Using multitype branching processes to quantify statistics of disease outbreaks in zoonotic epidemics

USDA-ARS?s Scientific Manuscript database

Despite the enormous relevance of zoonotic infections to world-wide public health, and despite much effort in modeling individual zoonoses, a fundamental understanding of the disease dynamics and the nature of outbreaks emanating from such a complex system is still lacking. We introduce a simple sto...

Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research

PubMed Central

Wangler, Michael F.; Yamamoto, Shinya; Chao, Hsiao-Tuan; Posey, Jennifer E.; Westerfield, Monte; Postlethwait, John; Hieter, Philip; Boycott, Kym M.; Campeau, Philippe M.; Bellen, Hugo J.

2017-01-01

Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material, File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies. PMID:28874452

Association of the host immune response with protection using a live attenuated African swine fever virus model

USDA-ARS?s Scientific Manuscript database

African swine fever virus (ASFV) causes a lethal disease of swine. Infection with attenuated strains protect against challenge but there is limited knowledge of the immune mechanisms generating that protection. ASFV Pret4 produces a fatal disease, while its derivative, lacking virulence-associated g...

Development of model infectious disease protocols for fire and EMS personnel.

PubMed

Miller, Nancy L; Gudmestad, Tom; Eisenberg, Mickey S

2005-01-01

To develop model infectious disease exposure plans for emergency medical services agencies in King County, Washington. All fire departments in King County, Washington, were surveyed to determine their pathogen exposure policies. After these agencies were surveyed, model response plans were developed for both bloodborne and airborne pathogen exposure. Twenty-four of the 35 fire departments in King County submitted infectious disease exposure policies. There was diversity among the plans, and not all were deemed able to provide prophylaxis in a timely fashion. Based on this lack of uniformity among response plans, model response plans were developed for bloodborne and airborne infectious disease pathogens. Great variety was present throughout the exposure plans currently in use throughout King County, Washington. Model plans would likely universalize response to pathogen exposure and help to ensure prompt and appropriate postexposure prophylaxis.

[The complement system in the pathogenesis of antineutrophil cytoplasm antibodies-associated vasculitis].

PubMed

Flores-Suárez, Luis F

2011-12-01

One of the main characteristics of the vasculitis associated with antineutrophil cytoplasm autoantibodies (AASV) is the absence of immune complex deposition in biopsies of affected tissues as well as a lack of complement depletion. However, in early stages of disease induced in animal models, it has been observed that the complement system may be involved in the generation of these diseases. There are various animal models which have been developed with the aim of knowing which are the pathogenic mechanisms in granulomatosis with polyangiitis (Wegener) (GPA) and microscopic polyangiitis (MPA), the latter being explained using these approaches in a more satisfactory manner, as there is lack of a model which reproduces the changes leading to a granulomatous vasculitis associated with antibodies against proteinase-3, as in GPA. This short review presents recent evidence of the presence of complement in biopsies of patients with AASV and the most recent animal models, which show the participation of complement in their etiology. Copyright © 2011 Elsevier España, S.L. All rights reserved.

A Tol2 Gateway-Compatible Toolbox for the Study of the Nervous System and Neurodegenerative Disease.

PubMed

Don, Emily K; Formella, Isabel; Badrock, Andrew P; Hall, Thomas E; Morsch, Marco; Hortle, Elinor; Hogan, Alison; Chow, Sharron; Gwee, Serene S L; Stoddart, Jack J; Nicholson, Garth; Chung, Roger; Cole, Nicholas J

2017-02-01

Currently there is a lack in fundamental understanding of disease progression of most neurodegenerative diseases, and, therefore, treatments and preventative measures are limited. Consequently, there is a great need for adaptable, yet robust model systems to both investigate elementary disease mechanisms and discover effective therapeutics. We have generated a Tol2 Gateway-compatible toolbox to study neurodegenerative disorders in zebrafish, which includes promoters for astrocytes, microglia and motor neurons, multiple fluorophores, and compatibility for the introduction of genes of interest or disease-linked genes. This toolbox will advance the rapid and flexible generation of zebrafish models to discover the biology of the nervous system and the disease processes that lead to neurodegeneration.

Mice lacking liver-specific β-catenin develop steatohepatitis and fibrosis after iron overload.

PubMed

Preziosi, Morgan E; Singh, Sucha; Valore, Erika V; Jung, Grace; Popovic, Branimir; Poddar, Minakshi; Nagarajan, Shanmugam; Ganz, Tomas; Monga, Satdarshan P

2017-08-01

Iron overload disorders such as hereditary hemochromatosis and iron loading anemias are a common cause of morbidity from liver diseases and increase risk of hepatic fibrosis and hepatocellular carcinoma (HCC). Treatment options for iron-induced damage are limited, partly because there is lack of animal models of human disease. Therefore, we investigated the effect of iron overload in liver-specific β-catenin knockout mice (KO), which are susceptible to injury, fibrosis and tumorigenesis following chemical carcinogen exposure. Iron overload diet was administered to KO and littermate control (CON) mice for various times. To ameliorate an oxidant-mediated component of tissue injury, N-Acetyl-L-(+)-cysteine (NAC) was added to drinking water of mice on iron overload diet. KO on iron diet (KO +Fe) exhibited remarkable inflammation, followed by steatosis, oxidative stress, fibrosis, regenerating nodules and occurrence of occasional HCC. Increased injury in KO +Fe was associated with activated protein kinase B (AKT), ERK, and NF-κB, along with reappearance of β-catenin and target gene Cyp2e1, which promoted lipid peroxidation and hepatic damage. Addition of NAC to drinking water protected KO +Fe from hepatic steatosis, injury and fibrosis, and prevented activation of AKT, ERK, NF-κB and reappearance of β-catenin. The absence of hepatic β-catenin predisposes mice to hepatic injury and fibrosis following iron overload, which was reminiscent of hemochromatosis and associated with enhanced steatohepatitis and fibrosis. Disease progression was notably alleviated by antioxidant therapy, which supports its chemopreventive role in the management of chronic iron overload disorders. Lack of animal models for iron overload disorders makes it hard to study the disease process for improving therapies. Feeding high iron diet to mice that lack the β-catenin gene in liver cells led to increased inflammation followed by fat accumulation, cell death and wound healing that mimicked human disease. Administration of an antioxidant prevented hepatic injury in this model. Copyright © 2017 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

An approach to and web-based tool for infectious disease outbreak intervention analysis

NASA Astrophysics Data System (ADS)

Daughton, Ashlynn R.; Generous, Nicholas; Priedhorsky, Reid; Deshpande, Alina

2017-04-01

Infectious diseases are a leading cause of death globally. Decisions surrounding how to control an infectious disease outbreak currently rely on a subjective process involving surveillance and expert opinion. However, there are many situations where neither may be available. Modeling can fill gaps in the decision making process by using available data to provide quantitative estimates of outbreak trajectories. Effective reduction of the spread of infectious diseases can be achieved through collaboration between the modeling community and public health policy community. However, such collaboration is rare, resulting in a lack of models that meet the needs of the public health community. Here we show a Susceptible-Infectious-Recovered (SIR) model modified to include control measures that allows parameter ranges, rather than parameter point estimates, and includes a web user interface for broad adoption. We apply the model to three diseases, measles, norovirus and influenza, to show the feasibility of its use and describe a research agenda to further promote interactions between decision makers and the modeling community.

Drosophila lacks C20 and C22 polyunsaturated fatty acids

USDA-ARS?s Scientific Manuscript database

Drosophila melanogaster has been considered an ideal model organism to investigate human diseases and genetic pathways. Whether Drosophila is an ideal model for nutrigenomics, especially for fatty acid metabolism, however, remains to be illustrated. This study was to examine the metabolism of C20 an...

An individual-based model of rabbit viral haemorrhagic disease on European wild rabbits (Oryctolagus cuniculus)

USGS Publications Warehouse

Fa, John E.; Sharples, Colin M.; Bell, Diana J.; DeAngelis, Donald L.

2001-01-01

We developed an individual-based model of Rabbit Viral Hemorrhagic Disease (RVHD) for European wild rabbits (Oryctolagus cuniculus L.), representing up to 1000 rabbits in four hectares. Model output for productivity and recruitment matched published values. The disease was density-dependent and virulence affected outcome. Strains that caused death after several days produced greater overall mortality than strains in which rabbits either died or recovered very quickly. Disease effect also depended on time of year. We also elaborated a larger scale model representing 25 km2 and 100,000+ rabbits, split into a number of grid-squares. This was a more traditional model that did not represent individual rabbits, but employed a system of dynamic equations for each grid-square. Disease spread depended on probability of transmission between neighboring grid-squares. Potential recovery from a major population crash caused by the disease relied on disease virulence and frequency of recurrence. The model's dependence on probability of disease transmission between grid-squares suggests the way that the model represents the spatial distribution of the population affects simulation. Although data on RVHD in Europe are lacking, our models provide a basis for describing the disease in realistic detail and for assessing influence of various social and spatial factors on spread.

Revisiting the NIH Taskforce on the Research needs of Eosinophil-Associated Diseases (RE-TREAD).

PubMed

Khoury, Paneez; Akuthota, Praveen; Ackerman, Steven J; Arron, Joseph R; Bochner, Bruce S; Collins, Margaret H; Kahn, Jean-Emmanuel; Fulkerson, Patricia C; Gleich, Gerald J; Gopal-Srivastava, Rashmi; Jacobsen, Elizabeth A; Leiferman, Kristen M; Francesca, Levi-Schaffer; Mathur, Sameer K; Minnicozzi, Michael; Prussin, Calman; Rothenberg, Marc E; Roufosse, Florence; Sable, Kathleen; Simon, Dagmar; Simon, Hans-Uwe; Spencer, Lisa A; Steinfeld, Jonathan; Wardlaw, Andrew J; Wechsler, Michael E; Weller, Peter F; Klion, Amy D

2018-04-19

Eosinophil-associated diseases (EADs) are rare, heterogeneous disorders characterized by the presence of eosinophils in tissues and/or peripheral blood resulting in immunopathology. The heterogeneity of tissue involvement, lack of sufficient animal models, technical challenges in working with eosinophils, and lack of standardized histopathologic approaches have hampered progress in basic research. Additionally, clinical trials and drug development for rare EADs are limited by the lack of primary and surrogate endpoints, biomarkers, and validated patient-reported outcomes. Researchers with expertise in eosinophil biology and eosinophil-related diseases reviewed the state of current eosinophil research, resources, progress, and unmet needs in the field since the 2012 meeting of the NIH Taskforce on the Research of Eosinophil-Associated Diseases (TREAD). RE-TREAD focused on gaps in basic science, translational, and clinical research on eosinophils and eosinophil-related pathogenesis. Improved recapitulation of human eosinophil biology and pathogenesis in murine models was felt to be of importance. Characterization of eosinophil phenotypes, the role of eosinophil subsets in tissues, identification of biomarkers of eosinophil activation and tissue load, and a better understanding of the role of eosinophils in human disease were prioritized. Finally, an unmet need for tools for use in clinical trials was emphasized. Histopathologic scoring, patient- and clinician-reported outcomes, and appropriate coding were deemed of paramount importance for research collaborations, drug development, and approval by regulatory agencies. Further exploration of the eosinophil genome, epigenome, and proteome was also encouraged. Although progress has been made since 2012, unmet needs in eosinophil research remain a priority. ©2018 Society for Leukocyte Biology.

Candidacy for Kidney Transplantation of Older Adults

PubMed Central

Grams, Morgan E.; Kucirka, Lauren M.; Hanrahan, Colleen F.; Montgomery, Robert A.; Massie, Allan B.; Segev, Dorry L.

2013-01-01

OBJECTIVES To develop a prediction model for kidney transplantation (KT) outcomes specific to older adults with end-stage renal disease (ESRD) and to use this model to estimate the number of excellent older KT candidates who lack access to KT. DESIGN Secondary analysis of data collected by the United Network for Organ Sharing and U.S. Renal Disease System. SETTING Retrospective analysis of national registry data. PARTICIPANTS Model development: Medicare-primary older recipients (aged ≥ 65) of a first KT between 1999 and 2006 (N = 6,988). Model application: incident Medicare-primary older adults with ESRD between 1999 and 2006 without an absolute or relative contraindication to transplantation (N = 128,850). MEASUREMENTS Comorbid conditions were extracted from U.S. Renal Disease System Form 2728 data and Medicare claims. RESULTS The prediction model used 19 variables to estimate post-KT outcome and showed good calibration (Hosmer–Lemeshow P = .44) and better prediction than previous population-average models (P < .001). Application of the model to the population with incident ESRD identified 11,756 excellent older transplant candidates (defined as >87% predicted 3-year post-KT survival, corresponding to the top 20% of transplanted older adults used in model development), of whom 76.3% (n = 8,966) lacked access. It was estimated that 11% of these candidates would have identified a suitable live donor had they been referred for KT. CONCLUSION A risk-prediction model specific to older adults can identify excellent KT candidates. Appropriate referral could result in significantly greater rates of KT in older adults. PMID:22239290

Cholangiocytes derived from human induced pluripotent stem cells for disease modeling and drug validation.

PubMed

Sampaziotis, Fotios; de Brito, Miguel Cardoso; Madrigal, Pedro; Bertero, Alessandro; Saeb-Parsy, Kourosh; Soares, Filipa A C; Schrumpf, Elisabeth; Melum, Espen; Karlsen, Tom H; Bradley, J Andrew; Gelson, William Th; Davies, Susan; Baker, Alastair; Kaser, Arthur; Alexander, Graeme J; Hannan, Nicholas R F; Vallier, Ludovic

2015-08-01

The study of biliary disease has been constrained by a lack of primary human cholangiocytes. Here we present an efficient, serum-free protocol for directed differentiation of human induced pluripotent stem cells into cholangiocyte-like cells (CLCs). CLCs show functional characteristics of cholangiocytes, including bile acids transfer, alkaline phosphatase activity, γ-glutamyl-transpeptidase activity and physiological responses to secretin, somatostatin and vascular endothelial growth factor. We use CLCs to model in vitro key features of Alagille syndrome, polycystic liver disease and cystic fibrosis (CF)-associated cholangiopathy. Furthermore, we use CLCs generated from healthy individuals and patients with polycystic liver disease to reproduce the effects of the drugs verapamil and octreotide, and we show that the experimental CF drug VX809 rescues the disease phenotype of CF cholangiopathy in vitro. Our differentiation protocol will facilitate the study of biological mechanisms controlling biliary development, as well as disease modeling and drug screening.

Lethal Zika Virus Disease Models in Young and Older Interferon α/β Receptor Knock Out Mice.

PubMed

Marzi, Andrea; Emanuel, Jackson; Callison, Julie; McNally, Kristin L; Arndt, Nicolette; Chadinha, Spencer; Martellaro, Cynthia; Rosenke, Rebecca; Scott, Dana P; Safronetz, David; Whitehead, Stephen S; Best, Sonja M; Feldmann, Heinz

2018-01-01

The common small animal disease models for Zika virus (ZIKV) are mice lacking the interferon responses, but infection of interferon receptor α/β knock out (IFNAR -/- ) mice is not uniformly lethal particularly in older animals. Here we sought to advance this model in regard to lethality for future countermeasure efficacy testing against more recent ZIKV strains from the Asian lineage, preferably the American sublineage. We first infected IFNAR -/- mice subcutaneously with the contemporary ZIKV-Paraiba strain resulting in predominantly neurological disease with ~50% lethality. Infection with ZIKV-Paraiba by different routes established a uniformly lethal model only in young mice (4-week old) upon intraperitoneal infection. However, intraperitoneal inoculation of ZIKV-French Polynesia resulted in uniform lethality in older IFNAR -/- mice (10-12-weeks old). In conclusion, we have established uniformly lethal mouse disease models for efficacy testing of antivirals and vaccines against recent ZIKV strains representing the Asian lineage.

In Silico Investigations of the Anti-Catabolic Effects of Pamidronate and Denosumab on Multiple Myeloma-Induced Bone Disease

PubMed Central

Wang, Yan; Lin, Bo

2012-01-01

It is unclear whether the new anti-catabolic agent denosumab represents a viable alternative to the widely used anti-catabolic agent pamidronate in the treatment of Multiple Myeloma (MM)-induced bone disease. This lack of clarity primarily stems from the lack of sufficient clinical investigations, which are costly and time consuming. However, in silico investigations require less time and expense, suggesting that they may be a useful complement to traditional clinical investigations. In this paper, we aim to (i) develop integrated computational models that are suitable for investigating the effects of pamidronate and denosumab on MM-induced bone disease and (ii) evaluate the responses to pamidronate and denosumab treatments using these integrated models. To achieve these goals, pharmacokinetic models of pamidronate and denosumab are first developed and then calibrated and validated using different clinical datasets. Next, the integrated computational models are developed by incorporating the simulated transient concentrations of pamidronate and denosumab and simulations of their actions on the MM-bone compartment into the previously proposed MM-bone model. These integrated models are further calibrated and validated by different clinical datasets so that they are suitable to be applied to investigate the responses to the pamidronate and denosumab treatments. Finally, these responses are evaluated by quantifying the bone volume, bone turnover, and MM-cell density. This evaluation identifies four denosumab regimes that potentially produce an overall improved bone-related response compared with the recommended pamidronate regime. This in silico investigation supports the idea that denosumab represents an appropriate alternative to pamidronate in the treatment of MM-induced bone disease. PMID:23028650

Systemic inflammation in chronic obstructive pulmonary disease and lung cancer: common driver of pulmonary cachexia?

PubMed

Ceelen, Judith J M; Langen, Ramon C J; Schols, Annemie M W J

2014-12-01

In this article, a putative role of systemic inflammation as a driver of pulmonary cachexia induced by either chronic obstructive pulmonary disease or nonsmall cell lung cancer is reviewed. Gaps in current translational research approaches are discussed and alternative strategies are proposed to provide new insights. Activation of the ubiquitin proteasome system has generally been considered a cause of pulmonary cachexia, but current animal models lack specificity and evidence is lacking in nonsmall cell lung cancer and conflicting in chronic obstructive pulmonary disease patients. Recent studies have shown activation of the autophagy-lysosome pathway in both nonsmall cell lung cancer and chronic obstructive pulmonary disease. Myonuclear loss, as a consequence of increased apoptotic events in myofibers, has been suggested in cancer-cachexia-associated muscle atrophy. Plasma transfer on myotube cultures can be used to detect early inflammatory signals in patients and presence of atrophy-inducing activity within the circulation. Comparative clinical research between nonsmall cell lung cancer and chronic obstructive pulmonary disease in different disease stages is useful to unravel disease-specific versus common denominators of pulmonary cachexia.

Monitoring Method of Cow Anthrax Based on Gis and Spatial Statistical Analysis

NASA Astrophysics Data System (ADS)

Li, Lin; Yang, Yong; Wang, Hongbin; Dong, Jing; Zhao, Yujun; He, Jianbin; Fan, Honggang

Geographic information system (GIS) is a computer application system, which possesses the ability of manipulating spatial information and has been used in many fields related with the spatial information management. Many methods and models have been established for analyzing animal diseases distribution models and temporal-spatial transmission models. Great benefits have been gained from the application of GIS in animal disease epidemiology. GIS is now a very important tool in animal disease epidemiological research. Spatial analysis function of GIS can be widened and strengthened by using spatial statistical analysis, allowing for the deeper exploration, analysis, manipulation and interpretation of spatial pattern and spatial correlation of the animal disease. In this paper, we analyzed the cow anthrax spatial distribution characteristics in the target district A (due to the secret of epidemic data we call it district A) based on the established GIS of the cow anthrax in this district in combination of spatial statistical analysis and GIS. The Cow anthrax is biogeochemical disease, and its geographical distribution is related closely to the environmental factors of habitats and has some spatial characteristics, and therefore the correct analysis of the spatial distribution of anthrax cow for monitoring and the prevention and control of anthrax has a very important role. However, the application of classic statistical methods in some areas is very difficult because of the pastoral nomadic context. The high mobility of livestock and the lack of enough suitable sampling for the some of the difficulties in monitoring currently make it nearly impossible to apply rigorous random sampling methods. It is thus necessary to develop an alternative sampling method, which could overcome the lack of sampling and meet the requirements for randomness. The GIS computer application software ArcGIS9.1 was used to overcome the lack of data of sampling sites.Using ArcGIS 9.1 and GEODA to analyze the cow anthrax spatial distribution of district A. we gained some conclusions about cow anthrax' density: (1) there is a spatial clustering model. (2) there is an intensely spatial autocorrelation. We established a prediction model to estimate the anthrax distribution based on the spatial characteristic of the density of cow anthrax. Comparing with the true distribution, the prediction model has a well coincidence and is feasible to the application. The method using a GIS tool facilitates can be implemented significantly in the cow anthrax monitoring and investigation, and the space statistics - related prediction model provides a fundamental use for other study on space-related animal diseases.

Bounded rationality alters the dynamics of paediatric immunization acceptance.

PubMed

Oraby, Tamer; Bauch, Chris T

2015-06-02

Interactions between disease dynamics and vaccinating behavior have been explored in many coupled behavior-disease models. Cognitive effects such as risk perception, framing, and subjective probabilities of adverse events can be important determinants of the vaccinating behaviour, and represent departures from the pure "rational" decision model that are often described as "bounded rationality". However, the impact of such cognitive effects in the context of paediatric infectious disease vaccines has received relatively little attention. Here, we develop a disease-behavior model that accounts for bounded rationality through prospect theory. We analyze the model and compare its predictions to a reduced model that lacks bounded rationality. We find that, in general, introducing bounded rationality increases the dynamical richness of the model and makes it harder to eliminate a paediatric infectious disease. In contrast, in other cases, a low cost, highly efficacious vaccine can be refused, even when the rational decision model predicts acceptance. Injunctive social norms can prevent vaccine refusal, if vaccine acceptance is sufficiently high in the beginning of the vaccination campaign. Cognitive processes can have major impacts on the predictions of behaviour-disease models, and further study of such processes in the context of vaccination is thus warranted.

Non-alcoholic fatty liver disease (NAFLD) models in drug discovery.

PubMed

Cole, Banumathi K; Feaver, Ryan E; Wamhoff, Brian R; Dash, Ajit

2018-02-01

The progressive disease spectrum of non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), is a rapidly emerging public health crisis with no approved therapy. The diversity of various therapies under development highlights the lack of consensus around the most effective target, underscoring the need for better translatable preclinical models to study the complex progressive disease and effective therapies. Areas covered: This article reviews published literature of various mouse models of NASH used in preclinical studies, as well as complex organotypic in vitro and ex vivo liver models being developed. It discusses translational challenges associated with both kinds of models, and describes some of the studies that validate their application in NAFLD. Expert opinion: Animal models offer advantages of understanding drug distribution and effects in a whole body context, but are limited by important species differences. Human organotypic in vitro and ex vivo models with physiological relevance and translatability need to be used in a tiered manner with simpler screens. Leveraging newer technologies, like metabolomics, proteomics, and transcriptomics, and the future development of validated disease biomarkers will allow us to fully utilize the value of these models to understand disease and evaluate novel drugs in isolation or combination.

Bounded rationality alters the dynamics of paediatric immunization acceptance

PubMed Central

Oraby, Tamer; Bauch, Chris T.

2015-01-01

Interactions between disease dynamics and vaccinating behavior have been explored in many coupled behavior-disease models. Cognitive effects such as risk perception, framing, and subjective probabilities of adverse events can be important determinants of the vaccinating behaviour, and represent departures from the pure “rational” decision model that are often described as “bounded rationality”. However, the impact of such cognitive effects in the context of paediatric infectious disease vaccines has received relatively little attention. Here, we develop a disease-behavior model that accounts for bounded rationality through prospect theory. We analyze the model and compare its predictions to a reduced model that lacks bounded rationality. We find that, in general, introducing bounded rationality increases the dynamical richness of the model and makes it harder to eliminate a paediatric infectious disease. In contrast, in other cases, a low cost, highly efficacious vaccine can be refused, even when the rational decision model predicts acceptance. Injunctive social norms can prevent vaccine refusal, if vaccine acceptance is sufficiently high in the beginning of the vaccination campaign. Cognitive processes can have major impacts on the predictions of behaviour-disease models, and further study of such processes in the context of vaccination is thus warranted. PMID:26035413

Evaluation of spatio-temporal Bayesian models for the spread of infectious diseases in oil palm.

PubMed

Denis, Marie; Cochard, Benoît; Syahputra, Indra; de Franqueville, Hubert; Tisné, Sébastien

2018-02-01

In the field of epidemiology, studies are often focused on mapping diseases in relation to time and space. Hierarchical modeling is a common flexible and effective tool for modeling problems related to disease spread. In the context of oil palm plantations infected by the fungal pathogen Ganoderma boninense, we propose and compare two spatio-temporal hierarchical Bayesian models addressing the lack of information on propagation modes and transmission vectors. We investigate two alternative process models to study the unobserved mechanism driving the infection process. The models help gain insight into the spatio-temporal dynamic of the infection by identifying a genetic component in the disease spread and by highlighting a spatial component acting at the end of the experiment. In this challenging context, we propose models that provide assumptions on the unobserved mechanism driving the infection process while making short-term predictions using ready-to-use software. Copyright © 2018 Elsevier Ltd. All rights reserved.

Mouse Models of Neurodevelopmental Disease of the Basal Ganglia and Associated Circuits

PubMed Central

Pappas, Samuel S.; Leventhal, Daniel K.; Albin, Roger L.; Dauer, William T.

2014-01-01

This chapter focuses on neurodevelopmental diseases that are tightly linked to abnormal function of the striatum and connected structures. We begin with an overview of three representative diseases in which striatal dysfunction plays a key role—Tourette syndrome and obsessive-compulsive disorder, Rett's syndrome, and primary dystonia. These diseases highlight distinct etiologies that disrupt striatal integrity and function during development, and showcase the varied clinical manifestations of striatal dysfunction. We then review striatal organization and function, including evidence for striatal roles in online motor control/action selection, reinforcement learning, habit formation, and action sequencing. A key barrier to progress has been the relative lack of animal models of these diseases, though recently there has been considerable progress. We review these efforts, including their relative merits providing insight into disease pathogenesis, disease symptomatology, and basal ganglia function. PMID:24947237

Bayesian Model Averaging with Change Points to Assess the Impact of Vaccination and Public Health Interventions

PubMed Central

Warren, Joshua L.; Schuck-Paim, Cynthia; Lustig, Roger; Lewnard, Joseph A.; Fuentes, Rodrigo; Bruhn, Christian A. W.; Taylor, Robert J.; Simonsen, Lone; Weinberger, Daniel M.

2017-01-01

Background: Pneumococcal conjugate vaccines (PCVs) prevent invasive pneumococcal disease and pneumonia. However, some low-and middle-income countries have yet to introduce PCV into their immunization programs due, in part, to lack of certainty about the potential impact. Assessing PCV benefits is challenging because specific data on pneumococcal disease are often lacking, and it can be difficult to separate the effects of factors other than the vaccine that could also affect pneumococcal disease rates. Methods: We assess PCV impact by combining Bayesian model averaging with change-point models to estimate the timing and magnitude of vaccine-associated changes, while controlling for seasonality and other covariates. We applied our approach to monthly time series of age-stratified hospitalizations related to pneumococcal infection in children younger 5 years of age in the United States, Brazil, and Chile. Results: Our method accurately detected changes in data in which we knew true and noteworthy changes occurred, i.e., in simulated data and for invasive pneumococcal disease. Moreover, 24 months after the vaccine introduction, we detected reductions of 14%, 9%, and 9% in the United States, Brazil, and Chile, respectively, in all-cause pneumonia (ACP) hospitalizations for age group 0 to <1 years of age. Conclusions: Our approach provides a flexible and sensitive method to detect changes in disease incidence that occur after the introduction of a vaccine or other intervention, while avoiding biases that exist in current approaches to time-trend analyses. PMID:28767518

Efficient Learning of Continuous-Time Hidden Markov Models for Disease Progression

PubMed Central

Liu, Yu-Ying; Li, Shuang; Li, Fuxin; Song, Le; Rehg, James M.

2016-01-01

The Continuous-Time Hidden Markov Model (CT-HMM) is an attractive approach to modeling disease progression due to its ability to describe noisy observations arriving irregularly in time. However, the lack of an efficient parameter learning algorithm for CT-HMM restricts its use to very small models or requires unrealistic constraints on the state transitions. In this paper, we present the first complete characterization of efficient EM-based learning methods for CT-HMM models. We demonstrate that the learning problem consists of two challenges: the estimation of posterior state probabilities and the computation of end-state conditioned statistics. We solve the first challenge by reformulating the estimation problem in terms of an equivalent discrete time-inhomogeneous hidden Markov model. The second challenge is addressed by adapting three approaches from the continuous time Markov chain literature to the CT-HMM domain. We demonstrate the use of CT-HMMs with more than 100 states to visualize and predict disease progression using a glaucoma dataset and an Alzheimer’s disease dataset. PMID:27019571

Concise Review: Cardiac Disease Modeling Using Induced Pluripotent Stem Cells.

PubMed

Yang, Chunbo; Al-Aama, Jumana; Stojkovic, Miodrag; Keavney, Bernard; Trafford, Andrew; Lako, Majlinda; Armstrong, Lyle

2015-09-01

Genetic cardiac diseases are major causes of morbidity and mortality. Although animal models have been created to provide some useful insights into the pathogenesis of genetic cardiac diseases, the significant species differences and the lack of genetic information for complex genetic diseases markedly attenuate the application values of such data. Generation of induced pluripotent stem cells (iPSCs) from patient-specific specimens and subsequent derivation of cardiomyocytes offer novel avenues to study the mechanisms underlying cardiac diseases, to identify new causative genes, and to provide insights into the disease aetiology. In recent years, the list of human iPSC-based models for genetic cardiac diseases has been expanding rapidly, although there are still remaining concerns on the level of functionality of iPSC-derived cardiomyocytes and their ability to be used for modeling complex cardiac diseases in adults. This review focuses on the development of cardiomyocyte induction from pluripotent stem cells, the recent progress in heart disease modeling using iPSC-derived cardiomyocytes, and the challenges associated with understanding complex genetic diseases. To address these issues, we examine the similarity between iPSC-derived cardiomyocytes and their ex vivo counterparts and how this relates to the method used to differentiate the pluripotent stem cells into a cardiomyocyte phenotype. We progress to examine categories of congenital cardiac abnormalities that are suitable for iPSC-based disease modeling. © AlphaMed Press.

An approach to and web-based tool for infectious disease outbreak intervention analysis

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

Daughton, Ashlynn R.; Generous, Nicholas; Priedhorsky, Reid

Infectious diseases are a leading cause of death globally. Decisions surrounding how to control an infectious disease outbreak currently rely on a subjective process involving surveillance and expert opinion. However, there are many situations where neither may be available. Modeling can fill gaps in the decision making process by using available data to provide quantitative estimates of outbreak trajectories. Effective reduction of the spread of infectious diseases can be achieved through collaboration between the modeling community and public health policy community. However, such collaboration is rare, resulting in a lack of models that meet the needs of the public healthmore » community. Here we show a Susceptible-Infectious-Recovered (SIR) model modified to include control measures that allows parameter ranges, rather than parameter point estimates, and includes a web user interface for broad adoption. We apply the model to three diseases, measles, norovirus and influenza, to show the feasibility of its use and describe a research agenda to further promote interactions between decision makers and the modeling community.« less

An approach to and web-based tool for infectious disease outbreak intervention analysis

DOE PAGES

Daughton, Ashlynn R.; Generous, Nicholas; Priedhorsky, Reid; ...

2017-04-18

Infectious diseases are a leading cause of death globally. Decisions surrounding how to control an infectious disease outbreak currently rely on a subjective process involving surveillance and expert opinion. However, there are many situations where neither may be available. Modeling can fill gaps in the decision making process by using available data to provide quantitative estimates of outbreak trajectories. Effective reduction of the spread of infectious diseases can be achieved through collaboration between the modeling community and public health policy community. However, such collaboration is rare, resulting in a lack of models that meet the needs of the public healthmore » community. Here we show a Susceptible-Infectious-Recovered (SIR) model modified to include control measures that allows parameter ranges, rather than parameter point estimates, and includes a web user interface for broad adoption. We apply the model to three diseases, measles, norovirus and influenza, to show the feasibility of its use and describe a research agenda to further promote interactions between decision makers and the modeling community.« less

Adeno-associated virus–targeted disruption of the CFTR gene in cloned ferrets

PubMed Central

Sun, Xingshen; Yan, Ziying; Yi, Yaling; Li, Ziyi; Lei, Diana; Rogers, Christopher S.; Chen, Juan; Zhang, Yulong; Welsh, Michael J.; Leno, Gregory H.; Engelhardt, John F.

2008-01-01

Somatic cell gene targeting combined with nuclear transfer cloning presents tremendous potential for the creation of new, large-animal models of human diseases. Mouse disease models often fail to reproduce human phenotypes, underscoring the need for the generation and study of alternative disease models. Mice deficient for CFTR have been poor models for cystic fibrosis (CF), lacking many aspects of human CF lung disease. In this study, we describe the production of a CFTR gene–deficient model in the domestic ferret using recombinant adeno-associated virus–mediated gene targeting in fibroblasts, followed by nuclear transfer cloning. As part of this approach, we developed a somatic cell rejuvenation protocol using serial nuclear transfer to produce live CFTR-deficient clones from senescent gene-targeted fibroblasts. We transferred 472 reconstructed embryos into 11 recipient jills and obtained 8 healthy male ferret clones heterozygous for a disruption in exon 10 of the CFTR gene. To our knowledge, this study represents the first description of genetically engineered ferrets and describes an approach that may be of substantial utility in modeling not only CF, but also other genetic diseases. PMID:18324338

Using the Drosophila Nephrocyte to Model Podocyte Function and Disease

PubMed Central

Helmstädter, Martin; Huber, Tobias B.; Hermle, Tobias

2017-01-01

Glomerular disorders are a major cause of end-stage renal disease and effective therapies are often lacking. Nephrocytes are considered to be part of the Drosophila excretory system and form slit diaphragms across cellular membrane invaginations. Nehphrocytes have been shown to share functional, morphological, and molecular features with podocytes, which form the glomerular filter in vertebrates. Here, we report the progress and the evolving tool-set of this model system. Combining a functional, accessible slit diaphragm with the power of the genetic tool-kit in Drosophila, the nephrocyte has the potential to greatly advance our understanding of the glomerular filtration barrier in health and disease. PMID:29270398

Epidemiologic natural history and clinical management of Human Papillomavirus (HPV) Disease: a critical and systematic review of the literature in the development of an HPV dynamic transmission model

PubMed Central

2009-01-01

Background Natural history models of human papillomavirus (HPV) infection and disease have been used in a number of policy evaluations of technologies to prevent and screen for HPV disease (e.g., cervical cancer, anogenital warts), sometimes with wide variation in values for epidemiologic and clinical inputs. The objectives of this study are to: (1) Provide an updated critical and systematic review of the evidence base to support epidemiologic and clinical modeling of key HPV disease-related parameters in the context of an HPV multi-type disease transmission model which we have applied within a U.S. population context; (2) Identify areas where additional studies are particularly needed. Methods Consistent with our and other prior HPV natural history models, the literature review was confined to cervical disease and genital warts. Between October 2005 and January 2006, data were gathered from the published English language medical literature through a search of the PubMed database and references were examined from prior HPV natural history models and review papers. Study design and data quality from individual studies were compared and analyses meeting pre-defined criteria were selected. Results Published data meeting review eligibility criteria were most plentiful for natural history parameters relating to the progression and regression of cervical intraepithelial neoplasia (CIN) without HPV typing, and data concerning the natural history of HPV disease due to specific HPV types were often lacking. Epidemiologic evidence to support age-dependency in the risk of progression and regression of HPV disease was found to be weak, and an alternative hypothesis concerning the time-dependence of transition rates is explored. No data were found on the duration of immunity following HPV infection. In the area of clinical management, data were observed to be lacking on the proportion of clinically manifest anogenital warts that are treated and the proportion of cervical cancer cases that become symptomatic by stage. Conclusion Knowledge of the natural history of HPV disease has been considerably enhanced over the past two decades, through the publication of an increasing number of relevant studies. However, considerable opportunity remains for advancing our understanding of HPV natural history and the quality of associated models, particularly with respect to examining HPV age- and type-specific outcomes, and acquired immunity following infection. PMID:19640281

Rural Latino Immigrant Caregivers’ Conceptions of Their Children’s Oral Disease

PubMed Central

Horton, Sarah; Barker, Judith C.

2012-01-01

Objective To examine Latino immigrant caregivers’ explanatory models of the causes of early childhood caries (ECC). Methods In a rural area, we conducted 71 open-ended qualitative interviews with 26 Mexican immigrant and 12 Salvadoran immigrant caregivers of children under six about the causes of ECC. Two researchers independently read each interview and classified each interviewee’s response. Results Caregivers mentioned three biomedical causes of oral disease (sweets, poor oral hygiene, and bottle-feeding) and two lay or popular causes (lack of milk consumption and “bad” genes). Although caregivers were aware that the consumption of sweet foods causes decay, they expressed particular confusion about how bottle-feeding causes decay. Nineteen caregivers attributed decay specifically to bottle-feeding, yet 14 believed the cause of decay was the bottle’s nipple. Seven Mexican immigrant caregivers attributed their children’s decay specifically to a lack of calcium, and six immigrant caregivers to “bad teeth genes.” Conclusions Conceptions of oral disease derived from caregivers’ own dental experiences, their conceptions of the body, and interactions with dental professionals. The fact that biomedical explanations dominate the list of causes of caries for both groups indicates that caregivers’ explanatory models of oral disease are powerfully shaped by interactions with health professionals. Immigrant caregivers’ mistaking of the baby bottle’s nipple as the source of decay indicates the need for more effective oral health promotion. Yet Mexican immigrants’ conceptions of a lack of calcium as a major factor in their children’s decay may illustrate a strong cultural link between teeth and milk. PMID:18248338

Rural Latino immigrant caregivers' conceptions of their children's oral disease.

