. It is still unclear whether this asymmetry may affect vocal emotion perception. Here, we tested 22 PD patients (10 with predominantly left-sided [LPD] and 12 with predominantly right-sided motor symptoms) and 22 healthy controls in an event-related potential study. Sentences conveying different emotional intonations were presented in lexical and pseudo-speech versions. Task varied between an explicit and an implicit instruction. Of specific interest was emotional salience detection from prosody, reflected in the P200 component. We predicted that patients with predominantly right-striatal dysfunction (LPD) would exhibit P200 alterations. Our results support this assumption. LPD patients showed enhanced P200 amplitudes, and specific deficits were observed for disgust prosody, explicit anger processing and implicit processing of happy prosody. Lexical speech was predominantly affected while the processing of pseudo-speech was largely intact. P200 amplitude in patients correlated significantly with left motor scores and asymmetry indices. The data suggest that emotional salience detection from prosody is affected by asymmetric neuronal degeneration in PD. PMID:22956665

Modeling Patient-Specific Deformable Mitral Valves.

PubMed

Ginty, Olivia; Moore, John; Peters, Terry; Bainbridge, Daniel

2018-06-01

Medical imaging has advanced enormously over the last few decades, revolutionizing patient diagnostics and care. At the same time, additive manufacturing has emerged as a means of reproducing physical shapes and models previously not possible. In combination, they have given rise to 3-dimensional (3D) modeling, an entirely new technology for physicians. In an era in which 3D imaging has become a standard for aiding in the diagnosis and treatment of cardiac disease, this visualization now can be taken further by bringing the patient's anatomy into physical reality as a model. The authors describe the generalized process of creating a model of cardiac anatomy from patient images and their experience creating patient-specific dynamic mitral valve models. This involves a combination of image processing software and 3D printing technology. In this article, the complexity of 3D modeling is described and the decision-making process for cardiac anesthesiologists is summarized. The management of cardiac disease has been altered with the emergence of 3D echocardiography, and 3D modeling represents the next paradigm shift. Copyright © 2017 Elsevier Inc. All rights reserved.

German dentists' websites on periodontitis have low quality of information.

PubMed

Schwendicke, Falk; Stange, Jörg; Stange, Claudia; Graetz, Christian

2017-08-02

The internet is an increasingly relevant source of health information. We aimed to assess the quality of German dentists' websites on periodontitis, hypothesizing that it was significantly associated with a number of practice-specific parameters. We searched four electronic search engines and included pages which were freely accessible, posted by a dental practice in Germany, and mentioned periodontal disease/therapy. Websites were assessed for (1) technical and functional aspects, (2) generic quality and risk of bias, (3) disease-specific information. For 1 and 2, validated tools (LIDA/DISCERN) were used for assessment. For 3, we developed a criterion catalogue encompassing items on etiologic and prognostic factors for periodontitis, the diagnostic and treatment process, and the generic chance of tooth retention in periodontitis patients. Inter- and intra-rater reliabilities were largely moderate. Generalized linear modeling was used to assess the association between the information quality (measured as % of maximally available scores) and practice-specific characteristics. Seventy-one websites were included. Technical and functional aspects were reported in significantly higher quality (median: 71%, 25/75th percentiles: 67/79%) than all other aspects (p < 0.05). Generic risk of bias and most disease-specific aspects showed significantly lower reporting quality (median range was 0-40%), with poorest reporting for prognostic factors (9;0/27%), diagnostic process (0;0/33%) and chances of tooth retention (0;0/2%). We found none of the practice-specific parameters to have significant impact on the overall quality of the websites. Most German dentists' websites on periodontitis are not fully trustworthy and relevant information are not or insufficiently considered. There is great need to improve the information quality from such websites at least with regards to periodontitis.

Rituximab for the treatment of refractory simultaneous anti-glomerular basement membrane (anti-GBM) and membranous nephropathy.

PubMed

Bandak, Ghassan; Jones, Bruce A; Li, Jian; Yee, Jerry; Umanath, Kausik

2014-02-01

Antibody-mediated anti-glomerular basement membrane (anti-GBM) disease occurs rarely in the presence of another B-cell disorder, membranous nephropathy. The coexistence of these two autoimmune disorders would be anticipated to require differing, specific therapies targeted to each disease process. We describe a case of concomitant membranous nephropathy and anti-GBM disease in which conventional therapy, including steroids, plasmapheresis and cyclophosphamide, failed to attenuate the anti-GBM disease, yet responded to an alternative treatment of rituximab. This B-cell directed, monoclonal, chimeric antibody treatment substantially reduced anti-GBM antibody titers and led to discontinuation of plasmapheresis, while maintaining the remission of membranous nephropathy and anti-GBM disease.

Mitigating amphibian disease: strategies to maintain wild populations and control chytridiomycosis

USGS Publications Warehouse

Woodhams, Douglas C.; Bosch, Jaime; Briggs, Cheryl J.; Cashins, Scott; Davis, Leyla R.; Lauer, Antje; Muths, Erin L.; Puschendorf, Robert; Schmidt, Benedikt R.; Sheafor, Brandon; Voyles, Jamie

2011-01-01

Because sustainable conservation of amphibians in nature is dependent on long-term population persistence and co-evolution with potentially lethal pathogens, we suggest that disease mitigation not focus exclusively on the elimination or containment of the pathogen, or on the captive breeding of amphibian hosts. Rather, successful disease mitigation must be context specific with epidemiologically informed strategies to manage already infected populations by decreasing pathogenicity and host susceptibility. We propose population level treatments based on three steps: first, identify mechanisms of disease suppression; second, parameterize epizootiological models of disease and population dynamics for testing under semi-natural conditions; and third, begin a process of adaptive management in field trials with natural populations.

Impaired neural processing of dynamic faces in left-onset Parkinson's disease.

PubMed

Garrido-Vásquez, Patricia; Pell, Marc D; Paulmann, Silke; Sehm, Bernhard; Kotz, Sonja A

2016-02-01

Parkinson's disease (PD) affects patients beyond the motor domain. According to previous evidence, one mechanism that may be impaired in the disease is face processing. However, few studies have investigated this process at the neural level in PD. Moreover, research using dynamic facial displays rather than static pictures is scarce, but highly warranted due to the higher ecological validity of dynamic stimuli. In the present study we aimed to investigate how PD patients process emotional and non-emotional dynamic face stimuli at the neural level using event-related potentials. Since the literature has revealed a predominantly right-lateralized network for dynamic face processing, we divided the group into patients with left (LPD) and right (RPD) motor symptom onset (right versus left cerebral hemisphere predominantly affected, respectively). Participants watched short video clips of happy, angry, and neutral expressions and engaged in a shallow gender decision task in order to avoid confounds of task difficulty in the data. In line with our expectations, the LPD group showed significant face processing deficits compared to controls. While there were no group differences in early, sensory-driven processing (fronto-central N1 and posterior P1), the vertex positive potential, which is considered the fronto-central counterpart of the face-specific posterior N170 component, had a reduced amplitude and delayed latency in the LPD group. This may indicate disturbances of structural face processing in LPD. Furthermore, the effect was independent of the emotional content of the videos. In contrast, static facial identity recognition performance in LPD was not significantly different from controls, and comprehensive testing of cognitive functions did not reveal any deficits in this group. We therefore conclude that PD, and more specifically the predominant right-hemispheric affection in left-onset PD, is associated with impaired processing of dynamic facial expressions, which could be one of the mechanisms behind the often reported problems of PD patients in their social lives. Copyright © 2016 Elsevier Ltd. All rights reserved.

Methodology and Applications of Disease Biomarker Identification in Human Serum

PubMed Central

Sahab, Ziad J.; Semaan, Suzan M.; Sang, Qing-Xiang Amy

2007-01-01

Biomarkers are biomolecules that serve as indicators of biological and pathological processes, or physiological and pharmacological responses to a drug treatment. Because of the high abundance of albumin and heterogeneity of plasma lipoproteins and glycoproteins, biomarkers are difficult to identify in human serum. Due to the clinical significance the identification of disease biomarkers in serum holds great promise for personalized medicine, especially for disease diagnosis and prognosis. This review summarizes some common and emerging proteomics techniques utilized in the separation of serum samples and identification of disease signatures. The practical application of each protein separation or identification technique is analyzed using specific examples. Biomarkers of cancers of prostate, breast, ovary, and lung in human serum have been reviewed, as well as those of heart disease, arthritis, asthma, and cystic fibrosis. Despite the advancement of technology few biomarkers have been approved by the Food and Drug Administration for disease diagnosis and prognosis due to the complexity of structure and function of protein biomarkers and lack of high sensitivity, specificity, and reproducibility for those putative biomarkers. The combination of different types of technologies and statistical analysis may provide more effective methods to identify and validate new disease biomarkers in blood. PMID:19662190

Targeting RNA Splicing for Disease Therapy

PubMed Central

Havens, Mallory A.; Duelli, Dominik M.

2013-01-01

Splicing of pre-messenger RNA into mature messenger RNA is an essential step for expression of most genes in higher eukaryotes. Defects in this process typically affect cellular function and can have pathological consequences. Many human genetic diseases are caused by mutations that cause splicing defects. Furthermore, a number of diseases are associated with splicing defects that are not attributed to overt mutations. Targeting splicing directly to correct disease-associated aberrant splicing is a logical approach to therapy. Splicing is a favorable intervention point for disease therapeutics, because it is an early step in gene expression and does not alter the genome. Significant advances have been made in the development of approaches to manipulate splicing for therapy. Splicing can be manipulated with a number of tools including antisense oligonucleotides, modified small nuclear RNAs (snRNAs), trans-splicing, and small molecule compounds, all of which have been used to increase specific alternatively spliced isoforms or to correct aberrant gene expression resulting from gene mutations that alter splicing. Here we describe clinically relevant splicing defects in disease states, the current tools used to target and alter splicing, specific mutations and diseases that are being targeted using splice-modulating approaches, and emerging therapeutics. PMID:23512601

Targeting RNA splicing for disease therapy.

PubMed

Havens, Mallory A; Duelli, Dominik M; Hastings, Michelle L

2013-01-01

Splicing of pre-messenger RNA into mature messenger RNA is an essential step for the expression of most genes in higher eukaryotes. Defects in this process typically affect cellular function and can have pathological consequences. Many human genetic diseases are caused by mutations that cause splicing defects. Furthermore, a number of diseases are associated with splicing defects that are not attributed to overt mutations. Targeting splicing directly to correct disease-associated aberrant splicing is a logical approach to therapy. Splicing is a favorable intervention point for disease therapeutics, because it is an early step in gene expression and does not alter the genome. Significant advances have been made in the development of approaches to manipulate splicing for therapy. Splicing can be manipulated with a number of tools including antisense oligonucleotides, modified small nuclear RNAs (snRNAs), trans-splicing, and small molecule compounds, all of which have been used to increase specific alternatively spliced isoforms or to correct aberrant gene expression resulting from gene mutations that alter splicing. Here we describe clinically relevant splicing defects in disease states, the current tools used to target and alter splicing, specific mutations and diseases that are being targeted using splice-modulating approaches, and emerging therapeutics. Copyright © 2013 John Wiley & Sons, Ltd.

Toxin-Induced Experimental Models of Learning and Memory Impairment

PubMed Central

More, Sandeep Vasant; Kumar, Hemant; Cho, Duk-Yeon; Yun, Yo-Sep; Choi, Dong-Kug

2016-01-01

Animal models for learning and memory have significantly contributed to novel strategies for drug development and hence are an imperative part in the assessment of therapeutics. Learning and memory involve different stages including acquisition, consolidation, and retrieval and each stage can be characterized using specific toxin. Recent studies have postulated the molecular basis of these processes and have also demonstrated many signaling molecules that are involved in several stages of memory. Most insights into learning and memory impairment and to develop a novel compound stems from the investigations performed in experimental models, especially those produced by neurotoxins models. Several toxins have been utilized based on their mechanism of action for learning and memory impairment such as scopolamine, streptozotocin, quinolinic acid, and domoic acid. Further, some toxins like 6-hydroxy dopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amyloid-β are known to cause specific learning and memory impairment which imitate the disease pathology of Parkinson’s disease dementia and Alzheimer’s disease dementia. Apart from these toxins, several other toxins come under a miscellaneous category like an environmental pollutant, snake venoms, botulinum, and lipopolysaccharide. This review will focus on the various classes of neurotoxin models for learning and memory impairment with their specific mechanism of action that could assist the process of drug discovery and development for dementia and cognitive disorders. PMID:27598124

Toxin-Induced Experimental Models of Learning and Memory Impairment.

PubMed

More, Sandeep Vasant; Kumar, Hemant; Cho, Duk-Yeon; Yun, Yo-Sep; Choi, Dong-Kug

2016-09-01

Animal models for learning and memory have significantly contributed to novel strategies for drug development and hence are an imperative part in the assessment of therapeutics. Learning and memory involve different stages including acquisition, consolidation, and retrieval and each stage can be characterized using specific toxin. Recent studies have postulated the molecular basis of these processes and have also demonstrated many signaling molecules that are involved in several stages of memory. Most insights into learning and memory impairment and to develop a novel compound stems from the investigations performed in experimental models, especially those produced by neurotoxins models. Several toxins have been utilized based on their mechanism of action for learning and memory impairment such as scopolamine, streptozotocin, quinolinic acid, and domoic acid. Further, some toxins like 6-hydroxy dopamine (6-OHDA), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and amyloid-β are known to cause specific learning and memory impairment which imitate the disease pathology of Parkinson's disease dementia and Alzheimer's disease dementia. Apart from these toxins, several other toxins come under a miscellaneous category like an environmental pollutant, snake venoms, botulinum, and lipopolysaccharide. This review will focus on the various classes of neurotoxin models for learning and memory impairment with their specific mechanism of action that could assist the process of drug discovery and development for dementia and cognitive disorders.

Concise review: modeling central nervous system diseases using induced pluripotent stem cells.

PubMed

Zeng, Xianmin; Hunsberger, Joshua G; Simeonov, Anton; Malik, Nasir; Pei, Ying; Rao, Mahendra

2014-12-01

Induced pluripotent stem cells (iPSCs) offer an opportunity to delve into the mechanisms underlying development while also affording the potential to take advantage of a number of naturally occurring mutations that contribute to either disease susceptibility or resistance. Just as with any new field, several models of screening are being explored, and innovators are working on the most efficient methods to overcome the inherent limitations of primary cell screens using iPSCs. In the present review, we provide a background regarding why iPSCs represent a paradigm shift for central nervous system (CNS) disease modeling. We describe the efforts in the field to develop more biologically relevant CNS disease models, which should provide screening assays useful for the pharmaceutical industry. We also provide some examples of successful uses for iPSC-based screens and suggest that additional development could revolutionize the field of drug discovery. The development and implementation of these advanced iPSC-based screens will create a more efficient disease-specific process underpinned by the biological mechanism in a patient- and disease-specific manner rather than by trial-and-error. Moreover, with careful and strategic planning, shared resources can be developed that will enable exponential advances in the field. This will undoubtedly lead to more sensitive and accurate screens for early diagnosis and allow the identification of patient-specific therapies, thus, paving the way to personalized medicine. ©AlphaMed Press.

Protein and amino acid supplementation in older humans.

PubMed

Fukagawa, Naomi K

2013-06-01

The aging process is a continuum throughout life and often associated with deterioration of body function as well as accumulation of chronic disabilities and of disease. The impact of nutritional status on morbidity and mortality is unquestioned. Malnutrition increases the risk for frailty and nutritional deficits can influence immune status, response to medical treatments and recovery from acute illnesses, including surgery. Health-promoting interventions implemented individually, such as exercise programs, preventive home visits, comprehensive geriatric evaluation and management, and attention to adequate nutrition with or without nutritional supplements, have been shown in separate studies to be both feasible and effective in reducing age-related deterioration. Protein and its constituent amino acids (AA) are key components of any healthy diet. Sarcopenia, the slow but progressive loss of lean muscle mass associated with advancing age, has been the focus of many studies but there is no clear-cut answer to the question of how to restrain the process. The more general question of how the requirements for protein and specific AA change with age continues to be investigated. A shift towards studying the efficacy and safety of specific AA or combination of AA that may sustain and/or enhance physiologic processes, ranging from specific tissue metabolism to overall function (e.g. exercise performance, immune function, cognition, and chronic disease development) has occurred. This review focuses on recent studies examining the use of specific AA or mixtures as supplements in the elderly and whether/how AA may assist in the maintenance of health and independence.

SMN control of RNP assembly: from post-transcriptional gene regulation to motor neuron disease

PubMed Central

Li, Darrick K.; Tisdale, Sarah; Lotti, Francesco; Pellizzoni, Livio

2014-01-01

At the post-transcriptional level, expression of protein-coding genes is controlled by a series of RNA regulatory events including nuclear processing of primary transcripts, transport of mature mRNAs to specific cellular compartments, translation and ultimately, turnover. These processes are orchestrated through the dynamic association of mRNAs with RNA binding proteins and ribonucleoprotein (RNP) complexes. Accurate formation of RNPs in vivo is fundamentally important to cellular development and function, and its impairment often leads to human disease. The survival motor neuron (SMN) protein is key to this biological paradigm: SMN is essential for the biogenesis of various RNPs that function in mRNA processing, and genetic mutations leading to SMN deficiency cause the neurodegenerative disease spinal muscular atrophy. Here we review the expanding role of SMN in the regulation of gene expression through its multiple functions in RNP assembly. We discuss advances in our understanding of SMN activity as a chaperone of RNPs and how disruption of SMN-dependent RNA pathways can cause motor neuron disease. PMID:24769255

Plasmalemma vesicle-associated protein: A crucial component of vascular homeostasis

PubMed Central

Guo, Ling; Zhang, Hongyan; Hou, Yinglong; Wei, Tianshu; Liu, Ju

2016-01-01

Endothelial subcellular structures, including caveolae, fenestrae and transendothelial channels, are crucial for regulating microvascular function. Plasmalemma vesicle-associated protein (PLVAP) is an endothelial cell-specific protein that forms the stomatal and fenestral diaphragms of blood vessels and regulates basal permeability, leukocyte migration and angiogenesis. Loss of PLVAP in mice leads to premature mortality due to disrupted homeostasis. Evidence from previous studies suggested that PLVAP is involved in cancer, traumatic spinal cord injury, acute ischemic brain disease, transplant glomerulopathy, Norrie disease and diabetic retinopathy. Specifically, PLVAP expression has been demonstrated to be upregulated in these diseases, accompanied by pro-angiogenic or pro-inflammatory responses. Therefore, PLVAP is considered a novel therapeutic target, in addition to an endothelial cell marker. The present review summarizes the structure and functions of PLVAP, and its roles in pathophysiological processes. PMID:27602081

Discovering transnosological molecular basis of human brain diseases using biclustering analysis of integrated gene expression data.

PubMed

Cha, Kihoon; Hwang, Taeho; Oh, Kimin; Yi, Gwan-Su

2015-01-01

It has been reported that several brain diseases can be treated as transnosological manner implicating possible common molecular basis under those diseases. However, molecular level commonality among those brain diseases has been largely unexplored. Gene expression analyses of human brain have been used to find genes associated with brain diseases but most of those studies were restricted either to an individual disease or to a couple of diseases. In addition, identifying significant genes in such brain diseases mostly failed when it used typical methods depending on differentially expressed genes. In this study, we used a correlation-based biclustering approach to find coexpressed gene sets in five neurodegenerative diseases and three psychiatric disorders. By using biclustering analysis, we could efficiently and fairly identified various gene sets expressed specifically in both single and multiple brain diseases. We could find 4,307 gene sets correlatively expressed in multiple brain diseases and 3,409 gene sets exclusively specified in individual brain diseases. The function enrichment analysis of those gene sets showed many new possible functional bases as well as neurological processes that are common or specific for those eight diseases. This study introduces possible common molecular bases for several brain diseases, which open the opportunity to clarify the transnosological perspective assumed in brain diseases. It also showed the advantages of correlation-based biclustering analysis and accompanying function enrichment analysis for gene expression data in this type of investigation.

Discovering transnosological molecular basis of human brain diseases using biclustering analysis of integrated gene expression data

PubMed Central

2015-01-01

Background It has been reported that several brain diseases can be treated as transnosological manner implicating possible common molecular basis under those diseases. However, molecular level commonality among those brain diseases has been largely unexplored. Gene expression analyses of human brain have been used to find genes associated with brain diseases but most of those studies were restricted either to an individual disease or to a couple of diseases. In addition, identifying significant genes in such brain diseases mostly failed when it used typical methods depending on differentially expressed genes. Results In this study, we used a correlation-based biclustering approach to find coexpressed gene sets in five neurodegenerative diseases and three psychiatric disorders. By using biclustering analysis, we could efficiently and fairly identified various gene sets expressed specifically in both single and multiple brain diseases. We could find 4,307 gene sets correlatively expressed in multiple brain diseases and 3,409 gene sets exclusively specified in individual brain diseases. The function enrichment analysis of those gene sets showed many new possible functional bases as well as neurological processes that are common or specific for those eight diseases. Conclusions This study introduces possible common molecular bases for several brain diseases, which open the opportunity to clarify the transnosological perspective assumed in brain diseases. It also showed the advantages of correlation-based biclustering analysis and accompanying function enrichment analysis for gene expression data in this type of investigation. PMID:26043779

Myelin basic protein-specific T helper 2 (Th2) cells cause experimental autoimmune encephalomyelitis in immunodeficient hosts rather than protect them from the disease.

PubMed

Lafaille, J J; Keere, F V; Hsu, A L; Baron, J L; Haas, W; Raine, C S; Tonegawa, S

1997-07-21

Chronic inflammatory autoimmune diseases such as multiple sclerosis, diabetes, and rheumatoid arthritis are caused by CD4(+) Th1 cells. Because Th2 cells antagonize Th1 cell functions in several ways, it is believed that immune deviation towards Th2 can prevent or cure autoimmune diseases. Experimental autoimmune encephalomyelitis (EAE) is a demyelinating disease used as a model for multiple sclerosis. Using an adoptive transfer system we assessed the role of Th1 and Th2 cells in EAE. In vitro generated Th1 and Th2 cells from myelin basic protein (MBP)-specific TCR transgenic mice were transferred into normal and immunodeficient mice. Th1 cells caused EAE in all recipients after a brief preclinical phase. Surprisingly, Th2 cells also caused EAE in RAG-1 KO mice and in alphabeta T cell-deficient mice, albeit after a longer preclinical phase. Normal or gammadelta T cell-deficient mice were resistant to EAE induced by Th2 cells. The histopathological features of this disease resembled those of an allergic process. In addition, disease induction by Th1 cells was not altered by coadmininstration of Th2 cells in any of the recipients. These findings indicate that MBP-specific Th2 cells have the potential to induce EAE and that the disease induced by previously activated Th1 cells cannot be prevented by normal lymphocytes nor by previously activated Th2 cells.

Developing new treatments for Alzheimer’s disease

PubMed Central

Lyketsos, Constantine G.; Szekely, Christine A.; Mielke, Michelle M.; Rosenberg, Paul B.; Zandi, Peter P.

2008-01-01

This synthetic review presents an approach to the use of biomarkers for the development of new treatments for Alzheimer’s disease (AD). After reviewing the process of translation as applied to AD, the paper provides a general update on what is known about the biology of the disease, and highlights currently available treatments. This is followed by a discussion of future drug development for AD emphasizing the roles that biomarkers are likely to play in this process: (1) Define patients who are going to progress rapidly for the purpose of trial enrichment; (2) Differentiate disease and therapeutically relevant AD subtypes; (3) Assess the potential activity of specific therapies in vivo or ex vivo; and (4) Measure the underlying disease state, so as to (a) detect disease and assess drug response in asymptomatic patients, (b) serve as a secondary outcome measures in clinical trials of symptomatic patients, (c) decide if further development of a treatment should be stopped as it is not likely to be effective. Several examples are used to illustrate each biomarker utility in the AD context. PMID:18498669

Monitoring-Based Model for Personalizing the Clinical Process of Crohn’s Disease

PubMed Central

de Ramón-Fernández, Alberto; Ruiz-Fernández, Daniel; Vives-Boix, Víctor

2017-01-01

Crohn’s disease is a chronic pathology belonging to the group of inflammatory bowel diseases. Patients suffering from Crohn’s disease must be supervised by a medical specialist for the rest of their lives; furthermore, each patient has its own characteristics and is affected by the disease in a different way, so health recommendations and treatments cannot be generalized and should be individualized for a specific patient. To achieve this personalization in a cost-effective way using technology, we propose a model based on different information flows: control, personalization, and monitoring. As a result of the model and to perform a functional validation, an architecture based on services and a prototype of the system has been defined. In this prototype, a set of different devices and technologies to monitor variables from patients and their environment has been integrated. Artificial intelligence algorithms are also included to reduce the workload related to the review and analysis of the information gathered. Due to the continuous and automated monitoring of the Crohn’s patient, this proposal can help in the personalization of the Crohn’s disease clinical process. PMID:28678162

Preferential degradation of cognitive networks differentiates Alzheimer's disease from ageing.

PubMed

Chhatwal, Jasmeer P; Schultz, Aaron P; Johnson, Keith A; Hedden, Trey; Jaimes, Sehily; Benzinger, Tammie L S; Jack, Clifford; Ances, Beau M; Ringman, John M; Marcus, Daniel S; Ghetti, Bernardino; Farlow, Martin R; Danek, Adrian; Levin, Johannes; Yakushev, Igor; Laske, Christoph; Koeppe, Robert A; Galasko, Douglas R; Xiong, Chengjie; Masters, Colin L; Schofield, Peter R; Kinnunen, Kirsi M; Salloway, Stephen; Martins, Ralph N; McDade, Eric; Cairns, Nigel J; Buckles, Virginia D; Morris, John C; Bateman, Randall; Sperling, Reisa A

2018-05-01

Converging evidence from structural, metabolic and functional connectivity MRI suggests that neurodegenerative diseases, such as Alzheimer's disease, target specific neural networks. However, age-related network changes commonly co-occur with neuropathological cascades, limiting efforts to disentangle disease-specific alterations in network function from those associated with normal ageing. Here we elucidate the differential effects of ageing and Alzheimer's disease pathology through simultaneous analyses of two functional connectivity MRI datasets: (i) young participants harbouring highly-penetrant mutations leading to autosomal-dominant Alzheimer's disease from the Dominantly Inherited Alzheimer's Network (DIAN), an Alzheimer's disease cohort in which age-related comorbidities are minimal and likelihood of progression along an Alzheimer's disease trajectory is extremely high; and (ii) young and elderly participants from the Harvard Aging Brain Study, a cohort in which imaging biomarkers of amyloid burden and neurodegeneration can be used to disambiguate ageing alone from preclinical Alzheimer's disease. Consonant with prior reports, we observed the preferential degradation of cognitive (especially the default and dorsal attention networks) over motor and sensory networks in early autosomal-dominant Alzheimer's disease, and found that this distinctive degradation pattern was magnified in more advanced stages of disease. Importantly, a nascent form of the pattern observed across the autosomal-dominant Alzheimer's disease spectrum was also detectable in clinically normal elderly with clear biomarker evidence of Alzheimer's disease pathology (preclinical Alzheimer's disease). At the more granular level of individual connections between node pairs, we observed that connections within cognitive networks were preferentially targeted in Alzheimer's disease (with between network connections relatively spared), and that connections between positively coupled nodes (correlations) were preferentially degraded as compared to connections between negatively coupled nodes (anti-correlations). In contrast, ageing in the absence of Alzheimer's disease biomarkers was characterized by a far less network-specific degradation across cognitive and sensory networks, of between- and within-network connections, and of connections between positively and negatively coupled nodes. We go on to demonstrate that formalizing the differential patterns of network degradation in ageing and Alzheimer's disease may have the practical benefit of yielding connectivity measurements that highlight early Alzheimer's disease-related connectivity changes over those due to age-related processes. Together, the contrasting patterns of connectivity in Alzheimer's disease and ageing add to prior work arguing against Alzheimer's disease as a form of accelerated ageing, and suggest multi-network composite functional connectivity MRI metrics may be useful in the detection of early Alzheimer's disease-specific alterations co-occurring with age-related connectivity changes. More broadly, our findings are consistent with a specific pattern of network degradation associated with the spreading of Alzheimer's disease pathology within targeted neural networks.

Regulation of MicroRNAs-Mediated Autophagic Flux: A New Regulatory Avenue for Neurodegenerative Diseases With Focus on Prion Diseases

PubMed Central

Shah, Syed Zahid Ali; Zhao, Deming; Hussain, Tariq; Sabir, Naveed; Yang, Lifeng

2018-01-01

Prion diseases are fatal neurological disorders affecting various mammalian species including humans. Lack of proper diagnostic tools and non-availability of therapeutic remedies are hindering the control strategies for prion diseases. MicroRNAs (miRNAs) are abundant endogenous short non-coding essential RNA molecules that negatively regulate the target genes after transcription. Several biological processes depend on miRNAs, and altered profiles of these miRNAs are potential biomarkers for various neurodegenerative diseases, including prion diseases. Autophagic flux degrades the misfolded prion proteins to reduce chronic endoplasmic reticulum stress and enhance cell survival. Recent evidence suggests that specific miRNAs target and regulate the autophagic mechanism, which is critical for alleviating cellular stress. miRNAs-mediated regulation of these specific proteins involved in the autophagy represents a new target with highly significant therapeutic prospects. Here, we will briefly describe the biology of miRNAs, the use of miRNAs as potential biomarkers with their credibility, the regulatory mechanism of miRNAs in major neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and prion diseases, degradation pathways for aggregated prion proteins, the role of autophagy in prion diseases. Finally, we will discuss the miRNAs-modulated autophagic flux in neurodegenerative diseases and employ them as potential therapeutic intervention strategy in prion diseases. PMID:29867448

Nanomedicine Meets microRNA: Current Advances in RNA-Based Nanotherapies for Atherosclerosis.

PubMed

Gadde, Suresh; Rayner, Katey J

2016-09-01

Cardiovascular disease (CVD) accounts for almost half of all deaths worldwide and has now surpassed infectious disease as the leading cause of death and disability in developing countries. At present, therapies such as low-density lipoprotein-lowering statins and antihypertensive drugs have begun to bend the morality curve for coronary artery disease (CAD); yet, as we come to appreciate the more complex pathophysiological processes in the vessel wall, there is an opportunity to fine-tune therapies to more directly target mechanisms that drive CAD. MicroRNAs (miRNAs) have been identified that control vascular cell homeostasis,(1-3) lipoprotein metabolism,(4-9) and inflammatory cell function.(10) Despite the importance of these miRNAs in driving atherosclerosis and vascular dysfunction, therapeutic modulation of miRNAs in a cell- and context-specific manner has been a challenge. In this review, we summarize the emergence of miRNA-based therapies as an approach to treat CAD by specifically targeting the pathways leading to the disease. We focus on the latest development of nanoparticles (NPs) as a means to specifically target the vessel wall and what the future of these nanomedicines may hold for the treatment of CAD. © 2016 American Heart Association, Inc.

Mathematical Modeling of Protein Misfolding Mechanisms in Neurological Diseases: A Historical Overview.

PubMed

Carbonell, Felix; Iturria-Medina, Yasser; Evans, Alan C

2018-01-01

Protein misfolding refers to a process where proteins become structurally abnormal and lose their specific 3-dimensional spatial configuration. The histopathological presence of misfolded protein (MP) aggregates has been associated as the primary evidence of multiple neurological diseases, including Prion diseases, Alzheimer's disease, Parkinson's disease, and Creutzfeldt-Jacob disease. However, the exact mechanisms of MP aggregation and propagation, as well as their impact in the long-term patient's clinical condition are still not well understood. With this aim, a variety of mathematical models has been proposed for a better insight into the kinetic rate laws that govern the microscopic processes of protein aggregation. Complementary, another class of large-scale models rely on modern molecular imaging techniques for describing the phenomenological effects of MP propagation over the whole brain. Unfortunately, those neuroimaging-based studies do not take full advantage of the tremendous capabilities offered by the chemical kinetics modeling approach. Actually, it has been barely acknowledged that the vast majority of large-scale models have foundations on previous mathematical approaches that describe the chemical kinetics of protein replication and propagation. The purpose of the current manuscript is to present a historical review about the development of mathematical models for describing both microscopic processes that occur during the MP aggregation and large-scale events that characterize the progression of neurodegenerative MP-mediated diseases.

Biological Ageing, Inflammation and Nutrition: How Might They Impact on Systemic Sclerosis?

PubMed

Shiels, Paul G; Ritzau-Reid, Kaja

2015-01-01

The number of aged individuals within the global population is increasing, which foreshadows a major societal and global health challenge. By 2050 those over 65 years old will outnumber children under 15 years of age. This situation will bring with it multifarious variations in health and functional status, occurring with increasing age and which remain incompletely understood. Ageing, however, is not solely a passive degenerative process but one that is actively regulated by distinct molecular pathways. Understanding this molecular basis of ageing is an essential step for therapeutic manipulation to combat age-related disease. Diseases such as SSc, RA and SLE may share common age related pathways of early dysregulation with other diseases of ageing, such that the biomarkers and interventions applied to prevent late stage disease will also tackle common fundamental pathways of ageing processes. This chapter will seek to explore and discuss the possible influence of these factors and their impact on disease processes, with specific reference to SSc in the context of it being a disease of ageing. It will address the contribution of socioeconomic, psychosocial and nutritional confounders of health span through the life course. In particular, it will seek to contextualize the development of inflammatory burden and allostatic overload and their contribution to morbidity and mortality. Importantly, this chapter will provide a context for transgenerational and other epigenetic effects, which are emerging as contributory components in disease susceptibility and progression.

Epidemiology of Chronic Wasting Disease: PrPres Detection, Shedding, and Environmental Contamination

DTIC Science & Technology

2008-08-01

encephalopathies (TSEs) in that it occurs in free- ranging as well as captive wild ruminants and environmental contamination appears to play a...sensitivity and high specificity and second, dogma suggests that current assays for the detection of PrPres utilize protease digestion . Proving a highly...to achieve specificity as samples require protease digestion , protein precipitation, or extensive processing in order to distinguish PrPres from the

Amyotrophic lateral sclerosis: cell vulnerability or system vulnerability?

PubMed

Talbot, Kevin

2014-01-01

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with clinical, pathological and genetic overlap with frontotemporal dementia (FTD). No longer viewed as one disease with a single unified cause, ALS is now considered to be a clinicopathological syndrome resulting from a complex convergence of genetic susceptibility, age-related loss of cellular homeostasis, and possible environmental influences. The rapid increase in recent years of the number of genes in which mutations have been associated with ALS has led to in vitro and in vivo models that have generated a wealth of data indicating disruption of specific biochemical pathways and sub-cellular compartments. Data implicating pathways including protein misfolding, mRNA splicing, oxidative stress, proteosome and mitochondrial dysfunction in the pathogenesis of ALS reinforce a disease model based on selective age-dependent vulnerability of a specific population of cells. To the clinical neurologist, however, ALS presents as a disease of focal onset and contiguous spread. Characteristic regional patterns of involvement and progression suggest that the disease does not proceed randomly but via a restricted number of anatomical pathways. These clinical observations combined with electrophysiological and brain-imaging studies underpin the concept of ALS at the macroscopic level as a 'system degeneration'. This dichotomy between cellular and systems neurobiology raises the fundamental questions of what initiates the disease process in a specific anatomical site and how the disease is propagated. Is the essence of ALS a cell-to-cell transmission of pathology with, for example, a 'prion-like' mechanism, or does the cellular pathology follow degeneration of specific synaptic networks? Elucidating the interaction between cellular degeneration and system level degeneration will aid modeling of the disease in the earliest phases, improve the development of sensitive markers of disease progression and response to therapy, and expand our understanding of the biological basis of clinical and pathological heterogeneity. © 2013 Anatomical Society.

Early Nutrition as a Major Determinant of 'Immune Health': Implications for Allergy, Obesity and Other Noncommunicable Diseases.

PubMed

Prescott, Susan L

2016-01-01

Early-life nutritional exposures are significant determinants of the development and future health of all organ systems. The dramatic rise in infant immune diseases, most notably allergy, indicates the specific vulnerability of the immune system to early environmental changes. Dietary changes are at the center of the emerging epigenetic paradigms that underpin the rise in many modern inflammatory and metabolic diseases. There is growing evidence that exposures in pregnancy and the early postnatal period can modify gene expression and disease susceptibility. Although modern dietary changes are complex and involve changing patterns of many nutrients, there is also interest in the developmental effects of specific nutrients. Oligosaccharides (soluble fiber), antioxidants, polyunsaturated fatty acids, folate and other vitamins have documented effects on immune function as well as metabolism. Some have also been implicated in modified risk of allergic diseases in observational studies. Intervention studies are largely limited to trials with polyunsaturated fatty acids and oligosaccharides, showing preliminary but yet unconfirmed benefits in allergy prevention. Understanding how environmental influences disrupt the finely balanced development of immune and metabolic programming is of critical importance. Diet-sensitive pathways are likely to be crucial in these processes. While an epigenetic mechanism provides a strong explanation of how nutritional exposures can affect fetal gene expression and subsequent disease risk, other diet-induced tissue compositional changes may also contribute directly to altered immune and metabolic function--including diet-induced changes in the microbiome. A better understanding of nutritional programming of immune health, nutritional epigenetics and the biological processes sensitive to nutritional exposures early in life may lead to dietary strategies that provide more tolerogenic conditions during early immune programming and reduce the burden of many inflammatory diseases--not just allergy. © 2016 Nestec Ltd., Vevey/S. Karger AG, Basel.

The strain-encoded relationship between PrP replication, stability and processing in neurons is predictive of the incubation period of disease.

PubMed

Ayers, Jacob I; Schutt, Charles R; Shikiya, Ronald A; Aguzzi, Adriano; Kincaid, Anthony E; Bartz, Jason C

2011-03-01

Prion strains are characterized by differences in the outcome of disease, most notably incubation period and neuropathological features. While it is established that the disease specific isoform of the prion protein, PrP(Sc), is an essential component of the infectious agent, the strain-specific relationship between PrP(Sc) properties and the biological features of the resulting disease is not clear. To investigate this relationship, we examined the amplification efficiency and conformational stability of PrP(Sc) from eight hamster-adapted prion strains and compared it to the resulting incubation period of disease and processing of PrP(Sc) in neurons and glia. We found that short incubation period strains were characterized by more efficient PrP(Sc) amplification and higher PrP(Sc) conformational stabilities compared to long incubation period strains. In the CNS, the short incubation period strains were characterized by the accumulation of N-terminally truncated PrP(Sc) in the soma of neurons, astrocytes and microglia in contrast to long incubation period strains where PrP(Sc) did not accumulate to detectable levels in the soma of neurons but was detected in glia similar to short incubation period strains. These results are inconsistent with the hypothesis that a decrease in conformational stability results in a corresponding increase in replication efficiency and suggest that glia mediated neurodegeneration results in longer survival times compared to direct replication of PrP(Sc) in neurons.

Implementation of a drug-use and disease-state management program.

PubMed

Skledar, S J; Hess, M M

2000-12-15

A drug-use and disease-state management (DUDSM) program was instituted in 1996 at a teaching hospital associated with a large nonprofit health care system. The program's goals are to optimize pharmacotherapeutic regimens, evaluate health outcomes of identified disease states, and evaluate the economic impact of pharmacotherapeutic options for given disease states by developing practice guidelines. Through a re-engineering process, resources within the pharmacy department were identified that could be devoted to the DUDSM program, including the use of clinical pharmacy specialists, promotion of staff pharmacists into the DUDSM program, a pharmacy technician, and information systems support. A strength of the program is its systematic approach for developing and implementing new initiatives, as well as monitoring compliance with all initiatives on an ongoing basis. The initiative-design process incorporates continuous quality improvement principles, outcome design and evaluation, competency assessment for all pharmacists, multidisciplinary collaboration, and sophisticated information systems. Seventy-five initiatives have been implemented, ranging from simple dose-optimization strategies for specific drugs to complicated practice guidelines for managing specific disease states. Improved patient outcomes have been documented, including reduced length of stay, postsurgical wound infection, adverse drug reactions, and medication errors. Documented cost savings exceeded $4 million annually for fiscal years 1996-97 through 1999-2000. Overall compliance with DUDSM initiatives exceeds 80%, and physician service profiling has been initiated to monitor variant prescribing. The DUDSM program has successfully integrated practice guidelines into therapeutic decision-making, resulting in improved patient-care outcomes and cost savings.

Sustainable improvement of animal health care by systematic quality risk management according to the HACCP concept.

PubMed

Noordhuizen, J P; Welpelo, H J

1996-12-01

This paper addresses the principles of the Hazard Analysis Critical Control Point (HACCP) concept as applied to animal health management strategy. Characteristics of the concept were analysed and compared with those of current animal health care strategies for disease risk identification and herd health management, insurance, and certification. HACCP is a hybrid strategy of quality control at both production process and product level. Animal health is considered a particular quality feature. We show that process control (expressed in terms of controlling both general and specific disease risk factors) and product control (expressed in terms of testing animals or animal products for specific disease agents) could form the basis for improving animal health. We conclude that HACCP provides ample opportunity for preventive health action and risk management at a relatively low cost in terms of labour, finance and documentation expenditure, at both the farm and sector level. Epidemiological field studies are currently needed to identify critical control points and to design HACCP procedures for livestock producers. In the long run, HACCP based animal health care can be further developed into a quality control systems approach to cover all aspects that are related, either directly or indirectly, to animal health.

Functional O-GlcNAc modifications: Implications in molecular regulation and pathophysiology

PubMed Central

Wells, Lance

2016-01-01

O-linked β-N-acetylglucosamine (O-GlcNAc) is a regulatory post-translational modification of intracellular proteins. The dynamic and inducible cycling of the modification is governed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) in response to UDP-GlcNAc levels in the hexosamine biosynthetic pathway (HBP). Due to its reliance on glucose flux and substrate availability, a major focus in the field has been on how O-GlcNAc contributes to metabolic disease. For years this post-translational modification has been known to modify thousands of proteins implicated in various disorders, but direct functional connections have until recently remained elusive. New research is beginning to reveal the specific mechanisms through which O-GlcNAc influences cell dynamics and disease pathology including clear examples of O-GlcNAc modification at a specific site on a given protein altering its biological functions. The following review intends to focus primarily on studies in the last half decade linking O-GlcNAc modification of proteins with chromatin-directed gene regulation, developmental processes, and several metabolically related disorders including Alzheimer’s, heart disease and cancer. These studies illustrate the emerging importance of this post-translational modification in biological processes and multiple pathophysiologies. PMID:24524620

Bioactive molecules in milk and their role in health and disease: the role of transforming growth factor-beta.

PubMed

Donnet-Hughes, A; Duc, N; Serrant, P; Vidal, K; Schiffrin, E J

2000-02-01

Human breast milk is rich in nutrients, hormones, growth factors and immunoactive molecules, which influence the growth, development and immune status of the newborn infant. Although several of these factors are also present in bovine milk, the greater susceptibility of the formula-fed infant to infection and disease and the development of allergy is often attributed to the reduced level of protective factors in milk formulas. Nevertheless, modifying manufacturing processes may preserve the biological activity of some bioactive molecules in end products. Transforming growth factor (TGF)-beta is one such molecule. TGF-beta is a polypeptide, which has been described in both human and bovine milk. It is implicated in many processes, including epithelial cell growth and differentiation, development, carcinogenesis and immune regulation. The present article discusses the biological activity of TGF-beta2 that has been preserved and activated in a cow's milk-based product. More specifically, it addresses possible mechanisms of action in the intestinal lumen and speculates on how milk products containing naturally occurring TGF-beta2 could be exploited in functional foods for the infant or as therapies for specific intestinal diseases.

Specialized Nursing Practice for Chronic Disease Management in the Primary Care Setting

PubMed Central

2013-01-01

Background In response to the increasing demand for better chronic disease management and improved health care efficiency in Ontario, nursing roles have expanded in the primary health care setting. Objectives To determine the effectiveness of specialized nurses who have a clinical role in patient care in optimizing chronic disease management among adults in the primary health care setting. Data Sources and Review Methods A literature search was performed using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database. Results were limited to randomized controlled trials and systematic reviews and were divided into 2 models: Model 1 (nurse alone versus physician alone) and Model 2 (nurse and physician versus physician alone). Effectiveness was determined by comparable outcomes between groups in Model 1, or improved outcomes or efficiency in Model 2. Results Six studies were included. In Model 1, there were no significant differences in health resource use, disease-specific measures, quality of life, or patient satisfaction. In Model 2, there was a reduction in hospitalizations and improved management of blood pressure and lipids among patients with coronary artery disease. Among patients with diabetes, there was a reduction in hemoglobin A1c but no difference in other disease-specific measures. There was a trend toward improved process measures, including medication prescribing and clinical assessments. Results related to quality of life were inconsistent, but patient satisfaction with the nurse-physician team was improved. Overall, there were more and longer visits to the nurse, and physician workload did not change. Limitations There was heterogeneity across patient populations, and in the titles, roles, and scope of practice of the specialized nurses. Conclusions Specialized nurses with an autonomous role in patient care had comparable outcomes to physicians alone (Model 1) based on moderate quality evidence, with consistent results among a subgroup analysis of patients with diabetes based on low quality evidence. Model 2 showed an overall improvement in appropriate process measures, disease-specific measures, and patient satisfaction based on low to moderate quality evidence. There was low quality evidence that nurses working under Model 2 may reduce hospitalizations for patients with coronary artery disease. The specific role of the nurse in supplementing or substituting physician care was unclear, making it difficult to determine the impact on efficiency. Plain Language Summary Nurses with additional skills, training, or scope of practice may help improve the primary care of patients with chronic diseases. This review found that specialized nurses working on their own could achieve health outcomes that were similar to those of doctors. It also found that specialized nurses who worked with doctors could reduce hospital visits and improve certain patient outcomes related to diabetes, coronary artery disease, or heart failure. Patients who had nurse-led care were more satisfied and tended to receive more tests and medications. It is unclear whether specialized nurses improve quality of life or doctor workload. PMID:24194798

MACF1, versatility in tissue-specific function and in human disease.

PubMed

Hu, Lifang; Xiao, Yunyun; Xiong, Zhipeng; Zhao, Fan; Yin, Chong; Zhang, Yan; Su, Peihong; Li, Dijie; Chen, Zhihao; Ma, Xiaoli; Zhang, Ge; Qian, Airong

2017-09-01

Spectraplakins are a family of evolutionarily conserved gigantic proteins and play critical roles in many cytoskeleton-related processes. Microtubule actin crosslinking factor 1 (MACF1) is one of the most versatile spectraplakin with multiple isoforms. As a broadly expressed mammalian spectraplakin, MACF1 is important in maintaining normal functions of many tissues. The loss-of-function studies using knockout mouse models reveal the pivotal roles of MACF1 in embryo development, skin integrity maintenance, neural development, bone formation, and colonic paracellular permeability. Mutation in the human MACF1 gene causes a novel myopathy genetic disease. In addition, abnormal expression of MACF1 is associated with schizophrenia, Parkinson's disease, cancer and osteoporosis. This demonstrates the crucial roles of MACF1 in physiology and pathology. Here, we review the research advances of MACF1's roles in specific tissue and in human diseases, providing the perspectives of MACF1 for future studies. Copyright © 2017. Published by Elsevier Ltd.

Asia-Pacific consensus statements on Crohn's disease. Part 2: Management.