PubMed

Horton, Sarah; Barker, Judith C

2008-01-01

The aim of this study was to examine Latino immigrant caregivers' explanatory models of the causes of early childhood caries (ECC). In a rural area, we conducted 71 open-ended qualitative interviews with 26 Mexican immigrant and 12 Salvadoran immigrant caregivers of children under 6 about the causes of ECC. Two researchers independently read each interview and classified each interviewee's response. Caregivers mentioned three biomedical causes of oral disease (sweets, poor oral hygiene, and bottle-feeding) and two lay or popular causes (lack of milk consumption and "bad" genes). Although caregivers were aware that the consumption of sweet foods causes decay they expressed particular confusion about how bottle-feeding causes decay. Nineteen caregivers attributed decay specifically to bottle-feeding, yet 14 believed the cause of decay was the bottle's nipple. Seven Mexican immigrant caregivers attributed their children's decay specifically to a lack of calcium, and six immigrant caregivers to "bad teeth genes." Conceptions of oral disease derived from the caregivers' own dental experiences, their conceptions of the body, and interactions with dental professionals. The fact that biomedical explanations dominate the list of causes of caries for both groups indicates that the caregivers' explanatory models of oral disease are powerfully shaped by interactions with health professionals. Immigrant caregivers' mistaking of the baby bottle's nipple as the source of decay indicates the need for more effective oral health promotion. Yet the Mexican immigrants' conceptions of a lack of calcium as a major factor in their children's decay may illustrate a strong cultural link between teeth and milk.

Loss of corneodesmosin leads to severe skin barrier defect, pruritus, and atopy: unraveling the peeling skin disease.

PubMed

Oji, Vinzenz; Eckl, Katja-Martina; Aufenvenne, Karin; Nätebus, Marc; Tarinski, Tatjana; Ackermann, Katharina; Seller, Natalia; Metze, Dieter; Nürnberg, Gudrun; Fölster-Holst, Regina; Schäfer-Korting, Monika; Hausser, Ingrid; Traupe, Heiko; Hennies, Hans Christian

2010-08-13

Generalized peeling skin disease is an autosomal-recessive ichthyosiform erythroderma characterized by lifelong patchy peeling of the skin. After genome-wide linkage analysis, we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin. In contrast to hypotrichosis simplex, which can be associated with specific dominant CDSN mutations, peeling skin disease is characterized by a complete loss of CDSN expression. The skin phenotype is consistent with a recent murine Cdsn knockout model. Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule. Therefore, peeling skin disease will represent a new model disorder for atopic diseases, similarly to Netherton syndrome and ichthyosis vulgaris in the recent past.

Loss of Corneodesmosin Leads to Severe Skin Barrier Defect, Pruritus, and Atopy: Unraveling the Peeling Skin Disease

PubMed Central

Oji, Vinzenz; Eckl, Katja-Martina; Aufenvenne, Karin; Nätebus, Marc; Tarinski, Tatjana; Ackermann, Katharina; Seller, Natalia; Metze, Dieter; Nürnberg, Gudrun; Fölster-Holst, Regina; Schäfer-Korting, Monika; Hausser, Ingrid; Traupe, Heiko; Hennies, Hans Christian

2010-01-01

Generalized peeling skin disease is an autosomal-recessive ichthyosiform erythroderma characterized by lifelong patchy peeling of the skin. After genome-wide linkage analysis, we have identified a homozygous nonsense mutation in CDSN in a large consanguineous family with generalized peeling skin, pruritus, and food allergies, which leads to a complete loss of corneodesmosin. In contrast to hypotrichosis simplex, which can be associated with specific dominant CDSN mutations, peeling skin disease is characterized by a complete loss of CDSN expression. The skin phenotype is consistent with a recent murine Cdsn knockout model. Using three-dimensional human skin models, we demonstrate that lack of corneodesmosin causes an epidermal barrier defect supposed to account for the predisposition to atopic diseases, and we confirm the role of corneodesmosin as a decisive epidermal adhesion molecule. Therefore, peeling skin disease will represent a new model disorder for atopic diseases, similarly to Netherton syndrome and ichthyosis vulgaris in the recent past. PMID:20691404

Surveillance of dengue fever virus: a review of epidemiological models and early warning systems.

PubMed

Racloz, Vanessa; Ramsey, Rebecca; Tong, Shilu; Hu, Wenbiao

2012-01-01

Dengue fever affects over a 100 million people annually hence is one of the world's most important vector-borne diseases. The transmission area of this disease continues to expand due to many direct and indirect factors linked to urban sprawl, increased travel and global warming. Current preventative measures include mosquito control programs, yet due to the complex nature of the disease and the increased importation risk along with the lack of efficient prophylactic measures, successful disease control and elimination is not realistic in the foreseeable future. Epidemiological models attempt to predict future outbreaks using information on the risk factors of the disease. Through a systematic literature review, this paper aims at analyzing the different modeling methods and their outputs in terms of acting as an early warning system. We found that many previous studies have not sufficiently accounted for the spatio-temporal features of the disease in the modeling process. Yet with advances in technology, the ability to incorporate such information as well as the socio-environmental aspect allowed for its use as an early warning system, albeit limited geographically to a local scale.

Predicting microRNA-disease associations using label propagation based on linear neighborhood similarity.

PubMed

Li, Guanghui; Luo, Jiawei; Xiao, Qiu; Liang, Cheng; Ding, Pingjian

2018-05-12

Interactions between microRNAs (miRNAs) and diseases can yield important information for uncovering novel prognostic markers. Since experimental determination of disease-miRNA associations is time-consuming and costly, attention has been given to designing efficient and robust computational techniques for identifying undiscovered interactions. In this study, we present a label propagation model with linear neighborhood similarity, called LPLNS, to predict unobserved miRNA-disease associations. Additionally, a preprocessing step is performed to derive new interaction likelihood profiles that will contribute to the prediction since new miRNAs and diseases lack known associations. Our results demonstrate that the LPLNS model based on the known disease-miRNA associations could achieve impressive performance with an AUC of 0.9034. Furthermore, we observed that the LPLNS model based on new interaction likelihood profiles could improve the performance to an AUC of 0.9127. This was better than other comparable methods. In addition, case studies also demonstrated our method's outstanding performance for inferring undiscovered interactions between miRNAs and diseases, especially for novel diseases. Copyright © 2018. Published by Elsevier Inc.

Parameterization and Sensitivity Analysis of a Complex Simulation Model for Mosquito Population Dynamics, Dengue Transmission, and Their Control

PubMed Central

Ellis, Alicia M.; Garcia, Andres J.; Focks, Dana A.; Morrison, Amy C.; Scott, Thomas W.

2011-01-01

Models can be useful tools for understanding the dynamics and control of mosquito-borne disease. More detailed models may be more realistic and better suited for understanding local disease dynamics; however, evaluating model suitability, accuracy, and performance becomes increasingly difficult with greater model complexity. Sensitivity analysis is a technique that permits exploration of complex models by evaluating the sensitivity of the model to changes in parameters. Here, we present results of sensitivity analyses of two interrelated complex simulation models of mosquito population dynamics and dengue transmission. We found that dengue transmission may be influenced most by survival in each life stage of the mosquito, mosquito biting behavior, and duration of the infectious period in humans. The importance of these biological processes for vector-borne disease models and the overwhelming lack of knowledge about them make acquisition of relevant field data on these biological processes a top research priority. PMID:21813844

Characterization of a Novel Murine Model to Study Zika Virus.

PubMed

Rossi, Shannan L; Tesh, Robert B; Azar, Sasha R; Muruato, Antonio E; Hanley, Kathryn A; Auguste, Albert J; Langsjoen, Rose M; Paessler, Slobodan; Vasilakis, Nikos; Weaver, Scott C

2016-06-01

The mosquito-borne Zika virus (ZIKV) is responsible for an explosive ongoing outbreak of febrile illness across the Americas. ZIKV was previously thought to cause only a mild, flu-like illness, but during the current outbreak, an association with Guillain-Barré syndrome and microcephaly in neonates has been detected. A previous study showed that ZIKV requires murine adaptation to generate reproducible murine disease. In our study, a low-passage Cambodian isolate caused disease and mortality in mice lacking the interferon (IFN) alpha receptor (A129 mice) in an age-dependent manner, but not in similarly aged immunocompetent mice. In A129 mice, viremia peaked at ∼10(7) plaque-forming units/mL by day 2 postinfection (PI) and reached high titers in the spleen by day 1. ZIKV was detected in the brain on day 3 PI and caused signs of neurologic disease, including tremors, by day 6. Robust replication was also noted in the testis. In this model, all mice infected at the youngest age (3 weeks) succumbed to illness by day 7 PI. Older mice (11 weeks) showed signs of illness, viremia, and weight loss but recovered starting on day 8. In addition, AG129 mice, which lack both type I and II IFN responses, supported similar infection kinetics to A129 mice, but with exaggerated disease signs. This characterization of an Asian lineage ZIKV strain in a murine model, and one of the few studies reporting a model of Zika disease and demonstrating age-dependent morbidity and mortality, could provide a platform for testing the efficacy of antivirals and vaccines. © The American Society of Tropical Medicine and Hygiene.

Systemic autoimmunity induced by the TLR7/8 agonist Resiquimod causes myocarditis and dilated cardiomyopathy in a new mouse model of autoimmune heart disease

PubMed Central

Hasham, Muneer G.; Baxan, Nicoleta; Stuckey, Daniel J.; Branca, Jane; Perkins, Bryant; Dent, Oliver; Duffy, Ted; Hameed, Tolani S.; Stella, Sarah E.; Bellahcene, Mohammed; Schneider, Michael D.; Harding, Sian E.; Rosenthal, Nadia

2017-01-01

ABSTRACT Systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) show significant heart involvement and cardiovascular morbidity, which can be due to systemically increased levels of inflammation or direct autoreactivity targeting cardiac tissue. Despite high clinical relevance, cardiac damage secondary to systemic autoimmunity lacks inducible rodent models. Here, we characterise immune-mediated cardiac tissue damage in a new model of SLE induced by topical application of the Toll-like receptor 7/8 (TLR7/8) agonist Resiquimod. We observe a cardiac phenotype reminiscent of autoimmune-mediated dilated cardiomyopathy, and identify auto-antibodies as major contributors to cardiac tissue damage. Resiquimod-induced heart disease is a highly relevant mouse model for mechanistic and therapeutic studies aiming to protect the heart during autoimmunity. PMID:28250051

Rapid Inflammation in Mice Lacking Both SOCS1 and SOCS3 in Hematopoietic Cells

PubMed Central

Ushiki, Takashi; Huntington, Nicholas D.; Glaser, Stefan P.; Kiu, Hiu; Georgiou, Angela; Zhang, Jian-Guo; Nicola, Nicos A.; Roberts, Andrew W.; Alexander, Warren S.

2016-01-01

The Suppressors of Cytokine Signalling (SOCS) proteins are negative regulators of cytokine signalling required to prevent excess cellular responses. SOCS1 and SOCS3 are essential to prevent inflammatory disease, SOCS1 by attenuating responses to IFNγ and gamma-common (γc) cytokines, and SOCS3 via regulation of G-CSF and IL-6 signalling. SOCS1 and SOCS3 show significant sequence homology and are the only SOCS proteins to possess a KIR domain. The possibility of overlapping or redundant functions was investigated in inflammatory disease via generation of mice lacking both SOCS1 and SOCS3 in hematopoietic cells. Loss of SOCS3 significantly accelerated the pathology and inflammatory disease characteristic of SOCS1 deficiency. We propose a model in which SOCS1 and SOCS3 operate independently to control specific cytokine responses and together modulate the proliferation and activation of lymphoid and myeloid cells to prevent rapid inflammatory disease. PMID:27583437

ProvenCare-Psoriasis: A disease management model to optimize care.

PubMed

Gionfriddo, Michael R; Pulk, Rebecca A; Sahni, Dev R; Vijayanagar, Sonal G; Chronowski, Joseph J; Jones, Laney K; Evans, Michael A; Feldman, Steven R; Pride, Howard

2018-03-15

There are a variety of evidence-based treatments available for psoriasis. The transition of this evidence into practice is challenging. In this article, we describe the design of our disease management approach for Psoriasis (ProvenCare®) and present preliminary evidence of the effect of its implementation. In designing our approach, we identified three barriers to optimal care: 1) lack of a standardized and discrete disease activity measure within the electronic health record, 2) lack of a system-wide, standardized approach to care, and 3) non-uniform financial access to appropriate non-pharmacologic treatments. We implemented several solutions, which collectively form our approach. We standardized the documentation of clinical data such as body surface area (BSA), created a disease management algorithm for psoriasis, and aligned incentives to facilitate the implementation of the algorithm. This approach provides more coordinated, cost effective care for psoriasis, while being acceptable to key stakeholders. Future work will examine the effect of the implementation of our approach on important clinical and patient outcomes.

Applicability of the SMART Model of Transition Readiness for Sickle-Cell Disease

PubMed Central

Valenzuela, Jessica M.; Crosby, Lori E.; Diaz Pow Sang, Claudia

2016-01-01

Objectives This study aimed to examine the applicability of the Social-ecological Model of Adolescent and Young Adult Readiness to Transition (SMART) model for adolescents and young adults (AYA) with sickle-cell disease (SCD). Methods 14 AYA with SCD (14–24 years old) and 10 clinical experts (6–20 years of experience) completed semi-structured interviews. AYA completed brief questionnaires. Interviews were coded for themes, which were reviewed to determine their fit within the SMART model. Results Overall, most themes were consistent with the model (e.g., sociodemographics/culture, neurocognition/IQ, etc.). Factors related to race/culture, pain management, health-care navigation skills, societal stigma, and lack of awareness about SCD were salient for AYA with SCD. Conclusions Findings suggest the SMART model may be appropriate in SCD with the consideration of disease-related stigma. This study is a step toward developing a disease-specific model of transition readiness for SCD. Future directions include the development of a measure of transition readiness for this population. PMID:26717957

Of Mice, Cattle, and Humans: The Immunology and Treatment of River Blindness

PubMed Central

Allen, Judith E.; Adjei, Ohene; Bain, Odile; Hoerauf, Achim; Hoffmann, Wolfgang H.; Makepeace, Benjamin L.; Schulz-Key, Hartwig; Tanya, Vincent N.; Trees, Alexander J.; Wanji, Samuel; Taylor, David W.

2008-01-01

River blindness is a seriously debilitating disease caused by the filarial parasite Onchocerca volvulus, which infects millions in Africa as well as in South and Central America. Research has been hampered by a lack of good animal models, as the parasite can only develop fully in humans and some primates. This review highlights the development of two animal model systems that have allowed significant advances in recent years and hold promise for the future. Experimental findings with Litomosoides sigmodontis in mice and Onchocerca ochengi in cattle are placed in the context of how these models can advance our ability to control the human disease. PMID:18446236

A nonhuman primate model of chikungunya disease

PubMed Central

Higgs, Stephen; Ziegler, Sarah A.

2010-01-01

Chikungunya disease is a severely debilitating, mosquito-borne, viral illness that has reached epidemic proportions in Africa, Asia, and the islands of the Indian Ocean. A mutation enhancing the ability of the chikungunya virus (CHIKV) to infect and be transmitted by Aedes albopictus has increased the geographical range at risk for infection due to the continuing global spread of this mosquito. Research into disease pathogenesis, vaccine development, and therapeutic design has been hindered by the lack of appropriate animal models of this disease. The meticulous study reported in this issue of the JCI by Labadie et al. is one of the first reports describing CHIKV infection of adult immunocompetent nonhuman primates. Using traditional and modern molecular and immunological approaches, the authors demonstrate that macaques infected with CHIKV are a good model of human CHIKV infection and also show that persistent arthralgia in humans may be caused by persistent CHIKV infection of macrophages. PMID:20179348

Current preclinical models for the advancement of translational bladder cancer research.

PubMed

DeGraff, David J; Robinson, Victoria L; Shah, Jay B; Brandt, William D; Sonpavde, Guru; Kang, Yibin; Liebert, Monica; Wu, Xue-Ru; Taylor, John A

2013-02-01

Bladder cancer is a common disease representing the fifth most diagnosed solid tumor in the United States. Despite this, advances in our understanding of the molecular etiology and treatment of bladder cancer have been relatively lacking. This is especially apparent when recent advances in other cancers, such as breast and prostate, are taken into consideration. The field of bladder cancer research is ready and poised for a series of paradigm-shifting discoveries that will greatly impact the way this disease is clinically managed. Future preclinical discoveries with translational potential will require investigators to take full advantage of recent advances in molecular and animal modeling methodologies. We present an overview of current preclinical models and their potential roles in advancing our understanding of this deadly disease and for advancing care. ©2012 AACR.

Bioelectric characterization of epithelia from neonatal CFTR knockout ferrets.

PubMed

Fisher, John T; Tyler, Scott R; Zhang, Yulong; Lee, Ben J; Liu, Xiaoming; Sun, Xingshen; Sui, Hongshu; Liang, Bo; Luo, Meihui; Xie, Weiliang; Yi, Yaling; Zhou, Weihong; Song, Yi; Keiser, Nicholas; Wang, Kai; de Jonge, Hugo R; Engelhardt, John F

2013-11-01

Cystic fibrosis (CF) is a life-shortening, recessive, multiorgan genetic disorder caused by the loss of CF transmembrane conductance regulator (CFTR) chloride channel function found in many types of epithelia. Animal models that recapitulate the human disease phenotype are critical to understanding pathophysiology in CF and developing therapies. CFTR knockout ferrets manifest many of the phenotypes observed in the human disease, including lung infections, pancreatic disease and diabetes, liver disease, malnutrition, and meconium ileus. In the present study, we have characterized abnormalities in the bioelectric properties of the trachea, stomach, intestine, and gallbladder of newborn CF ferrets. Short-circuit current (ISC) analysis of CF and wild-type (WT) tracheas revealed the following similarities and differences: (1) amiloride-sensitive sodium currents were similar between genotypes; (2) responses to 4,4'-diisothiocyano-2,2'-stilbene disulphonic acid were 3.3-fold greater in CF animals, suggesting elevated baseline chloride transport through non-CFTR channels in a subset of CF animals; and (3) a lack of 3-isobutyl-1-methylxanthine (IBMX)/forskolin-stimulated and N-(2-Naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide (GlyH-101)-inhibited currents in CF animals due to the lack of CFTR. CFTR mRNA was present throughout all levels of the WT ferret and IBMX/forskolin-inducible ISC was only observed in WT animals. However, despite the lack of CFTR function in the knockout ferret, the luminal pH of the CF ferret gallbladder, stomach, and intestines was not significantly changed relative to WT. The WT stomach and gallbladder exhibited significantly enhanced IBMX/forskolin ISC responses and inhibition by GlyH-101 relative to CF samples. These findings demonstrate that multiple organs affected by disease in the CF ferret have bioelectric abnormalities consistent with the lack of cAMP-mediated chloride transport.

Thermoneutral housing exacerbates non-alcoholic fatty liver disease in mice and allows for sex-independent disease modeling

PubMed Central

Giles, Daniel A; Moreno-Fernandez, Maria E; Stankiewicz, Traci E; Graspeuntner, Simon; Cappelletti, Monica; Wu, David; Mukherjee, Rajib; Chan, Calvin C; Lawson, Matthew J; Klarquist, Jared; Sünderhauf, Annika; Softic, Samir; Kahn, C Ronald; Stemmer, Kerstin; Iwakura, Yoichiro; Aronow, Bruce J; Karns, Rebekah; Steinbrecher, Kris A; Karp, Christopher L; Sheridan, Rachel; Shanmukhappa, Shiva K; Reynaud, Damien; Haslam, David B; Sina, Christian; Rupp, Jan; Hogan, Simon P; Divanovic, Senad

2017-01-01

Non-alcoholic fatty liver disease (NAFLD), a common prelude to cirrhosis and hepatocellular carcinoma, is the most common chronic liver disease worldwide. Defining the molecular mechanisms underlying the pathogenesis of NAFLD has been hampered by a lack of animal models that closely recapitulate the severe end of the human disease spectrum, including bridging hepatic fibrosis. Here, we demonstrate that a novel experimental model employing thermoneutral housing, as opposed to standard housing, resulted in lower stress-driven production of corticosterone, augmented mouse proinflammatory immune responses and markedly exacerbated high fat diet (HFD)-induced NAFLD pathogenesis. Disease exacerbation at thermoneutrality was conserved across multiple mouse strains and was associated with augmented intestinal permeability, an altered microbiome and activation of inflammatory pathways associated with human disease. Depletion of Gram-negative microbiota, hematopoietic cell deletion of Toll-like receptor 4 (TLR4) and inactivation of the interleukin-17 (IL-17) axis resulted in altered immune responsiveness and protection from thermoneutral housing-driven NAFLD amplification. Finally, female mice, typically resistant to HFD-induced obesity and NAFLD, develop full-blown disease at thermoneutrality. Thus, thermoneutral housing provides a sex-independent model of exacerbated NAFLD in mice and represents a novel approach for interrogation of the cellular and molecular mechanisms underlying disease pathogenesis. PMID:28604704

Modeling the Western Diet for Preclinical Investigations.

PubMed

Hintze, Korry J; Benninghoff, Abby D; Cho, Clara E; Ward, Robert E

2018-05-01

Rodent models have been invaluable for biomedical research. Preclinical investigations with rodents allow researchers to investigate diseases by using study designs that are not suitable for human subjects. The primary criticism of preclinical animal models is that results are not always translatable to humans. Some of this lack of translation is due to inherent differences between species. However, rodent models have been refined over time, and translatability to humans has improved. Transgenic animals have greatly aided our understanding of interactions between genes and disease and have narrowed the translation gap between humans and model animals. Despite the technological innovations of animal models through advances in genetics, relatively little attention has been given to animal diets. Namely, developing diets that replicate what humans eat will help make animal models more relevant to human populations. This review focuses on commonly used rodent diets that are used to emulate the Western dietary pattern in preclinical studies of obesity and type 2 diabetes, nonalcoholic liver disease, maternal nutrition, and colorectal cancer.

Bioprinting technologies for disease modeling.

PubMed

Memic, Adnan; Navaei, Ali; Mirani, Bahram; Cordova, Julio Alvin Vacacela; Aldhahri, Musab; Dolatshahi-Pirouz, Alireza; Akbari, Mohsen; Nikkhah, Mehdi

2017-09-01

There is a great need for the development of biomimetic human tissue models that allow elucidation of the pathophysiological conditions involved in disease initiation and progression. Conventional two-dimensional (2D) in vitro assays and animal models have been unable to fully recapitulate the critical characteristics of human physiology. Alternatively, three-dimensional (3D) tissue models are often developed in a low-throughput manner and lack crucial native-like architecture. The recent emergence of bioprinting technologies has enabled creating 3D tissue models that address the critical challenges of conventional in vitro assays through the development of custom bioinks and patient derived cells coupled with well-defined arrangements of biomaterials. Here, we provide an overview on the technological aspects of 3D bioprinting technique and discuss how the development of bioprinted tissue models have propelled our understanding of diseases' characteristics (i.e. initiation and progression). The future perspectives on the use of bioprinted 3D tissue models for drug discovery application are also highlighted.

Educating Patients about CKD: The Path to Self-Management and Patient-Centered Care

PubMed Central

Norton, Jenna M.; Boulware, L. Ebony

2016-01-01

Patient education is associated with better patient outcomes and supported by international guidelines and organizations, but a range of barriers prevent widespread implementation of comprehensive education for people with progressive kidney disease, especially in the United States. Among United States patients, obstacles to education include the complex nature of kidney disease information, low baseline awareness, limited health literacy and numeracy, limited availability of CKD information, and lack of readiness to learn. For providers, lack of time and clinical confidence combine with competing education priorities and confusion about diagnosing CKD to limit educational efforts. At the system level, lack of provider incentives, limited availability of practical decision support tools, and lack of established interdisciplinary care models inhibit patient education. Despite these barriers, innovative education approaches for people with CKD exist, including self-management support, shared decision making, use of digital media, and engaging families and communities. Education efficiency may be increased by focusing on people with progressive disease, establishing interdisciplinary care management including community health workers, and providing education in group settings. New educational approaches are being developed through research and quality improvement efforts, but challenges to evaluating public awareness and patient education programs inhibit identification of successful strategies for broader implementation. However, growing interest in improving patient-centered outcomes may provide new approaches to effective education of people with CKD. PMID:26536899

Deep Learning for Image-Based Cassava Disease Detection.

PubMed

Ramcharan, Amanda; Baranowski, Kelsee; McCloskey, Peter; Ahmed, Babuali; Legg, James; Hughes, David P

2017-01-01

Cassava is the third largest source of carbohydrates for human food in the world but is vulnerable to virus diseases, which threaten to destabilize food security in sub-Saharan Africa. Novel methods of cassava disease detection are needed to support improved control which will prevent this crisis. Image recognition offers both a cost effective and scalable technology for disease detection. New deep learning models offer an avenue for this technology to be easily deployed on mobile devices. Using a dataset of cassava disease images taken in the field in Tanzania, we applied transfer learning to train a deep convolutional neural network to identify three diseases and two types of pest damage (or lack thereof). The best trained model accuracies were 98% for brown leaf spot (BLS), 96% for red mite damage (RMD), 95% for green mite damage (GMD), 98% for cassava brown streak disease (CBSD), and 96% for cassava mosaic disease (CMD). The best model achieved an overall accuracy of 93% for data not used in the training process. Our results show that the transfer learning approach for image recognition of field images offers a fast, affordable, and easily deployable strategy for digital plant disease detection.

Integrating telecare for chronic disease management in the community: What needs to be done?

PubMed Central

2011-01-01

Background Telecare could greatly facilitate chronic disease management in the community, but despite government promotion and positive demonstrations its implementation has been limited. This study aimed to identify factors inhibiting the implementation and integration of telecare systems for chronic disease management in the community. Methods Large scale comparative study employing qualitative data collection techniques: semi-structured interviews with key informants, task-groups, and workshops; framework analysis of qualitative data informed by Normalization Process Theory. Drawn from telecare services in community and domestic settings in England and Scotland, 221 participants were included, consisting of health professionals and managers; patients and carers; social care professionals and managers; and service suppliers and manufacturers. Results Key barriers to telecare integration were uncertainties about coherent and sustainable service and business models; lack of coordination across social and primary care boundaries, lack of financial or other incentives to include telecare within primary care services; a lack of a sense of continuity with previous service provision and self-care work undertaken by patients; and general uncertainty about the adequacy of telecare systems. These problems led to poor integration of policy and practice. Conclusion Telecare services may offer a cost effective and safe form of care for some people living with chronic illness. Slow and uneven implementation and integration do not stem from problems of adoption. They result from incomplete understanding of the role of telecare systems and subsequent adaption and embeddedness to context, and uncertainties about the best way to develop, coordinate, and sustain services that assist with chronic disease management. Interventions are therefore needed that (i) reduce uncertainty about the ownership of implementation processes and that lock together health and social care agencies; and (ii) ensure user centred rather than biomedical/service-centred models of care. PMID:21619596

Integrating telecare for chronic disease management in the community: what needs to be done?

PubMed

May, Carl R; Finch, Tracy L; Cornford, James; Exley, Catherine; Gately, Claire; Kirk, Sue; Jenkings, K Neil; Osbourne, Janice; Robinson, A Louise; Rogers, Anne; Wilson, Robert; Mair, Frances S

2011-05-27

Telecare could greatly facilitate chronic disease management in the community, but despite government promotion and positive demonstrations its implementation has been limited. This study aimed to identify factors inhibiting the implementation and integration of telecare systems for chronic disease management in the community. Large scale comparative study employing qualitative data collection techniques: semi-structured interviews with key informants, task-groups, and workshops; framework analysis of qualitative data informed by Normalization Process Theory. Drawn from telecare services in community and domestic settings in England and Scotland, 221 participants were included, consisting of health professionals and managers; patients and carers; social care professionals and managers; and service suppliers and manufacturers. Key barriers to telecare integration were uncertainties about coherent and sustainable service and business models; lack of coordination across social and primary care boundaries, lack of financial or other incentives to include telecare within primary care services; a lack of a sense of continuity with previous service provision and self-care work undertaken by patients; and general uncertainty about the adequacy of telecare systems. These problems led to poor integration of policy and practice. Telecare services may offer a cost effective and safe form of care for some people living with chronic illness. Slow and uneven implementation and integration do not stem from problems of adoption. They result from incomplete understanding of the role of telecare systems and subsequent adaption and embeddedness to context, and uncertainties about the best way to develop, coordinate, and sustain services that assist with chronic disease management. Interventions are therefore needed that (i) reduce uncertainty about the ownership of implementation processes and that lock together health and social care agencies; and (ii) ensure user centred rather than biomedical/service-centred models of care.

A cellular model for sporadic ALS using patient-derived induced pluripotent stem cells

PubMed Central

Burkhardt, Matthew F; Martinez, Fernando J; Wright, Sarah; Ramos, Carla; Volfson, Dmitri; Mason, Michael; Garnes, Jeff; Dang, Vu; Lievers, Jeffery; Shoukat-Mumtaz, Uzma; Martinez, Rita; Gai, Hui; Blake, Robert; Vaisberg, Eugeni; Grskovic, Marica; Johnson, Charles; Irion, Stefan; Bright, Jessica; Cooper, Bonnie; Nguyen, Leane; Griswold-Prenner, Irene; Javaherian, Ashkan

2016-01-01

Development of therapeutics for genetically complex neurodegenerative diseases such as sporadic amyotrophic lateral sclerosis (ALS) has largely been hampered by lack of relevant disease models. Reprogramming of sporadic ALS patients’ fibroblasts into induced pluripotent stem cells (iPSC) and differentiation into affected neurons that show a disease phenotype could provide a cellular model for disease mechanism studies and drug discovery. Here we report the reprogramming to pluripotency of fibroblasts from a large cohort of healthy controls and ALS patients and their differentiation into motor neurons. We demonstrate that motor neurons derived from three sALS patients show de novo TDP-43 aggregation and that the aggregates recapitulate pathology in postmortem tissue from one of the same patients from which the iPSC were derived. We configured a high-content chemical screen using the TDP-43 aggregate endpoint both in lower motor neurons and upper motor neuron like cells and identified FDA-approved small molecule modulators including Digoxin demonstrating the feasibility of patient-derived iPSC-based disease modelling for drug screening. PMID:23891805

Unresolved issues in theories of autoimmune disease using myocarditis as a framework

PubMed Central

Root-Bernstein, Robert; Fairweather, DeLisa

2014-01-01

Many theories of autoimmune disease have been proposed since the discovery that the immune system can attack the body. These theories include the hidden or cryptic antigen theory, modified antigen theory, T cell bypass, T cell-B cell mismatch, epitope spread or drift, the bystander effect, molecular mimicry, anti-idiotype theory, antigenic complementarity, and dual-affinity T cell receptors. We critically review these theories and relevant mathematical models as they apply to autoimmune myocarditis. All theories share the common assumption that autoimmune diseases are triggered by environmental factors such as infections or chemical exposure. Most, but not all, theories and mathematical models are unifactorial assuming single-agent causation of disease. Experimental and clinical evidence and mathematical models exist to support some aspects of most theories, but evidence/models that support one theory almost invariably supports other theories as well. More importantly, every theory (and every model) lacks the ability to account for some key autoimmune disease phenomena such as the fundamental roles of innate immunity, sex differences in disease susceptibility, the necessity for adjuvants in experimental animal models, and the often paradoxical effect of exposure timing and dose on disease induction. We argue that a more comprehensive and integrated theory of autoimmunity associated with new mathematical models is needed and suggest specific experimental and clinical tests for each major theory that might help to clarify how they relate to clinical disease and reveal how theories are related. PMID:25484004

Unresolved issues in theories of autoimmune disease using myocarditis as a framework.

PubMed

Root-Bernstein, Robert; Fairweather, DeLisa

2015-06-21

Many theories of autoimmune disease have been proposed since the discovery that the immune system can attack the body. These theories include the hidden or cryptic antigen theory, modified antigen theory, T cell bypass, T cell-B cell mismatch, epitope spread or drift, the bystander effect, molecular mimicry, anti-idiotype theory, antigenic complementarity, and dual-affinity T cell receptors. We critically review these theories and relevant mathematical models as they apply to autoimmune myocarditis. All theories share the common assumption that autoimmune diseases are triggered by environmental factors such as infections or chemical exposure. Most, but not all, theories and mathematical models are unifactorial assuming single-agent causation of disease. Experimental and clinical evidence and mathematical models exist to support some aspects of most theories, but evidence/models that support one theory almost invariably supports other theories as well. More importantly, every theory (and every model) lacks the ability to account for some key autoimmune disease phenomena such as the fundamental roles of innate immunity, sex differences in disease susceptibility, the necessity for adjuvants in experimental animal models, and the often paradoxical effect of exposure timing and dose on disease induction. We argue that a more comprehensive and integrated theory of autoimmunity associated with new mathematical models is needed and suggest specific experimental and clinical tests for each major theory that might help to clarify how they relate to clinical disease and reveal how theories are related. Copyright © 2014 Elsevier Ltd. All rights reserved.

Albumin contributes to kidney disease progression in Alport syndrome

PubMed Central

Knutsen, Russell H.; Mecham, Robert P.

2016-01-01

Alport syndrome is a familial kidney disease caused by defects in the collagen type IV network of the glomerular basement membrane. Lack of collagen-α3α4α5(IV) changes the glomerular basement membrane morphologically and functionally, rendering it leaky to albumin and other plasma proteins. Filtered albumin has been suggested to be a cause of the glomerular and tubular injuries observed at advanced stages of Alport syndrome. To directly investigate the role that albumin plays in the progression of disease in Alport syndrome, we generated albumin knockout (Alb−/−) mice to use as a tool for removing albuminuria as a component of kidney disease. Mice lacking albumin were healthy and indistinguishable from control littermates, although they developed hypertriglyceridemia. Dyslipidemia was observed in Alb+/− mice, which displayed half the normal plasma albumin concentration. Alb mutant mice were bred to collagen-α3(IV) knockout (Col4a3−/−) mice, which are a model for human Alport syndrome. Lack of circulating and filtered albumin in Col4a3−/−;Alb−/− mice resulted in dramatically improved kidney disease outcomes, as these mice lived 64% longer than did Col4a3−/−;Alb+/+ and Col4a3−/−;Alb+/− mice, despite similar blood pressures and serum triglyceride levels. Further investigations showed that the absence of albumin correlated with reduced transforming growth factor-β1 signaling as well as reduced tubulointerstitial, glomerular, and podocyte pathology. We conclude that filtered albumin is injurious to kidney cells in Alport syndrome and perhaps in other proteinuric kidney diseases, including diabetic nephropathy. PMID:27147675

Albumin contributes to kidney disease progression in Alport syndrome.

PubMed

Jarad, George; Knutsen, Russell H; Mecham, Robert P; Miner, Jeffrey H

2016-07-01

Alport syndrome is a familial kidney disease caused by defects in the collagen type IV network of the glomerular basement membrane. Lack of collagen-α3α4α5(IV) changes the glomerular basement membrane morphologically and functionally, rendering it leaky to albumin and other plasma proteins. Filtered albumin has been suggested to be a cause of the glomerular and tubular injuries observed at advanced stages of Alport syndrome. To directly investigate the role that albumin plays in the progression of disease in Alport syndrome, we generated albumin knockout (Alb(-/-)) mice to use as a tool for removing albuminuria as a component of kidney disease. Mice lacking albumin were healthy and indistinguishable from control littermates, although they developed hypertriglyceridemia. Dyslipidemia was observed in Alb(+/-) mice, which displayed half the normal plasma albumin concentration. Alb mutant mice were bred to collagen-α3(IV) knockout (Col4a3(-/-)) mice, which are a model for human Alport syndrome. Lack of circulating and filtered albumin in Col4a3(-/-);Alb(-/-) mice resulted in dramatically improved kidney disease outcomes, as these mice lived 64% longer than did Col4a3(-/-);Alb(+/+) and Col4a3(-/-);Alb(+/-) mice, despite similar blood pressures and serum triglyceride levels. Further investigations showed that the absence of albumin correlated with reduced transforming growth factor-β1 signaling as well as reduced tubulointerstitial, glomerular, and podocyte pathology. We conclude that filtered albumin is injurious to kidney cells in Alport syndrome and perhaps in other proteinuric kidney diseases, including diabetic nephropathy. Copyright © 2016 the American Physiological Society.

Suppressing disease spreading by using information diffusion on multiplex networks.

PubMed

Wang, Wei; Liu, Quan-Hui; Cai, Shi-Min; Tang, Ming; Braunstein, Lidia A; Stanley, H Eugene

2016-07-06

Although there is always an interplay between the dynamics of information diffusion and disease spreading, the empirical research on the systemic coevolution mechanisms connecting these two spreading dynamics is still lacking. Here we investigate the coevolution mechanisms and dynamics between information and disease spreading by utilizing real data and a proposed spreading model on multiplex network. Our empirical analysis finds asymmetrical interactions between the information and disease spreading dynamics. Our results obtained from both the theoretical framework and extensive stochastic numerical simulations suggest that an information outbreak can be triggered in a communication network by its own spreading dynamics or by a disease outbreak on a contact network, but that the disease threshold is not affected by information spreading. Our key finding is that there is an optimal information transmission rate that markedly suppresses the disease spreading. We find that the time evolution of the dynamics in the proposed model qualitatively agrees with the real-world spreading processes at the optimal information transmission rate.

Empiric antibiotic treatment of erythema migrans-like skin lesions as a function of geography: a clinical and cost effectiveness modeling study.