PubMed

Ooi, Choon Jin; Makharia, Govind K; Hilmi, Ida; Gibson, Peter R; Fock, Kwong Ming; Ahuja, Vineet; Ling, Khoon Lin; Lim, Wee Chian; Thia, Kelvin T; Wei, Shu-chen; Leung, Wai Keung; Koh, Poh Koon; Gearry, Richard B; Goh, Khean Lee; Ouyang, Qin; Sollano, Jose; Manatsathit, Sathaporn; de Silva, H Janaka; Rerknimitr, Rungsun; Pisespongsa, Pises; Abu Hassan, Muhamad Radzi; Sung, Joseph; Hibi, Toshifumi; Boey, Christopher C M; Moran, Neil; Leong, Rupert W L

2016-01-01

The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology (APAGE) with the goal of developing best management practices, coordinating research and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis (UC) with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis and management of Crohn's disease (CD). The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses and treatment availability. It does not intend to be all-comprehensive and future revisions are likely to be required in this ever-changing field. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Diabetic Cardiomyopathy and Metabolic Remodeling of the Heart

PubMed Central

Battiprolu, Pavan K.; Lopez-Crisosto, Camila; Wang, Zhao V.; Nemchenko, Andriy; Lavandero, Sergio; Hill, Joseph A.

2012-01-01

The incidence and prevalence of diabetes mellitus are each increasing rapidly in societies around the globe. The majority of patients with diabetes succumb ultimately to heart disease, much of which stems from atherosclerotic disease and hypertension. However, the diabetic milieu is itself intrinsically noxious to the heart, and cardiomyopathy can develop independent of elevated blood pressure or coronary artery disease. This process, termed diabetic cardiomyopathy, is characterized by significant changes in the physiology, structure, and mechanical function of the heart. Presently, therapy for patients with diabetes focuses largely on glucose control, and attention to the heart commences with the onset of symptoms. When the latter develops, standard therapy for heart failure is applied. However, recent studies highlight that specific elements of the pathogenesis of diabetic heart disease are unique, raising the prospect of diabetes-specific therapeutic intervention. Here, we review recently unveiled insights into the pathogenesis of diabetic cardiomyopathy and associated metabolic remodeling with an eye toward identifying novel targets with therapeutic potential. PMID:23123443

Recapitulating cortical development with organoid culture in vitro and modeling abnormal spindle-like (ASPM related primary) microcephaly disease.

PubMed

Li, Rui; Sun, Le; Fang, Ai; Li, Peng; Wu, Qian; Wang, Xiaoqun

2017-11-01

The development of a cerebral organoid culture in vitro offers an opportunity to generate human brain-like organs to investigate mechanisms of human disease that are specific to the neurogenesis of radial glial (RG) and outer radial glial (oRG) cells in the ventricular zone (VZ) and subventricular zone (SVZ) of the developing neocortex. Modeling neuronal progenitors and the organization that produces mature subcortical neuron subtypes during early stages of development is essential for studying human brain developmental diseases. Several previous efforts have shown to grow neural organoid in culture dishes successfully, however we demonstrate a new paradigm that recapitulates neocortical development process with VZ, OSVZ formation and the lamination organization of cortical layer structure. In addition, using patient-specific induced pluripotent stem cells (iPSCs) with dysfunction of the Aspm gene from a primary microcephaly patient, we demonstrate neurogenesis defects result in defective neuronal activity in patient organoids, suggesting a new strategy to study human developmental diseases in central nerve system.

Nutritional programming of disease: unravelling the mechanism

PubMed Central

Langley-Evans, Simon C

2009-01-01

Nutritional programming is the process through which variation in the quality or quantity of nutrients consumed during pregnancy exerts permanent effects upon the developing fetus. Programming of fetal development is considered to be an important risk factor for non-communicable diseases of adulthood, including coronary heart disease and other disorders related to insulin resistance. The study of programming in relation to disease processes has been advanced by development of animal models, which have utilized restriction or over-feeding of specific nutrients in either rodents or sheep. These consistently demonstrate the biological plausibility of the nutritional programming hypothesis and, importantly, provide tools with which to examine the mechanisms through which programming may occur. Studies of animals subject to undernutrition in utero generally exhibit changes in the structure of key organs such as the kidney, heart and brain. These appear consistent with remodelling of development, associated with disruption of cellular proliferation and differentiation. Whilst the causal pathways which extend from this tissue remodelling to disease can be easily understood, the processes which lead to this disordered organ development are poorly defined. Even minor variation in maternal nutritional status is capable of producing important shifts in the fetal environment. It is suggested that these environmental changes are associated with altered expression of key genes, which are responsible for driving the tissue remodelling response and future disease risk. Nutrition-related factors may drive these processes by disturbing placental function, including control of materno-fetal endocrine exchanges, or the epigenetic regulation of gene expression. PMID:19175805

Development of a disease-specific quality of life questionnaire in Addison's disease.

PubMed

Løvås, Kristian; Curran, Suzanne; Oksnes, Marianne; Husebye, Eystein S; Huppert, Felicia A; Chatterjee, V Krishna K

2010-02-01

Patients with Addison's disease reproducibly self-report impairment in specific dimensions of general well-being questionnaires, suggesting particular deficiencies in health-related quality-of-life (HRQoL). We sought to develop an Addison's disease-specific questionnaire (AddiQoL) that could better quantify altered well-being and treatment effects. Design, Setting, Patients, Intervention, and Outcomes: We reviewed the literature to identify HRQoL issues in Addison's disease and interviewed patients and their partners in-depth to explore various symptom domains. A list of items was generated, and nine expert clinicians and five expert patients assessed the list for impact and clarity. A preliminary questionnaire was presented to 100 Addison's outpatients; the number of items was reduced after analysis of the distribution of the responses. The final questionnaire responses were assessed by Cronbach's alpha and Rasch analysis. Published studies of HRQoL in Addison's disease indicated reduced vitality and general health perception and limitations in physical and emotional functioning. In-depth interviews of 14 patients and seven partners emphasized the impact of the disease on the emotional domain. Seventy HRQoL items were generated; after the expert consultation process and pretesting in 100 patients, the number of items was reduced to 36. Eighty-six patients completed the final questionnaire; the responses showed high internal consistency with Cronbach's alpha 0.95 and Person Separation Index 0.94 (Rasch analysis). We envisage AddiQoL having utility in trials of hormone replacement and management of patients with Addison's disease, analogous to similar questionnaires in GH deficiency (AGHDA) and acromegaly (AcroQoL).

Gene-environment interactions in the aetiology of systemic lupus erythematosus.

PubMed

Jönsen, Andreas; Bengtsson, Anders A; Nived, Ola; Truedsson, Lennart; Sturfelt, Gunnar

2007-12-01

Systemic lupus erythematosus (SLE) is a disease that displays a multitude of symptoms and a vast array of autoantibodies. The disease course may vary substantially between patients. The current understanding of SLE aetiology includes environmental factors acting on a genetically prone individual during an undetermined time period resulting in autoimmunity and finally surpassing that individual's disease threshold. Genetic differences and environmental factors may interact specifically in the pathogenetic processes and may influence disease development and modify the disease course. Identification of these factors and their interactions in the pathogenesis of SLE is vital in understanding the disease and may contribute to identify new treatment targets and perhaps also aid in disease prevention. However, there are several problems that need to be overcome, such as the protracted time frame of environmental influence, time dependent epigenetic alterations and the possibility that different pathogenetic pathways may result in a similar disease phenotype. This is mirrored by the relatively few studies that suggest specific gene-environment interactions. These include an association between SLE diagnosis and glutation S-transferase gene variants combined with occupational sun exposure as well as variants of the N-acetyl transferase gene in combination with either aromatic amine exposure or hydralazine. With increased knowledge on SLE pathogenesis, the role of environmental factors and their genetic interactions may be further elucidated.

Integrated care and optimal management of pulmonary arterial hypertension

PubMed Central

Strange, Geoff; Fowler, Robin; Jary, Corina; Dalton, Brad; Stewart, Simon; Gabbay, Eli

2009-01-01

Pulmonary arterial hypertension (PAH) may occur as an idiopathic process or as a component of a variety of diseases, including connective tissue diseases, congenital heart disease, and exposure to appetite suppressants or infectious agents such as HIV. Untreated, it is a potentially devastating disease; however, diagnosis can be difficult due to the non-specific nature of symptoms during the early stages, and the fact that patients often present to a range of different medical specialties. The past decade has seen remarkable improvements in our understanding of the pathology associated with the condition and the development of PAH-specific therapies with the ability to alter the natural history of the disease. This article reviews the evidence for screening and diagnosis of susceptible patient groups and discusses treatment selection and recommendations based on data available from randomized controlled trials. In addition, due to the complexity of the diagnostic evaluation required and the treatment options available, this review mandates for a multidisciplinary approach to the management of PAH. We discuss the roles and organizational structure of a specialized PAH center in Perth, Western Australia to highlight these issues. PMID:21197349

Monitoring for the management of disease risk in animal translocation programmes

USGS Publications Warehouse

Nichols, James D.; Hollmen, Tuula E.; Grand, James B.

2017-01-01

Monitoring is best viewed as a component of some larger programme focused on science or conservation. The value of monitoring is determined by the extent to which it informs the parent process. Animal translocation programmes are typically designed to augment or establish viable animal populations without changing the local community in any detrimental way. Such programmes seek to minimize disease risk to local wild animals, to translocated animals, and in some cases to humans. Disease monitoring can inform translocation decisions by (1) providing information for state-dependent decisions, (2) assessing progress towards programme objectives, and (3) permitting learning in order to make better decisions in the future. Here we discuss specific decisions that can be informed by both pre-release and post-release disease monitoring programmes. We specify state variables and vital rates needed to inform these decisions. We then discuss monitoring data and analytic methods that can be used to estimate these state variables and vital rates. Our discussion is necessarily general, but hopefully provides a basis for tailoring disease monitoring approaches to specific translocation programmes.

Oxidation-specific epitopes are dominant targets of innate natural antibodies in mice and humans

PubMed Central

Chou, Meng-Yun; Fogelstrand, Linda; Hartvigsen, Karsten; Hansen, Lotte F.; Woelkers, Douglas; Shaw, Peter X.; Choi, Jeomil; Perkmann, Thomas; Bäckhed, Fredrik; Miller, Yury I.; Hörkkö, Sohvi; Corr, Maripat; Witztum, Joseph L.; Binder, Christoph J.

2009-01-01

Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of oxidized lipoproteins and apoptotic cells. Adaptive immune responses to various oxidation-specific epitopes play an important role in atherogenesis. However, accumulating evidence suggests that these epitopes are also recognized by innate receptors, such as scavenger receptors on macrophages, and plasma proteins, such as C-reactive protein (CRP). Here, we provide multiple lines of evidence that oxidation-specific epitopes constitute a dominant, previously unrecognized target of natural Abs (NAbs) in both mice and humans. Using reconstituted mice expressing solely IgM NAbs, we have shown that approximately 30% of all NAbs bound to model oxidation-specific epitopes, as well as to atherosclerotic lesions and apoptotic cells. Because oxidative processes are ubiquitous, we hypothesized that these epitopes exert selective pressure to expand NAbs, which in turn play an important role in mediating homeostatic functions consequent to inflammation and cell death, as demonstrated by their ability to facilitate apoptotic cell clearance. These findings provide novel insights into the functions of NAbs in mediating host homeostasis and into their roles in health and diseases, such as chronic inflammatory diseases and atherosclerosis. PMID:19363291

Does chaos theory have major implications for philosophy of medicine?

PubMed

Holm, S

2002-12-01

In the literature it is sometimes claimed that chaos theory, non-linear dynamics, and the theory of fractals have major implications for philosophy of medicine, especially for our analysis of the concept of disease and the concept of causation. This paper gives a brief introduction to the concepts underlying chaos theory and non-linear dynamics. It is then shown that chaos theory has only very minimal implications for the analysis of the concept of disease and the concept of causation, mainly because the mathematics of chaotic processes entail that these processes are fully deterministic. The practical unpredictability of chaotic processes, caused by their extreme sensitivity to initial conditions, may raise practical problems in diagnosis, prognosis, and treatment, but it raises no major theoretical problems. The relation between chaos theory and the problem of free will is discussed, and it is shown that chaos theory may remove the problem of predictability of decisions, but does not solve the problem of free will. Chaos theory may thus be very important for our understanding of physiological processes, and specific disease entities, without having any major implications for philosophy of medicine.

From adolescents to adults with congenital heart disease: the role of transition.

PubMed

Moceri, Pamela; Goossens, Eva; Hascoet, Sebastien; Checler, Carine; Bonello, Béatrice; Ferrari, Emile; Acar, Philippe; Fraisse, Alain

2015-07-01

Improved surgical care during the last decades, together with advances in medical management, led to a remarkable increase in survival of patients with congenital heart disease (CHD). However, aging of the CHD population brings new challenges, and loss of follow-up of adolescents and adults with CHD is a major concern. It is crucial to optimize the transfer of patients with CHD from paediatric to adult health care services to prevent loss to follow-up. The transition process plays a central role in the future health and follow-up of the patient. The aim of this review is to explain and discuss the clinical impact of the transition process in adolescents with CHD. We will also discuss specific CHD adolescents' problems. Adolescence is a crucial phase for the formation of the personality. Understanding and acceptance of the responsibility for health at this stage through a transition process with a multidisciplinary team will determine the quality of future medical follow-up and probably limit psychosocial issues in their adult life. • Aging of the congenital heart disease population brings new challenges to the organisation of care. • Loss of follow-up is a major concern for patients with congenital heart disease. What is new: • The quality of a formal transition process during adolescence will determine future outcomes in patients with congenital heart disease.

Mycobacteriosis-associated mortality in wild striped bass (Morone saxatilis) from Chesapeake Bay, U.S.A.

PubMed

Gauthier, D T; Latour, R J; Heisey, D M; Bonzek, C F; Gartland, J; Burge, E J; Vogelbein, W K

2008-10-01

The striped bass (Morone saxatilis) is an economically and ecologically important finfish species along the Atlantic seaboard of the United States. Recent stock assessments in Chesapeake Bay (U.S.A.) indicate that non-fishing mortality in striped bass has increased since 1999, concomitant with very high (>50%) prevalence of visceral and dermal disease caused by Mycobacterium spp. Current fishery assessment models do not differentiate between disease and other components of non-fishing mortality (e.g., senescence, predation); therefore, disease impact on the striped bass population has not been established. Specific measurement of mortality associated with mycobacteriosis in wild striped bass is complicated because the disease is chronic and mortality is cryptic. Epidemiological models have been developed to estimate disease-associated mortality from cross-sectional prevalence data and have recently been generalized to represent disease processes more realistically. Here, we used this generalized approach to demonstrate disease-associated mortality in striped bass from Chesapeake Bay. To our knowledge this is the first demonstration of cryptic mortality associated with a chronic infectious disease in a wild finfish. This finding has direct implications for management and stock assessment of striped bass, as it demonstrates population-level negative impacts of a chronic disease. Additionally, this research provides a framework by which disease-associated mortality may be specifically addressed within fisheries models for resource management.

Contribution of dot-blot assay to the diagnosis and management of myositis: a three-year practice at a university hospital centre.

PubMed

Martel, Clothilde; Vignaud, Guillaume; Liozon, Eric; Magy, Laurent; Gallouedec, Gael; Ly, Kim; Bezanahary, Holly; Cypierre, Anne; Lapébie, François-Xavier; Palat, Sylvain; Gondran, Guillaume; Jauberteau, Marie-Odile; Fauchais, Anne-Laure

2016-01-01

Idiopathic inflammatory myopathies (IIM) are heterogeneous autoimmune diseases with wide clinical spectrum that may lead to delayed diagnosis. The aim of this study was to examine the impact of IIM-specific dot-blot assay on diagnostic process of patients presenting with muscular or systemic symptoms evocating of IIM. We collected all the prescriptions of an IIM specific dot-blot assay (8 autoantigens including Jo-1, PL-7, PL-12, SRP, Mi-2, Ku, PM/Scl and Scl-70) over a 38-month period. 316 myositis dot-blot assays (MSD) were performed in 274 patients (156 women, mean age 53±10.6 years) referring for muscular and/or systemic symptoms suggesting IIM. The timing of dot prescription through the diagnostic process was highly variable: without (35%), concomitantly (16%) or after electromyographic studies (35%). Fifty-nine patients (22%) had IIM according to Bohan and Peter's criteria. Among them, 29 (49%) had positive dot (8 Jo-1, 6 PM-Scl, 5 PL-12, 5 SRP, 2 Mi-2, 2 PL-7 and 1 Ku). Various other diagnoses were performed including 35 autoimmune disease or granulomatosis (12%), 19 inflammatory rheumatic disease (7%), 16 non inflammatory muscular disorders (6%), 10 drug-induced myalgia (4%), 11 infectious myositis (4%). Except 11 borderline SRP results and one transient PM-Scl, MSD was positive only in one case of IIM. Dot allowed clinicians to correct diagnosis in 4 cases and improved the diagnosis of IIM subtypes in 4 cases. This study reflects the interest of myositis dot in the rapid diagnosis process of patients with non-specific muscular symptoms leading to various diagnoses including IIM.

Community Size Effects on Epidemic Spreading in Multiplex Social Networks.

PubMed

Liu, Ting; Li, Ping; Chen, Yan; Zhang, Jie

2016-01-01

The dynamical process of epidemic spreading has drawn much attention of the complex network community. In the network paradigm, diseases spread from one person to another through the social ties amongst the population. There are a variety of factors that govern the processes of disease spreading on the networks. A common but not negligible factor is people's reaction to the outbreak of epidemics. Such reaction can be related information dissemination or self-protection. In this work, we explore the interactions between disease spreading and population response in terms of information diffusion and individuals' alertness. We model the system by mapping multiplex networks into two-layer networks and incorporating individuals' risk awareness, on the assumption that their response to the disease spreading depends on the size of the community they belong to. By comparing the final incidence of diseases in multiplex networks, we find that there is considerable mitigation of diseases spreading for full phase of spreading speed when individuals' protection responses are introduced. Interestingly, the degree of community overlap between the two layers is found to be critical factor that affects the final incidence. We also analyze the consequences of the epidemic incidence in communities with different sizes and the impacts of community overlap between two layers. Specifically, as the diseases information makes individuals alert and take measures to prevent the diseases, the effective protection is more striking in small community. These phenomena can be explained by the multiplexity of the networked system and the competition between two spreading processes.

Community Size Effects on Epidemic Spreading in Multiplex Social Networks

PubMed Central

Liu, Ting; Li, Ping; Chen, Yan; Zhang, Jie

2016-01-01

The dynamical process of epidemic spreading has drawn much attention of the complex network community. In the network paradigm, diseases spread from one person to another through the social ties amongst the population. There are a variety of factors that govern the processes of disease spreading on the networks. A common but not negligible factor is people’s reaction to the outbreak of epidemics. Such reaction can be related information dissemination or self-protection. In this work, we explore the interactions between disease spreading and population response in terms of information diffusion and individuals’ alertness. We model the system by mapping multiplex networks into two-layer networks and incorporating individuals’ risk awareness, on the assumption that their response to the disease spreading depends on the size of the community they belong to. By comparing the final incidence of diseases in multiplex networks, we find that there is considerable mitigation of diseases spreading for full phase of spreading speed when individuals’ protection responses are introduced. Interestingly, the degree of community overlap between the two layers is found to be critical factor that affects the final incidence. We also analyze the consequences of the epidemic incidence in communities with different sizes and the impacts of community overlap between two layers. Specifically, as the diseases information makes individuals alert and take measures to prevent the diseases, the effective protection is more striking in small community. These phenomena can be explained by the multiplexity of the networked system and the competition between two spreading processes. PMID:27007112

Long non-coding RNAs involved in autophagy regulation

PubMed Central

Yang, Lixian; Wang, Hanying; Shen, Qi; Feng, Lifeng; Jin, Hongchuan

2017-01-01

Autophagy degrades non-functioning or damaged proteins and organelles to maintain cellular homeostasis in a physiological or pathological context. Autophagy can be protective or detrimental, depending on its activation status and other conditions. Therefore, autophagy has a crucial role in a myriad of pathophysiological processes. From the perspective of autophagy-related (ATG) genes, the molecular dissection of autophagy process and the regulation of its level have been largely unraveled. However, the discovery of long non-coding RNAs (lncRNAs) provides a new paradigm of gene regulation in almost all important biological processes, including autophagy. In this review, we highlight recent advances in autophagy-associated lncRNAs and their specific autophagic targets, as well as their relevance to human diseases such as cancer, cardiovascular disease, diabetes and cerebral ischemic stroke. PMID:28981093

Towards data integration automation for the French rare disease registry.

PubMed

Maaroufi, Meriem; Choquet, Rémy; Landais, Paul; Jaulent, Marie-Christine

2015-01-01

Building a medical registry upon an existing infrastructure and rooted practices is not an easy task. It is the case for the BNDMR project, the French rare disease registry, that aims to collect administrative and medical data of rare disease patients seen in different hospitals. To avoid duplicating data entry for health professionals, the project plans to deploy connectors with the existing systems to automatically retrieve data. Given the data heterogeneity and the large number of source systems, the automation of connectors creation is required. In this context, we propose a methodology that optimizes the use of existing alignment approaches in the data integration processes. The generated mappings are formalized in exploitable mapping expressions. Following this methodology, a process has been experimented on specific data types of a source system: Boolean and predefined lists. As a result, effectiveness of the used alignment approach has been enhanced and more good mappings have been detected. Nonetheless, further improvements could be done to deal with the semantic issue and process other data types.

Towards data integration automation for the French rare disease registry

PubMed Central

Maaroufi, Meriem; Choquet, Rémy; Landais, Paul; Jaulent, Marie-Christine

2015-01-01

Building a medical registry upon an existing infrastructure and rooted practices is not an easy task. It is the case for the BNDMR project, the French rare disease registry, that aims to collect administrative and medical data of rare disease patients seen in different hospitals. To avoid duplicating data entry for health professionals, the project plans to deploy connectors with the existing systems to automatically retrieve data. Given the data heterogeneity and the large number of source systems, the automation of connectors creation is required. In this context, we propose a methodology that optimizes the use of existing alignment approaches in the data integration processes. The generated mappings are formalized in exploitable mapping expressions. Following this methodology, a process has been experimented on specific data types of a source system: Boolean and predefined lists. As a result, effectiveness of the used alignment approach has been enhanced and more good mappings have been detected. Nonetheless, further improvements could be done to deal with the semantic issue and process other data types. PMID:26958224

Understanding Neurological Disease Mechanisms in the Era of Epigenetics

PubMed Central

Qureshi, Irfan A.; Mehler, Mark F.

2015-01-01

The burgeoning field of epigenetics is making a significant impact on our understanding of brain evolution, development, and function. In fact, it is now clear that epigenetic mechanisms promote seminal neurobiological processes, ranging from neural stem cell maintenance and differentiation to learning and memory. At the molecular level, epigenetic mechanisms regulate the structure and activity of the genome in response to intracellular and environmental cues, including the deployment of cell type–specific gene networks and those underlying synaptic plasticity. Pharmacological and genetic manipulation of epigenetic factors can, in turn, induce remarkable changes in neural cell identity and cognitive and behavioral phenotypes. Not surprisingly, it is also becoming apparent that epigenetics is intimately involved in neurological disease pathogenesis. Herein, we highlight emerging paradigms for linking epigenetic machinery and processes with neurological disease states, including how (1) mutations in genes encoding epigenetic factors cause disease, (2) genetic variation in genes encoding epigenetic factors modify disease risk, (3) abnormalities in epigenetic factor expression, localization, or function are involved in disease pathophysiology, (4) epigenetic mechanisms regulate disease-associated genomic loci, gene products, and cellular pathways, and (5) differential epigenetic profiles are present in patient-derived central and peripheral tissues. PMID:23571666

Neurological and Psychiatric Diseases and Their Unique Cognitive Profiles: Implications for Nursing Practice and Research

PubMed Central

Vance, David E.; Dodson, Joan E.; Watkins, Jason; Kennedy, Bridgett H.; Keltner, Norman L.

2013-01-01

To successfully negotiate and interact with one’s environment, optimal cognitive functioning is needed. Unfortunately, many neurological and psychiatric diseases impede certain cognitive abilities such as executive functioning or speed of processing; this can produce a poor fit between the patient and the cognitive demands of his or her environment. Such non-dementia diseases include bipolar disorder, schizophrenia, post-traumatic stress syndrome, depression, and anxiety disorders, just to name a few. Each of these diseases negatively affects particular areas of the brain, resulting in distinct cognitive profiles (e.g., deficits in executive functioning but normal speed of processing as seen in schizophrenia). In fact, it is from these cognitive deficits in which such behavioral and emotional symptoms may manifest (e.g., delusions, paranoia). This article highlights the distinct cognitive profiles of such common neurological and psychiatric diseases. An understanding of such disease-specific cognitive profiles can assist nurses in providing care to patients by knowing what cognitive deficits are associated with each disease and how these cognitive deficits impact everyday functioning and social interactions. Implications for nursing practice and research are posited within the framework of cognitive reserve and neuroplasticity. PMID:23422693

[Specificities of the logopenic variant of primary progressive aphasia].

PubMed

Magnin, E; Teichmann, M; Martinaud, O; Moreaud, O; Ryff, I; Belliard, S; Pariente, J; Moulin, T; Vandel, P; Démonet, J-F

2015-01-01

The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Fluorescence multi-scale endoscopy and its applications in the study and diagnosis of gastro-intestinal diseases: set-up design and software implementation

NASA Astrophysics Data System (ADS)

Gómez-García, Pablo Aurelio; Arranz, Alicia; Fresno, Manuel; Desco, Manuel; Mahmood, Umar; Vaquero, Juan José; Ripoll, Jorge

2015-06-01

Endoscopy is frequently used in the diagnosis of several gastro-intestinal pathologies as Crohn disease, ulcerative colitis or colorectal cancer. It has great potential as a non-invasive screening technique capable of detecting suspicious alterations in the intestinal mucosa, such as inflammatory processes. However, these early lesions usually cannot be detected with conventional endoscopes, due to lack of cellular detail and the absence of specific markers. Due to this lack of specificity, the development of new endoscopy technologies, which are able to show microscopic changes in the mucosa structure, are necessary. We here present a confocal endomicroscope, which in combination with a wide field fluorescence endoscope offers fast and specific macroscopic information through the use of activatable probes and a detailed analysis at cellular level of the possible altered tissue areas. This multi-modal and multi-scale imaging module, compatible with commercial endoscopes, combines near-infrared fluorescence (NIRF) measurements (enabling specific imaging of markers of disease and prognosis) and confocal endomicroscopy making use of a fiber bundle, providing a cellular level resolution. The system will be used in animal models exhibiting gastro-intestinal diseases in order to analyze the use of potential diagnostic markers in colorectal cancer. In this work, we present in detail the set-up design and the software implementation in order to obtain simultaneous RGB/NIRF measurements and short confocal scanning times.

Mouse Models of Rare Craniofacial Disorders.

PubMed

Achilleos, Annita; Trainor, Paul A

2015-01-01

A rare disease is defined as a condition that affects less than 1 in 2000 individuals. Currently more than 7000 rare diseases have been documented, and most are thought to be of genetic origin. Rare diseases primarily affect children, and congenital craniofacial syndromes and disorders constitute a significant proportion of rare diseases, with over 700 having been described to date. Modeling craniofacial disorders in animal models has been instrumental in uncovering the etiology and pathogenesis of numerous conditions and in some cases has even led to potential therapeutic avenues for their prevention. In this chapter, we focus primarily on two general classes of rare disorders, ribosomopathies and ciliopathies, and the surprising finding that the disruption of fundamental, global processes can result in tissue-specific craniofacial defects. In addition, we discuss recent advances in understanding the pathogenesis of an extremely rare and specific craniofacial condition known as syngnathia, based on the first mouse models for this condition. Approximately 1% of all babies are born with a minor or major developmental anomaly, and individuals suffering from rare diseases deserve the same quality of treatment and care and attention to their disease as other patients. © 2015 Elsevier Inc. All rights reserved.

Asia Pacific Consensus Statements on Crohn's disease. Part 1: Definition, diagnosis, and epidemiology: (Asia Pacific Crohn's Disease Consensus--Part 1).

PubMed

Ooi, Choon Jin; Makharia, Govind K; Hilmi, Ida; Gibson, Peter R; Fock, Kwong Ming; Ahuja, Vineet; Ling, Khoon Lin; Lim, Wee Chian; Thia, Kelvin T; Wei, Shu-chen; Leung, Wai Keung; Koh, Poh Koon; Gearry, Richard B; Goh, Khean Lee; Ouyang, Qin; Sollano, Jose; Manatsathit, Sathaporn; de Silva, H Janaka; Rerknimitr, Rungsun; Pisespongsa, Pises; Abu Hassan, Muhamad Radzi; Sung, Joseph; Hibi, Toshifumi; Boey, Christopher C M; Moran, Neil; Leong, Rupert W L

2016-01-01

Inflammatory bowel disease (IBD) was previously thought to be rare in Asia, but emerging data indicate rising incidence and prevalence of IBD in the region. The Asia Pacific Working Group on Inflammatory Bowel Disease was established in Cebu, Philippines, at the Asia Pacific Digestive Week conference in 2006 under the auspices of the Asian Pacific Association of Gastroenterology with the goal of developing best management practices, coordinating research, and raising awareness of IBD in the region. The consensus group previously published recommendations for the diagnosis and management of ulcerative colitis with specific relevance to the Asia-Pacific region. The present consensus statements were developed following a similar process to address the epidemiology, diagnosis, and management of Crohn's disease. The goals of these statements are to pool the pertinent literature specifically highlighting relevant data and conditions in the Asia-Pacific region relating to the economy, health systems, background infectious diseases, differential diagnoses, and treatment availability. It does not intend to be all comprehensive and future revisions are likely to be required in this ever-changing field. © 2015 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Explosion of autoimmune diseases and the mosaic of old and novel factors

PubMed Central

Agmon-Levin, Nancy; Lian, Zhexiong; Shoenfeld, Yehuda

2011-01-01

In recent decades, an enormous effort has been made to elucidate the pathogenesis of autoimmune and autoinflammatory diseases. Autoimmunity is a multifactorial process in which genetic, immunological, environmental and hormonal factors play in concert, together representing what was termed years ago the ‘mosaic of autoimmunity'. To date, more than 80 systemic and organ-specific autoimmune diseases have been defined, and their cumulative burden is substantial, both medically and financially. Furthermore, the burden of autoimmune and autoinflammatory diseases is rising, making these diseases a ubiquitous global phenomenon that is predicted to further increase in the coming decades. In this issue of the journal, additional aspects of autoimmunity are detailed. Immune dysregulation and loss of self-tolerance are the cornerstones of autoimmunity. PMID:21358666

Object-oriented business process analysis of the cooperative soft tissue sarcoma trial of the german society for paediatric oncology and haematology (GPOH).

PubMed

Weber, R; Knaup, P; Knietitg, R; Haux, R; Merzweiler, A; Mludek, V; Schilling, F H; Wiedemann, T

2001-01-01

The German Society for Paediatric Oncology and Haematology (GPOH) runs nation-wide multicentre clinical trials to improve the treatment of children suffering from malignant diseases. We want to provide methods and tools to support the centres of these trials in developing trial specific modules for the computer-based DOcumentation System for Paediatric Oncology (DOSPO). For this we carried out an object-oriented business process analysis for the Cooperative Soft Tissue Sarcoma Trial at the Olgahospital Stuttgart for Child and Adolescent Medicine. The result is a comprehensive business process model consisting of UML-diagrams and use case specifications. We recommend the object-oriented business process analysis as a method for the definition of requirements in information processing projects in the field of clinical trials in general. For this our model can serve as basis because it slightly can be adjusted to each type of clinical trial.

An integrated database-pipeline system for studying single nucleotide polymorphisms and diseases.

PubMed

Yang, Jin Ok; Hwang, Sohyun; Oh, Jeongsu; Bhak, Jong; Sohn, Tae-Kwon

2008-12-12

Studies on the relationship between disease and genetic variations such as single nucleotide polymorphisms (SNPs) are important. Genetic variations can cause disease by influencing important biological regulation processes. Despite the needs for analyzing SNP and disease correlation, most existing databases provide information only on functional variants at specific locations on the genome, or deal with only a few genes associated with disease. There is no combined resource to widely support gene-, SNP-, and disease-related information, and to capture relationships among such data. Therefore, we developed an integrated database-pipeline system for studying SNPs and diseases. To implement the pipeline system for the integrated database, we first unified complicated and redundant disease terms and gene names using the Unified Medical Language System (UMLS) for classification and noun modification, and the HUGO Gene Nomenclature Committee (HGNC) and NCBI gene databases. Next, we collected and integrated representative databases for three categories of information. For genes and proteins, we examined the NCBI mRNA, UniProt, UCSC Table Track and MitoDat databases. For genetic variants we used the dbSNP, JSNP, ALFRED, and HGVbase databases. For disease, we employed OMIM, GAD, and HGMD databases. The database-pipeline system provides a disease thesaurus, including genes and SNPs associated with disease. The search results for these categories are available on the web page http://diseasome.kobic.re.kr/, and a genome browser is also available to highlight findings, as well as to permit the convenient review of potentially deleterious SNPs among genes strongly associated with specific diseases and clinical phenotypes. Our system is designed to capture the relationships between SNPs associated with disease and disease-causing genes. The integrated database-pipeline provides a list of candidate genes and SNP markers for evaluation in both epidemiological and molecular biological approaches to diseases-gene association studies. Furthermore, researchers then can decide semi-automatically the data set for association studies while considering the relationships between genetic variation and diseases. The database can also be economical for disease-association studies, as well as to facilitate an understanding of the processes which cause disease. Currently, the database contains 14,674 SNP records and 109,715 gene records associated with human diseases and it is updated at regular intervals.

The Case for 8, 5’-Cyclopurine-2’-Deoxynucleosides as Endogenous DNA Lesions That Cause Neurodegeneration in Xeroderma Pigmentosum

PubMed Central

Brooks, PJ

2007-01-01

Patients with the genetic disease xeroderma pigmentosum (XP) lack the capacity to carry out a specific type of DNA repair process called nucleotide excision repair (NER). The NER pathway plays a critical role in the repair of DNA damage resulting from UV radiation. A subset of XP patients develop a profound neurodegenerative condition known as XP neurological disease. Robbins and colleagues (PNAS 75:1984–88, 1978) hypothesized that since UV light cannot reach into the human brain, XP neurological disease results from some form of endogenous DNA damage that is normally repaired by the NER pathway. In the absence of NER, the damage accumulates, causing neuronal death by blocking transcription. In this manuscript, I consider the evidence that a particular class of oxidative DNA lesions, the 8, 5’-cyclopurine-2’-deoxynucleosides, fulfills many of the criteria expected of neurodegenerative DNA lesions in XP. Specifically, these lesions are chemically stable, endogenous DNA lesions that are repaired by the NER pathway but not by any other known process, and strongly block transcription by RNA polymerase II in cells from XP patients. A similar set of criteria might be used to evaluate other candidate DNA lesions responsible for neurological diseases resulting from defects in other DNA repair mechanisms as well. PMID:17184928

Drug discovery for neglected tropical diseases at the Sandler Center.

PubMed

Robertson, Stephanie A; Renslo, Adam R

2011-08-01

The Sandler Center's approach to target-based drug discovery for neglected tropical diseases is to focus on parasite targets that are homologous to human targets being actively investigated in the pharmaceutical industry. In this way we attempt to use both the know-how and actual chemical matter from other drug-development efforts to jump start the discovery process for neglected tropical diseases. Our approach is akin to drug repurposing, except that we seek to repurpose leads rather than drugs. Medicinal chemistry can then be applied to optimize the leads specifically for the desired antiparasitic indication.

[Should disease management be feared? (1): hospital care].

PubMed

Gaspoz, J M; Rutschmann, O

2005-11-23

The goals of disease management are: (1) an integrated health care delivery system; (2) knowledge-based care; (3) elaborate information systems; (4) continuous quality improvement. In-hospital disease management and, more specifically, critical pathways, establish standardized care plans, set goals and time actions to reach these goals. They can reduce variations in practice patterns and resource utilization without compromising quality of care. Such strategies participate to quality improvement programs in hospitals when they involve and empower all actors of a given process of care, are not imposed from outside, and use sound and rigorous development and evaluation methods.

Drug discovery for neglected tropical diseases at the Sandler Center

PubMed Central

Robertson, Stephanie A; Renslo, Adam R

2011-01-01

The Sandler Center’s approach to target-based drug discovery for neglected tropical diseases is to focus on parasite targets that are homologous to human targets being actively investigated in the pharmaceutical industry. In this way we attempt to use both the know-how and actual chemical matter from other drug-development efforts to jump start the discovery process for neglected tropical diseases. Our approach is akin to drug repurposing, except that we seek to repurpose leads rather than drugs. Medicinal chemistry can then be applied to optimize the leads specifically for the desired antiparasitic indication. PMID:21859302

Phage M13 for the treatment of Alzheimer and Parkinson disease.

PubMed

Messing, Joachim

2016-06-01

The studies of microbes have been instrumental in combatting infectious diseases, but they have also led to great insights into basic biological mechanism like DNA replication, transcription, and translation of mRNA. In particular, the studies of bacterial viruses, also called bacteriophage, have been quite useful to study specific cellular processes because of the ease to isolate their DNA, mRNA, and proteins. Here, I review the recent discovery of how properties of the filamentous phage M13 emerge as a novel approach to combat neurodegenerative diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

Arabidopsis EDS1 connects pathogen effector recognition to cell compartment-specific immune responses.

PubMed

Heidrich, Katharina; Wirthmueller, Lennart; Tasset, Céline; Pouzet, Cécile; Deslandes, Laurent; Parker, Jane E

2011-12-09

Pathogen effectors are intercepted by plant intracellular nucleotide binding-leucine-rich repeat (NB-LRR) receptors. However, processes linking receptor activation to downstream defenses remain obscure. Nucleo-cytoplasmic basal resistance regulator EDS1 (ENHANCED DISEASE SUSCEPTIBILITY1) is indispensible for immunity mediated by TIR (Toll-interleukin-1 receptor)-NB-LRR receptors. We show that Arabidopsis EDS1 molecularly connects TIR-NB-LRR disease resistance protein RPS4 recognition of bacterial effector AvrRps4 to defense pathways. RPS4-EDS1 and AvrRps4-EDS1 complexes are detected inside nuclei of living tobacco cells after transient coexpression and in Arabidopsis soluble leaf extracts after resistance activation. Forced AvrRps4 localization to the host cytoplasm or nucleus reveals cell compartment-specific RPS4-EDS1 defense branches. Although nuclear processes restrict bacterial growth, programmed cell death and transcriptional resistance reinforcement require nucleo-cytoplasmic coordination. Thus, EDS1 behaves as an effector target and activated TIR-NB-LRR signal transducer for defenses across cell compartments.

The Role of Gluten in Celiac Disease and Type 1 Diabetes.

PubMed

Serena, Gloria; Camhi, Stephanie; Sturgeon, Craig; Yan, Shu; Fasano, Alessio

2015-08-26

Celiac disease (CD) and type 1 diabetes (T1D) are autoimmune conditions in which dietary gluten has been proven or suggested to play a pathogenic role. In CD; gluten is established as the instigator of autoimmunity; the autoimmune process is halted by removing gluten from the diet; which allows for resolution of celiac autoimmune enteropathy and subsequent normalization of serological markers of the disease. However; an analogous causative agent has not yet been identified for T1D. Nevertheless; the role of dietary gluten in development of T1D and the potentially beneficial effect of removing gluten from the diet of patients with T1D are still debated. In this review; we discuss the comorbid occurrence of CD and T1D and explore current evidences for the specific role of gluten in both conditions; specifically focusing on current evidence on the effect of gluten on the immune system and the gut microbiota.

Family Wellness, Not HIV Prevention

PubMed Central

Swendeman, Dallas; Flannery, Diane

2010-01-01

HIV exceptionalism (and disease-specific programs generally) garner both unbalanced funding and the most talented personnel, distorting local health priorities. In support of HIV exceptionalism, the successful mobilization of significant global health sector resources was not possible prior to HIV. Both sides of the debate have merits; rather than perpetuating polarization, we suggest that sustained improvements in global health require creating a prevention infrastructure to meet multiple health challenges experienced by local communities. We propose four fundamental shifts in HIV and disease prevention: (1) horizontally integrating prevention at one site locally, with priorities tailored to local health challenges and managed by local community leaders; (2) using a family wellness metaphor for services, not disease prevention; (3) implementing evidence-based prevention programs (EBPP) based on common principles, factors, and processes, rather than replication of specific programs; and (4) utilizing the expertise of private enterprise to re-design EBPP into highly attractive, engaging, and accessible experiences. PMID:19148744

Evidence-Based mHealth Chronic Disease Mobile App Intervention Design: Development of a Framework.

PubMed

Wilhide Iii, Calvin C; Peeples, Malinda M; Anthony Kouyaté, Robin C

2016-02-16

Mobile technology offers new capabilities that can help to drive important aspects of chronic disease management at both an individual and population level, including the ability to deliver real-time interventions that can be connected to a health care team. A framework that supports both development and evaluation is needed to understand the aspects of mHealth that work for specific diseases, populations, and in the achievement of specific outcomes in real-world settings. This framework should incorporate design structure and process, which are important to translate clinical and behavioral evidence, user interface, experience design and technical capabilities into scalable, replicable, and evidence-based mobile health (mHealth) solutions to drive outcomes. The purpose of this paper is to discuss the identification and development of an app intervention design framework, and its subsequent refinement through development of various types of mHealth apps for chronic disease. The process of developing the framework was conducted between June 2012 and June 2014. Informed by clinical guidelines, standards of care, clinical practice recommendations, evidence-based research, best practices, and translated by subject matter experts, a framework for mobile app design was developed and the refinement of the framework across seven chronic disease states and three different product types is described. The result was the development of the Chronic Disease mHealth App Intervention Design Framework. This framework allowed for the integration of clinical and behavioral evidence for intervention and feature design. The application to different diseases and implementation models guided the design of mHealth solutions for varying levels of chronic disease management. The framework and its design elements enable replicable product development for mHealth apps and may provide a foundation for the digital health industry to systematically expand mobile health interventions and validate their effectiveness across multiple implementation settings and chronic diseases.

Evidence-Based mHealth Chronic Disease Mobile App Intervention Design: Development of a Framework

PubMed Central

Peeples, Malinda M; Anthony Kouyaté, Robin C

2016-01-01

Background Mobile technology offers new capabilities that can help to drive important aspects of chronic disease management at both an individual and population level, including the ability to deliver real-time interventions that can be connected to a health care team. A framework that supports both development and evaluation is needed to understand the aspects of mHealth that work for specific diseases, populations, and in the achievement of specific outcomes in real-world settings. This framework should incorporate design structure and process, which are important to translate clinical and behavioral evidence, user interface, experience design and technical capabilities into scalable, replicable, and evidence-based mobile health (mHealth) solutions to drive outcomes. Objective The purpose of this paper is to discuss the identification and development of an app intervention design framework, and its subsequent refinement through development of various types of mHealth apps for chronic disease. Methods The process of developing the framework was conducted between June 2012 and June 2014. Informed by clinical guidelines, standards of care, clinical practice recommendations, evidence-based research, best practices, and translated by subject matter experts, a framework for mobile app design was developed and the refinement of the framework across seven chronic disease states and three different product types is described. Results The result was the development of the Chronic Disease mHealth App Intervention Design Framework. This framework allowed for the integration of clinical and behavioral evidence for intervention and feature design. The application to different diseases and implementation models guided the design of mHealth solutions for varying levels of chronic disease management. Conclusions The framework and its design elements enable replicable product development for mHealth apps and may provide a foundation for the digital health industry to systematically expand mobile health interventions and validate their effectiveness across multiple implementation settings and chronic diseases. PMID:26883135

Recall and recognition of verbal paired associates in early Alzheimer's disease.

PubMed

Lowndes, G J; Saling, M M; Ames, D; Chiu, E; Gonzalez, L M; Savage, G R

2008-07-01

The primary impairment in early Alzheimer's disease (AD) is encoding/consolidation, resulting from medial temporal lobe (MTL) pathology. AD patients perform poorly on cued-recall paired associate learning (PAL) tasks, which assess the ability of the MTLs to encode relational memory. Since encoding and retrieval processes are confounded within performance indexes on cued-recall PAL, its specificity for AD is limited. Recognition paradigms tend to show good specificity for AD, and are well tolerated, but are typically less sensitive than recall tasks. Associate-recognition is a novel PAL task requiring a combination of recall and recognition processes. We administered a verbal associate-recognition test and cued-recall analogue to 22 early AD patients and 55 elderly controls to compare their ability to discriminate these groups. Both paradigms used eight arbitrarily related word pairs (e.g., pool-teeth) with varying degrees of imageability. Associate-recognition was equally effective as the cued-recall analogue in discriminating the groups, and logistic regression demonstrated classification rates by both tasks were equivalent. These preliminary findings provide support for the clinical value of this recognition tool. Conceptually it has potential for greater specificity in informing neuropsychological diagnosis of AD in clinical samples but this requires further empirical support.

Computational Modeling and Neuroimaging Techniques for Targeting during Deep Brain Stimulation

PubMed Central

Sweet, Jennifer A.; Pace, Jonathan; Girgis, Fady; Miller, Jonathan P.

2016-01-01

Accurate surgical localization of the varied targets for deep brain stimulation (DBS) is a process undergoing constant evolution, with increasingly sophisticated techniques to allow for highly precise targeting. However, despite the fastidious placement of electrodes into specific structures within the brain, there is increasing evidence to suggest that the clinical effects of DBS are likely due to the activation of widespread neuronal networks directly and indirectly influenced by the stimulation of a given target. Selective activation of these complex and inter-connected pathways may further improve the outcomes of currently treated diseases by targeting specific fiber tracts responsible for a particular symptom in a patient-specific manner. Moreover, the delivery of such focused stimulation may aid in the discovery of new targets for electrical stimulation to treat additional neurological, psychiatric, and even cognitive disorders. As such, advancements in surgical targeting, computational modeling, engineering designs, and neuroimaging techniques play a critical role in this process. This article reviews the progress of these applications, discussing the importance of target localization for DBS, and the role of computational modeling and novel neuroimaging in improving our understanding of the pathophysiology of diseases, and thus paving the way for improved selective target localization using DBS. PMID:27445709

Unveiling molecular events in the brain by noninvasive imaging.

PubMed

Klohs, Jan; Rudin, Markus

2011-10-01

Neuroimaging allows researchers and clinicians to noninvasively assess structure and function of the brain. With the advances of imaging modalities such as magnetic resonance, nuclear, and optical imaging; the design of target-specific probes; and/or the introduction of reporter gene assays, these technologies are now capable of visualizing cellular and molecular processes in vivo. Undoubtedly, the system biological character of molecular neuroimaging, which allows for the study of molecular events in the intact organism, will enhance our understanding of physiology and pathophysiology of the brain and improve our ability to diagnose and treat diseases more specifically. Technical/scientific challenges to be faced are the development of highly sensitive imaging modalities, the design of specific imaging probe molecules capable of penetrating the CNS and reporting on endogenous cellular and molecular processes, and the development of tools for extracting quantitative, biologically relevant information from imaging data. Today, molecular neuroimaging is still an experimental approach with limited clinical impact; this is expected to change within the next decade. This article provides an overview of molecular neuroimaging approaches with a focus on rodent studies documenting the exploratory state of the field. Concepts are illustrated by discussing applications related to the pathophysiology of Alzheimer's disease.

Disease-aging network reveals significant roles of aging genes in connecting genetic diseases.

PubMed

Wang, Jiguang; Zhang, Shihua; Wang, Yong; Chen, Luonan; Zhang, Xiang-Sun

2009-09-01

One of the challenging problems in biology and medicine is exploring the underlying mechanisms of genetic diseases. Recent studies suggest that the relationship between genetic diseases and the aging process is important in understanding the molecular mechanisms of complex diseases. Although some intricate associations have been investigated for a long time, the studies are still in their early stages. In this paper, we construct a human disease-aging network to study the relationship among aging genes and genetic disease genes. Specifically, we integrate human protein-protein interactions (PPIs), disease-gene associations, aging-gene associations, and physiological system-based genetic disease classification information in a single graph-theoretic framework and find that (1) human disease genes are much closer to aging genes than expected by chance; and (2) diseases can be categorized into two types according to their relationships with aging. Type I diseases have their genes significantly close to aging genes, while type II diseases do not. Furthermore, we examine the topological characters of the disease-aging network from a systems perspective. Theoretical results reveal that the genes of type I diseases are in a central position of a PPI network while type II are not; (3) more importantly, we define an asymmetric closeness based on the PPI network to describe relationships between diseases, and find that aging genes make a significant contribution to associations among diseases, especially among type I diseases. In conclusion, the network-based study provides not only evidence for the intricate relationship between the aging process and genetic diseases, but also biological implications for prying into the nature of human diseases.

On the analysis of EEG power, frequency and asymmetry in Parkinson's disease during emotion processing.

PubMed

Yuvaraj, Rajamanickam; Murugappan, Murugappan; Mohamed Ibrahim, Norlinah; Iqbal, Mohd; Sundaraj, Kenneth; Mohamad, Khairiyah; Palaniappan, Ramaswamy; Mesquita, Edgar; Satiyan, Marimuthu

2014-04-09

While Parkinson's disease (PD) has traditionally been described as a movement disorder, there is growing evidence of disruption in emotion information processing associated with the disease. The aim of this study was to investigate whether there are specific electroencephalographic (EEG) characteristics that discriminate PD patients and normal controls during emotion information processing. EEG recordings from 14 scalp sites were collected from 20 PD patients and 30 age-matched normal controls. Multimodal (audio-visual) stimuli were presented to evoke specific targeted emotional states such as happiness, sadness, fear, anger, surprise and disgust. Absolute and relative power, frequency and asymmetry measures derived from spectrally analyzed EEGs were subjected to repeated ANOVA measures for group comparisons as well as to discriminate function analysis to examine their utility as classification indices. In addition, subjective ratings were obtained for the used emotional stimuli. Behaviorally, PD patients showed no impairments in emotion recognition as measured by subjective ratings. Compared with normal controls, PD patients evidenced smaller overall relative delta, theta, alpha and beta power, and at bilateral anterior regions smaller absolute theta, alpha, and beta power and higher mean total spectrum frequency across different emotional states. Inter-hemispheric theta, alpha, and beta power asymmetry index differences were noted, with controls exhibiting greater right than left hemisphere activation. Whereas intra-hemispheric alpha power asymmetry reduction was exhibited in patients bilaterally at all regions. Discriminant analysis correctly classified 95.0% of the patients and controls during emotional stimuli. These distributed spectral powers in different frequency bands might provide meaningful information about emotional processing in PD patients.

The Neural Mechanisms of Meditative Practices: Novel Approaches for Healthy Aging.

PubMed

Acevedo, Bianca P; Pospos, Sarah; Lavretsky, Helen

2016-01-01

Meditation has been shown to have physical, cognitive, and psychological health benefits that can be used to promote healthy aging. However, the common and specific mechanisms of response remain elusive due to the diverse nature of mind-body practices. In this review, we aim to compare the neural circuits implicated in focused-attention meditative practices that focus on present-moment awareness to those involved in active-type meditative practices (e.g., yoga) that combine movement, including chanting, with breath practices and meditation. Recent meta-analyses and individual studies demonstrated common brain effects for attention-based meditative practices and active-based meditations in areas involved in reward processing and learning, attention and memory, awareness and sensory integration, and self-referential processing and emotional control, while deactivation was seen in the amygdala, an area implicated in emotion processing. Unique effects for mindfulness practices were found in brain regions involved in body awareness, attention, and the integration of emotion and sensory processing. Effects specific to active-based meditations appeared in brain areas involved in self-control, social cognition, language, speech, tactile stimulation, sensorimotor integration, and motor function. This review suggests that mind-body practices can target different brain systems that are involved in the regulation of attention, emotional control, mood, and executive cognition that can be used to treat or prevent mood and cognitive disorders of aging, such as depression and caregiver stress, or serve as "brain fitness" exercise. Benefits may include improving brain functional connectivity in brain systems that generally degenerate with Alzheimer's disease, Parkinson's disease, and other aging-related diseases.

Smart cloud system with image processing server in diagnosing brain diseases dedicated for hospitals with limited resources.

PubMed

Fahmi, Fahmi; Nasution, Tigor H; Anggreiny, Anggreiny

2017-01-01

The use of medical imaging in diagnosing brain disease is growing. The challenges are related to the big size of data and complexity of the image processing. High standard of hardware and software are demanded, which can only be provided in big hospitals. Our purpose was to provide a smart cloud system to help diagnosing brain diseases for hospital with limited infrastructure. The expertise of neurologists was first implanted in cloud server to conduct an automatic diagnosis in real time using image processing technique developed based on ITK library and web service. Users upload images through website and the result, in this case the size of tumor was sent back immediately. A specific image compression technique was developed for this purpose. The smart cloud system was able to measure the area and location of tumors, with average size of 19.91 ± 2.38 cm2 and an average response time 7.0 ± 0.3 s. The capability of the server decreased when multiple clients accessed the system simultaneously: 14 ± 0 s (5 parallel clients) and 27 ± 0.2 s (10 parallel clients). The cloud system was successfully developed to process and analyze medical images for diagnosing brain diseases in this case for tumor.

Mechanism of Aromatic Hydrocarbon Induced Mammary Tumorigenesis

DTIC Science & Technology

1999-07-01

the de-differentiation process of one form of cancer. These studies have been reported (Ashba and Traish, 1999; cf enclosed manuscript). SPECIFIC...be a multi-stage process . The progression of this disease is associated with cellular and molecular changes. Thus, initiation and progression may be...9,10,17-21). Whole aqueous extracts, decaffeinated extracts and purified components of tea have been found effective to varying degrees in the different

Pain processing in atypical Parkinsonisms and Parkinson disease: A comparative neurophysiological study.

PubMed

Avenali, Micol; Tassorelli, Cristina; De Icco, Roberto; Perrotta, Armando; Serrao, Mariano; Fresia, Mauro; Pacchetti, Claudio; Sandrini, Giorgio

2017-10-01

Pain is a frequent non-motor feature in Parkinsonism but mechanistic data on the alteration of pain processing are insufficient to understand the possible causes and to define specifically-targeted treatments. we investigated spinal nociception through the neurophysiological measure of the threshold (TR) of nociceptive withdrawal reflex (NWR) and its temporal summation threshold (TST) comparatively in 12 Progressive Supranuclear Palsy (PSP) subjects, 11 Multiple System Atrophy (MSA) patients, 15 Parkinson's disease (PD) subjects and 24 healthy controls (HC). We also investigated the modulatory effect of L-Dopa in these three parkinsonian groups. We found a significant reduction in the TR of NWR and in the TST of NWR in PSP, MSA and PD patients compared with HC. L-Dopa induced an increase in the TR of NWR in the PSP group while TST of NWR increased in both PSP and PD. Our neurophysiological findings identify a facilitation of nociceptive processing in PSP that is broadly similar to that observed in MSA and PD. Specific peculiarities have emerged for PSP. Our data advance the knowledge of the neurophysiology of nociception in the advanced phases of parkinsonian syndromes and on the role of dopaminergic pathways in the control on pain processing. Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

Proposal for an integrated evaluation model for the study of whole systems health care in cancer.

PubMed

Jonas, Wayne B; Beckner, William; Coulter, Ian

2006-12-01

For more than 200 years, biomedicine has approached the treatment of disease by studying disease processes (patho-genesis), inferring causal connections and developing specific approaches for therapeutically interfering with those processes. This pathogenic approach has been highly successful in acute and traumatic disease but less successful in chronic disease, primarily because of the complex, multi-factorial nature of most chronic disease, which does not allow for simple causal inference or for simple therapeutic interventions. This article suggests that chronic disease is best approached by enhancing healing processes (salutogenesis) as a whole system. Because of the nature of complex systems in chronic disease, an evaluation model based on integrative medicine is felt to be more appropriate than a disease model. The authors propose and describe an integrated model for the evaluation of healing (IMEH) that collects multilevel "thick case" observational data in assessing complex practices for chronic disease. If successful, this approach could become a blueprint for studying healing capacity in whole medical systems, including complementary medicine, traditional medicine, and conventional primary care. In addition, streamlining data collection and applying rapid informatics management might allow for such data to be used in guiding clinical practice. The IMEH involves collection, integration, and potentially feedback of relevant variables in the following areas: (1) sociocultural, (2) psychological and behavioral, (3) clinical (diagnosis based), and (4) biological. Evaluation and integration of these components would involve specialized research teams that feed their data into a single data management and information analysis center. These data can then be subjected to descriptive and pathway analysis providing "bench and bedside" information.

Serum Metabolomics to Identify the Liver Disease-Specific Biomarkers for the Progression of Hepatitis to Hepatocellular Carcinoma

NASA Astrophysics Data System (ADS)

Gao, Rong; Cheng, Jianhua; Fan, Chunlei; Shi, Xiaofeng; Cao, Yuan; Sun, Bo; Ding, Huiguo; Hu, Chengjin; Dong, Fangting; Yan, Xianzhong

2015-12-01

Hepatocellular carcinoma (HCC) is a common malignancy that has region specific etiologies. Unfortunately, 85% of cases of HCC are diagnosed at an advanced stage. Reliable biomarkers for the early diagnosis of HCC are urgently required to reduced mortality and therapeutic expenditure. We established a non-targeted gas chromatography-time of flight-mass spectrometry (GC-TOFMS) metabolomics method in conjunction with Random Forests (RF) analysis based on 201 serum samples from healthy controls (NC), hepatitis B virus (HBV), liver cirrhosis (LC) and HCC patients to explore the metabolic characteristics in the progression of hepatocellular carcinogenesis. Ultimately, 15 metabolites were identified intimately associated with the process. Phenylalanine, malic acid and 5-methoxytryptamine for HBV vs. NC, palmitic acid for LC vs. HBV, and asparagine and β-glutamate for HCC vs. LC were screened as the liver disease-specific potential biomarkers with an excellent discriminant performance. All the metabolic perturbations in these liver diseases are associated with pathways for energy metabolism, macromolecular synthesis, and maintaining the redox balance to protect tumor cells from oxidative stress.

Airway epithelial repair in health and disease: Orchestrator or simply a player?

PubMed

Iosifidis, Thomas; Garratt, Luke W; Coombe, Deirdre R; Knight, Darryl A; Stick, Stephen M; Kicic, Anthony

2016-04-01

Epithelial cells represent the most important surface of contact in the body and form the first line of defence of the body to external environment. Consequently, epithelia have numerous roles in order to maintain a homeostatic defence barrier. Although the epithelium has been extensively studied over several decades, it remains the focus of new research, indicating a lack of understanding that continues to exist around these cells in specific disease settings. Importantly, evidence is emerging that airway epithelial cells in particular have varied complex functions rather than simple passive roles. One area of current interest is its role following injury. In particular, the epithelial-specific cellular mechanisms regulating their migration during wound repair remain poorly understood and remain an area that requires much needed investigation. A better understanding of the physiological, cellular and molecular wound repair mechanisms could assist in elucidating pathological processes that contribute to airway epithelial pathology. This review attempts to highlight migration-specific and cell-extracellular matrix (ECM) aspects of repair used by epithelial cells under normal and disease settings, in the context of human airways. © 2016 Asian Pacific Society of Respirology.

Nonviral siRNA delivery for gene silencing in neurodegenerative diseases.

PubMed

Prakash, Satya; Malhotra, Meenakshi; Rengaswamy, Venkatesh

2010-01-01

Linking genes with the underlying mechanisms of diseases is one of the biggest challenges of genomics-driven drug discovery research. Designing an inhibitor for any neurodegenerative disease that effectively halts the pathogenicity of the disease is yet to be achieved. The challenge lies in crossing the blood-brain barrier (BBB)/blood-cerebrospinal fluid barrier (BCSFB) to reach the catalytic pockets of the enzyme/protein involved in the molecular mechanism of the disease process. Designing siRNA with exquisite specificity may result in selective suppression of the disease-linked gene. Although siRNA is the most promising method, it loses its potency in downregulating the gene due to its inherent instability, off-target effects, and lack of on-target effective delivery systems. Viral as well as nonviral delivery methods have been effectively tested in vivo for silencing of molecular targets and have resulted in significant efficacy in animal models of Alzheimer's disease, amyotrophic lateral sclerosis (ALS), anxiety, depression, encephalitis, glioblastoma, Huntington's disease, neuropathic pain, and spinocerebellar ataxia. To realize the full therapeutic potential of siRNA for neurodegenerative diseases, we need to overcome many hurdles and challenges such as selecting suitable tissue-specific delivery vectors, minimizing the off-target effects, and achieving distribution in sufficient concentrations at the target tissue without any side effects. Cationic nanoparticle-mediated targeted siRNA delivery for therapeutic purposes has gained considerable clinical importance as a result of its promising efficacy.

[Sleep disturbances in Parkinson's disease: characteristics, evaluation and therapeutic approaches].

PubMed

Faludi, Béla; Janszky, József; Komoly, Sámuel; Kovács, Norbert

2015-07-05

Parkinson's disease is a well known representent of the movement disorder group of neurological disorders. The diagnosis of Parkinson's disease is based on specific symptoms and signs of movement abnormalities. In addition to classic motor symptoms, Parkinson's disease has characteristic non-motor features, and some of these emerges the classic signs. The authors discuss characteristics and therapeutic interventions in Parkinson's disease related sleep disturbances. The authors reviewed and summarised literature data on sleep disorders in Parkinson's disease published in the PubMed database up to January 2015. Sleep problems are important non-motor complains (insomnia, hypersomnia, REM behaviour disorder, sleep apnea and restless legs syndrome). The neurodegenerative process of the brain-stem, the effect of symptoms of Parkinson's disease on sleep and concomitant sleep disorders constitute the background of the patient's complains. Appropriate diagnosis and therapy of the consequential or concomitant sleep disorders in Parkinson's disease will help to improve the patient's quality of life.

Humoral Epitope Spreading in Autoimmune Bullous Diseases

PubMed Central

Didona, Dario; Di Zenzo, Giovanni

2018-01-01

Autoimmune blistering diseases are characterized by autoantibodies against structural adhesion proteins of the skin and mucous membranes. Extensive characterization of their autoantibody targets has improved understanding of pathogenesis and laid the basis for the study of antigens/epitopes diversification, a process termed epitope spreading (ES). In this review, we have reported and discussed ES phenomena in autoimmune bullous diseases and underlined their functional role in disease pathogenesis. A functional ES has been proposed: (1) in bullous pemphigoid patients and correlates with the initial phase of the disease, (2) in pemphigus vulgaris patients with mucosal involvement during the clinical transition to a mucocutaneous form, (3) in endemic pemphigus foliaceus, underlining its role in disease pathogenesis, and (4) in numerous cases of disease transition associated with an intermolecular diversification of immune response. All these findings could give useful information to better understand autoimmune disease pathogenesis and to design antigen/epitope specific therapeutic approaches. PMID:29719538

Patients' self-efficacy within online health communities: facilitating chronic disease self-management behaviors through peer education.

PubMed

Willis, Erin

2016-01-01

In order to combat the growing burden of chronic disease, evidence-based self-management programs have been designed to teach patients about the disease and its affect on their lives. Self-efficacy is a key component in chronic disease self-management. This research used online ethnography and discourse analysis (N = 8,231) to examine self-efficacy within the computer-mediated communication (CMC) of four online health communities used by people with arthritis. Specifically, online opinion leaders were identified for examination. Across the four communities, there was a cyclical process that involved "disease veterans" sharing their experiences and gaining credibility within the community, new(er) members suffering from disease symptoms and sharing their experiences online, and finally, asking others for help with arthritis self-management behaviors. Three themes follow: (1) sharing disease experience, (2) suffering from disease symptoms, and (3) asking for help. Practical implications for health promotion and education are discussed.

The potential of epigenetic therapies in neurodegenerative diseases

PubMed Central

Coppedè, Fabio

2014-01-01

Available treatments for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease, do not arrest disease progression but mainly help keeping patients from getting worse for a limited period of time. Increasing evidence suggests that epigenetic mechanisms such as DNA methylation and histone tail modifications are dynamically regulated in neurons and play a fundamental role in learning and memory processes. In addition, both global and gene-specific epigenetic changes and deregulated expression of the writer and eraser proteins of epigenetic marks are believed to contribute to the onset and progression of neurodegeneration. Studies in animal models of neurodegenerative diseases have highlighted the potential role of epigenetic drugs, including inhibitors of histone deacetylases and methyl donor compounds, in ameliorating the cognitive symptoms and preventing or delaying the motor symptoms of the disease, thereby opening the way for a potential application in human pathology. PMID:25071843

[Celiac disease in disguise].

PubMed

de Gottardi, A; de Saussure, P

2005-09-07

Contrarily to a widely prevalent opinion, celiac disease frequently affects adults, and only rarely reveals itself by the classical triad of diarrhea--weight loss--nutritional deficiency. In addition to isolated deficiencies, most frequently iron and calcium-vitamin D, celiac disease is commonly associated with atypical, sometimes very commonplace manifestations, such as abdominal symptoms reminiscent of those of irritable bowel syndrome, or type I diabetes. The diagnostic process is now made easier by the availability of antitransglutaminase antibodies dosage, a simple, trustworthy, sensitive and specific test. This review article discusses the many clinical pictures which should prompt the clinician to rule out celiac disease, and provides practical guidelines as to the use and interpretation of serologic tests.

Alzheimer’s Disease as the Product of a Progressive Energy Deficiency Syndrome in the Central Nervous System: The Neuroenergetic Hypothesis

PubMed Central

Blonz, Edward R.

2017-01-01

The decreased availability of metabolizable energy resources in the central nervous system is hypothesized to be a key factor in the pathogenesis of Alzheimer’s disease. More specifically, the age-related decline in the ability of glucose to cross the blood-brain barrier creates a metabolic stress that shifts the normal, benign processing of amyloid-β protein precursor toward pathways associated with the production of amyloid-β plaques and tau-containing neurofibrillary tangles that are characteristic of the disease. The neuroenergetic hypothesis provides insight into the etiology of Alzheimer’s disease and illuminates new approaches for diagnosis, monitoring, and treatment. PMID:28946565

Fab antibodies capable of blocking T cells by competitive binding have the identical specificity but a higher affinity to the MHC-peptide-complex than the T cell receptor.

PubMed

Neumann, Frank; Sturm, Christine; Hülsmeyer, Martin; Dauth, Nina; Guillaume, Philippe; Luescher, Immanuel F; Pfreundschuh, Michael; Held, Gerhard

2009-08-15

In transplant rejection, graft versus host or autoimmune diseases T cells are mediating the pathophysiological processes. Compared to unspecific pharmacological immune suppression specific inhibition of those T cells, that are involved in the disease, would be an alternative and attractive approach. T cells are activated after their T cell receptor (TCR) recognizes an antigenic peptide displayed by the Major Histocompatibility Complex (MHC). Molecules that interact with MHC-peptide-complexes in a specific fashion should block T cells with identical specificity. Using the model of the SSX2 (103-111)/HLA-A*0201 complex we investigated a panel of MHC-peptide-specific Fab antibodies for their capacity blocking specific T cell clones. Like TCRs all Fab antibodies reacted with the MHC complex only when the SSX2 (103-111) peptide was displayed. By introducing single amino acid mutations in the HLA-A*0201 heavy chain we identified the K66 residue as the most critical binding similar to that of TCRs. However, some Fab antibodies did not inhibit the reactivity of a specific T cell clone against peptide pulsed, artificial targets, nor cells displaying the peptide after endogenous processing. Measurements of binding kinetics revealed that only those Fab antibodies were capable of blocking T cells that interacted with an affinity in the nanomolar range. Fab antibodies binding like TCRs with affinities on the lower micromolar range did not inhibit T cell reactivity. These results indicate that molecules that block T cells by competitive binding with the TCR must have the same specificity but higher affinity for the MHC-peptide-complex than the TCR.

Human risk of diseases associated with red meat intake: Analysis of current theories and proposed role for metabolic incorporation of a non-human sialic acid.

PubMed

Alisson-Silva, Frederico; Kawanishi, Kunio; Varki, Ajit

2016-10-01

One of the most consistent epidemiological associations between diet and human disease risk is the impact of red meat consumption (beef, pork, and lamb, particularly in processed forms). While risk estimates vary, associations are reported with all-cause mortality, colorectal and other carcinomas, atherosclerotic cardiovascular disease, type II diabetes, and possibly other inflammatory processes. There are many proposed explanations for these associations, some long discussed in the literature. Attempts to explain the effects of red meat consumption have invoked various red meat-associated agents, including saturated fat, high salt intake, Trimethylamine-N-oxide (TMAO) generation by microbiota, and environmental pollutants contaminating red meat, none of which are specific for red meat. Even the frequently mentioned polycyclic aromatic carcinogens arising from high temperature cooking methods are not red meat specific, as these are also generated by grilling poultry or fish, as well as by other forms of cooking. The traditional explanations that appear to be more red meat specific invoke the impact of N-nitroso compounds, heme iron, and the potential of heme to catalyze endogenous nitrosation. However, heme can be denatured by cooking, high levels of plasma hemopexin will block its tissue delivery, and much higher amounts of heme likely originate from red blood cell breakdown in vivo. Therefore, red meat-derived heme could only contribute to colorectal carcinoma risk, via direct local effects. Also, none of these mechanisms explain the apparent human propensity i.e., other carnivores have not been reported at high risk for all these diseases. A more recently proposed hypothesis involves infectious agents in beef from specific dairy cattle as agents of colorectal cancer. We have also described another mechanistic explanation for the human propensity for risk of red-meat associated diseases that is consistent with most observations: metabolic incorporation of a non-human sialic acid N-glycolylneuraminic acid (Neu5Gc) into the tissues of red meat consumers and the subsequent interaction with inflammation-provoking antibodies against this "xenoautoantigen". Overall, we conclude that while multiple mechanisms are likely operative, many proposed theories to date are not specific for red meat, and that the viral and xenoautoantigen theories deserve further consideration. Importantly, there are potential non-toxic dietary antidotes, if the xenoautoantigen theory is indeed correct. Copyright © 2016 Elsevier Ltd. All rights reserved.

Human Risk of Diseases Associated with Red Meat Intake: Analysis of Current Theories and Proposed Role for Metabolic Incorporation of a Non-Human Sialic Acid

PubMed Central

Alisson-Silva, Frederico; Kawanishi, Kunio; Varki, Ajit

2016-01-01

One of the most consistent epidemiological associations between diet and human disease risk is the impact of red meat consumption (beef, pork, and lamb, particularly in processed forms). While risk estimates vary, associations are reported with all-cause mortality, colorectal and other carcinomas, atherosclerotic cardiovascular disease, type II diabetes, and possibly other inflammatory processes. There are many proposed explanations for these associations, some long discussed in the literature. Attempts to explain the effects of red meat consumption have invoked various red meat-associated agents, including saturated fat, high salt intake, Trimethylamine–N-oxide (TMAO) generation by microbiota, and environmental pollutants contaminating red meat, none of which are specific for red meat. Even the frequently mentioned polycyclic aromatic carcinogens arising from high temperature cooking methods are not red meat specific, as these are also generated by grilling poultry or fish, as well as by other forms of cooking. The traditional explanations that appear to be more red meat specific invoke the impact of N-nitroso compounds, heme iron, and the potential of heme to catalyze endogenous nitrosation. However, heme can be denatured by cooking, high levels of plasma hemopexin will block its tissue delivery, and much higher amounts of heme likely originate from red blood cell breakdown in vivo. Therefore, red meat-derived heme could only contribute to colorectal carcinoma risk, via direct local effects. Also, none of these mechanisms explain the apparent human propensity i.e., other carnivores have not been reported at high risk for all these diseases. A more recently proposed hypothesis involves infectious agents in beef from specific dairy cattle as agents of colorectal cancer. We have also described another mechanistic explanation for the human propensity for risk of red-meat associated diseases that is consistent with most observations: metabolic incorporation of a non-human sialic acid N-glycolylneuraminic acid (Neu5Gc) into the tissues of red meat consumers and the subsequent interaction with inflammation-provoking antibodies against this “xenoautoantigen”. Overall, we conclude that while multiple mechanisms are likely operative, many proposed theories to date are not specific for red meat, and that the viral and xenoautoantigen theories deserve further consideration. Importantly, there are potential non-toxic dietary antidotes, if the xenoautoantigen is indeed correct. PMID:27421909

Environmentally Induced Epigenetic Transgenerational Inheritance of Altered Sertoli Cell Transcriptome and Epigenome: Molecular Etiology of Male Infertility

PubMed Central

Guerrero-Bosagna, Carlos; Savenkova, Marina; Haque, Md. Muksitul; Nilsson, Eric; Skinner, Michael K.

2013-01-01

Environmental toxicants have been shown to induce the epigenetic transgenerational inheritance of adult onset disease, including testis disease and male infertility. The current study was designed to determine the impact of an altered sperm epigenome on the subsequent development of an adult somatic cell (Sertoli cell) that influences the onset of a specific disease (male infertility). A gestating female rat (F0 generation) was exposed to the agriculture fungicide vinclozolin during gonadal sex determination and then the subsequent F3 generation progeny used for the isolation of Sertoli cells and assessment of testis disease. As previously observed, enhanced spermatogenic cell apoptosis was observed. The Sertoli cells provide the physical and nutritional support for the spermatogenic cells. Over 400 genes were differentially expressed in the F3 generation control versus vinclozolin lineage Sertoli cells. A number of specific cellular pathways were identified to be transgenerationally altered. One of the key metabolic processes affected was pyruvate/lactate production that is directly linked to spermatogenic cell viability. The Sertoli cell epigenome was also altered with over 100 promoter differential DNA methylation regions (DMR) modified. The genomic features and overlap with the sperm DMR were investigated. Observations demonstrate that the transgenerational sperm epigenetic alterations subsequently alters the development of a specific somatic cell (Sertoli cell) epigenome and transcriptome that correlates with adult onset disease (male infertility). The environmentally induced epigenetic transgenerational inheritance of testis disease appears to be a component of the molecular etiology of male infertility. PMID:23555832

Comprehensive evaluation of gene expression signatures in response to electroacupuncture stimulation at Zusanli (ST36) acupoint by transcriptomic analysis.

PubMed

Wu, Jing-Shan; Lo, Hsin-Yi; Li, Chia-Cheng; Chen, Feng-Yuan; Hsiang, Chien-Yun; Ho, Tin-Yun

2017-08-15

Electroacupuncture (EA) has been applied to treat and prevent diseases for years. However, molecular events happened in both the acupunctured site and the internal organs after EA stimulation have not been clarified. Here we applied transcriptomic analysis to explore the gene expression signatures after EA stimulation. Mice were applied EA stimulation at ST36 for 15 min and nine tissues were collected three hours later for microarray analysis. We found that EA affected the expression of genes not only in the acupunctured site but also in the internal organs. EA commonly affected biological networks involved in cytoskeleton and cell adhesion, and also regulated unique process networks in specific organs, such as γ-aminobutyric acid-ergic neurotransmission in brain and inflammation process in lung. In addition, EA affected the expression of genes related to various diseases, such as neurodegenerative diseases in brain and obstructive pulmonary diseases in lung. This report applied, for the first time, a global comprehensive genome-wide approach to analyze the gene expression profiling of acupunctured site and internal organs after EA stimulation. The connection between gene expression signatures, biological processes, and diseases might provide a basis for prediction and explanation on the therapeutic potentials of acupuncture in organs.

Antibodies and antimatter: the resurgence of immuno-PET.

PubMed

Wu, Anna M

2009-01-01

The completion of the human genome, coupled with parallel major research efforts in proteomics and systems biology, has led to a flood of information on the roles of individual genes and proteins in normal physiologic processes and their disruptions in disease. In practical terms, this information has opened the door to increasingly targeted therapies as specific molecular markers are identified and validated. The ongoing transition from empiric to molecular medicine has engendered a need for corresponding molecular diagnostics, including noninvasive molecular imaging. Convergence of knowledge regarding key biomarkers that define normal biologic processes and disease with protein and imaging technology makes this an opportune time to revisit the combination of antibodies and PET, or immuno-PET.

Risk of thromboembolic complications in adult congenital heart disease: A literature review.

PubMed

Karsenty, Clement; Zhao, Alexandre; Marijon, Eloi; Ladouceur, Magalie

2018-05-30

Adult congenital heart disease (ACHD) is a constantly expanding population with challenging issues. Initial medical and surgical treatments are seldom curative, and the majority of patients still experience late sequelae and complications, especially thromboembolic events. These common and potentially life-threating adverse events are probably dramatically underdiagnosed. Better identification and understanding of thromboembolic risk factors are essential to prevent long-term related morbidities. In addition to specific situations associated with a high risk of thromboembolic events (Fontan circulation, cyanotic congenital heart disease), atrial arrhythmia has been recognized as an important risk factor for thromboembolic events in ACHD. Unlike in patients without ACHD, thromboembolic risk stratification scores, such as the CHA 2 DS 2 -VASc score, may not be applicable in ACHD. Overall, after a review of the scientific data published so far, it is clear that the complexity of the underlying congenital heart disease represents a major risk factor for thromboembolic events. As a consequence, prophylactic anticoagulation is indicated in patients with complex congenital heart disease and atrial arrhythmia, regardless of the other risk factors, as opposed to simple heart defects. The landscape of ACHD is an ongoing evolving process, and specific thromboembolic risk scores are needed, especially in the setting of simple heart defects; these should be coupled with specific trials or long-term follow-up of multicentre cohorts. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Determining the Roles of Inositol Trisphosphate Receptors in Neurodegeneration: Interdisciplinary Perspectives on a Complex Topic.

PubMed

Takada, Silvia Honda; Ikebara, Juliane Midori; de Sousa, Erica; Cardoso, Débora Sterzeck; Resende, Rodrigo Ribeiro; Ulrich, Henning; Rückl, Martin; Rüdiger, Sten; Kihara, Alexandre Hiroaki

2017-11-01

It is well known that calcium (Ca 2+ ) is involved in the triggering of neuronal death. Ca 2+ cytosolic levels are regulated by Ca 2+ release from internal stores located in organelles, such as the endoplasmic reticulum. Indeed, Ca 2+ transit from distinct cell compartments follows complex dynamics that are mediated by specific receptors, notably inositol trisphosphate receptors (IP3Rs). Ca 2+ release by IP3Rs plays essential roles in several neurological disorders; however, details of these processes are poorly understood. Moreover, recent studies have shown that subcellular location, molecular identity, and density of IP3Rs profoundly affect Ca 2+ transit in neurons. Therefore, regulation of IP3R gene products in specific cellular vicinities seems to be crucial in a wide range of cellular processes from neuroprotection to neurodegeneration. In this regard, microRNAs seem to govern not only IP3Rs translation levels but also subcellular accumulation. Combining new data from molecular cell biology with mathematical modelling, we were able to summarize the state of the art on this topic. In addition to presenting how Ca 2+ dynamics mediated by IP3R activation follow a stochastic regimen, we integrated a theoretical approach in an easy-to-apply, cell biology-coherent fashion. Following the presented premises and in contrast to previously tested hypotheses, Ca 2+ released by IP3Rs may play different roles in specific neurological diseases, including Alzheimer's disease and Parkinson's disease.

Phage display and kinetic selection of antibodies that specifically inhibit amyloid self-replication.

PubMed

Munke, Anna; Persson, Jonas; Weiffert, Tanja; De Genst, Erwin; Meisl, Georg; Arosio, Paolo; Carnerup, Anna; Dobson, Christopher M; Vendruscolo, Michele; Knowles, Tuomas P J; Linse, Sara

2017-06-20

The aggregation of the amyloid β peptide (Aβ) into amyloid fibrils is a defining characteristic of Alzheimer's disease. Because of the complexity of this aggregation process, effective therapeutic inhibitors will need to target the specific microscopic steps that lead to the production of neurotoxic species. We introduce a strategy for generating fibril-specific antibodies that selectively suppress fibril-dependent secondary nucleation of the 42-residue form of Aβ (Aβ42). We target this step because it has been shown to produce the majority of neurotoxic species during aggregation of Aβ42. Starting from large phage display libraries of single-chain antibody fragments (scFvs), the three-stage approach that we describe includes ( i ) selection of scFvs with high affinity for Aβ42 fibrils after removal of scFvs that bind Aβ42 in its monomeric form; ( ii ) ranking, by surface plasmon resonance affinity measurements, of the resulting candidate scFvs that bind to the Aβ42 fibrils; and ( iii ) kinetic screening and analysis to find the scFvs that inhibit selectively the fibril-catalyzed secondary nucleation process in Aβ42 aggregation. By applying this approach, we have identified four scFvs that inhibit specifically the fibril-dependent secondary nucleation process. Our method also makes it possible to discard antibodies that inhibit elongation, an important factor because the suppression of elongation does not target directly the production of toxic oligomers and may even lead to its increase. On the basis of our results, we suggest that the method described here could form the basis for rationally designed immunotherapy strategies to combat Alzheimer's and related neurodegenerative diseases.

A fast-response two-photon fluorescent probe for imaging endogenous H2O2 in living cells and tissues

NASA Astrophysics Data System (ADS)

Lu, Yanan; Shi, Xiaomin; Fan, Wenlong; Black, Cory A.; Lu, Zhengliang; Fan, Chunhua

2018-02-01

As a second messenger, hydrogen peroxide plays significant roles in numerous physiological and pathological processes and is related to various diseases including inflammatory disease, diabetes, neurodegenerative disorders, cardiovascular disease and Alzheimer's disease. Two-photon (TP) fluorescent probes reported for the detection of endogenous H2O2 are rare and most have drawbacks such as slow response and low sensitivity. In this report, we demonstrate a simple H2O2-specific TP fluorescent probe (TX-HP) containing a two-photon dye 6-hydroxy-2,3,4,4a-tetrahydro-1H-xanthen-1-one (TX) on the modulation of the ICT process. The probe exhibits a rapid fluorescent response to H2O2 in 9 min with both high sensitivity and selectivity. The probe can detect exogenous H2O2 in living cells. Furthermore, the probe is successfully utilized for imaging H2O2 in liver tissues.

The Impact of Traumatic Brain Injury on the Aging Brain.

PubMed

Young, Jacob S; Hobbs, Jonathan G; Bailes, Julian E

2016-09-01

Traumatic brain injury (TBI) has come to the forefront of both the scientific and popular culture. Specifically, sports-related concussions or mild TBI (mTBI) has become the center of scientific scrutiny with a large amount of research focusing on the long-term sequela of this type of injury. As the populace continues to age, the impact of TBI on the aging brain will become clearer. Currently, reports have come to light that link TBI to neurodegenerative disorders such as Alzheimer's and Parkinson's diseases, as well as certain psychiatric diseases. Whether these associations are causations, however, is yet to be determined. Other long-term sequelae, such as chronic traumatic encephalopathy (CTE), appear to be associated with repetitive injuries. Going forward, as we gain better understanding of the pathophysiological process involved in TBI and subclinical head traumas, and individual traits that influence susceptibility to neurocognitive diseases, a clearer, more comprehensive understanding of the connection between brain injury and resultant disease processes in the aging brain will become evident.

Association Between Dietary Factors and Mortality From Heart Disease, Stroke, and Type 2 Diabetes in the United States.

PubMed

Micha, Renata; Peñalvo, Jose L; Cudhea, Frederick; Imamura, Fumiaki; Rehm, Colin D; Mozaffarian, Dariush

2017-03-07

In the United States, national associations of individual dietary factors with specific cardiometabolic diseases are not well established. To estimate associations of intake of 10 specific dietary factors with mortality due to heart disease, stroke, and type 2 diabetes (cardiometabolic mortality) among US adults. A comparative risk assessment model incorporated data and corresponding uncertainty on population demographics and dietary habits from National Health and Nutrition Examination Surveys (1999-2002: n = 8104; 2009-2012: n = 8516); estimated associations of diet and disease from meta-analyses of prospective studies and clinical trials with validity analyses to assess potential bias; and estimated disease-specific national mortality from the National Center for Health Statistics. Consumption of 10 foods/nutrients associated with cardiometabolic diseases: fruits, vegetables, nuts/seeds, whole grains, unprocessed red meats, processed meats, sugar-sweetened beverages (SSBs), polyunsaturated fats, seafood omega-3 fats, and sodium. Estimated absolute and percentage mortality due to heart disease, stroke, and type 2 diabetes in 2012. Disease-specific and demographic-specific (age, sex, race, and education) mortality and trends between 2002 and 2012 were also evaluated. In 2012, 702 308 cardiometabolic deaths occurred in US adults, including 506 100 from heart disease (371 266 coronary heart disease, 35 019 hypertensive heart disease, and 99 815 other cardiovascular disease), 128 294 from stroke (16 125 ischemic, 32 591 hemorrhagic, and 79 578 other), and 67 914 from type 2 diabetes. Of these, an estimated 318 656 (95% uncertainty interval [UI], 306 064-329 755; 45.4%) cardiometabolic deaths per year were associated with suboptimal intakes-48.6% (95% UI, 46.2%-50.9%) of cardiometabolic deaths in men and 41.8% (95% UI, 39.3%-44.2%) in women; 64.2% (95% UI, 60.6%-67.9%) at younger ages (25-34 years) and 35.7% (95% UI, 33.1%-38.1%) at older ages (≥75 years); 53.1% (95% UI, 51.6%-54.8%) among blacks, 50.0% (95% UI, 48.2%-51.8%) among Hispanics, and 42.8% (95% UI, 40.9%-44.5%) among whites; and 46.8% (95% UI, 44.9%-48.7%) among lower-, 45.7% (95% UI, 44.2%-47.4%) among medium-, and 39.1% (95% UI, 37.2%-41.2%) among higher-educated individuals. The largest numbers of estimated diet-related cardiometabolic deaths were related to high sodium (66 508 deaths in 2012; 9.5% of all cardiometabolic deaths), low nuts/seeds (59 374; 8.5%), high processed meats (57 766; 8.2%), low seafood omega-3 fats (54 626; 7.8%), low vegetables (53 410; 7.6%), low fruits (52 547; 7.5%), and high SSBs (51 694; 7.4%). Between 2002 and 2012, population-adjusted US cardiometabolic deaths per year decreased by 26.5%. The greatest decline was associated with insufficient polyunsaturated fats (-20.8% relative change [95% UI, -18.5% to -22.8%]), nuts/seeds (-18.0% [95% UI, -14.6% to -21.0%]), and excess SSBs (-14.5% [95% UI, -12.0% to -16.9%]). The greatest increase was associated with unprocessed red meats (+14.4% [95% UI, 9.1%-19.5%]). Dietary factors were estimated to be associated with a substantial proportion of deaths from heart disease, stroke, and type 2 diabetes. These results should help identify priorities, guide public health planning, and inform strategies to alter dietary habits and improve health.

Mucosal-associated invariant T cells in autoimmunity, immune-mediated diseases and airways disease.

PubMed

Hinks, Timothy S C

2016-05-01

Mucosal-associated invariant T (MAIT) cells are a novel class of innate-like T cells, expressing a semi-invariant T-cell receptor (TCR) and able to recognize small molecules presented on the non-polymorphic MHC-related protein 1. Their intrinsic effector-memory phenotype, enabling secretion of pro-inflammatory cytokines, and their relative abundance in humans imply a significant potential to contribute to autoimmune processes. However, as MAIT cells were unknown until recently and specific immunological tools were unavailable, little is known of their roles in disease. Here I review observations from clinical studies and animal models of autoimmune and immune-mediated diseases including the roles of MAIT cells in systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease and airways diseases. MAIT cell deficiencies are frequently observed in peripheral blood, and at sites of disease such as the airways in asthma. However, MAIT cells have a specific sensitivity to suppression by therapeutic corticosteroids that may confound many of these observations, as may the tendency of the surface marker CD161 to activation-induced down-regulation. Nonetheless, the dependence on bacteria for the development of MAIT cells suggests a potentially important protective role linking the influences of early life microbial exposures and subsequent development of autoimmunity. Conversely, MAIT cells could contribute to chronic inflammation either through TCR-independent activation, or potentially by TCR recognition of as yet undiscovered ligands. Future research will be greatly facilitated by the immunological tools that are now available, including murine genetic models and human and murine specific tetramers. © 2016 The Authors. Immunology published by John Wiley & Sons Ltd.

The African Turquoise Killifish: A Model for Exploring Vertebrate Aging and Diseases in the Fast Lane.

PubMed

Harel, Itamar; Brunet, Anne

2015-01-01

Why and how organisms age remains a mystery, and it defines one of the biggest challenges in biology. Aging is also the primary risk factor for many human pathologies, such as cancer, diabetes, cardiovascular diseases, and neurodegenerative diseases. Thus, manipulating the aging rate and potentially postponing the onset of these devastating diseases could have a tremendous impact on human health. Recent studies, relying primarily on nonvertebrate short-lived model systems, have shown the importance of both genetic and environmental factors in modulating the aging rate. However, relatively little is known about aging in vertebrates or what processes may be unique and specific to these complex organisms. Here we discuss how advances in genomics and genome editing have significantly expanded our ability to probe the aging process in a vertebrate system. We highlight recent findings from a naturally short-lived vertebrate, the African turquoise killifish, which provides an attractive platform for exploring mechanisms underlying vertebrate aging and age-related diseases. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

Differential Diagnosis of Erythmato-Squamous Diseases Using Classification and Regression Tree.

PubMed

Maghooli, Keivan; Langarizadeh, Mostafa; Shahmoradi, Leila; Habibi-Koolaee, Mahdi; Jebraeily, Mohamad; Bouraghi, Hamid

2016-10-01

Differential diagnosis of Erythmato-Squamous Diseases (ESD) is a major challenge in the field of dermatology. The ESD diseases are placed into six different classes. Data mining is the process for detection of hidden patterns. In the case of ESD, data mining help us to predict the diseases. Different algorithms were developed for this purpose. we aimed to use the Classification and Regression Tree (CART) to predict differential diagnosis of ESD. we used the Cross Industry Standard Process for Data Mining (CRISP-DM) methodology. For this purpose, the dermatology data set from machine learning repository, UCI was obtained. The Clementine 12.0 software from IBM Company was used for modelling. In order to evaluation of the model we calculate the accuracy, sensitivity and specificity of the model. The proposed model had an accuracy of 94.84% (. 24.42) in order to correct prediction of the ESD disease. Results indicated that using of this classifier could be useful. But, it would be strongly recommended that the combination of machine learning methods could be more useful in terms of prediction of ESD.

Epidemiologic insights into pediatric kidney stone disease.

PubMed

Matlaga, Brian R; Schaeffer, Anthony J; Novak, Thomas E; Trock, Bruce J

2010-12-01

The epidemiology of pediatric kidney stone has not yet been as rigorously defined as that of adult kidney stone disease. Herein, we review our recent epidemiologic works characterizing pediatric stone disease using the Kids' Inpatient Database (KID). Specifically we investigated the age and gender distribution of pediatric kidney stone disease, changes in disease prevalence over time, and medical comorbidities associated with this disorder. We identified patients by International Classification of Disease 9th Edition (ICD-9) codes for renal and ureteral calculi as the primary diagnosis. Medical comorbidities were identified using specific comorbidity software. Statistical comparisons between children with and without stone disease were performed. In the first decade of life, stone disease was more prevalent among males than females; however, in the second decade of life females were more commonly affected. Of note, there was a significant increase in treated stone disease across both genders between 1997 and 2003. We also found that the risk of kidney stone diagnosis in children younger than 6 years of age was significantly associated with hypertension and diabetes mellitus. The gender distribution among pediatric stone formers varies significantly by age, although overall females have a greater prevalence than males. There is also a strong association of stone disease and both diabetes and hypertension, although this was only observed in children less than 6 years of age. Taken all together, these findings suggest that urolithiasis in the young child is a complex systemic disease process.

Spectroturbidimitry as applied to biomedical and immunological investigations

NASA Astrophysics Data System (ADS)

Shchyogolev, Sergei Y.; Khlebtsov, Nikolai G.; Schwartsburd, Boris I.

1993-06-01

Methods of optical shifting spectroscopy and laser nephelometry may be used to register antigen-antibody reaction. Usage of laser nephelometry in serodiagnostics, characteristics of a specific step in humoral immune reaction in infections, postinfectious and postinoculation processes response and immunity tension in some infectious diseases were investigated.

Neurobehavioral Mechanisms of Temporal Processing Deficits In Parkinson’s Disease

DTIC Science & Technology

2011-01-01

Foam padding was used to limit head motion. Auditory stimuli were delivered binaurally through a headphone that together with earplugs attenuated...core timer.’ Specifically, by the striatal beat frequency (SBF) model, Figure 5. Percent signal change in regions showing abnormal activation OFF

Assessing cognitive functioning in ALS: A focus on frontal lobe processes.

PubMed

Gillingham, S M; Yunusova, Y; Ganda, A; Rogaeva, E; Black, S E; Stuss, D T; Zinman, L

2017-05-01

It is generally acknowledged that at least 50% of individuals with amyotrophic lateral sclerosis (ALS) will exhibit cognitive deficits outside of the characteristic motor neuron involvement. However, a specific cognitive profile has been difficult to ascertain due to disease-related testing barriers and limitations in the sensitivity and specificity of available assessment methods. This study assessed the level of functioning of extramotor frontal cognitive processes in ALS, and the amount of change in the functioning in these processes over time as disease progresses. Empirical tests validated for a model of frontal lobe functioning were modified into an assessment battery appropriate for individuals with ALS in a clinical setting (the ALS-CFB, Computerised Frontal Battery). Twenty ALS participants and 36 age- and education-matched neurologically healthy controls were tested, and a sub-sample of each group (11 ALS and 20 controls) re-tested after approximately nine months. Compared to standard neuropsychological screening tests that did not show a difference between ALS participants and healthy controls, the ALS-CFB illustrated a profile of extramotor frontal dysfunction involving energisation (preparing the neural system to respond) and executive functions, a profile that may be indicative of the nature of neurodegeneration in ALS.

SP and KLF Transcription Factors in Digestive Physiology and Diseases.

PubMed

Kim, Chang-Kyung; He, Ping; Bialkowska, Agnieszka B; Yang, Vincent W

2017-06-01

Specificity proteins (SPs) and Krüppel-like factors (KLFs) belong to the family of transcription factors that contain conserved zinc finger domains involved in binding to target DNA sequences. Many of these proteins are expressed in different tissues and have distinct tissue-specific activities and functions. Studies have shown that SPs and KLFs regulate not only physiological processes such as growth, development, differentiation, proliferation, and embryogenesis, but pathogenesis of many diseases, including cancer and inflammatory disorders. Consistently, these proteins have been shown to regulate normal functions and pathobiology in the digestive system. We review recent findings on the tissue- and organ-specific functions of SPs and KLFs in the digestive system including the oral cavity, esophagus, stomach, small and large intestines, pancreas, and liver. We provide a list of agents under development to target these proteins. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Lipids in the cell: organisation regulates function.

PubMed

Santos, Ana L; Preta, Giulio

2018-06-01

Lipids are fundamental building blocks of all cells and play important roles in the pathogenesis of different diseases, including inflammation, autoimmune disease, cancer, and neurodegeneration. The lipid composition of different organelles can vary substantially from cell to cell, but increasing evidence demonstrates that lipids become organised specifically in each compartment, and this organisation is essential for regulating cell function. For example, lipid microdomains in the plasma membrane, known as lipid rafts, are platforms for concentrating protein receptors and can influence intra-cellular signalling. Lipid organisation is tightly regulated and can be observed across different model organisms, including bacteria, yeast, Drosophila, and Caenorhabditis elegans, suggesting that lipid organisation is evolutionarily conserved. In this review, we summarise the importance and function of specific lipid domains in main cellular organelles and discuss recent advances that investigate how these specific and highly regulated structures contribute to diverse biological processes.