PubMed

Lantos, Paul M; Brinkerhoff, R Jory; Wormser, Gary P; Clemen, Robert

2013-12-01

The skin lesion of early Lyme disease, erythema migrans (EM), is so characteristic that routine practice is to treat all such patients with antibiotics. Because other skin lesions may resemble EM, it is not known whether presumptive treatment of EM is appropriate in regions where Lyme disease is rare. We constructed a decision model to compare the cost and clinical effectiveness of three strategies for the management of EM: Treat All, Observe, and Serology as a function of the probability that an EM-like lesion is Lyme disease. Treat All was found to be the preferred strategy in regions that are endemic for Lyme disease. Where Lyme disease is rare, Observe is the preferred strategy, as presumptive treatment would be expected to produce excessive harm and increased costs. Where Lyme disease is rare, clinicians and public health officials should consider observing patients with EM-like lesions who lack travel to Lyme disease-endemic areas.

Disease model curation improvements at Mouse Genome Informatics

PubMed Central

Bello, Susan M.; Richardson, Joel E.; Davis, Allan P.; Wiegers, Thomas C.; Mattingly, Carolyn J.; Dolan, Mary E.; Smith, Cynthia L.; Blake, Judith A.; Eppig, Janan T.

2012-01-01

Optimal curation of human diseases requires an ontology or structured vocabulary that contains terms familiar to end users, is robust enough to support multiple levels of annotation granularity, is limited to disease terms and is stable enough to avoid extensive reannotation following updates. At Mouse Genome Informatics (MGI), we currently use disease terms from Online Mendelian Inheritance in Man (OMIM) to curate mouse models of human disease. While OMIM provides highly detailed disease records that are familiar to many in the medical community, it lacks structure to support multilevel annotation. To improve disease annotation at MGI, we evaluated the merged Medical Subject Headings (MeSH) and OMIM disease vocabulary created by the Comparative Toxicogenomics Database (CTD) project. Overlaying MeSH onto OMIM provides hierarchical access to broad disease terms, a feature missing from the OMIM. We created an extended version of the vocabulary to meet the genetic disease-specific curation needs at MGI. Here we describe our evaluation of the CTD application, the extensions made by MGI and discuss the strengths and weaknesses of this approach. Database URL: http://www.informatics.jax.org/ PMID:22434831

Lentiviral Gene Therapy Using Cellular Promoters Cures Type 1 Gaucher Disease in Mice

PubMed Central

Dahl, Maria; Doyle, Alexander; Olsson, Karin; Månsson, Jan-Eric; Marques, André R A; Mirzaian, Mina; Aerts, Johannes M; Ehinger, Mats; Rothe, Michael; Modlich, Ute; Schambach, Axel; Karlsson, Stefan

2015-01-01

Gaucher disease is caused by an inherited deficiency of the enzyme glucosylceramidase. Due to the lack of a fully functional enzyme, there is progressive build-up of the lipid component glucosylceramide. Insufficient glucosylceramidase activity results in hepatosplenomegaly, cytopenias, and bone disease in patients. Gene therapy represents a future therapeutic option for patients unresponsive to enzyme replacement therapy and lacking a suitable bone marrow donor. By proof-of-principle experiments, we have previously demonstrated a reversal of symptoms in a murine disease model of type 1 Gaucher disease, using gammaretroviral vectors harboring strong viral promoters to drive glucosidase β-acid (GBA) gene expression. To investigate whether safer vectors can correct the enzyme deficiency, we utilized self-inactivating lentiviral vectors (SIN LVs) with the GBA gene under the control of human phosphoglycerate kinase (PGK) and CD68 promoter, respectively. Here, we report prevention of, as well as reversal of, manifest disease symptoms after lentiviral gene transfer. Glucosylceramidase activity above levels required for clearance of glucosylceramide from tissues resulted in reversal of splenomegaly, reduced Gaucher cell infiltration and a restoration of hematological parameters. These findings support the use of SIN-LVs with cellular promoters in future clinical gene therapy protocols for type 1 Gaucher disease. PMID:25655314

Abnormal response to the anorexic effect of GHS-R inhibitors and exenatide in male Snord116 deletion mouse model for Prader-Willi Syndrome

USDA-ARS?s Scientific Manuscript database

Prader-Willi syndrome (PWS) is a genetic disease characterized by persistent hunger and hyperphagia. The lack of the Snord116 small nucleolar RNA cluster has been identified as the major contributor to PWS symptoms. The Snord116 deletion (Snord116del) mouse model manifested a subset of PWS symptoms ...

Metering Self-Reported Adherence to Clinical Outcomes in Malaysian Patients with Hypertension: Applying the Stages of Change Model to Healthful Behaviors in the CORFIS Study

ERIC Educational Resources Information Center

Karupaiah, Tilakavati; Wong, Kimberly; Chinna, Karuthan; Arasu, Kanimolli; Chee, Winnie Siew Swee

2015-01-01

The CORFIS ("Community-Based Cardiovascular Risk Factors Intervention Strategies") program was piloted in community clinics in Malaysia to address the lack of health education in chronic disease management. The stages of change model was applied in a multicenter quasi-experimental design to evaluate adherence to advocated behaviors in…

Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development.

PubMed

Swat, M J; Moodie, S; Wimalaratne, S M; Kristensen, N R; Lavielle, M; Mari, A; Magni, P; Smith, M K; Bizzotto, R; Pasotti, L; Mezzalana, E; Comets, E; Sarr, C; Terranova, N; Blaudez, E; Chan, P; Chard, J; Chatel, K; Chenel, M; Edwards, D; Franklin, C; Giorgino, T; Glont, M; Girard, P; Grenon, P; Harling, K; Hooker, A C; Kaye, R; Keizer, R; Kloft, C; Kok, J N; Kokash, N; Laibe, C; Laveille, C; Lestini, G; Mentré, F; Munafo, A; Nordgren, R; Nyberg, H B; Parra-Guillen, Z P; Plan, E; Ribba, B; Smith, G; Trocóniz, I F; Yvon, F; Milligan, P A; Harnisch, L; Karlsson, M; Hermjakob, H; Le Novère, N

2015-06-01

The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps.

Pharmacometrics Markup Language (PharmML): Opening New Perspectives for Model Exchange in Drug Development

PubMed Central

Swat, MJ; Moodie, S; Wimalaratne, SM; Kristensen, NR; Lavielle, M; Mari, A; Magni, P; Smith, MK; Bizzotto, R; Pasotti, L; Mezzalana, E; Comets, E; Sarr, C; Terranova, N; Blaudez, E; Chan, P; Chard, J; Chatel, K; Chenel, M; Edwards, D; Franklin, C; Giorgino, T; Glont, M; Girard, P; Grenon, P; Harling, K; Hooker, AC; Kaye, R; Keizer, R; Kloft, C; Kok, JN; Kokash, N; Laibe, C; Laveille, C; Lestini, G; Mentré, F; Munafo, A; Nordgren, R; Nyberg, HB; Parra-Guillen, ZP; Plan, E; Ribba, B; Smith, G; Trocóniz, IF; Yvon, F; Milligan, PA; Harnisch, L; Karlsson, M; Hermjakob, H; Le Novère, N

2015-01-01

The lack of a common exchange format for mathematical models in pharmacometrics has been a long-standing problem. Such a format has the potential to increase productivity and analysis quality, simplify the handling of complex workflows, ensure reproducibility of research, and facilitate the reuse of existing model resources. Pharmacometrics Markup Language (PharmML), currently under development by the Drug Disease Model Resources (DDMoRe) consortium, is intended to become an exchange standard in pharmacometrics by providing means to encode models, trial designs, and modeling steps. PMID:26225259

Development of an anaesthetized-rat model of exercise hyperpnoea: an integrative model of respiratory control using an equilibrium diagram.

PubMed

Miyamoto, Tadayoshi; Manabe, Kou; Ueda, Shinya; Nakahara, Hidehiro

2018-05-01

What is the central question of this study? The lack of useful small-animal models for studying exercise hyperpnoea makes it difficult to investigate the underlying mechanisms of exercise-induced ventilatory abnormalities in various disease states. What is the main finding and its importance? We developed an anaesthetized-rat model for studying exercise hyperpnoea, using a respiratory equilibrium diagram for quantitative characterization of the respiratory chemoreflex feedback system. This experimental model will provide an opportunity to clarify the major determinant mechanisms of exercise hyperpnoea, and will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models. Exercise-induced ventilatory abnormalities in various disease states seem to arise from pathological changes of respiratory regulation. Although experimental studies in small animals are essential to investigate the pathophysiological basis of various disease models, the lack of an integrated framework for quantitatively characterizing respiratory regulation during exercise prevents us from resolving these problems. The purpose of this study was to develop an anaesthetized-rat model for studying exercise hyperpnoea for quantitative characterization of the respiratory chemoreflex feedback system. In 24 anaesthetized rats, we induced muscle contraction by stimulating bilateral distal sciatic nerves at low and high voltage to mimic exercise. We recorded breath-by-breath respiratory gas analysis data and cardiorespiratory responses while running two protocols to characterize the controller and plant of the respiratory chemoreflex. The controller was characterized by determining the linear relationship between end-tidal CO 2 pressure (P ETC O2) and minute ventilation (V̇E), and the plant by the hyperbolic relationship between V̇E and P ETC O2. During exercise, the controller curve shifted upward without change in controller gain, accompanying increased oxygen uptake. The hyperbolic plant curve shifted rightward and downward depending on exercise intensity as predicted by increased metabolism. Exercise intensity-dependent changes in operating points (V̇E and P ETC O2) were estimated by integrating the controller and plant curves in a respiratory equilibrium diagram. In conclusion, we developed an anaesthetized-rat model for studying exercise hyperpnoea, using systems analysis for quantitative characterization of the respiratory system. This novel experimental model will be useful for understanding the mechanisms responsible for abnormal ventilatory responses to exercise in disease models. © 2018 Morinomiya University of Medical Sciences. Experimental Physiology © 2018 The Physiological Society.

Revisiting the case for genetically engineered mouse models in human myelodysplastic syndrome research.

PubMed

Zhou, Ting; Kinney, Marsha C; Scott, Linda M; Zinkel, Sandra S; Rebel, Vivienne I

2015-08-27

Much-needed attention has been given of late to diseases specifically associated with an expanding elderly population. Myelodysplastic syndrome (MDS), a hematopoietic stem cell-based blood disease, is one of these. The lack of clear understanding of the molecular mechanisms underlying the pathogenesis of this disease has hampered the development of efficacious therapies, especially in the presence of comorbidities. Mouse models could potentially provide new insights into this disease, although primary human MDS cells grow poorly in xenografted mice. This makes genetically engineered murine models a more attractive proposition, although this approach is not without complications. In particular, it is unclear if or how myelodysplasia (abnormal blood cell morphology), a key MDS feature in humans, presents in murine cells. Here, we evaluate the histopathologic features of wild-type mice and 23 mouse models with verified myelodysplasia. We find that certain features indicative of myelodysplasia in humans, such as Howell-Jolly bodies and low neutrophilic granularity, are commonplace in healthy mice, whereas other features are similarly abnormal in humans and mice. Quantitative hematopoietic parameters, such as blood cell counts, are required to distinguish between MDS and related diseases. We provide data that mouse models of MDS can be genetically engineered and faithfully recapitulate human disease. © 2015 by The American Society of Hematology.

The Drosophila junctophilin gene is functionally equivalent to its four mammalian counterparts and is a modifier of a Huntingtin poly-Q expansion and the Notch pathway

PubMed Central

Calpena, Eduardo; López del Amo, Víctor; Chakraborty, Mouli

2018-01-01

ABSTRACT Members of the Junctophilin (JPH) protein family have emerged as key actors in all excitable cells, with crucial implications for human pathophysiology. In mammals, this family consists of four members (JPH1-JPH4) that are differentially expressed throughout excitable cells. The analysis of knockout mice lacking JPH subtypes has demonstrated their essential contribution to physiological functions in skeletal and cardiac muscles and in neurons. Moreover, mutations in the human JPH2 gene are associated with hypertrophic and dilated cardiomyopathies; mutations in JPH3 are responsible for the neurodegenerative Huntington's disease-like-2 (HDL2), whereas JPH1 acts as a genetic modifier in Charcot–Marie–Tooth 2K peripheral neuropathy. Drosophila melanogaster has a single junctophilin (jp) gene, as is the case in all invertebrates, which might retain equivalent functions of the four homologous JPH genes present in mammalian genomes. Therefore, owing to the lack of putatively redundant genes, a jp Drosophila model could provide an excellent platform to model the Junctophilin-related diseases, to discover the ancestral functions of the JPH proteins and to reveal new pathways. By up- and downregulation of Jp in a tissue-specific manner in Drosophila, we show that altering its levels of expression produces a phenotypic spectrum characterized by muscular deficits, dilated cardiomyopathy and neuronal alterations. Importantly, our study has demonstrated that Jp modifies the neuronal degeneration in a Drosophila model of Huntington's disease, and it has allowed us to uncover an unsuspected functional relationship with the Notch pathway. Therefore, this Drosophila model has revealed new aspects of Junctophilin function that can be relevant for the disease mechanisms of their human counterparts. PMID:29208631

Steryl ester synthesis, storage and hydrolysis: A contribution to sterol homeostasis.

PubMed

Korber, Martina; Klein, Isabella; Daum, Günther

2017-12-01

Sterols are essential lipids of all eukaryotic cells, appearing either as free sterols or steryl esters. Besides other regulatory mechanisms, esterification of sterols and hydrolysis of steryl esters serve to buffer both an excess and a lack of free sterols. In this review, the esterification process, the storage of steryl esters and their mobilization will be described. Several model organisms are discussed but the focus was set on mammals and the yeast Saccharomyces cerevisiae. The contribution of imbalanced cholesterol homeostasis to several human diseases, namely Wolman disease, cholesteryl ester storage disease, atherosclerosis and Alzheimer's disease, Niemann-Pick type C and Tangier disease is described. Copyright © 2017 Elsevier B.V. All rights reserved.

Gene Therapy for Cardiovascular Disease

PubMed Central

2003-01-01

The last decade has seen substantial advances in the development of gene therapy strategies and vector technology for the treatment of a diverse number of diseases, with a view to translating the successes observed in animal models into the clinic. Perhaps the overwhelming drive for the increase in vascular gene transfer studies is the current lack of successful long-term pharmacological treatments for complex cardiovascular diseases. The increase in cardiovascular disease to epidemic proportions has also led many to conclude that drug therapy may have reached a plateau in its efficacy and that gene therapy may represent a realistic solution to a long-term problem. Here, we discuss gene delivery approaches and target diseases. PMID:12721517

Long-Term Adult Feline Liver Organoid Cultures for Disease Modeling of Hepatic Steatosis.

PubMed

Kruitwagen, Hedwig S; Oosterhoff, Loes A; Vernooij, Ingrid G W H; Schrall, Ingrid M; van Wolferen, Monique E; Bannink, Farah; Roesch, Camille; van Uden, Lisa; Molenaar, Martijn R; Helms, J Bernd; Grinwis, Guy C M; Verstegen, Monique M A; van der Laan, Luc J W; Huch, Meritxell; Geijsen, Niels; Vries, Robert G; Clevers, Hans; Rothuizen, Jan; Schotanus, Baukje A; Penning, Louis C; Spee, Bart

2017-04-11

Hepatic steatosis is a highly prevalent liver disease, yet research is hampered by the lack of tractable cellular and animal models. Steatosis also occurs in cats, where it can cause severe hepatic failure. Previous studies demonstrate the potential of liver organoids for modeling genetic diseases. To examine the possibility of using organoids to model steatosis, we established a long-term feline liver organoid culture with adult liver stem cell characteristics and differentiation potential toward hepatocyte-like cells. Next, organoids from mouse, human, dog, and cat liver were provided with fatty acids. Lipid accumulation was observed in all organoids and interestingly, feline liver organoids accumulated more lipid droplets than human organoids. Finally, we demonstrate effects of interference with β-oxidation on lipid accumulation in feline liver organoids. In conclusion, feline liver organoids can be successfully cultured and display a predisposition for lipid accumulation, making them an interesting model in hepatic steatosis research. Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

Development of a sheep challenge model for Rift Valley fever

USDA-ARS?s Scientific Manuscript database

Rift Valley fever is a zoonotic disease responsible for severe outbreaks in ruminant livestock characterized by mass abortion and high mortality rates in younger animals. The lack of a fully licensed vaccine in the US has spurred increased demand for a protective vaccine. Thus, development of a reli...

IDENTIFICATION OF SPONTANEOUS FELINE IDIOPATHIC PULMONARY FIBROSIS: MORPHOLOGY AND ULTRASTRUCTURAL EVIDENCE FOR A TYPE II PNEUMOCYTE DEFECT

EPA Science Inventory

Abstract
Idiopathic pulmonary fibrosis currently lacks an animal model that develops the persistent, progressive lung fibrosis characteristic of the disease. Sixteen domestic cats developed dyspnea that was not responsive to therapy and which rapidly progressed until death/eu...

Complete genome sequence of Clavibacter michiganensis subsp. insidiosus

USDA-ARS?s Scientific Manuscript database

Clavibacter michiganensis subsp. insidiosus (Cmi) causes bacterial wilt disease of alfalfa (Medicago sativa L.) and can also infect the model legume plant M. truncatula. The virulence mechanisms of Cmi are yet to be identified, hampered by the lack of efficient mutagenesis tools as well as by the la...

Curcumin and neurodegenerative diseases

PubMed Central

Monroy, Adriana; Lithgow, Gordon J.; Alavez, Silvestre

2013-01-01

Over the last ten years curcumin has been reported to be effective against a wide variety of diseases and is characterized as having anti-carcinogenic, hepatoprotective, thrombosuppressive, cardioprotective, anti-arthritic, and anti-infectious properties. Recent studies performed in both vertebrate and invertebrate models have been conducted to determine whether curcumin was also neuroprotective. The efficacy of curcumin in several pre-clinical trials for neurodegenerative diseases has created considerable excitement mainly due to its lack of toxicity and low cost. This suggests that curcumin could be a worthy candidate for nutraceutical intervention. Since aging is a common risk factor for neurodegenerative diseases, it is possible that some compounds that target aging mechanisms could also prevent these kinds of diseases. One potential mechanism to explain several of the general health benefits associated with curcumin is that it may prevent aging-associated changes in cellular proteins that lead to protein insolubility and aggregation. This loss in protein homeostasis is associated with several age-related diseases. Recently, curcumin has been found to help maintain protein homeostasis and extend lifespan in the model invertebrate Caenorhabditis elegans. Here, we review the evidence from several animal models that curcumin improves healthspan by preventing or delaying the onset of various neurodegenerative diseases. PMID:23303664

A Hierarchical Network Approach for Modeling Rift Valley Fever Epidemics with Applications in North America

PubMed Central

Xue, Ling; Cohnstaedt, Lee W.; Scott, H. Morgan; Scoglio, Caterina

2013-01-01

Rift Valley fever is a vector-borne zoonotic disease which causes high morbidity and mortality in livestock. In the event Rift Valley fever virus is introduced to the United States or other non-endemic areas, understanding the potential patterns of spread and the areas at risk based on disease vectors and hosts will be vital for developing mitigation strategies. Presented here is a general network-based mathematical model of Rift Valley fever. Given a lack of empirical data on disease vector species and their vector competence, this discrete time epidemic model uses stochastic parameters following several PERT distributions to model the dynamic interactions between hosts and likely North American mosquito vectors in dispersed geographic areas. Spatial effects and climate factors are also addressed in the model. The model is applied to a large directed asymmetric network of 3,621 nodes based on actual farms to examine a hypothetical introduction to some counties of Texas, an important ranching area in the United States of America. The nodes of the networks represent livestock farms, livestock markets, and feedlots, and the links represent cattle movements and mosquito diffusion between different nodes. Cattle and mosquito (Aedes and Culex) populations are treated with different contact networks to assess virus propagation. Rift Valley fever virus spread is assessed under various initial infection conditions (infected mosquito eggs, adults or cattle). A surprising trend is fewer initial infectious organisms result in a longer delay before a larger and more prolonged outbreak. The delay is likely caused by a lack of herd immunity while the infection expands geographically before becoming an epidemic involving many dispersed farms and animals almost simultaneously. Cattle movement between farms is a large driver of virus expansion, thus quarantines can be efficient mitigation strategy to prevent further geographic spread. PMID:23667453

A hierarchical network approach for modeling Rift Valley fever epidemics with applications in North America.

PubMed

Xue, Ling; Cohnstaedt, Lee W; Scott, H Morgan; Scoglio, Caterina

2013-01-01

Rift Valley fever is a vector-borne zoonotic disease which causes high morbidity and mortality in livestock. In the event Rift Valley fever virus is introduced to the United States or other non-endemic areas, understanding the potential patterns of spread and the areas at risk based on disease vectors and hosts will be vital for developing mitigation strategies. Presented here is a general network-based mathematical model of Rift Valley fever. Given a lack of empirical data on disease vector species and their vector competence, this discrete time epidemic model uses stochastic parameters following several PERT distributions to model the dynamic interactions between hosts and likely North American mosquito vectors in dispersed geographic areas. Spatial effects and climate factors are also addressed in the model. The model is applied to a large directed asymmetric network of 3,621 nodes based on actual farms to examine a hypothetical introduction to some counties of Texas, an important ranching area in the United States of America. The nodes of the networks represent livestock farms, livestock markets, and feedlots, and the links represent cattle movements and mosquito diffusion between different nodes. Cattle and mosquito (Aedes and Culex) populations are treated with different contact networks to assess virus propagation. Rift Valley fever virus spread is assessed under various initial infection conditions (infected mosquito eggs, adults or cattle). A surprising trend is fewer initial infectious organisms result in a longer delay before a larger and more prolonged outbreak. The delay is likely caused by a lack of herd immunity while the infection expands geographically before becoming an epidemic involving many dispersed farms and animals almost simultaneously. Cattle movement between farms is a large driver of virus expansion, thus quarantines can be efficient mitigation strategy to prevent further geographic spread.

Biological therapies in Crohn's disease: are they cost-effective? A critical appraisal of model-based analyses.

PubMed

Marchetti, Monia; Liberato, Nicola Lucio

2014-12-01

In refractory Crohn's disease, anti-TNF and anti-α 4 integrin agents are used for ameliorating disease activity but impose high costs to health-care systems. The authors systematically reviewed cost-effectiveness analyses based on decision models: most of the studies were judged to have a good quality, but a large portion assessed health and costs in a short time horizon, usually disregarding fistulizing disease and not considering safety. Infliximab induction followed by on-demand retreatment consistently proved to have a good cost per quality-adjusted life year, while maintenance treatment never satisfied commonly accepted cost-utility thresholds. Challenges in cost-effectiveness analysis include the lack of a standard model structure, a large variability in the costs of surgery and poor data on indirect costs. As clinical practice is moving to mucosal healing as a robust response marker, personalized schedules of anti-TNF therapies might prove cost-effective even in the perspective of the health-care system in the near future.

Dengue viruses – an overview

PubMed Central

Bäck, Anne Tuiskunen; Lundkvist, Åke

2013-01-01

Dengue viruses (DENVs) cause the most common arthropod-borne viral disease in man with 50–100 million infections per year. Because of the lack of a vaccine and antiviral drugs, the sole measure of control is limiting the Aedes mosquito vectors. DENV infection can be asymptomatic or a self-limited, acute febrile disease ranging in severity. The classical form of dengue fever (DF) is characterized by high fever, headache, stomach ache, rash, myalgia, and arthralgia. Severe dengue, dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS) are accompanied by thrombocytopenia, vascular leakage, and hypotension. DSS, which can be fatal, is characterized by systemic shock. Despite intensive research, the underlying mechanisms causing severe dengue is still not well understood partly due to the lack of appropriate animal models of infection and disease. However, even though it is clear that both viral and host factors play important roles in the course of infection, a fundamental knowledge gap still remains to be filled regarding host cell tropism, crucial host immune response mechanisms, and viral markers for virulence. PMID:24003364

Insight into "Calculated Risk": An Application to the Prioritization of Emerging Infectious Diseases for Blood Transfusion Safety.

PubMed

Neslo, R E J; Oei, W; Janssen, M P

2017-09-01

Increasing identification of transmissions of emerging infectious diseases (EIDs) by blood transfusion raised the question which of these EIDs poses the highest risk to blood safety. For a number of the EIDs that are perceived to be a threat to blood safety, evidence on actual disease or transmission characteristics is lacking, which might render measures against such EIDs disputable. On the other hand, the fact that we call them "emerging" implies almost by definition that we are uncertain about at least some of their characteristics. So what is the relative importance of various disease and transmission characteristics, and how are these influenced by the degree of uncertainty associated with their actual values? We identified the likelihood of transmission by blood transfusion, the presence of an asymptomatic phase of infection, prevalence of infection, and the disease impact as the main characteristics of the perceived risk of disease transmission by blood transfusion. A group of experts in the field of infectious diseases and blood transfusion ranked sets of (hypothetical) diseases with varying degrees of uncertainty associated with their disease characteristics, and used probabilistic inversion to obtain probability distributions for the weight of each of these risk characteristics. These distribution weights can be used to rank both existing and newly emerging infectious diseases with (partially) known characteristics. Analyses show that in case there is a lack of data concerning disease characteristics, it is the uncertainty concerning the asymptomatic phase and the disease impact that are the most important drivers of the perceived risk. On the other hand, if disease characteristics are well established, it is the prevalence of infection and the transmissibility of the disease by blood transfusion that will drive the perceived risk. The risk prioritization model derived provides an easy to obtain and rational expert assessment of the relative importance of an (emerging) infectious disease, requiring only a limited amount of information. Such a model might be used to justify a rational and proportional response to an emerging infectious disease, especially in situations where little or no specific information is available. © 2017 Society for Risk Analysis.

Quantitative magnetic resonance imaging assessments of autosomal recessive polycystic kidney disease progression and response to therapy in an animal model.

PubMed

Erokwu, Bernadette O; Anderson, Christian E; Flask, Chris A; Dell, Katherine M

2018-05-01

BackgroundAutosomal recessive polycystic kidney disease (ARPKD) is associated with significant mortality and morbidity, and currently, there are no disease-specific treatments available for ARPKD patients. One major limitation in establishing new therapies for ARPKD is a lack of sensitive measures of kidney disease progression. Magnetic resonance imaging (MRI) can provide multiple quantitative assessments of the disease.MethodsWe applied quantitative image analysis of high-resolution (noncontrast) T2-weighted MRI techniques to study cystic kidney disease progression and response to therapy in the PCK rat model of ARPKD.ResultsSerial imaging over a 2-month period demonstrated that renal cystic burden (RCB, %)=[total cyst volume (TCV)/total kidney volume (TKV) × 100], TCV, and, to a lesser extent, TKV detected cystic kidney disease progression, as well as the therapeutic effect of octreotide, a clinically available medication shown previously to slow both kidney and liver disease progression in this model. All three MRI measures correlated significantly with histologic measures of renal cystic area, although the correlation of RCB and TCV was stronger than that of TKV.ConclusionThese preclinical MRI results provide a basis for applying these quantitative MRI techniques in clinical studies, to stage and measure progression in human ARPKD kidney disease.

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

PubMed Central

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

2013-01-01

Establishing human cell models of spinal muscular atrophy (SMA) to mimic motor neuron-specific phenotypes holds the key to understanding the pathogenesis of this devastating disease. Here, we developed a closely representative cell model of SMA by knocking down the disease-determining gene, survival motor neuron (SMN), in human embryonic stem cells (hESCs). Our study with this cell model demonstrated that knocking down of SMN does not interfere with neural induction or the initial specification of spinal motor neurons. Notably, the axonal outgrowth of spinal motor neurons was significantly impaired and these disease-mimicking neurons subsequently degenerated. Furthermore, these disease phenotypes were caused by SMN-full length (SMN-FL) but not SMN-Δ7 (lacking exon 7) knockdown, and were specific to spinal motor neurons. Restoring the expression of SMN-FL completely ameliorated all of the disease phenotypes, including specific axonal defects and motor neuron loss. Finally, knockdown of SMN-FL led to excessive mitochondrial oxidative stress in human motor neuron progenitors. The involvement of oxidative stress in the degeneration of spinal motor neurons in the SMA cell model was further confirmed by the administration of N-acetylcysteine, a potent antioxidant, which prevented disease-related apoptosis and subsequent motor neuron death. Thus, we report here the successful establishment of an hESC-based SMA model, which exhibits disease gene isoform specificity, cell type specificity, and phenotype reversibility. Our model provides a unique paradigm for studying how motor neurons specifically degenerate and highlights the potential importance of antioxidants for the treatment of SMA. PMID:23208423

Role of APOE Isoforms in the Pathogenesis of TBI induced Alzheimer’s Disease

DTIC Science & Technology

2016-10-01

deletion, APOE targeted replacement, complex breeding, CCI model optimization, mRNA library generation, high throughput massive parallel sequencing...demonstrate that the lack of Abca1 increases amyloid plaques and decreased APOE protein levels in AD-model mice. In this proposal we will test the hypothesis...injury, inflammatory reaction, transcriptome, high throughput massive parallel sequencing, mRNA-seq., behavioral testing, memory impairment, recovery 3

Stem cell-derived organoids to model gastrointestinal facets of cystic fibrosis

PubMed Central

Hohwieler, Meike; Perkhofer, Lukas; Liebau, Stefan; Seufferlein, Thomas; Müller, Martin

2016-01-01

Cystic fibrosis (CF) is one of the most frequently occurring inherited human diseases caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) which lead to ample defects in anion transport and epithelial fluid secretion. Existing models lack both access to early stages of CF development and a coeval focus on the gastrointestinal CF phenotypes, which become increasingly important due increased life span of the affected individuals. Here, we provide a comprehensive overview of gastrointestinal facets of CF and the opportunity to model these in various systems in an attempt to understand and treat CF. A particular focus is given on forward-leading organoid cultures, which may circumvent current limitations of existing models and thereby provide a platform for drug testing and understanding of disease pathophysiology in gastrointestinal organs. PMID:28815024

Urine-derived induced pluripotent stem cells as a modeling tool to study rare human diseases

PubMed Central

Shi, Liang; Cui, Yazhou; Luan, Jing; Zhou, Xiaoyan; Han, Jinxiang

2016-01-01

Summary Rare diseases with a low prevalence are a key public health issue because the causes of those diseases are difficult to determine and those diseases lack a clearly established or curative treatment. Thus, investigating the molecular mechanisms that underlie the pathology of rare diseases and facilitating the development of novel therapies using disease models is crucial. Human induced pluripotent stem cells (iPSCs) are well suited to modeling rare diseases since they have the capacity for self-renewal and pluripotency. In addition, iPSC technology provides a valuable tool to generate patient-specific iPSCs. These cells can be differentiated into cell types that have been affected by a disease. These cells would circumvent ethical concerns and avoid immunological rejection, so they could be used in cell replacement therapy or regenerative medicine. To date, human iPSCs could have been generated from multiple donor sources, such as skin, adipose tissue, and peripheral blood. However, these cells are obtained via invasive procedures. In contrast, several groups of researchers have found that urine may be a better source for producing iPSCs from normal individuals or patients. This review discusses urinary iPSC (UiPSC) as a candidate for modeling rare diseases. Cells obtained from urine have overwhelming advantages compared to other donor sources since they are safely, affordably, and frequently obtained and they are readily obtained from patients. The use of iPSC-based models is also discussed. UiPSCs may prove to be a key means of modeling rare diseases and they may facilitate the treatment of those diseases in the future. PMID:27672542

Improvement of Disease Prediction and Modeling through the Use of Meteorological Ensembles: Human Plague in Uganda

PubMed Central

Moore, Sean M.; Monaghan, Andrew; Griffith, Kevin S.; Apangu, Titus; Mead, Paul S.; Eisen, Rebecca J.

2012-01-01

Climate and weather influence the occurrence, distribution, and incidence of infectious diseases, particularly those caused by vector-borne or zoonotic pathogens. Thus, models based on meteorological data have helped predict when and where human cases are most likely to occur. Such knowledge aids in targeting limited prevention and control resources and may ultimately reduce the burden of diseases. Paradoxically, localities where such models could yield the greatest benefits, such as tropical regions where morbidity and mortality caused by vector-borne diseases is greatest, often lack high-quality in situ local meteorological data. Satellite- and model-based gridded climate datasets can be used to approximate local meteorological conditions in data-sparse regions, however their accuracy varies. Here we investigate how the selection of a particular dataset can influence the outcomes of disease forecasting models. Our model system focuses on plague (Yersinia pestis infection) in the West Nile region of Uganda. The majority of recent human cases have been reported from East Africa and Madagascar, where meteorological observations are sparse and topography yields complex weather patterns. Using an ensemble of meteorological datasets and model-averaging techniques we find that the number of suspected cases in the West Nile region was negatively associated with dry season rainfall (December-February) and positively with rainfall prior to the plague season. We demonstrate that ensembles of available meteorological datasets can be used to quantify climatic uncertainty and minimize its impacts on infectious disease models. These methods are particularly valuable in regions with sparse observational networks and high morbidity and mortality from vector-borne diseases. PMID:23024750

Determination of Highly Sensitive Biological Cell Model Systems to Screen BPA-Related Health Hazards Using Pathway Studio.

PubMed

Ryu, Do-Yeal; Rahman, Md Saidur; Pang, Myung-Geol

2017-09-06

Bisphenol-A (BPA) is a ubiquitous endocrine-disrupting chemical. Recently, many issues have arisen surrounding the disease pathogenesis of BPA. Therefore, several studies have been conducted to investigate the proteomic biomarkers of BPA that are associated with disease processes. However, studies on identifying highly sensitive biological cell model systems in determining BPA health risk are lacking. Here, we determined suitable cell model systems and potential biomarkers for predicting BPA-mediated disease using the bioinformatics tool Pathway Studio. We compiled known BPA-mediated diseases in humans, which were categorized into five major types. Subsequently, we investigated the differentially expressed proteins following BPA exposure in several cell types, and analyzed the efficacy of altered proteins to investigate their associations with BPA-mediated diseases. Our results demonstrated that colon cancer cells (SW480), mammary gland, and Sertoli cells were highly sensitive biological model systems, because of the efficacy of predicting the majority of BPA-mediated diseases. We selected glucose-6-phosphate dehydrogenase (G6PD), cytochrome b-c1 complex subunit 1 (UQCRC1), and voltage-dependent anion-selective channel protein 2 (VDAC2) as highly sensitive biomarkers to predict BPA-mediated diseases. Furthermore, we summarized proteomic studies in spermatozoa following BPA exposure, which have recently been considered as another suitable cell type for predicting BPA-mediated diseases.

Determination of Highly Sensitive Biological Cell Model Systems to Screen BPA-Related Health Hazards Using Pathway Studio

PubMed Central

Ryu, Do-Yeal

2017-01-01

Bisphenol-A (BPA) is a ubiquitous endocrine-disrupting chemical. Recently, many issues have arisen surrounding the disease pathogenesis of BPA. Therefore, several studies have been conducted to investigate the proteomic biomarkers of BPA that are associated with disease processes. However, studies on identifying highly sensitive biological cell model systems in determining BPA health risk are lacking. Here, we determined suitable cell model systems and potential biomarkers for predicting BPA-mediated disease using the bioinformatics tool Pathway Studio. We compiled known BPA-mediated diseases in humans, which were categorized into five major types. Subsequently, we investigated the differentially expressed proteins following BPA exposure in several cell types, and analyzed the efficacy of altered proteins to investigate their associations with BPA-mediated diseases. Our results demonstrated that colon cancer cells (SW480), mammary gland, and Sertoli cells were highly sensitive biological model systems, because of the efficacy of predicting the majority of BPA-mediated diseases. We selected glucose-6-phosphate dehydrogenase (G6PD), cytochrome b-c1 complex subunit 1 (UQCRC1), and voltage-dependent anion-selective channel protein 2 (VDAC2) as highly sensitive biomarkers to predict BPA-mediated diseases. Furthermore, we summarized proteomic studies in spermatozoa following BPA exposure, which have recently been considered as another suitable cell type for predicting BPA-mediated diseases. PMID:28878155

Modeling of leishmaniasis infection dynamics: novel application to the design of effective therapies

PubMed Central

2012-01-01

Background The WHO considers leishmaniasis as one of the six most important tropical diseases worldwide. It is caused by parasites of the genus Leishmania that are passed on to humans and animals by the phlebotomine sandfly. Despite all of the research, there is still a lack of understanding on the metabolism of the parasite and the progression of the disease. In this study, a mathematical model of disease progression was developed based on experimental data of clinical symptoms, immunological responses, and parasite load for Leishmania amazonensis in BALB/c mice. Results Four biologically significant variables were chosen to develop a differential equation model based on the GMA power-law formalism. Parameters were determined to minimize error in the model dynamics and time series experimental data. Subsequently, the model robustness was tested and the model predictions were verified by comparing them with experimental observations made in different experimental conditions. The model obtained helps to quantify relationships between the selected variables, leads to a better understanding of disease progression, and aids in the identification of crucial points for introducing therapeutic methods. Conclusions Our model can be used to identify the biological factors that must be changed to minimize parasite load in the host body, and contributes to the design of effective therapies. PMID:22222070

iPSC-derived neurons as a higher-throughput readout for autism: Promises and pitfalls

PubMed Central

Prilutsky, Daria; Palmer, Nathan P.; Smedemark-Margulies, Niklas; Schlaeger, Thorsten M.; Margulies, David M.; Kohane, Isaac S.

2014-01-01

The elucidation of disease etiologies and establishment of robust, scalable, high-throughput screening assays for autism spectrum disorders (ASDs) have been impeded by both inaccessibility of disease-relevant neuronal tissue and the genetic heterogeneity of the disorder. Neuronal cells derived from induced pluripotent stem cells (iPSCs) from autism patients may circumvent these obstacles and serve as relevant cell models. To date, derived cells are characterized and screened by assessing their neuronal phenotypes. These characterizations are often etiology-specific or lack reproducibility and stability. In this manuscript, we present an overview of efforts to study iPSC-derived neurons as a model for autism, and we explore the plausibility of gene expression profiling as a reproducible and stable disease marker. PMID:24374161

Reprogramming neurodegeneration in the big data era.