Addressing implementation challenges during guideline development - a case study of Swedish national guidelines for methods of preventing disease.

PubMed

Richter-Sundberg, Linda; Kardakis, Therese; Weinehall, Lars; Garvare, Rickard; Nyström, Monica E

2015-01-22

Many of the world's life threatening diseases (e.g. cancer, heart disease, stroke) could be prevented by eliminating life-style habits such as tobacco use, unhealthy diet, physical inactivity and excessive alcohol use. Incorporating evidence-based research on methods to change unhealthy lifestyle habits in clinical practice would be equally valuable. However gaps between guideline development and implementation are well documented, with implications for health care quality, safety and effectiveness. The development phase of guidelines has been shown to be important both for the quality in guideline content and for the success of implementation. There are, however, indications that guidelines related to general disease prevention methods encounter specific barriers compared to guidelines that are diagnosis-specific. In 2011 the Swedish National board for Health and Welfare launched guidelines with a preventive scope. The aim of this study was to investigate how implementation challenges were addressed during the development process of these disease preventive guidelines. Seven semi-structured interviews were conducted with members of the guideline development management group. Archival data detailing the guideline development process were also collected and used in the analysis. Qualitative data were analysed using content analysis as the analytical framework. The study identified several strategies and approaches that were used to address implementation challenges during guideline development. Four themes emerged from the analysis: broad agreements and consensus about scope and purpose; a formalized and structured development procedure; systematic and active involvement of stakeholders; and openness and transparency in the specific guideline development procedure. Additional factors concerning the scope of prevention and the work environment of guideline developers were perceived to influence the possibilities to address implementation issues. This case study provides examples of how guideline developers perceive and approach the issue of implementation during the development and early launch of prevention guidelines. Models for guideline development could benefit from an initial assessment of how the guideline topic, its target context and stakeholders will affect the upcoming implementation.

Deciphering membrane-associated molecular processes in target tissue of autoimmune uveitis by label-free quantitative mass spectrometry.

PubMed

Hauck, Stefanie M; Dietter, Johannes; Kramer, Roxane L; Hofmaier, Florian; Zipplies, Johanna K; Amann, Barbara; Feuchtinger, Annette; Deeg, Cornelia A; Ueffing, Marius

2010-10-01

Autoimmune uveitis is a blinding disease presenting with autoantibodies against eye-specific proteins as well as autoagressive T cells invading and attacking the immune-privileged target tissue retina. The molecular events enabling T cells to invade and attack the tissue have remained elusive. Changes in membrane protein expression patterns between diseased and healthy stages are especially interesting because initiating events of disease will most likely occur at membranes. Since disease progression is accompanied with a break-down of the blood-retinal barrier, serum-derived proteins mask the potential target tissue-related changes. To overcome this limitation, we used membrane-enriched fractions derived from retinas of the only available spontaneous animal model for the disease equine recurrent uveitis, and compared expression levels by a label-free LC-MSMS-based strategy to healthy control samples. We could readily identify a total of 893 equine proteins with 57% attributed to the Gene Ontology project term "membrane." Of these, 179 proteins were found differentially expressed in equine recurrent uveitis tissue. Pathway enrichment analyses indicated an increase in proteins related to antigen processing and presentation, TNF receptor signaling, integrin cell surface interactions and focal adhesions. Additionally, loss of retina-specific proteins reflecting decrease of vision was observed as well as an increase in Müller glial cell-specific proteins indicating glial reactivity. Selected protein candidates (caveolin 1, integrin alpha 1 and focal adhesion kinase) were validated by immunohistochemistry and tissue staining pattern pointed to a significant increase of these proteins at the level of the outer limiting membrane which is part of the outer blood-retinal barrier. Taken together, the membrane enrichment in combination with LC-MSMS-based label-free quantification greatly increased the sensitivity of the comparative tissue profiling and resulted in detection of novel molecular pathways related to equine recurrent uveitis.

Predictive Biomarkers for Linking Disease Pathology and Drug Effect.

PubMed

Mayer, Bernd; Heinzel, Andreas; Lukas, Arno; Perco, Paul

2017-01-01

Productivity in drug R&D continues seeing significant attrition in clinical stage testing. Approval of new molecular entities proceeds with slow pace specifically when it comes to chronic, age-related diseases, calling for new conceptual approaches, methodological implementation and organizational adoption in drug development. Detailed phenotyping of disease presentation together with comprehensive representation of drug mechanism of action is considered as a path forward, and a big data spectrum has become available covering behavioral, clinical and molecular characteristics, the latter combining reductionist and explorative strategies. On this basis integrative analytics in the realm of Systems Biology has emerged, essentially aiming at traversing associations into causal relationships for bridging molecular disease specifics and clinical phenotype surrogates and finally explaining drug response and outcome. From a conceptual perspective bottom-up modeling approaches are available, with dynamical hierarchies as formalism capable of describing clinical findings as emergent properties of an underlying molecular process network comprehensively resembling disease pathology. In such representation biomarker candidates serve as proxy of a molecular process set, at the interface of a corresponding representation of drug mechanism of action allowing patient stratification and prediction of drug response. In practical implementation network analytics on a protein coding gene level has provided a number of example cases for matching disease presentation and drug molecular effect, and workflows combining computational hypothesis generation and experimental evaluation have become available for systematically optimizing biomarker candidate selection. With biomarker-based enrichment strategies in adaptive clinical trials, implementation routes for tackling development attrition are provided. Predictive biomarkers add precision in drug development and as companion diagnostics in clinical practice. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Adolescents with congenital heart disease: their opinions about the preparation for transfer to adult care.

PubMed

Burström, Åsa; Bratt, Ewa-Lena; Frenckner, Björn; Nisell, Margret; Hanséus, Katarina; Rydberg, Annika; Öjmyr-Joelsson, Maria

2017-07-01

The aim of the study was to explore what adolescents with congenital heart disease (CHD) view as important in the preparation for the transfer to adult care. We performed interviews in four focus groups with adolescents (14-18 years old) at four university hospitals in Sweden. Data was analysed using qualitative content analysis. The analysis revealed one main category; Becoming a manager of the condition and four subcategories; Sufficient knowledge about the health, Be a participant in the care, Parental support, and Communicate with others about the health. The adolescents' ages differentiated the discussion in the groups. The older adolescents seemed to have more interest in transition planning, information and transfer. The younger described more frustrations about communication and handling the disease. To become a manager of the CHD in daily life, the adolescents want disease specific knowledge, which should be communicated in a developmentally appropriate way. Adolescents want to participate and be involved in the transition process. They need support and guidance in how to communicate their CHD. Parental support is fundamental but it change over time. Moreover, peer-support is becoming more significant during the transition process. What is Known: • Transition during adolescence and transfer to adult care for adolescents with CHD is complex, and there is a shift in roles. • Adolescents often have poor knowledge and understanding about their heart condition and the consequences. What is New: • Adolescents call for disease specific information regarding health issues of importance for them in daily life. • Communicating the disease with other is a challenge- peer support from other adolescents with CHD could be a facilitator.

The Screening of Genes Sensitive to Long-Term, Low-Level Microwave Exposure and Bioinformatic Analysis of Potential Correlations to Learning and Memory.

PubMed

Zhao, Ya Li; Li, Ying Xian; Ma, Hong Bo; Li, Dong; Li, Hai Liang; Jiang, Rui; Kan, Guang Han; Yang, Zhen Zhong; Huang, Zeng Xin

2015-08-01

To gain a better understanding of gene expression changes in the brain following microwave exposure in mice. This study hopes to reveal mechanisms contributing to microwave-induced learning and memory dysfunction. Mice were exposed to whole body 2100 MHz microwaves with specific absorption rates (SARs) of 0.45 W/kg, 1.8 W/kg, and 3.6 W/kg for 1 hour daily for 8 weeks. Differentially expressing genes in the brains were screened using high-density oligonucleotide arrays, with genes showing more significant differences further confirmed by RT-PCR. The gene chip results demonstrated that 41 genes (0.45 W/kg group), 29 genes (1.8 W/kg group), and 219 genes (3.6 W/kg group) were differentially expressed. GO analysis revealed that these differentially expressed genes were primarily involved in metabolic processes, cellular metabolic processes, regulation of biological processes, macromolecular metabolic processes, biosynthetic processes, cellular protein metabolic processes, transport, developmental processes, cellular component organization, etc. KEGG pathway analysis showed that these genes are mainly involved in pathways related to ribosome, Alzheimer's disease, Parkinson's disease, long-term potentiation, Huntington's disease, and Neurotrophin signaling. Construction of a protein interaction network identified several important regulatory genes including synbindin (sbdn), Crystallin (CryaB), PPP1CA, Ywhaq, Psap, Psmb1, Pcbp2, etc., which play important roles in the processes of learning and memorye. Long-term, low-level microwave exposure may inhibit learning and memory by affecting protein and energy metabolic processes and signaling pathways relating to neurological functions or diseases. Copyright © 2015 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

Lymph nodes fine needle cytology in the diagnosis of infectious diseases: clinical settings.

PubMed

Natella, Valentina; Cozzolino, Immacolata; Sosa Fernandez, Laura Virginia; Vigliar, Elena

2012-01-01

Lymph node reactive hyperplasia, caused by specific infectious etiologic factors, represents the most frequent cause of enlarged peripheral lymph nodes. The main infectious agents are viruses, pyogenic bacteria, mycobacteria, fungi and protozoa that may determine unspecific or specific pathological entities, such as cat-scratch disease, toxoplasmosis or infectious mononucleosis. Lymph node fine needle cytology (FNC) is a safe, simple, cost-effective and efficient technique that quickly provides information about the cell population and the nature of the process. FNC can also provide suitable material for ancillary techniques, such as flow cytometry, immunocytochemistry, molecular biology and microbiological examinations. This study focuses on the cytological features of benign lymphadenopathy of infectious origin and their possible contribution to the clinical setting definition of corresponding patients.

The tropics, science, and leishmaniasis: an analysis of the circulation of knowledge and asymmetries.

PubMed

Jogas, Denis Guedes

2017-01-01

The article investigates the process of circulation of knowledge which occurred during the first decades of the twentieth century between the South American researchers Edmundo Escomel (Peru) and Alfredo Da Matta (Brazil) and the Europeans Alphonse Laveran (France) and Patrick Manson (England) with regard to the definition and validation of espundia as a disease specific to South America, while simultaneously the need to insert this illness into the newly created group of diseases called the "leishmaniasis" was proposed. Sharing recent concerns in considering historical research beyond the limits imposed by the Nation-state as a category that organizes narratives, it dialogs with some apologists of global and transnational history, situating this specific case within this analytical perspective.

Targets for therapy in sarcomeric cardiomyopathies

PubMed Central

Tardiff, Jil C.; Carrier, Lucie; Bers, Donald M.; Poggesi, Corrado; Ferrantini, Cecilia; Coppini, Raffaele; Maier, Lars S.; Ashrafian, Houman; Huke, Sabine; van der Velden, Jolanda

2015-01-01

To date, no compounds or interventions exist that treat or prevent sarcomeric cardiomyopathies. Established therapies currently improve the outcome, but novel therapies may be able to more fundamentally affect the disease process and course. Investigations of the pathomechanisms are generating molecular insights that can be useful for the design of novel specific drugs suitable for clinical use. As perturbations in the heart are stage-specific, proper timing of drug treatment is essential to prevent initiation and progression of cardiac disease in mutation carrier individuals. In this review, we emphasize potential novel therapies which may prevent, delay, or even reverse hypertrophic cardiomyopathy caused by sarcomeric gene mutations. These include corrections of genetic defects, altered sarcomere function, perturbations in intracellular ion homeostasis, and impaired myocardial energetics. PMID:25634554

MicroRNAs in the intracellular space, regulation of organelle specific pathways in health and disease.

PubMed

Nguyen, Thao T; Brenu, Ekua W; Staines, Don R; Marshall-Gradisnik, Sonya M

2014-01-01

MicroRNAs (miRNA) are small (~22 nucleotide] non-coding RNA molecules originally characterised as nonsense or junk DNA. Emerging research suggests that these molecules have diverse regulatory roles in an array of molecular, cellular and physiological processes. MiRNAs are versatile and highly stable molecules, therefore, they are able to exist as intracellular or extracellular miRNAs. The purpose of this paper is to review the function and role of miRNAs in the intracellular space with specific focus on the interactions between miRNAs and organelles such as the mitochondria and the rough endoplasmic reticulum. Understanding the role of miRNAs in the intracellular space may be vital in understanding the mechanism of certain diseases.

De-boned beef - an example of a commodity for which specific standards could be developed to ensure an appropriate level of protection for international trade.

PubMed

Thomson, G R; Leyland, T J; Donaldson, A I

2009-03-01

De-boned beef from which lymph nodes and risk material associated with bovine spongiform encephalopathy have been removed, is a product which can be produced for safe international trade irrespective of whether the locality of production is recognized as free from so-called transboundary diseases or not. Further processing of such beef provides an additional safety factor. However, this approach requires specific control measures being in place, supported by appropriate auditing and certification procedures. This document presents the arguments supporting this concept and details how safety in respect of both animal diseases and human food safety can be achieved using an integrated hazard analysis and critical control points approach.

Legume carotenoids.

PubMed

Sri Kantha, S; Erdman, J W

1987-01-01

In recent years, the results of research studies have suggested a positive beneficial relationship between a vegetarian-based diet and low incidence of diseases, including coronary heart disease, cancer, obesity, dental caries, and osteoporosis. beta-Carotene has specifically been suggested as a nutrient with antitumorigenic properties. In this regard there is a need to evaluate the carotenoid content of foods. Legumes are one of the staple components of a vegetarian diet. This review specifically surveys the prevalence of carotenoids in food and forage legumes. In addition, the methods available for carotenoid analysis are discussed; factors affecting the determination of carotenoid content during maturation, germination, processing and storage are identified; research areas which have been inadequately explored are identified; and suggestions are made for future lines of investigation.

Development of a disease-specific quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency (HAE-QoL): Spanish multi-centre research project.

PubMed

Prior, Nieves; Remor, Eduardo; Gómez-Traseira, Carmen; López-Serrano, Concepción; Cabañas, Rosario; Contreras, Javier; Campos, Ángel; Cardona, Victoria; Cimbollek, Stefan; González-Quevedo, Teresa; Guilarte, Mar; de Rojas, Dolores Hernández Fernández; Marcos, Carmen; Rubio, María; Tejedor-Alonso, Miguel Ángel; Caballero, Teresa

2012-07-20

There is a need for a disease-specific instrument for assessing health-related quality of life in adults with hereditary angioedema due to C1 inhibitor deficiency, a rare, disabling and life-threatening disease. In this paper we report the protocol for the development and validation of a specific questionnaire, with details on the results of the process of item generation, domain selection, and the expert and patient rating phase. Semi-structured interviews were completed by 45 patients with hereditary angioedema and 8 experts from 8 regions in Spain. A qualitative content analysis of the responses was carried out. Issues raised by respondents were grouped into categories. Content analysis identified 240 different responses, which were grouped into 10 conceptual domains. Sixty- four items were generated. A total of 8 experts and 16 patients assessed the items for clarity, relevance to the disease, and correct dimension assignment. The preliminary version of the specific health-related quality of life questionnaire for hereditary angioedema (HAE-QoL v 1.1) contained 44 items grouped into 9 domains. To the best of our knowledge, this is the first multi-centre research project that aims to develop a specific health-related quality of life questionnaire for adult patients with hereditary angioedema due to C1 inhibitor deficiency. A preliminary version of the specific HAE-QoL questionnaire was obtained. The qualitative analysis of interviews together with the expert and patient rating phase helped to ensure content validity. A pilot study will be performed to assess the psychometric properties of the questionnaire and to decide on the final version.

Implications of the Institute of Medicine Report: Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease.

PubMed

Wagner, J A; Ball, J R

2015-07-01

The Institute of Medicine (IOM) released a groundbreaking 2010 report, Evaluation of Biomarkers and Surrogate Endpoints in Chronic Disease. Key recommendations included a harmonized scientific process and a general framework for biomarker evaluation with three interrelated steps: (1) Analytical validation -- is the biomarker measurement accurate? (2) Qualification -- is the biomarker associated with the clinical endpoint of concern? (3) Utilization -- what is the specific context of the proposed use? © 2015 American Society for Clinical Pharmacology and Therapeutics.

Impaired activity-dependent neural circuit assembly and refinement in autism spectrum disorder genetic models

PubMed Central

Doll, Caleb A.; Broadie, Kendal

2014-01-01

Early-use activity during circuit-specific critical periods refines brain circuitry by the coupled processes of eliminating inappropriate synapses and strengthening maintained synapses. We theorize these activity-dependent (A-D) developmental processes are specifically impaired in autism spectrum disorders (ASDs). ASD genetic models in both mouse and Drosophila have pioneered our insights into normal A-D neural circuit assembly and consolidation, and how these developmental mechanisms go awry in specific genetic conditions. The monogenic fragile X syndrome (FXS), a common cause of heritable ASD and intellectual disability, has been particularly well linked to defects in A-D critical period processes. The fragile X mental retardation protein (FMRP) is positively activity-regulated in expression and function, in turn regulates excitability and activity in a negative feedback loop, and appears to be required for the A-D remodeling of synaptic connectivity during early-use critical periods. The Drosophila FXS model has been shown to functionally conserve the roles of human FMRP in synaptogenesis, and has been centrally important in generating our current mechanistic understanding of the FXS disease state. Recent advances in Drosophila optogenetics, transgenic calcium reporters, highly-targeted transgenic drivers for individually-identified neurons, and a vastly improved connectome of the brain are now being combined to provide unparalleled opportunities to both manipulate and monitor A-D processes during critical period brain development in defined neural circuits. The field is now poised to exploit this new Drosophila transgenic toolbox for the systematic dissection of A-D mechanisms in normal versus ASD brain development, particularly utilizing the well-established Drosophila FXS disease model. PMID:24570656

Endophytic bacterial community of grapevine leaves influenced by sampling date and phytoplasma infection process

PubMed Central

2014-01-01

Background Endophytic bacteria benefit host plant directly or indirectly, e.g. by biocontrol of the pathogens. Up to now, their interactions with the host and with other microorganisms are poorly understood. Consequently, a crucial step for improving the knowledge of those relationships is to determine if pathogens or plant growing season influence endophytic bacterial diversity and dynamic. Results Four healthy, four phytoplasma diseased and four recovered (symptomatic plants that spontaneously regain a healthy condition) grapevine plants were sampled monthly from June to October 2010 in a vineyard in north-western Italy. Metagenomic DNA was extracted from sterilized leaves and the endophytic bacterial community dynamic and diversity were analyzed by taxon specific real-time PCR, Length-Heterogeneity PCR and genus-specific PCR. These analyses revealed that both sampling date and phytoplasma infection influenced the endophytic bacterial composition. Interestingly, in June, when the plants are symptomless and the pathogen is undetectable (i) the endophytic bacterial community associated with diseased grapevines was different from those in the other sampling dates, when the phytoplasmas are detectable inside samples; (ii) the microbial community associated with recovered plants differs from that living inside healthy and diseased plants. Interestingly, LH-PCR database identified bacteria previously reported as biocontrol agents in the examined grapevines. Of these, Burkholderia, Methylobacterium and Pantoea dynamic was influenced by the phytoplasma infection process and seasonality. Conclusion Results indicated that endophytic bacterial community composition in grapevine is correlated to both phytoplasma infection and sampling date. For the first time, data underlined that, in diseased plants, the pathogen infection process can decrease the impact of seasonality on community dynamic. Moreover, based on experimental evidences, it was reasonable to hypothesize that after recovery the restructured microbial community could maintain the main structure between seasons. PMID:25048741

Endophytic bacterial community of grapevine leaves influenced by sampling date and phytoplasma infection process.

PubMed

Bulgari, Daniela; Casati, Paola; Quaglino, Fabio; Bianco, Piero A

2014-07-21

Endophytic bacteria benefit host plant directly or indirectly, e.g. by biocontrol of the pathogens. Up to now, their interactions with the host and with other microorganisms are poorly understood. Consequently, a crucial step for improving the knowledge of those relationships is to determine if pathogens or plant growing season influence endophytic bacterial diversity and dynamic. Four healthy, four phytoplasma diseased and four recovered (symptomatic plants that spontaneously regain a healthy condition) grapevine plants were sampled monthly from June to October 2010 in a vineyard in north-western Italy. Metagenomic DNA was extracted from sterilized leaves and the endophytic bacterial community dynamic and diversity were analyzed by taxon specific real-time PCR, Length-Heterogeneity PCR and genus-specific PCR. These analyses revealed that both sampling date and phytoplasma infection influenced the endophytic bacterial composition. Interestingly, in June, when the plants are symptomless and the pathogen is undetectable (i) the endophytic bacterial community associated with diseased grapevines was different from those in the other sampling dates, when the phytoplasmas are detectable inside samples; (ii) the microbial community associated with recovered plants differs from that living inside healthy and diseased plants. Interestingly, LH-PCR database identified bacteria previously reported as biocontrol agents in the examined grapevines. Of these, Burkholderia, Methylobacterium and Pantoea dynamic was influenced by the phytoplasma infection process and seasonality. Results indicated that endophytic bacterial community composition in grapevine is correlated to both phytoplasma infection and sampling date. For the first time, data underlined that, in diseased plants, the pathogen infection process can decrease the impact of seasonality on community dynamic. Moreover, based on experimental evidences, it was reasonable to hypothesize that after recovery the restructured microbial community could maintain the main structure between seasons.

Proteostasis and Diseases of the Motor Unit.

PubMed

Rinaldi, Carlo; Mäger, Imre; Wood, Matthew J

2016-01-01

The accumulation in neurons of aberrant protein species, the pathological hallmark of many neurodegenerative diseases, results from a global impairment of key cellular processes governing protein synthesis/degradation and repair mechanisms, also known as the proteostasis network (PN). The growing number of connections between dysfunction of this intricate network of pathways and diseases of the motor unit, where both motor neurons and muscle are primarily affected, has provided momentum to investigate the muscle- and motor neuron-specific response to physiological and pathological stressors and to explore the therapeutic opportunities that manipulation of this process may offer. Furthermore, these diseases offer an unparalleled opportunity to deepen our understanding of the molecular mechanisms behind the intertissue communication and transfer of signals of proteostasis. The most compelling aspect of these investigations is their immediate potential for therapeutic impact: targeting muscle to stem degeneration of the motor unit would represent a dramatic paradigm therapeutic shift for treating these devastating diseases. Here we will review the current state of the art of the research on the alterations of the PN in diseases of the motor unit and its potential to result in effective treatments for these devastating neuromuscular disorders.

Genomic background-related activation of microglia and reduced β-amyloidosis in a mouse model of Alzheimer's disease.

PubMed

Fröhlich, Christina; Paarmann, Kristin; Steffen, Johannes; Stenzel, Jan; Krohn, Markus; Heinze, Hans-Jochen; Pahnke, Jens

2013-03-01

Alzheimer's disease (AD) is by far the most common neurodegenerative disease. AD is histologically characterized not only by extracellular senile plaques and vascular deposits consisting of β-amyloid (Aβ) but also by accompanying neuroinflammatory processes involving the brain's microglia. The importance of the microglia is still in controversial discussion, which currently favors a protective function in disease progression. Recent findings by different research groups highlighted the importance of strain-specific and mitochondria-specific genomic variations in mouse models of cerebral β-amyloidosis. Here, we want to summarize our previously presented data and add new results that draw attention towards the consideration of strain-specific genomic alterations in the setting of APP transgenes. We present data from APP-transgenic mice in commonly used C57Bl/6J and FVB/N genomic backgrounds and show a direct influence on the kinetics of Aβ deposition and the activity of resident microglia. Plaque size, plaque deposition rate and the total amount of Aβ are highest in C57Bl/6J mice as compared to the FVB/N genomic background, which can be explained at least partially by a reduced microglia activity towards amyloid deposits in the C57BL/6J strain.

[Signaling mechanisms involved in resolution of inflammation].

PubMed

Cervantes-Villagrana, Rodolfo Daniel; Cervantes-Villagrana, Alberto Rafael; Presno-Bernal, José Miguel

2014-01-01

Inflammation is a physiological process, which eliminates pathogens and induces repair of damaged tissue. This process is controlled by negative feedback mechanisms, but if the inflammation persists, it generates a deleterious autoimmune process or can to contribute with diseases such as obesity or cancer. The inflammation resolution involves mechanisms such as decrease of proliferation and maturation of immune cells, phagocytosis and apoptosis of immune cells, and decrease of proinflammatory mediators. Therefore, is relevant to study the physiological effects of specific receptors that participate in inflammation resolution and the design of specific agonists as conventional anti-inflammatory therapeutics, without dramatic collateral effects. In this review, we study some mechanisms associated with inflammation inhibition, particularly the transduction of receptors for ligands with anti-inflammatory effects and that are relevant for their potential therapeutic.

The usefulness of administrative databases for identifying disease cohorts is increased with a multivariate model.

PubMed

van Walraven, Carl; Austin, Peter C; Manuel, Douglas; Knoll, Greg; Jennings, Allison; Forster, Alan J

2010-12-01

Administrative databases commonly use codes to indicate diagnoses. These codes alone are often inadequate to accurately identify patients with particular conditions. In this study, we determined whether we could quantify the probability that a person has a particular disease-in this case renal failure-using other routinely collected information available in an administrative data set. This would allow the accurate identification of a disease cohort in an administrative database. We determined whether patients in a randomly selected 100,000 hospitalizations had kidney disease (defined as two or more sequential serum creatinines or the single admission creatinine indicating a calculated glomerular filtration rate less than 60 mL/min/1.73 m²). The independent association of patient- and hospitalization-level variables with renal failure was measured using a multivariate logistic regression model in a random 50% sample of the patients. The model was validated in the remaining patients. Twenty thousand seven hundred thirteen patients had kidney disease (20.7%). A diagnostic code of kidney disease was strongly associated with kidney disease (relative risk: 34.4), but the accuracy of the code was poor (sensitivity: 37.9%; specificity: 98.9%). Twenty-nine patient- and hospitalization-level variables entered the kidney disease model. This model had excellent discrimination (c-statistic: 90.1%) and accurately predicted the probability of true renal failure. The probability threshold that maximized sensitivity and specificity for the identification of true kidney disease was 21.3% (sensitivity: 80.0%; specificity: 82.2%). Multiple variables available in administrative databases can be combined to quantify the probability that a person has a particular disease. This process permits accurate identification of a disease cohort in an administrative database. These methods may be extended to other diagnoses or procedures and could both facilitate and clarify the use of administrative databases for research and quality improvement. Copyright © 2010 Elsevier Inc. All rights reserved.

Emerging prion disease drives host selection in a wildlife population

USGS Publications Warehouse

Robinson, Stacie J.; Samuel, Michael D.; Johnson, Chad J.; Adams, Marie; McKenzie, Debbie I.

2012-01-01

Infectious diseases are increasingly recognized as an important force driving population dynamics, conservation biology, and natural selection in wildlife populations. Infectious agents have been implicated in the decline of small or endangered populations and may act to constrain population size, distribution, growth rates, or migration patterns. Further, diseases may provide selective pressures that shape the genetic diversity of populations or species. Thus, understanding disease dynamics and selective pressures from pathogens is crucial to understanding population processes, managing wildlife diseases, and conserving biological diversity. There is ample evidence that variation in the prion protein gene (PRNP) impacts host susceptibility to prion diseases. Still, little is known about how genetic differences might influence natural selection within wildlife populations. Here we link genetic variation with differential susceptibility of white-tailed deer to chronic wasting disease (CWD), with implications for fitness and disease-driven genetic selection. We developed a single nucleotide polymorphism (SNP) assay to efficiently genotype deer at the locus of interest (in the 96th codon of the PRNP gene). Then, using a Bayesian modeling approach, we found that the more susceptible genotype had over four times greater risk of CWD infection; and, once infected, deer with the resistant genotype survived 49% longer (8.25 more months). We used these epidemiological parameters in a multi-stage population matrix model to evaluate relative fitness based on genotype-specific population growth rates. The differences in disease infection and mortality rates allowed genetically resistant deer to achieve higher population growth and obtain a long-term fitness advantage, which translated into a selection coefficient of over 1% favoring the CWD-resistant genotype. This selective pressure suggests that the resistant allele could become dominant in the population within an evolutionarily short time frame. Our work provides a rare example of a quantifiable disease-driven selection process in a wildlife population, demonstrating the potential for infectious diseases to alter host populations. This will have direct bearing on the epidemiology, dynamics, and future trends in CWD transmission and spread. Understanding genotype-specific epidemiology will improve predictive models and inform management strategies for CWD-affected cervid populations.

Specific Amino Acids Affect Cardiovascular Diseases and Atherogenesis via Protection against Macrophage Foam Cell Formation: Review Article.

PubMed

Grajeda-Iglesias, Claudia; Aviram, Michael

2018-06-20

The strong relationship between cardiovascular diseases (CVD), atherosclerosis, and endogenous or exogenous lipids has been recognized for decades, underestimating the contribution of other dietary components, such as amino acids, to the initiation of the underlying inflammatory disease. Recently, specific amino acids have been associated with incident cardiovascular disorders, suggesting their significant role in the pathogenesis of CVD. Special attention has been paid to the group of branched-chain amino acids (BCAA), leucine, isoleucine, and valine, since their plasma values are frequently found in high concentrations in individuals with CVD risk. Nevertheless, dietary BCAA, leucine in particular, have been associated with improved indicators of atherosclerosis. Therefore, their potential role in the process of atherogenesis and concomitant CVD development remains unclear. Macrophages play pivotal roles in the development of atherosclerosis. They can accumulate high amounts of circulating lipids, through a process known as macrophage foam cell formation, and initiate the atherogenesis process. We have recently screened for anti- or pro-atherogenic amino acids in the macrophage model system. Our study showed that glycine, cysteine, alanine, leucine, glutamate, and glutamine significantly affected macrophage atherogenicity mainly through modulation of the cellular triglyceride metabolism. The anti-atherogenic properties of glycine and leucine, and the pro-atherogenic effects of glutamine, were also confirmed in vivo. Further investigation is warranted to define the role of these amino acids in atherosclerosis and CVD, which may serve as a basis for the development of anti-atherogenic nutritional and therapeutic approaches.

Molecular magnetic resonance imaging of atherosclerotic vessel wall disease.

PubMed

Nörenberg, Dominik; Ebersberger, Hans U; Diederichs, Gerd; Hamm, Bernd; Botnar, René M; Makowski, Marcus R

2016-03-01

Molecular imaging aims to improve the identification and characterization of pathological processes in vivo by visualizing the underlying biological mechanisms. Molecular imaging techniques are increasingly used to assess vascular inflammation, remodeling, cell migration, angioneogenesis and apoptosis. In cardiovascular diseases, molecular magnetic resonance imaging (MRI) offers new insights into the in vivo biology of pathological vessel wall processes of the coronary and carotid arteries and the aorta. This includes detection of early vascular changes preceding plaque development, visualization of unstable plaques and assessment of response to therapy. The current review focuses on recent developments in the field of molecular MRI to characterise different stages of atherosclerotic vessel wall disease. A variety of molecular MR-probes have been developed to improve the non-invasive detection and characterization of atherosclerotic plaques. Specifically targeted molecular probes allow for the visualization of key biological steps in the cascade leading to the development of arterial vessel wall lesions. Early detection of processes which lead to the development of atherosclerosis and the identification of vulnerable atherosclerotic plaques may enable the early assessment of response to therapy, improve therapy planning, foster the prevention of cardiovascular events and may open the door for the development of patient-specific treatment strategies. Targeted MR-probes allow the characterization of atherosclerosis on a molecular level. Molecular MRI can identify in vivo markers for the differentiation of stable and unstable plaques. Visualization of early molecular changes has the potential to improve patient-individualized risk-assessment.

Differentially Coexpressed Disease Gene Identification Based on Gene Coexpression Network.

PubMed

Jiang, Xue; Zhang, Han; Quan, Xiongwen

2016-01-01

Screening disease-related genes by analyzing gene expression data has become a popular theme. Traditional disease-related gene selection methods always focus on identifying differentially expressed gene between case samples and a control group. These traditional methods may not fully consider the changes of interactions between genes at different cell states and the dynamic processes of gene expression levels during the disease progression. However, in order to understand the mechanism of disease, it is important to explore the dynamic changes of interactions between genes in biological networks at different cell states. In this study, we designed a novel framework to identify disease-related genes and developed a differentially coexpressed disease-related gene identification method based on gene coexpression network (DCGN) to screen differentially coexpressed genes. We firstly constructed phase-specific gene coexpression network using time-series gene expression data and defined the conception of differential coexpression of genes in coexpression network. Then, we designed two metrics to measure the value of gene differential coexpression according to the change of local topological structures between different phase-specific networks. Finally, we conducted meta-analysis of gene differential coexpression based on the rank-product method. Experimental results demonstrated the feasibility and effectiveness of DCGN and the superior performance of DCGN over other popular disease-related gene selection methods through real-world gene expression data sets.

Alternative splicing in plant immunity.

PubMed

Yang, Shengming; Tang, Fang; Zhu, Hongyan

2014-06-10

Alternative splicing (AS) occurs widely in plants and can provide the main source of transcriptome and proteome diversity in an organism. AS functions in a range of physiological processes, including plant disease resistance, but its biological roles and functional mechanisms remain poorly understood. Many plant disease resistance (R) genes undergo AS, and several R genes require alternatively spliced transcripts to produce R proteins that can specifically recognize pathogen invasion. In the finely-tuned process of R protein activation, the truncated isoforms generated by AS may participate in plant disease resistance either by suppressing the negative regulation of initiation of immunity, or by directly engaging in effector-triggered signaling. Although emerging research has shown the functional significance of AS in plant biotic stress responses, many aspects of this topic remain to be understood. Several interesting issues surrounding the AS of R genes, especially regarding its functional roles and regulation, will require innovative techniques and additional research to unravel.

Memory loss in Alzheimer's disease: implications for development of therapeutics

PubMed Central

Gold, Carl A; Budson, Andrew E

2009-01-01

Alzheimer's disease (AD) is a progressive neurodegenerative disease marked by a constellation of cognitive disturbances, the earliest and most prominent being impaired episodic memory. Episodic memory refers to the memory system that allows an individual to consciously retrieve a previously experienced item or episode of life. Many recent studies have focused on characterizing how AD pathology impacts particular aspects of episodic memory and underlying mental and neural processes. This review summarizes the findings of those studies and discusses the effects of current and promising treatments for AD on episodic memory. The goal of this review is to raise awareness of the strides that cognitive neuroscientists have made in understanding intact and dysfunctional memory. Knowledge of the specific memorial processes that are impaired in AD may be of great value to basic scientists developing novel therapies and to clinical researchers assessing the efficacy of those therapies. PMID:19086882

Review article: mitogen-activated protein kinases in chronic intestinal inflammation - targeting ancient pathways to treat modern diseases.

PubMed

Waetzig, G H; Schreiber, S

2003-07-01

Conventional treatment of chronic inflammatory disorders, including inflammatory bowel diseases, employs broad-range anti-inflammatory drugs. In order to reduce the side-effects and increase the efficacy of treatment, several strategies have been developed in the last decade to interfere with intercellular and intracellular inflammatory signalling processes. The highly conserved mitogen-activated protein kinase pathways regulate most cellular processes, particularly defence mechanisms such as stress reactions and inflammation. In this review, we provide an overview of the current knowledge of the specificity and interconnection of mitogen-activated protein kinase pathways, their functions in the gut immune system and published and ongoing studies on the role of mitogen-activated protein kinases in inflammatory bowel disease. The development of mitogen-activated protein kinase inhibitors and their use for the therapy of inflammatory disorders is a paradigm of the successful bridging of the gap between basic research and clinical practice.

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease.

PubMed

Baillie, J Kenneth; Bretherick, Andrew; Haley, Christopher S; Clohisey, Sara; Gray, Alan; Neyton, Lucile P A; Barrett, Jeffrey; Stahl, Eli A; Tenesa, Albert; Andersson, Robin; Brown, J Ben; Faulkner, Geoffrey J; Lizio, Marina; Schaefer, Ulf; Daub, Carsten; Itoh, Masayoshi; Kondo, Naoto; Lassmann, Timo; Kawai, Jun; Mole, Damian; Bajic, Vladimir B; Heutink, Peter; Rehli, Michael; Kawaji, Hideya; Sandelin, Albin; Suzuki, Harukazu; Satsangi, Jack; Wells, Christine A; Hacohen, Nir; Freeman, Thomas C; Hayashizaki, Yoshihide; Carninci, Piero; Forrest, Alistair R R; Hume, David A

2018-03-01

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn's disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits.

Shared activity patterns arising at genetic susceptibility loci reveal underlying genomic and cellular architecture of human disease

PubMed Central

Gray, Alan; Neyton, Lucile P. A.; Barrett, Jeffrey; Stahl, Eli A.; Tenesa, Albert; Andersson, Robin; Brown, J. Ben; Faulkner, Geoffrey J.; Lizio, Marina; Schaefer, Ulf; Daub, Carsten; Kondo, Naoto; Lassmann, Timo; Kawai, Jun; Kawaji, Hideya; Suzuki, Harukazu; Satsangi, Jack; Wells, Christine A.; Hacohen, Nir; Freeman, Thomas C.; Hayashizaki, Yoshihide; Forrest, Alistair R. R.; Hume, David A.

2018-01-01

Genetic variants underlying complex traits, including disease susceptibility, are enriched within the transcriptional regulatory elements, promoters and enhancers. There is emerging evidence that regulatory elements associated with particular traits or diseases share similar patterns of transcriptional activity. Accordingly, shared transcriptional activity (coexpression) may help prioritise loci associated with a given trait, and help to identify underlying biological processes. Using cap analysis of gene expression (CAGE) profiles of promoter- and enhancer-derived RNAs across 1824 human samples, we have analysed coexpression of RNAs originating from trait-associated regulatory regions using a novel quantitative method (network density analysis; NDA). For most traits studied, phenotype-associated variants in regulatory regions were linked to tightly-coexpressed networks that are likely to share important functional characteristics. Coexpression provides a new signal, independent of phenotype association, to enable fine mapping of causative variants. The NDA coexpression approach identifies new genetic variants associated with specific traits, including an association between the regulation of the OCT1 cation transporter and genetic variants underlying circulating cholesterol levels. NDA strongly implicates particular cell types and tissues in disease pathogenesis. For example, distinct groupings of disease-associated regulatory regions implicate two distinct biological processes in the pathogenesis of ulcerative colitis; a further two separate processes are implicated in Crohn’s disease. Thus, our functional analysis of genetic predisposition to disease defines new distinct disease endotypes. We predict that patients with a preponderance of susceptibility variants in each group are likely to respond differently to pharmacological therapy. Together, these findings enable a deeper biological understanding of the causal basis of complex traits. PMID:29494619

Leveraging Collaborative Filtering to Accelerate Rare Disease Diagnosis

PubMed Central

Shen, Feichen; Liu, Sijia; Wang, Yanshan; Wang, Liwei; Afzal, Naveed; Liu, Hongfang

2017-01-01

In the USA, rare diseases are defined as those affecting fewer than 200,000 patients at any given time. Patients with rare diseases are frequently misdiagnosed or undiagnosed which may due to the lack of knowledge and experience of care providers. We hypothesize that patients’ phenotypic information available in electronic medical records (EMR) can be leveraged to accelerate disease diagnosis based on the intuition that providers need to document associated phenotypic information to support the diagnosis decision, especially for rare diseases. In this study, we proposed a collaborative filtering system enriched with natural language processing and semantic techniques to assist rare disease diagnosis based on phenotypic characterization. Specifically, we leveraged four similarity measurements with two neighborhood algorithms on 2010-2015 Mayo Clinic unstructured large patient cohort and evaluated different approaches. Preliminary results demonstrated that the use of collaborative filtering with phenotypic information is able to stratify patients with relatively similar rare diseases. PMID:29854225

Leveraging Collaborative Filtering to Accelerate Rare Disease Diagnosis.

PubMed

Shen, Feichen; Liu, Sijia; Wang, Yanshan; Wang, Liwei; Afzal, Naveed; Liu, Hongfang

2017-01-01

In the USA, rare diseases are defined as those affecting fewer than 200,000 patients at any given time. Patients with rare diseases are frequently misdiagnosed or undiagnosed which may due to the lack of knowledge and experience of care providers. We hypothesize that patients' phenotypic information available in electronic medical records (EMR) can be leveraged to accelerate disease diagnosis based on the intuition that providers need to document associated phenotypic information to support the diagnosis decision, especially for rare diseases. In this study, we proposed a collaborative filtering system enriched with natural language processing and semantic techniques to assist rare disease diagnosis based on phenotypic characterization. Specifically, we leveraged four similarity measurements with two neighborhood algorithms on 2010-2015 Mayo Clinic unstructured large patient cohort and evaluated different approaches. Preliminary results demonstrated that the use of collaborative filtering with phenotypic information is able to stratify patients with relatively similar rare diseases.

Research, practice, and policy partnerships in pan-Canadian coalitions for cancer and chronic disease prevention.

PubMed

Manafò, Elizabeth; Petermann, Lisa; Lobb, Rebecca; Keen, Deb; Kerner, Jon

2011-01-01

To describe the development stages of the Coalitions Linking Action and Science for Prevention (CLASP) initiative of the Canadian Partnership Against Cancer to support research, practice, and policy coalitions focused on cancer and chronic disease prevention in Canada. Coalitions Linking Action and Science for Prevention was implemented in 3 stages. This article describes Stage 1 that consisted of an online concept-mapping consultation process, 3 topic specific networking and consultation workshops, and 3 context-specific networking, coalition development, and planning meetings. These were all completed using a participatory engagement approach to encourage knowledge exchange across jurisdictions and sectors in Canada. Toronto, Ontario; Calgary, Alberta; Montreal, Québec; and Ottawa, Ontario. More than 500 researchers, practitioners, and policy specialists were invited to take part in the first stage activities. (1) Participant-identified high-priority opportunities for strategic collaboration; (2) Cross-jurisdictional and cross-sector representation; and (3) Participant feedback on the CLASP processes and activities. Participants from Stage 1 activities were distributed across all provinces/territories; 3 jurisdictional levels; and research, practice, and policy sectors. Ninety priority opportunities for strategic collaboration were identified across all 3 workshops. Participants provided detailed feedback about transparency of the RFP (Request for Proposals) application process, support needed to level the playing field for potential applicants, and valuable suggestions for the adjudication process. Coalitions Linking Action and Science for Prevention engaged hundreds of research, practice, and policy experts across Canada focusing social-behavioral, clinical, and environmental and occupational opportunities for cancer and chronic disease prevention. Given the extent of expert and jurisdictional engagement, the substantial Partnership investment in a participatory engagement approach to RFP development and potential applicant response suggests that efforts to link cancer and chronic disease prevention efforts across jurisdictions and through research, practice, and policy collaboration may require this type of a priori investment in networking, communication, coordination, and collaboration.

Diffuse Parenchymal Diseases Associated With Aluminum Use and Primary Aluminum Production

PubMed Central

2014-01-01

Aluminum use and primary aluminum production results in the generation of various particles, fumes, gases, and airborne materials with the potential for inducing a wide range of lung pathology. Nevertheless, the presence of diffuse parenchymal or interstitial lung disease related to these processes remains controversial. The relatively uncommon occurrence of interstitial lung diseases in aluminum-exposed workers—despite the extensive industrial use of aluminum—the potential for concurrent exposure to other fibrogenic fibers, and the previous use of inhaled aluminum powder for the prevention of silicosis without apparent adverse respiratory effects are some of the reasons for this continuing controversy. Specific aluminum-induced parenchymal diseases described in the literature, including existing evidence of interstitial lung diseases, associated with primary aluminum production are reviewed. PMID:24806728

The Onset of Type 2 Diabetes: Proposal for a Multi-Scale Model

PubMed Central

Tieri, Paolo; De Graaf, Albert; Franceschi, Claudio; Liò, Pietro; Van Ommen, Ben; Mazzà, Claudia; Tuchel, Alexander; Bernaschi, Massimo; Samson, Clare; Colombo, Teresa; Castellani, Gastone C; Capri, Miriam; Garagnani, Paolo; Salvioli, Stefano; Nguyen, Viet Anh; Bobeldijk-Pastorova, Ivana; Krishnan, Shaji; Cappozzo, Aurelio; Sacchetti, Massimo; Morettini, Micaela; Ernst, Marc

2013-01-01

Background Type 2 diabetes mellitus (T2D) is a common age-related disease, and is a major health concern, particularly in developed countries where the population is aging, including Europe. The multi-scale immune system simulator for the onset of type 2 diabetes (MISSION-T2D) is a European Union-funded project that aims to develop and validate an integrated, multilevel, and patient-specific model, incorporating genetic, metabolic, and nutritional data for the simulation and prediction of metabolic and inflammatory processes in the onset and progression of T2D. The project will ultimately provide a tool for diagnosis and clinical decision making that can estimate the risk of developing T2D and predict its progression in response to possible therapies. Recent data showed that T2D and its complications, specifically in the heart, kidney, retina, and feet, should be considered a systemic disease that is sustained by a pervasive, metabolically-driven state of inflammation. Accordingly, there is an urgent need (1) to understand the complex mechanisms underpinning the onset of this disease, and (2) to identify early patient-specific diagnostic parameters and related inflammatory indicators. Objective We aim to accomplish this mission by setting up a multi-scale model to study the systemic interactions of the biological mechanisms involved in response to a variety of nutritional and metabolic stimuli and stressors. Methods Specifically, we will be studying the biological mechanisms of immunological/inflammatory processes, energy intake/expenditure ratio, and cell cycle rate. The overall architecture of the model will exploit an already established immune system simulator as well as several discrete and continuous mathematical methods for modeling of the processes critically involved in the onset and progression of T2D. We aim to validate the predictions of our models using actual biological and clinical data. Results This study was initiated in March 2013 and is expected to be completed by February 2016. Conclusions MISSION-T2D aims to pave the way for translating validated multilevel immune-metabolic models into the clinical setting of T2D. This approach will eventually generate predictive biomarkers for this disease from the integration of clinical data with metabolic, nutritional, immune/inflammatory, genetic, and gut microbiota profiles. Eventually, it should prove possible to translate these into cost-effective and mobile-based diagnostic tools. PMID:24176906

Longitudinal Health Research in the U.S. Navy.

DTIC Science & Technology

1979-12-01

while morbidity variables would be the presence or absence of a specific disease or condition, or perhaps a continuous response such S as level of...Cardiovascular routine electrocardiogram * * * * startle electrocardiogram * computer processed electrocardiogram * * exercise electrocardiogram...basal metabolic rate * other * * Anthropometry somatotype * * * measurements (in addition to height & weight) e * * Teleoroentgenograms

Transcriptional regulation of podocyte specification and differentiation.

PubMed

Quaggin, Susan E

2002-05-15

Glomerular visceral epithelial cells (podocytes) are highly specialized cells found in the vertebrate and invertebrate kidney and make up a major portion of the filtration barrier between blood and urinary spaces. During development, specification and differentiation of the podocyte lineage must be tightly orchestrated to produce highly specialized characteristics such as foot processes and slit diaphragms. Furthermore, podocytes are poised to direct incoming endothelial and mesangial cells during glomerular development. They express a number of growth factors that likely play a major role in these processes. Recent findings from transgenic and knockout mouse models and the identification of genes responsible for human podocyte disease have provided insight into transcriptional regulation of some of these processes. These transcription factors include Pax2, WT1 (the Wilms tumor suppressor gene), Pod1 (capsulin, epicardin), Kreisler (maf-1), lmx1b, and mf2. Furthermore, regulatory regions from a podocyte-restricted gene, NPHS1 (nephrin) that are required to direct podocyte-specific expression have been identified from both human and murine genes and provide a tool to further dissect the transcriptional regulation of podocyte-specific gene expression. This article reviews the present state of knowledge regarding transcriptional regulation of podocyte specification and differentiation. Copyright 2002 Wiley-Liss, Inc.