PubMed

Zhou, Lujia; Verstreken, Patrik

2018-02-01

Recent genome-wide association studies (GWAS) have identified numerous genetic risk variants for late-onset Alzheimer's disease (AD) and Parkinson's disease (PD). However, deciphering the functional consequences of GWAS data is challenging due to a lack of reliable model systems to study the genetic variants that are often of low penetrance and non-coding identities. Pluripotent stem cell (PSC) technologies offer unprecedented opportunities for molecular phenotyping of GWAS variants in human neurons and microglia. Moreover, rapid technological advances in whole-genome RNA-sequencing and epigenome mapping fuel comprehensive and unbiased investigations of molecular alterations in PSC-derived disease models. Here, we review and discuss how integrated studies that utilize PSC technologies and genome-wide approaches may bring new mechanistic insight into the pathogenesis of AD and PD. Copyright © 2018 Elsevier Ltd. All rights reserved.

Need for improved methods to collect and present spatial epidemiologic data for vectorborne diseases.

PubMed

Eisen, Lars; Eisen, Rebecca J

2007-12-01

Improved methods for collection and presentation of spatial epidemiologic data are needed for vectorborne diseases in the United States. Lack of reliable data for probable pathogen exposure site has emerged as a major obstacle to the development of predictive spatial risk models. Although plague case investigations can serve as a model for how to ideally generate needed information, this comprehensive approach is cost-prohibitive for more common and less severe diseases. New methods are urgently needed to determine probable pathogen exposure sites that will yield reliable results while taking into account economic and time constraints of the public health system and attending physicians. Recent data demonstrate the need for a change from use of the county spatial unit for presentation of incidence of vectorborne diseases to more precise ZIP code or census tract scales. Such fine-scale spatial risk patterns can be communicated to the public and medical community through Web-mapping approaches.

Deer density and disease prevalence influence transmission of Chronic Wasting Disease in White-tailed Deer

USGS Publications Warehouse

Samuel, Michael D.; Richards, Bryan J.; Storm, Daniel J.; Rolley, Robert E.; Shelton, Paul; Nicholas S. Keuler,; Timothy R. Van Deelen,

2013-01-01

Host-parasite dynamics and strategies for managing infectious diseases of wildlife depend on the functional relationship between disease transmission rates and host density. However, the disease transmission function is rarely known for free-living wildlife, leading to uncertainty regarding the impacts of diseases on host populations and effective control actions. We evaluated the influence of deer density, landscape features, and soil clay content on transmission of chronic wasting disease (CWD) in young (<2-year-old) white-tailed deer (Odocoileus virginianus) in south-central Wisconsin, USA. We evaluated how frequency-dependent, density-dependent, and intermediate transmission models predicted CWD incidence rates in harvested yearling deer. An intermediate transmission model, incorporating both disease prevalence and density of infected deer, performed better than simple density- and frequency-dependent models. Our results indicate a combination of social structure, non-linear relationships between infectious contact and deer density, and distribution of disease among groups are important factors driving CWD infection in young deer. The landscape covariates % deciduous forest cover and forest edge density also were positively associated with infection rates, but soil clay content had no measurable influences on CWD transmission. Lack of strong density-dependent transmission rates indicates that controlling CWD by reducing deer density will be difficult. The consequences of non-linear disease transmission and aggregation of disease on cervid populations deserves further consideration.

Bioelectric Characterization of Epithelia from Neonatal CFTR Knockout Ferrets

PubMed Central

Fisher, John T.; Tyler, Scott R.; Zhang, Yulong; Lee, Ben J.; Liu, Xiaoming; Sun, Xingshen; Sui, Hongshu; Liang, Bo; Luo, Meihui; Xie, Weiliang; Yi, Yaling; Zhou, Weihong; Song, Yi; Keiser, Nicholas; Wang, Kai; de Jonge, Hugo R.

2013-01-01

Cystic fibrosis (CF) is a life-shortening, recessive, multiorgan genetic disorder caused by the loss of CF transmembrane conductance regulator (CFTR) chloride channel function found in many types of epithelia. Animal models that recapitulate the human disease phenotype are critical to understanding pathophysiology in CF and developing therapies. CFTR knockout ferrets manifest many of the phenotypes observed in the human disease, including lung infections, pancreatic disease and diabetes, liver disease, malnutrition, and meconium ileus. In the present study, we have characterized abnormalities in the bioelectric properties of the trachea, stomach, intestine, and gallbladder of newborn CF ferrets. Short-circuit current (ISC) analysis of CF and wild-type (WT) tracheas revealed the following similarities and differences: (1) amiloride-sensitive sodium currents were similar between genotypes; (2) responses to 4,4′-diisothiocyano-2,2′-stilbene disulphonic acid were 3.3-fold greater in CF animals, suggesting elevated baseline chloride transport through non-CFTR channels in a subset of CF animals; and (3) a lack of 3-isobutyl-1-methylxanthine (IBMX)/forskolin–stimulated and N-(2-Naphthalenyl)-((3,5-dibromo-2,4-dihydroxyphenyl)methylene)glycine hydrazide (GlyH-101)–inhibited currents in CF animals due to the lack of CFTR. CFTR mRNA was present throughout all levels of the WT ferret and IBMX/forskolin–inducible ISC was only observed in WT animals. However, despite the lack of CFTR function in the knockout ferret, the luminal pH of the CF ferret gallbladder, stomach, and intestines was not significantly changed relative to WT. The WT stomach and gallbladder exhibited significantly enhanced IBMX/forskolin ISC responses and inhibition by GlyH-101 relative to CF samples. These findings demonstrate that multiple organs affected by disease in the CF ferret have bioelectric abnormalities consistent with the lack of cAMP-mediated chloride transport. PMID:23782101

Lack of magnetic resonance imaging lesion activity as a treatment target in multiple sclerosis: An evaluation using electronically collected outcomes.

PubMed

Conway, Devon S; Thompson, Nicolas R; Cohen, Jeffrey A

2016-09-01

The appropriate treatment target in multiple sclerosis (MS) is unclear. Lack of magnetic resonance imaging (MRI) lesion activity, a component of the no evidence of disease activity concept, has been proposed as a treatment target in MS. We used our MS database to investigate whether aggressively pursuing MRI stability by changing disease modifying therapy (DMT) when MRI activity is observed leads to better clinical and imaging outcomes. The Knowledge Program (KP) is a database linked to our electronic medical record allowing capture of patient and clinician reported outcomes. Through KP query and chart review, we identified all relapsing-remitting MS patients visiting between 1 January 2008 and 31 December 2014 with active MRIs despite DMT. Propensity modeling based on demographic and disease characteristics was used to match DMT switchers to non-switchers. KP and MRI outcomes were compared 18 months after the active MRI using mixed-effects linear regression models. We identified 417 patients who met criteria for our analysis. After propensity matching, 78 switchers and 91 non-switchers were analyzed. There was no difference in clinical or radiologic outcomes between these groups at 18 months. We did not find a short-term benefit of changing DMT to pursue MRI stability. Copyright © 2016 Elsevier B.V. All rights reserved.

3D bioprinting of biomimetic aortic vascular constructs with self-supporting cells.

PubMed

Kucukgul, Can; Ozler, S Burce; Inci, Ilyas; Karakas, Ezgi; Irmak, Ster; Gozuacik, Devrim; Taralp, Alpay; Koc, Bahattin

2015-04-01

Cardiovascular diseases are the leading cause of deaths throughout the world. Vascular diseases are mostly treated with autografts and blood vessel transplantations. However, traditional grafting methods have several problems including lack of suitable harvest sites, additional surgical costs for harvesting procedure, pain, infection, lack of donors, and even no substitutes at all. Recently, tissue engineering and regenerative medicine approaches are used to regenerate damaged or diseased tissues. Most of the tissue engineering investigations have been based on the cell seeding into scaffolds by providing a suitable environment for cell attachment, proliferation, and differentiation. Because of the challenges such as difficulties in seeding cells spatially, rejection, and inflammation of biomaterials used, the recent tissue engineering studies focus on scaffold-free techniques. In this paper, the development of novel computer aided algorithms and methods are developed for 3D bioprinting of scaffold-free biomimetic macrovascular structures. Computer model mimicking a real human aorta is generated using imaging techniques and the proposed computational algorithms. An optimized three-dimensional bioprinting path planning are developed with the proposed self-supported model. Mouse embryonic fibroblast (MEF) cell aggregates and support structures (hydrogels) are 3D bioprinted layer-by-layer according to the proposed self-supported method to form an aortic tissue construct. © 2014 Wiley Periodicals, Inc.

The relevance of human stem cell-derived organoid models for epithelial translational medicine

PubMed Central

Hynds, Robert E.; Giangreco, Adam

2014-01-01

Epithelial organ remodeling is a major contributing factor to worldwide death and disease, costing healthcare systems billions of dollars every year. Despite this, most fundamental epithelial organ research fails to produce new therapies and mortality rates for epithelial organ diseases remain unacceptably high. In large part, this failure in translating basic epithelial research into clinical therapy is due to a lack of relevance in existing preclinical models. To correct this, new models are required that improve preclinical target identification, pharmacological lead validation, and compound optimization. In this review, we discuss the relevance of human stem cell-derived, three-dimensional organoid models for addressing each of these challenges. We highlight the advantages of stem cell-derived organoid models over existing culture systems, discuss recent advances in epithelial tissue-specific organoids, and present a paradigm for using organoid models in human translational medicine. PMID:23203919

An extended set of yeast-based functional assays accurately identifies human disease mutations

PubMed Central

Sun, Song; Yang, Fan; Tan, Guihong; Costanzo, Michael; Oughtred, Rose; Hirschman, Jodi; Theesfeld, Chandra L.; Bansal, Pritpal; Sahni, Nidhi; Yi, Song; Yu, Analyn; Tyagi, Tanya; Tie, Cathy; Hill, David E.; Vidal, Marc; Andrews, Brenda J.; Boone, Charles; Dolinski, Kara; Roth, Frederick P.

2016-01-01

We can now routinely identify coding variants within individual human genomes. A pressing challenge is to determine which variants disrupt the function of disease-associated genes. Both experimental and computational methods exist to predict pathogenicity of human genetic variation. However, a systematic performance comparison between them has been lacking. Therefore, we developed and exploited a panel of 26 yeast-based functional complementation assays to measure the impact of 179 variants (101 disease- and 78 non-disease-associated variants) from 22 human disease genes. Using the resulting reference standard, we show that experimental functional assays in a 1-billion-year diverged model organism can identify pathogenic alleles with significantly higher precision and specificity than current computational methods. PMID:26975778

Astaxanthin as a Potential Neuroprotective Agent for Neurological Diseases

PubMed Central

Wu, Haijian; Niu, Huanjiang; Shao, Anwen; Wu, Cheng; Dixon, Brandon J.; Zhang, Jianmin; Yang, Shuxu; Wang, Yirong

2015-01-01

Neurological diseases, which consist of acute injuries and chronic neurodegeneration, are the leading causes of human death and disability. However, the pathophysiology of these diseases have not been fully elucidated, and effective treatments are still lacking. Astaxanthin, a member of the xanthophyll group, is a red-orange carotenoid with unique cell membrane actions and diverse biological activities. More importantly, there is evidence demonstrating that astaxanthin confers neuroprotective effects in experimental models of acute injuries, chronic neurodegenerative disorders, and neurological diseases. The beneficial effects of astaxanthin are linked to its oxidative, anti-inflammatory, and anti-apoptotic characteristics. In this review, we will focus on the neuroprotective properties of astaxanthin and explore the underlying mechanisms in the setting of neurological diseases. PMID:26378548

Evaluation of the impacts of climate change on disease vectors through ecological niche modelling.

PubMed

Carvalho, B M; Rangel, E F; Vale, M M

2017-08-01

Vector-borne diseases are exceptionally sensitive to climate change. Predicting vector occurrence in specific regions is a challenge that disease control programs must meet in order to plan and execute control interventions and climate change adaptation measures. Recently, an increasing number of scientific articles have applied ecological niche modelling (ENM) to study medically important insects and ticks. With a myriad of available methods, it is challenging to interpret their results. Here we review the future projections of disease vectors produced by ENM, and assess their trends and limitations. Tropical regions are currently occupied by many vector species; but future projections indicate poleward expansions of suitable climates for their occurrence and, therefore, entomological surveillance must be continuously done in areas projected to become suitable. The most commonly applied methods were the maximum entropy algorithm, generalized linear models, the genetic algorithm for rule set prediction, and discriminant analysis. Lack of consideration of the full-known current distribution of the target species on models with future projections has led to questionable predictions. We conclude that there is no ideal 'gold standard' method to model vector distributions; researchers are encouraged to test different methods for the same data. Such practice is becoming common in the field of ENM, but still lags behind in studies of disease vectors.

Conserved gene regulation during acute inflammation between zebrafish and mammals

PubMed Central

Forn-Cuní, G.; Varela, M.; Pereiro, P.; Novoa, B.; Figueras, A.

2017-01-01

Zebrafish (Danio rerio), largely used as a model for studying developmental processes, has also emerged as a valuable system for modelling human inflammatory diseases. However, in a context where even mice have been questioned as a valid model for these analysis, a systematic study evaluating the reproducibility of human and mammalian inflammatory diseases in zebrafish is still lacking. In this report, we characterize the transcriptomic regulation to lipopolysaccharide in adult zebrafish kidney, liver, and muscle tissues using microarrays and demonstrate how the zebrafish genomic responses can effectively reproduce the mammalian inflammatory process induced by acute endotoxin stress. We provide evidence that immune signaling pathways and single gene expression is well conserved throughout evolution and that the zebrafish and mammal acute genomic responses after lipopolysaccharide stimulation are highly correlated despite the differential susceptibility between species to that compound. Therefore, we formally confirm that zebrafish inflammatory models are suited to study the basic mechanisms of inflammation in human inflammatory diseases, with great translational impact potential. PMID:28157230

Canine Models for Copper Homeostasis Disorders.

PubMed

Wu, Xiaoyan; Leegwater, Peter A J; Fieten, Hille

2016-02-04

Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted.

Canine Models for Copper Homeostasis Disorders

PubMed Central

Wu, Xiaoyan; Leegwater, Peter A. J.; Fieten, Hille

2016-01-01

Copper is an essential trace nutrient metal involved in a multitude of cellular processes. Hereditary defects in copper metabolism result in disorders with a severe clinical course such as Wilson disease and Menkes disease. In Wilson disease, copper accumulation leads to liver cirrhosis and neurological impairments. A lack in genotype-phenotype correlation in Wilson disease points toward the influence of environmental factors or modifying genes. In a number of Non-Wilsonian forms of copper metabolism, the underlying genetic defects remain elusive. Several pure bred dog populations are affected with copper-associated hepatitis showing similarities to human copper metabolism disorders. Gene-mapping studies in these populations offer the opportunity to discover new genes involved in copper metabolism. Furthermore, due to the relatively large body size and long life-span of dogs they are excellent models for development of new treatment strategies. One example is the recent use of canine organoids for disease modeling and gene therapy of copper storage disease. This review addresses the opportunities offered by canine genetics for discovery of genes involved in copper metabolism disorders. Further, possibilities for the use of dogs in development of new treatment modalities for copper storage disorders, including gene repair in patient-derived hepatic organoids, are highlighted. PMID:26861285

Association of a Bacteriophage with Meningococcal Disease in Young Adults

PubMed Central

Gray, Stephen J.; Kaczmarski, Edward B.; McCarthy, Noel D.; Nassif, Xavier; Maiden, Martin C. J.; Tinsley, Colin R.

2008-01-01

Despite being the agent of life-threatening meningitis, Neisseria meningitidis is usually carried asymptomatically in the nasopharynx of humans and only occasionally causes disease. The genetic bases for virulence have not been entirely elucidated and the search for new virulence factors in this species is hampered by the lack of an animal model representative of the human disease. As an alternative strategy we employ a molecular epidemiological approach to establish a statistical association of a candidate virulence gene with disease in the human population. We examine the distribution of a previously-identified genetic element, a temperate bacteriophage, in 1288 meningococci isolated from cases of disease and asymptomatic carriage. The phage was over-represented in disease isolates from young adults indicating that it may contribute to invasive disease in this age group. Further statistical analysis indicated that between 20% and 45% of the pathogenic potential of the five most common disease-causing meningococcal groups was linked to the presence of the phage. In the absence of an animal model of human disease, this molecular epidemiological approach permitted the estimation of the influence of the candidate virulence factor. Such an approach is particularly valuable in the investigation of exclusively human diseases. PMID:19065260

Robust Phagocyte Recruitment Controls the Opportunistic Fungal Pathogen Mucor circinelloides in Innate Granulomas In Vivo

PubMed Central

2018-01-01

ABSTRACT Mucormycosis is an emerging fungal infection with extremely high mortality rates in patients with defects in their innate immune response, specifically in functions mediated through phagocytes. However, we currently have a limited understanding of the molecular and cellular interactions between these innate immune effectors and mucormycete spores during the early immune response. Here, the early events of innate immune recruitment in response to infection by Mucor circinelloides spores are modeled by a combined in silico modeling approach and real-time in vivo microscopy. Phagocytes are rapidly recruited to the site of infection in a zebrafish larval model of mucormycosis. This robust early recruitment protects from disease onset in vivo. In silico analysis identified that protection is dependent on the number of phagocytes at the infection site, but not the speed of recruitment. The mathematical model highlights the role of proinflammatory signals for phagocyte recruitment and the importance of inhibition of spore germination for protection from active fungal disease. These in silico data are supported by an in vivo lack of fungal spore killing and lack of reactive oxygen burst, which together result in latent fungal infection. During this latent stage of infection, spores are controlled in innate granulomas in vivo. Disease can be reactivated by immunosuppression. Together, these data represent the first in vivo real-time analysis of innate granuloma formation during the early stages of a fungal infection. The results highlight a potential latent stage during mucormycosis that should urgently be considered for clinical management of patients. PMID:29588406

Estimating potential stylet penetration of southern green stink bug (Hemiptera: Pentatomidae) - A mathematical modeling approach

USDA-ARS?s Scientific Manuscript database

Southern green stink bugs, Nezara viridula (L.), and related species are significant pests of cotton in the U.S. Cotton Belt. Using their stylets, adults introduce disease pathogens of cotton into cotton bolls, and preliminary data indicates nymphs can also ingest these pathogens. Data is lacking ...

Behavioral assays with mouse models of Alzheimer’s disease: practical considerations and guidelines

PubMed Central

Puzzo, Daniela; Lee, Linda; Palmeri, Agostino; Calabrese, Giorgio; Arancio, Ottavio

2014-01-01

In Alzheimer’s disease (AD) basic research and drug discovery, mouse models are essential resources for uncovering biological mechanisms, validating molecular targets and screening potential compounds. Both transgenic and non-genetically modified mouse models enable access to different types of AD-like pathology in vivo. Although there is a wealth of genetic and biochemical studies on proposed AD pathogenic pathways, as a disease that centrally features cognitive failure, the ultimate readout for any interventions should be measures of learning and memory. This is particularly important given the lack of knowledge on disease etiology – assessment by cognitive assays offers the advantage of targeting relevant memory systems without requiring assumptions about pathogenesis. A multitude of behavioral assays are available for assessing cognitive functioning in mouse models, including ones specific for hippocampal-dependent learning and memory. Here we review the basics of available transgenic and non-transgenic AD mouse models and detail three well-established behavioral tasks commonly used for testing hippocampal-dependent cognition in mice – contextual fear conditioning, radial arm water maze and Morris water maze. In particular, we discuss the practical considerations, requirements and caveats of these behavioral testing paradigms. PMID:24462904

The impact of race on metabolic disease risk factors in women with and without posttraumatic stress disorder.

PubMed

Dedert, Eric A; Harper, Leia A; Calhoun, Patrick S; Dennis, Michelle F; Beckham, Jean C

2013-03-01

The literature on PTSD and metabolic disease risk factors has been limited by lacking investigation of the potential influence of commonly comorbid disorders and the role of race. In this study data were provided by a sample of 134 women (63 PTSD and 71 without PTSD). Separate sets of models examining associations of psychiatric disorder classifications with metabolic disease risk factors were used. Each model included race (African American or Caucasian), psychiatric disorder, and their interaction. There was an interaction of race and PTSD on body mass index, abdominal obesity, and triglycerides. While PTSD was not generally associated with deleterious health effects in African American participants, PTSD was related to worse metabolic disease risk factors in Caucasians. MDD was associated with metabolic disease risk factors, but there were no interactions with race. Results support the importance of race in the relationship between PTSD and metabolic disease risk factors. Future research would benefit from analysis of cultural factors to explain how race might influence metabolic disease risk factors in PTSD.

Sapronosis: a distinctive type of infectious agent

USGS Publications Warehouse

Kuris, Armand M.; Lafferty, Kevin D.; Sokolow, Susanne H.

2014-01-01

Sapronotic disease agents have evolutionary and epidemiological properties unlike other infectious organisms. Their essential saprophagic existence prevents coevolution, and no host–parasite virulence trade-off can evolve. However, the host may evolve defenses. Models of pathogens show that sapronoses, lacking a threshold of transmission, cannot regulate host populations, although they can reduce host abundance and even extirpate their hosts. Immunocompromised hosts are relatively susceptible to sapronoses. Some particularly important sapronoses, such as cholera and anthrax, can sustain an epidemic in a host population. However, these microbes ultimately persist as saprophages. One-third of human infectious disease agents are sapronotic, including nearly all fungal diseases. Recognition that an infectious disease is sapronotic illuminates a need for effective environmental control strategies.

Computational modeling of neurostimulation in brain diseases.

PubMed

Wang, Yujiang; Hutchings, Frances; Kaiser, Marcus

2015-01-01

Neurostimulation as a therapeutic tool has been developed and used for a range of different diseases such as Parkinson's disease, epilepsy, and migraine. However, it is not known why the efficacy of the stimulation varies dramatically across patients or why some patients suffer from severe side effects. This is largely due to the lack of mechanistic understanding of neurostimulation. Hence, theoretical computational approaches to address this issue are in demand. This chapter provides a review of mechanistic computational modeling of brain stimulation. In particular, we will focus on brain diseases, where mechanistic models (e.g., neural population models or detailed neuronal models) have been used to bridge the gap between cellular-level processes of affected neural circuits and the symptomatic expression of disease dynamics. We show how such models have been, and can be, used to investigate the effects of neurostimulation in the diseased brain. We argue that these models are crucial for the mechanistic understanding of the effect of stimulation, allowing for a rational design of stimulation protocols. Based on mechanistic models, we argue that the development of closed-loop stimulation is essential in order to avoid inference with healthy ongoing brain activity. Furthermore, patient-specific data, such as neuroanatomic information and connectivity profiles obtainable from neuroimaging, can be readily incorporated to address the clinical issue of variability in efficacy between subjects. We conclude that mechanistic computational models can and should play a key role in the rational design of effective, fully integrated, patient-specific therapeutic brain stimulation. © 2015 Elsevier B.V. All rights reserved.

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.

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.

Mathematical analysis of a power-law form time dependent vector-borne disease transmission model.

PubMed

Sardar, Tridip; Saha, Bapi

2017-06-01

In the last few years, fractional order derivatives have been used in epidemiology to capture the memory phenomena. However, these models do not have proper biological justification in most of the cases and lack a derivation from a stochastic process. In this present manuscript, using theory of a stochastic process, we derived a general time dependent single strain vector borne disease model. It is shown that under certain choice of time dependent transmission kernel this model can be converted into the classical integer order system. When the time-dependent transmission follows a power law form, we showed that the model converted into a vector borne disease model with fractional order transmission. We explicitly derived the disease-free and endemic equilibrium of this new fractional order vector borne disease model. Using mathematical properties of nonlinear Volterra type integral equation it is shown that the unique disease-free state is globally asymptotically stable under certain condition. We define a threshold quantity which is epidemiologically known as the basic reproduction number (R 0 ). It is shown that if R 0 > 1, then the derived fractional order model has a unique endemic equilibrium. We analytically derived the condition for the local stability of the endemic equilibrium. To test the model capability to capture real epidemic, we calibrated our newly proposed model to weekly dengue incidence data of San Juan, Puerto Rico for the time period 30th April 1994 to 23rd April 1995. We estimated several parameters, including the order of the fractional derivative of the proposed model using aforesaid data. It is shown that our proposed fractional order model can nicely capture real epidemic. Copyright © 2017 Elsevier Inc. All rights reserved.

Neuropeptides and the social brain: potential rodent models of autism.

PubMed

Lim, Miranda M; Bielsky, Isadora F; Young, Larry J

2005-01-01

Conducting basic scientific research on a complex psychiatric disorder, such as autism, is a challenging prospect. It is difficult to dissociate the fundamental neurological and psychological processes that are disturbed in autism and, therefore, it is a challenge to discover accurate and reliable animal models of the disease. Because of their role in animal models of social processing and social bonding, the neuropeptides oxytocin and vasopressin are strong candidates for dysregulation in autism. In this review, we discuss the current animal models which have investigated oxytocin and vasopressin systems in the brain and their effects on social behavior. For example, mice lacking the oxytocin gene have profound deficits in social processing and social recognition, as do rats lacking vasopressin or mice lacking the vasopressin V1a receptor (V1aR). In another rodent model, monogamous prairie voles are highly social and form strong pair bonds with their mates. Pair bonds can be facilitated or disrupted by perturbing the oxytocin and vasopressin systems. Non-monogamous vole species that do not pair bond have different oxytocin and V1aR distribution patterns in the brain than monogamous vole species. Potential ties from these rodent models to the human autistic condition are then discussed. Given the hallmark disturbances in social function, the study of animal models of social behavior may provide novel therapeutic targets for the treatment of autism.

A selective EP4 PGE2 receptor agonist alleviates disease in a new mouse model of X-linked nephrogenic diabetes insipidus

PubMed Central

Li, Jian Hua; Chou, Chung-Lin; Li, Bo; Gavrilova, Oksana; Eisner, Christoph; Schnermann, Jürgen; Anderson, Stasia A.; Deng, Chu-Xia; Knepper, Mark A.; Wess, Jürgen

2009-01-01

X-linked nephrogenic diabetes insipidus (XNDI) is a severe kidney disease caused by inactivating mutations in the V2 vasopressin receptor (V2R) gene that result in the loss of renal urine-concentrating ability. At present, no specific pharmacological therapy has been developed for XNDI, primarily due to the lack of suitable animal models. To develop what we believe to be the first viable animal model of XNDI, we generated mice in which the V2R gene could be conditionally deleted during adulthood by administration of 4-OH-tamoxifen. Radioligand-binding studies confirmed the lack of V2R-binding sites in kidneys following 4-OH-tamoxifen treatment, and further analysis indicated that upon V2R deletion, adult mice displayed all characteristic symptoms of XNDI, including polyuria, polydipsia, and resistance to the antidiuretic actions of vasopressin. Gene expression analysis suggested that activation of renal EP4 PGE2 receptors might compensate for the lack of renal V2R activity in XNDI mice. Strikingly, both acute and chronic treatment of the mutant mice with a selective EP4 receptor agonist greatly reduced all major manifestations of XNDI, including changes in renal morphology. These physiological improvements were most likely due to a direct action on EP4 receptors expressed on collecting duct cells. These findings illustrate the usefulness of the newly generated V2R mutant mice for elucidating and testing new strategies for the potential treatment of humans with XNDI. PMID:19729836

Increased Alzheimer's disease-like pathology in the APP/ PS1ΔE9 mouse model lacking Nrf2 through modulation of autophagy.

PubMed

Joshi, Gururaj; Gan, Kok Ann; Johnson, Delinda A; Johnson, Jeffrey A

2015-02-01

The presence of senile plaques is one of the major pathologic hallmarks of the brain with Alzheimer's disease (AD). The plaques predominantly contain insoluble amyloid β-peptide, a cleavage product of the larger amyloid precursor protein (APP). Two enzymes, named β and γ secretase, generate the neurotoxic amyloid-β peptide from APP. Mature APP is also turned over endogenously by autophagy, more specifically by the endosomal-lysosomal pathway. A defective lysosomal system is known to be pathogenic in AD. Modulation of NF-E2 related factor 2 (Nrf2) has been shown in several neurodegenerative disorders, and Nrf2 has become a potential therapeutic target for various neurodegenerative disorders, including AD, Parkinson's disease, and amyotrophic lateral sclerosis. In the current study, we explored the effect of genetic ablation of Nrf2 on APP/Aβ processing and/or aggregation as well as changes in autophagic dysfunction in APP/PS1 mice. There was a significant increase in inflammatory response in APP/PS1 mice lacking Nrf2. This was accompanied by increased intracellular levels of APP, Aβ (1-42), and Aβ (1-40), without a change total full-length APP. There was a shift of APP and Aβ into the insoluble fraction, as well as increased poly-ubiquitin conjugated proteins in mice lacking Nrf2. APP/PS1-mediated autophagic dysfunction is also enhanced in Nrf2-deficient mice. Finally, neurons in the APP/PS1/Nrf2-/- mice had increased accumulation of multivesicular bodies, endosomes, and lysosomes. These outcomes provide a better understanding of the role of Nrf2 in modulating autophagy in an AD mouse model and may help design better Nrf2 targeted therapeutics that could be efficacious in the treatment of AD. Published by Elsevier Inc.

Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer.

PubMed

Lawler, Mark; Alsina, Deborah; Adams, Richard A; Anderson, Annie S; Brown, Gina; Fearnhead, Nicola S; Fenwick, Stephen W; Halloran, Stephen P; Hochhauser, Daniel; Hull, Mark A; Koelzer, Viktor H; McNair, Angus G K; Monahan, Kevin J; Näthke, Inke; Norton, Christine; Novelli, Marco R; Steele, Robert J C; Thomas, Anne L; Wilde, Lisa M; Wilson, Richard H; Tomlinson, Ian

2018-01-01

Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes. RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants. Fifteen critical RGs are summarised below: RG1 : Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment; RG2 : Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk; RG3 : Pressing need for prevention trials; RG4 : Lack of integration of different prevention approaches; RG5 : Lack of optimal strategies for CRC screening; RG6 : Lack of effective triage systems for invasive investigations; RG7 : Imprecise pathological assessment of CRC; RG8 : Lack of qualified personnel in genomics, data sciences and digital pathology; RG9 : Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices; RG10 : Need for novel technologies/interventions to improve curative outcomes; RG11 : Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment; RG12 : Lack of reliable biomarkers to guide stage IV treatment; RG13 : Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution; RG14 : Lack of coordination of CRC research/funding; RG15 : Lack of effective communication between relevant stakeholders. Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Critical research gaps and recommendations to inform research prioritisation for more effective prevention and improved outcomes in colorectal cancer

PubMed Central

Lawler, Mark; Alsina, Deborah; Adams, Richard A; Anderson, Annie S; Brown, Gina; Fearnhead, Nicola S; Fenwick, Stephen W; Hochhauser, Daniel; Koelzer, Viktor H; McNair, Angus G K; Norton, Christine; Novelli, Marco R; Steele, Robert J C; Thomas, Anne L; Wilde, Lisa M; Wilson, Richard H

2018-01-01

Objective Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes. Design RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science; risk; prevention; early diagnosis and screening; pathology; curative treatment; stage IV disease; and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants. Results Fifteen critical RGs are summarised below: RG1: Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment; RG2: Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk; RG3: Pressing need for prevention trials; RG4: Lack of integration of different prevention approaches; RG5: Lack of optimal strategies for CRC screening; RG6: Lack of effective triage systems for invasive investigations; RG7: Imprecise pathological assessment of CRC; RG8: Lack of qualified personnel in genomics, data sciences and digital pathology; RG9: Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices; RG10: Need for novel technologies/interventions to improve curative outcomes; RG11: Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment; RG12: Lack of reliable biomarkers to guide stage IV treatment; RG13: Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution; RG14: Lack of coordination of CRC research/funding; RG15: Lack of effective communication between relevant stakeholders. Conclusion Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years. PMID:29233930

Risk Factors for Pneumococcal Colonization of the Nasopharynx in Alaska Native Adults and Children.

PubMed

Reisman, Jonathan; Rudolph, Karen; Bruden, Dana; Hurlburt, Debby; Bruce, Michael G; Hennessy, Thomas

2014-06-01

Alaska Native children have high invasive pneumococcal disease (IPD) rates, and lack of in-home running water has been shown to have a significant association with infection. Pneumococcal conjugate vaccines reduced IPD; however, this population saw substantial replacement disease and colonization with nonvaccine serotypes. We evaluated risk factors for nasopharyngeal pneumococcal colonization in Alaska Native adults and children. We conducted annual surveys from 2008 through 2011 of residents of all ages in 8 rural Alaskan villages. Interviews were conducted, medical charts were reviewed, and nasopharyngeal swabs were cultured for Streptococcus pneumoniae. Multivariate logistic regression models were developed for 3 age groups (under 10 years, 10-17 years, and 18 years and older) to determine risk factors for colonization. We obtained 12 535 nasopharyngeal swabs from 4980 participants. Our population lived in severely crowded conditions, and 48% of households lacked in-home running water. In children <10 years, colonization was associated with lack of in-home running water, household crowding, and more children in the home. Pneumococcal vaccination status was not associated with colonization. In older children and adults, increased number of persons in the household was associated with pneumococcal colonization. Higher colonization prevalence may partially explain increased IPD rates seen in those lacking in-home water services. Improving availability of sanitation services and reducing household crowding may reduce the burden of IPD in this population. © The Author 2013. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The use of personal data from medical records and biological materials: ethical perspectives and the basis for legal restrictions in health research.

PubMed

Regidor, Enrique

2004-11-01

This paper discusses the moral justification for using personal data without informed consent, from both medical records and biological materials, in research where subjects are not physically present in the study and will never have any contact with the study investigators. Although the idea of waiving the requirement for informed consent in certain investigations has been mentioned in several ethical guidelines formulated by epidemiologists and physicians since the late 1980s, these guidelines are now of limited use due to legal restrictions on the use of personal data in most western countries. Several misconceptions that form the basis for legal restriction of health research are discussed: lack of knowledge of the need to link personal information from health services with personal information produced outside the health system in many biomedical investigations; the assumption of a deterministic model of disease causation in which the prediction of disease occurrence is based on a genetic association despite the fact that most genotypes for common diseases are incompletely penetrant; the lack of a logical rationale for the recommendation in the Declaration of Helsinki that only research that offers some benefit to study subjects is justified; the great lack of knowledge about research methodology revealed in some alternatives proposed to avoid using personal data; and the lack of a debate about the ethical double standard of institutions and investigators in countries that prohibit the use of personal data but finance and carry out studies in other countries where it is permitted.

Translational research in brain metastasis is identifying molecular pathways that may lead to the development of new therapeutic strategies

PubMed Central

Gril, Brunilde; Evans, Lynda; Palmieri, Diane; Steeg, Patricia S.

2010-01-01

Central nervous system (CNS) or brain metastasis is an emerging area of interest in organ-specific metastasis research. Lung and breast cancers are the most common types of primary tumors to develop brain metastases. This disease complication contributes significantly to the morbidity and mortality of both of these common cancers; as such, brain metastasis is designated an unmet medical need by the US Food and Drug Administration. Recently, an increase in incidence of CNS disease has been noted in the literature for breast cancer, while it has been an ongoing major complication from lung cancer. Progress in treating brain metastases has been hampered by a lack of model systems, a lack of human tissue samples, and the exclusion of brain metastatic patients from many clinical trials. While each of those is significant, the major impediment to effectively treating brain metastatic disease is the blood–brain barrier (BBB). This barrier excludes most chemotherapeutics from the brain and creates a sanctuary site for metastatic tumors. Recent findings on the biology of this disease and translational leads identified by molecular studies are discussed in this article. PMID:20303257

Translational research in brain metastasis is identifying molecular pathways that may lead to the development of new therapeutic strategies.

PubMed

Gril, Brunilde; Evans, Lynda; Palmieri, Diane; Steeg, Patricia S

2010-05-01

Central nervous system (CNS) or brain metastasis is an emerging area of interest in organ-specific metastasis research. Lung and breast cancers are the most common types of primary tumors to develop brain metastases. This disease complication contributes significantly to the morbidity and mortality of both of these common cancers; as such, brain metastasis is designated an unmet medical need by the US Food and Drug Administration (FDA). Recently, an increase in incidence of CNS disease has been noted in the literature for breast cancer, while it has been an ongoing major complication from lung cancer. Progress in treating brain metastases has been hampered by a lack of model systems, a lack of human tissue samples, and the exclusion of brain metastatic patients from many clinical trials. While each of those is significant, the major impediment to effectively treating brain metastatic disease is the blood-brain barrier (BBB). This barrier excludes most chemotherapeutics from the brain and creates a sanctuary site for metastatic tumors. Recent findings on the biology of this disease and translational leads identified by molecular studies are discussed in this article. Published by Elsevier Ltd.

Factors influencing integrated wellbeing in older Chinese outpatients with chronic diseases.

PubMed

Huang, Fei; Li, Hongyu

2018-03-16

To evaluate wellbeing and its determinants among older Chinese outpatients with non-communicable diseases (NCDs), outpatients (aged ≥60 years) with NCDs between September 2012 and September 2014 were enrolled in the study by convenience sampling. Each subject completed an integrated wellbeing questionnaire for subjective, psychological and social dimensions of wellbeing. Statistical analyses were performed using t-test, ANOVA, Spearman rank correlation and multivariate regression analysis to identify correlates of wellbeing status. The average integrated wellbeing score was 52.57 out of 98, with maximum of 72. Educational background and monthly income were positively associated with wellbeing (Spearman r=0.226 and 0.394 respectively; all P<0.001). The number of co-morbid conditions and the disease duration showed a negative correlation with wellbeing (Spearman r=-0.373 and -0.538 respectively; all P<0.001). Lack of access to health insurance, being single and presence of complications were associated with lower wellbeing (all P≤0.001). As the first study using an integrated wellbeing model, the results suggested wellbeing promotion among older outpatients with chronic diseases, especially those with lower income, lower education level, those who lack health insurance, single individuals, those with co-morbid conditions, longer disease duration and those with complications.