Temporal Expression Profiling Identifies Pathways Mediating Effect of Causal Variant on Phenotype

PubMed Central

Gupta, Saumya; Radhakrishnan, Aparna; Raharja-Liu, Pandu; Lin, Gen; Steinmetz, Lars M.; Gagneur, Julien; Sinha, Himanshu

2015-01-01

Even with identification of multiple causal genetic variants for common human diseases, understanding the molecular processes mediating the causal variants’ effect on the disease remains a challenge. This understanding is crucial for the development of therapeutic strategies to prevent and treat disease. While static profiling of gene expression is primarily used to get insights into the biological bases of diseases, it makes differentiating the causative from the correlative effects difficult, as the dynamics of the underlying biological processes are not monitored. Using yeast as a model, we studied genome-wide gene expression dynamics in the presence of a causal variant as the sole genetic determinant, and performed allele-specific functional validation to delineate the causal effects of the genetic variant on the phenotype. Here, we characterized the precise genetic effects of a functional MKT1 allelic variant in sporulation efficiency variation. A mathematical model describing meiotic landmark events and conditional activation of MKT1 expression during sporulation specified an early meiotic role of this variant. By analyzing the early meiotic genome-wide transcriptional response, we demonstrate an MKT1-dependent role of novel modulators, namely, RTG1/3, regulators of mitochondrial retrograde signaling, and DAL82, regulator of nitrogen starvation, in additively effecting sporulation efficiency. In the presence of functional MKT1 allele, better respiration during early sporulation was observed, which was dependent on the mitochondrial retrograde regulator, RTG3. Furthermore, our approach showed that MKT1 contributes to sporulation independent of Puf3, an RNA-binding protein that steady-state transcription profiling studies have suggested to mediate MKT1-pleiotropic effects during mitotic growth. These results uncover interesting regulatory links between meiosis and mitochondrial retrograde signaling. In this study, we highlight the advantage of analyzing allele-specific transcriptional dynamics of mediating genes. Applications in higher eukaryotes can be valuable for inferring causal molecular pathways underlying complex dynamic processes, such as development, physiology and disease progression. PMID:26039065

Frontotemporal dementia: insights into the biological underpinnings of disease through gene co-expression network analysis.

PubMed

Ferrari, Raffaele; Forabosco, Paola; Vandrovcova, Jana; Botía, Juan A; Guelfi, Sebastian; Warren, Jason D; Momeni, Parastoo; Weale, Michael E; Ryten, Mina; Hardy, John

2016-02-24

In frontotemporal dementia (FTD) there is a critical lack in the understanding of biological and molecular mechanisms involved in disease pathogenesis. The heterogeneous genetic features associated with FTD suggest that multiple disease-mechanisms are likely to contribute to the development of this neurodegenerative condition. We here present a systems biology approach with the scope of i) shedding light on the biological processes potentially implicated in the pathogenesis of FTD and ii) identifying novel potential risk factors for FTD. We performed a gene co-expression network analysis of microarray expression data from 101 individuals without neurodegenerative diseases to explore regional-specific co-expression patterns in the frontal and temporal cortices for 12 genes (MAPT, GRN, CHMP2B, CTSC, HLA-DRA, TMEM106B, C9orf72, VCP, UBQLN2, OPTN, TARDBP and FUS) associated with FTD and we then carried out gene set enrichment and pathway analyses, and investigated known protein-protein interactors (PPIs) of FTD-genes products. Gene co-expression networks revealed that several FTD-genes (such as MAPT and GRN, CTSC and HLA-DRA, TMEM106B, and C9orf72, VCP, UBQLN2 and OPTN) were clustering in modules of relevance in the frontal and temporal cortices. Functional annotation and pathway analyses of such modules indicated enrichment for: i) DNA metabolism, i.e. transcription regulation, DNA protection and chromatin remodelling (MAPT and GRN modules); ii) immune and lysosomal processes (CTSC and HLA-DRA modules), and; iii) protein meta/catabolism (C9orf72, VCP, UBQLN2 and OPTN, and TMEM106B modules). PPI analysis supported the results of the functional annotation and pathway analyses. This work further characterizes known FTD-genes and elaborates on their biological relevance to disease: not only do we indicate likely impacted regional-specific biological processes driven by FTD-genes containing modules, but also do we suggest novel potential risk factors among the FTD-genes interactors as targets for further mechanistic characterization in hypothesis driven cell biology work.

Protection of primary neurons and mouse brain from Alzheimer’s pathology by molecular tweezers

PubMed Central

Attar, Aida; Ripoli, Cristian; Riccardi, Elisa; Maiti, Panchanan; Li Puma, Domenica D.; Liu, Tingyu; Hayes, Jane; Jones, Mychica R.; Lichti-Kaiser, Kristin; Yang, Fusheng; Gale, Greg D.; Tseng, Chi-hong; Tan, Miao; Xie, Cui-Wei; Straudinger, Jeffrey L.; Klärner, Frank-Gerrit; Schrader, Thomas; Frautschy, Sally A.; Grassi, Claudio

2012-01-01

Alzheimer’s disease is a devastating cureless neurodegenerative disorder affecting >35 million people worldwide. The disease is caused by toxic oligomers and aggregates of amyloid β protein and the microtubule-associated protein tau. Recently, the Lys-specific molecular tweezer CLR01 has been shown to inhibit aggregation and toxicity of multiple amyloidogenic proteins, including amyloid β protein and tau, by disrupting key interactions involved in the assembly process. Following up on these encouraging findings, here, we asked whether CLR01 could protect primary neurons from Alzheimer’s disease-associated synaptotoxicity and reduce Alzheimer’s disease–like pathology in vivo. Using cell culture and brain slices, we found that CLR01 effectively inhibited synaptotoxicity induced by the 42-residue isoform of amyloid β protein, including ∼80% inhibition of changes in dendritic spines density and long-term potentiation and complete inhibition of changes in basal synaptic activity. Using a radiolabelled version of the compound, we found that CLR01 crossed the mouse blood–brain barrier at ∼2% of blood levels. Treatment of 15-month-old triple-transgenic mice for 1 month with CLR01 resulted in a decrease in brain amyloid β protein aggregates, hyperphosphorylated tau and microglia load as observed by immunohistochemistry. Importantly, no signs of toxicity were observed in the treated mice, and CLR01 treatment did not affect the amyloidogenic processing of amyloid β protein precursor. Examining induction or inhibition of the cytochrome P450 metabolism system by CLR01 revealed minimal interaction. Together, these data suggest that CLR01 is safe for use at concentrations well above those showing efficacy in mice. The efficacy and toxicity results support a process-specific mechanism of action of molecular tweezers and suggest that these are promising compounds for developing disease-modifying therapy for Alzheimer’s disease and related disorders. PMID:23183235

Vaccination and the TAP-independent antigen processing pathways.

PubMed

López, Daniel; Lorente, Elena; Barriga, Alejandro; Johnstone, Carolina; Mir, Carmen

2013-09-01

The cytotoxic CD8(+) T lymphocyte-mediated cellular response is important for the elimination of virus-infected cells and requires the prior recognition of short viral peptide antigens previously translocated to the endoplasmic reticulum by the transporter associated with antigen processing (TAP). However, individuals with nonfunctional TAP complexes or infected cells with TAP molecules blocked by specific viral proteins, such as the cowpoxvirus, a component of the first source of early empirical vaccination against smallpox, are still able to present several HLA class I ligands generated by the TAP-independent antigen processing pathways to specific cytotoxic CD8(+) T lymphocytes. Currently, bioterrorism and emerging infectious diseases have renewed interest in poxviruses. Recent works that have identified HLA class I ligands and epitopes in virus-infected TAP-deficient cells have implications for the study of both the effectiveness of early empirical vaccination and the analysis of HLA class I antigen processing in TAP-deficient subjects.

Hydrogen Sulfide in Renal Physiology and Disease.

PubMed

Feliers, Denis; Lee, Hak Joo; Kasinath, Balakuntalam S

2016-11-01

Hydrogen sulfide (H2S) has only recently gained recognition for its physiological effects. It is synthesized widely in the mammalian tissues and regulates several biologic processes ranging from development, angiogenesis, neurotransmission to protein synthesis. Recent Advances: The aim of this review is to critically evaluate the evidence for a role for H2S in kidney function and disease. H2S regulates fundamental kidney physiologic processes such as glomerular filtration and sodium reabsorption. In kidney disease states H2S appears to play a complex role in a context-dependent manner. In some disease states such as ischemia-reperfusion and diabetic kidney disease it can serve as an agent that ameliorates kidney injury. In other diseases such as cis-platinum-induced kidney disease it may mediate kidney injury although more investigation is needed. Recent studies have revealed that the actions of nitric oxide and H2S may be integrated in kidney cells. Further studies are needed to understand the full impact of H2S on kidney physiology. As it is endowed with the properties of regulating blood flow, oxidative stress, and inflammation, H2S should be investigated for its role in inflammatory and toxic diseases of the kidney. Such in-depth exploration may identify specific kidney diseases in which H2S may constitute a unique target for therapeutic intervention. Antioxid. Redox Signal. 25, 720-731.

Aberrant activation of the human sex-determining gene in early embryonic development results in postnatal growth retardation and lethality in mice.

PubMed

Kido, Tatsuo; Sun, Zhaoyu; Lau, Yun-Fai Chris

2017-06-23

Sexual dimorphisms are prevalent in development, physiology and diseases in humans. Currently, the contributions of the genes on the male-specific region of the Y chromosome (MSY) in these processes are uncertain. Using a transgene activation system, the human sex-determining gene hSRY is activated in the single-cell embryos of the mouse. Pups with hSRY activated (hSRY ON ) are born of similar sizes as those of non-activated controls. However, they retard significantly in postnatal growth and development and all die of multi-organ failure before two weeks of age. Pathological and molecular analyses indicate that hSRY ON pups lack innate suckling activities, and develop fatty liver disease, arrested alveologenesis in the lung, impaired neurogenesis in the brain and occasional myocardial fibrosis and minimized thymus development. Transcriptome analysis shows that, in addition to those unique to the respective organs, various cell growth and survival pathways and functions are differentially affected in the transgenic mice. These observations suggest that ectopic activation of a Y-located SRY gene could exert male-specific effects in development and physiology of multiple organs, thereby contributing to sexual dimorphisms in normal biological functions and disease processes in affected individuals.

Microorganisms in periradicular tissues: Do they exist? A perennial controversy

PubMed Central

Dudeja, Pooja Gupta; Dudeja, Krishan Kumar; Srivastava, Dhirendra; Grover, Shibani

2015-01-01

There is no greater association between the basic science and the practice of endodontics than that of microbiology. One of the strongest factors contributing to the controversies often encountered in the endodontic field is the lack of understanding that the disease processes of the pulp and periradicular tissues generally have a microbiological etiology. The vast majority of diseases of dental pulp and periradicular tissues are associated with microorganisms. After the microbial invasion of these tissues, the host responds with both nonspecific inflammatory responses and with specific immunologic responses to encounter such infections. The aim of this study is to fill the gaps in our knowledge regarding the role of microorganisms in endodontics and to discuss in depth whether their presence in periradicular lesions is a myth or a reality. An electronic search was carried out on PubMed database (custom range of almost 50 years) and Google using specific keywords and phrases. Inclusion and exclusion criteria were specified and around 50 articles were found suitable for inclusion. Full text of all the articles was retrieved and studied. Appropriate data were extracted and pooled and finally synthesized. It is important to understand the close relationship between the presence of microorganisms and endodontic disease process to develop an effective rationale for treatment. PMID:26980965

Radiotherapy for non-malignant disorders: state of the art and update of the evidence-based practice guidelines

PubMed Central

Micke, O; Muecke, R

2015-01-01

Every year in Germany about 50,000 patients are referred and treated by radiotherapy (RT) for “non-malignant disorders”. This highly successful treatment is applied only for specific indications such as preservation or recovery of the quality of life by means of pain reduction or resolution and/or an improvement of formerly impaired physical body function owing to specific disease-related symptoms. Since 1995, German radiation oncologists have treated non-malignant disorders according to national consensus guidelines; these guidelines were updated and further developed over 3 years by implementation of a systematic consensus process to achieve national upgraded and accepted S2e clinical practice guidelines. Throughout this process, international standards of evaluation were implemented. This review summarizes most of the generally accepted indications for the application of RT for non-malignant diseases and presents the special treatment concepts. The following disease groups are addressed: painful degenerative skeletal disorders, hyperproliferative disorders and symptomatic functional disorders. These state of the art guidelines may serve as a platform for daily clinical work; they provide a new starting point for quality assessment, future clinical research, including the design of prospective clinical trials, and outcome research in the underrepresented and less appreciated field of RT for non-malignant disorders. PMID:25955230

Hypoxia and Redox Signaling on Extracellular Matrix Remodeling: From Mechanisms to Pathological Implications.

PubMed

Labrousse-Arias, David; Martínez-Ruiz, Antonio; Calzada, María J

2017-10-20

The extracellular matrix (ECM) is an essential modulator of cell behavior that influences tissue organization. It has a strong relevance in homeostasis and translational implications for human disease. In addition to ECM structural proteins, matricellular proteins are important regulators of the ECM that are involved in a myriad of different pathologies. Recent Advances: Biochemical studies, animal models, and study of human diseases have contributed to the knowledge of molecular mechanisms involved in remodeling of the ECM, both in homeostasis and disease. Some of them might help in the development of new therapeutic strategies. This review aims to review what is known about some of the most studied matricellular proteins and their regulation by hypoxia and redox signaling, as well as the pathological implications of such regulation. Matricellular proteins have complex regulatory functions and are modulated by hypoxia and redox signaling through diverse mechanisms, in some cases with controversial effects that can be cell or tissue specific and context dependent. Therefore, a better understanding of these regulatory processes would be of great benefit and will open new avenues of considerable therapeutic potential. Characterizing the specific molecular mechanisms that modulate matricellular proteins in pathological processes that involve hypoxia and redox signaling warrants additional consideration to harness the potential therapeutic value of these regulatory proteins. Antioxid. Redox Signal. 27, 802-822.

Cyclic Nucleotide Phosphodiesterases: important signaling modulators and therapeutic targets

PubMed Central

Ahmad, Faiyaz; Murata, Taku; Simizu, Kasumi; Degerman, Eva; Maurice, Donald; Manganiello, Vincent

2014-01-01

By catalyzing hydrolysis of cAMP and cGMP, cyclic nucleotide phosphodiesterases are critical regulators of their intracellular concentrations and their biological effects. Since these intracellular second messengers control many cellular homeostatic processes, dysregulation of their signals and signaling pathways initiate or modulate pathophysiological pathways related to various disease states, including erectile dysfunction, pulmonary hypertension, acute refractory cardiac failure, intermittent claudication, chronic obstructive pulmonary disease, and psoriasis. Alterations in expression of PDEs and PDE-gene mutations (especially mutations in PDE6, PDE8B, PDE11A and PDE4) have been implicated in various diseases and cancer pathologies. PDEs also play important role in formation and function of multi-molecular signaling/regulatory complexes called signalosomes. At specific intracellular locations, individual PDEs, together with pathway-specific signaling molecules, regulators, and effectors, are incorporated into specific signalosomes, where they facilitate and regulate compartmentalization of cyclic nucleotide signaling pathways and specific cellular functions. Currently, only a limited number of PDE inhibitors (PDE3, PDE4, PDE5 inhibitors) are used in clinical practice. Future paths to novel drug discovery include the crystal structure-based design approach, which has resulted in generation of more effective family-selective inhibitors, as well as burgeoning development of strategies to alter compartmentalized cyclic nucleotide signaling pathways by selectively targeting individual PDEs and their signalosome partners. PMID:25056711

Modeling specific phobias and posttraumatic stress disorder in rodents: the challenge to convey both cognitive and emotional features.

PubMed

Berardi, Andrea; Trezza, Viviana; Campolongo, Campolongo

2012-01-01

Aberrant emotional memory processing is a core, disabling feature of both specific phobias and posttraumatic stress disorder (PTSD), two psychiatric diseases of significant prevalence and morbidity whose cognitive symptoms cannot be adequately treated by current psychopharmacological tools. Elucidating the neurobiological mechanisms involved in the etiology of these diseases is of great interest for the identification of new therapeutics that improve not only the symptomatology but also the full recovery from the pathology. To this aim, several animal models have been proposed based on substantial resemblance between the behavioral alterations seen in animals and the human pathology. The purpose of this review is to describe and comment on the most commonly used rodent models of specific phobias and PTSD. A particular focus will be reserved to the cued version of fear conditioning, as the highly specific stimulus-bound conditioned fear response seems to fit well with clinical descriptions of phobic fear.Moreover, animal models of PTSD will be evaluated by referring to three elements that are considered essential ina valid model of this disease: stressor exposure, memory for the stressor, and anxiety-related behaviors. Finally, current therapeutic directions, with a focus on cannabinoid and glucocorticoid compounds, will be briefly outlined.

Differential C3NET reveals disease networks of direct physical interactions

PubMed Central

2011-01-01

Background Genes might have different gene interactions in different cell conditions, which might be mapped into different networks. Differential analysis of gene networks allows spotting condition-specific interactions that, for instance, form disease networks if the conditions are a disease, such as cancer, and normal. This could potentially allow developing better and subtly targeted drugs to cure cancer. Differential network analysis with direct physical gene interactions needs to be explored in this endeavour. Results C3NET is a recently introduced information theory based gene network inference algorithm that infers direct physical gene interactions from expression data, which was shown to give consistently higher inference performances over various networks than its competitors. In this paper, we present, DC3net, an approach to employ C3NET in inferring disease networks. We apply DC3net on a synthetic and real prostate cancer datasets, which show promising results. With loose cutoffs, we predicted 18583 interactions from tumor and normal samples in total. Although there are no reference interactions databases for the specific conditions of our samples in the literature, we found verifications for 54 of our predicted direct physical interactions from only four of the biological interaction databases. As an example, we predicted that RAD50 with TRF2 have prostate cancer specific interaction that turned out to be having validation from the literature. It is known that RAD50 complex associates with TRF2 in the S phase of cell cycle, which suggests that this predicted interaction may promote telomere maintenance in tumor cells in order to allow tumor cells to divide indefinitely. Our enrichment analysis suggests that the identified tumor specific gene interactions may be potentially important in driving the growth in prostate cancer. Additionally, we found that the highest connected subnetwork of our predicted tumor specific network is enriched for all proliferation genes, which further suggests that the genes in this network may serve in the process of oncogenesis. Conclusions Our approach reveals disease specific interactions. It may help to make experimental follow-up studies more cost and time efficient by prioritizing disease relevant parts of the global gene network. PMID:21777411

Naturally Occurring Human Urinary Peptides for Use in Diagnosis of Chronic Kidney Disease*

PubMed Central

Good, David M.; Zürbig, Petra; Argilés, Àngel; Bauer, Hartwig W.; Behrens, Georg; Coon, Joshua J.; Dakna, Mohammed; Decramer, Stéphane; Delles, Christian; Dominiczak, Anna F.; Ehrich, Jochen H. H.; Eitner, Frank; Fliser, Danilo; Frommberger, Moritz; Ganser, Arnold; Girolami, Mark A.; Golovko, Igor; Gwinner, Wilfried; Haubitz, Marion; Herget-Rosenthal, Stefan; Jankowski, Joachim; Jahn, Holger; Jerums, George; Julian, Bruce A.; Kellmann, Markus; Kliem, Volker; Kolch, Walter; Krolewski, Andrzej S.; Luppi, Mario; Massy, Ziad; Melter, Michael; Neusüss, Christian; Novak, Jan; Peter, Karlheinz; Rossing, Kasper; Rupprecht, Harald; Schanstra, Joost P.; Schiffer, Eric; Stolzenburg, Jens-Uwe; Tarnow, Lise; Theodorescu, Dan; Thongboonkerd, Visith; Vanholder, Raymond; Weissinger, Eva M.; Mischak, Harald; Schmitt-Kopplin, Philippe

2010-01-01

Because of its availability, ease of collection, and correlation with physiology and pathology, urine is an attractive source for clinical proteomics/peptidomics. However, the lack of comparable data sets from large cohorts has greatly hindered the development of clinical proteomics. Here, we report the establishment of a reproducible, high resolution method for peptidome analysis of naturally occurring human urinary peptides and proteins, ranging from 800 to 17,000 Da, using samples from 3,600 individuals analyzed by capillary electrophoresis coupled to MS. All processed data were deposited in an Structured Query Language (SQL) database. This database currently contains 5,010 relevant unique urinary peptides that serve as a pool of potential classifiers for diagnosis and monitoring of various diseases. As an example, by using this source of information, we were able to define urinary peptide biomarkers for chronic kidney diseases, allowing diagnosis of these diseases with high accuracy. Application of the chronic kidney disease-specific biomarker set to an independent test cohort in the subsequent replication phase resulted in 85.5% sensitivity and 100% specificity. These results indicate the potential usefulness of capillary electrophoresis coupled to MS for clinical applications in the analysis of naturally occurring urinary peptides. PMID:20616184

Diagnostic value of computed tomography in dogs with chronic nasal disease.

PubMed

Saunders, Jimmy H; van Bree, Henri; Gielen, Ingrid; de Rooster, Hilde

2003-01-01

Computed tomographic (CT) studies of 80 dogs with chronic nasal disease (nasal neoplasia (n = 19), nasal aspergillosis (n = 46), nonspecific rhinitis (n = 11), and foreign body rhinitis (n = 4)) were reviewed retrospectively by two independent observers. Each observer filled out a custom-designed list to record his or her interpretation of the CT signs and selected a diagnosis. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated for the diagnosis of each disease. The agreement between observers was evaluated. The CT signs corresponded to those previously described in the literature. CT had an accuracy greater than 90% for each observer in all disease processes. The sensitivity, specificity, PPV, and NPV were greater than 80% in all dogs with the exception of the PPV of foreign body rhinitis (80% for observer A and 44% for observer B). There was a substantial, to almost perfect, agreement between the two observers regarding the CT signs and diagnosis. This study indicates a high accuracy of CT for diagnosis of dogs with chronic nasal disease. The differentiation between nasal aspergillosis restricted to the nasal passages and foreign body rhinitis may be difficult when the foreign body is not visible.

Streptococcal pharyngitis and rheumatic heart disease: the superantigen hypothesis revisited.

PubMed

Hurst, Jacklyn R; Kasper, Katherine J; Sule, Akshay N; McCormick, John K

2018-07-01

Streptococcus pyogenes is a human-specific and globally prominent bacterial pathogen that despite causing numerous human infections, this bacterium is normally found in an asymptomatic carrier state. This review provides an overview of both bacterial and human factors that likely play an important role in nasopharyngeal colonization and pharyngitis, as well as the development of acute rheumatic fever and rheumatic heart disease. Here we highlight a recently described role for bacterial superantigens in promoting acute nasopharyngeal infection, and discuss how these immune system activating toxins could be crucial to initiate the autoimmune process in rheumatic heart disease. Copyright © 2018. Published by Elsevier B.V.

Exploring Genetic, Genomic, and Phenotypic Data at the Rat Genome Database

PubMed Central

Laulederkind, Stanley J. F.; Hayman, G. Thomas; Wang, Shur-Jen; Lowry, Timothy F.; Nigam, Rajni; Petri, Victoria; Smith, Jennifer R.; Dwinell, Melinda R.; Jacob, Howard J.; Shimoyama, Mary

2013-01-01

The laboratory rat, Rattus norvegicus, is an important model of human health and disease, and experimental findings in the rat have relevance to human physiology and disease. The Rat Genome Database (RGD, http://rgd.mcw.edu) is a model organism database that provides access to a wide variety of curated rat data including disease associations, phenotypes, pathways, molecular functions, biological processes and cellular components for genes, quantitative trait loci, and strains. We present an overview of the database followed by specific examples that can be used to gain experience in employing RGD to explore the wealth of functional data available for the rat. PMID:23255149

Malnutrition: Modulator of Immune Responses in Tuberculosis

PubMed Central

Chandrasekaran, Padmapriyadarsini; Saravanan, Natarajan; Bethunaickan, Ramalingam; Tripathy, Srikanth

2017-01-01

Nutrition plays a major role in the management of both acute and chronic diseases, in terms of body’s response to the pathogenic organism. An array of nutrients like macro- and micro-nutrients, vitamins, etc., are associated with boosting the host’s immune responses against intracellular pathogens including mycobacterium tuberculosis (M.tb). These nutrients have an immunomodulatory effects in controlling the infection and inflammation process and nutritional deficiency of any form, i.e., malnutrition may lead to nutritionally acquired immunodeficiency syndrome, which greatly increases an individual’s susceptibility to progression of infection to disease. This narrative review looks at the various mechanisms by which nutrition or its deficiency leads to impaired cell mediated and humoral immune responses, which in turn affects the ability of an individual to fight M.tb infection or disease. There is very little evidence in the literature that any specific food on its own or a specific quantity can alter the course of TB disease or be effective in the treatment of malnutrition. Further clinical trials or studies will be needed to recommend and to better understand the link between malnutrition, tuberculosis, and impaired immunity. PMID:29093710

Inherited Paediatric Motor Neuron Disorders: Beyond Spinal Muscular Atrophy

PubMed Central

Sampaio, Hugo; Mowat, David; Roscioli, Tony

2017-01-01

Paediatric motor neuron diseases encompass a group of neurodegenerative diseases characterised by the onset of muscle weakness and atrophy before the age of 18 years, attributable to motor neuron loss across various neuronal networks in the brain and spinal cord. While the genetic underpinnings are diverse, advances in next generation sequencing have transformed diagnostic paradigms. This has reinforced the clinical phenotyping and molecular genetic expertise required to navigate the complexities of such diagnoses. In turn, improved genetic technology and subsequent gene identification have enabled further insights into the mechanisms of motor neuron degeneration and how these diseases form part of a neurodegenerative disorder spectrum. Common pathophysiologies include abnormalities in axonal architecture and function, RNA processing, and protein quality control. This review incorporates an overview of the clinical manifestations, genetics, and pathophysiology of inherited paediatric motor neuron disorders beyond classic SMN1-related spinal muscular atrophy and describes recent advances in next generation sequencing and its clinical application. Specific disease-modifying treatment is becoming a clinical reality in some disorders of the motor neuron highlighting the importance of a timely and specific diagnosis. PMID:28634552

Targeting mechanotransduction pathways in osteoarthritis: a focus on the pericellular matrix.

PubMed

Vincent, Tonia L

2013-06-01

Mechanical joint loading is an essential factor in joint homeostasis but it is also the most important aetiological factor in the development of osteoarthritis (OA). Although OA has long been regarded a disease of 'wear and tear', data arising from studies over the past 10 years have put pay to a mechanical 'attrition' theory of OA and place the induction and activation of specific matrix degrading enzymes centrally in the disease process. The finding that these enzymes are induced in vivo in a mechanosensitive manner provides a clear and sensible unifying hypothesis for disease pathogenesis; namely that mechanical 'wear' actively drives the enzymes that produce 'tear'. This review focuses on recent advances in our knowledge of the molecular mechanisms by which chondrocytes (and most likely other cells of the joint) sense and respond to changes in their mechanical environment. As mechanical signals drive both beneficial responses as well as those that drive disease, modulation of specific pathways provides a choice of strategies for treating OA. Copyright © 2013 Elsevier Ltd. All rights reserved.

Transfer RNA and human disease.

PubMed

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.

DNA methylation as a dynamic regulator of development and disease processes: spotlight on the prostate.

PubMed

Keil, Kimberly P; Vezina, Chad M

2015-01-01

Prostate development, benign hyperplasia and cancer involve androgen and growth factor signaling as well as stromal-epithelial interactions. We review how DNA methylation influences these and related processes in other organ systems such as how proliferation is restricted to specific cell populations during defined temporal windows, how androgens elicit their actions and how cells establish, maintain and remodel DNA methylation in a time and cell specific fashion. We also discuss mechanisms by which hormones and endocrine disrupting chemicals reprogram DNA methylation in the prostate and elsewhere and examine evidence for a reawakening of developmental epigenetic pathways as drivers of prostate cancer and benign prostate hyperplasia.

DNA methylation as a dynamic regulator of development and disease processes: spotlight on the prostate

PubMed Central

Keil, Kimberly P; Vezina, Chad M

2015-01-01

Prostate development, benign hyperplasia and cancer involve androgen and growth factor signaling as well as stromal–epithelial interactions. We review how DNA methylation influences these and related processes in other organ systems such as how proliferation is restricted to specific cell populations during defined temporal windows, how androgens elicit their actions and how cells establish, maintain and remodel DNA methylation in a time and cell specific fashion. We also discuss mechanisms by which hormones and endocrine disrupting chemicals reprogram DNA methylation in the prostate and elsewhere and examine evidence for a reawakening of developmental epigenetic pathways as drivers of prostate cancer and benign prostate hyperplasia. PMID:26077429

Hallucinations in schizophrenia and Parkinson's disease: an analysis of sensory modalities involved and the repercussion on patients.

PubMed

Llorca, P M; Pereira, B; Jardri, R; Chereau-Boudet, I; Brousse, G; Misdrahi, D; Fénelon, G; Tronche, A-M; Schwan, R; Lançon, C; Marques, A; Ulla, M; Derost, P; Debilly, B; Durif, F; de Chazeron, I

2016-12-01

Hallucinations have been described in various clinical populations, but they are neither disorder nor disease specific. In schizophrenia patients, hallucinations are hallmark symptoms and auditory ones are described as the more frequent. In Parkinson's disease, the descriptions of hallucination modalities are sparse, but the hallucinations do tend to have less negative consequences. Our study aims to explore the phenomenology of hallucinations in both hallucinating schizophrenia patients and Parkinson's disease patients using the Psycho-Sensory hAllucinations Scale (PSAS). The main objective is to describe the phenomena of these clinical symptoms in those two specific populations. Each hallucinatory sensory modality significantly differed between Parkinson's disease and schizophrenia patients. Auditory, olfactory/gustatory and cœnesthetic hallucinations were more frequent in schizophrenia than visual hallucinations. The guardian angel item, usually not explored in schizophrenia, was described by 46% of these patients. The combination of auditory and visual hallucinations was the most frequent for both Parkinson's disease and schizophrenia. The repercussion index summing characteristics of each hallucination (frequency, duration, negative aspects, conviction, impact, control and sound intensity) was always higher for schizophrenia. A broader view including widespread characteristics and interdisciplinary works must be encouraged to better understand the complexity of the process involved in hallucinations.

Hallucinations in schizophrenia and Parkinson’s disease: an analysis of sensory modalities involved and the repercussion on patients

PubMed Central

Llorca, P. M.; Pereira, B.; Jardri, R.; Chereau-Boudet, I.; Brousse, G.; Misdrahi, D.; Fénelon, G.; Tronche, A.-M.; Schwan, R.; Lançon, C.; Marques, A.; Ulla, M.; Derost, P.; Debilly, B.; Durif, F.; de Chazeron, I.

2016-01-01

Hallucinations have been described in various clinical populations, but they are neither disorder nor disease specific. In schizophrenia patients, hallucinations are hallmark symptoms and auditory ones are described as the more frequent. In Parkinson’s disease, the descriptions of hallucination modalities are sparse, but the hallucinations do tend to have less negative consequences. Our study aims to explore the phenomenology of hallucinations in both hallucinating schizophrenia patients and Parkinson’s disease patients using the Psycho-Sensory hAllucinations Scale (PSAS). The main objective is to describe the phenomena of these clinical symptoms in those two specific populations. Each hallucinatory sensory modality significantly differed between Parkinson’s disease and schizophrenia patients. Auditory, olfactory/gustatory and cœnesthetic hallucinations were more frequent in schizophrenia than visual hallucinations. The guardian angel item, usually not explored in schizophrenia, was described by 46% of these patients. The combination of auditory and visual hallucinations was the most frequent for both Parkinson’s disease and schizophrenia. The repercussion index summing characteristics of each hallucination (frequency, duration, negative aspects, conviction, impact, control and sound intensity) was always higher for schizophrenia. A broader view including widespread characteristics and interdisciplinary works must be encouraged to better understand the complexity of the process involved in hallucinations. PMID:27905557

Diseases in marine invertebrates associated with mariculture and commercial fisheries

NASA Astrophysics Data System (ADS)

Sweet, Michael J.; Bateman, Kelly S.

2015-10-01

Diseases in marine invertebrates are increasing in both frequency and intensity around the globe. Diseases in individuals which offer some commercial value are often well documented and subsequently well studied in comparison to those wild groups offering little commercial gain. This is particularly the case with those associated with mariculture or the commercial fisheries. Specifically, these include many Holothuroidea, and numerous crustacea and mollusca species. Pathogens/parasites consisting of both prokaryotes and eukaryotes from all groups have been associated with diseases from such organisms, including bacteria, viruses, fungi and protozoa. Viral pathogens in particular, appear to be an increasingly important group and research into this group will likely highlight a larger number of diseases and pathogens being described in the near future. Interestingly, although there are countless examples of the spread of disease usually associated with transportation of specific infected hosts for development of aquaculture practices, this process appears to be continuing with no real sign of effective management and mitigation strategies being implicated. Notably, even in well developed countries such as the UK and the US, even though live animal trade may be well managed, the transport of frozen food appears to be less well so and as evidence suggests, even these to have the potential to transmit pathogens when used as a food source for example.

Reprint of 'Diseases in marine invertebrates associated with mariculture and commercial fisheries'

NASA Astrophysics Data System (ADS)

Sweet, Michael J.; Bateman, Kelly S.

2016-07-01

Diseases in marine invertebrates are increasing in both frequency and intensity around the globe. Diseases in individuals which offer some commercial value are often well documented and subsequently well studied in comparison to those wild groups offering little commercial gain. This is particularly the case with those associated with mariculture or the commercial fisheries. Specifically, these include many Holothuroidea, and numerous crustacea and mollusca species. Pathogens/parasites consisting of both prokaryotes and eukaryotes from all groups have been associated with diseases from such organisms, including bacteria, viruses, fungi and protozoa. Viral pathogens in particular, appear to be an increasingly important group and research into this group will likely highlight a larger number of diseases and pathogens being described in the near future. Interestingly, although there are countless examples of the spread of disease usually associated with transportation of specific infected hosts for development of aquaculture practices, this process appears to be continuing with no real sign of effective management and mitigation strategies being implicated. Notably, even in well developed countries such as the UK and the US, even though live animal trade may be well managed, the transport of frozen food appears to be less well so and as evidence suggests, even these to have the potential to transmit pathogens when used as a food source for example.

Compendium of Immune Signatures Identifies Conserved and Species-Specific Biology in Response to Inflammation.

PubMed

Godec, Jernej; Tan, Yan; Liberzon, Arthur; Tamayo, Pablo; Bhattacharya, Sanchita; Butte, Atul J; Mesirov, Jill P; Haining, W Nicholas

2016-01-19

Gene-expression profiling has become a mainstay in immunology, but subtle changes in gene networks related to biological processes are hard to discern when comparing various datasets. For instance, conservation of the transcriptional response to sepsis in mouse models and human disease remains controversial. To improve transcriptional analysis in immunology, we created ImmuneSigDB: a manually annotated compendium of ∼5,000 gene-sets from diverse cell states, experimental manipulations, and genetic perturbations in immunology. Analysis using ImmuneSigDB identified signatures induced in activated myeloid cells and differentiating lymphocytes that were highly conserved between humans and mice. Sepsis triggered conserved patterns of gene expression in humans and mouse models. However, we also identified species-specific biological processes in the sepsis transcriptional response: although both species upregulated phagocytosis-related genes, a mitosis signature was specific to humans. ImmuneSigDB enables granular analysis of transcriptomic data to improve biological understanding of immune processes of the human and mouse immune systems. Copyright © 2016 Elsevier Inc. All rights reserved.

Heart Failure with Preserved Ejection Fraction: Molecular Pathways of the Aging Myocardium

PubMed Central

Loffredo, Francesco S.; Nikolova, Andriana P.; Pancoast, James R.; Lee, Richard T.

2014-01-01

Age-related diastolic dysfunction is a major factor in the epidemic of heart failure. In patients hospitalized with heart failure, diastolic heart failure is now as common as systolic heart failure. We now have many successful treatments for HFrEF, while specific treatment options for HFpEF patients remain elusive. The lack of treatments for HFpEF reflects our very incomplete understanding of this constellation of diseases. There are many pathophysiological factors in HFpEF, but aging appears to play an important role. Here we propose that aging of the myocardium is itself a specific pathophysiological process. New insights into the aging heart, including hormonal controls and specific molecular pathways such as microRNAs, are pointing to myocardial aging as a potentially reversible process. While the overall process of aging remains mysterious, understanding the molecular pathways of myocardial aging has never been more important. Unraveling these pathways could lead to new therapies for the enormous and growing problem of HFpEF. PMID:24951760

Interest of fecal calprotectine dosage in inflammatory bowel diseases, state of the art and perspectives.

PubMed

Chaabouni, Tarek; Manceau, Hana; Peoc'h, Katell

2016-08-01

Inflammatory bowel diseases are chronic diseases that result from an inflammation of the intestinal wall. They are suspected in any patient presenting with intestinal symptoms. Until recently, diagnosis was mainly based both on clinical and endoscopic arguments. The use of an easy, fast, reliable, non-invasive and inexpensive test must not only assist in the diagnosis but also contribute to their evolutionary and therapeutic monitoring. To date, fecal calprotectin is the most documented in this perspective. This marker allows to discriminate between functional and organic bowel processes with good sensitivity and good specificity. The determination of the fecal calprotectin level in stools contributes to the evaluation of the degree of disease activity and monitoring of therapeutic response.

Clinical management of iron deficiency anemia in adults: Systemic review on advances in diagnosis and treatment.

PubMed

De Franceschi, Lucia; Iolascon, Achille; Taher, Ali; Cappellini, Maria Domenica

2017-07-01

Global burden disease studies point out that one of the top cause-specific anemias is iron deficiency (ID). Recent advances in knowledge of iron homeostasis have shown that fragile patients are a new target population in which the correction of ID might impact their morbidity, mortality and quality of life. We did a systematic review using specific search strategy, carried out the review of PubMed database, Cochrane Database of systemic reviews and international guidelines on diagnosis and clinical management of ID from 2010 to 2016. The International guidelines were limited to those with peer-review process and published in journal present in citation index database. The eligible studies show that serum ferritin and transferrin saturation are the key tests in early decision-making process to identify iron deficiency anemia (IDA). The clinician has to carefully consider fragile and high-risk subset of patients such as elders or individuals with chronic diseases (i.e chronic kidney disease, inflammatory bowel disease, chronic heart failure). Treatment is based on iron supplementation. Infusion route should be preferentially considered in frail patients especially in the view of new iron available formulations. The available evidences indicate that (i) recurrent IDA should always be investigated, considering uncommon causes; (ii) IDA might worse the performance and the clinical outcome of fragile and high-risk patients and require an intensive treatment. Copyright © 2017 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.

Impaired Processing of Serial Order Determines Working Memory Impairments in Alzheimer's Disease.

PubMed

De Belder, Maya; Santens, Patrick; Sieben, Anne; Fias, Wim

2017-01-01

Working memory (WM) problems are commonly observed in Alzheimer's disease (AD), but the affected mechanisms leading to impaired WM are still insufficiently understood. The ability to efficiently process serial order in WM has been demonstrated to be fundamental to fluent daily life functioning. The decreased capability to mentally process serial position in WM has been put forward as the underlying explanation for generally compromised WM performance. Determine which mechanisms, such as order processing, are responsible for deficient WM functioning in AD. A group of AD patients (n = 32) and their partners (n = 25), assigned to the control group, were submitted to an extensive battery of neuropsychological and experimental tasks, assessing general cognitive state and functioning of several aspects related to serial order WM. The results revealed an impaired ability to bind item information to serial position within WM in AD patients compared to controls. It was additionally observed that AD patients experienced specific difficulties with directing spatial attention when searching for item information stored in WM. The processing of serial order and the allocation of attentional resources are both disrupted, explaining the generally reduced WM functioning in AD patients. Further studies should now clarify whether this observation could explain disease-related problems for other cognitive functions such as verbal expression, auditory comprehension, or planning.

Human intronless genes: Functional groups, associated diseases, evolution, and mRNA processing in absence of splicing

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grzybowska, Ewa A., E-mail: ewag@coi.waw.pl

2012-07-20

Highlights: Black-Right-Pointing-Pointer Functional characteristics of intronless genes (IGs). Black-Right-Pointing-Pointer Diseases associated with IGs. Black-Right-Pointing-Pointer Origin and evolution of IGs. Black-Right-Pointing-Pointer mRNA processing without splicing. -- Abstract: Intronless genes (IGs) constitute approximately 3% of the human genome. Human IGs are essentially different in evolution and functionality from the IGs of unicellular eukaryotes, which represent the majority in their genomes. Functional analysis of IGs has revealed a massive over-representation of signal transduction genes and genes encoding regulatory proteins important for growth, proliferation, and development. IGs also often display tissue-specific expression, usually in the nervous system and testis. These characteristics translate into IG-associatedmore » diseases, mainly neuropathies, developmental disorders, and cancer. IGs represent recent additions to the genome, created mostly by retroposition of processed mRNAs with retained functionality. Processing, nuclear export, and translation of these mRNAs should be hampered dramatically by the lack of splice factors, which normally tightly cover mature transcripts and govern their fate. However, natural IGs manage to maintain satisfactory expression levels. Different mechanisms by which IGs solve the problem of mRNA processing and nuclear export are discussed here, along with their possible impact on reporter studies.« less

T regulatory cells in contact hypersensitivity.

PubMed

Cavani, Andrea

2008-08-01

The review summarizes the recent investigations focused on T regulatory cells in hapten diseases. Multiple mechanisms ensure tolerance to small chemicals penetrating the skin. Among these, specific T regulatory cells play a major role in controlling harmful immune responses to environmental antigens. Most of the T regulatory cells involved in this process belongs to the CD4 subset and suppress hapten-specific immune response through the release of IL-10 and through direct interaction with effector T cells, blocking their function. Methods for in-vitro and in-vivo expansion of specific T regulatory cells may represent an innovative approach for the cure of contact hypersensitivity.

On the analysis of EEG power, frequency and asymmetry in Parkinson’s disease during emotion processing

PubMed Central

2014-01-01

Objective While Parkinson’s disease (PD) has traditionally been described as a movement disorder, there is growing evidence of disruption in emotion information processing associated with the disease. The aim of this study was to investigate whether there are specific electroencephalographic (EEG) characteristics that discriminate PD patients and normal controls during emotion information processing. Method EEG recordings from 14 scalp sites were collected from 20 PD patients and 30 age-matched normal controls. Multimodal (audio-visual) stimuli were presented to evoke specific targeted emotional states such as happiness, sadness, fear, anger, surprise and disgust. Absolute and relative power, frequency and asymmetry measures derived from spectrally analyzed EEGs were subjected to repeated ANOVA measures for group comparisons as well as to discriminate function analysis to examine their utility as classification indices. In addition, subjective ratings were obtained for the used emotional stimuli. Results Behaviorally, PD patients showed no impairments in emotion recognition as measured by subjective ratings. Compared with normal controls, PD patients evidenced smaller overall relative delta, theta, alpha and beta power, and at bilateral anterior regions smaller absolute theta, alpha, and beta power and higher mean total spectrum frequency across different emotional states. Inter-hemispheric theta, alpha, and beta power asymmetry index differences were noted, with controls exhibiting greater right than left hemisphere activation. Whereas intra-hemispheric alpha power asymmetry reduction was exhibited in patients bilaterally at all regions. Discriminant analysis correctly classified 95.0% of the patients and controls during emotional stimuli. Conclusion These distributed spectral powers in different frequency bands might provide meaningful information about emotional processing in PD patients. PMID:24716619

Supervisory and routine processes in noun and verb generation in nondemented patients with Parkinson's disease.

PubMed

Crescentini, Cristiano; Mondolo, Federica; Biasutti, Emanuele; Shallice, Tim

2008-01-31

Despite the increased comprehension of the role of the basal ganglia in cognitive functions such as learning, attention, and executive functions, the exact implication of these structures in language remains unclear. A specific role of basal ganglia in language has been proposed. Nonetheless, a recent hypothesis gives the basal ganglia a non-language specific role in the inhibition of competing alternatives during later controlled processes of language production. In this study we assessed the production of both nouns and verbs in a population of 20 nondemented patients with Parkinson's disease (NDPD). Aspects of selection demands and stimulus-response association strength were investigated in both tasks. Performance of NDPD patients was compared with that of 20 matched elderly subjects. An impairment in verb production was found in PD patients. A selection effect on verb production was found in PD patients along with a greater effect of stimulus-response association strength. PD patients had the greatest difficulty in situations of weak stimulus-response association strength. A "Task-Relevant-Response" analysis carried out on stimuli (nouns) in condition of free association suggested that verb production happens in the context of strongly activated nouns. This means that, in order to produce a verb a switch has to be done from a task irrelevant to a task relevant response. Our results are in line with the proposed non-language specific involvement of the basal ganglia in the supervisory rather than the routine semantic processes required during lexical retrieval.

Longitudinal Study of Gray Matter Changes in Parkinson Disease.

PubMed

Jia, X; Liang, P; Li, Y; Shi, L; Wang, D; Li, K

2015-12-01

The pathology of Parkinson disease leads to morphological brain volume changes. So far, the progressive gray matter volume change across time specific to patients with Parkinson disease compared controls remains unclear. Our aim was to investigate the pattern of gray matter changes in patients with Parkinson disease and to explore the progressive gray matter volume change specific to patients with Parkinson disease with disease progression by using voxel-based morphometry analysis. Longitudinal cognitive assessment and structural MR imaging of 89 patients with Parkinson disease (62 men) and 55 healthy controls (33 men) were from the Parkinson's Progression Markers Initiative data base, including the initial baseline and 12-month follow-up data. Two-way analysis of covariance was performed with covariates of age, sex, years of education, imaging data from multiple centers, and total intracranial volume by using Diffeomorphic Anatomical Registration Through Exponentiated Lie Algebra tool from SPM8 software. Gray matter volume changes for patients with Parkinson disease were detected with decreased gray matter volume in the frontotemporoparietal areas and the bilateral caudate, with increased gray matter volume in the bilateral limbic/paralimbic areas, medial globus pallidus/putamen, and the right occipital cortex compared with healthy controls. Progressive gray matter volume decrease in the bilateral caudate was found for both patients with Parkinson disease and healthy controls, and this caudate volume was positively associated with cognitive ability for both groups. The progressive gray matter volume increase specific to the patients with Parkinson disease was identified close to the left ventral lateral nucleus of thalamus, and a positive relationship was found between the thalamic volume and the tremor scores in a subgroup with tremor-dominant patients with Parkinson disease. The observed progressive changes in gray matter volume in Parkinson disease may provide new insights into the neurodegenerative process. The current findings suggest that the caudate volume loss may contribute to cognitive decline in patients with Parkinson disease and the progressive thalamus enlargement may have relevance to tremor severity in Parkinson disease. © 2015 by American Journal of Neuroradiology.

Broad-spectrum antivirals against viral fusion

PubMed Central

Vigant, Frederic; Santos, Nuno C.; Lee, Benhur

2015-01-01

Effective antivirals have been developed against specific viruses, such as HIV, Hepatitis C virus and influenza virus. This ‘one bug–one drug’ approach to antiviral drug development can be successful, but it may be inadequate for responding to an increasing diversity of viruses that cause significant diseases in humans. The majority of viral pathogens that cause emerging and re-emerging infectious diseases are membrane-enveloped viruses, which require the fusion of viral and cell membranes for virus entry. Therefore, antivirals that target the membrane fusion process represent new paradigms for broad-spectrum antiviral discovery. In this Review, we discuss the mechanisms responsible for the fusion between virus and cell membranes and explore how broad-spectrum antivirals target this process to prevent virus entry. PMID:26075364

Neurophysiological Changes Measured Using Somatosensory Evoked Potentials.