Non-invasive quantification of hemodynamics in human choriocapillaries

NASA Astrophysics Data System (ADS)

Yu, Huidan (Whitney); Chen, Rou; An, Senyou; McDonough, James; Gelfand, Bradley; Yao, Jun

2016-11-01

The development of retinal disease is inextricably linked to defects in the choroidal blood supply. However, to date a description of the hemodynamics in the human choroidal circulation is lacking. Through high resolution choroidal vascular network mapped from immunofluorescent labeling and confocal microscopy of human cadaver donor eyes. We noninvasively quantify hemodynamics including velocity, pressure, and wall-shear stress (WSS) in choriocapillaries through mesoscale modeling and GPU-accelerated fast computation. This is the first-ever map of hemodynamic parameters (WSS, pressure, and velocity) in anatomically accurate human choroidal vasculature in health and disease. The pore scale simulation results are used to evaluate porous media models with the same porosity and boundary conditions. School of Medicine, Indiana University.

Endothelial Dysfunction and Diabetes: Effects on Angiogenesis, Vascular Remodeling, and Wound Healing

PubMed Central

Kolluru, Gopi Krishna; Bir, Shyamal C.; Kevil, Christopher G.

2012-01-01

Diabetes mellitus (DM) is a chronic metabolic disorder characterized by inappropriate hyperglycemia due to lack of or resistance to insulin. Patients with DM are frequently afflicted with ischemic vascular disease or wound healing defect. It is well known that type 2 DM causes amplification of the atherosclerotic process, endothelial cell dysfunction, glycosylation of extracellular matrix proteins, and vascular denervation. These complications ultimately lead to impairment of neovascularization and diabetic wound healing. Therapeutic angiogenesis remains an attractive treatment modality for chronic ischemic disorders including PAD and/or diabetic wound healing. Many experimental studies have identified better approaches for diabetic cardiovascular complications, however, successful clinical translation has been limited possibly due to the narrow therapeutic targets of these agents or the lack of rigorous evaluation of pathology and therapeutic mechanisms in experimental models of disease. This paper discusses the current body of evidence identifying endothelial dysfunction and impaired angiogenesis during diabetes. PMID:22611498

The value of animal to study immunopathology of primary human Sjögren's syndrome symptoms

PubMed Central

Donate, Amy; Voigt, Alexandria; Nguyen, Cuong Q.

2018-01-01

Sjögren’s syndrome (SjS) is a complex chronic autoimmune disease of multifactorial etiology that results in eventual loss of secretory function in the exocrine glands. The challenges towards finding a therapeutic prevention or treatment for SjS are due primarily to a lack of understanding in the pathophysiological and clinical progression of the disease. In order to circumnavigate this problem, there is a need for appropriate animal models that resemble the major phenotypes of human SjS and deliver a clear underlying biological or molecular mechanism capable of defining various aspects for the disease. Here, we present an overview of SjS mouse models that are providing insight into the autoimmune process of SjS and advance our focus on potential diagnostic and therapeutic targets. PMID:24506531

Modeling of Wildlife-Associated Zoonoses: Applications and Caveats

PubMed Central

Lewis, Bryan L.; Marathe, Madhav; Eubank, Stephen; Blackburn, Jason K.

2012-01-01

Abstract Wildlife species are identified as an important source of emerging zoonotic disease. Accordingly, public health programs have attempted to expand in scope to include a greater focus on wildlife and its role in zoonotic disease outbreaks. Zoonotic disease transmission dynamics involving wildlife are complex and nonlinear, presenting a number of challenges. First, empirical characterization of wildlife host species and pathogen systems are often lacking, and insight into one system may have little application to another involving the same host species and pathogen. Pathogen transmission characterization is difficult due to the changing nature of population size and density associated with wildlife hosts. Infectious disease itself may influence wildlife population demographics through compensatory responses that may evolve, such as decreased age to reproduction. Furthermore, wildlife reservoir dynamics can be complex, involving various host species and populations that may vary in their contribution to pathogen transmission and persistence over space and time. Mathematical models can provide an important tool to engage these complex systems, and there is an urgent need for increased computational focus on the coupled dynamics that underlie pathogen spillover at the human–wildlife interface. Often, however, scientists conducting empirical studies on emerging zoonotic disease do not have the necessary skill base to choose, develop, and apply models to evaluate these complex systems. How do modeling frameworks differ and what considerations are important when applying modeling tools to the study of zoonotic disease? Using zoonotic disease examples, we provide an overview of several common approaches and general considerations important in the modeling of wildlife-associated zoonoses. PMID:23199265

Mouse models to study the effect of cardiovascular risk factors on brain structure and cognition

PubMed Central

Bink, Diewertje I; Ritz, Katja; Aronica, Eleonora; van der Weerd, Louise; Daemen, Mat JAP

2013-01-01

Recent clinical data indicates that hemodynamic changes caused by cardiovascular diseases such as atherosclerosis, heart failure, and hypertension affect cognition. Yet, the underlying mechanisms of the resulting vascular cognitive impairment (VCI) are poorly understood. One reason for the lack of mechanistic insights in VCI is that research in dementia primarily focused on Alzheimer's disease models. To fill in this gap, we critically reviewed the published data and various models of VCI. Typical findings in VCI include reduced cerebral perfusion, blood–brain barrier alterations, white matter lesions, and cognitive deficits, which have also been reported in different cardiovascular mouse models. However, the tests performed are incomplete and differ between models, hampering a direct comparison between models and studies. Nevertheless, from the currently available data we conclude that a few existing surgical animal models show the key features of vascular cognitive decline, with the bilateral common carotid artery stenosis hypoperfusion mouse model as the most promising model. The transverse aortic constriction and myocardial infarction models may be good alternatives, but these models are as yet less characterized regarding the possible cerebral changes. Mixed models could be used to study the combined effects of different cardiovascular diseases on the deterioration of cognition during aging. PMID:23963364

Cardiovascular Disease Risk Varies by Birth Month in Canines.

PubMed

Boland, Mary Regina; Kraus, Marc S; Dziuk, Eddie; Gelzer, Anna R

2018-05-17

The canine heart is a robust physiological model for the human heart. Recently, birth month associations have been reported and replicated in humans using clinical health records. While animals respond readily to their environment in the wild, a systematic investigation of birth season dependencies among pets and specifically canines remains lacking. We obtained data from the Orthopedic Foundation of Animals on 129,778 canines representing 253 distinct breeds. Among canines that were not predisposed to cardiovascular disease, a clear birth season relationship is observed with peak risk occurring in June-August. Our findings indicate that acquired cardiovascular disease among canines, especially those that are not predisposed to cardiovascular disease, appears birth season dependent. The relative risk of cardiovascular disease for canines not predisposed to cardiovascular disease was as high as 1.47 among July pups. The overall adjusted odds ratio, when mixed breeds were excluded, for the birth season effect was 1.02 (95% CI: 1.002, 1.047, p = 0.032) after adjusting for breed and genetic cardiovascular predisposition effects. Studying birth season effects in model organisms can help to elucidate potential mechanisms behind the reported associations.

Iron overload cardiomyopathy: from diagnosis to management.

PubMed

Díez-López, Carles; Comín-Colet, Josep; González-Costello, José

2018-05-01

Iron overload cardiomyopathy (IOC) is an important predictor of prognosis in a significant number of patients with hereditary hemochromatosis and hematologic diseases. Its prevalence is increasing because of improved treatment strategies, which significantly improve life expectancy. We will review diagnosis, treatment, and recent findings in the field. The development of preclinical translational disease models during the last years have helped our understanding of specific disease pathophysiological pathways that might eventually change the outcomes of these patients. IOC is an overlooked disease because of the progressive silent disease pattern and the lack of physicians' expertise. It mainly affects patients with hemochromatosis and hematologic diseases and its prevalence is expected to increase with the improvement in life expectancy of hematologic disorders. Early diagnosis of IOC in patients at risk by means of biochemical parameters and cardiac imaging can lead to early treatment and improved prognosis. The mainstay of treatment of IOC is conventional heart failure treatment, combined with phlebotomies or iron chelation in the context of anemia. The development of preclinical models has provided a comprehensive look into specific pathophysiological pathways with potential treatment strategies that must be sustained by future randomized trials.

Pets, Purity and Pollution: Why Conventional Models of Disease Transmission Do Not Work for Pet Rat Owners.

PubMed

Robin, Charlotte; Perkins, Elizabeth; Watkins, Francine; Christley, Robert

2017-12-07

In the United Kingdom, following the emergence of Seoul hantavirus in pet rat owners in 2012, public health authorities tried to communicate the risk of this zoonotic disease, but had limited success. To explore this lack of engagement with health advice, we conducted in-depth, semi-structured interviews with pet rat owners and analysed them using a grounded theory approach. The findings from these interviews suggest that rat owners construct their pets as different from wild rats, and by elevating the rat to the status of a pet, the powerful associations that rats have with dirt and disease are removed. Removing the rat from the contaminated outside world moves their pet rat from being 'out of place' to 'in place'. A concept of 'bounded purity' keeps the rat protected within the home, allowing owners to interact with their pet, safe in the knowledge that it is clean and disease-free. Additionally, owners constructed a 'hierarchy of purity' for their pets, and it is on this structure of disease and risk that owners base their behaviour, not conventional biomedical models of disease.

Evaluation of the Centers for Disease Control and Prevention's chronic disease state-based epidemiology for public health program support (STEPPS) program.

PubMed

Frey, Catherine A; Remington, Patrick L; Lengerich, Eugene

2003-01-01

To identify effective strategies for improving epidemiology capacity in state chronic disease programs, staff epidemiologists and program directors from 25 states were interviewed using a structured questionnaire by phone or in person. Respondents reported three chief barriers to chronic disease epidemiology capacity: lack of institutional commitment and support for chronic disease epidemiology; lack of professional opportunities to engage with peers, colleagues, and scientists; and lack of trained epidemiology staff and resources to support chronic disease functions and activities. Epidemiology capacity in states would be improved by expanding the role and scope of staff placement programs; assisting states in establishing formal collaborations with academic institutions; and providing technical assistance to staff currently employed in states through training, consultation, and networking.

Herd immunity acquired indirectly from interactions between the ecology of infectious diseases, demography and economics

PubMed Central

Bonds, Matthew H.; Rohani, Pejman

2010-01-01

Patterns of morbidity and mortality around the globe are determined by interactions between infectious diseases and systematic human socioeconomic processes. The most obvious of these patterns is that the greatest burdens of infectious diseases are found among the poor, who lack the basic resources for disease prevention and treatment. Yet, it is becoming increasingly clear that many infectious diseases are themselves causes of poverty owing to their effects on labour productivity. A particularly subtle phenomenon that receives little attention in the epidemiology literature and is especially important for poor communities is the role of the birth rate as an important direct cause of high disease burdens. Because of their high rates of transmission and life-long immunity, the persistence of many child diseases such as measles relies on high rates of reproduction as their source of susceptible individuals. Thus, there are significant direct health benefits of lower fertility rates, which are further enhanced by interactions with economic processes. Indeed, fertility, poverty and disease all interact with each other in important and predictable ways that can be built into traditional disease ecology models. We present such a model here that provides insights into the long-term effect of policy interventions. For example, because of indirect income effects, herd immunity may be acquired with lower vaccine coverage than previously thought. Reductions in the disease burden can also occur through lower fertility. Our model thus provides a disease ecology framework that is useful for the analysis of demographic transitions. PMID:19740924

Cannabidiol Reverses Deficits in Hippocampal LTP in a Model of Alzheimer's Disease.

PubMed

Hughes, Blathnaid; Herron, Caroline E

2018-03-24

Here we demonstrate for the first time that cannabidiol (CBD) acts to protect synaptic plasticity in an in vitro model of Alzheimer's disease (AD). The non-psycho active component of Cannabis sativa, CBD has previously been shown to protect against the neurotoxic effects of beta amyloid peptide (Aβ) in cell culture and cognitive behavioural models of neurodegeneration. Hippocampal long-term potentiation (LTP) is an activity dependent increase in synaptic efficacy often used to study cellular mechanisms related to memory. Here we show that acute application of soluble oligomeric beta amyloid peptide (Aβ 1-42 ) associated with AD, attenuates LTP in the CA 1 region of hippocampal slices from C57Bl/6 mice. Application of CBD alone did not alter LTP, however pre-treatment of slices with CBD rescued the Aβ 1-42 mediated deficit in LTP. We found that the neuroprotective effects of CBD were not reversed by WAY100635, ZM241385 or AM251, demonstrating a lack of involvement of 5HT 1A , adenosine (A 2A ) or Cannabinoid type 1 (CB 1 ) receptors respectively. However in the presence of the PPARγ antagonist GW9662 the neuroprotective effect of CBD was prevented. Our data suggests that this major component of Cannabis sativa, which lacks psychoactivity may have therapeutic potential for the treatment of AD.

Antibody-dependent enhancement of severe dengue disease in humans*

PubMed Central

Katzelnick, Leah C.; Gresh, Lionel; Halloran, M. Elizabeth; Mercado, Juan Carlos; Kuan, Guillermina; Gordon, Aubree; Balmaseda, Angel; Harris, Eva

2018-01-01

For dengue viruses (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such antibody-dependent enhancement (ADE) of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of pre-existing anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern. PMID:29097492

Toward unraveling the complexity of simple epithelial keratins in human disease.

PubMed

Omary, M Bishr; Ku, Nam-On; Strnad, Pavel; Hanada, Shinichiro

2009-07-01

Simple epithelial keratins (SEKs) are found primarily in single-layered simple epithelia and include keratin 7 (K7), K8, K18-K20, and K23. Genetically engineered mice that lack SEKs or overexpress mutant SEKs have helped illuminate several keratin functions and served as important disease models. Insight into the contribution of SEKs to human disease has indicated that K8 and K18 are the major constituents of Mallory-Denk bodies, hepatic inclusions associated with several liver diseases, and are essential for inclusion formation. Furthermore, mutations in the genes encoding K8, K18, and K19 predispose individuals to a variety of liver diseases. Hence, as we discuss here, the SEK cytoskeleton is involved in the orchestration of several important cellular functions and contributes to the pathogenesis of human liver disease.

Toward unraveling the complexity of simple epithelial keratins in human disease

PubMed Central

Omary, M. Bishr; Ku, Nam-On; Strnad, Pavel; Hanada, Shinichiro

2009-01-01

Simple epithelial keratins (SEKs) are found primarily in single-layered simple epithelia and include keratin 7 (K7), K8, K18–K20, and K23. Genetically engineered mice that lack SEKs or overexpress mutant SEKs have helped illuminate several keratin functions and served as important disease models. Insight into the contribution of SEKs to human disease has indicated that K8 and K18 are the major constituents of Mallory-Denk bodies, hepatic inclusions associated with several liver diseases, and are essential for inclusion formation. Furthermore, mutations in the genes encoding K8, K18, and K19 predispose individuals to a variety of liver diseases. Hence, as we discuss here, the SEK cytoskeleton is involved in the orchestration of several important cellular functions and contributes to the pathogenesis of human liver disease. PMID:19587454

Galleria mellonella larvae as an infection model for group A streptococcus

PubMed Central

Loh, Jacelyn MS; Adenwalla, Nazneen; Wiles, Siouxsie; Proft, Thomas

2013-01-01

Group A streptococcus is a strict human pathogen that can cause a wide range of diseases, such as tonsillitis, impetigo, necrotizing fasciitis, toxic shock, and acute rheumatic fever. Modeling human diseases in animals is complicated, and rapid, simple, and cost-effective in vivo models of GAS infection are clearly lacking. Recently, the use of non-mammalian models to model human disease is starting to re-attract attention. Galleria mellonella larvae, also known as wax worms, have been investigated for modeling a number of bacterial pathogens, and have been shown to be a useful model to study pathogenesis of the M3 serotype of GAS. In this study we provide further evidence of the validity of the wax worm model by testing different GAS M-types, as well as investigating the effect of bacterial growth phase and incubation temperature on GAS virulence in this model. In contrast to previous studies, we show that the M-protein, among others, is an important virulence factor that can be effectively modeled in the wax worm. We also highlight the need for a more in-depth investigation of the effects of experimental design and wax worm supply before we can properly vindicate the wax worm model for studying GAS pathogenesis. PMID:23652836

Use of ferrets for electrophysiologic monitoring of ion transport

PubMed Central

Kaza, Niroop; Raju, S. Vamsee; Cadillac, Joan M.; Trombley, John A.; Rasmussen, Lawrence; Tang, Liping; Dohm, Erik; Harrod, Kevin S.

2017-01-01

Limited success achieved in translating basic science discoveries into clinical applications for chronic airway diseases is attributed to differences in respiratory anatomy and physiology, poor approximation of pathologic processes, and lack of correlative clinical endpoints between humans and laboratory animal models. Here, we discuss advantages of using ferrets (Mustela putorus furo) as a model for improved understanding of human airway physiology and demonstrate assays for quantifying airway epithelial ion transport in vivo and ex vivo, and establish air-liquid interface cultures of ferret airway epithelial cells as a complementary in vitro model for mechanistic studies. We present data here that establishes the feasibility of measuring these human disease endpoints in ferrets. Briefly, potential difference across the nasal and the lower airway epithelium in ferrets could be consistently assessed, were highly reproducible, and responsive to experimental interventions. Additionally, ferret airway epithelial cells were amenable to primary cell culture methods for in vitro experiments as was the use of ferret tracheal explants as an ex vivo system for assessing ion transport. The feasibility of conducting multiple assessments of disease outcomes supports the adoption of ferrets as a highly relevant model for research in obstructive airway diseases. PMID:29077751

Use of ferrets for electrophysiologic monitoring of ion transport.

PubMed

Kaza, Niroop; Raju, S Vamsee; Cadillac, Joan M; Trombley, John A; Rasmussen, Lawrence; Tang, Liping; Dohm, Erik; Harrod, Kevin S; Rowe, Steven M

2017-01-01

Limited success achieved in translating basic science discoveries into clinical applications for chronic airway diseases is attributed to differences in respiratory anatomy and physiology, poor approximation of pathologic processes, and lack of correlative clinical endpoints between humans and laboratory animal models. Here, we discuss advantages of using ferrets (Mustela putorus furo) as a model for improved understanding of human airway physiology and demonstrate assays for quantifying airway epithelial ion transport in vivo and ex vivo, and establish air-liquid interface cultures of ferret airway epithelial cells as a complementary in vitro model for mechanistic studies. We present data here that establishes the feasibility of measuring these human disease endpoints in ferrets. Briefly, potential difference across the nasal and the lower airway epithelium in ferrets could be consistently assessed, were highly reproducible, and responsive to experimental interventions. Additionally, ferret airway epithelial cells were amenable to primary cell culture methods for in vitro experiments as was the use of ferret tracheal explants as an ex vivo system for assessing ion transport. The feasibility of conducting multiple assessments of disease outcomes supports the adoption of ferrets as a highly relevant model for research in obstructive airway diseases.

Texture analysis of pulmonary parenchymateous changes related to pulmonary thromboembolism in dogs - a novel approach using quantitative methods.

PubMed

Marschner, C B; Kokla, M; Amigo, J M; Rozanski, E A; Wiinberg, B; McEvoy, F J

2017-07-11

Diagnosis of pulmonary thromboembolism (PTE) in dogs relies on computed tomography pulmonary angiography (CTPA), but detailed interpretation of CTPA images is demanding for the radiologist and only large vessels may be evaluated. New approaches for better detection of smaller thrombi include dual energy computed tomography (DECT) as well as computer assisted diagnosis (CAD) techniques. The purpose of this study was to investigate the performance of quantitative texture analysis for detecting dogs with PTE using grey-level co-occurrence matrices (GLCM) and multivariate statistical classification analyses. CT images from healthy (n = 6) and diseased (n = 29) dogs with and without PTE confirmed on CTPA were segmented so that only tissue with CT numbers between -1024 and -250 Houndsfield Units (HU) was preserved. GLCM analysis and subsequent multivariate classification analyses were performed on texture parameters extracted from these images. Leave-one-dog-out cross validation and receiver operator characteristic (ROC) showed that the models generated from the texture analysis were able to predict healthy dogs with optimal levels of performance. Partial Least Square Discriminant Analysis (PLS-DA) obtained a sensitivity of 94% and a specificity of 96%, while Support Vector Machines (SVM) yielded a sensitivity of 99% and a specificity of 100%. The models, however, performed worse in classifying the type of disease in the diseased dog group: In diseased dogs with PTE sensitivities were 30% (PLS-DA) and 38% (SVM), and specificities were 80% (PLS-DA) and 89% (SVM). In diseased dogs without PTE the sensitivities of the models were 59% (PLS-DA) and 79% (SVM) and specificities were 79% (PLS-DA) and 82% (SVM). The results indicate that texture analysis of CTPA images using GLCM is an effective tool for distinguishing healthy from abnormal lung. Furthermore the texture of pulmonary parenchyma in dogs with PTE is altered, when compared to the texture of pulmonary parenchyma of healthy dogs. The models' poorer performance in classifying dogs within the diseased group, may be related to the low number of dogs compared to texture variables, a lack of balanced number of dogs within each group or a real lack of difference in the texture features among the diseased dogs.

Prognostic models for stable coronary artery disease based on electronic health record cohort of 102 023 patients.

PubMed

Rapsomaniki, Eleni; Shah, Anoop; Perel, Pablo; Denaxas, Spiros; George, Julie; Nicholas, Owen; Udumyan, Ruzan; Feder, Gene Solomon; Hingorani, Aroon D; Timmis, Adam; Smeeth, Liam; Hemingway, Harry

2014-04-01

The population with stable coronary artery disease (SCAD) is growing but validated models to guide their clinical management are lacking. We developed and validated prognostic models for all-cause mortality and non-fatal myocardial infarction (MI) or coronary death in SCAD. Models were developed in a linked electronic health records cohort of 102 023 SCAD patients from the CALIBER programme, with mean follow-up of 4.4 (SD 2.8) years during which 20 817 deaths and 8856 coronary outcomes were observed. The Kaplan-Meier 5-year risk was 20.6% (95% CI, 20.3, 20.9) for mortality and 9.7% (95% CI, 9.4, 9.9) for non-fatal MI or coronary death. The predictors in the models were age, sex, CAD diagnosis, deprivation, smoking, hypertension, diabetes, lipids, heart failure, peripheral arterial disease, atrial fibrillation, stroke, chronic kidney disease, chronic pulmonary disease, liver disease, cancer, depression, anxiety, heart rate, creatinine, white cell count, and haemoglobin. The models had good calibration and discrimination in internal (external) validation with C-index 0.811 (0.735) for all-cause mortality and 0.778 (0.718) for non-fatal MI or coronary death. Using these models to identify patients at high risk (defined by guidelines as 3% annual mortality) and support a management decision associated with hazard ratio 0.8 could save an additional 13-16 life years or 15-18 coronary event-free years per 1000 patients screened, compared with models with just age, sex, and deprivation. These validated prognostic models could be used in clinical practice to support risk stratification as recommended in clinical guidelines.

Multi-omics analysis of inflammatory bowel disease.

PubMed

Huang, Hu; Vangay, Pajau; McKinlay, Christopher E; Knights, Dan

2014-12-01

Crohn's disease and ulcerative colitis, known together as inflammatory bowel disease (IBD), are severe autoimmune disorders now causing gut inflammation and ulceration, among other symptoms, in up to 1 in 250 people worldwide. Incidence and prevalence of IBD have been increasing dramatically over the past several decades, although the causes for this increase are still unknown. IBD has both a complex genotype and a complex phenotype, and although it has received substantial attention from the medical research community over recent years, much of the etiology remains unexplained. Genome-wide association studies have identified a rich genetic signature of disease risk in patients with IBD, consisting of at least 163 genetic loci. Many of these loci contain genes directly involved in microbial handling, indicating that the genetic architecture of the disease has been driven by host-microbe interactions. In addition, systematic shifts in gut microbiome structure (enterotype) and function have been observed in patients with IBD. Furthermore, both the host genotype and enterotype are associated with aspects of the disease phenotype, including location of the disease. This provides strong evidence of interactions between host genotype and enterotype; however, there is a lack of published multi-omics data from IBD patients, and a lack of bioinformatics tools for modeling such systems. In this article we discuss, from a computational biologist's point of view, the potential benefits of and the challenges involved in designing and analyzing such multi-omics studies of IBD. Copyright © 2014 Elsevier B.V. All rights reserved.

The provision of generalist and specialist palliative care for patients with non-malignant respiratory disease in the North and Republic of Ireland: a qualitative study.

PubMed

Veigh, Clare Mc; Reid, Joanne; Larkin, Philip; Porter, Sam; Hudson, Peter

2017-07-11

Previous research and key guidelines have suggested potential models of palliative care for patients with COPD and interstitial lung disease. However, these recommendations are often not effectively implemented in clinical practice and are void of guidance regarding palliative care for patients with bronchiectasis, another form of non-malignant respiratory disease. The aim of this research was to explore generalist and specialist palliative care service provision for people with non-malignant respiratory disease in the North and Republic of Ireland. Qualitative study involving a convenience sample of 17 bereaved carers and 18 healthcare professionals recruited from 2 rural and 2 urban sites on the Island of Ireland. Data collection consisted of semi-structured interviews with carers of patients with COPD, interstitial lung disease or bronchiectasis who had died 3-18 months previously; and 4 focus groups with healthcare professionals. Data analysed using thematic analysis. Findings highlighted the lack of a clear model of holistic care delivery for patients with non-malignant respiratory disease and illuminated the varying levels of palliative care provision this client group experienced. Additionally, ambiguity amongst healthcare professionals regarding prognostication illuminated the importance of the provision of palliative care being based on patient need, not prognosis. This research developed a potential model of palliative care which may help healthcare professionals introduce palliative care, and specialist respiratory care, early in the disease trajectory of non-malignant respiratory disease, whilst also encouraging the involvement of specialist palliative care for complex symptom management. This research provides an important insight into a potential model of palliative care for people with non-malignant respiratory disease, inclusive of bronchiectasis. However, the feasibility of integrating this model into clinical practice requires further exploration.

A Guide for the Design of Pre-clinical Studies on Sex Differences in Metabolism.

PubMed

Mauvais-Jarvis, Franck; Arnold, Arthur P; Reue, Karen

2017-06-06

In animal models, the physiological systems involved in metabolic homeostasis exhibit a sex difference. Investigators often use male rodents because they show metabolic disease better than females. Thus, females are not used precisely because of an acknowledged sex difference that represents an opportunity to understand novel factors reducing metabolic disease more in one sex than the other. The National Institutes of Health (NIH) mandate to consider sex as a biological variable in preclinical research places new demands on investigators and peer reviewers who often lack expertise in model systems and experimental paradigms used in the study of sex differences. This Perspective discusses experimental design and interpretation in studies addressing the mechanisms of sex differences in metabolic homeostasis and disease, using animal models and cells. We also highlight current limitations in research tools and attitudes that threaten to delay progress in studies of sex differences in basic animal research. Copyright © 2017 Elsevier Inc. All rights reserved.

Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities.

PubMed

Seferovic, Maxim; Martín, Claudia Sánchez-San; Tardif, Suzette D; Rutherford, Julienne; Castro, Eumenia C C; Li, Tony; Hodara, Vida L; Parodi, Laura M; Giavedoni, Luis; Layne-Colon, Donna; Tamhankar, Manasi; Yagi, Shigeo; Martyn, Calla; Reyes, Kevin; Suter, Melissa A; Aagaard, Kjersti M; Chiu, Charles Y; Patterson, Jean L

2018-05-01

During its most recent outbreak across the Americas, Zika virus (ZIKV) was surprisingly shown to cause fetal loss and congenital malformations in acutely and chronically infected pregnant women. However, understanding the underlying pathogenesis of ZIKV congenital disease has been hampered by a lack of relevant in vivo experimental models. Here we present a candidate New World monkey model of ZIKV infection in pregnant marmosets that faithfully recapitulates human disease. ZIKV inoculation at the human-equivalent of early gestation caused an asymptomatic seroconversion, induction of type I/II interferon-associated genes and proinflammatory cytokines, and persistent viremia and viruria. Spontaneous pregnancy loss was observed 16-18 days post-infection, with extensive active placental viral replication and fetal neurocellular disorganization similar to that seen in humans. These findings underscore the key role of the placenta as a conduit for fetal infection, and demonstrate the utility of marmosets as a highly relevant model for studying congenital ZIKV disease and pregnancy loss.

Remote monitoring of the progression of primary pneumonic plague in Brown Norway rats in high-capacity, high-containment housing

PubMed Central

Coate, Eric A.; Kocsis, Andrew G.; Peters, Kristen N.; Anderson, Paul E.; Ellersieck, Mark R.; Fine, Deborah M.; Anderson, Deborah M.

2014-01-01

Development of new vaccines, diagnostics and therapeutics for biodefense or other relatively rare infectious diseases is hindered by the lack of naturally occurring human disease on which to conduct clinical trials of efficacy. To overcome this experimental gap, the U.S. Food and Drug Administration established the Animal Rule, in which efficacy testing in two well-characterized animal models that closely resemble human disease may be accepted in lieu of large scale clinical trials for diseases with limited natural human incidence. In this report, we evaluated the Brown Norway rat as a model for pneumonic plague and describe the natural history of clinical disease following inhalation exposure to Yersinia pestis. In high-capacity, high-containment housing, we monitored temperature, activity, heart rate and rhythm by capturing electronic impulses transmitted from abdominal telemeter implants. Using this system, we show that reduced activity and development of fever are sensitive indications of disease progression. Furthermore, we identified heart arrhythmias as contributing factors to the rapid progression to lethality following the fever response. Together these data validate the Brown Norway rat as an experimental model for human pneumonic plague and provide new insight that may ultimately lead to novel approaches in post-exposure treatment of this devastating infection. PMID:24719212

The healthy learner model for student chronic condition management--part I.

PubMed

Erickson, Cecelia DuPlessis; Splett, Patricia L; Mullett, Sara Stoltzfus; Heiman, Mary Bielski

2006-12-01

A significant number of children have chronic health conditions that interfere with normal activities, including school attendance and active participation in the learning process. Management of students' chronic conditions is complex and requires an integrated system. Models to improve chronic disease management have been developed for the medical system and public health. Programs that address specific chronic disease management or coordinate school health services have been implemented in schools. Lacking is a comprehensive, integrated model that links schools, students, parents, health care, and other community providers. The Healthy Learner Model for chronic condition management identifies seven elements for creating, implementing, and sustaining an efficient and effective, comprehensive community-based system for improving the management of chronic conditions for school children. It has provided the framework for successful chronic condition management in an urban school district and is proposed for replication in other districts and communities.

Modeling virus survival and transport in the subsurface

NASA Astrophysics Data System (ADS)

Yates, Marylynn V.; Yates, S. R.; Wagner, Jan; Gerba, Charles P.

1987-03-01

The significance of viruses as agents of waterborne disease in the United States is just beginning to be recognized. The ability to predict how far viruses can be transported and how long they can remain infective in soil and groundwater is desirable from the standpoint of planning the placement of sources of contamination so that they will not have an impact on drinking-water wells. This, in turn should have the effect of decreasing the number of waterborne disease outbreaks caused by viruses. This article reviews the factors that affect the survival and migration of viruses in soils and groundwater. It also discusses the efforts that have been made to mathematically model the movement of viruses in the subsurface, including the assumptions made by the modelers. At this time, it appears that modeling efforts are constrained by a lack of quantitative information on virus interactions with soil and fluid media, rather than on mathematical solution techniques.

A brucellosis disease control strategy for the Kakheti region of the country of Georgia: an agent-based model.

PubMed

Havas, K A; Boone, R B; Hill, A E; Salman, M D

2014-06-01

Brucellosis has been reported in livestock and humans in the country of Georgia with Brucella melitensis as the most common species causing disease. Georgia lacked sufficient data to assess effectiveness of the various potential control measures utilizing a reliable population-based simulation model of animal-to-human transmission of this infection. Therefore, an agent-based model was built using data from previous studies to evaluate the effect of an animal-level infection control programme on human incidence and sheep flock and cattle herd prevalence of brucellosis in the Kakheti region of Georgia. This model simulated the patterns of interaction of human-animal workers, sheep flocks and cattle herds with various infection control measures and returned population-based data. The model simulates the use of control measures needed for herd and flock prevalence to fall below 2%. As per the model output, shepherds had the greatest disease reduction as a result of the infection control programme. Cattle had the greatest influence on the incidence of human disease. Control strategies should include all susceptible animal species, sheep and cattle, identify the species of brucellosis present in the cattle population and should be conducted at the municipality level. This approach can be considered as a model to other countries and regions when assessment of control strategies is needed but data are scattered. © 2013 Blackwell Verlag GmbH.

The Cost-Effectiveness of Low-Cost Essential Antihypertensive Medicines for Hypertension Control in China: A Modelling Study.

PubMed

Gu, Dongfeng; He, Jiang; Coxson, Pamela G; Rasmussen, Petra W; Huang, Chen; Thanataveerat, Anusorn; Tzong, Keane Y; Xiong, Juyang; Wang, Miao; Zhao, Dong; Goldman, Lee; Moran, Andrew E

2015-08-01

Hypertension is China's leading cardiovascular disease risk factor. Improved hypertension control in China would result in result in enormous health gains in the world's largest population. A computer simulation model projected the cost-effectiveness of hypertension treatment in Chinese adults, assuming a range of essential medicines list drug costs. The Cardiovascular Disease Policy Model-China, a Markov-style computer simulation model, simulated hypertension screening, essential medicines program implementation, hypertension control program administration, drug treatment and monitoring costs, disease-related costs, and quality-adjusted life years (QALYs) gained by preventing cardiovascular disease or lost because of drug side effects in untreated hypertensive adults aged 35-84 y over 2015-2025. Cost-effectiveness was assessed in cardiovascular disease patients (secondary prevention) and for two blood pressure ranges in primary prevention (stage one, 140-159/90-99 mm Hg; stage two, ≥160/≥100 mm Hg). Treatment of isolated systolic hypertension and combined systolic and diastolic hypertension were modeled as a reduction in systolic blood pressure; treatment of isolated diastolic hypertension was modeled as a reduction in diastolic blood pressure. One-way and probabilistic sensitivity analyses explored ranges of antihypertensive drug effectiveness and costs, monitoring frequency, medication adherence, side effect severity, background hypertension prevalence, antihypertensive medication treatment, case fatality, incidence and prevalence, and cardiovascular disease treatment costs. Median antihypertensive costs from Shanghai and Yunnan province were entered into the model in order to estimate the effects of very low and high drug prices. Incremental cost-effectiveness ratios less than the per capita gross domestic product of China (11,900 international dollars [Int$] in 2015) were considered cost-effective. Treating hypertensive adults with prior cardiovascular disease for secondary prevention was projected to be cost saving in the main simulation and 100% of probabilistic simulation results. Treating all hypertension for primary and secondary prevention would prevent about 800,000 cardiovascular disease events annually (95% uncertainty interval, 0.6 to 1.0 million) and was borderline cost-effective incremental to treating only cardiovascular disease and stage two patients (2015 Int$13,000 per QALY gained [95% uncertainty interval, Int$10,000 to Int$18,000]). Of all one-way sensitivity analyses, assuming adherence to taking medications as low as 25%, high Shanghai drug costs, or low medication efficacy led to the most unfavorable results (treating all hypertension, about Int$47,000, Int$37,000, and Int$27,000 per QALY were gained, respectively). The strengths of this study were the use of a recent Chinese national health survey, vital statistics, health care costs, and cohort study outcomes data as model inputs and reliance on clinical-trial-based estimates of coronary heart disease and stroke risk reduction due to antihypertensive medication treatment. The limitations of the study were the use of several sources of data, limited clinical trial evidence for medication effectiveness and harms in the youngest and oldest age groups, lack of information about geographic and ethnic subgroups, lack of specific information about indirect costs borne by patients, and uncertainty about the future epidemiology of cardiovascular diseases in China. Expanded hypertension treatment has the potential to prevent about 800,000 cardiovascular disease events annually and be borderline cost-effective in China, provided low-cost essential antihypertensive medicines programs can be implemented.

Fatigue in employees with diabetes: its relation with work characteristics and diabetes related burden

PubMed Central

Weijman, I; Ros, W; Rutten, G; Schaufeli, W; Schabracq, M; Winnubst, J

2003-01-01

Aims: To examine the relations between work characteristics as defined by the Job Demand-Control-Support model (JDCS) (that is, job demands, decision latitude, and social support), diabetes related burden (symptoms, seriousness of disease, self care activities, and disease duration), and fatigue in employees with diabetes mellitus. Methods: Employees (n = 292) aged 30–60 years, with insulin treated diabetes, filled in self administered questionnaires that assess the above mentioned components of the JDCS model and diabetes related burdens. Results: Both work and diabetes related factors are related to fatigue in employees with diabetes. Regression analyses revealed that work characteristics explain 19.1% of the variance in fatigue; lack of support, and the interaction of job demands and job control contribute significantly. Diabetes related factors explain another 29.0% of the variance, with the focus on diabetes related symptoms and the burden of adjusting insulin dosage to circumstances. Fatigue is more severe in case of lack of social support at work, high job demands in combination with a lack of decision latitude, more burden of adjusting insulin dosage to circumstances, and more diabetic symptoms. Furthermore, regression analysis revealed that diabetic symptoms and the burden of adjusting the insulin dosage to circumstances are especially relevant in combination with high job demands. Conclusions: Both diabetes and work should be taken into consideration—by (occupational) physicians as well as supervisors—in the communication with people with diabetes. PMID:12782754

Highly dynamic animal contact network and implications on disease transmission

PubMed Central

Chen, Shi; White, Brad J.; Sanderson, Michael W.; Amrine, David E.; Ilany, Amiyaal; Lanzas, Cristina

2014-01-01

Contact patterns among hosts are considered as one of the most critical factors contributing to unequal pathogen transmission. Consequently, networks have been widely applied in infectious disease modeling. However most studies assume static network structure due to lack of accurate observation and appropriate analytic tools. In this study we used high temporal and spatial resolution animal position data to construct a high-resolution contact network relevant to infectious disease transmission. The animal contact network aggregated at hourly level was highly variable and dynamic within and between days, for both network structure (network degree distribution) and individual rank of degree distribution in the network (degree order). We integrated network degree distribution and degree order heterogeneities with a commonly used contact-based, directly transmitted disease model to quantify the effect of these two sources of heterogeneity on the infectious disease dynamics. Four conditions were simulated based on the combination of these two heterogeneities. Simulation results indicated that disease dynamics and individual contribution to new infections varied substantially among these four conditions under both parameter settings. Changes in the contact network had a greater effect on disease dynamics for pathogens with smaller basic reproduction number (i.e. R0 < 2). PMID:24667241

Modeling the natural history of Pelizaeus–Merzbacher disease

PubMed Central

Mayer, Joshua A.; Griffiths, Ian R.; Goldman, James E.; Smith, Chelsey M.; Cooksey, Elizabeth; Radcliff, Abigail B.; Duncan, Ian D.