PubMed

Macerollo, Antonella; Brown, Matt J N; Kilner, James M; Chen, Robert

2018-05-01

Measurements of somatosensory evoked potentials (SEPs), recorded using electroencephalography during different phases of movement, have been fundamental in understanding the neurophysiological changes related to motor control. SEP recordings have also been used to investigate adaptive plasticity changes in somatosensory processing related to active and observational motor learning tasks. Combining noninvasive brain stimulation with SEP recordings and intracranial SEP depth recordings, including recordings from deep brain stimulation electrodes, has been critical in identifying neural areas involved in specific temporal stages of somatosensory processing. Consequently, this fundamental information has furthered our understanding of the maladaptive plasticity changes related to pathophysiology of diseases characterized by abnormal movements, such as Parkinson's disease, dystonia, and functional movement disorders. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

Post-traumatic stress disorder and cardiometabolic disease: improving causal inference to inform practice.

PubMed

Koenen, K C; Sumner, J A; Gilsanz, P; Glymour, M M; Ratanatharathorn, A; Rimm, E B; Roberts, A L; Winning, A; Kubzansky, L D

2017-01-01

Post-traumatic stress disorder (PTSD) has been declared 'a life sentence' based on evidence that the disorder leads to a host of physical health problems. Some of the strongest empirical research - in terms of methodology and findings - has shown that PTSD predicts higher risk of cardiometabolic diseases, specifically cardiovascular disease (CVD) and type 2 diabetes (T2D). Despite mounting evidence, PTSD is not currently acknowledged as a risk factor by cardiovascular or endocrinological medicine. This view is unlikely to change absent compelling evidence that PTSD causally contributes to cardiometabolic disease. This review suggests that with developments in methods for epidemiological research and the rapidly expanding knowledge of the behavioral and biological effects of PTSD the field is poised to provide more definitive answers to questions of causality. First, we discuss methods to improve causal inference using the observational data most often used in studies of PTSD and health, with particular reference to issues of temporality and confounding. Second, we consider recent work linking PTSD with specific behaviors and biological processes, and evaluate whether these may plausibly serve as mechanisms by which PTSD leads to cardiometabolic disease. Third, we evaluate how looking more comprehensively into the PTSD phenotype provides insight into whether specific aspects of PTSD phenomenology are particularly relevant to cardiometabolic disease. Finally, we discuss new areas of research that are feasible and could enhance understanding of the PTSD-cardiometabolic relationship, such as testing whether treatment of PTSD can halt or even reverse the cardiometabolic risk factors causally related to CVD and T2D.

Uneven dietary development: linking the policies and processes of globalization with the nutrition transition, obesity and diet-related chronic diseases

PubMed Central

Hawkes, Corinna

2006-01-01

In a "nutrition transition", the consumption of foods high in fats and sweeteners is increasing throughout the developing world. The transition, implicated in the rapid rise of obesity and diet-related chronic diseases worldwide, is rooted in the processes of globalization. Globalization affects the nature of agri-food systems, thereby altering the quantity, type, cost and desirability of foods available for consumption. Understanding the links between globalization and the nutrition transition is therefore necessary to help policy makers develop policies, including food policies, for addressing the global burden of chronic disease. While the subject has been much discussed, tracing the specific pathways between globalization and dietary change remains a challenge. To help address this challenge, this paper explores how one of the central mechanisms of globalization, the integration of the global marketplace, is affecting the specific diet patterns. Focusing on middle-income countries, it highlights the importance of three major processes of market integration: (I) production and trade of agricultural goods; (II) foreign direct investment in food processing and retailing; and (III) global food advertising and promotion. The paper reveals how specific policies implemented to advance the globalization agenda account in part for some recent trends in the global diet. Agricultural production and trade policies have enabled more vegetable oil consumption; policies on foreign direct investment have facilitated higher consumption of highly-processed foods, as has global food marketing. These dietary outcomes also reflect the socioeconomic and cultural context in which these policies are operating. An important finding is that the dynamic, competitive forces unleashed as a result of global market integration facilitates not only convergence in consumption habits (as is commonly assumed in the "Coca-Colonization" hypothesis), but adaptation to products targeted at different niche markets. This convergence-divergence duality raises the policy concern that globalization will exacerbate uneven dietary development between rich and poor. As high-income groups in developing countries accrue the benefits of a more dynamic marketplace, lower-income groups may well experience convergence towards poor quality obseogenic diets, as observed in western countries. Global economic polices concerning agriculture, trade, investment and marketing affect what the world eats. They are therefore also global food and health policies. Health policy makers should pay greater attention to these policies in order to address some of the structural causes of obesity and diet-related chronic diseases worldwide, especially among the groups of low socioeconomic status. PMID:16569239

Regulatory Role of N6 -methyladenosine (m6 A) Methylation in RNA Processing and Human Diseases.

PubMed

Wei, Wenqiang; Ji, Xinying; Guo, Xiangqian; Ji, Shaoping

2017-09-01

N 6 -methyladenosine (m 6 A) modification is an abundant and conservative RNA modification in bacterial and eukaryotic cells. m 6 A modification mainly occurs in the 3' untranslated regions (UTRs) and near the stop codons of mRNA. Diverse strategies have been developed for identifying m 6 A sites in single nucleotide resolution. Dynamic regulation of m 6 A is found in metabolism, embryogenesis, and developmental processes, indicating a possible epigenetic regulation role along RNA processing and exerting biological functions. It has been known that m 6 A editing involves in nuclear RNA export, mRNA degradation, protein translation, and RNA splicing. Deficiency of m 6 A modification will lead to kinds of diseases, such as obesity, cancer, type 2 diabetes mellitus (T2DM), infertility, and developmental arrest. Some specific inhibitors against methyltransferase and demethylase have been developed to selectively regulate m 6 A modification, which may be advantageous for treatment of m 6 A related diseases. J. Cell. Biochem. 118: 2534-2543, 2017. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

Studies on nonsense mediated decay reveal novel therapeutic options for genetic diseases.

PubMed

Bashyam, Murali D

2009-01-01

Scientific breakthroughs have often led to commercially viable patents mainly in the field of engineering. Commercialization in the field of medicine has been restricted mostly to machinery and engineering on the one hand and therapeutic drugs for common chronic ailments such as cough, cold, headache, etc, on the other. Sequencing of the human genome has attracted the attention of pharmaceutical companies and now biotechnology has become a goldmine for commercialization of products and processes. Recent advances in our understanding of basic biological processes have resulted in the opening of new avenues for treatment of human genetic diseases, especially single gene disorders. A significant proportion of human genetic disorders have been shown to be caused due to degradation of transcripts for specific genes through a process called nonsense mediated decay (NMD). The modulation of NMD provides a viable therapeutic option for treatment of several genetic disorders and therefore has been a good prospect for patenting and commercialization. In this review the molecular basis for NMD and attempts to treat genetic diseases which result from NMD are discussed.

[The correlations between aging of the human body, oxidative stress and reduced efficiency of repair systems].

PubMed

Michalak, Aleksandra; Krzeszowiak, Jakub; Markiewicz-Górka, Iwona

2014-12-15

The article presents an current knowledge overview about the importance of oxidative stress and reduced efficiency of repair processes during the aging process of the human body. Oxidative damage to cellular macromolecules (proteins, lipids, nucleic acids), are formed under the influence of reactive oxygen species (ROS). They are the part of important mechanism which is responsible for the process of aging and the development of many diseases. The most important effects result from DNA damage, due to the mutations formation, which can lead to the development of tumors. However, a well-functioning repair systems (i.a. homologous recombination) remove the damage and prevent harmful changes in the cells. Lipid peroxidation products also cause oxidative modification of nucleic acids (and proteins). Proteins and fats also have repair systems, but much simpler than those responsible for the repair of nucleic acids. Unfortunately, with increasing age, they are more weakened, which contributes to increase numbers of cell damage, and consequently development of diseases specific to old age: cancer, neurodegenerative diseases or atherosclerosis.

A national survey of organizational transfer practices in chronic disease prevention in Canada.

PubMed

Hanusaik, Nancy; O'Loughlin, Jennifer L; Paradis, Gilles; Kishchuk, Natalie

2011-08-01

Underuse of best practices in chronic disease prevention (CDP) represents missed opportunities to promote healthy living and prevent chronic disease. Better understanding of how CDP programs, practices and policies (PPPs) are transferred from 'resource' organizations that develop them to 'user' organizations that implement them is crucial. The objectives of this work were to develop psychometrically sound measures of transfer practices occurring within resource organizations; describe the use of these transfer practices and identify correlates of the transfer process. Cross-sectional data were collected in structured telephone interviews with the person most knowledgeable about PPP transfer in 77 Canadian organizations that develop PPPs. Independent correlates of transfer were identified using multiple linear regression. The transfer practices most commonly used included: identification of barriers to PPP adoption/implementation, tailoring transfer strategies and designing a transfer plan. Skill at planning/implementing transfer, external sources of funding specifically allocated for transfer, type of resource organization, attitude toward process of collaboration and user-centeredness were all positively associated with the transfer process. These factors represent possible targets for interventions to improve transfer of CDP PPPs.

A detailed comparison of analysis processes for MCC-IMS data in disease classification—Automated methods can replace manual peak annotations

PubMed Central

Horsch, Salome; Kopczynski, Dominik; Kuthe, Elias; Baumbach, Jörg Ingo; Rahmann, Sven

2017-01-01

Motivation Disease classification from molecular measurements typically requires an analysis pipeline from raw noisy measurements to final classification results. Multi capillary column—ion mobility spectrometry (MCC-IMS) is a promising technology for the detection of volatile organic compounds in the air of exhaled breath. From raw measurements, the peak regions representing the compounds have to be identified, quantified, and clustered across different experiments. Currently, several steps of this analysis process require manual intervention of human experts. Our goal is to identify a fully automatic pipeline that yields competitive disease classification results compared to an established but subjective and tedious semi-manual process. Method We combine a large number of modern methods for peak detection, peak clustering, and multivariate classification into analysis pipelines for raw MCC-IMS data. We evaluate all combinations on three different real datasets in an unbiased cross-validation setting. We determine which specific algorithmic combinations lead to high AUC values in disease classifications across the different medical application scenarios. Results The best fully automated analysis process achieves even better classification results than the established manual process. The best algorithms for the three analysis steps are (i) SGLTR (Savitzky-Golay Laplace-operator filter thresholding regions) and LM (Local Maxima) for automated peak identification, (ii) EM clustering (Expectation Maximization) and DBSCAN (Density-Based Spatial Clustering of Applications with Noise) for the clustering step and (iii) RF (Random Forest) for multivariate classification. Thus, automated methods can replace the manual steps in the analysis process to enable an unbiased high throughput use of the technology. PMID:28910313

Beryllium sensitization and disease among long-term and short-term workers in a beryllium ceramics plant.

PubMed

Henneberger, P K; Cumro, D; Deubner, D D; Kent, M S; McCawley, M; Kreiss, K

2001-04-01

Workers at a beryllium ceramics plant were tested for beryllium sensitization and disease in 1998 to determine whether the plant-wide prevalence of sensitization and disease had declined since the last screening in 1992; an elevated prevalence was associated with specific processes or with high exposures; exposure-response relationships differed for long-term workers hired before the last plant-wide screening and short-term workers hired since then. Current workers were asked to complete a questionnaire and to provide blood for the beryllium lymphocyte proliferation test (BeLPT). Those with an abnormal BeLPT were classified as sensitized, and were offered clinical evaluation for beryllium disease. Task- and time-specific measurements of airborne beryllium were combined with individual work histories to compute mean, cumulative, and peak beryllium exposures for each worker. The 151 participants represented 90% of 167 eligible workers. Fifteen (9.9% of 151) had an abnormal BeLPT and were split between long-term workers (8/77 = 10.4%) and short-term workers (7/74 = 9.5%). Beryllium disease was detected in 9.1% (7/77) of long-term workers but in only 1.4% (1/74) of short-term workers (P = 0.06), for an overall prevalence of 5.3% (8/151). These prevalences were similar to those observed in the earlier survey. The prevalence of sensitization was elevated in 1992 among machinists, and was still elevated in 1998 among long-term workers (7/40 = 18%) but not among short-term workers (2/36 = 6%) with machining experience. The prevalence of sensitization was also elevated in both groups of workers for the processes of lapping, forming, firing, and packaging. The data suggested a positive relationship between peak beryllium exposure and sensitization for long-term workers and between mean, cumulative, and peak exposure and sensitization for short-term workers, although these findings were not statistically significant. Long-term workers with either a high peak exposure or work experience in forming were more likely to have an abnormal BeLPT (8/51 = 16%) than the other long-term workers (0/26, P = 0.05). All seven sensitized short-term workers either had high mean beryllium exposure or had worked longest in forming or machining (7/55 = 13% versus 0/19, P = 0.18). A plant-wide decline in beryllium exposures between the 1992 and 1998 surveys was not matched by a decline in the prevalence of sensitization and disease. Similar to findings from other studies, beryllium sensitization/disease was associated with specific processes and elevated exposures. The contrast in disease prevalence between long-term and short-term workers suggests that beryllium sensitization can occur after a short period of exposure, but beryllium disease usually requires a longer latency and/or period of exposure. The findings from this study motivated interventions to more aggressively protect and test workers, and new research into skin exposure as a route of sensitization and the contribution of individual susceptibility.

Molecular insights into the pathogenesis of Alzheimer's disease and its relationship to normal aging.

PubMed

Podtelezhnikov, Alexei A; Tanis, Keith Q; Nebozhyn, Michael; Ray, William J; Stone, David J; Loboda, Andrey P

2011-01-01

Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression. © 2011 Podtelezhnikov et al.

Molecular Insights into the Pathogenesis of Alzheimer's Disease and Its Relationship to Normal Aging

PubMed Central

Podtelezhnikov, Alexei A.; Tanis, Keith Q.; Nebozhyn, Michael; Ray, William J.

2011-01-01

Alzheimer's disease (AD) is a complex neurodegenerative disorder that diverges from the process of normal brain aging by unknown mechanisms. We analyzed the global structure of age- and disease-dependent gene expression patterns in three regions from more than 600 brains. Gene expression variation could be almost completely explained by four transcriptional biomarkers that we named BioAge (biological age), Alz (Alzheimer), Inflame (inflammation), and NdStress (neurodegenerative stress). BioAge captures the first principal component of variation and includes genes statistically associated with neuronal loss, glial activation, and lipid metabolism. Normally BioAge increases with chronological age, but in AD it is prematurely expressed as if some of the subjects were 140 years old. A component of BioAge, Lipa, contains the AD risk factor APOE and reflects an apparent early disturbance in lipid metabolism. The rate of biological aging in AD patients, which cannot be explained by BioAge, is associated instead with NdStress, which includes genes related to protein folding and metabolism. Inflame, comprised of inflammatory cytokines and microglial genes, is broadly activated and appears early in the disease process. In contrast, the disease-specific biomarker Alz was selectively present only in the affected areas of the AD brain, appears later in pathogenesis, and is enriched in genes associated with the signaling and cell adhesion changes during the epithelial to mesenchymal (EMT) transition. Together these biomarkers provide detailed description of the aging process and its contribution to Alzheimer's disease progression. PMID:22216330

Caffeine, Adenosine Receptors and Estrogen in Toxin Models of Parkinson’s Disease

DTIC Science & Technology

2010-10-30

processed for A2A receptor immunohistochemsitry (B) with a HRP-coupled secondary antibody yielding a (brown) DAB reaction product more but specifically...the striatum of ‘floxed’ A2A gene mice treated 6-8 weeks later with saline or MPTP. The processing and analyses of their brain tissues is currently...coffee (but not decaffeinated coffee). The mechanisms that underlie this epidemiological correla- tion remain unclear. One hypothesis that caffeine

A Typology for Modeling Processes in Clinical Guidelines and Protocols

NASA Astrophysics Data System (ADS)

Tu, Samson W.; Musen, Mark A.

We analyzed the graphical representations that are used by various guideline-modeling methods to express process information embodied in clinical guidelines and protocols. From this analysis, we distilled four modeling formalisms and the processes they typically model: (1) flowcharts for capturing problem-solving processes, (2) disease-state maps that link decision points in managing patient problems over time, (3) plans that specify sequences of activities that contribute toward a goal, (4) workflow specifications that model care processes in an organization. We characterized the four approaches and showed that each captures some aspect of what a guideline may specify. We believe that a general guideline-modeling system must provide explicit representation for each type of process.

Apathy, but not depression, is associated with executive dysfunction in cerebral small vessel disease

PubMed Central

Hollocks, Matthew J.; Morris, Robin G.; Markus, Hugh S.

2017-01-01

Objective To determine the prevalence of apathy and depression in cerebral small vessel disease (SVD), and the relationships between both apathy and depression with cognition. To examine whether apathy is specifically related to impairment in executive functioning and processing speed. Methods 196 patients with a clinical lacunar stroke and an anatomically corresponding lacunar infarct on MRI were compared to 300 stroke-free controls. Apathy and depression were measured using the Geriatric Depression Scale, and cognitive functioning was assessed using an SVD cognitive screening tool, the Brief Memory and Executive Test, which measures executive functioning/processing speed and memory/orientation. Path analysis and binary logistic regression were used to assess the relation between apathy, depression and cognitive impairment. Results 31 participants with SVD (15.8%) met criteria for apathy only, 23 (11.8%) for both apathy and depression, and 2 (1.0%) for depression only. In the SVD group the presence of apathy was related to global cognition, and specifically to impaired executive functioning/processing speed, but not memory/orientation. The presence of depression was not related to global cognition, impaired executive functioning/processing speed or memory/orientation. Conclusions Apathy is a common feature of SVD and is associated with impaired executive functioning/processing speed suggesting the two may share biological mechanisms. Screening for apathy should be considered in SVD, and further work is required to develop and evaluate effective apathy treatment or management in SVD. PMID:28493898

Spatial and Temporal Coordination of Bone Marrow-Derived Cell Activity During Arteriogenesis: Regulation of the Endogenous Response and Therapeutic Implications

PubMed Central

Meisner, Joshua K.; Price, Richard J.

2010-01-01

Arterial occlusive disease (AOD) is the leading cause of morbidity and mortality through the developed world, which creates a significant need for effective therapies to halt disease progression. Despite success of animal and small-scale human therapeutic arteriogenesis studies, this promising concept for treating AOD has yielded largely disappointing results in large-scale clinical trials. One reason for this lack of successful translation is that endogenous arteriogenesis is highly dependent on a poorly understood sequence of events and interactions between bone marrow derived cells (BMCs) and vascular cells, which makes designing effective therapies difficult. We contend that the process follows a complex, ordered sequence of events with multiple, specific BMC populations recruited at specific times and locations. Here we present the evidence suggesting roles for multiple BMC populations from neutrophils and mast cells to progenitor cells and propose how and where these cell populations fit within the sequence of events during arteriogenesis. Disruptions in these various BMC populations can impair the arteriogenesis process in patterns that characterize specific patient populations. We propose that an improved understanding of how arteriogenesis functions as a system can reveal individual BMC populations and functions that can be targeted for overcoming particular impairments in collateral vessel development. PMID:21044213

Mannose-binding lectin-associated serine protease 2 (MASP-2) contributes to poor disease outcome in humans and mice with pneumococcal meningitis.

PubMed

Kasanmoentalib, E Soemirien; Valls Seron, Mercedes; Ferwerda, Bart; Tanck, Michael W; Zwinderman, Aeilko H; Baas, Frank; van der Ende, Arie; Brouwer, Matthijs C; van de Beek, Diederik

2017-01-03

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the pro-inflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. We investigated mannose-binding lectin-associated serine protease (MASP-2) levels in cerebrospinal fluid (CSF) samples derived from the diagnostic lumbar puncture, which was available for 307 of 792 pneumococcal meningitis episodes included in our prospective nationwide cohort study (39%), and the association between these levels and clinical outcome. Subsequently, we studied the role of MASP-2 in our experimental pneumococcal meningitis mouse model using Masp2 -/- mice and evaluated the potential of adjuvant treatment with MASP-2-specific monoclonal antibodies in wild-type (WT) mice. MASP-2 levels in cerebrospinal fluid of patients with bacterial meningitis were correlated with poor functional outcome. Consistent with these human data, Masp2-deficient mice with pneumococcal meningitis had lower cytokine levels and increased survival compared to WT mice. Adjuvant treatment with MASP-2-specific monoclonal antibodies led to reduced complement activation and decreased disease severity. MASP-2 contributes to poor disease outcome in human and mice with pneumococcal meningitis. MASP-2-specific monoclonal antibodies can be used to attenuate the inflammatory response in pneumococcal meningitis.

Prostate-specific Membrane Antigen PET: Clinical Utility in Prostate Cancer, Normal Patterns, Pearls, and Pitfalls.

PubMed

Hofman, Michael S; Hicks, Rodney J; Maurer, Tobias; Eiber, Matthias

2018-01-01

Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein that is overexpressed in prostate cancer. Radiolabeled small molecules that bind with high affinity to its active extracellular center have emerged as a potential new diagnostic standard of reference for prostate cancer, resulting in images with extraordinary tumor-to-background contrast. Currently, gallium 68 ( 68 Ga)-PSMA-11 (or HBED-PSMA) is the most widely used radiotracer for PSMA positron emission tomography (PET)/computed tomography (CT) or PSMA PET/magnetic resonance (MR) imaging. Evolving evidence demonstrates superior sensitivity and specificity of PSMA PET compared to conventional imaging, with frequent identification of subcentimeter prostate cancer lesions. PSMA PET is effective for imaging disease in the prostate, lymph nodes, soft tissue, and bone in a "one-stop-shop" examination. There is emerging evidence for its clinical value in staging of high-risk primary prostate cancer and localization of disease in biochemical recurrence. The high sensitivity provided by PSMA PET, with frequent identification of small-volume disease, is redefining patterns of disease spread compared with those seen at conventional imaging. In metastatic castration-resistant prostate cancer, PSMA PET is frequently used for theranostic selection (eg, lutetium 177-PSMA radionuclide therapy), but its potential use for therapy monitoring is still under debate. However, evidence on its proper use to improve patient-related outcomes, particularly in the setting of early biochemical recurrence and targeted treatment of oligometastatic disease, is still missing. Despite the term prostate specific, PSMA functions as a folate hydrolase and is expressed in a range of normal tissues and in other benign and malignant processes. Knowledge of its physiologic distribution and other causes of uptake is essential to minimize false-positive imaging findings. © RSNA, 2018.

A double-labeling immunohistochemical study of tau exon 10 in Alzheimer's disease, progressive supranuclear palsy and Pick's disease.

PubMed

Ishizawa, K; Ksiezak-Reding, H; Davies, P; Delacourte, A; Tiseo, P; Yen, S H; Dickson, D W

2000-09-01

Neurofibrillary tangles (NFT), one of the histopathological hallmarks of Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), and Pick bodies in Pick's disease (PiD) are composed of microtubule-associated protein tau, which is the product of alternative splicing of a gene on chromosome 17. Alternative expression of exon 10 leads to formation of three- or four-repeat tau isoforms. To study the differential expression of exon 10, we performed double-labeling immunohistochemistry of the hippocampal formation in nine AD, four PSP and three PiD cases. Cryostat sections were processed with and without formic acid (FA) treatment, and double-stained with anti-tau (Alz-50 or PHF-1) or anti-amyloid P component antibodies and one of two specific anti-exon 10 antibodies (E-10). The effect of proteinase-K treatment was also evaluated. The results suggest the following. First, in AD, E-10 immunoreactivity is present in most intracellular NFT, but not in most dystrophic neurites and neuropil threads, suggesting differential expression of tau isoforms in specific cellular domains. Second, in AD, E-10 immunoreactivity is lost or blocked in most extracellular NFT, possibly due to proteolysis. Third, in PSP, E-10 immunoreactivity is hidden or blocked in NFT and tau-positive glial inclusions, but FA treatment exposes the epitope consistent with the hypothesis that PSP inclusions contain four-repeat tau. Fourth, E-10 immunoreactivity is present in dentate fascia NFT in AD and PSP, but not in Pick bodies in the dentate fascia or other areas. The results suggest that expression of exon 10 in tau is specific for cellular domains in a disease-specific manner.

Deciphering the functions of O-GlcNAc glycosylation in the brain: The role of site-specific quantitative O-GlcNAcomics.

PubMed

Thompson, John W; Sorum, Alexander W; Hsieh-Wilson, Linda C

2018-06-23

The dynamic posttranslational modification O-linked β-N-acetylglucosamine glycosylation (O-GlcNAcylation) is present on thousands of intracellular proteins in the brain. Like phosphorylation, O-GlcNAcylation is inducible and plays important functional roles in both physiology and disease. Recent advances in mass spectrometry (MS) and bioconjugation methods are now enabling the mapping of O-GlcNAcylation events to individual sites in proteins. However, our understanding of which glycosylation events are necessary for regulating protein function and controlling specific processes, phenotypes, or diseases remains in its infancy. Given the sheer number of O-GlcNAc sites, methods are greatly needed to identify promising sites and prioritize them for time- and resource-intensive functional studies. Revealing sites that are dynamically altered by different stimuli or disease states will likely to go a long way in this regard. Here, we describe advanced methods for identifying O-GlcNAc sites on individual proteins and across the proteome, and for determining their stoichiometry in vivo. We also highlight emerging technologies for quantitative, site-specific MS-based O-GlcNAc proteomics (O-GlcNAcomics), which allow proteome-wide tracking of O-GlcNAcylation dynamics at individual sites. These cutting-edge technologies are beginning to bridge the gap between the high-throughput cataloging of O-GlcNAcylated proteins and the relatively low-throughput study of individual proteins. By uncovering the O-GlcNAcylation events that change in specific physiological and disease contexts, these new approaches are providing key insights into the regulatory functions of O-GlcNAc in the brain, including their roles in neuroprotection, neuronal signaling, learning and memory, and neurodegenerative diseases.

Disease-specific dynamic biomarkers selected by integrating inflammatory mediators with clinical informatics in ARDS patients with severe pneumonia.

PubMed

Chen, Chengshui; Shi, Lin; Li, Yuping; Wang, Xiangdong; Yang, Shuanying

2016-06-01

Acute respiratory distress syndrome (ARDS) is a heterogeneous syndrome that occurs as a result of various risk factors, including either direct or indirect lung injury, and systemic inflammation triggered also by severe pneumonia (SP). SP-ARDS-associated morbidity and mortality remains high also due to the lack of disease-specific biomarkers. The present study aimed at identifying disease-specific biomarkers in SP or SP-ARDS by integrating proteomic profiles of inflammatory mediators with clinical informatics. Plasma was sampled from the healthy as controls or patients with SP infected with bacteria or infection-associated SP-ARDS on the day of admission, day 3, and day 7. About 15 or 52 cytokines showed significant difference between SP and SP-ARDS patients with controls or 13 between SP-ARDS with SP alone and controls, including bone morphogenetic protein-15 (BMP-15), chemokine (C-X-C motif) ligand 16 (CXCL16), chemokine (C-X-C motif) receptor 3 (CXCR3), interleukin-6 (IL-6), protein NOV homolog (NOV/CCN3), glypican 3, insulin-like growth factor binding protein 4 (IGFBP-4), IL-5, IL-5 R alpha, IL-22 BP, leptin, MIP-1d, and orexin B with a significant correlation with Digital Evaluation Score System (DESS) scores. ARDS patients with overexpressed IL-6, CXCL16, or IGFBP-4 had significantly longer hospital stay and higher incidence of secondary infection. We also found higher levels of those mediators were associated with poor survival rates in patients with lung cancer and involved in the process of the epithelial mesenchymal transition of alveolar epithelial cells. Our preliminary study suggested that integration of proteomic profiles with clinical informatics as part of clinical bioinformatics is important to validate and optimize disease-specific and disease-staged biomarkers.

Imaging epigenetics in Alzheimer's disease.

PubMed

Lista, Simone; Garaci, Francesco G; Toschi, Nicola; Hampel, Harald

2013-01-01

Sporadic Alzheimer's disease (AD) is a prevalent, complex and chronically progressive brain disease. Its course is non-linear, dynamic, adaptive to maladaptive, and compensatory to decompensatory, affecting large-scale neural networks through a plethora of mechanistic and signaling pathway alterations that converge into regional and cell type-specific neurodegeneration and, finally, into clinically overt cognitive and behavioral decline. This decline includes reductions in the activities of daily living, quality of life, independence, and life expectancy. Evolving lines of research suggest that epigenetic mechanisms may play a crucial role during AD development and progression. Epigenetics designates molecular mechanisms that alter gene expression without modifications of the genetic code. This topic includes modifications on DNA and histone proteins, the primary elements of chromatin structure. Accumulating evidence has revealed the relevant processes that mediate epigenetic modifications and has begun to elucidate how these processes are apparently dysregulated in AD. This evidence has led to the clarification of the roles of specific classes of therapeutic compounds that affect epigenetic pathways and characteristics of the epigenome. This insight is accompanied by the development of new methods for studying the global patterns of DNA methylation and chromatin alterations. In particular, high-throughput sequencing approaches, such as next-generation DNA sequencing techniques, are beginning to drive the field into the next stage of development. In parallel, genetic imaging is beginning to answer additional questions through its ability to uncover genetic variants, with or without genome-wide significance, that are related to brain structure, function and metabolism, which impact disease risk and fundamental network-based cognitive processes. Neuroimaging measures can further be used to define AD systems and endophenotypes. The integration of genetic neuroimaging methods with epigenetic markers in humans appears promising. This evolving development may lead to a new research discipline - imaging epigenetics - that will provide deeper insight into the causative pathogenetic and pathophysiological pathways through which genes and environment interrelate during life and impact human brain development, physiology, aging and disease. This knowledge may open doors for the development of novel biomarkers and preventive and disease-modifying treatments.

Human pluripotent stem cells as tools for neurodegenerative and neurodevelopmental disease modeling and drug discovery.

PubMed

Corti, Stefania; Faravelli, Irene; Cardano, Marina; Conti, Luciano

2015-06-01

Although intensive efforts have been made, effective treatments for neurodegenerative and neurodevelopmental diseases have not been yet discovered. Possible reasons for this include the lack of appropriate disease models of human neurons and a limited understanding of the etiological and neurobiological mechanisms. Recent advances in pluripotent stem cell (PSC) research have now opened the path to the generation of induced pluripotent stem cells (iPSCs) starting from somatic cells, thus offering an unlimited source of patient-specific disease-relevant neuronal cells. In this review, the authors focus on the use of human PSC-derived cells in modeling neurological disorders and discovering of new drugs and provide their expert perspectives on the field. The advent of human iPSC-based disease models has fuelled renewed enthusiasm and enormous expectations for insights of disease mechanisms and identification of more disease-relevant and novel molecular targets. Human PSCs offer a unique tool that is being profitably exploited for high-throughput screening (HTS) platforms. This process can lead to the identification and optimization of molecules/drugs and thus move forward new pharmacological therapies for a wide range of neurodegenerative and neurodevelopmental conditions. It is predicted that improvements in the production of mature neuronal subtypes, from patient-specific human-induced pluripotent stem cells and their adaptation to culture, to HTS platforms will allow the increased exploitation of human pluripotent stem cells in drug discovery programs.

The intersection between growth factors, autophagy and ER stress: A new target to treat neurodegenerative diseases?

PubMed

Garcia-Huerta, Paula; Troncoso-Escudero, Paulina; Jerez, Carolina; Hetz, Claudio; Vidal, Rene L

2016-10-15

One of the salient features of most neurodegenerative diseases is the aggregation of specific proteins in the brain. This proteostasis imbalance is proposed as a key event triggering the neurodegenerative cascade. The unfolded protein response (UPR) and autophagy pathways are emerging as critical processes implicated in handling disease-related misfolded proteins. However, in some conditions, perturbations in the buffering capacity of the proteostasis network may be part of the etiology of the disease. Thus, pharmacological or gene therapy strategies to enhance autophagy or UPR responses are becoming an attractive target for disease intervention. Here, we discuss current evidence depicting the complex involvement of autophagy and ER stress in brain diseases. Novel pathways to modulate protein misfolding are discussed including the relation between aging and growth factor signaling. This article is part of a Special Issue entitled SI:Autophagy. Copyright © 2016 Elsevier B.V. All rights reserved.

Genetically manipulated mouse models of lung disease: potential and pitfalls

PubMed Central

Choi, Alexander J. S.; Owen, Caroline A.; Choi, Augustine M. K.

2012-01-01

Gene targeting in mice (transgenic and knockout) has provided investigators with an unparalleled armamentarium in recent decades to dissect the cellular and molecular basis of critical pathophysiological states. Fruitful information has been derived from studies using these genetically engineered mice with significant impact on our understanding, not only of specific biological processes spanning cell proliferation to cell death, but also of critical molecular events involved in the pathogenesis of human disease. This review will focus on the use of gene-targeted mice to study various models of lung disease including airways diseases such as asthma and chronic obstructive pulmonary disease, and parenchymal lung diseases including idiopathic pulmonary fibrosis, pulmonary hypertension, pneumonia, and acute lung injury. We will attempt to review the current technological approaches of generating gene-targeted mice and the enormous dataset derived from these studies, providing a template for lung investigators. PMID:22198907

[Reliable health information for patients with rare diseases : Quality demands defined by the National Action Plan and how they are put into practice].

PubMed

Schaefer, Corinna; Brunsmann, Frank; Siegert, Svenja

2017-05-01

Information for patients with rare diseases has to adhere to strict quality criteria in order to support individual treatment decisions or coping strategies. However, developers are facing specific challenges: For example, the evidence is often insufficient or of very low quality. In the context of the National Action League for People with Rare Diseases (NAMSE), criteria have been developed that assure high-quality information on rare diseases. Core criteria comprise the involvement of patients or their advocates in all stages of the development process, the systematic search and assessment of the evidence, systematic collection of patient experience, transparency in terms of people involved and funding, and nondirective and neutral formulation of content and documentation of the process. In a joint project between the Alliance for Chronic Rare Diseases (ACHSE e. V.) and the German Agency for Quality in Medicine (ÄZQ), ten short information leaflets on different rare diseases have been developed in the past three years, conceived to show the applicability of these criteria. First experiences with this format show that the criteria are adaptive to a broad range of diverse rare diseases and settings. Involving patients and their advocates throughout the whole development process - from prioritization to development of methods and provision of patient experience and coping strategies - is crucial. Insufficient evidence remains a challenge. The examples show that in the absence of proven findings, information that matters to patients and reflects this uncertainty is feasible.

Using Big Data to Discover Diagnostics and Therapeutics for Gastrointestinal and Liver Diseases

PubMed Central

Wooden, Benjamin; Goossens, Nicolas; Hoshida, Yujin; Friedman, Scott L.

2016-01-01

Technologies such as genome sequencing, gene expression profiling, proteomic and metabolomic analyses, electronic medical records, and patient-reported health information have produced large amounts of data, from various populations, cell types, and disorders (big data). However, these data must be integrated and analyzed if they are to produce models or concepts about physiologic function or mechanisms of pathogenesis. Many of these data are available to the public, allowing researchers anywhere to search for markers of specific biologic processes or therapeutic targets for specific diseases or patient types. We review recent advances in the fields of computational and systems biology, and highlight opportunities for researchers to use big data sets in the fields of gastroenterology and hepatology, to complement traditional means of diagnostic and therapeutic discovery. PMID:27773806

[Diagnosis and treatment of pulmonary hypertension].

PubMed

Román, J Sánchez; Hernández, F J García; Palma, M J Castillo; Medina, C Ocaña

2008-03-01

Pulmonary arterial hypertension is an idiopathic process or can be associated with another circumstances (connective tissue diseases, congenital heart disease, portal hypertension, exposure to appetite suppressants or another drugs or infectious agents such as HIV). Most patients are diagnosed as the result of an evaluation of symptoms, whereas others are diagnosed incidentally or during screening of asymptomatic populations at risk. We reviews systematic screening for the approach to diagnosing pulmonary arterial hypertension. A diagnostic algorithm can guide the evaluation but it can be modified according to specific clinical circumstances. The number of therapeutic options has increased.in the last years. We reviews the use of calcium-channel blockers, prostacyclin (and analogues), endothelin-receptor antagonists, and phosphodiesterase-5 inhibitors, and the use of combination therapy, and provides specific recommendations about the actual treatment.

Electrical engram: how deep brain stimulation affects memory.

PubMed

Lee, Hweeling; Fell, Jürgen; Axmacher, Nikolai

2013-11-01

Deep brain stimulation (DBS) is a surgical procedure involving implantation of a pacemaker that sends electric impulses to specific brain regions. DBS has been applied in patients with Parkinson's disease, depression, and obsessive-compulsive disorder (among others), and more recently in patients with Alzheimer's disease to improve memory functions. Current DBS approaches are based on the concept that high-frequency stimulation inhibits or excites specific brain regions. However, because DBS entails the application of repetitive electrical stimuli, it primarily exerts an effect on extracellular field-potential oscillations similar to those recorded with electroencephalography. Here, we suggest a new perspective on how DBS may ameliorate memory dysfunction: it may enhance normal electrophysiological patterns underlying long-term memory processes within the medial temporal lobe. Copyright © 2013 Elsevier Ltd. All rights reserved.

Single Insulin-Specific CD8+ T Cells Show Characteristic Gene Expression Profiles in Human Type 1 Diabetes

PubMed Central

Luce, Sandrine; Lemonnier, François; Briand, Jean-Paul; Coste, Joel; Lahlou, Najiba; Muller, Sylviane; Larger, Etienne; Rocha, Benedita; Mallone, Roberto; Boitard, Christian

2011-01-01

OBJECTIVE Both the early steps and the high recurrence of autoimmunity once the disease is established are unexplained in human type 1 diabetes. Because CD8+ T cells are central and insulin is a key autoantigen in the disease process, our objective was to characterize HLA class I–restricted autoreactive CD8+ T cells specific for preproinsulin (PPI) in recent-onset and long-standing type 1 diabetic patients and healthy control subjects. RESEARCH DESIGN AND METHODS We used HLA-A*02:01 tetramers complexed to PPI peptides to enumerate circulating PPI-specific CD8+ T cells in patients and characterize them using membrane markers and single-cell PCR. RESULTS Most autoreactive CD8+ T cells detected in recent-onset type 1 diabetic patients are specific for leader sequence peptides, notably PPI6–14, whereas CD8+ T cells in long-standing patients recognize the B-chain peptide PPI33–42 (B9–18). Both CD8+ T-cell specificities are predominantly naïve, central, and effector memory cells, and their gene expression profile differs from cytomegalovirus-specific CD8+ T cells. PPI6–14–specific CD8+ T cells detected in one healthy control displayed Il-10 mRNA expression, which was not observed in diabetic patients. CONCLUSIONS PPI-specific CD8+ T cells in type 1 diabetic patients include central memory and target different epitopes in new-onset versus long-standing disease. Our data support the hypothesis that insulin therapy may contribute to the expansion of autoreactive CD8+ T cells in the long term. PMID:21998398

A mixture model with a reference-based automatic selection of components for disease classification from protein and/or gene expression levels

PubMed Central

2011-01-01

Background Bioinformatics data analysis is often using linear mixture model representing samples as additive mixture of components. Properly constrained blind matrix factorization methods extract those components using mixture samples only. However, automatic selection of extracted components to be retained for classification analysis remains an open issue. Results The method proposed here is applied to well-studied protein and genomic datasets of ovarian, prostate and colon cancers to extract components for disease prediction. It achieves average sensitivities of: 96.2 (sd = 2.7%), 97.6% (sd = 2.8%) and 90.8% (sd = 5.5%) and average specificities of: 93.6% (sd = 4.1%), 99% (sd = 2.2%) and 79.4% (sd = 9.8%) in 100 independent two-fold cross-validations. Conclusions We propose an additive mixture model of a sample for feature extraction using, in principle, sparseness constrained factorization on a sample-by-sample basis. As opposed to that, existing methods factorize complete dataset simultaneously. The sample model is composed of a reference sample representing control and/or case (disease) groups and a test sample. Each sample is decomposed into two or more components that are selected automatically (without using label information) as control specific, case specific and not differentially expressed (neutral). The number of components is determined by cross-validation. Automatic assignment of features (m/z ratios or genes) to particular component is based on thresholds estimated from each sample directly. Due to the locality of decomposition, the strength of the expression of each feature across the samples can vary. Yet, they will still be allocated to the related disease and/or control specific component. Since label information is not used in the selection process, case and control specific components can be used for classification. That is not the case with standard factorization methods. Moreover, the component selected by proposed method as disease specific can be interpreted as a sub-mode and retained for further analysis to identify potential biomarkers. As opposed to standard matrix factorization methods this can be achieved on a sample (experiment)-by-sample basis. Postulating one or more components with indifferent features enables their removal from disease and control specific components on a sample-by-sample basis. This yields selected components with reduced complexity and generally, it increases prediction accuracy. PMID:22208882

Entrepreneurship in health education and health promotion: five cardinal rules.

PubMed

Eddy, James M; Stellefson, Michael L

2009-07-01

The nature of health education and health promotion (HE/HP) offers a fertile ground for entrepreneurial activity. As primary prevention of chronic diseases becomes a more central component of the health and/ or medical care continuum, entrepreneurial opportunities for health educators will continue to expand. The process used to design, implement, and evaluate health promotion and disease prevention has clear articulation with entrepreneurial, marketing management, and other business processes. Thus, entrepreneurs in HE/HP must be able to utilize business process to facilitate creative, new HE/HP business ideas. The purpose of this article is to weave theory and practical application into a primer on entrepreneurial applications in HE/HP. More specifically, the authors meld their prospective experiences and expertise to provide background thoughts on entrepreneurship in HE/HP and develop a framework for establishing an entrepreneurial venture in HE/HP. Five Cardinal Rules for Entrepreneurs in HE/HP are proposed.

[AGING AND OSTEOARTHRITIS. CHRONIC NONSPECIFIC INFLAMMATION AS A LINK BETWEEN AGING AND OSTEOARTHRITIS (REVIEW)].

PubMed

Mendel, O I; Luchihina, L V; Mendel, W

2015-01-01

This article presents review on the processes underlying aging and the most common age-associated diseases. Special attention is given to the role of chronic nonspecific inflammation. Based on the literature data it was demonstrated that aging and osteoarthritis have the same basic molecular and cellular mechanisms, among which general are cascades intracellular transcription chronic nonspecific inflammation and metabolic disturbances plays an important role. It is concluded that the process of normal aging is not a disease, but makes the human body, and particularly the musculoskeletal system, susceptible to age-associated changes. Number of changes in the human body that accompany the aging process, and play a role in the development and progression of OA, are potentially reversible, regardless of age (eg, chronic non-specific inflammation), and can be considered as a possible entry points for the effective prevention and complex therapy of OA in elderly people.

Epigenetic regulatory mechanisms in vertebrate eye development and disease

PubMed Central

Cvekl, A; Mitton, KP

2014-01-01

Eukaryotic DNA is organized as a nucleoprotein polymer termed chromatin with nucleosomes serving as its repetitive architectural units. Cellular differentiation is a dynamic process driven by activation and repression of specific sets of genes, partitioning the genome into transcriptionally active and inactive chromatin domains. Chromatin architecture at individual genes/loci may remain stable through cell divisions, from a single mother cell to its progeny during mitosis, and represents an example of epigenetic phenomena. Epigenetics refers to heritable changes caused by mechanisms distinct from the primary DNA sequence. Recent studies have shown a number of links between chromatin structure, gene expression, extracellular signaling, and cellular differentiation during eye development. This review summarizes recent advances in this field, and the relationship between sequence-specific DNA-binding transcription factors and their roles in recruitment of chromatin remodeling enzymes. In addition, lens and retinal differentiation is accompanied by specific changes in the nucleolar organization, expression of non-coding RNAs, and DNA methylation. Epigenetic regulatory mechanisms in ocular tissues represent exciting areas of research that have opened new avenues for understanding normal eye development, inherited eye diseases and eye diseases related to aging and the environment. PMID:20179734

Pharmacogenomics in cardiovascular clinical trials.

PubMed

Shah, R; Darne, B; Atar, D; Abadie, E; Adams, K F; Zannad, F

2004-12-01

Genomics - having quickly emerged as the central discipline in basic science and biomedical research - is poised to take the center stage in clinical medicine as well over the next few decades. Although there is no specific regulatory guideline on the application of pharmacogenetics to drug development, some recommendations are already included in several published guidelines on drug development. The patients more likely to provide the most valuable information on the specific contribution of a given gene or its variant are those who fail to respond to a drug ('therapeutic failures') and those who develop toxicity to the drug. However, before drawing definite conclusions on subgroups following pharmacogenomic analyses, one must be aware of disease classification, data collection, and how much is known about the disease process. It seems reasonable to collect genomic DNA from all patients enrolled in clinical drug trials (along with appropriate consent to permit pharmacogenetic studies) for the purpose of post hoc analyses. One exception to post hoc genomic analysis is when patients with a specific genotype are excluded from randomization into a clinical trial. Physicians will need to understand the concept of genetic variability, its interactions with the environment (e.g. drug-drug or drug-disease interactions), and its implication for patient care.

Sudden Infant Death Syndrome, FY 1983. Special Report to Congress.

ERIC Educational Resources Information Center

National Inst. of Child Health and Human Development (NIH), Bethesda, MD.

This report describes research programs focusing on the sudden infant death syndrome (SIDS) and indicates some presently available results. Specific attention is given to research on sleep apnea, respiratory control, and hypoxia, as well as to infectious disease processes and immunology. Findings of a large-scale multidisciplinary SIDS project are…

Striatal Degeneration Impairs Language Learning: Evidence from Huntington's Disease

ERIC Educational Resources Information Center

De Diego-Balaguer, R.; Couette, M.; Dolbeau, G.; Durr, A.; Youssov, K.; Bachoud-Levi, A.-C.

2008-01-01

Although the role of the striatum in language processing is still largely unclear, a number of recent proposals have outlined its specific contribution. Different studies report evidence converging to a picture where the striatum may be involved in those aspects of rule-application requiring non-automatized behaviour. This is the main…

The multiple roles of EG-VEGF/PROK1 in normal and pathological placental angiogenesis.

PubMed

Alfaidy, Nadia; Hoffmann, Pascale; Boufettal, Houssine; Samouh, Naima; Aboussaouira, Touria; Benharouga, Mohamed; Feige, Jean-Jacques; Brouillet, Sophie

2014-01-01

Placentation is associated with several steps of vascular adaptations throughout pregnancy. These vascular changes occur both on the maternal and fetal sides, consisting of maternal uterine spiral arteries remodeling and placental vasculogenesis and angiogenesis, respectively. Placental angiogenesis is a pivotal process for efficient fetomaternal exchanges and placental development. This process is finely controlled throughout pregnancy, and it involves ubiquitous and pregnancy-specific angiogenic factors. In the last decade, endocrine gland derived vascular endothelial growth factor (EG-VEGF), also called prokineticin 1 (PROK1), has emerged as specific placental angiogenic factor that controls many aspects of normal and pathological placental angiogenesis such as recurrent pregnancy loss (RPL), gestational trophoblastic diseases (GTD), fetal growth restriction (FGR), and preeclampsia (PE). This review recapitulates EG-VEGF mediated-angiogenesis within the placenta and at the fetomaternal interface and proposes that its deregulation might contribute to the pathogenesis of several placental diseases including FGR and PE. More importantly this paper argues for EG-VEGF clinical relevance as a potential biomarker of the onset of pregnancy pathologies and discusses its potential usefulness for future therapeutic directions.