2015-01-01

Major gaps in our understanding of the leukodystrophies result from their rarity and the lack of tissue for the interdisciplinary studies required to extend our knowledge of the pathophysiology of the diseases. This study details the natural evolution of changes in the CNS of the shaking pup (shp), a model of the classical form of the X-linked disorder Pelizaeus–Merzbacher disease, in particular in glia, myelin, and axons, which is likely representative of what occurs over time in the human disease. The mutation in the proteolipid protein gene, PLP1, leads to a delay in differentiation, increased cell death, and a marked distension of the rough endoplasmic reticulum in oligodendrocytes. However, over time, more oligodendrocytes differentiate and survive in the spinal cord leading to an almost total recovery of myelination, In contrast, the brain remains persistently hypomyelinated. These data suggest that shp oligodendrocytes may be more functional than previously realized and that their early recruitment could have therapeutic value. PMID:25562656

Disease Model Discovery from 3,328 Gene Knockouts by The International Mouse Phenotyping Consortium

PubMed Central

Meehan, Terrence F.; Conte, Nathalie; West, David B.; Jacobsen, Julius O.; Mason, Jeremy; Warren, Jonathan; Chen, Chao-Kung; Tudose, Ilinca; Relac, Mike; Matthews, Peter; Karp, Natasha; Santos, Luis; Fiegel, Tanja; Ring, Natalie; Westerberg, Henrik; Greenaway, Simon; Sneddon, Duncan; Morgan, Hugh; Codner, Gemma F; Stewart, Michelle E; Brown, James; Horner, Neil; Haendel, Melissa; Washington, Nicole; Mungall, Christopher J.; Reynolds, Corey L; Gallegos, Juan; Gailus-Durner, Valerie; Sorg, Tania; Pavlovic, Guillaume; Bower, Lynette R; Moore, Mark; Morse, Iva; Gao, Xiang; Tocchini-Valentini, Glauco P; Obata, Yuichi; Cho, Soo Young; Seong, Je Kyung; Seavitt, John; Beaudet, Arthur L.; Dickinson, Mary E.; Herault, Yann; Wurst, Wolfgang; de Angelis, Martin Hrabe; Lloyd, K.C. Kent; Flenniken, Ann M; Nutter, Lauryl MJ; Newbigging, Susan; McKerlie, Colin; Justice, Monica J.; Murray, Stephen A.; Svenson, Karen L.; Braun, Robert E.; White, Jacqueline K.; Bradley, Allan; Flicek, Paul; Wells, Sara; Skarnes, William C.; Adams, David J.; Parkinson, Helen; Mallon, Ann-Marie; Brown, Steve D.M.; Smedley, Damian

2017-01-01

Although next generation sequencing has revolutionised the ability to associate variants with human diseases, diagnostic rates and development of new therapies are still limited by our lack of knowledge of function and pathobiological mechanism for most genes. To address this challenge, the International Mouse Phenotyping Consortium (IMPC) is creating a genome- and phenome-wide catalogue of gene function by characterizing new knockout mouse strains across diverse biological systems through a broad set of standardised phenotyping tests, with all mice made readily available to the biomedical community. Analysing the first 3328 genes reveals models for 360 diseases including the first for type C Bernard-Soulier, Bardet-Biedl-5 and Gordon Holmes syndromes. 90% of our phenotype annotations are novel, providing the first functional evidence for 1092 genes and candidates in unsolved diseases such as Arrhythmogenic Right Ventricular Dysplasia 3. Finally, we describe our role in variant functional validation with the 100,000 Genomes and other projects. PMID:28650483

Preclinical immunogenicity and safety of a Group A streptococcal M protein-based vaccine candidate.

PubMed

Batzloff, Michael R; Fane, Anne; Gorton, Davina; Pandey, Manisha; Rivera-Hernandez, Tania; Calcutt, Ainslie; Yeung, Grace; Hartas, Jon; Johnson, Linda; Rush, Catherine M; McCarthy, James; Ketheesan, Natkunam; Good, Michael F

2016-12-01

Streptococcus pyogenes (group A streptococcus, GAS) causes a wide range of clinical manifestations ranging from mild self-limiting pyoderma to invasive diseases such as sepsis. Also of concern are the post-infectious immune-mediated diseases including rheumatic heart disease. The development of a vaccine against GAS would have a large health impact on populations at risk of these diseases. However, there is a lack of suitable models for the safety evaluation of vaccines with respect to post-infectious complications. We have utilized the Lewis Rat model for cardiac valvulitis to evaluate the safety of the J8-DT vaccine formulation in parallel with a rabbit toxicology study. These studies demonstrated that the vaccine did not induce abnormal pathology. We also show that in mice the vaccine is highly immunogenic but that 3 doses are required to induce protection from a GAS skin challenge even though 2 doses are sufficient to induce a high antibody titer.

Preclinical immunogenicity and safety of a Group A streptococcal M protein-based vaccine candidate

PubMed Central

Batzloff, Michael R.; Fane, Anne; Gorton, Davina; Pandey, Manisha; Rivera-Hernandez, Tania; Calcutt, Ainslie; Yeung, Grace; Hartas, Jon; Johnson, Linda; Rush, Catherine M.; McCarthy, James; Ketheesan, Natkunam; Good, Michael F.

2016-01-01

ABSTRACT Streptococcus pyogenes (group A streptococcus, GAS) causes a wide range of clinical manifestations ranging from mild self-limiting pyoderma to invasive diseases such as sepsis. Also of concern are the post-infectious immune-mediated diseases including rheumatic heart disease. The development of a vaccine against GAS would have a large health impact on populations at risk of these diseases. However, there is a lack of suitable models for the safety evaluation of vaccines with respect to post-infectious complications. We have utilized the Lewis Rat model for cardiac valvulitis to evaluate the safety of the J8-DT vaccine formulation in parallel with a rabbit toxicology study. These studies demonstrated that the vaccine did not induce abnormal pathology. We also show that in mice the vaccine is highly immunogenic but that 3 doses are required to induce protection from a GAS skin challenge even though 2 doses are sufficient to induce a high antibody titer. PMID:27541593

Need for Improved Methods to Collect and Present Spatial Epidemiologic Data for Vectorborne Diseases

PubMed Central

Eisen, Rebecca J.

2007-01-01

Improved methods for collection and presentation of spatial epidemiologic data are needed for vectorborne diseases in the United States. Lack of reliable data for probable pathogen exposure site has emerged as a major obstacle to the development of predictive spatial risk models. Although plague case investigations can serve as a model for how to ideally generate needed information, this comprehensive approach is cost-prohibitive for more common and less severe diseases. New methods are urgently needed to determine probable pathogen exposure sites that will yield reliable results while taking into account economic and time constraints of the public health system and attending physicians. Recent data demonstrate the need for a change from use of the county spatial unit for presentation of incidence of vectorborne diseases to more precise ZIP code or census tract scales. Such fine-scale spatial risk patterns can be communicated to the public and medical community through Web-mapping approaches. PMID:18258029

Reverse and Forward Translational Neuropharmacology in Psychiatric Drug Discovery.

PubMed

Shaffer, Christopher L

2018-02-01

The probability of achieving marketing approval of a novel therapeutic for psychiatric indications is extremely low due largely to the inability to demonstrate durable and reproducible efficacy in phase II trials and beyond. These failures are often attributed to the lack of translation of the underlying neuropharmacology from animal model(s) to the disease population. However, how assured is such a conclusion considering the clinical efficacy path rarely meticulously parallels the preclinical experiment(s) that underwrote it? © 2017 American Society for Clinical Pharmacology and Therapeutics.

Mesenchymal stromal cells: a novel therapy for the treatment of chronic obstructive pulmonary disease?

PubMed Central

Broekman, Winifred; Khedoe, Padmini P S J; Schepers, Koen; Roelofs, Helene; Stolk, Jan; Hiemstra, Pieter S

2018-01-01

COPD is characterised by tissue destruction and inflammation. Given the lack of curative treatments and the progressive nature of the disease, new treatments for COPD are highly relevant. In vitro cell culture and animal studies have demonstrated that mesenchymal stromal cells (MSCs) have the capacity to modify immune responses and to enhance tissue repair. These properties of MSCs provided a rationale to investigate their potential for treatment of a variety of diseases, including COPD. Preclinical models support the hypothesis that MSCs may have clinical efficacy in COPD. However, although clinical trials have demonstrated the safety of MSC treatment, thus far they have not provided evidence for MSC efficacy in the treatment of COPD. In this review, we discuss the rationale for MSC-based cell therapy in COPD, the main findings from in vitro and in vivo preclinical COPD model studies, clinical trials in patients with COPD and directions for further research. PMID:29653970

Financial and risk considerations for successful disease management programs.

PubMed

Baldwin, A L

1999-11-01

Results for disease management [DM] programs have not been as positive as hoped because of clinical issues, lack of access to capital, and administrative issues. The financial experience of DM programs can be quite volatile. Financial projections that are protocol-based, rather than experience-based, may understate the revenue required and the range of possible costs for a DM program by understating the impact of complicating conditions and comorbidities. Actuarial tools (risk analysis and risk projection models) support better understanding of DM contracts. In particular, these models can provide the ability to quantify the impact of the factors that drive costs of a contract and the volatility of those costs. This analysis can assist DM companies in setting appropriate revenue and capital targets. Similar analysis by health plans can identify diseases that are good candidates for DM programs and can provide the basis for performance targets.

Single Agent Polysaccharopeptide Delays Metastases and Improves Survival in Naturally Occurring Hemangiosarcoma

PubMed Central

Brown, Dorothy Cimino; Reetz, Jennifer

2012-01-01

The 2008 World Health Organization World Cancer Report describes global cancer incidence soaring with many patients living in countries that lack resources for cancer control. Alternative treatment strategies that can reduce the global disease burden at manageable costs must be developed. Polysaccharopeptide (PSP) is the bioactive agent from the mushroom Coriolus versicolor. Studies indicate PSP has in vitro antitumor activities and inhibits the growth of induced tumors in animal models. Clear evidence of clinically relevant benefits of PSP in cancer patients, however, is lacking. The investment of resources required to complete large-scale, randomized controlled trials of PSP in cancer patients is more easily justified if antitumor and survival benefits are documented in a complex animal model of a naturally occurring cancer that parallels human disease. Because of its high metastatic rate and vascular origin, canine hemangiosarcoma is used for investigations in antimetastatic and antiangiogenic therapies. In this double-blind randomized multidose pilot study, high-dose PSP significantly delayed the progression of metastases and afforded the longest survival times reported in canine hemangiosarcoma. These data suggest that, for those cancer patients for whom advanced treatments are not accessible, PSP as a single agent might offer significant improvements in morbidity and mortality. PMID:22988473

Absolute quantification of prion protein (90-231) using stable isotope-labeled chymotryptic peptide standards in a LC-MRM AQUA workflow.

PubMed

Sturm, Robert; Sheynkman, Gloria; Booth, Clarissa; Smith, Lloyd M; Pedersen, Joel A; Li, Lingjun

2012-09-01

Substantial evidence indicates that the disease-associated conformer of the prion protein (PrP(TSE)) constitutes the etiologic agent in prion diseases. These diseases affect multiple mammalian species. PrP(TSE) has the ability to convert the conformation of the normal prion protein (PrP(C)) into a β-sheet rich form resistant to proteinase K digestion. Common immunological techniques lack the sensitivity to detect PrP(TSE) at subfemtomole levels, whereas animal bioassays, cell culture, and in vitro conversion assays offer higher sensitivity but lack the high-throughput the immunological assays offer. Mass spectrometry is an attractive alternative to the above assays as it offers high-throughput, direct measurement of a protein's signature peptide, often with subfemtomole sensitivities. Although a liquid chromatography-multiple reaction monitoring (LC-MRM) method has been reported for PrP(TSE), the chemical composition and lack of amino acid sequence conservation of the signature peptide may compromise its accuracy and make it difficult to apply to multiple species. Here, we demonstrate that an alternative protease (chymotrypsin) can produce signature peptides suitable for a LC-MRM absolute quantification (AQUA) experiment. The new method offers several advantages, including: (1) a chymotryptic signature peptide lacking chemically active residues (Cys, Met) that can confound assay accuracy; (2) low attomole limits of detection and quantitation (LOD and LOQ); and (3) a signature peptide retaining the same amino acid sequence across most mammals naturally susceptible to prion infection as well as important laboratory models. To the authors' knowledge, this is the first report on the use of a non-tryptic peptide in a LC-MRM AQUA workflow.

Absolute quantification of prion protein (90-231) using stable isotope-labeled chymotryptic peptide standards in a LC-MRM AQUA workflow

PubMed Central

Sturm, Robert; Kreitinger, Gloria; Booth, Clarissa; Smith, Lloyd; Pedersen, Joel; Li, Lingjun

2012-01-01

Substantial evidence indicates that the disease-associated conformer of the prion protein (PrPTSE) constitutes the etiological agent in prion diseases. These diseases affect multiple mammalian species. PrPTSE has the ability to convert the conformation of the normal prion protein (PrPC) into a β-sheet rich form resistant to proteinase K digestion. Common immunological techniques lack the sensitivity to detect PrPTSE at sub-femtomole levels while animal bioassays, cell culture, and in vitro conversion assays offer ultrasensitivity but lack the high-throughput the immunological assays offer. Mass spectrometry is an attractive alternative to the above assays as it offers high-throughput, direct measurement of a protein’s signature peptide, often with sub-femtomole sensitivities. Although a liquid chromatography-multiple reaction monitoring (LC-MRM) method has been reported for PrPTSE, the chemical composition and lack of amino acid sequence conservation of the signature peptide may compromise its accuracy and make it difficult to apply to multiple species. Here, we demonstrate that an alternative protease (chymotrypsin) can produce signature peptides suitable for a LC-MRM absolute quantification (AQUA) experiment. The new method offers several advantages, including: (1) a chymotryptic signature peptide lacking chemically active residues (Cys, Met) that can confound assay accuracy; (2) low attomole limits of detection and quantitation (LOD and LOQ); and (3) a signature peptide retaining the same amino acid sequence across most mammals naturally susceptible to prion infection as well as important laboratory models. To the authors’ knowledge, this is the first report of the use of a non-tryptic peptide in a LC-MRM AQUA workflow. PMID:22714949

Absolute Quantification of Prion Protein (90-231) Using Stable Isotope-Labeled Chymotryptic Peptide Standards in a LC-MRM AQUA Workflow

NASA Astrophysics Data System (ADS)

Sturm, Robert; Sheynkman, Gloria; Booth, Clarissa; Smith, Lloyd M.; Pedersen, Joel A.; Li, Lingjun

2012-09-01

Substantial evidence indicates that the disease-associated conformer of the prion protein (PrPTSE) constitutes the etiologic agent in prion diseases. These diseases affect multiple mammalian species. PrPTSE has the ability to convert the conformation of the normal prion protein (PrPC) into a β-sheet rich form resistant to proteinase K digestion. Common immunological techniques lack the sensitivity to detect PrPTSE at subfemtomole levels, whereas animal bioassays, cell culture, and in vitro conversion assays offer higher sensitivity but lack the high-throughput the immunological assays offer. Mass spectrometry is an attractive alternative to the above assays as it offers high-throughput, direct measurement of a protein's signature peptide, often with subfemtomole sensitivities. Although a liquid chromatography-multiple reaction monitoring (LC-MRM) method has been reported for PrPTSE, the chemical composition and lack of amino acid sequence conservation of the signature peptide may compromise its accuracy and make it difficult to apply to multiple species. Here, we demonstrate that an alternative protease (chymotrypsin) can produce signature peptides suitable for a LC-MRM absolute quantification (AQUA) experiment. The new method offers several advantages, including: (1) a chymotryptic signature peptide lacking chemically active residues (Cys, Met) that can confound assay accuracy; (2) low attomole limits of detection and quantitation (LOD and LOQ); and (3) a signature peptide retaining the same amino acid sequence across most mammals naturally susceptible to prion infection as well as important laboratory models. To the authors' knowledge, this is the first report on the use of a non-tryptic peptide in a LC-MRM AQUA workflow.

Cigarette Smoke Attenuates the Nasal Host Response to Streptococcus pneumoniae and Predisposes to Invasive Pneumococcal Disease in Mice

PubMed Central

Shen, Pamela; Morissette, Mathieu C.; Vanderstocken, Gilles; Gao, Yang; Hassan, Muhammad; Roos, Abraham; Thayaparan, Danya; Merlano, Maria; Dorrington, Michael G.; Nikota, Jake K.; Bauer, Carla M. T.; Kwiecien, Jacek M.; Labiris, Renee; Bowdish, Dawn M. E.; Stevenson, Christopher S.

2016-01-01

Streptococcus pneumoniae is a leading cause of invasive bacterial infections, with nasal colonization an important first step in disease. While cigarette smoking is a strong risk factor for invasive pneumococcal disease, the underlying mechanisms remain unknown. This is partly due to a lack of clinically relevant animal models investigating nasal pneumococcal colonization in the context of cigarette smoke exposure. We present a model of nasal pneumococcal colonization in cigarette smoke-exposed mice and document, for the first time, that cigarette smoke predisposes to invasive pneumococcal infection and mortality in an animal model. Cigarette smoke increased the risk of bacteremia and meningitis without prior lung infection. Mechanistically, deficiency in interleukin 1α (IL-1α) or platelet-activating factor receptor (PAFR), an important host receptor thought to bind and facilitate pneumococcal invasiveness, did not rescue cigarette smoke-exposed mice from invasive pneumococcal disease. Importantly, we observed cigarette smoke to attenuate nasal inflammatory mediator expression, particularly that of neutrophil-recruiting chemokines, normally elicited by pneumococcal colonization. Smoking cessation during nasal pneumococcal colonization rescued nasal neutrophil recruitment and prevented invasive disease in mice. We propose that cigarette smoke predisposes to invasive pneumococcal disease by suppressing inflammatory processes of the upper respiratory tract. Given that smoking prevalence remains high worldwide, these findings are relevant to the continued efforts to reduce the invasive pneumococcal disease burden. PMID:26930709

Report on the Symposium “Molecular Mechanisms Involved in Neurodegeneration”

PubMed Central

Pentón-Rol, Giselle; Cervantes-Llanos, Majel

2018-01-01

The prevalence of neurodegenerative diseases is currently a major concern in public health because of the lack of neuroprotective and neuroregenerative drugs. The symposium on Molecular Mechanisms Involved in Neurodegeneration held in Varadero, Cuba, updated the participants on the basic mechanisms of neurodegeneration, on the different approaches for drug discovery, and on early research results on therapeutic approaches for the treatment of neurodegenerative diseases. Alzheimer’s disease and in silico research were covered by many of the presentations in the symposium, under the umbrella of the “State of the Art of Non-clinical Models for Neurodegenerative Diseases” International Congress, held from 20 to 24 June 2017. This paper summarizes the highlights of the symposium. PMID:29346273

H2RM: A Hybrid Rough Set Reasoning Model for Prediction and Management of Diabetes Mellitus.

PubMed

Ali, Rahman; Hussain, Jamil; Siddiqi, Muhammad Hameed; Hussain, Maqbool; Lee, Sungyoung

2015-07-03

Diabetes is a chronic disease characterized by high blood glucose level that results either from a deficiency of insulin produced by the body, or the body's resistance to the effects of insulin. Accurate and precise reasoning and prediction models greatly help physicians to improve diagnosis, prognosis and treatment procedures of different diseases. Though numerous models have been proposed to solve issues of diagnosis and management of diabetes, they have the following drawbacks: (1) restricted one type of diabetes; (2) lack understandability and explanatory power of the techniques and decision; (3) limited either to prediction purpose or management over the structured contents; and (4) lack competence for dimensionality and vagueness of patient's data. To overcome these issues, this paper proposes a novel hybrid rough set reasoning model (H2RM) that resolves problems of inaccurate prediction and management of type-1 diabetes mellitus (T1DM) and type-2 diabetes mellitus (T2DM). For verification of the proposed model, experimental data from fifty patients, acquired from a local hospital in semi-structured format, is used. First, the data is transformed into structured format and then used for mining prediction rules. Rough set theory (RST) based techniques and algorithms are used to mine the prediction rules. During the online execution phase of the model, these rules are used to predict T1DM and T2DM for new patients. Furthermore, the proposed model assists physicians to manage diabetes using knowledge extracted from online diabetes guidelines. Correlation-based trend analysis techniques are used to manage diabetic observations. Experimental results demonstrate that the proposed model outperforms the existing methods with 95.9% average and balanced accuracies.

H2RM: A Hybrid Rough Set Reasoning Model for Prediction and Management of Diabetes Mellitus

PubMed Central

Ali, Rahman; Hussain, Jamil; Siddiqi, Muhammad Hameed; Hussain, Maqbool; Lee, Sungyoung

2015-01-01

Diabetes is a chronic disease characterized by high blood glucose level that results either from a deficiency of insulin produced by the body, or the body’s resistance to the effects of insulin. Accurate and precise reasoning and prediction models greatly help physicians to improve diagnosis, prognosis and treatment procedures of different diseases. Though numerous models have been proposed to solve issues of diagnosis and management of diabetes, they have the following drawbacks: (1) restricted one type of diabetes; (2) lack understandability and explanatory power of the techniques and decision; (3) limited either to prediction purpose or management over the structured contents; and (4) lack competence for dimensionality and vagueness of patient’s data. To overcome these issues, this paper proposes a novel hybrid rough set reasoning model (H2RM) that resolves problems of inaccurate prediction and management of type-1 diabetes mellitus (T1DM) and type-2 diabetes mellitus (T2DM). For verification of the proposed model, experimental data from fifty patients, acquired from a local hospital in semi-structured format, is used. First, the data is transformed into structured format and then used for mining prediction rules. Rough set theory (RST) based techniques and algorithms are used to mine the prediction rules. During the online execution phase of the model, these rules are used to predict T1DM and T2DM for new patients. Furthermore, the proposed model assists physicians to manage diabetes using knowledge extracted from online diabetes guidelines. Correlation-based trend analysis techniques are used to manage diabetic observations. Experimental results demonstrate that the proposed model outperforms the existing methods with 95.9% average and balanced accuracies. PMID:26151207

The immunomodulating V and W proteins of Nipah virus determine disease course.

PubMed

Satterfield, Benjamin A; Cross, Robert W; Fenton, Karla A; Agans, Krystle N; Basler, Christopher F; Geisbert, Thomas W; Mire, Chad E

2015-06-24

The viral determinants that contribute to Nipah virus (NiV)-mediated disease are poorly understood compared with other paramyxoviruses. Here we use recombinant NiVs (rNiVs) to examine the contributions of the NiV V and W proteins to NiV pathogenesis in a ferret model. We show that a V-deficient rNiV is susceptible to the innate immune response in vitro and behaves as a replicating non-lethal virus in vivo. Remarkably, rNiV lacking W expression results in a delayed and altered disease course with decreased respiratory disease and increased terminal neurological disease associated with altered in vitro inflammatory cytokine production. This study confirms the V protein as the major determinant of pathogenesis, also being the first in vivo study to show that the W protein modulates the inflammatory host immune response in a manner that determines the disease course.

A Systematic Review: Costing and Financing of Water, Sanitation, and Hygiene (WASH) in Schools

PubMed Central

McGinnis, Shannon M.; McKeon, Thomas; Desai, Richa; Ejelonu, Akudo; Laskowski, Stanley; Murphy, Heather M.

2017-01-01

Despite the success of recent efforts to increase access to improved water, sanitation, and hygiene (WASH) globally, approximately one-third of schools around the world still lack adequate WASH services. A lack of WASH in schools can lead to the spread of preventable disease and increase school absences, especially among women. Inadequate financing and budgeting has been named as a key barrier for integrating successful and sustainable WASH programs into school settings. For this reason, the purpose of this review is to describe the current knowledge around the costs of WASH components as well as financing models that could be applied to WASH in schools. Results show a lack of information around WASH costing, particularly around software elements as well as a lack of data overall for WASH in school settings as compared to community WASH. This review also identifies several key considerations when designing WASH budgets or selecting financing mechanisms. Findings may be used to advise future WASH in school programs. PMID:28425945

A Systematic Review: Costing and Financing of Water, Sanitation, and Hygiene (WASH) in Schools.

PubMed

McGinnis, Shannon M; McKeon, Thomas; Desai, Richa; Ejelonu, Akudo; Laskowski, Stanley; Murphy, Heather M

2017-04-20

Despite the success of recent efforts to increase access to improved water, sanitation, and hygiene (WASH) globally, approximately one-third of schools around the world still lack adequate WASH services. A lack of WASH in schools can lead to the spread of preventable disease and increase school absences, especially among women. Inadequate financing and budgeting has been named as a key barrier for integrating successful and sustainable WASH programs into school settings. For this reason, the purpose of this review is to describe the current knowledge around the costs of WASH components as well as financing models that could be applied to WASH in schools. Results show a lack of information around WASH costing, particularly around software elements as well as a lack of data overall for WASH in school settings as compared to community WASH. This review also identifies several key considerations when designing WASH budgets or selecting financing mechanisms. Findings may be used to advise future WASH in school programs.

The protective role of nitric oxide in a neurotoxicant-induced demyelinating model.

PubMed

Arnett, Heather A; Hellendall, Ron P; Matsushima, Glenn K; Suzuki, Kinuko; Laubach, Victor E; Sherman, Paula; Ting, Jenny P-Y

2002-01-01

Demyelination is often associated with acute inflammatory events involving the recruitment-activation of microglia/macrophage, astrocytes, and leukocytes. The ultimate role of inflammatory products in demyelinating disease and in the survival of oligodendrocytes, the myelin forming cells, is unresolved. The current study examines the role of inducible NO synthase (iNOS)-derived NO in a neurotoxicant-induced model of demyelination. NO levels were greatly elevated in the midline corpus callosum during demyelination in genetically intact C57BL/6 mice, and this NO was due solely to the induction of iNOS, as the correlates of NO were not found in mice lacking iNOS. C57BL/6 mice lacking iNOS exhibited more demyelination, but did not display an increased overall cellularity in the corpus callosum, attributable to an unimpeded microglia/macrophage presence. An enhanced course of pathology was noted in mice lacking iNOS. This was associated with a greater depletion of mature oligodendrocytes, most likely due to apoptosis of oligodendrocytes. Microglia and astrocytes did not undergo apoptosis during treatment. Our results suggest a moderately protective role for NO during acute inflammation-association demyelination.

Ecosocial consequences and policy implications of disease management in East African agropastoral systems.

PubMed

Gutierrez, Andrew Paul; Gilioli, Gianni; Baumgärtner, Johann

2009-08-04

International research and development efforts in Africa have brought ecological and social change, but analyzing the consequences of this change and developing policy to manage it for sustainable development has been difficult. This has been largely due to a lack of conceptual and analytical models to access the interacting dynamics of the different components of ecosocial systems. Here, we examine the ecological and social changes resulting from an ongoing suppression of trypanosomiasis disease in cattle in an agropastoral community in southwest Ethiopia to illustrate how such problems may be addressed. The analysis combines physiologically based demographic models of pasture, cattle, and pastoralists and a bioeconomic model that includes the demographic models as dynamic constraints in the economic objective function that maximizes the utility of individual consumption under different level of disease risk in cattle. Field data and model analysis show that suppression of trypanosomiasis leads to increased cattle and human populations and to increased agricultural development. However, in the absence of sound management, these changes will lead to a decline in pasture quality and increase the risk from tick-borne diseases in cattle and malaria in humans that would threaten system sustainability and resilience. The analysis of these conflicting outcomes of trypanosomiasis suppression is used to illustrate the need for and utility of conceptual bioeconomic models to serve as a basis for developing policy for sustainable agropastoral resource management in sub-Saharan Africa.

Whole-body iron transport and metabolism: Mechanistic, multi-scale model to improve treatment of anemia in chronic kidney disease

PubMed Central

Sarkar, Joydeep

2018-01-01

Iron plays vital roles in the human body including enzymatic processes, oxygen-transport via hemoglobin and immune response. Iron metabolism is characterized by ~95% recycling and minor replenishment through diet. Anemia of chronic kidney disease (CKD) is characterized by a lack of synthesis of erythropoietin leading to reduced red blood cell (RBC) formation and aberrant iron recycling. Treatment of CKD anemia aims to normalize RBC count and serum hemoglobin. Clinically, the various fluxes of iron transport and accumulation are not measured so that changes during disease (e.g., CKD) and treatment are unknown. Unwanted iron accumulation in patients is known to lead to adverse effects. Current whole-body models lack the mechanistic details of iron transport related to RBC maturation, transferrin (Tf and TfR) dynamics and assume passive iron efflux from macrophages. Hence, they are not predictive of whole-body iron dynamics and cannot be used to design individualized patient treatment. For prediction, we developed a mechanistic, multi-scale computational model of whole-body iron metabolism incorporating four compartments containing major pools of iron and RBC generation process. The model accounts for multiple forms of iron in vivo, mechanisms involved in iron uptake and release and their regulation. Furthermore, the model is interfaced with drug pharmacokinetics to allow simulation of treatment dynamics. We calibrated our model with experimental and clinical data from peer-reviewed literature to reliably simulate CKD anemia and the effects of current treatment involving combination of epoietin-alpha and iron dextran. This in silico whole-body model of iron metabolism predicts that a year of treatment can potentially lead to 90% downregulation of ferroportin (FPN) levels, 15-fold increase in iron stores with only a 20% increase in iron flux from the reticulo-endothelial system (RES). Model simulations quantified unmeasured iron fluxes, previously unknown effects of treatment on FPN-level and iron stores in the RES. This mechanistic whole-body model can be the basis for future studies that incorporate iron metabolism together with related clinical experiments. Such an approach could pave the way for development of effective personalized treatment of CKD anemia. PMID:29659573

Increased infectivity of anchorless mouse scrapie prions in transgenic mice overexpressing human prion protein.

PubMed

Race, Brent; Phillips, Katie; Meade-White, Kimberly; Striebel, James; Chesebro, Bruce

2015-06-01

Prion protein (PrP) is found in all mammals, mostly as a glycoprotein anchored to the plasma membrane by a C-terminal glycosylphosphatidylinositol (GPI) linkage. Following prion infection, host protease-sensitive prion protein (PrPsen or PrPC) is converted into an abnormal, disease-associated, protease-resistant form (PrPres). Biochemical characteristics, such as the PrP amino acid sequence, and posttranslational modifications, such as glycosylation and GPI anchoring, can affect the transmissibility of prions as well as the biochemical properties of the PrPres generated. Previous in vivo studies on the effects of GPI anchoring on prion infectivity have not examined cross-species transmission. In this study, we tested the effect of lack of GPI anchoring on a species barrier model using mice expressing human PrP. In this model, anchorless 22L prions derived from tg44 mice were more infectious than 22L prions derived from C57BL/10 mice when tested in tg66 transgenic mice, which expressed wild-type anchored human PrP at 8- to 16-fold above normal. Thus, the lack of the GPI anchor on the PrPres from tg44 mice appeared to reduce the effect of the mouse-human PrP species barrier. In contrast, neither source of prions induced disease in tgRM transgenic mice, which expressed human PrP at 2- to 4-fold above normal. Prion protein (PrP) is found in all mammals, usually attached to cells by an anchor molecule called GPI. Following prion infection, PrP is converted into a disease-associated form (PrPres). While most prion diseases are species specific, this finding is not consistent, and species barriers differ in strength. The amino acid sequence of PrP varies among species, and this variability affects prion species barriers. However, other PrP modifications, including glycosylation and GPI anchoring, may also influence cross-species infectivity. We studied the effect of PrP GPI anchoring using a mouse-to-human species barrier model. Experiments showed that prions produced by mice expressing only anchorless PrP were more infectious than prions produced in mice expressing anchored PrP. Thus, the lack of the GPI anchor on prions reduced the effect of the mouse-human species barrier. Our results suggest that prion diseases that produce higher levels of anchorless PrP may pose an increased risk for cross-species infection. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Clostridium perfringens Epsilon Toxin: A Malevolent Molecule for Animals and Man?

PubMed Central

Stiles, Bradley G.; Barth, Gillian; Barth, Holger; Popoff, Michel R.

2013-01-01

Clostridium perfringens is a prolific, toxin-producing anaerobe causing multiple diseases in humans and animals. One of these toxins is epsilon, a 33 kDa protein produced by Clostridium perfringens (types B and D) that induces fatal enteric disease of goats, sheep and cattle. Epsilon toxin (Etx) belongs to the aerolysin-like toxin family. It contains three distinct domains, is proteolytically-activated and forms oligomeric pores on cell surfaces via a lipid raft-associated protein(s). Vaccination controls Etx-induced disease in the field. However, therapeutic measures are currently lacking. This review initially introduces C. perfringens toxins, subsequently focusing upon the Etx and its biochemistry, disease characteristics in various animals that include laboratory models (in vitro and in vivo), and finally control mechanisms (vaccines and therapeutics). PMID:24284826

Clostridium perfringens epsilon toxin: a malevolent molecule for animals and man?

PubMed

Stiles, Bradley G; Barth, Gillian; Barth, Holger; Popoff, Michel R

2013-11-12

Clostridium perfringens is a prolific, toxin-producing anaerobe causing multiple diseases in humans and animals. One of these toxins is epsilon, a 33 kDa protein produced by Clostridium perfringens (types B and D) that induces fatal enteric disease of goats, sheep and cattle. Epsilon toxin (Etx) belongs to the aerolysin-like toxin family. It contains three distinct domains, is proteolytically-activated and forms oligomeric pores on cell surfaces via a lipid raft-associated protein(s). Vaccination controls Etx-induced disease in the field. However, therapeutic measures are currently lacking. This review initially introduces C. perfringens toxins, subsequently focusing upon the Etx and its biochemistry, disease characteristics in various animals that include laboratory models (in vitro and in vivo), and finally control mechanisms (vaccines and therapeutics).

Comparative Pathology of Smallpox and Monkeypox in Man and Macaques

PubMed Central

Cann, J. A.; Jahrling, P. B.; Hensley, L. E.; Wahl-Jensen, V.

2012-01-01

Summary In the three decades since the eradication of smallpox and cessation of routine vaccination, the collective memory of the devastating epidemics caused by this orthopoxvirus has waned, and the human population has become increasingly susceptible to a disease that remains high on the list of possible bioterrorism agents. Research using surrogate orthopoxviruses in their natural hosts, as well as limited variola virus research in animal models, continues worldwide; however, interpretation of findings is often limited by our relative lack of knowledge about the naturally occurring disease. For modern comparative pathologists, many of whom have no first-hand knowledge of naturally occurring smallpox, this work provides a contemporary review of this historical disease, as well as discussion of how it compares with human monkeypox and the corresponding diseases in macaques. PMID:22884034

Design of a framework for the deployment of collaborative independent rare disease-centric registries: Gaucher disease registry model.

PubMed

Bellgard, Matthew I; Napier, Kathryn R; Bittles, Alan H; Szer, Jeffrey; Fletcher, Sue; Zeps, Nikolajs; Hunter, Adam A; Goldblatt, Jack

2018-02-01

Orphan drug clinical trials often are adversely affected by a lack of high quality treatment efficacy data that can be reliably compared across large patient cohorts derived from multiple governmental and country jurisdictions. It is critical that these patient data be captured with limited corporate involvement. For some time, there have been calls to develop collaborative, non-proprietary, patient-centric registries for post-market surveillance of aspects related to orphan drug efficacy. There is an urgent need for the development and sustainable deployment of these 'independent' registries that can capture comprehensive clinical, genetic and therapeutic information on patients with rare diseases. We therefore extended an open-source registry platform, the Rare Disease Registry Framework (RDRF) to establish an Independent Rare Disease Registry (IRDR). We engaged with an established rare disease community for Gaucher disease to determine system requirements, methods of data capture, consent, and reporting. A non-proprietary IRDR model is presented that can serve as autonomous data repository, but more importantly ensures that the relevant data can be made available to appropriate stakeholders in a secure, timely and efficient manner to improve clinical decision-making and the lives of those with a rare disease. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Induced pluripotent stem cells (iPSC)-derived retinal cells in disease modeling and regenerative medicine.

PubMed

Rathod, Reena; Surendran, Harshini; Battu, Rajani; Desai, Jogin; Pal, Rajarshi

2018-02-12

Retinal degenerative disorders are a leading cause of the inherited, irreversible and incurable vision loss. While various rodent model systems have provided crucial information in this direction, lack of disease-relevant tissue availability and species-specific differences have proven to be a major roadblock. Human induced pluripotent stem cells (iPSC) have opened up a whole new avenue of possibilities not just in understanding the disease mechanism but also potential therapeutic approaches towards a cure. In this review, we have summarized recent advances in the methods of deriving retinal cell types from iPSCs which can serve as a renewable source of disease-relevant cell population for basic as well as translational studies. We also provide an overview of the ongoing efforts towards developing a suitable in vitro model for modeling retinal degenerative diseases. This basic understanding in turn has contributed to advances in translational goals such as drug screening and cell-replacement therapies. Furthermore we discuss gene editing approaches for autologous repair of genetic disorders and allogeneic transplantation of stem cell-based retinal derivatives for degenerative disorders with an ultimate goal to restore vision. It is pertinent to note however, that these exciting new developments throw up several challenges that need to be overcome before their full clinical potential can be realized. Copyright © 2018 Elsevier B.V. All rights reserved.

Delays reducing waterborne and water-related infectious diseases in China under climate change

PubMed Central

Hodges, Maggie; Belle, Jessica H.; Carlton, Elizabeth J.; Liang, Song; Li, Huazhong; Luo, Wei; Freeman, Matthew C.; Liu, Yang; Gao, Yang; Hess, Jeremy J.; Remais, Justin V.

2014-01-01

Despite China’s rapid progress improving water, sanitation and hygiene (WSH) access, in 2011, 471 million people lacked access to improved sanitation and 401 million to household piped water. Because certain infectious diseases are sensitive to changes in both climate and WSH conditions, we projected impacts of climate change on WSH-attributable diseases in China in 2020 and 2030 by coupling estimates of the temperature sensitivity of diarrheal diseases and three vector-borne diseases, temperature projections from global climate models, WSH-infrastructure development scenarios, and projected demographic changes. By 2030, climate change is projected to delay China’s rapid progress toward reducing WSH-attributable infectious disease burden by 8–85 months. This development delay summarizes the adverse impact of climate change on WSH-attributable infectious diseases in China, and can be used in other settings where a significant health burden may accompany future changes in climate even as the total burden of disease falls due to non-climate reasons. PMID:25530812

Delays in reducing waterborne and water-related infectious diseases in China under climate change

NASA Astrophysics Data System (ADS)

Hodges, Maggie; Belle, Jessica H.; Carlton, Elizabeth J.; Liang, Song; Li, Huazhong; Luo, Wei; Freeman, Matthew C.; Liu, Yang; Gao, Yang; Hess, Jeremy J.; Remais, Justin V.

2014-12-01

Despite China's rapid progress in improving water, sanitation and hygiene (WSH) access, in 2011, 471 million people lacked access to improved sanitation and 401 million to household piped water. As certain infectious diseases are sensitive to changes in both climate and WSH conditions, we projected impacts of climate change on WSH-attributable diseases in China in 2020 and 2030 by coupling estimates of the temperature sensitivity of diarrhoeal diseases and three vector-borne diseases, temperature projections from global climate models, WSH-infrastructure development scenarios, and projected demographic changes. By 2030, climate change is projected to delay China's rapid progress towards reducing WSH-attributable infectious disease burden by 8-85 months. This development delay summarizes the adverse impact of climate change on WSH-attributable infectious diseases in China, and can be used in other settings where a significant health burden may accompany future changes in climate even as the total burden of disease falls owing to non-climate reasons.

Delays reducing waterborne and water-related infectious diseases in China under climate change.

PubMed

Hodges, Maggie; Belle, Jessica H; Carlton, Elizabeth J; Liang, Song; Li, Huazhong; Luo, Wei; Freeman, Matthew C; Liu, Yang; Gao, Yang; Hess, Jeremy J; Remais, Justin V

2014-12-01

Despite China's rapid progress improving water, sanitation and hygiene (WSH) access, in 2011, 471 million people lacked access to improved sanitation and 401 million to household piped water. Because certain infectious diseases are sensitive to changes in both climate and WSH conditions, we projected impacts of climate change on WSH-attributable diseases in China in 2020 and 2030 by coupling estimates of the temperature sensitivity of diarrheal diseases and three vector-borne diseases, temperature projections from global climate models, WSH-infrastructure development scenarios, and projected demographic changes. By 2030, climate change is projected to delay China's rapid progress toward reducing WSH-attributable infectious disease burden by 8-85 months. This development delay summarizes the adverse impact of climate change on WSH-attributable infectious diseases in China, and can be used in other settings where a significant health burden may accompany future changes in climate even as the total burden of disease falls due to non-climate reasons.

Pets, Purity and Pollution: Why Conventional Models of Disease Transmission Do Not Work for Pet Rat Owners

PubMed Central

Robin, Charlotte; Perkins, Elizabeth; Watkins, Francine

2017-01-01

In the United Kingdom, following the emergence of Seoul hantavirus in pet rat owners in 2012, public health authorities tried to communicate the risk of this zoonotic disease, but had limited success. To explore this lack of engagement with health advice, we conducted in-depth, semi-structured interviews with pet rat owners and analysed them using a grounded theory approach. The findings from these interviews suggest that rat owners construct their pets as different from wild rats, and by elevating the rat to the status of a pet, the powerful associations that rats have with dirt and disease are removed. Removing the rat from the contaminated outside world moves their pet rat from being ‘out of place’ to ‘in place’. A concept of ‘bounded purity’ keeps the rat protected within the home, allowing owners to interact with their pet, safe in the knowledge that it is clean and disease-free. Additionally, owners constructed a ‘hierarchy of purity’ for their pets, and it is on this structure of disease and risk that owners base their behaviour, not conventional biomedical models of disease. PMID:29215554

Empirical Bayes Estimation of Semi-parametric Hierarchical Mixture Models for Unbiased Characterization of Polygenic Disease Architectures

PubMed Central

Nishino, Jo; Kochi, Yuta; Shigemizu, Daichi; Kato, Mamoru; Ikari, Katsunori; Ochi, Hidenori; Noma, Hisashi; Matsui, Kota; Morizono, Takashi; Boroevich, Keith A.; Tsunoda, Tatsuhiko; Matsui, Shigeyuki

2018-01-01

Genome-wide association studies (GWAS) suggest that the genetic architecture of complex diseases consists of unexpectedly numerous variants with small effect sizes. However, the polygenic architectures of many diseases have not been well characterized due to lack of simple and fast methods for unbiased estimation of the underlying proportion of disease-associated variants and their effect-size distribution. Applying empirical Bayes estimation of semi-parametric hierarchical mixture models to GWAS summary statistics, we confirmed that schizophrenia was extremely polygenic [~40% of independent genome-wide SNPs are risk variants, most within odds ratio (OR = 1.03)], whereas rheumatoid arthritis was less polygenic (~4 to 8% risk variants, significant portion reaching OR = 1.05 to 1.1). For rheumatoid arthritis, stratified estimations revealed that expression quantitative loci in blood explained large genetic variance, and low- and high-frequency derived alleles were prone to be risk and protective, respectively, suggesting a predominance of deleterious-risk and advantageous-protective mutations. Despite genetic correlation, effect-size distributions for schizophrenia and bipolar disorder differed across allele frequency. These analyses distinguished disease polygenic architectures and provided clues for etiological differences in complex diseases. PMID:29740473

Inhibition of acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) prevents dietary cholesterol-associated steatosis by enhancing hepatic triglyceride mobilization.

PubMed

Alger, Heather M; Brown, J Mark; Sawyer, Janet K; Kelley, Kathryn L; Shah, Ramesh; Wilson, Martha D; Willingham, Mark C; Rudel, Lawrence L

2010-05-07

Acyl-CoA:cholesterol O-acyl transferase 2 (ACAT2) promotes cholesterol absorption by the intestine and the secretion of cholesteryl ester-enriched very low density lipoproteins by the liver. Paradoxically, mice lacking ACAT2 also exhibit mild hypertriglyceridemia. The present study addresses the unexpected role of ACAT2 in regulation of hepatic triglyceride (TG) metabolism. Mouse models of either complete genetic deficiency or pharmacological inhibition of ACAT2 were fed low fat diets containing various amounts of cholesterol to induce hepatic steatosis. Mice genetically lacking ACAT2 in both the intestine and the liver were dramatically protected against hepatic neutral lipid (TG and cholesteryl ester) accumulation, with the greatest differences occurring in situations where dietary cholesterol was elevated. Further studies demonstrated that liver-specific depletion of ACAT2 with antisense oligonucleotides prevents dietary cholesterol-associated hepatic steatosis both in an inbred mouse model of non-alcoholic fatty liver disease (SJL/J) and in a humanized hyperlipidemic mouse model (LDLr(-/-), apoB(100/100)). All mouse models of diminished ACAT2 function showed lowered hepatic triglyceride concentrations and higher plasma triglycerides secondary to increased hepatic secretion of TG into nascent very low density lipoproteins. This work demonstrates that inhibition of hepatic ACAT2 can prevent dietary cholesterol-driven hepatic steatosis in mice. These data provide the first evidence to suggest that ACAT2-specific inhibitors may hold unexpected therapeutic potential to treat both atherosclerosis and non-alcoholic fatty liver disease.

Genetically Engineered Mouse Models of Pancreatic Cancer: The KPC Model (LSL-Kras(G12D/+) ;LSL-Trp53(R172H/+) ;Pdx-1-Cre), Its Variants, and Their Application in Immuno-oncology Drug Discovery.

PubMed

Lee, Jae W; Komar, Chad A; Bengsch, Fee; Graham, Kathleen; Beatty, Gregory L

2016-06-01

Pancreatic ductal adenocarcinoma (PDAC) ranks fourth among cancer-related deaths in the United States. For patients with unresectable disease, treatment options are limited and lack curative potential. Preclinical mouse models of PDAC that recapitulate the biology of human pancreatic cancer offer an opportunity for the rational development of novel treatment approaches that may improve patient outcomes. With the recent success of immunotherapy for subsets of patients with solid malignancies, interest is mounting in the possible use of immunotherapy for the treatment of PDAC. Considered in this unit is the value of genetic mouse models for characterizing the immunobiology of PDAC and for investigating novel immunotherapeutics. Several variants of these models are described, all of which may be used in drug development and for providing information on unique aspects of disease biology and therapeutic responsiveness. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Caenorhabditis elegans as an experimental tool for the study of complex neurological diseases: Parkinson's disease, Alzheimer's disease and autism spectrum disorder.

PubMed

Calahorro, Fernando; Ruiz-Rubio, Manuel

2011-12-01

The nematode Caenorhabditis elegans has a very well-defined and genetically tractable nervous system which offers an effective model to explore basic mechanistic pathways that might be underpin complex human neurological diseases. Here, the role C. elegans is playing in understanding two neurodegenerative conditions, Parkinson's and Alzheimer's disease (AD), and a complex neurological condition, autism, is used as an exemplar of the utility of this model system. C. elegans is an imperfect model of Parkinson's disease because it lacks orthologues of the human disease-related genes PARK1 and LRRK2 which are linked to the autosomal dominant form of this disease. Despite this fact, the nematode is a good model because it allows transgenic expression of these human genes and the study of the impact on dopaminergic neurons in several genetic backgrounds and environmental conditions. For AD, C. elegans has orthologues of the amyloid precursor protein and both human presenilins, PS1 and PS2. In addition, many of the neurotoxic properties linked with Aβ amyloid and tau peptides can be studied in the nematode. Autism spectrum disorder is a complex neurodevelopmental disorder characterised by impairments in human social interaction, difficulties in communication, and restrictive and repetitive behaviours. Establishing C. elegans as a model for this complex behavioural disorder is difficult; however, abnormalities in neuronal synaptic communication are implicated in the aetiology of the disorder. Numerous studies have associated autism with mutations in several genes involved in excitatory and inhibitory synapses in the mammalian brain, including neuroligin, neurexin and shank, for which there are C. elegans orthologues. Thus, several molecular pathways and behavioural phenotypes in C. elegans have been related to autism. In general, the nematode offers a series of advantages that combined with knowledge from other animal models and human research, provides a powerful complementary experimental approach for understanding the molecular mechanisms and underlying aetiology of complex neurological diseases.

TLRs to cytokines: mechanistic insights from the imiquimod mouse model of psoriasis.

PubMed

Flutter, Barry; Nestle, Frank O

2013-12-01

Psoriasis is an inflammatory disease of the skin affecting 2-3% of the population, characterized by a thickening of the epidermis and immune infiltrates throughout the dermis and epidermis, causing skin lesions that can seriously affect quality of life. The study of psoriasis has historically been hampered by the lack of good animal models. Various genetically induced models exist, which have provided some information about possible mechanisms of disease, but these models rely mostly on intrinsic imbalances of homeostasis. However, a mouse model of psoriasiform dermatitis caused by the repeated topical application of Aldara™ containing 5% imiquimod was described in 2009. The mechanisms of action of Aldara™ are complex. Imiquimod is an effective ligand for TLR7 (and TLR8 in humans) and also interferes with adenosine receptor signaling. In addition, isostearic acid present in the Aldara™ vehicle has been shown to be biologically active and of importance for activating the inflammasome. Interestingly, the repetitive application of Aldara™ reveals a complex aetiology involving multiple cell types, cytokines, and inflammatory pathways. In this review, we will dissect the findings of the imiquimod model to date and ask how this model can inform us about the immunological aspects of human disease. © 2013 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Behavioural change models for infectious disease transmission: a systematic review (2010–2015)

PubMed Central

2016-01-01

We review behavioural change models (BCMs) for infectious disease transmission in humans. Following the Cochrane collaboration guidelines and the PRISMA statement, our systematic search and selection yielded 178 papers covering the period 2010–2015. We observe an increasing trend in published BCMs, frequently coupled to (re)emergence events, and propose a categorization by distinguishing how information translates into preventive actions. Behaviour is usually captured by introducing information as a dynamic parameter (76/178) or by introducing an economic objective function, either with (26/178) or without (37/178) imitation. Approaches using information thresholds (29/178) and exogenous behaviour formation (16/178) are also popular. We further classify according to disease, prevention measure, transmission model (with 81/178 population, 6/178 metapopulation and 91/178 individual-level models) and the way prevention impacts transmission. We highlight the minority (15%) of studies that use any real-life data for parametrization or validation and note that BCMs increasingly use social media data and generally incorporate multiple sources of information (16/178), multiple types of information (17/178) or both (9/178). We conclude that individual-level models are increasingly used and useful to model behaviour changes. Despite recent advancements, we remain concerned that most models are purely theoretical and lack representative data and a validation process. PMID:28003528

Configuration interaction of hydropathic waves enables ubiquitin functionality

NASA Astrophysics Data System (ADS)

Allan, Douglas C.; Phillips, J. C.

2018-02-01

Ubiquitin, discovered less than 50 years ago, tags thousands of diseased proteins for destruction. It is small (only 76 amino acids), and is found unchanged in mammals, birds, fish and even worms. Key features of its functionality are identified here using critical point thermodynamic scaling theory. These include Fano interference between first- and second-order elements of correlated long-range globular surface shape transitions. Comparison with its closest relative, 76 amino acid Nedd8, shows that the latter lacks these features. A cracked elastic network model is proposed for the common target shared by many diseased proteins.

Optimized oral cholera vaccine distribution strategies to minimize disease incidence: A mixed integer programming model and analysis of a Bangladesh scenario.

PubMed

Smalley, Hannah K; Keskinocak, Pinar; Swann, Julie; Hinman, Alan

2015-11-17

In addition to improved sanitation, hygiene, and better access to safe water, oral cholera vaccines can help to control the spread of cholera in the short term. However, there is currently no systematic method for determining the best allocation of oral cholera vaccines to minimize disease incidence in a population where the disease is endemic and resources are limited. We present a mathematical model for optimally allocating vaccines in a region under varying levels of demographic and incidence data availability. The model addresses the questions of where, when, and how many doses of vaccines to send. Considering vaccine efficacies (which may vary based on age and the number of years since vaccination), we analyze distribution strategies which allocate vaccines over multiple years. Results indicate that, given appropriate surveillance data, targeting age groups and regions with the highest disease incidence should be the first priority, followed by other groups primarily in order of disease incidence, as this approach is the most life-saving and cost-effective. A lack of detailed incidence data results in distribution strategies which are not cost-effective and can lead to thousands more deaths from the disease. The mathematical model allows for what-if analysis for various vaccine distribution strategies by providing the ability to easily vary parameters such as numbers and sizes of regions and age groups, risk levels, vaccine price, vaccine efficacy, production capacity and budget. Copyright © 2015 Elsevier Ltd. All rights reserved.

Improved amino acid, bioenergetic metabolite and neurotransmitter profiles following human amnion epithelial cell transplant in intermediate maple syrup urine disease mice.

PubMed

Skvorak, Kristen J; Dorko, Kenneth; Marongiu, Fabio; Tahan, Veysel; Hansel, Marc C; Gramignoli, Roberto; Arning, Erland; Bottiglieri, Teodoro; Gibson, K Michael; Strom, Stephen C

2013-06-01

Orthotopic liver transplant (OLT) significantly improves patient outcomes in maple syrup urine disease (MSUD; OMIM: 248600), yet organ shortages point to the need for alternative therapies. Hepatocyte transplantation has shown both clinical and preclinical efficacy as an intervention for metabolic liver diseases, yet the availability of suitable livers for hepatocyte isolation is also limited. Conversely, human amnion epithelial cells (hAEC) may have utility as a hepatocyte substitute, and they share many of the characteristics of pluripotent embryonic stem cells while lacking their safety and ethical concerns. We reported that like hepatocytes, transplantation of hAEC significantly improved survival and lifespan, normalized body weight, and significantly improved branched-chain amino acid (BCAA) levels in sera and brain in a transgenic murine model of intermediate maple syrup urine disease (imsud). In the current report, we detail the neural and peripheral metabolic improvements associated with hAEC transplant in imsud mice, including amino acids associated with bioenergetics, the urea cycle, as well as the neurotransmitter systems for serotonin, dopamine, and gamma-aminobutyric acid (GABA). This stem cell therapy results in significant global correction of the metabolic profile that characterizes the disease, both in the periphery and the central nervous system, the target organ for toxicity in iMSUD. The significant correction of the disease phenotype, coupled with the theoretical benefits of hAEC, particularly their lack of immunogenicity and tumorigenicity, suggests that human amnion epithelial cells deserve serious consideration for clinical application to treat metabolic liver diseases. Copyright © 2013. Published by Elsevier Inc.

Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease

PubMed Central

El Machhour, Fala; Keuylian, Zela; Kavvadas, Panagiotis; Dussaule, Jean-Claude

2015-01-01

Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN. PMID:25421557

The Role of Negative Affect in the Assessment of Quality of Life among Women with Type 1 Diabetes Mellitus

PubMed Central

Gawlik, Nicola R.

2018-01-01

Background The purpose of this study is to determine the impact of negative affect (defined in terms of lack of optimism, depressogenic attributional style, and hopelessness depression) on the quality of life of women with type 1 diabetes mellitus. Methods Participants (n=177) completed either an online or paper questionnaire made available to members of Australian diabetes support groups. Measures of optimism, attributional style, hopelessness depression, disease-specific data, and diabetes-related quality of life were sought. Bivariate correlations informed the construction of a structural equation model. Results Participants were 36.3±11.3 years old, with a disease duration of 18.4±11.2 years. Age and recent glycosylated hemoglobin readings were significant contextual variables in the model. All bivariate associations involving the components of negative affect were as hypothesized. That is, poorer quality of life was associated with a greater depressogenic attributional style, higher hopelessness depression, and lower optimism. The structural equation model demonstrated significant direct effects of depressogenic attributional style and hopelessness depression on quality of life, while (lack of) optimism contributed to quality of life indirectly by way of these variables. Conclusion The recognition of negative affect presentations among patients, and an understanding of its relevance to diabetes-related quality of life, is a valuable tool for the practitioner. PMID:29199406

Modeling Human Bone Marrow Failure Syndromes Using Pluripotent Stem Cells and Genome Engineering.

PubMed

Jung, Moonjung; Dunbar, Cynthia E; Winkler, Thomas

2015-12-01

The combination of epigenetic reprogramming with advanced genome editing technologies opened a new avenue to study disease mechanisms, particularly of disorders with depleted target tissue. Bone marrow failure syndromes (BMFS) typically present with a marked reduction of peripheral blood cells due to a destroyed or dysfunctional bone marrow compartment. Somatic and germline mutations have been etiologically linked to many cases of BMFS. However, without the ability to study primary patient material, the exact pathogenesis for many entities remained fragmentary. Capturing the pathological genotype in induced pluripotent stem cells (iPSCs) allows studying potential developmental defects leading to a particular phenotype. The lack of hematopoietic stem and progenitor cells in these patients can also be overcome by differentiating patient-derived iPSCs into hematopoietic lineages. With fast growing genome editing techniques, such as CRISPR/Cas9, correction of disease-causing mutations in iPSCs or introduction of mutations in cells from healthy individuals enable comparative studies that may identify other genetic or epigenetic events contributing to a specific disease phenotype. In this review, we present recent progresses in disease modeling of inherited and acquired BMFS using reprogramming and genome editing techniques. We also discuss the challenges and potential shortcomings of iPSC-based models for hematological diseases.

Induced Pluripotent Stem Cells Can Be Used to Model the Genomic Imprinting Disorder Prader-Willi Syndrome*

PubMed Central

Yang, Jiayin; Cai, Jie; Zhang, Ya; Wang, Xianming; Li, Wen; Xu, Jianyong; Li, Feng; Guo, Xiangpeng; Deng, Kang; Zhong, Mei; Chen, Yonglong; Lai, Liangxue; Pei, Duanqing; Esteban, Miguel A.

2010-01-01

The recent discovery of induced pluripotent stem cell (iPSC) technology provides an invaluable tool for creating in vitro representations of human genetic conditions. This is particularly relevant for those diseases that lack adequate animal models or where the species comparison is difficult, e.g. imprinting diseases such as the neurogenetic disorder Prader-Willi syndrome (PWS). However, recent reports have unveiled transcriptional and functional differences between iPSCs and embryonic stem cells that in cases are attributable to imprinting errors. This has suggested that human iPSCs may not be useful to model genetic imprinting diseases. Here, we describe the generation of iPSCs from a patient with PWS bearing a partial translocation of the paternally expressed chromosome 15q11-q13 region to chromosome 4. The resulting iPSCs match all standard criteria of bona fide reprogramming and could be readily differentiated into tissues derived from the three germ layers, including neurons. Moreover, these iPSCs retain a high level of DNA methylation in the imprinting center of the maternal allele and show concomitant reduced expression of the disease-associated small nucleolar RNA HBII-85/SNORD116. These results indicate that iPSCs may be a useful tool to study PWS and perhaps other genetic imprinting diseases as well. PMID:20956530

Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease.

PubMed

Kozak, Robert; He, Shihua; Kroeker, Andrea; de La Vega, Marc-Antoine; Audet, Jonathan; Wong, Gary; Urfano, Chantel; Antonation, Kym; Embury-Hyatt, Carissa; Kobinger, Gary P; Qiu, Xiangguo

2016-10-15

Bundibugyo virus (BDBV) is the etiological agent of a severe hemorrhagic fever in humans with a case-fatality rate ranging from 25 to 36%. Despite having been known to the scientific and medical communities for almost 1 decade, there is a dearth of studies on this pathogen due to the lack of a small animal model. Domestic ferrets are commonly used to study other RNA viruses, including members of the order Mononegavirales To investigate whether ferrets were susceptible to filovirus infections, ferrets were challenged with a clinical isolate of BDBV. Animals became viremic within 4 days and succumbed to infection between 8 and 9 days, and a petechial rash was observed with moribund ferrets. Furthermore, several hallmarks of human filoviral disease were recapitulated in the ferret model, including substantial decreases in lymphocyte and platelet counts and dysregulation of key biochemical markers related to hepatic/renal function, as well as coagulation abnormalities. Virological, histopathological, and immunohistochemical analyses confirmed uncontrolled BDBV replication in the major organs. Ferrets were also infected with Ebola virus (EBOV) to confirm their susceptibility to another filovirus species and to potentially establish a virus transmission model. Similar to what was seen with BDBV, important hallmarks of human filoviral disease were observed in EBOV-infected ferrets. This study demonstrates the potential of this small animal model for studying BDBV and EBOV using wild-type isolates and will accelerate efforts to understand filovirus pathogenesis and transmission as well as the development of specific vaccines and antivirals. The 2013-2016 outbreak of Ebola virus in West Africa has highlighted the threat posed by filoviruses to global public health. Bundibugyo virus (BDBV) is a member of the genus Ebolavirus and has caused outbreaks in the past but is relatively understudied, likely due to the lack of a suitable small animal model. Such a model for BDBV is crucial to evaluating vaccines and therapies and potentially understanding transmission. To address this, we demonstrated that ferrets are susceptible models to BDBV infection as well as to Ebola virus infection and that no virus adaptation is required. Moreover, these animals develop a disease that is similar to that seen in humans and nonhuman primates. We believe that this will improve the ability to study BDBV and provide a platform to test vaccines and therapeutics. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Ferrets Infected with Bundibugyo Virus or Ebola Virus Recapitulate Important Aspects of Human Filovirus Disease

PubMed Central

Kozak, Robert; He, Shihua; Kroeker, Andrea; de La Vega, Marc-Antoine; Audet, Jonathan; Wong, Gary; Urfano, Chantel; Antonation, Kym; Embury-Hyatt, Carissa; Kobinger, Gary P.

2016-01-01

ABSTRACT Bundibugyo virus (BDBV) is the etiological agent of a severe hemorrhagic fever in humans with a case-fatality rate ranging from 25 to 36%. Despite having been known to the scientific and medical communities for almost 1 decade, there is a dearth of studies on this pathogen due to the lack of a small animal model. Domestic ferrets are commonly used to study other RNA viruses, including members of the order Mononegavirales. To investigate whether ferrets were susceptible to filovirus infections, ferrets were challenged with a clinical isolate of BDBV. Animals became viremic within 4 days and succumbed to infection between 8 and 9 days, and a petechial rash was observed with moribund ferrets. Furthermore, several hallmarks of human filoviral disease were recapitulated in the ferret model, including substantial decreases in lymphocyte and platelet counts and dysregulation of key biochemical markers related to hepatic/renal function, as well as coagulation abnormalities. Virological, histopathological, and immunohistochemical analyses confirmed uncontrolled BDBV replication in the major organs. Ferrets were also infected with Ebola virus (EBOV) to confirm their susceptibility to another filovirus species and to potentially establish a virus transmission model. Similar to what was seen with BDBV, important hallmarks of human filoviral disease were observed in EBOV-infected ferrets. This study demonstrates the potential of this small animal model for studying BDBV and EBOV using wild-type isolates and will accelerate efforts to understand filovirus pathogenesis and transmission as well as the development of specific vaccines and antivirals. IMPORTANCE The 2013-2016 outbreak of Ebola virus in West Africa has highlighted the threat posed by filoviruses to global public health. Bundibugyo virus (BDBV) is a member of the genus Ebolavirus and has caused outbreaks in the past but is relatively understudied, likely due to the lack of a suitable small animal model. Such a model for BDBV is crucial to evaluating vaccines and therapies and potentially understanding transmission. To address this, we demonstrated that ferrets are susceptible models to BDBV infection as well as to Ebola virus infection and that no virus adaptation is required. Moreover, these animals develop a disease that is similar to that seen in humans and nonhuman primates. We believe that this will improve the ability to study BDBV and provide a platform to test vaccines and therapeutics. PMID:27489269

Lack of Parkin Anticipates the Phenotype and Affects Mitochondrial Morphology and mtDNA Levels in a Mouse Model of Parkinson's Disease.

PubMed

Pinto, Milena; Nissanka, Nadee; Moraes, Carlos T

2018-01-24

PARK2 is the most common gene mutated in monogenic recessive familial cases of Parkinson's disease (PD). Pathogenic mutations cause a loss of function of the encoded protein Parkin. ParkinKO mice, however, poorly represent human PD symptoms as they only exhibit mild motor phenotypes, minor dopamine metabolism abnormalities, and no signs of dopaminergic neurodegeneration. Parkin has been shown to participate in mitochondrial turnover, by targeting damaged mitochondria with low membrane potential to mitophagy. We studied the role of Parkin on mitochondrial quality control in vivo by knocking out Parkin in the PD-mito- Pst I mouse (males), where the mitochondrial DNA (mtDNA) undergoes double-strand breaks only in dopaminergic neurons. The lack of Parkin promoted earlier onset of dopaminergic neurodegeneration and motor defects in the PD-mito- Pst I mice, but it did not worsen the pathology. The lack of Parkin affected mitochondrial morphology in dopaminergic axons and was associated with an increase in mtDNA levels (mutant and wild type). Unexpectedly, it did not cause a parallel increase in mitochondrial mass or mitophagy. Our results suggest that Parkin affects mtDNA levels in a mitophagy-independent manner. SIGNIFICANCE STATEMENT Parkinson's disease is characterized by progressive motor symptoms due to the selective loss of dopaminergic neurons in the substantia nigra. Loss-of-function mutations of Parkin cause some monogenic forms of Parkinson's disease, possibly through its role in mitochondrial turnover and quality control. To study whether Parkin has a role in vivo in the context of mitochondrial damage, we knocked out Parkin in a mouse model in which the mitochondrial DNA is damaged in dopaminergic neurons. We found that the loss of Parkin did not exacerbate the parkinsonian pathology already present in the mice, but it was associated with an increase in mtDNA levels (mutant and wild-type) without altering mitochondrial mass. These results shed new light on the function of Parkin in vivo . Copyright © 2018 the authors 0270-6474/18/381042-12$15.00/0.

The paradox of nutrition-related diseases in the Arab countries: the need for action.

PubMed

Musaiger, Abdulrahman O; Hassan, Abdelmonem S; Obeid, Omar

2011-09-01

The aim of this review was to highlight the current situation of nutrition-related diseases in the Arab countries, and factors associated with prevalence of these diseases. PubMed and Google Scholar were searched for data relating to such nutrition-related diseases published between January 1990 and May 2011. The picture of nutritional status in the Arab countries has changed drastically over the past 30 years as a result of changes in the social and economic situation. Two contrasting nutrition-related diseases exist, those associated with inadequate intake of nutrients and unhealthy dietary habits such as growth retardation among young children and micronutrient deficiencies; and those associated with changes in lifestyle such as cardiovascular disease, cancer, osteoporosis, diabetes and obesity (diet-related non-communicable diseases). Factors contributing to nutritional problems vary from country to country, depending on socio-economic status. In general, unsound dietary habits, poor sanitation, poverty, ignorance and lack of access to safe water and health services are mainly responsible for under-nutrition. Changes in lifestyle and dietary habits as well as inactivity are associated with the occurrence of diet-related non-communicable diseases. Programs to prevent and control nutrition-related diseases are insufficient and ineffective, due mainly to a focus on curative care at the expense of preventive health care services, lack of epidemiological studies, lack of nutritional surveillance, inadequate nutrition information and lack of assessment of the cost-effectiveness of nutrition intervention programs.

The Paradox of Nutrition-Related Diseases in the Arab Countries: The Need for Action

PubMed Central

Musaiger, Abdulrahman O.; Hassan, Abdelmonem S.; Obeid, Omar

2011-01-01

The aim of this review was to highlight the current situation of nutrition-related diseases in the Arab countries, and factors associated with prevalence of these diseases. PubMed and Google Scholar were searched for data relating to such nutrition-related diseases published between January 1990 and May 2011. The picture of nutritional status in the Arab countries has changed drastically over the past 30 years as a result of changes in the social and economic situation. Two contrasting nutrition-related diseases exist, those associated with inadequate intake of nutrients and unhealthy dietary habits such as growth retardation among young children and micronutrient deficiencies; and those associated with changes in lifestyle such as cardiovascular disease, cancer, osteoporosis, diabetes and obesity (diet-related non-communicable diseases). Factors contributing to nutritional problems vary from country to country, depending on socio-economic status. In general, unsound dietary habits, poor sanitation, poverty, ignorance and lack of access to safe water and health services are mainly responsible for under-nutrition. Changes in lifestyle and dietary habits as well as inactivity are associated with the occurrence of diet-related non-communicable diseases. Programs to prevent and control nutrition-related diseases are insufficient and ineffective, due mainly to a focus on curative care at the expense of preventive health care services, lack of epidemiological studies, lack of nutritional surveillance, inadequate nutrition information and lack of assessment of the cost-effectiveness of nutrition intervention programs. PMID:22016708

Modeling Alzheimer’s disease with human induced pluripotent stem (iPS) cells

PubMed Central

Mungenast, Alison E.; Siegert, Sandra; Tsai, Li-Huei

2018-01-01

In the last decade, induced pluripotent stem (iPS) cells have revolutionized the utility of human in vitro models of neurological disease. The iPS-derived and differentiated cells allow researchers to study the impact of a distinct cell type in health and disease as well as performing therapeutic drug screens on a human genetic background. In particular, clinical trials for Alzheimer’s disease (AD) have been often failing. Two of the potential reasons are first, the species gap involved in proceeding from initial discoveries in rodent models to human studies, and second, an unsatisfying patient stratification, meaning subgrouping patients based on the disease severity due to the lack of phenotypic and genetic markers. iPS cells overcome this obstacles and will improve our understanding of disease subtypes in AD. They allow researchers conducting in depth characterization of neural cells from both familial and sporadic AD patients as well as preclinical screens on human cells. In this review, we briefly outline the status quo of iPS cell research in neurological diseases along with the general advantages and pitfalls of these models. We summarize how genome-editing techniques such as CRISPR/Cas will allow researchers to reduce the problem of genomic variability inherent to human studies, followed by recent iPS cell studies relevant to AD. We then focus on current techniques for the differentiation of iPS cells into neural cell types that are relevant to AD research. Finally, we discuss how the generation of three-dimensional cell culture systems will be important for understanding AD phenotypes in a complex cellular milieu, and how both two- and three-dimensional iPS cell models can provide platforms for drug discovery and translational studies into the treatment of AD. PMID:26657644

Modeling Alzheimer's disease with human induced pluripotent stem (iPS) cells.

PubMed

Mungenast, Alison E; Siegert, Sandra; Tsai, Li-Huei

2016-06-01

In the last decade, induced pluripotent stem (iPS) cells have revolutionized the utility of human in vitro models of neurological disease. The iPS-derived and differentiated cells allow researchers to study the impact of a distinct cell type in health and disease as well as performing therapeutic drug screens on a human genetic background. In particular, clinical trials for Alzheimer's disease (AD) have been failing. Two of the potential reasons are first, the species gap involved in proceeding from initial discoveries in rodent models to human studies, and second, an unsatisfying patient stratification, meaning subgrouping patients based on the disease severity due to the lack of phenotypic and genetic markers. iPS cells overcome this obstacles and will improve our understanding of disease subtypes in AD. They allow researchers conducting in depth characterization of neural cells from both familial and sporadic AD patients as well as preclinical screens on human cells. In this review, we briefly outline the status quo of iPS cell research in neurological diseases along with the general advantages and pitfalls of these models. We summarize how genome-editing techniques such as CRISPR/Cas9 will allow researchers to reduce the problem of genomic variability inherent to human studies, followed by recent iPS cell studies relevant to AD. We then focus on current techniques for the differentiation of iPS cells into neural cell types that are relevant to AD research. Finally, we discuss how the generation of three-dimensional cell culture systems will be important for understanding AD phenotypes in a complex cellular milieu, and how both two- and three-dimensional iPS cell models can provide platforms for drug discovery and translational studies into the treatment of AD. Copyright © 2015 Elsevier Inc. All rights reserved.

A new glucocerebrosidase-deficient neuronal cell model provides a tool to probe pathophysiology and therapeutics for Gaucher disease

PubMed Central

Westbroek, Wendy; Nguyen, Matthew; Siebert, Marina; Lindstrom, Taylor; Burnett, Robert A.; Aflaki, Elma; Jung, Olive; Tamargo, Rafael; Rodriguez-Gil, Jorge L.; Acosta, Walter; Hendrix, An; Behre, Bahafta; Tayebi, Nahid; Fujiwara, Hideji; Sidhu, Rohini; Renvoise, Benoit; Ginns, Edward I.; Dutra, Amalia; Pak, Evgenia; Cramer, Carole; Ory, Daniel S.; Pavan, William J.

2016-01-01

ABSTRACT Glucocerebrosidase is a lysosomal hydrolase involved in the breakdown of glucosylceramide. Gaucher disease, a recessive lysosomal storage disorder, is caused by mutations in the gene GBA1. Dysfunctional glucocerebrosidase leads to accumulation of glucosylceramide and glycosylsphingosine in various cell types and organs. Mutations in GBA1 are also a common genetic risk factor for Parkinson disease and related synucleinopathies. In recent years, research on the pathophysiology of Gaucher disease, the molecular link between Gaucher and Parkinson disease, and novel therapeutics, have accelerated the need for relevant cell models with GBA1 mutations. Although induced pluripotent stem cells, primary rodent neurons, and transfected neuroblastoma cell lines have been used to study the effect of glucocerebrosidase deficiency on neuronal function, these models have limitations because of challenges in culturing and propagating the cells, low yield, and the introduction of exogenous mutant GBA1. To address some of these difficulties, we established a high yield, easy-to-culture mouse neuronal cell model with nearly complete glucocerebrosidase deficiency representative of Gaucher disease. We successfully immortalized cortical neurons from embryonic null allele gba−/− mice and the control littermate (gba+/+) by infecting differentiated primary cortical neurons in culture with an EF1α-SV40T lentivirus. Immortalized gba−/− neurons lack glucocerebrosidase protein and enzyme activity, and exhibit a dramatic increase in glucosylceramide and glucosylsphingosine accumulation, enlarged lysosomes, and an impaired ATP-dependent calcium-influx response; these phenotypical characteristics were absent in gba+/+ neurons. This null allele gba−/− mouse neuronal model provides a much-needed tool to study the pathophysiology of Gaucher disease and to evaluate new therapies. PMID:27482815

Spatially-Explicit Simulation Modeling of Ecological Response to Climate Change: Methodological Considerations in Predicting Shifting Population Dynamics of Infectious Disease Vectors.