Prediction of proprotein convertase cleavage sites.

PubMed

Duckert, Peter; Brunak, Søren; Blom, Nikolaj

2004-01-01

Many secretory proteins and peptides are synthesized as inactive precursors that in addition to signal peptide cleavage undergo post-translational processing to become biologically active polypeptides. Precursors are usually cleaved at sites composed of single or paired basic amino acid residues by members of the subtilisin/kexin-like proprotein convertase (PC) family. In mammals, seven members have been identified, with furin being the one first discovered and best characterized. Recently, the involvement of furin in diseases ranging from Alzheimer's disease and cancer to anthrax and Ebola fever has created additional focus on proprotein processing. We have developed a method for prediction of cleavage sites for PCs based on artificial neural networks. Two different types of neural networks have been constructed: a furin-specific network based on experimental results derived from the literature, and a general PC-specific network trained on data from the Swiss-Prot protein database. The method predicts cleavage sites in independent sequences with a sensitivity of 95% for the furin neural network and 62% for the general PC network. The ProP method is made publicly available at http://www.cbs.dtu.dk/services/ProP.

A Flow Adhesion Assay to Study Leucocyte Recruitment to Human Hepatic Sinusoidal Endothelium Under Conditions of Shear Stress

PubMed Central

Shetty, Shishir; Weston, Christopher J.; Adams, David H.; Lalor, Patricia F.

2014-01-01

Leucocyte infiltration into human liver tissue is a common process in all adult inflammatory liver diseases. Chronic infiltration can drive the development of fibrosis and progression to cirrhosis. Understanding the molecular mechanisms that mediate leucocyte recruitment to the liver could identify important therapeutic targets for liver disease. The key interaction during leucocyte recruitment is that of inflammatory cells with endothelium under conditions of shear stress. Recruitment to the liver occurs within the low shear channels of the hepatic sinusoids which are lined by hepatic sinusoidal endothelial cells (HSEC). The conditions within the hepatic sinusoids can be recapitulated by perfusing leucocytes through channels lined by human HSEC monolayers at specific flow rates. In these conditions leucocytes undergo a brief tethering step followed by activation and firm adhesion, followed by a crawling step and subsequent transmigration across the endothelial layer. Using phase contrast microscopy, each step of this 'adhesion cascade' can be visualized and recorded followed by offline analysis. Endothelial cells or leucocytes can be pretreated with inhibitors to determine the role of specific molecules during this process. PMID:24686418

Sarcopenia in Patients with Chronic Liver Disease: Can It Be Altered by Diet and Exercise?

PubMed

Kappus, Matthew R; Mendoza, Mardeli Saire; Nguyen, Douglas; Medici, Valentina; McClave, Stephen A

2016-08-01

Sarcopenia, a loss of muscle mass, is being increasingly recognized to have a deleterious effect on outcomes in patients with chronic liver disease. Factors related to diet and the inflammatory nature of chronic liver disease contribute to the occurrence of sarcopenia in these patients. Sarcopenia adversely influences quality of life, performance, morbidity, success of transplantation, and even mortality. Specific deficiencies in macronutrients (protein, polyunsaturated fatty acids) and micronutrients (vitamins C, D, and E, carotenoids, and selenium) have been linked to sarcopenia. Lessons learned from nutritional therapy in geriatric patient populations may provide strategies to manage sarcopenia in patients with liver disease. Combining diet modification and nutrient supplementation with an organized program of exercise may help ameliorate or even reverse the effects of sarcopenia on an already complex disease process.

New Radiotracers for Imaging of Vascular Targets in Angiogenesis-related Diseases

PubMed Central

Hong, Hao; Chen, Feng; Zhang, Yin; Cai, Weibo

2014-01-01

Tremendous advances over the last several decades in positron emission tomography (PET) and single photon emission computed tomography (SPECT) allow for targeted imaging of molecular and cellular events in the living systems. Angiogenesis, a multistep process regulated by the network of different angiogenic factors, has attracted world-wide interests, due to its pivotal role in the formation and progression of different diseases including cancer, cardiovascular diseases (CVD), and inflammation. In this review article, we will summarize the recent progress in PET or SPECT imaging of a wide variety of vascular targets in three major angiogenesis-related diseases: cancer, cardiovascular diseases, and inflammation. Faster drug development and patient stratification for a specific therapy will become possible with the facilitation of PET or SPECT imaging and it will be critical for the maximum benefit of patients. PMID:25086372

Epilepsy: habilitation and rehabilitation.

PubMed

Marks, Warren A; Hernandez, Angel; Gabriel, Marsha

2003-06-01

Rehabilitation represents not only a distinct field of medicine, but also a philosophical and practical treatment approach that can be applied to a variety of chronic disorders. Neurology encompasses many chronic disorders, making it ideal for the application of rehabilitation principles in daily practice. Epilepsy offers a unique opportunity to incorporate rehabilitation principles into the management of a complex medical disorder. Epilepsy is an evolving disease process that changes with the maturation of the central nervous system. The rehabilitative model provides the framework for a dynamic treatment plan to meet the changing needs of the child with epilepsy through the social and developmental changes of childhood, adolescence, and adulthood. The development of epilepsy may complicate the recovery from many acute and chronic conditions that affect the central nervous system. The rehabilitation process must address these many aspects of the disease process and its sequelae. This makes neurologists uniquely qualified to manage the rehabilitation team. The impact of the therapeutic milieu on the recovery process may be as important as any specific medical or surgical intervention.

Takayasu's disease in a young black boy.

PubMed

Oguntona, S A

2010-12-01

Takayusu's disease is a rare disease affecting women predominantly during the child- bearing age. It is a primary vasculitis condition of large-vessels that responds well to steroid therapy. Immunosuppressives and vascular reconstruction may be needed as necessary. Reference was made to the case note of this young boy who was being co-managed by cardiology and vascular clinics. The diagnosis of Takayasu's disease was confirmed by the rheumatology unit and appropriate literature search was done. Takayusu's disease responds well to steroid therapy as exemplified by this patient. There was no relapse of the active inflammation after six months of steroid therapy. A high index of suspicion must be exercise in diagnosing Takayasu's disease. It could be difficult to have a clue early in the disease process because of non-specific presentations. Appropriate referral should however be made to Rheumatologist when the diagnosis is suspected. This will go a long way in delaying the morbidity that is associated with this rare disease.

Inhibition of Super-Enhancer Activity in Autoinflammatory Site-Derived T Cells Reduces Disease-Associated Gene Expression.

PubMed

Peeters, Janneke G C; Vervoort, Stephin J; Tan, Sander C; Mijnheer, Gerdien; de Roock, Sytze; Vastert, Sebastiaan J; Nieuwenhuis, Edward E S; van Wijk, Femke; Prakken, Berent J; Creyghton, Menno P; Coffer, Paul J; Mokry, Michal; van Loosdregt, Jorg

2015-09-29

The underlying molecular mechanisms for many autoimmune diseases are poorly understood. Juvenile idiopathic arthritis (JIA) is an exceptionally well-suited model for studying autoimmune diseases due to its early onset and the possibility to analyze cells derived from the site of inflammation. Epigenetic profiling, utilizing primary JIA patient-derived cells, can contribute to the understanding of autoimmune diseases. With H3K27ac chromatin immunoprecipitation, we identified a disease-specific, inflammation-associated, typical enhancer and super-enhancer signature in JIA patient synovial-fluid-derived CD4(+) memory/effector T cells. RNA sequencing of autoinflammatory site-derived patient T cells revealed that BET inhibition, utilizing JQ1, inhibited immune-related super-enhancers and preferentially reduced disease-associated gene expression, including cytokine-related processes. Altogether, these results demonstrate the potential use of enhancer profiling to identify disease mediators and provide evidence for BET inhibition as a possible therapeutic approach for the treatment of autoimmune diseases. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Zebrafish models flex their muscles to shed light on muscular dystrophies.

PubMed

Berger, Joachim; Currie, Peter D

2012-11-01

Muscular dystrophies are a group of genetic disorders that specifically affect skeletal muscle and are characterized by progressive muscle degeneration and weakening. To develop therapies and treatments for these diseases, a better understanding of the molecular basis of muscular dystrophies is required. Thus, identification of causative genes mutated in specific disorders and the study of relevant animal models are imperative. Zebrafish genetic models of human muscle disorders often closely resemble disease pathogenesis, and the optical clarity of zebrafish embryos and larvae enables visualization of dynamic molecular processes in vivo. As an adjunct tool, morpholino studies provide insight into the molecular function of genes and allow rapid assessment of candidate genes for human muscular dystrophies. This unique set of attributes makes the zebrafish model system particularly valuable for the study of muscle diseases. This review discusses how recent research using zebrafish has shed light on the pathological basis of muscular dystrophies, with particular focus on the muscle cell membrane and the linkage between the myofibre cytoskeleton and the extracellular matrix.

Systematic and progressive implementation of the centers of excellence for rheumatoid arthritis: a methodological proposal.

PubMed

Santos-Moreno, Pedro; Caballero-Uribe, Carlo V; Massardo, Maria Loreto; Maldonado, Claudio Galarza; Soriano, Enrique R; Pineda, Carlos; Cardiel, Mario; Benavides, Juan Alberto; Beltrán, Paula Andrea

2017-12-01

The implementation of excellence centers in specific diseases has been gaining recognition in the field of health; specifically in rheumatoid arthritis, where the prognosis of the disease is related to an early diagnosis and a timely intervention, it is necessary that the provision of health services is developed in an environment of quality, opportunity, and safety with the highest standards of care. A methodology that allows this implementation in such a way that is achievable by the most of the care centers is a priority to achieve a better attention to populations with this disease. In this paper, we propose a systematic and progressive methodology that will help all the institutions to develop successful models without faltering in the process. The expected impact on public health is defined by a better effective coverage of high-quality treatments, obtaining better health outcomes with safety and accessibility that reduces the budgetary impact for the health systems of our countries.

TGF-β1 in Vascular Wall Pathology: Unraveling Chronic Venous Insufficiency Pathophysiology.

PubMed

Serralheiro, Pedro; Soares, Andreia; Costa Almeida, Carlos M; Verde, Ignacio

2017-11-26

Chronic venous insufficiency and varicose veins occur commonly in affluent countries and are a socioeconomic burden. However, there remains a relative lack of knowledge about venous pathophysiology. Various theories have been suggested, yet the molecular sequence of events is poorly understood. Transforming growth factor-beta one (TGF-β1) is a highly complex polypeptide with multifunctional properties that has an active role during embryonic development, in adult organ physiology and in the pathophysiology of major diseases, including cancer and various autoimmune, fibrotic and cardiovascular diseases. Therefore, an emphasis on understanding its signaling pathways (and possible disruptions) will be an essential requirement for a better comprehension and management of specific diseases. This review aims at shedding more light on venous pathophysiology by describing the TGF-β1 structure, function, activation and signaling, and providing an overview of how this growth factor and disturbances in its signaling pathway may contribute to specific pathological processes concerning the vessel wall which, in turn, may have a role in chronic venous insufficiency.

Reprogramming the metabolome rescues retinal degeneration.

PubMed

Park, Karen Sophia; Xu, Christine L; Cui, Xuan; Tsang, Stephen H

2018-05-01

Metabolomics studies in the context of ophthalmology have largely focused on identifying metabolite concentrations that characterize specific retinal diseases. Studies involving mass spectrometry (MS) and nuclear magnetic resonance (NMR) spectroscopy have shown that individuals suffering from retinal diseases exhibit metabolic profiles that markedly differ from those of control individuals, supporting the notion that metabolites may serve as easily identifiable biomarkers for specific conditions. An emerging branch of metabolomics resulting from biomarker studies, however, involves the study of retinal metabolic dysfunction as causes of degeneration. Recent publications have identified a number of metabolic processes-including but not limited to glucose and oxygen metabolism-that, when perturbed, play a role in the degeneration of photoreceptor cells. As a result, such studies have led to further research elucidating methods for prolonging photoreceptor survival in an effort to halt degeneration in its early stages. This review will explore the ways in which metabolomics has deepened our understanding of the causes of retinal degeneration and discuss how metabolomics can be used to prevent retinal degeneration from progressing to its later disease stages.

[Constitutional syndrome: clinical entity or a mixed bag].

PubMed

Suárez-Ortega, Saturnino; Puente-Fernández, Alicia; Santana-Baez, Sergio; Godoy-Díaz, Davinia; Serrano-Fuentes, Miriam; Sanz-Peláez, Oscar

2013-01-01

Fatigue, anorexia and involuntary weight loss have been included under the term constitutional syndrome. These manifestations accompany many diseases in which the diagnosis is made by specific symptoms and signs. However, these events are generally the main reason for consultation and the patient does not report other specific data. This forces us to rigorously investigate the possible causes of the disorder. Usually, three manifestations coexist: asthenia, anorexia and weight loss, but sometimes the patient has only one or two of them. The causes of constitutional symptoms are varied and can be divided into three groups: psychiatric diseases, neoplasms and non-neoplastic diseases. The etiological identification is usually done with a simple protocol, which rules out malignancy; the rest of the cases of uncertain etiology are subject to evolution. The constitutional syndrome correlates well with good prognosis or medical functional processes. Although no clinical guidelines have been developed, score scales may help for the etiological assessment. Given the myriad of different causes of the constitutional syndrome, the treatment of this illness depends primarily on the etiology.

An improved, rapid competitive ELISA using a novel conserved 3B epitope for the detection of serum antibodies to foot-and-mouth disease virus.

PubMed

Chung, Chungwon J; Clavijo, Alfonso; Bounpheng, Mangkey A; Uddowla, Sabena; Sayed, Abu; Dancho, Brooke; Olesen, Ian C; Pacheco, Juan; Kamicker, Barbara J; Brake, David A; Bandaranayaka-Mudiyanselage, Carey L; Lee, Stephen S; Rai, Devendra K; Rieder, Elizabeth

2018-06-01

The highly contagious foot-and-mouth disease virus (FMDV) afflicts cloven-hoofed animals, resulting in significant costs because of loss of trade and recovery from disease. We developed a sensitive, specific, and rapid competitive ELISA (cELISA) to detect serum antibodies to FMDV. The cELISA utilized a monoclonal blocking antibody specific for a highly conserved FMDV nonstructural 3B epitope, a recombinant mutant FMDV 3ABC coating protein, and optimized format variables including serum incubation for 90 min at 20-25°C. Samples from 16 animals experimentally infected with one FMDV serotype (A, O, Asia, or SAT-1) demonstrated early detection capacity beginning 7 d post-inoculation. All samples from 55 vesicular stomatitis virus antibody-positive cattle and 44 samples from cloven-hoofed animals affected by non-FMD vesicular diseases were negative in the cELISA, demonstrating 100% analytical specificity. The diagnostic sensitivity was 100% against sera from 128 cattle infected with isolates of all FMDV serotypes, emphasizing serotype-agnostic results. Diagnostic specificities of U.S. cattle ( n = 1135) and swine ( n = 207) sera were 99.4% and 100%, respectively. High repeatability and reproducibility were demonstrated with 3.1% coefficient of variation in percent inhibition data and 100% agreement using 2 kit lots and 400 negative control serum samples, with no difference between bench and biosafety cabinet operation. Negative results from vaccinated, uninfected cattle, pig, and sheep sera confirmed the DIVA (differentiate infected from vaccinated animals) capability. This rapid (<3 h), select agent-free assay with high sensitivity and specificity, DIVA capability, and room temperature processing capability will serve as a useful tool in FMDV surveillance, emergency preparedness, response, and outbreak recovery programs.

Health-related quality of life measurement in patients with chronic respiratory failure.

PubMed

Oga, Toru; Windisch, Wolfram; Handa, Tomohiro; Hirai, Toyohiro; Chin, Kazuo

2018-05-01

The improvement of health-related quality of life (HRQL) is an important goal in managing patients with chronic respiratory failure (CRF) receiving long-term oxygen therapy (LTOT) and/or domiciliary noninvasive ventilation (NIV). Two condition-specific HRQL questionnaires have been developed to specifically assess these patients: the Maugeri Respiratory Failure Questionnaire (MRF) and the Severe Respiratory Insufficiency Questionnaire (SRI). The MRF is more advantageous in its ease of completion; conversely, the SRI measures diversified health impairments more multi-dimensionally and discriminatively with greater balance, especially in patients receiving NIV. The SRI is available in many different languages as a result of back-translation and validation processes, and is widely validated for various disorders such as chronic obstructive pulmonary disease, restrictive thoracic disorders, neuromuscular disorders, and obesity hypoventilation syndrome, among others. Dyspnea and psychological status were the main determinants for both questionnaires, while the MRF tended to place more emphasis on activity limitations than SRI. In comparison to existing generic questionnaires such as the Medical Outcomes Study 36-item short form (SF-36) and disease-specific questionnaires such as the St. George's Respiratory Questionnaire (SGRQ) and the Chronic Respiratory Disease Questionnaire (CRQ), both the MRF and the SRI have been shown to be valid and reliable, and have better discriminatory, evaluative, and predictive features than other questionnaires. Thus, in assessing the HRQL of patients with CRF using LTOT and/or NIV, we might consider avoiding the use of the SF-36 or even the SGRQ or CRQ alone and consider using the CRF-specific SRI and MRF in addition to existing generic and/or disease-specific questionnaires. Copyright © 2018 The Japanese Respiratory Society. Published by Elsevier B.V. All rights reserved.

Differential Diagnosis of Erythmato-Squamous Diseases Using Classification and Regression Tree

PubMed Central

Maghooli, Keivan; Langarizadeh, Mostafa; Shahmoradi, Leila; Habibi-koolaee, Mahdi; Jebraeily, Mohamad; Bouraghi, Hamid

2016-01-01

Introduction: Differential diagnosis of Erythmato-Squamous Diseases (ESD) is a major challenge in the field of dermatology. The ESD diseases are placed into six different classes. Data mining is the process for detection of hidden patterns. In the case of ESD, data mining help us to predict the diseases. Different algorithms were developed for this purpose. Objective: we aimed to use the Classification and Regression Tree (CART) to predict differential diagnosis of ESD. Methods: we used the Cross Industry Standard Process for Data Mining (CRISP-DM) methodology. For this purpose, the dermatology data set from machine learning repository, UCI was obtained. The Clementine 12.0 software from IBM Company was used for modelling. In order to evaluation of the model we calculate the accuracy, sensitivity and specificity of the model. Results: The proposed model had an accuracy of 94.84% ( Standard Deviation: 24.42) in order to correct prediction of the ESD disease. Conclusions: Results indicated that using of this classifier could be useful. But, it would be strongly recommended that the combination of machine learning methods could be more useful in terms of prediction of ESD. PMID:28077889

Combining Image and Non-Image Data for Automatic Detection of Retina Disease in a Telemedicine Network

DOE Office of Scientific and Technical Information (OSTI.GOV)

Aykac, Deniz; Chaum, Edward; Fox, Karen

A telemedicine network with retina cameras and automated quality control, physiological feature location, and lesion/anomaly detection is a low-cost way of achieving broad-based screening for diabetic retinopathy (DR) and other eye diseases. In the process of a routine eye-screening examination, other non-image data is often available which may be useful in automated diagnosis of disease. In this work, we report on the results of combining this non-image data with image data, using the protocol and processing steps of a prototype system for automated disease diagnosis of retina examinations from a telemedicine network. The system includes quality assessments, automated physiology detection,more » and automated lesion detection to create an archive of known cases. Non-image data such as diabetes onset date and hemoglobin A1c (HgA1c) for each patient examination are included as well, and the system is used to create a content-based image retrieval engine capable of automated diagnosis of disease into 'normal' and 'abnormal' categories. The system achieves a sensitivity and specificity of 91.2% and 71.6% using hold-one-out validation testing.« less

Chagas disease drug discovery: toward a new era.

PubMed

Chatelain, Eric

2015-01-01

American trypanosomiasis, or Chagas disease, is the result of infection by the Trypanosoma cruzi parasite. Endemic in Latin America where it is the major cause of death from cardiomyopathy, the impact of the disease is reaching global proportions through migrating populations. New drugs that are safe, efficacious, low cost, and adapted to the field are critically needed. Over the past five years, there has been increased interest in the disease and a surge in activities within various organizations. However, recent clinical trials with azoles, specifically posaconazole and the ravuconazole prodrug E1224, were disappointing, with treatment failure in Chagas patients reaching 70% to 90%, as opposed to 6% to 30% failure for benznidazole-treated patients. The lack of translation from in vitro and in vivo models to the clinic observed for the azoles raises several questions. There is a scientific requirement to review and challenge whether we are indeed using the right tools and decision-making processes to progress compounds forward for the treatment of this disease. New developments in the Chagas field, including new technologies and tools now available, will be discussed, and a redesign of the current screening strategy during the discovery process is proposed. © 2014 Society for Laboratory Automation and Screening.

Post-approval Studies for Rare Disease Treatments and Orphan Drugs.

PubMed

Maier, William C; Christensen, Ronald A; Anderson, Patricia

2017-01-01

Drug development involves a multi-stage process of drug discovery, animal studies and human clinical trials to assess the safety and efficacy of new medications. Rare disease drug development involves a much smaller number of affected patients, a predominance of pediatric patients and more complicated disease presentation. Post-approval studies are designed to address several limitations associated with the rare disease clinical trials.National and international regulatory agencies in the US and Europe have adopted similar approaches to requirements post-approval data for rare diseases and orphan drug indications. The US FDA published guidance in 2011 and the European Medicines Agency in 2015.Post-approval studies for rare diseases include observational studies, pragmatic trials and randomized controlled studies. Observational studies include both original data collection studies and the use of secondary data (retrospective studies). Original data collection can address limitations of retrospective studies resulting from incomplete information in secondary data sources. Disease registries focus on detail about a broad range of patients with a rare disease while product-related registries focus on specific health care outcomes associated with a single product and may incorporate a comparator of an alternative therapy or therapies.Rare disease patients can be difficult to find and enroll in a registry using conventional physician based driven recruitment. The study process also needs to recognize changes in the patient's disease and lifestyle and adapt both the study design and methods over time. Many rare diseases have strong patient advocacy groups that can in aid the design and execution of rare disease registries.

Associations of specific phobia and its subtypes with physical diseases: an adult community study.

PubMed

Witthauer, Cornelia; Ajdacic-Gross, Vladeta; Meyer, Andrea Hans; Vollenweider, Peter; Waeber, Gerard; Preisig, Martin; Lieb, Roselind

2016-05-21

Specific phobia is the most prevalent anxiety disorder in the community and is associated with substantial impairment. Comorbidity with physical diseases is assumed and has important implications for etiology, treatment, or prevention of the comorbid conditions. However, due to methodological issues data are limited and subtypes of specific phobia have not been investigated yet. We examined the association of specific phobia and its subtypes with physical diseases in a representative community sample with physician-diagnosed physical diseases and diagnostic criteria of specific phobia. Data of the German Mental Health Survey from 4181 subjects aged 18-65 years were used. Specific phobia was diagnosed using M-CIDI/DIA-X interview; physical diseases were assessed through a self-report questionnaire and a medical interview. Logistic regression analyses adjusted for sex were calculated. Specific phobia was associated with cardiac diseases, gastrointestinal diseases, respiratory diseases, arthritic conditions, migraine, and thyroid diseases (odds ratios between 1.49 and 2.53). Among the subtypes, different patterns of associations with physical diseases were established. The findings were partially replicated in the Swiss PsyCoLaus Study. Our analyses show that subjects with specific phobia have an increased probability for specific physical diseases. From these analyses etiological mechanisms of specific phobia and physical disease can be deduced. As subtypes differed in their patterns of associations with physical diseases, different etiological mechanisms may play a role. The findings are highly relevant for public health in terms of prevention and therapy of the comorbid conditions.

Common Elements in Rare Kidney Diseases: Conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

PubMed

Aymé, Ségolène; Bockenhauer, Detlef; Day, Simon; Devuyst, Olivier; Guay-Woodford, Lisa M; Ingelfinger, Julie R; Klein, Jon B; Knoers, Nine V A M; Perrone, Ronald D; Roberts, Julia; Schaefer, Franz; Torres, Vicente E; Cheung, Michael; Wheeler, David C; Winkelmayer, Wolfgang C

2017-10-01

Rare kidney diseases encompass at least 150 different conditions, most of which are inherited. Although individual rare kidney diseases raise specific issues, as a group these rare diseases can have overlapping challenges in diagnosis and treatment. These challenges include small numbers of affected patients, unidentified causes of disease, lack of biomarkers for monitoring disease progression, and need for complex care. To address common clinical and patient issues among rare kidney diseases, the KDIGO Controversies Conference entitled, Common Elements in Rare Kidney Diseases, brought together a panel of multidisciplinary clinical providers and patient advocates to address five central issues for rare kidney diseases. These issues encompassed diagnostic challenges, management of kidney functional decline and progression of chronic kidney disease, challenges in clinical study design, translation of advances in research to clinical care, and provision of practical and integrated patient support. Thus, by a process of consensus, guidance for addressing these challenges was developed and is presented here. Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Rumination and behavioural factors in Parkinson's disease depression.

PubMed

Julien, Camille L; Rimes, Katharine A; Brown, Richard G

2016-03-01

Parkinson's disease is associated with high rates of depression. There is growing interest in non-pharmacological management including psychological approaches such as Cognitive Behaviour Therapy. To date, little research has investigated whether processes that underpin cognitive models of depression, on which such treatment is based, apply in patients with Parkinson's disease. The study aimed to investigate the contribution of core psychological factors to the presence and degree of depressive symptoms. 104 participants completed questionnaires measuring mood, motor disability and core psychological variables, including maladaptive assumptions, rumination, cognitive-behavioural avoidance, illness representations and cognitive-behavioural responses to symptoms. Regression analyses revealed that a small number of psychological factors accounted for the majority of depression variance, over and above that explained by overall disability. Participants reporting high levels of rumination, avoidance and symptom focusing experienced more severe depressive symptoms. In contrast, pervasive negative dysfunctional beliefs did not independently contribute to depression variance. Specific cognitive (rumination and symptom focusing) and behavioural (avoidance) processes may be key psychological markers of depression in Parkinson's disease and therefore offer important targets for tailored psychological interventions. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Irritable bowel syndrome in quiescent inflammatory bowel disease: a review.

PubMed

Burgell, R E; Asthana, A K; Gibson, P R

2015-12-01

Ongoing troublesome bowel symptoms despite quiescent inflammatory disease are a frequent management challenge when caring for patients with inflammatory bowel disease (IBD). Even when active disease has been excluded the prevalence of residual gastrointestinal symptoms is surprisingly high and the cause often obscure. The presence of a concurrent functional disorder such as irritable bowel syndrome (IBS) is associated with worse quality of life, worse physical functioning, higher prevalence of anxiety and greater health care utilization. Potential etiological mechanisms leading to the development of IBS like symptoms include the development of visceral hypersensitivity following the original inflammatory insult, alteration in cortical processing, dysbiosis and residual subacute inflammation. Therapeutic options for managing IBS in patients with IBD include dietary modification, interventions targeted at correction of visceral sensory dysfunction or cortical processing and modulation of the gut microbiota. As there are few studies specifically examining the treatment of IBS in patients with IBD, the majority of therapeutic interventions are extrapolated from the IBS literature. Given the frequency of residual functional symptoms in IBS, significantly more research is warranted in this field.

Tau truncation is a productive posttranslational modification of neurofibrillary degeneration in Alzheimer's disease.

PubMed

Kovacech, B; Novak, M

2010-12-01

Deposits of the misfolded neuronal protein tau are major hallmarks of neurodegeneration in Alzheimer's disease (AD) and other tauopathies. The etiology of the transformation process of the intrinsically disordered soluble protein tau into the insoluble misordered aggregate has attracted much attention. Tau undergoes multiple modifications in AD, most notably hyperphosphorylation and truncation. Hyperphosphorylation is widely regarded as the hottest candidate for the inducer of the neurofibrillary pathology. However, the true nature of the impetus that initiates the whole process in the human brains remains unknown. In AD, several site-specific tau cleavages were identified and became connected to the progression of the disease. In addition, western blot analyses of tau species in AD brains reveal multitudes of various truncated forms. In this review we summarize evidence showing that tau truncation alone is sufficient to induce the complete cascade of neurofibrillary pathology, including hyperphosphorylation and accumulation of misfolded insoluble forms of tau. Therefore, proteolytical abnormalities in the stressed neurons and production of aberrant tau cleavage products deserve closer attention and should be considered as early therapeutic targets for Alzheimer's disease.

An Energy Efficient ECG Signal Processor Detecting Cardiovascular Diseases on Smartphone.

PubMed

Jain, Sanjeev Kumar; Bhaumik, Basabi

2017-04-01

A novel disease diagnostic algorithm for ECG signal processing based on forward search is implemented in Application Specific Integrated Circuit (ASIC) for cardiovascular disease diagnosis on smartphone. An ASIC is fabricated using 130-nm CMOS low leakage process technology. The area of our PQRST ASIC is 1.21 mm 2 . The energy dissipation of PQRST ASIC is 96 pJ with a supply voltage of 0.9 V. The outputs from the ASIC are fed to an Android application that generates diagnostic report and can be sent to a cardiologist via email. The ASIC and Android application are verified for the detection of bundle branch block, hypertrophy, arrhythmia and myocardial infarction using Physionet PTB diagnostic ECG database. The failed detection rate is 0.69%, 0.69%, 0.34% and 1.72% for bundle branch block, hypertrophy, arrhythmia and myocardial infarction respectively. The AV block is detected in all the three patients in the Physionet St. Petersburg arrhythmia database. Our proposed ASIC together with our Android application is the most suitable for an energy efficient wearable cardiovascular disease detection system.

A new direction for Alzheimer's research

PubMed Central

Weinstein, James D.

2018-01-01

Despite decades of research, at present there is no curative therapy for Alzheimer's disease. Changes in the way new drugs are tested appear to be necessary. Three changes are presented here and will be discussed. The first change is that Alzheimer's disease must be considered a disease of four major pathological processes, not one. The four processes are: 1) vascular hypoperfusion of the brain with associated mitochondrial dysfunction, 2) destructive protein inclusions, 3) uncontrolled oxidative stress, and 4) proinflammatory immune processes secondary to microglial and astrocytic dysfunction in the brain. The second change recommended is to alter the standard cognitive measurement tools used to quantify mental decline in test patients. Specifically the Dementia Severity Rating Scale (DSRS) should supersede Mini-Mental State Examination (MMSE) and other popular tests, and a measurement scale developed in research should be used to produce a linear and non-irregular baseline. Finally, accepting the concept that four etiologies cause Alzheimer's disease leads to the last necessary change, that new therapies must be employed directed against all four causes, likely as a combination. There are drugs ready to be employed in such a combinations which are available and used clinically for other purposes so can be used “off label” and one such combination is suggested. PMID:29557358

Peptide fingerprinting of Alzheimer's disease in cerebrospinal fluid: identification and prospective evaluation of new synaptic biomarkers.

PubMed

Jahn, Holger; Wittke, Stefan; Zürbig, Petra; Raedler, Thomas J; Arlt, Sönke; Kellmann, Markus; Mullen, William; Eichenlaub, Martin; Mischak, Harald; Wiedemann, Klaus

2011-01-01

Today, dementias are diagnosed late in the course of disease. Future treatments have to start earlier in the disease process to avoid disability requiring new diagnostic tools. The objective of this study is to develop a new method for the differential diagnosis and identification of new biomarkers of Alzheimer's disease (AD) using capillary-electrophoresis coupled to mass-spectrometry (CE-MS) and to assess the potential of early diagnosis of AD. Cerebrospinal fluid (CSF) of 159 out-patients of a memory-clinic at a University Hospital suffering from neurodegenerative disorders and 17 cognitively-healthy controls was used to create differential peptide pattern for dementias and prospective blinded-comparison of sensitivity and specificity for AD diagnosis against the Criterion standard in a naturalistic prospective sample of patients. Sensitivity and specificity of the new method compared to standard diagnostic procedures and identification of new putative biomarkers for AD was the main outcome measure. CE-MS was used to reliably detect 1104 low-molecular-weight peptides in CSF. Training-sets of patients with clinically secured sporadic Alzheimer's disease, frontotemporal dementia, and cognitively healthy controls allowed establishing discriminative biomarker pattern for diagnosis of AD. This pattern was already detectable in patients with mild cognitive impairment (MCI). The AD-pattern was tested in a prospective sample of patients (n = 100) and AD was diagnosed with a sensitivity of 87% and a specificity of 83%. Using CSF measurements of beta-amyloid1-42, total-tau, and phospho(181)-tau, AD-diagnosis had a sensitivity of 88% and a specificity of 67% in the same sample. Sequence analysis of the discriminating biomarkers identified fragments of synaptic proteins like proSAAS, apolipoprotein J, neurosecretory protein VGF, phospholemman, and chromogranin A. The method may allow early differential diagnosis of various dementias using specific peptide fingerprints and identification of incipient AD in patients suffering from MCI. Identified biomarkers facilitate face validity for the use in AD diagnosis.

A cross-sectional study to investigate long-term cognitive function in people with treated pituitary Cushing's disease.

PubMed

Heald, A; Parr, C; Gibson, C; O'driscoll, K; Fowler, H

2006-10-01

It has been proposed that exposure to high levels of endogenous steroids in untreated pituitary Cushing's disease damages hippocampal structures leading to impairment in learning and memory processes. We hypothesised that patients with treated pituitary Cushing's disease would perform significantly worse on tests of cognitive ability than those with nonfunctioning pituitary adenomas. Sixteen adults with pituitary Cushing's disease (PCD) and 16 adults with non-functioning pituitary adenomas (NFA) undertook the following comprehensive neuropsychological assessments: National Adult Reading Test (NART: premorbid abilities), California Verbal Learning Test (CVLT 2 UK: learning and recall), Stroop (executive functioning), Trail-Making Test (TMT: executive functioning and attention), Adult Memory and Information Processing Battery (AMIPB: Information Processing Speed and Story Recall subtests). There was no significant difference in premorbid IQ scores (NFA mean=101 SD=13; PCD mean=102, SD=13), in verbal learning nor any significant difference in the percentage of verbal material retained in story recall (AMIPB). Performance on higher executive tasks Stroop and TMT and on measures of information processing was similar. However, there were significant decrements between some mean scores for both groups and published normative data with a clear association between higher HADS depression scores and impaired objective memory and attention which was not specific to PCD. We found no difference in cognitive function between patients with PCD and NFA. The results suggest a discrepancy between patients' subjective perception of functional cognitive impairments and objective findings on psychometric testing and point to the influence of affective symptoms on cognitive performance, particularly in Cushing's disease.

Dupuytren's: a systems biology disease

PubMed Central

2011-01-01

Dupuytren's disease (DD) is an ill-defined fibroproliferative disorder of the palm of the hands leading to digital contracture. DD commonly occurs in individuals of northern European extraction. Cellular components and processes associated with DD pathogenesis include altered gene and protein expression of cytokines, growth factors, adhesion molecules, and extracellular matrix components. Histology has shown increased but varying levels of particular types of collagen, myofibroblasts and myoglobin proteins in DD tissue. Free radicals and localised ischaemia have been suggested to trigger the proliferation of DD tissue. Although the existing available biological information on DD may contain potentially valuable (though largely uninterpreted) information, the precise aetiology of DD remains unknown. Systems biology combines mechanistic modelling with quantitative experimentation in studies of networks and better understanding of the interaction of multiple components in disease processes. Adopting systems biology may be the ideal approach for future research in order to improve understanding of complex diseases of multifactorial origin. In this review, we propose that DD is a disease of several networks rather than of a single gene, and show that this accounts for the experimental observations obtained to date from a variety of sources. We outline how DD may be investigated more effectively by employing a systems biology approach that considers the disease network as a whole rather than focusing on any specific single molecule. PMID:21943049

[Opinions and expectations of patients with health problems associated to asbestos exposure].

PubMed

Prieto, M A; Suess, A; March, J C; Danet, A; Corral, O Pérez; Martín, A

2011-01-01

The prevalence of diseases related to asbestos exposure requires the development of monitoring programs and specific health care protocols. The aim of this study is to determine the opinions and expectations of former workers of an asbestos factory, in order to adapt the care process to the needs of the affected population, and to learn about the activity of the association that represents them. Qualitative study. Focus groups with former employees of a corrugated asbestos factory, members of the association AVIDA (Seville). Recording and transcription of interviews. Discourse analysis with Nudist Vivo 1.0. All respondents have health problems, including asbestosis, lung cancer and mesothelioma. Through the association, they are involved in an ongoing process of negotiation with the public administration, to improve healthcare, achieve recognition as having an occupational disease and the payment of compensation. The lack of monitoring and continuity in care is designated as the major problem in the current care process. They welcome the creation of special care units, the good treatment received and the quality of technical instruments in the public health system. On the contrary, they criticize the difficulties in finding an accurate diagnosis, the lack of continuity of care, and the bureaucratic difficulties and lack of specific care directed to affected relatives. The participants' expectations highlight their intention to participate in the development of future programs and protocols. This study confirms the multifactor nature of diseases related to asbestos exposure and the importance of determining the needs and demands of the affected population in order to improve health care.

T-cell libraries allow simple parallel generation of multiple peptide-specific human T-cell clones.

PubMed

Theaker, Sarah M; Rius, Cristina; Greenshields-Watson, Alexander; Lloyd, Angharad; Trimby, Andrew; Fuller, Anna; Miles, John J; Cole, David K; Peakman, Mark; Sewell, Andrew K; Dolton, Garry

2016-03-01

Isolation of peptide-specific T-cell clones is highly desirable for determining the role of T-cells in human disease, as well as for the development of therapies and diagnostics. However, generation of monoclonal T-cells with the required specificity is challenging and time-consuming. Here we describe a library-based strategy for the simple parallel detection and isolation of multiple peptide-specific human T-cell clones from CD8(+) or CD4(+) polyclonal T-cell populations. T-cells were first amplified by CD3/CD28 microbeads in a 96U-well library format, prior to screening for desired peptide recognition. T-cells from peptide-reactive wells were then subjected to cytokine-mediated enrichment followed by single-cell cloning, with the entire process from sample to validated clone taking as little as 6 weeks. Overall, T-cell libraries represent an efficient and relatively rapid tool for the generation of peptide-specific T-cell clones, with applications shown here in infectious disease (Epstein-Barr virus, influenza A, and Ebola virus), autoimmunity (type 1 diabetes) and cancer. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Instruments to assess stigmatization in dermatology.

PubMed

Dimitrov, Dimitre; Szepietowski, Jacek C

2017-11-03

Stigmatization is the assignment of negative perceptions to an individual because of a perceived difference from the population at large. Skin conditions are frequently the reason of social rejection with a consequent negative influence on the personal and social life of patients. The aim of the current study was to review the available instruments that can be successfully utilized to measure the stigmatization level among dermatological patients. We performed our search on PubMed up to November 2016 and utilized combinations of key phrases containing such words as stigmatization, skin, dermatology, names of various skin conditions (psoriasis, vitiligo, acne, etc.), measurement. The search found a considerable number of articles - 548. After filtering them through a precise selection process, 58 articles remained. We concentrated only on the methodological aspects to assess stigmatization in various dermatoses. The review ascertained that there exist numerous instruments in the form of questionnaires. They were utilized in various researches in order to assess the stigmatization level in patients with skin problems. We divided them into two main groups: dermatology specific instruments (6 questionnaires) and dermatosis/disease specific ones (8 questionnaires). It is recommended to use dermatology-specific instruments to compare the stigmatization level in various skin conditions. They can be utilized as well as a first line tools to study the feeling of stigmatization in specific skin diseases; however, where it is possible, they should be supplemented with the disease-specific instrument for deeper analysis of both qualities of life and stigmatization.

Perspectives on Systems Modeling of Human Peripheral Blood Mononuclear Cells

PubMed Central

Sen, Partho; Kemppainen, Esko; Orešič, Matej

2018-01-01

Human peripheral blood mononuclear cells (PBMCs) are the key drivers of the immune responses. These cells undergo activation, proliferation and differentiation into various subsets. During these processes they initiate metabolic reprogramming, which is coordinated by specific gene and protein activities. PBMCs as a model system have been widely used to study metabolic and autoimmune diseases. Herein we review various omics and systems-based approaches such as transcriptomics, epigenomics, proteomics, and metabolomics as applied to PBMCs, particularly T helper subsets, that unveiled disease markers and the underlying mechanisms. We also discuss and emphasize several aspects of T cell metabolic modeling in healthy and disease states using genome-scale metabolic models. PMID:29376056

[The role of metalloprotease in pathogenesis of nervous system diseases].

PubMed

Mirowska, D; Członkowska, A

2001-01-01

Matrix Metalloproteases (MMPs) comprise a big family of proteolytic enzymes secreted into extracellular matrix and involved in remodelling of many tissues. The MMPs' activity is regulated on many levels. It is also determined by specific inhibitors known as tissue inhibitors of metalloproteases (TIMPs). Several studies revealed that MMPs have a role not only in physiological processes but also in pathophysiology of nervous system diseases, such as multiplex sclerosis, Guillan-Barré syndrome and strokes. Concerning demyelination MMPs are responsible for degradation of myelin components and facilitation of immune cells migration into inflammatory sites by degrading vascular basement membrane. We still investigate substances with positive clinical effect on the nervous system diseases due to MMPs inactivation.

Histone methylations in heart development, congenital and adult heart diseases.

PubMed

Zhang, Qing-Jun; Liu, Zhi-Ping

2015-01-01

Heart development comprises myocyte specification, differentiation and cardiac morphogenesis. These processes are regulated by a group of core cardiac transcription factors in a coordinated temporal and spatial manner. Histone methylation is an emerging epigenetic mechanism for regulating gene transcription. Interplay among cardiac transcription factors and histone lysine modifiers plays important role in heart development. Aberrant expression and mutation of the histone lysine modifiers during development and in adult life can cause either embryonic lethality or congenital heart diseases, and influences the response of adult hearts to pathological stresses. In this review, we describe current body of literature on the role of several common histone methylations and their modifying enzymes in heart development, congenital and adult heart diseases.

Blood Sampling and Preparation Procedures for Proteomic Biomarker Studies of Psychiatric Disorders.

PubMed

Guest, Paul C; Rahmoune, Hassan

2017-01-01

A major challenge in proteomic biomarker discovery and validation for psychiatric diseases is the inherent biological complexity underlying these conditions. There are also many technical issues which hinder this process such as the lack of standardization in sampling, processing and storage of bio-samples in preclinical and clinical settings. This chapter describes a reproducible procedure for sampling blood serum and plasma that is specifically designed for maximizing data quality output in two-dimensional gel electrophoresis, multiplex immunoassay and mass spectrometry profiling studies.

Anticipating the emergence of infectious diseases

PubMed Central

Drake, John M.; Rohani, Pejman

2017-01-01

In spite of medical breakthroughs, the emergence of pathogens continues to pose threats to both human and animal populations. We present candidate approaches for anticipating disease emergence prior to large-scale outbreaks. Through use of ideas from the theories of dynamical systems and stochastic processes we develop approaches which are not specific to a particular disease system or model, but instead have general applicability. The indicators of disease emergence detailed in this paper can be classified into two parallel approaches: a set of early-warning signals based around the theory of critical slowing down and a likelihood-based approach. To test the reliability of these two approaches we contrast theoretical predictions with simulated data. We find good support for our methods across a range of different model structures and parameter values. PMID:28679666

Noncoding RNAs in Neurodegenerative Diseases

PubMed Central

Rege, Shraddha D.; Geetha, Thangiah; Pondugula, Satyanarayana R.; Zizza, Claire A.; Wernette, Catherine M.

2013-01-01

Noncoding RNAs are widely known for their various essential roles in the development of central nervous system. It involves neurogenesis, neural stem cells generation, maintenance and maturation, neurotransmission, neural network plasticity, formation of synapses, and even brain aging and DNA damage responses. In this review, we will discuss the biogenesis of microRNA, various functions of noncoding RNA's specifically microRNAs (miRNAs) that act as the chief regulators of gene expression, and focus in particular on misregulation of miRNAs which leads to several neurodegenerative diseases as well as its therapeutic outcome. Recent evidences has shown that miRNAs expression levels are changed in patients with neurodegenerative diseases; hence, miRNA can be used as a potential diagnostic biomarker and serve as an effective therapeutic tool in overcoming various neurodegenerative disease processes. PMID:23738143

[Transitions in context: findings related to rural-to-urban migration and chronic non-communicable diseases in Peru].

PubMed

Miranda, J Jaime; Wells, Jonathan C K; Smeeth, Liam

2012-01-01

In order to better understand the emergence of chronic non-communicable diseases in low- and middle-income countries this article seeks to present, in context, different transitional processes which societies and populations are currently undergoing. Relevant factors for specific contexts such as Peru are described, including internal migration, urbanization and profiles of adversity in early life, all of them linked to chronic non-communicable diseases, including obesity and overweight. The capacity-load model, which considers chronic disease risk in adulthood as a function of two generic traits, metabolic capacity and metabolic load, is described. The contribution of rural-to-urban migration to this problem is also presented. Finally, these topics are framed within pending challenges for public health in Peru.

Joint-specific DNA methylation and transcriptome signatures in rheumatoid arthritis identify distinct pathogenic processes

PubMed Central

Ai, Rizi; Hammaker, Deepa; Boyle, David L.; Morgan, Rachel; Walsh, Alice M.; Fan, Shicai; Firestein, Gary S.; Wang, Wei

2016-01-01

Stratifying patients on the basis of molecular signatures could facilitate development of therapeutics that target pathways specific to a particular disease or tissue location. Previous studies suggest that pathogenesis of rheumatoid arthritis (RA) is similar in all affected joints. Here we show that distinct DNA methylation and transcriptome signatures not only discriminate RA fibroblast-like synoviocytes (FLS) from osteoarthritis FLS, but also distinguish RA FLS isolated from knees and hips. Using genome-wide methods, we show differences between RA knee and hip FLS in the methylation of genes encoding biological pathways, such as IL-6 signalling via JAK-STAT pathway. Furthermore, differentially expressed genes are identified between knee and hip FLS using RNA-sequencing. Double-evidenced genes that are both differentially methylated and expressed include multiple HOX genes. Joint-specific DNA signatures suggest that RA disease mechanisms might vary from joint to joint, thus potentially explaining some of the diversity of drug responses in RA patients. PMID:27282753

Aptamers as tools for target prioritization and lead identification.

PubMed

Burgstaller, Petra; Girod, Anne; Blind, Michael

2002-12-15

The increasing number of potential drug target candidates has driven the development of novel technologies designed to identify functionally important targets and enhance the subsequent lead discovery process. Highly specific synthetic nucleic acid ligands--also known as aptamers--offer a new exciting route in the drug discovery process by linking target validation directly with HTS. Recently, aptamers have proven to be valuable tools for modulating the function of endogenous cellular proteins in their natural environment. A set of technologies has been developed to use these sophisticated ligands for the validation of potential drug targets in disease models. Moreover, aptamers that are specific antagonists of protein function can act as substitute interaction partners in HTS assays to facilitate the identification of small-molecule lead compounds.

Recommendations from the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL).

PubMed

Annemans, Lieven; Aymé, Ségolène; Le Cam, Yann; Facey, Karen; Gunther, Penilla; Nicod, Elena; Reni, Michele; Roux, Jean-Louis; Schlander, Michael; Taylor, David; Tomino, Carlo; Torrent-Farnell, Josep; Upadhyaya, Sheela; Hutchings, Adam; Le Dez, Lugdivine

2017-03-10

Rare diseases are an important public health issue with high unmet need. The introduction of the EU Regulation on orphan medicinal products (OMP) has been successful in stimulating investment in the research and development of OMPs. Despite this advancement, patients do not have universal access to these new medicines. There are many factors that affect OMP uptake, but one of the most important is the difficulty of making pricing and reimbursement (P&R) decisions in rare diseases. Until now, there has been little consensus on the most appropriate assessment criteria, perspective or appraisal process. This paper proposes nine principles to help improve the consistency of OMP P&R assessment in Europe and ensure that value assessment, pricing and funding processes reflect the specificities of rare diseases and contribute to both the sustainability of healthcare systems and the sustainability of innovation in this field. These recommendations are the output of the European Working Group for Value Assessment and Funding Processes in Rare Diseases (ORPH-VAL), a collaboration between rare disease experts, patient representatives, academics, health technology assessment (HTA) practitioners, politicians and industry representatives. ORPH-VAL reached its recommendations through careful consideration of existing OMP P&R literature and through a wide consultation with expert stakeholders, including payers, regulators and patients. The principles cover four areas: OMP decision criteria, OMP decision process, OMP sustainable funding systems and European co-ordination. This paper also presents a guide to the core elements of value relevant to OMPs that should be consistently considered in all OMP appraisals. The principles outlined in this paper may be helpful in drawing together an emerging consensus on this topic and identifying areas where consistency in payer approach could be achievable and beneficial. All stakeholders have an obligation to work together to ensure that the promise of OMP's is realised.

Enhancing the incorporation of the patient's voice in drug development and evaluation.

PubMed

Chalasani, Meghana; Vaidya, Pujita; Mullin, Theresa

2018-01-01

People living with a condition are uniquely positioned to inform the understanding of the therapeutic context for drug development and evaluation. In 2012, the U.S. Food and Drug Administration (FDA) established the Patient-Focused Drug Development (PFDD) initiative to more systematically obtain the patient perspective on specific diseases and their currently available treatments. PFDD meetings are unique among FDA public meetings, with a format designed to engage patients and elicit their perspectives on two topic areas: (1) the most significant symptoms of their condition and the impact of the condition on daily life; and, (2) their current approaches to treatment. FDA has conducted 24 disease-specific PFDD meetings to date. The lessons learned from PFDD meetings range from experiences common across rare diseases to more disease specific experiences that matter most to patients. FDA recognizes that FDA-led PFDD meetings alone cannot address the gaps in information on the patient perspective. Patient-focused drug development is an ongoing effort and FDA looks forward to the next steps in advancing the science and the utilization of patient input throughout drug development and evaluation. The U.S. Food and Drug Administration (FDA) has multiple mechanisms for its regulators and staff to interact with patients -- but none quite like its novel Patient-Focused Drug Development (PFDD) initiative. FDA established the PFDD initiative to more systematically obtain the patient perspective on specific diseases and their currently available treatments. Since the initiative's inception in 2012, FDA has held 24 PFDD meetings, covering a range of disease areas and hearing directly from thousands of patients and caregivers. FDA's PFDD meetings have also provided key stakeholders, including patient advocates, researchers, drug developers, healthcare providers, and other government officials, an opportunity to hear the patient's voice. The lessons learned include but are not limited to specific experiences that matter most to patients, patient perspectives on meaningful treatment benefits and how patients want to be engaged in the drug development process. FDA recognizes that FDA-led PFDD meetings alone cannot address the gaps in information on the patient perspective. Further enhancing the incorporation of the patient's voice in drug development and evaluation continues to be a priority for FDA.

The effect of zinc on amyloid β-protein assembly and toxicity: A mechanistic investigation

NASA Astrophysics Data System (ADS)

Solomonov, Inna; Sagi, Irit

2014-10-01

Neurotoxic assemblies of amyloid β-protein (Aβ) are widely believed to be the cause for Alzheimer's disease (AD). Therefore, understanding the factors and mechanisms that control, modulate, and inhibit formation of these assemblies is crucial for the development of therapeutic intervention of AD. This information also can contribute significantly to our understanding of the mechanisms of other amyloidosis diseases, such as Parkinson's disease, Huntington's disease, type 2 diabetes, amyotrophic lateral sclerosis (Lou Gehrig's disease) and prion diseases (e.g. Mad Cow disease). We have developed a multidisciplinary experimental strategy to study structural and dynamic mechanistic aspects that underlie the Aβ assembly process. Utilizing this strategy, we explored the molecular basis leading to the perturbation of the Aβ assembly process by divalent metal ions, mainly Zn2+ ions. Using Zn2+ as reaction physiological relevant probes, it was demonstrated that Zn2+ rapidly (milliseconds) induce self-assembly of Aβ aggregates and stabilize them in a manner that prevents formation of Aβ fibrils. Importantly, the early-formed intermediates are substantially more neurotoxic than fibrils. Our results suggest that relevant Aβ modulators should be targeted against the rapidly evolved intermediate states of Aβ assembly. The design of such modulators is challenging, as they have to compete with different natural mediators (such as Zn2+) of Aβ aggregation, which diverse Aβ assemblies in both specific and nonspecific manners.

[Epigenetic heredity (deoxyribonucleic acid methylation): Clinical context in neurodegenerative disorders and ATXN2 gene].

PubMed

Laffita-Mesa, José Miguel; Bauer, Peter

2014-10-21

Epigenetics is the group of changes in the phenotype which are related with the process independently of the primary DNA sequence. These changes are intimately related with changes in the gene expression level and its profile across the body. These are mediated by histone tail modifications, DNA methylation, micro-RNAs, with chromatin remodeling remaining as the foundation of epigenetic changes. DNA methylation involves the covalent addition of methyl group to cytosine of the DNA, which is mediated by methyltransferases enzymes. DNA methylation regulates gene expression by repressing transcription, while de-methylation activates gene transcription. Several human diseases are related with the epigenetic process: cancer, Alzheimer disease, stroke, Parkinson disease, and diabetes. We present here the basis of epigenetic inheritance and show the pathogenic mechanisms relating epigenetics in human diseases, specifically with regard to neurodegeneration. We discuss current concepts aimed at understanding the contribution of epigenetics to human neurodegenerative diseases. We also discuss recent findings obtained in our and other centers regarding the ATXN2 gene that causes spinocerebellar ataxia 2 and amyotrophic lateral sclerosis. Epigenetics play a pivotal role in the pathogenesis of human diseases and in several neurodegenerative disorders, and this knowledge will illuminate the pathways in the diagnostic and therapeutic field, which ultimately will be translated into the clinic context of neurodegenerative diseases. Copyright © 2013 Elsevier España, S.L.U. All rights reserved.

Neurotoxicity of a Fragment of the Amyloid Precursor Associated with Alzheimer's Disease

NASA Astrophysics Data System (ADS)

Yankner, Bruce A.; Dawes, Linda R.; Fisher, Shannon; Villa-Komaroff, Lydia; Oster-Granite, Mary Lou; Neve, Rachael L.

1989-07-01

Amyloid deposition in senile plaques and the cerebral vasculature is a marker of Alzheimer's disease. Whether amyloid itself contributes to the neurodegenerative process or is simply a by-product of that process is unknown. Pheochromocytoma (PC12) and fibroblast (NIH 3T3) cell lines were transfected with portions of the gene for the human amyloid precursor protein. Stable PC12 cell transfectants expressing a specific amyloid-containing fragment of the precursor protein gradually degenerated when induced to differentiate into neuronal cells with nerve growth factor. Conditioned medium from these cells was toxic to neurons in primary hippocampal cultures, and the toxic agent could be removed by immunoabsorption with an antibody directed against the amyloid polypeptide. Thus, a peptide derived from the amyloid precursor may be neurotoxic.

A framework for a diabetes mellitus disease management system in southern Israel.

PubMed

Fox, Matthew A; Harman-Boehm, Ilana; Weitzman, Shimon; Zelingher, Julian

2002-01-01

Chronic diseases are a significant burden on western healthcare systems and national economies. It has been suggested that automated disease management for chronic disease, like diabetes mellitus (DM), improves the quality of care and reduces inappropriate utilization of diagnostic and therapeutic measures. We have designed a comprehensive DM Disease Management system for the Negev region in southern Israel. This system takes advantage of currently used clinical and administrative information systems. Algorithms for DM disease management have been created based on existing and accepted Israeli guidelines. All data fields and tables in the source information systems have been analyzed, and interfaces for periodic data loads from these systems have been specified. Based on this data, four subsets of decision support algorithms have been developed. The system generates alerts in these domains to multiple end users. We plan to use the products of this information system analysis and disease management specification in the actual development process of such a system shortly.

Surgical care of the pediatric Crohn's disease patient.

PubMed

Stewart, Dylan

2017-12-01

Despite the significant advances in the medical management of inflammatory bowel disease over the last decade, surgery continues to play a major role in the management of pediatric Crohn's disease (CD). While adult and pediatric Crohn's disease may share many clinical characteristics, pediatric Crohn's patients often have a more aggressive phenotype, and the operative care given by the pediatric surgeon to the newly diagnosed Crohn's patient is very different in nature to the surgical needs of adult patients after decades of disease progression. Children also have the unique surgical indication of growth failure to consider in the overall clinical decision making. While surgery is never curative in CD, it has the ability to transform the disease process in children, and appropriately timed operations may have tremendous impact on a child's physical and mental maturation. This monograph aims to address the surgical care of Crohn's disease in general, with a specific emphasis on the surgical treatment of small intestinal and ileocecal involvement. Copyright © 2017 Elsevier Inc. All rights reserved.

Genetic Factors of the Disease Course After Sepsis: Rare Deleterious Variants Are Predictive.

PubMed

Taudien, Stefan; Lausser, Ludwig; Giamarellos-Bourboulis, Evangelos J; Sponholz, Christoph; Schöneweck, Franziska; Felder, Marius; Schirra, Lyn-Rouven; Schmid, Florian; Gogos, Charalambos; Groth, Susann; Petersen, Britt-Sabina; Franke, Andre; Lieb, Wolfgang; Huse, Klaus; Zipfel, Peter F; Kurzai, Oliver; Moepps, Barbara; Gierschik, Peter; Bauer, Michael; Scherag, André; Kestler, Hans A; Platzer, Matthias

2016-10-01

Sepsis is a life-threatening organ dysfunction caused by dysregulated host response to infection. For its clinical course, host genetic factors are important and rare genomic variants are suspected to contribute. We sequenced the exomes of 59 Greek and 15 German patients with bacterial sepsis divided into two groups with extremely different disease courses. Variant analysis was focusing on rare deleterious single nucleotide variants (SNVs). We identified significant differences in the number of rare deleterious SNVs per patient between the ethnic groups. Classification experiments based on the data of the Greek patients allowed discrimination between the disease courses with estimated sensitivity and specificity>75%. By application of the trained model to the German patients we observed comparable discriminatory properties despite lower population-specific rare SNV load. Furthermore, rare SNVs in genes of cell signaling and innate immunity related pathways were identified as classifiers discriminating between the sepsis courses. Sepsis patients with favorable disease course after sepsis, even in the case of unfavorable preconditions, seem to be affected more often by rare deleterious SNVs in cell signaling and innate immunity related pathways, suggesting a protective role of impairments in these processes against a poor disease course. Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Pathogenesis and Treatment of Spine Disease in the Mucopolysaccharidoses

PubMed Central

Peck, Sun H.; Casal, Margret L.; Malhotra, Neil R.; Ficicioglu, Can; Smith, Lachlan J.

2016-01-01

The mucopolysaccharidoses (MPS) are a family of lysosomal storage disorders characterized by deficient activity of enzymes that degrade glycosaminoglycans (GAGs). Skeletal disease is common in MPS patients, with the severity varying both within and between subtypes. Within the spectrum of skeletal disease, spinal manifestations are particularly prevalent. Developmental and degenerative abnormalities affecting the substructures of the spine can result in compression of the spinal cord and associated neural elements. Resulting neurological complications, including pain and paralysis, significantly reduce patient quality of life and life expectancy. Systemic therapies for MPS such as hematopoietic stem cell transplantation and enzyme replacement therapy have shown limited efficacy for improving spinal manifestations in patients and animal models, and there is therefore a pressing need for new therapeutic approaches that specifically target this debilitating aspect of the disease. In this review, we examine how pathological abnormalities affecting the key substructures of the spine – the discs, vertebrae, odontoid process and dura – contribute to the progression of spinal deformity and symptomatic compression of neural elements. Specifically, we review current understanding of the underlying pathophysiology of spine disease in MPS, how the tissues of the spine respond to current clinical and experimental treatments, and discuss future strategies for improving the efficacy of these treatments. PMID:27296532

Complement component 5 contributes to poor disease outcome in humans and mice with pneumococcal meningitis

PubMed Central

Woehrl, Bianca; Brouwer, Matthijs C.; Murr, Carmen; Heckenberg, Sebastiaan G.B.; Baas, Frank; Pfister, Hans W.; Zwinderman, Aeilko H.; Morgan, B. Paul; Barnum, Scott R.; van der Ende, Arie; Koedel, Uwe; van de Beek, Diederik

2011-01-01

Pneumococcal meningitis is the most common and severe form of bacterial meningitis. Fatality rates are substantial, and long-term sequelae develop in about half of survivors. Disease outcome has been related to the severity of the proinflammatory response in the subarachnoid space. The complement system, which mediates key inflammatory processes, has been implicated as a modulator of pneumococcal meningitis disease severity in animal studies. Additionally, SNPs in genes encoding complement pathway proteins have been linked to susceptibility to pneumococcal infection, although no associations with disease severity or outcome have been established. Here, we have performed a robust prospective nationwide genetic association study in patients with bacterial meningitis and found that a common nonsynonymous complement component 5 (C5) SNP (rs17611) is associated with unfavorable disease outcome. C5 fragment levels in cerebrospinal fluid (CSF) of patients with bacterial meningitis correlated with several clinical indicators of poor prognosis. Consistent with these human data, C5a receptor–deficient mice with pneumococcal meningitis had lower CSF wbc counts and decreased brain damage compared with WT mice. Adjuvant treatment with C5-specific monoclonal antibodies prevented death in all mice with pneumococcal meningitis. Thus, our results suggest C5-specific monoclonal antibodies could be a promising new antiinflammatory adjuvant therapy for pneumococcal meningitis. PMID:21926466

Conservation of species, volume, and belief in patients with Alzheimer's disease: the issue of domain specificity and conceptual impairment.

PubMed

Zaitchik, Deborah; Solomon, Gregg E A

2009-09-01

Two studies investigated whether patients with Alzheimer's disease (AD) suffer high-level and category-specific impairment in the conceptual domain of living things. In Experiment 1, AD patients and healthy young and healthy elderly controls took part in three tasks: the conservation of species, volume, and belief. All 3 tasks required tracking an object's identity in the face of irrelevant but salient transformations. Healthy young and elderly controls performed at or near ceiling on all tasks. AD patients were at or near ceiling on the volume and belief tasks, but only about half succeeded on the species task. Experiment 2 demonstrated that the results were not due to simple task demands. AD patients' failure to conserve species indicates that they are impaired in their theoretical understanding of living things, and their success on the volume and belief tasks suggests that the impairment is domain-specific. Two hypotheses are put forward to explain the phenomenon: The first, a category-specific account, holds that the intuitive theory of biology undergoes pervasive degradation; the second, a hybrid domain-general/domain-specific account, holds that impairment to domain-general processes such as executive function interacts with core cognition, the primitive elements that are the foundation of domain-specific knowledge.

Conservation of species, volume, and belief in patients with Alzheimer’s disease: the issue of domain-specificity and conceptual impairment

PubMed Central

Zaitchik, Deborah; Solomon, Gregg E. A.

2009-01-01

Two studies investigated whether patients with Alzheimer’s disease (AD) suffer high-level and category-specific impairment in the conceptual domain of living things. In Study 1, AD patients and healthy young and healthy elderly controls took part in three tasks: the Conservation of Species, Volume, and Belief. All 3 tasks required tracking an object’s identity in the face of irrelevant but salient transformations. Healthy young and elderly controls performed at or near ceiling on all tasks. AD patients were at or near ceiling on the Volume and Belief tasks, but only about half succeeded on the Species task. Study 2 demonstrated that the results were not due to simple task demands. AD patients’ failure to conserve species indicates that they are impaired in their theoretical understanding of living things, and their success on the Volume and Belief tasks suggests that the impairment is domain-specific. Two hypotheses are put forward to explain the phenomenon: the first, a category-specific account, holds that the intuitive theory of biology undergoes pervasive degradation; the second, a hybrid domain-general/domain-specific account, holds that impairment to domain-general processes such as executive function interacts with core cognition, the primitive elements that are the foundation of domain-specific knowledge. PMID:20043252

In vivo molecular and genomic imaging: new challenges for imaging physics.

PubMed

Cherry, Simon R

2004-02-07

The emerging and rapidly growing field of molecular and genomic imaging is providing new opportunities to directly visualize the biology of living organisms. By combining our growing knowledge regarding the role of specific genes and proteins in human health and disease, with novel ways to target these entities in a manner that produces an externally detectable signal, it is becoming increasingly possible to visualize and quantify specific biological processes in a non-invasive manner. All the major imaging modalities are contributing to this new field, each with its unique mechanisms for generating contrast and trade-offs in spatial resolution, temporal resolution and sensitivity with respect to the biological process of interest. Much of the development in molecular imaging is currently being carried out in animal models of disease, but as the field matures and with the development of more individualized medicine and the molecular targeting of new therapeutics, clinical translation is inevitable and will likely forever change our approach to diagnostic imaging. This review provides an introduction to the field of molecular imaging for readers who are not experts in the biological sciences and discusses the opportunities to apply a broad range of imaging technologies to better understand the biology of human health and disease. It also provides a brief review of the imaging technology (particularly for x-ray, nuclear and optical imaging) that is being developed to support this new field.

TOPICAL REVIEW: In vivo molecular and genomic imaging: new challenges for imaging physics

NASA Astrophysics Data System (ADS)

Cherry, Simon R.

2004-02-01

The emerging and rapidly growing field of molecular and genomic imaging is providing new opportunities to directly visualize the biology of living organisms. By combining our growing knowledge regarding the role of specific genes and proteins in human health and disease, with novel ways to target these entities in a manner that produces an externally detectable signal, it is becoming increasingly possible to visualize and quantify specific biological processes in a non-invasive manner. All the major imaging modalities are contributing to this new field, each with its unique mechanisms for generating contrast and trade-offs in spatial resolution, temporal resolution and sensitivity with respect to the biological process of interest. Much of the development in molecular imaging is currently being carried out in animal models of disease, but as the field matures and with the development of more individualized medicine and the molecular targeting of new therapeutics, clinical translation is inevitable and will likely forever change our approach to diagnostic imaging. This review provides an introduction to the field of molecular imaging for readers who are not experts in the biological sciences and discusses the opportunities to apply a broad range of imaging technologies to better understand the biology of human health and disease. It also provides a brief review of the imaging technology (particularly for x-ray, nuclear and optical imaging) that is being developed to support this new field.

Sleep and Neurodegeneration: A Critical Appraisal.

PubMed

Pillai, Jagan A; Leverenz, James B

2017-06-01

Sleep abnormalities are clearly recognized as a distinct clinical symptom of concern in neurodegenerative disorders. Appropriate management of sleep-related symptoms has a positive impact on quality of life in patients with neurodegenerative disorders. This review provides an overview of mechanisms that are currently being considered that tie sleep with neurodegeneration. It appraises the literature regarding specific sleep changes seen in common neurodegenerative diseases, with a focus on Alzheimer disease and synucleinopathies (ie, Parkinson disease, dementia with Lewy bodies, multiple system atrophy), that have been better studied. Sleep changes may also serve as markers to identify patients in the preclinical stage of some neurodegenerative disorders. A hypothetical model is postulated founded on the conjecture that specific sleep abnormalities, when noted to increase in severity beyond that expected for age, could be a surrogate marker reflecting pathophysiological processes related to neurodegenerative disorders. This provides a clinical strategy for screening patients in the preclinical stages of neurodegenerative disorders to enable therapeutic trials to establish the efficacy of neuroprotective agents to prevent or delay the development of symptoms and functional decline. It is unclear if sleep disturbance directly impacts neurodegenerative processes or is a secondary outcome of neurodegeneration; this is an active area of research. The clinical importance of recognizing and managing sleep changes in neurodegenerative disorders is beyond doubt. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Processing of CT images for analysis of diffuse lung disease in the lung tissue research consortium

NASA Astrophysics Data System (ADS)

Karwoski, Ronald A.; Bartholmai, Brian; Zavaletta, Vanessa A.; Holmes, David; Robb, Richard A.

2008-03-01

The goal of Lung Tissue Resource Consortium (LTRC) is to improve the management of diffuse lung diseases through a better understanding of the biology of Chronic Obstructive Pulmonary Disease (COPD) and fibrotic interstitial lung disease (ILD) including Idiopathic Pulmonary Fibrosis (IPF). Participants are subjected to a battery of tests including tissue biopsies, physiologic testing, clinical history reporting, and CT scanning of the chest. The LTRC is a repository from which investigators can request tissue specimens and test results as well as semi-quantitative radiology reports, pathology reports, and automated quantitative image analysis results from the CT scan data performed by the LTRC core laboratories. The LTRC Radiology Core Laboratory (RCL), in conjunction with the Biomedical Imaging Resource (BIR), has developed novel processing methods for comprehensive characterization of pulmonary processes on volumetric high-resolution CT scans to quantify how these diseases manifest in radiographic images. Specifically, the RCL has implemented a semi-automated method for segmenting the anatomical regions of the lungs and airways. In these anatomic regions, automated quantification of pathologic features of disease including emphysema volumes and tissue classification are performed using both threshold techniques and advanced texture measures to determine the extent and location of emphysema, ground glass opacities, "honeycombing" (HC) and "irregular linear" or "reticular" pulmonary infiltrates and normal lung. Wall thickness measurements of the trachea, and its branches to the 3 rd and limited 4 th order are also computed. The methods for processing, segmentation and quantification are described. The results are reviewed and verified by an expert radiologist following processing and stored in the public LTRC database for use by pulmonary researchers. To date, over 1200 CT scans have been processed by the RCL and the LTRC project is on target for recruitment of the 2200 patients with 1800 CT scans in the repository for the 5-year effort. Ongoing analysis of the results in the LTRC database by the LTRC participating institutions and outside investigators are underway to look at the clinical and physiological significance of the imaging features of these diseases and correlate these findings with quality of life and other important prognostic indicators of severity. In the future, the quantitative measures of disease may have greater utility by showing correlation with prognosis, disease severity and other physiological parameters. These imaging features may provide non-invasive alternative endpoints or surrogate markers to alleviate the need for tissue biopsy or provide an accurate means to monitor rate of disease progression or response to therapy.

Predictive Big Data Analytics: A Study of Parkinson's Disease Using Large, Complex, Heterogeneous, Incongruent, Multi-Source and Incomplete Observations.

PubMed

Dinov, Ivo D; Heavner, Ben; Tang, Ming; Glusman, Gustavo; Chard, Kyle; Darcy, Mike; Madduri, Ravi; Pa, Judy; Spino, Cathie; Kesselman, Carl; Foster, Ian; Deutsch, Eric W; Price, Nathan D; Van Horn, John D; Ames, Joseph; Clark, Kristi; Hood, Leroy; Hampstead, Benjamin M; Dauer, William; Toga, Arthur W

2016-01-01

A unique archive of Big Data on Parkinson's Disease is collected, managed and disseminated by the Parkinson's Progression Markers Initiative (PPMI). The integration of such complex and heterogeneous Big Data from multiple sources offers unparalleled opportunities to study the early stages of prevalent neurodegenerative processes, track their progression and quickly identify the efficacies of alternative treatments. Many previous human and animal studies have examined the relationship of Parkinson's disease (PD) risk to trauma, genetics, environment, co-morbidities, or life style. The defining characteristics of Big Data-large size, incongruency, incompleteness, complexity, multiplicity of scales, and heterogeneity of information-generating sources-all pose challenges to the classical techniques for data management, processing, visualization and interpretation. We propose, implement, test and validate complementary model-based and model-free approaches for PD classification and prediction. To explore PD risk using Big Data methodology, we jointly processed complex PPMI imaging, genetics, clinical and demographic data. Collective representation of the multi-source data facilitates the aggregation and harmonization of complex data elements. This enables joint modeling of the complete data, leading to the development of Big Data analytics, predictive synthesis, and statistical validation. Using heterogeneous PPMI data, we developed a comprehensive protocol for end-to-end data characterization, manipulation, processing, cleaning, analysis and validation. Specifically, we (i) introduce methods for rebalancing imbalanced cohorts, (ii) utilize a wide spectrum of classification methods to generate consistent and powerful phenotypic predictions, and (iii) generate reproducible machine-learning based classification that enables the reporting of model parameters and diagnostic forecasting based on new data. We evaluated several complementary model-based predictive approaches, which failed to generate accurate and reliable diagnostic predictions. However, the results of several machine-learning based classification methods indicated significant power to predict Parkinson's disease in the PPMI subjects (consistent accuracy, sensitivity, and specificity exceeding 96%, confirmed using statistical n-fold cross-validation). Clinical (e.g., Unified Parkinson's Disease Rating Scale (UPDRS) scores), demographic (e.g., age), genetics (e.g., rs34637584, chr12), and derived neuroimaging biomarker (e.g., cerebellum shape index) data all contributed to the predictive analytics and diagnostic forecasting. Model-free Big Data machine learning-based classification methods (e.g., adaptive boosting, support vector machines) can outperform model-based techniques in terms of predictive precision and reliability (e.g., forecasting patient diagnosis). We observed that statistical rebalancing of cohort sizes yields better discrimination of group differences, specifically for predictive analytics based on heterogeneous and incomplete PPMI data. UPDRS scores play a critical role in predicting diagnosis, which is expected based on the clinical definition of Parkinson's disease. Even without longitudinal UPDRS data, however, the accuracy of model-free machine learning based classification is over 80%. The methods, software and protocols developed here are openly shared and can be employed to study other neurodegenerative disorders (e.g., Alzheimer's, Huntington's, amyotrophic lateral sclerosis), as well as for other predictive Big Data analytics applications.

Calculable People? Standardising Assessment Guidelines for Alzheimer’s Disease in 1980s Britain

PubMed Central

Wilson, Duncan

2017-01-01

This article shows how funding research on Alzheimer’s disease became a priority for the British Medical Research Council (MRC) in the late 1970s and 1980s, thanks to work that isolated new pathological and biochemical markers and showed that the disease affected a significant proportion of the elderly population. In contrast to histories that focus on the emergence of new and competing theories of disease causation in this period, I argue that concerns over the use of different assessment methods ensured the MRC’s immediate priority was standardising the ways in which researchers identified and recorded symptoms of Alzheimer’s disease in potential research subjects. I detail how the rationale behind the development of standard assessment guidelines was less about arriving at a firm diagnosis and more about facilitating research by generating data that could be easily compared across the disciplines and sites that constitute modern biomedicine. Drawing on criticism of specific tests in the MRC’s guidelines, which some psychiatrists argued were ‘middle class biased’, I also show that debates over standardisation did not simply reflect concerns specific to the fields or areas of research that the MRC sought to govern. Questions about the validity of standard assessment guidelines for Alzheimer’s disease embodied broader concerns about education and social class, which ensured that distinguishing normal from pathological in old age remained a contested and historically contingent process. PMID:28901868

[Health risks in the biotechnological industry].

PubMed

Colombi, A; Maroni, M; Foà, V

1989-01-01

Biotechnology has been defined as the application of biological organisms, systems or processes to manufacturing and service industries. In considering health aspects of biotechnological development it must be underlined that the use of microorganisms in traditional industries, such as the production of food, bread, beer and dairy products, has not added significantly to the more usual industrial hazards. The risk factors encountered in the biotechnology industry can be defined as general, i.e., common to other industrial activities, and specific, i.e., depending on the presence of microorganisms and/or their metabolic products. The specific health risks vary according to the type of process, but can be grouped into three main categories: immunological diseases, toxic effects; pathological effects of microorganisms. Allergic immunological diseases such as bronchial asthma, contact dermatitis, oculo-rhinitis and extrinsic allergic alveolitis are by far the most frequent and well known diseases occurring among workers employed on biotechnological production. Toxic effects were observed among workers employed on the production of antibiotics and hormones or single cell proteins, where absorption of endotoxins has been described. Infectious diseases may arise from uncontrolled dissemination of pathogenic microorganisms through aerosols, dusts, aqueous and semisolid sludge effluents from biotechnological plants. The greatest risks occur in the production of antiviral vaccines, in research laboratories and in waste-water treatment plants. Risk of pathogenic effects has also been speculated from exposure to engineered microorganisms in laboratory and environmental or agricultural applications. Safety precautions consisting of protective measures, and effective barriers of containment (both physical and biological) have to be advised according to the hazardous characteristics of the organisms.(ABSTRACT TRUNCATED AT 250 WORDS)

Synthesis and Evaluation of a Novel Adenosine-Ribose Probe for Global-Scale Profiling of Nucleoside and Nucleotide-Binding Proteins

PubMed Central

Mahajan, Shikha; Manetsch, Roman; Merkler, David J.; Stevens Jr., Stanley M.

2015-01-01

Proteomics is a powerful approach used for investigating the complex molecular mechanisms of disease pathogenesis and progression. An important challenge in modern protein profiling approaches involves targeting of specific protein activities in order to identify altered molecular processes associated with disease pathophysiology. Adenosine-binding proteins represent an important subset of the proteome where aberrant expression or activity changes of these proteins have been implicated in numerous human diseases. Herein, we describe an affinity-based approach for the enrichment of adenosine-binding proteins from a complex cell proteome. A novel N 6-biotinylated-8-azido-adenosine probe (AdoR probe) was synthesized, which contains a reactive group that forms a covalent bond with the target proteins, as well as a biotin tag for affinity enrichment using avidin chromatography. Probe specificity was confirmed with protein standards prior to further evaluation in a complex protein mixture consisting of a lysate derived from mouse neuroblastoma N18TG2 cells. Protein identification and relative quantitation using mass spectrometry allowed for the identification of small variations in abundance of nucleoside- and nucleotide-binding proteins in these samples where a significant enrichment of AdoR-binding proteins in the labeled proteome from the neuroblastoma cells was observed. The results from this study demonstrate the utility of this method to enrich for nucleoside- and nucleotide-binding proteins in a complex protein mixture, pointing towards a unique set of proteins that can be examined in the context of further understanding mechanisms of disease, or fundamental biological processes in general. PMID:25671571

Frontotemporal neural systems supporting semantic processing in Alzheimer's disease.

PubMed

Peelle, Jonathan E; Powers, John; Cook, Philip A; Smith, Edward E; Grossman, Murray

2014-03-01

We hypothesized that semantic memory for object concepts involves both representations of visual feature knowledge in modality-specific association cortex and heteromodal regions that are important for integrating and organizing this semantic knowledge so that it can be used in a flexible, contextually appropriate manner. We examined this hypothesis in an fMRI study of mild Alzheimer's disease (AD). Participants were presented with pairs of printed words and asked whether the words matched on a given visual-perceptual feature (e.g., guitar, violin: SHAPE). The stimuli probed natural kinds and manufactured objects, and the judgments involved shape or color. We found activation of bilateral ventral temporal cortex and left dorsolateral prefrontal cortex during semantic judgments, with AD patients showing less activation of these regions than healthy seniors. Moreover, AD patients showed less ventral temporal activation than did healthy seniors for manufactured objects, but not for natural kinds. We also used diffusion-weighted MRI of white matter to examine fractional anisotropy (FA). Patients with AD showed significantly reduced FA in the superior longitudinal fasciculus and inferior frontal-occipital fasciculus, which carry projections linking temporal and frontal regions of this semantic network. Our results are consistent with the hypothesis that semantic memory is supported in part by a large-scale neural network involving modality-specific association cortex, heteromodal association cortex, and projections between these regions. The semantic deficit in AD thus arises from gray matter disease that affects the representation of feature knowledge and processing its content, as well as white matter disease that interrupts the integrated functioning of this large-scale network.

Development and psychometric evaluation of a cardiovascular risk and disease management knowledge assessment tool.

PubMed

Rosneck, James S; Hughes, Joel; Gunstad, John; Josephson, Richard; Noe, Donald A; Waechter, Donna

2014-01-01

This article describes the systematic construction and psychometric analysis of a knowledge assessment instrument for phase II cardiac rehabilitation (CR) patients measuring risk modification disease management knowledge and behavioral outcomes derived from national standards relevant to secondary prevention and management of cardiovascular disease. First, using adult curriculum based on disease-specific learning outcomes and competencies, a systematic test item development process was completed by clinical staff. Second, a panel of educational and clinical experts used an iterative process to identify test content domain and arrive at consensus in selecting items meeting criteria. Third, the resulting 31-question instrument, the Cardiac Knowledge Assessment Tool (CKAT), was piloted in CR patients to ensure use of application. Validity and reliability analyses were performed on 3638 adults before test administrations with additional focused analyses on 1999 individuals completing both pretreatment and posttreatment administrations within 6 months. Evidence of CKAT content validity was substantiated, with 85% agreement among content experts. Evidence of construct validity was demonstrated via factor analysis identifying key underlying factors. Estimates of internal consistency, for example, Cronbach's α = .852 and Spearman-Brown split-half reliability = 0.817 on pretesting, support test reliability. Item analysis, using point biserial correlation, measured relationships between performance on single items and total score (P < .01). Analyses using item difficulty and item discrimination indices further verified item stability and validity of the CKAT. A knowledge instrument specifically designed for an adult CR population was systematically developed and tested in a large representative patient population, satisfying psychometric parameters, including validity and reliability.

Phytoalexins, miRNAs and breast cancer: a review of phytochemical mediated miRNA regulation in breast cancer

USDA-ARS?s Scientific Manuscript database

A specific class of endogenous, non-coding RNAs, classified as microRNAs (miRNAs), has been identified. It has been found that miRNAs are associated with many biological processes and disease states, including all stages of cancer from initiation to tumor promotion and progression. These studies d...

How to collect and process small polyhedral viruses of insects

Treesearch

Franklin B. Lewis

1960-01-01

The past few years have seen increased interest in and use of microbial agents for the control of destructive forest insects. One of the most successful applications of this control method has been the use of the polyhedral virus disease of the European pine sawfly, Neodiprion sertifer (Geoff.). Control of this insect by its specific pathogen has...

Nuclear mRNA Surveillance Mechanisms: Function and Links to Human Disease.

PubMed

Singh, Pragyan; Saha, Upasana; Paira, Sunirmal; Das, Biswadip

2018-05-11

Production of export-competent mRNAs involves transcription and a series of dynamic processing and modification events of pre-messenger RNAs in the nucleus. Mutations in the genes encoding the transcription and mRNP processing machinery and the complexities involved in the biogenesis events lead to the formation of aberrant messages. These faulty transcripts are promptly eliminated by the nuclear RNA exosome and its cofactors to safeguard the cells and organisms from genetic catastrophe. Mutations in the components of the core nuclear exosome and its cofactors lead to the tissue-specific dysfunction of exosomal activities, which are linked to diverse human diseases and disorders. In this article, we examine the structure and function of both the yeast and human RNA exosome complex and its cofactors, discuss the nature of the various altered amino acid residues implicated in these diseases with the speculative mechanisms of the mutation-induced disorders and project the frontier and prospective avenues of the future research in this field. Copyright © 2018 Elsevier Ltd. All rights reserved.

[CORRECTION OF METABOLIC DISTURBANCES IN PATIENTS WITH PULMONARY TUBERCULOSIS AND CONCOMITANT DISEASES].

PubMed

2010-01-01

Metabolic disturbances were corrected using the oral specialized formula Nutrien-phthisio (ZAO "Company Nutritec", Russia) in 53 patients with pulmonary tuberculosis and concomitant diseases. In the whole group, tuberculosis was first detected in 21 patients; 32 had a chronic process. Chemotherapy was discontinued in all the patients due to the intolerance phenomena caused by comorbidity (erosive gastritis, gastroduodenal peptic ulcer, hepatitis B and C, chronic pyelonephritis) in 24 patients, by adverse reactions in 19, and by a combination of both factors in 10. The criteria for objectively monitoring the efficiency of nutritional support (in combination with specific treatment) were body mass index, general blood analysis, by taking into account the percentage and absolute count of lymphocytes and the protein metabolism from the serum levels of total protein, albumin, and transferrin. The study determined clinical and laboratory indications for the use of Nutrien-phthisio and the favorable impact of nutritional support on the course of a tuberculous process and concomitant diseases.

Enhancing attention in neurodegenerative diseases: current therapies and future directions

PubMed Central

Davis, Thomas; Coulthard, Elizabeth

2016-01-01

Abstract We all experience at least occasional lapses in attention but in some neurological conditions, loss of attention is pervasive and debilitating. Treating deficits in attention first requires an understanding of the neurobiology of attention, which we now understand to be a set of different cognitive processes. Cholinesterase inhibitors are already established as effective attentional enhancers used in the treatment of certain dementias. Other stimulant agents such as modafanil, amphetamine and methylphenidate have demonstrated limited success in healthy individuals where attention is already optimal and clinical trials in patients with neurological disease are sparse. Dietary and lifestyle changes are gaining increasing prominence, as are experimental treatments such as deep brain stimulation and transcranial magnetic stimulation. As the therapeutic arsenal widens, clinicians will be able to match specific treatments to selective deficits in attention, giving patients a tailored management plan. Here we review common diseases that impair attention and emphasise how an understanding of attentional processing within the brain might lead to improved therapeutic strategies. PMID:28123829

Detecting Disease in Radiographs with Intuitive Confidence

PubMed Central

2015-01-01

This paper argues in favor of a specific type of confidence for use in computer-aided diagnosis and disease classification, namely, sine/cosine values of angles represented by points on the unit circle. The paper shows how this confidence is motivated by Chinese medicine and how sine/cosine values are directly related with the two forces Yin and Yang. The angle for which sine and cosine are equal (45°) represents the state of equilibrium between Yin and Yang, which is a state of nonduality that indicates neither normality nor abnormality in terms of disease classification. The paper claims that the proposed confidence is intuitive and can be readily understood by physicians. The paper underpins this thesis with theoretical results in neural signal processing, stating that a sine/cosine relationship between the actual input signal and the perceived (learned) input is key to neural learning processes. As a practical example, the paper shows how to use the proposed confidence values to highlight manifestations of tuberculosis in frontal chest X-rays. PMID:26495433

The normal and pathologic renal medulla: a comprehensive overview.

PubMed

López, José I; Larrinaga, Gorka; Kuroda, Naoto; Angulo, Javier C

2015-04-01

The renal medulla comprises an intricate system of tubules, blood vessels and interstitium that is not well understood by most general pathologists. We conducted an extensive review of the literature on the renal medulla, in both normal and pathologic conditions. We set out in detail the points of key interest to pathologists: normal and pathological development, physiology, microscopic anatomy, histology and immunohistochemistry; and the specific and most common other types of disease associated with this part of the kidney: developmental abnormalities, (multicystic dysplastic kidney, autosomal dominant and recessive polycystic kidney diseases, medullary cystic kidney disease), inflammatory conditions (xanthogranulomatous pyelonephritis, malakoplakia), hyperplasia and dysplasia, and neoplastic processes (oncocytoma, atypical oncocytic tumors, chromophobe cell carcinoma, collecting duct carcinoma, urothelial carcinoma, other carcinomas, renal medullary fibroma and metastatic tumors). This condensed overview of the origin, function and pathology of the renal medulla, both in terms of development, inflammation and neoplastic processes, should help focus the interest of clinical pathologists on this widely overlooked part of the kidney. Copyright © 2014 Elsevier GmbH. All rights reserved.

Diverse exocytic pathways for mast cell mediators.

PubMed

Xu, Hao; Bin, Na-Ryum; Sugita, Shuzo

2018-04-17

Mast cells play pivotal roles in innate and adaptive immunities but are also culprits in allergy, autoimmunity, and cardiovascular diseases. Mast cells respond to environmental changes by initiating regulated exocytosis/secretion of various biologically active compounds called mediators (e.g. proteases, amines, and cytokines). Many of these mediators are stored in granules/lysosomes and rely on intricate degranulation processes for release. Mast cell stabilizers (e.g. sodium cromoglicate), which prevent such degranulation processes, have therefore been clinically employed to treat asthma and allergic rhinitis. However, it has become increasingly clear that different mast cell diseases often involve multiple mediators that rely on overlapping but distinct mechanisms for release. This review illustrates existing evidence that highlights the diverse exocytic pathways in mast cells. We also discuss strategies to delineate these pathways so as to identify unique molecular components which could serve as new drug targets for more effective and specific treatments against mast cell-related diseases. © 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.

HMPAS: Human Membrane Protein Analysis System

PubMed Central

2013-01-01

Background Membrane proteins perform essential roles in diverse cellular functions and are regarded as major pharmaceutical targets. The significance of membrane proteins has led to the developing dozens of resources related with membrane proteins. However, most of these resources are built for specific well-known membrane protein groups, making it difficult to find common and specific features of various membrane protein groups. Methods We collected human membrane proteins from the dispersed resources and predicted novel membrane protein candidates by using ortholog information and our membrane protein classifiers. The membrane proteins were classified according to the type of interaction with the membrane, subcellular localization, and molecular function. We also made new feature dataset to characterize the membrane proteins in various aspects including membrane protein topology, domain, biological process, disease, and drug. Moreover, protein structure and ICD-10-CM based integrated disease and drug information was newly included. To analyze the comprehensive information of membrane proteins, we implemented analysis tools to identify novel sequence and functional features of the classified membrane protein groups and to extract features from protein sequences. Results We constructed HMPAS with 28,509 collected known membrane proteins and 8,076 newly predicted candidates. This system provides integrated information of human membrane proteins individually and in groups organized by 45 subcellular locations and 1,401 molecular functions. As a case study, we identified associations between the membrane proteins and diseases and present that membrane proteins are promising targets for diseases related with nervous system and circulatory system. A web-based interface of this system was constructed to facilitate researchers not only to retrieve organized information of individual proteins but also to use the tools to analyze the membrane proteins. Conclusions HMPAS provides comprehensive information about human membrane proteins including specific features of certain membrane protein groups. In this system, user can acquire the information of individual proteins and specified groups focused on their conserved sequence features, involved cellular processes, and diseases. HMPAS may contribute as a valuable resource for the inference of novel cellular mechanisms and pharmaceutical targets associated with the human membrane proteins. HMPAS is freely available at http://fcode.kaist.ac.kr/hmpas. PMID:24564858

Hepatic MR imaging for in vivo differentiation of steatosis, iron deposition and combined storage disorder: single-ratio in/opposed phase analysis vs. dual-ratio Dixon discrimination.

PubMed

Bashir, Mustafa R; Merkle, Elmar M; Smith, Alastair D; Boll, Daniel T

2012-02-01

To assess whether in vivo dual-ratio Dixon discrimination can improve detection of diffuse liver disease, specifically steatosis, iron deposition and combined disease over traditional single-ratio in/opposed phase analysis. Seventy-one patients with biopsy-proven (17.7 ± 17.0 days) hepatic steatosis (n = 16), iron deposition (n = 11), combined deposition (n = 3) and neither disease (n = 41) underwent MR examinations. Dual-echo in/opposed-phase MR with Dixon water/fat reconstructions were acquired. Analysis consisted of: (a) single-ratio hepatic region-of-interest (ROI)-based assessment of in/opposed ratios; (b) dual-ratio hepatic ROI assessment of in/opposed and fat/water ratios; (c) computer-aided dual-ratio assessment evaluating all hepatic voxels. Disease-specific thresholds were determined; statistical analyses assessed disease-dependent voxel ratios, based on single-ratio (a) and dual-ratio (b and c) techniques. Single-ratio discrimination succeeded in identifying iron deposition (I/O(Ironthreshold)<0.88) and steatosis (I/O(Fatthreshold>1.15)) from normal parenchyma, sensitivity 70.0%; it failed to detect combined disease. Dual-ratio discrimination succeeded in identifying abnormal hepatic parenchyma (F/W(Normalthreshold)>0.05), sensitivity 96.7%; logarithmic functions for iron deposition (I/O(Irondiscriminator)e((F/W(Fat)-0.01)/0.48)) differentiated combined from isolated diseases, sensitivity 100.0%; computer-aided dual-ratio analysis was comparably sensitive but less specific, 90.2% vs. 97.6%. MR two-point-Dixon imaging using dual-ratio post-processing based on in/opposed and fat/water ratios improved in vivo detection of hepatic steatosis, iron deposition, and combined storage disease beyond traditional in/opposed analysis. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Agent-Based Modeling of Chronic Diseases: A Narrative Review and Future Research Directions

PubMed Central

Lawley, Mark A.; Siscovick, David S.; Zhang, Donglan; Pagán, José A.

2016-01-01

The United States is experiencing an epidemic of chronic disease. As the US population ages, health care providers and policy makers urgently need decision models that provide systematic, credible prediction regarding the prevention and treatment of chronic diseases to improve population health management and medical decision-making. Agent-based modeling is a promising systems science approach that can model complex interactions and processes related to chronic health conditions, such as adaptive behaviors, feedback loops, and contextual effects. This article introduces agent-based modeling by providing a narrative review of agent-based models of chronic disease and identifying the characteristics of various chronic health conditions that must be taken into account to build effective clinical- and policy-relevant models. We also identify barriers to adopting agent-based models to study chronic diseases. Finally, we discuss future research directions of agent-based modeling applied to problems related to specific chronic health conditions. PMID:27236380

Agent-Based Modeling of Chronic Diseases: A Narrative Review and Future Research Directions.

PubMed

Li, Yan; Lawley, Mark A; Siscovick, David S; Zhang, Donglan; Pagán, José A

2016-05-26

The United States is experiencing an epidemic of chronic disease. As the US population ages, health care providers and policy makers urgently need decision models that provide systematic, credible prediction regarding the prevention and treatment of chronic diseases to improve population health management and medical decision-making. Agent-based modeling is a promising systems science approach that can model complex interactions and processes related to chronic health conditions, such as adaptive behaviors, feedback loops, and contextual effects. This article introduces agent-based modeling by providing a narrative review of agent-based models of chronic disease and identifying the characteristics of various chronic health conditions that must be taken into account to build effective clinical- and policy-relevant models. We also identify barriers to adopting agent-based models to study chronic diseases. Finally, we discuss future research directions of agent-based modeling applied to problems related to specific chronic health conditions.

The role of intestinal microbiota in the pathogenesis of metabolic diseases.

PubMed

Węgielska, Iwona; Suliburska, Joanna

2016-01-01

The incidence of metabolic diseases is increasing rapidly all over the world. This situation has led researchers to attempt to explain the pathomechanisms of these disorders and to develop specific recommendations for the prevention and treatment of diseases such as obesity, type-2 diabetes, and atherosclerosis. Recent studies show clear evidence of the role of human intestinal microbiota in health and in predispositions to diseases. Gut microbiota affect a number of complex metabolic reactions, significantly altering the functioning of the human body. Numerous experiments have shown the key role played by the formation process of the intestinal ecosystem in the early stages of human life for programming its metabolic health. The following article is a compilation of the literature available on the formation of the complex intestinal ecosystem and its impact on the incidence of diseases such as obesity, type-2 diabetes, and atherosclerosis.

The roles of the exoribonucleases DIS3L2 and XRN1 in human disease.

PubMed

Pashler, Amy L; Towler, Benjamin P; Jones, Christopher I; Newbury, Sarah F

2016-10-15

RNA degradation is a vital post-transcriptional process which ensures that transcripts are maintained at the correct level within the cell. DIS3L2 and XRN1 are conserved exoribonucleases that are critical for the degradation of cytoplasmic RNAs. Although the molecular mechanisms of RNA degradation by DIS3L2 and XRN1 have been well studied, less is known about their specific roles in the development of multicellular organisms or human disease. This review focusses on the roles of DIS3L2 and XRN1 in the pathogenesis of human disease, particularly in relation to phenotypes seen in model organisms. The known diseases associated with loss of activity of DIS3L2 and XRN1 are discussed, together with possible mechanisms and cellular pathways leading to these disease conditions. © 2016 The Author(s); published by Portland Press Limited on behalf of the Biochemical Society.