PubMed

Dhingra, Radhika; Jimenez, Violeta; Chang, Howard H; Gambhir, Manoj; Fu, Joshua S; Liu, Yang; Remais, Justin V

2013-09-01

Poikilothermic disease vectors can respond to altered climates through spatial changes in both population size and phenology. Quantitative descriptors to characterize, analyze and visualize these dynamic responses are lacking, particularly across large spatial domains. In order to demonstrate the value of a spatially explicit, dynamic modeling approach, we assessed spatial changes in the population dynamics of Ixodes scapularis , the Lyme disease vector, using a temperature-forced population model simulated across a grid of 4 × 4 km cells covering the eastern United States, using both modeled (Weather Research and Forecasting (WRF) 3.2.1) baseline/current (2001-2004) and projected (Representative Concentration Pathway (RCP) 4.5 and RCP 8.5; 2057-2059) climate data. Ten dynamic population features (DPFs) were derived from simulated populations and analyzed spatially to characterize the regional population response to current and future climate across the domain. Each DPF under the current climate was assessed for its ability to discriminate observed Lyme disease risk and known vector presence/absence, using data from the US Centers for Disease Control and Prevention. Peak vector population and month of peak vector population were the DPFs that performed best as predictors of current Lyme disease risk. When examined under baseline and projected climate scenarios, the spatial and temporal distributions of DPFs shift and the seasonal cycle of key questing life stages is compressed under some scenarios. Our results demonstrate the utility of spatial characterization, analysis and visualization of dynamic population responses-including altered phenology-of disease vectors to altered climate.

Spatially-Explicit Simulation Modeling of Ecological Response to Climate Change: Methodological Considerations in Predicting Shifting Population Dynamics of Infectious Disease Vectors

PubMed Central

Dhingra, Radhika; Jimenez, Violeta; Chang, Howard H.; Gambhir, Manoj; Fu, Joshua S.; Liu, Yang; Remais, Justin V.

2014-01-01

Poikilothermic disease vectors can respond to altered climates through spatial changes in both population size and phenology. Quantitative descriptors to characterize, analyze and visualize these dynamic responses are lacking, particularly across large spatial domains. In order to demonstrate the value of a spatially explicit, dynamic modeling approach, we assessed spatial changes in the population dynamics of Ixodes scapularis, the Lyme disease vector, using a temperature-forced population model simulated across a grid of 4 × 4 km cells covering the eastern United States, using both modeled (Weather Research and Forecasting (WRF) 3.2.1) baseline/current (2001–2004) and projected (Representative Concentration Pathway (RCP) 4.5 and RCP 8.5; 2057–2059) climate data. Ten dynamic population features (DPFs) were derived from simulated populations and analyzed spatially to characterize the regional population response to current and future climate across the domain. Each DPF under the current climate was assessed for its ability to discriminate observed Lyme disease risk and known vector presence/absence, using data from the US Centers for Disease Control and Prevention. Peak vector population and month of peak vector population were the DPFs that performed best as predictors of current Lyme disease risk. When examined under baseline and projected climate scenarios, the spatial and temporal distributions of DPFs shift and the seasonal cycle of key questing life stages is compressed under some scenarios. Our results demonstrate the utility of spatial characterization, analysis and visualization of dynamic population responses—including altered phenology—of disease vectors to altered climate. PMID:24772388

Carotid Artery Disease and Stroke

MedlinePlus

... Obesity: Excess weight raises the chances of having high blood pressure and diabetes.  Lack of exercise: A lack of exercise can ... worse. Some lifestyle changes include:  Quit smoking  Control high blood pressure, high cholesterol, diabetes, and heart disease.  See your doctor regularly  Eat ...

Parental anxiety associated with Kawasaki disease in previously healthy children.

PubMed

Chahal, Nita; Clarizia, Nadia A; McCrindle, Brian W; Boydell, Katherine M; Obadia, Maya; Manlhiot, Cedric; Dillenburg, Rejane; Yeung, Rae S M

2010-01-01

The objective of this study was to explore the lived experience of parents of children diagnosed with Kawasaki disease (KD) and to identify factors associated with increased levels of parental anxiety. Three focus groups were conducted including 25 parents of 17 patients with KD, seven (41%) of whom had coronary artery complications. A conceptual model was developed to depict parental experiences and illustrate the key issues related to heightened anxiety. Themes identified included anxiety related to the child's sudden illness and delay in obtaining a correct diagnosis because of the lack of health care providers' awareness and knowledge regarding KD. Parents were frustrated by the lack of information available in lay language and the limited scientific knowledge regarding the long-term consequences of the disease. Parents also reported positive transformations and different perspective toward challenges in life. However, the parents of children with coronary artery complications expressed persistent anxiety even years after the acute phase of the illness due to the uncertainty of the long-term prognosis. There remains a critical need for richly textured research data on the perspective and experience of families of children with KD. Copyright 2010 National Association of Pediatric Nurse Practitioners. Published by Mosby, Inc. All rights reserved.

Chloroquine inhibited Ebola virus replication in vitro but failed to protect against infection and disease in the in vivo guinea pig model.

PubMed

Dowall, Stuart D; Bosworth, Andrew; Watson, Robert; Bewley, Kevin; Taylor, Irene; Rayner, Emma; Hunter, Laura; Pearson, Geoff; Easterbrook, Linda; Pitman, James; Hewson, Roger; Carroll, Miles W

2015-12-01

Ebola virus (EBOV) is highly pathogenic, with a predisposition to cause outbreaks in human populations accompanied by significant mortality. Owing to the lack of approved therapies, screening programmes of potentially efficacious drugs have been undertaken. One of these studies has demonstrated the possible utility of chloroquine against EBOV using pseudotyped assays. In mouse models of EBOV disease there are conflicting reports of the therapeutic effects of chloroquine. There are currently no reports of its efficacy using the larger and more stringent guinea pig model of infection. In this study we have shown that replication of live EBOV is impaired by chloroquine in vitro. However, no protective effects were observed in vivo when EBOV-infected guinea pigs were treated with chloroquine. These results advocate that chloroquine should not be considered as a treatment strategy for EBOV.

Epidemic predictions in an imperfect world: modelling disease spread with partial data

PubMed Central

Dawson, Peter M.; Werkman, Marleen; Brooks-Pollock, Ellen; Tildesley, Michael J.

2015-01-01

‘Big-data’ epidemic models are being increasingly used to influence government policy to help with control and eradication of infectious diseases. In the case of livestock, detailed movement records have been used to parametrize realistic transmission models. While livestock movement data are readily available in the UK and other countries in the EU, in many countries around the world, such detailed data are not available. By using a comprehensive database of the UK cattle trade network, we implement various sampling strategies to determine the quantity of network data required to give accurate epidemiological predictions. It is found that by targeting nodes with the highest number of movements, accurate predictions on the size and spatial spread of epidemics can be made. This work has implications for countries such as the USA, where access to data is limited, and developing countries that may lack the resources to collect a full dataset on livestock movements. PMID:25948687

Rhesus monkey model of liver disease reflecting clinical disease progression and hepatic gene expression analysis

PubMed Central

Wang, Hong; Tan, Tao; Wang, Junfeng; Niu, Yuyu; Yan, Yaping; Guo, Xiangyu; Kang, Yu; Duan, Yanchao; Chang, Shaohui; Liao, Jianpeng; Si, Chenyang; Ji, Weizhi; Si, Wei

2015-01-01

Alcoholic liver disease (ALD) is a significant public health issue with heavy medical and economic burdens. The aetiology of ALD is not yet completely understood. The development of drugs and therapies for ALD is hampered by a lack of suitable animal models that replicate both the histological and metabolic features of human ALD. Here, we characterize a rhesus monkey model of alcohol-induced liver steatosis and hepatic fibrosis that is compatible with the clinical progression of the biochemistry and pathology in humans with ALD. Microarray analysis of hepatic gene expression was conducted to identify potential molecular signatures of ALD progression. The up-regulation of expression of hepatic genes related to liver steatosis (CPT1A, FASN, LEPR, RXRA, IGFBP1, PPARGC1A and SLC2A4) was detected in our rhesus model, as was the down-regulation of such genes (CYP7A1, HMGCR, GCK and PNPLA3) and the up-regulation of expression of hepatic genes related to liver cancer (E2F1, OPCML, FZD7, IGFBP1 and LEF1). Our results demonstrate that this ALD model reflects the clinical disease progression and hepatic gene expression observed in humans. These findings will be useful for increasing the understanding of ALD pathogenesis and will benefit the development of new therapeutic procedures and pharmacological reagents for treating ALD. PMID:26442469

Contribution of pertussis toxin to the pathogenesis of pertussis disease

PubMed Central

Carbonetti, Nicholas H.

2015-01-01

Pertussis toxin (PT) is a multisubunit protein toxin secreted by Bordetella pertussis, the bacterial agent of the disease pertussis or whooping cough. PT in detoxified form is a component of all licensed acellular pertussis vaccines, since it is considered to be an important virulence factor for this pathogen. PT inhibits G protein-coupled receptor signaling through Gi proteins in mammalian cells, an activity that has led to its widespread use as a cell biology tool. But how does this activity of PT contribute to pertussis, including the severe respiratory symptoms of this disease? In this minireview, the contribution of PT to the pathogenesis of pertussis disease will be considered based on evidence from both human infections and animal model studies. Although definitive proof of the role of PT in humans is lacking, substantial evidence supports the idea that PT is a major contributor to pertussis pathology, including the severe respiratory symptoms associated with this disease. PMID:26394801

Mapping X-Disease Phytoplasma Resistance in Prunus virginiana.

PubMed

Lenz, Ryan R; Dai, Wenhao

2017-01-01

Phytoplasmas such as " Candidatus Phytoplasma pruni," the causal agent of X-disease of stone fruits, lack detailed biological analysis. This has limited the understanding of plant resistance mechanisms. Chokecherry ( Prunus virginiana L.) is a promising model to be used for the plant-phytoplasma interaction due to its documented ability to resist X-disease infection. A consensus chokecherry genetic map "Cho" was developed with JoinMap 4.0 by joining two parental maps. The new map contains a complete set of 16 linkage groups, spanning a genetic distance of 2,172 cM with an average marker density of 3.97 cM. Three significant quantitative trait loci (QTL) associated with X-disease resistance were identified contributing to a total of 45.9% of the phenotypic variation. This updated genetic linkage map and the identified QTL will provide the framework needed to facilitate molecular genetics, genomics, breeding, and biotechnology research concerning X-disease in chokecherry and other Prunus species.

Adapting Knowledge Translation Strategies for Rare Rheumatic Diseases.

PubMed

Cellucci, Tania; Lee, Shirley; Webster, Fiona

2016-08-01

Rare rheumatic diseases present unique challenges to knowledge translation (KT) researchers. There is often an urgent need to transfer knowledge from research findings into clinical practice to facilitate earlier diagnosis and better outcomes. However, existing KT frameworks have not addressed the specific considerations surrounding rare diseases for which gold standard evidence is not available. Several widely adopted models provide guidance for processes and problems associated with KT. However, they do not address issues surrounding creation or synthesis of knowledge for rare diseases. Additional problems relate to lack of awareness or experience in intended knowledge users, low motivation, and potential barriers to changing practice or policy. Strategies to address the challenges of KT for rare rheumatic diseases include considering different levels of evidence available, linking knowledge creation and transfer directly, incorporating patient and physician advocacy efforts to generate awareness of conditions, and selecting strategies to address barriers to practice or policy change.

NYVAC vector modified by C7L viral gene insertion improves T cell immune responses and effectiveness against leishmaniasis.

PubMed

Sánchez-Sampedro, L; Mejías-Pérez, E; S Sorzano, Carlos Óscar; Nájera, J L; Esteban, M

2016-07-15

The NYVAC poxvirus vector is used as vaccine candidate for HIV and other diseases, although there is only limited experimental information on its immunogenicity and effectiveness for use against human pathogens. Here we defined the selective advantage of NYVAC vectors in a mouse model by comparing the immune responses and protection induced by vectors that express the LACK (Leishmania-activated C-kinase antigen), alone or with insertion of the viral host range gene C7L that allows the virus to replicate in human cells. Using DNA prime/virus boost protocols, we show that replication-competent NYVAC-LACK that expresses C7L (NYVAC-LACK-C7L) induced higher-magnitude polyfunctional CD8(+) and CD4(+) primary adaptive and effector memory T cell responses (IFNγ, TNFα, IL-2, CD107a) to LACK antigen than non-replicating NYVAC-LACK. Compared to NYVAC-LACK, the NYVAC-LACK-C7L-induced CD8(+) T cell population also showed higher proliferation when stimulated with LACK antigen. After a challenge by subcutaneous Leishmania major metacyclic promastigotes, NYVAC-LACK-C7L-vaccinated mouse groups showed greater protection than the NYVAC-LACK-vaccinated group. Our results indicate that the type and potency of immune responses induced by LACK-expressing NYVAC vectors is improved by insertion of the C7L gene, and that a replication-competent vector as a vaccine renders greater protection against a human pathogen than a non-replicating vector. Copyright © 2016 Elsevier B.V. All rights reserved.

Transient receptor potential ankyrin 1 mediates chronic pancreatitis pain in mice.

PubMed

Cattaruzza, Fiore; Johnson, Cali; Leggit, Alan; Grady, Eileen; Schenk, A Katrin; Cevikbas, Ferda; Cedron, Wendy; Bondada, Sandhya; Kirkwood, Rebekah; Malone, Brian; Steinhoff, Martin; Bunnett, Nigel; Kirkwood, Kimberly S

2013-06-01

Chronic pancreatitis (CP) is a devastating disease characterized by persistent and uncontrolled abdominal pain. Our lack of understanding is partially due to the lack of experimental models that mimic the human disease and also to the lack of validated behavioral measures of visceral pain. The ligand-gated cation channel transient receptor potential ankyrin 1 (TRPA1) mediates inflammation and pain in early experimental pancreatitis. It is unknown if TRPA1 causes fibrosis and sustained pancreatic pain. We induced CP by injecting the chemical agent trinitrobenzene sulfonic acid (TNBS), which causes severe acute pancreatitis, into the pancreatic duct of C57BL/6 trpa1(+/+) and trpa1(-/-) mice. Chronic inflammatory changes and pain behaviors were assessed after 2-3 wk. TNBS injection caused marked pancreatic fibrosis with increased collagen-staining intensity, atrophy, fatty replacement, monocyte infiltration, and pancreatic stellate cell activation, and these changes were reflected by increased histological damage scores. TNBS-injected animals showed mechanical hypersensitivity during von Frey filament probing of the abdomen, decreased daily voluntary wheel-running activity, and increased immobility scores during open-field testing. Pancreatic TNBS also reduced the threshold to hindpaw withdrawal to von Frey filament probing, suggesting central sensitization. Inflammatory changes and pain indexes were significantly reduced in trpa1(-/-) mice. In conclusion, we have characterized in mice a model of CP that resembles the human condition, with marked histological changes and behavioral measures of pain. We have demonstrated, using novel and objective pain measurements, that TRPA1 mediates inflammation and visceral hypersensitivity in CP and could be a therapeutic target for the treatment of sustained inflammatory abdominal pain.

Lethal Crimean-Congo hemorrhagic fever virus infection in interferon α/β receptor knockout mice is associated with high viral loads, proinflammatory responses, and coagulopathy.

PubMed

Zivcec, Marko; Safronetz, David; Scott, Dana; Robertson, Shelly; Ebihara, Hideki; Feldmann, Heinz

2013-06-15

Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed viral hemorrhagic fever characterized by rapid onset of flu-like symptoms often followed by hemorrhagic manifestations. CCHF virus (CCHFV), a bunyavirus in the Nairovirus genus, is capable of infecting a wide range of mammalian hosts in nature but so far only causes disease in humans. Recently, immunocompromised mice have been reported as CCHF disease models, but detailed characterization is lacking. Here, we closely followed infection and disease progression in CCHFV-infected interferon α/β receptor knockout (IFNAR(-/-)) mice and age-matched wild-type (WT) mice. WT mice quickly clear CCHFV without developing any disease signs. In contrast, CCHFV infected IFNAR(-/-) mice develop an acute fulminant disease with high viral loads leading to organ pathology (liver and lymphoid tissues), marked proinflammatory host responses, severe thrombocytopenia, coagulopathy, and death. Disease progression closely mimics hallmarks of human CCHF disease, making IFNAR(-/-) mice an excellent choice to assess medical countermeasures.

The potential investment impact of improved access to accelerated approval on the development of treatments for low prevalence rare diseases

PubMed Central

2011-01-01

Background Over 95% of rare diseases lack treatments despite many successful treatment studies in animal models. To improve access to treatments, the Accelerated Approval (AA) regulations were implemented allowing the use of surrogate endpoints to achieve drug approval and accelerate development of life-saving therapies. Many rare diseases have not utilized AA due to the difficulty in gaining acceptance of novel surrogate endpoints in untreated rare diseases. Methods To assess the potential impact of improved AA accessibility, we devised clinical development programs using proposed clinical or surrogate endpoints for fifteen rare disease treatments. Results We demonstrate that better AA access could reduce development costs by approximately 60%, increase investment value, and foster development of three times as many rare disease drugs for the same investment. Conclusion Our research brings attention to the need for well-defined and practical qualification criteria for the use of surrogate endpoints to allow more access to the AA approval pathway in clinical trials for rare diseases. PMID:21733145

The fused in sarcoma protein forms cytoplasmic aggregates in motor neurons derived from integration-free induced pluripotent stem cells generated from a patient with familial amyotrophic lateral sclerosis carrying the FUS-P525L mutation.

PubMed

Liu, Xinxiu; Chen, Jiayu; Liu, Wenchao; Li, Xiaogang; Chen, Qi; Liu, Tao; Gao, Shaorong; Deng, Min

2015-07-01

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons (MNs) and has no effective treatment. Mutations in the fused in sarcoma (FUS) gene and abnormal aggregation of FUS protein have been reported in ALS. However, the mechanisms involved in ALS are poorly understood. Clinical drug trails have failed due to a lack of appropriate disease models, including a lack of access to MNs from ALS patients. Induced pluripotent stem (iPS) cells derived from patients with ALS provide an indispensable resource for in vitro mechanistic studies and for future patient-specific cell-based therapies. Previous reports demonstrated that viral-based ALS-iPS cells generated from fibroblasts harvested from Caucasian populations are ideal for basic research; however, ALS-iPS cells are precluded from cell-based therapeutic applications because of the risks associated with the integration of viral sequences into the genome and inconvenience associated with dermal biopsies. To establish a model for use in clinical applications, using episomal vectors, we generated an integration-free iPS cell line from peripheral blood mononuclear cells (PBMCs) harvested from a familial ALS (FALS) patient carrying the FUS-P525L mutation and a healthy control. Furthermore, we successfully differentiated ALS patient-specific iPS cells into MNs and subsequently detected cytoplasmic mislocalization and formation of FUS protein aggregates in MNs due to the FUS-P525L mutation. Our findings offer a cell-based disease model for use in further elucidating ALS pathogenesis and provide a tool for exploring gene repair coupled with cell replacement therapy.

IMPACT: a generic tool for modelling and simulating public health policy.

PubMed

Ainsworth, J D; Carruthers, E; Couch, P; Green, N; O'Flaherty, M; Sperrin, M; Williams, R; Asghar, Z; Capewell, S; Buchan, I E

2011-01-01

Populations are under-served by local health policies and management of resources. This partly reflects a lack of realistically complex models to enable appraisal of a wide range of potential options. Rising computing power coupled with advances in machine learning and healthcare information now enables such models to be constructed and executed. However, such models are not generally accessible to public health practitioners who often lack the requisite technical knowledge or skills. To design and develop a system for creating, executing and analysing the results of simulated public health and healthcare policy interventions, in ways that are accessible and usable by modellers and policy-makers. The system requirements were captured and analysed in parallel with the statistical method development for the simulation engine. From the resulting software requirement specification the system architecture was designed, implemented and tested. A model for Coronary Heart Disease (CHD) was created and validated against empirical data. The system was successfully used to create and validate the CHD model. The initial validation results show concordance between the simulation results and the empirical data. We have demonstrated the ability to connect health policy-modellers and policy-makers in a unified system, thereby making population health models easier to share, maintain, reuse and deploy.

Probiotic-based strategies for therapeutic and prophylactic use against multiple gastrointestinal diseases

PubMed Central

Varankovich, Natallia V.; Nickerson, Michael T.; Korber, Darren R.

2015-01-01

Probiotic bacteria offer a number of potential health benefits when administered in sufficient amounts that in part include reducing the number of harmful organisms in the intestine, producing antimicrobial substances and stimulating the body’s immune response. However, precisely elucidating the probiotic effect of a specific bacterium has been challenging due to the complexity of the gut’s microbial ecosystem and a lack of definitive means for its characterization. This review provides an overview of widely used and recently described probiotics, their impact on the human’s gut microflora as a preventative treatment of disease, human/animal models being used to help show efficacy, and discusses the potential use of probiotics in gastrointestinal diseases associated with antibiotic administration. PMID:26236287

ChronicOnline: Implementing a mHealth solution for monitoring and early alerting in chronic obstructive pulmonary disease.

PubMed

Bitsaki, Marina; Koutras, Christos; Koutras, George; Leymann, Frank; Steimle, Frank; Wagner, Sebastian; Wieland, Matthias

2017-09-01

Lack of time or economic difficulties prevent chronic obstructive pulmonary disease patients from communicating regularly with their physicians, thus inducing exacerbation of their chronic condition and possible hospitalization. Enhancing Chronic patients' Health Online proposes a new, sustainable and innovative business model that provides at low cost and at significant savings to the national health system, a preventive health service for chronic obstructive pulmonary disease patients, by combining human medical expertise with state-of-the-art online service delivery based on cloud computing, service-oriented architecture, data analytics, and mobile applications. In this article, we implement the frontend applications of the Enhancing Chronic patients' Health Online system and describe their functionality and the interfaces available to the users.

Application of a theoretical model to evaluate COPD disease management.

PubMed

Lemmens, Karin M M; Nieboer, Anna P; Rutten-Van Mölken, Maureen P M H; van Schayck, Constant P; Asin, Javier D; Dirven, Jos A M; Huijsman, Robbert

2010-03-26

Disease management programmes are heterogeneous in nature and often lack a theoretical basis. An evaluation model has been developed in which theoretically driven inquiries link disease management interventions to outcomes. The aim of this study is to methodically evaluate the impact of a disease management programme for patients with chronic obstructive pulmonary disease (COPD) on process, intermediate and final outcomes of care in a general practice setting. A quasi-experimental research was performed with 12-months follow-up of 189 COPD patients in primary care in the Netherlands. The programme included patient education, protocolised assessment and treatment of COPD, structural follow-up and coordination by practice nurses at 3, 6 and 12 months. Data on intermediate outcomes (knowledge, psychosocial mediators, self-efficacy and behaviour) and final outcomes (dyspnoea, quality of life, measured by the CRQ and CCQ, and patient experiences) were obtained from questionnaires and electronic registries. Implementation of the programme was associated with significant improvements in dyspnoea (p < 0.001) and patient experiences (p < 0.001). No significant improvement was found in mean quality of life scores. Improvements were found in several intermediate outcomes, including investment beliefs (p < 0.05), disease-specific knowledge (p < 0.01; p < 0.001) and medication compliance (p < 0.01). Overall, process improvement was established. The model showed associations between significantly improved intermediate outcomes and improvements in quality of life and dyspnoea. The application of a theory-driven model enhances the design and evaluation of disease management programmes aimed at improving health outcomes. This study supports the notion that a theoretical approach strengthens the evaluation designs of complex interventions. Moreover, it provides prudent evidence that the implementation of COPD disease management programmes can positively influence outcomes of care.

Application of a theoretical model to evaluate COPD disease management

PubMed Central

2010-01-01

Background Disease management programmes are heterogeneous in nature and often lack a theoretical basis. An evaluation model has been developed in which theoretically driven inquiries link disease management interventions to outcomes. The aim of this study is to methodically evaluate the impact of a disease management programme for patients with chronic obstructive pulmonary disease (COPD) on process, intermediate and final outcomes of care in a general practice setting. Methods A quasi-experimental research was performed with 12-months follow-up of 189 COPD patients in primary care in the Netherlands. The programme included patient education, protocolised assessment and treatment of COPD, structural follow-up and coordination by practice nurses at 3, 6 and 12 months. Data on intermediate outcomes (knowledge, psychosocial mediators, self-efficacy and behaviour) and final outcomes (dyspnoea, quality of life, measured by the CRQ and CCQ, and patient experiences) were obtained from questionnaires and electronic registries. Results Implementation of the programme was associated with significant improvements in dyspnoea (p < 0.001) and patient experiences (p < 0.001). No significant improvement was found in mean quality of life scores. Improvements were found in several intermediate outcomes, including investment beliefs (p < 0.05), disease-specific knowledge (p < 0.01; p < 0.001) and medication compliance (p < 0.01). Overall, process improvement was established. The model showed associations between significantly improved intermediate outcomes and improvements in quality of life and dyspnoea. Conclusions The application of a theory-driven model enhances the design and evaluation of disease management programmes aimed at improving health outcomes. This study supports the notion that a theoretical approach strengthens the evaluation designs of complex interventions. Moreover, it provides prudent evidence that the implementation of COPD disease management programmes can positively influence outcomes of care. PMID:20346135

High-throughput 3D whole-brain quantitative histopathology in rodents

PubMed Central

Vandenberghe, Michel E.; Hérard, Anne-Sophie; Souedet, Nicolas; Sadouni, Elmahdi; Santin, Mathieu D.; Briet, Dominique; Carré, Denis; Schulz, Jocelyne; Hantraye, Philippe; Chabrier, Pierre-Etienne; Rooney, Thomas; Debeir, Thomas; Blanchard, Véronique; Pradier, Laurent; Dhenain, Marc; Delzescaux, Thierry

2016-01-01

Histology is the gold standard to unveil microscopic brain structures and pathological alterations in humans and animal models of disease. However, due to tedious manual interventions, quantification of histopathological markers is classically performed on a few tissue sections, thus restricting measurements to limited portions of the brain. Recently developed 3D microscopic imaging techniques have allowed in-depth study of neuroanatomy. However, quantitative methods are still lacking for whole-brain analysis of cellular and pathological markers. Here, we propose a ready-to-use, automated, and scalable method to thoroughly quantify histopathological markers in 3D in rodent whole brains. It relies on block-face photography, serial histology and 3D-HAPi (Three Dimensional Histology Analysis Pipeline), an open source image analysis software. We illustrate our method in studies involving mouse models of Alzheimer’s disease and show that it can be broadly applied to characterize animal models of brain diseases, to evaluate therapeutic interventions, to anatomically correlate cellular and pathological markers throughout the entire brain and to validate in vivo imaging techniques. PMID:26876372

Modeling of TREX1-Dependent Autoimmune Disease using Human Stem Cells Highlights L1 Accumulation as a Source of Neuroinflammation.

PubMed

Thomas, Charles A; Tejwani, Leon; Trujillo, Cleber A; Negraes, Priscilla D; Herai, Roberto H; Mesci, Pinar; Macia, Angela; Crow, Yanick J; Muotri, Alysson R

2017-09-07

Three-prime repair exonuclease 1 (TREX1) is an anti-viral enzyme that cleaves nucleic acids in the cytosol, preventing accumulation and a subsequent type I interferon-associated inflammatory response. Autoimmune diseases, including Aicardi-Goutières syndrome (AGS) and systemic lupus erythematosus, can arise when TREX1 function is compromised. AGS is a neuroinflammatory disorder with severe and persistent intellectual and physical problems. Here we generated a human AGS model that recapitulates disease-relevant phenotypes using pluripotent stem cells lacking TREX1. We observed abundant extrachromosomal DNA in TREX1-deficient neural cells, of which endogenous Long Interspersed Element-1 retrotransposons were a major source. TREX1-deficient neurons also exhibited increased apoptosis and formed three-dimensional cortical organoids of reduced size. TREX1-deficient astrocytes further contributed to the observed neurotoxicity through increased type I interferon secretion. In this model, reverse-transcriptase inhibitors rescued the neurotoxicity of AGS neurons and organoids, highlighting their potential utility in therapeutic regimens for AGS and related disorders. Copyright © 2017 Elsevier Inc. All rights reserved.

Dengue virus infection: current concepts in immune mechanisms and lessons from murine models

PubMed Central

Guabiraba, Rodrigo; Ryffel, Bernhard

2014-01-01

Dengue viruses (DENV), a group of four serologically distinct but related flaviviruses, are responsible for one of the most important emerging viral diseases. This mosquito-borne disease has a great impact in tropical and subtropical areas of the world in terms of illness, mortality and economic costs, mainly due to the lack of approved vaccine or antiviral drugs. Infections with one of the four serotypes of DENV (DENV-1–4) result in symptoms ranging from an acute, self-limiting febrile illness, dengue fever, to severe dengue haemorrhagic fever or dengue shock syndrome. We reviewed the existing mouse models of infection, including the DENV-2-adapted strain P23085. The role of CC chemokines, interleukin-17 (IL-17), IL-22 and invariant natural killer T cells in mediating the exacerbation of disease in immune-competent mice is highlighted. Investigations in both immune-deficient and immune-competent mouse models of DENV infection may help to identify key host–pathogen factors and devise novel therapies to restrain the systemic and local inflammatory responses associated with severe DENV infection. PMID:24182427

In vitro pathological modelling using patient-specific induced pluripotent stem cells: the case of progeria.

PubMed

Nissan, Xavier; Blondel, Sophie; Peschanski, Marc

2011-12-01

Progeria, also known as HGPS (Hutchinson-Gilford progeria syndrome), is a rare fatal genetic disease characterized by an appearance of accelerated aging in children. This syndrome is typically caused by mutations in codon 608 (C1804T) of the gene encoding lamins A and C, LMNA, leading to the production of a truncated form of the protein called progerin. Owing to their unique potential to self-renew and to differentiate into any cell types of the organism, pluripotent stem cells offer a unique tool to study molecular and cellular mechanisms related to this global and systemic disease. Recent studies have exploited this potential by generating human induced pluripotent stem cells from HGPS patients' fibroblasts displaying several phenotypic defects characteristic of HGPS such as nuclear abnormalities, progerin expression, altered DNA-repair mechanisms and premature senescence. Altogether, these findings provide new insights on the use of pluripotent stem cells for pathological modelling and may open original therapeutic perspectives for diseases that lack pre-clinical in vitro human models, such as HGPS.

Blood-based biomarkers in Alzheimer disease: Current state of the science and a novel collaborative paradigm for advancing from discovery to clinic.

PubMed

O'Bryant, Sid E; Mielke, Michelle M; Rissman, Robert A; Lista, Simone; Vanderstichele, Hugo; Zetterberg, Henrik; Lewczuk, Piotr; Posner, Holly; Hall, James; Johnson, Leigh; Fong, Yiu-Lian; Luthman, Johan; Jeromin, Andreas; Batrla-Utermann, Richard; Villarreal, Alcibiades; Britton, Gabrielle; Snyder, Peter J; Henriksen, Kim; Grammas, Paula; Gupta, Veer; Martins, Ralph; Hampel, Harald

2017-01-01

The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer's disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility and an unclear path for moving basic discovery toward clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state of the art. In addition, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and toward clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional handoff model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases. Copyright © 2016 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

Blood Based Biomarkers in Alzheimer Disease: Current State of the Science and a Novel Collaborative Paradigm for Advancing from Discovery to Clinic

PubMed Central

O’Bryant, Sid E.; Mielke, Michelle M.; Rissman, Robert A.; Lista, Simone; Vanderstichele, Hugo; Zetterberg, Henrik; Lewczuk, Piotr; Posner, Holly; Hall, James; Johnson, Leigh; Fong, Yiu-Lian; Luthman, Johan; Jeromin, Andreas; Batrla-Utermann, Richard; Villarreal, Alcibiades; Britton, Gabrielle; Snyder, Peter J.; Henriksen, Kim; Grammas, Paula; Gupta, Veer; Martins, Ralph; Hampel, Harald

2016-01-01

The last decade has seen a substantial increase in research focused on the identification of blood-based biomarkers that have utility in Alzheimer’s disease (AD). Blood-based biomarkers have significant advantages of being time- and cost-efficient as well as reduced invasiveness and increased patient acceptance. Despite these advantages and increased research efforts, the field has been hampered by lack of reproducibility as well as an unclear path for moving basic discovery towards clinical utilization. Here we reviewed the recent literature on blood-based biomarkers in AD to provide a current state-of-the-art. Additionally, a collaborative model is proposed that leverages academic and industry strengths to facilitate the field in moving past discovery only work and towards clinical use. Key resources are provided. This new public-private partnership model is intended to circumvent the traditional hand-off model and provide a clear and useful paradigm for the advancement of biomarker science in AD and other neurodegenerative diseases. PMID:27870940

Biomarker Discovery by Modeling Behçet's Disease with Patient-Specific Human Induced Pluripotent Stem Cells.

PubMed

Son, Mi-Young; Kim, Young-Dae; Seol, Binna; Lee, Mi-Ok; Na, Hee-Jun; Yoo, Bin; Chang, Jae-Suk; Cho, Yee Sook

2017-01-15

Behçet's disease (BD) is a chronic inflammatory and multisystemic autoimmune disease of unknown etiology. Due to the lack of a specific test for BD, its diagnosis is very difficult and therapeutic options are limited. Induced pluripotent stem cell (iPSC) technology, which provides inaccessible disease-relevant cell types, opens a new era for disease treatment. In this study, we generated BD iPSCs from patient somatic cells and differentiated them into hematopoietic precursor cells (BD iPSC-HPCs) as BD model cells. Based on comparative transcriptome analysis using our BD model cells, we identified eight novel BD-specific genes, AGTR2, CA9, CD44, CXCL1, HTN3, IL-2, PTGER4, and TSLP, which were differentially expressed in BD patients compared with healthy controls or patients with other immune diseases. The use of CXCL1 as a BD biomarker was further validated at the protein level using both a BD iPSC-HPC-based assay system and BD patient serum samples. Furthermore, we show that our BD iPSC-HPC-based drug screening system is highly effective for testing CXCL1 BD biomarkers, as determined by monitoring the efficacy of existing anti-inflammatory drugs. Our results shed new light on the usefulness of patient-specific iPSC technology in the development of a benchmarking platform for disease-specific biomarkers, phenotype- or target-driven drug discovery, and patient-tailored therapies.

Genetic depletion of brain 5HT reveals a common molecular pathway mediating compulsivity and impulsivity.

PubMed

Angoa-Pérez, Mariana; Kane, Michael J; Briggs, Denise I; Sykes, Catherine E; Shah, Mrudang M; Francescutti, Dina M; Rosenberg, David R; Thomas, David M; Kuhn, Donald M

2012-06-01

Neuropsychiatric disorders characterized by behavioral disinhibition, including disorders of compulsivity (e.g. obsessive-compulsive disorder; OCD) and impulse-control (e.g. impulsive aggression), are severe, highly prevalent and chronically disabling. Treatment options for these diseases are extremely limited. The pathophysiological bases of disorders of behavioral disinhibition are poorly understood but it has been suggested that serotonin dysfunction may play a role. Mice lacking the gene encoding brain tryptophan hydroxylase 2 (Tph2-/-), the initial and rate-limiting enzyme in the synthesis of serotonin, were tested in numerous behavioral assays that are well known for their utility in modeling human neuropsychiatric diseases. Mice lacking Tph2 (and brain 5HT) show intense compulsive and impulsive behaviors to include extreme aggression. The impulsivity is motor in form and not cognitive because Tph2-/- mice show normal acquisition and reversal learning on a spatial learning task. Restoration of 5HT levels by treatment of Tph2-/- mice with its immediate precursor 5-hydroxytryptophan attenuated compulsive and impulsive-aggressive behaviors. Surprisingly, in Tph2-/- mice, the lack of 5HT was not associated with anxiety-like behaviors. The results indicate that 5HT mediates behavioral disinhibition in the mammalian brain independent of anxiogenesis. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

[Drugs for 'neglected diseases': a bitter pill].

PubMed

Veeken, H; Pécoul, B

2000-06-24

Neglected diseases are diseases restricted to poor areas; diseases for which there exist no commercial incentives to invest in the development of new treatments. Patients suffering from these diseases often have no access to essential drugs; this can be a matter of life and death. Lack of research and patent protection play a crucial role. Both are cost driven; greed in the West curtails the availability of life-saving drugs for all. Treatment options for trypanosomiasis and visceral leishmaniasis are lacking. It is recommended that drugs for the treatment of 'neglected diseases' be developed via a centralised, public approach that is not based on profit, rather than leaving it to free enterprise.

Type 2 diabetes mellitus in the pathophysiology of Alzheimer's disease.

PubMed

de Nazareth, Aparecida Marcelino

2017-01-01

Both Alzheimer's disease (AD) and type 2 diabetes mellitus (DM) are two common forms of disease worldwide and many studies indicate that people with diabetes, especially DM, are at higher risk of developing AD. AD is characterized by progressive cognitive decline and accumulation of β-amyloid (Aβ) forming senile plaques. DM is a metabolic disorder characterized by hyperglycemia in the context of insulin resistance and relative lack of insulin. Both diseases also share common characteristics such as loss of cognitive function and inflammation. Inflammation resulting from Aβ further induces production of Aβ 1-42 peptides. Inflammation due to overnutrition induces insulin resistance and consequently DM. Memory deficit and a decrease in GLUT4 and hippocampal insulin signaling have been observed in animal models of insulin resistance. The objective of this review was to show the shared characteristics of AD and DM.

α-Synuclein-induced lysosomal dysfunction occurs through disruptions in protein trafficking in human midbrain synucleinopathy models.

PubMed

Mazzulli, Joseph R; Zunke, Friederike; Isacson, Ole; Studer, Lorenz; Krainc, Dimitri

2016-02-16

Parkinson's disease (PD) is an age-related neurodegenerative disorder characterized by the accumulation of protein aggregates comprised of α-synuclein (α-syn). A major barrier in treatment discovery for PD is the lack of identifiable therapeutic pathways capable of reducing aggregates in human neuronal model systems. Mutations in key components of protein trafficking and cellular degradation machinery represent important risk factors for PD; however, their precise role in disease progression and interaction with α-syn remains unclear. Here, we find that α-syn accumulation reduced lysosomal degradation capacity in human midbrain dopamine models of synucleinopathies through disrupting hydrolase trafficking. Accumulation of α-syn at the cell body resulted in aberrant association with cis-Golgi-tethering factor GM130 and disrupted the endoplasmic reticulum-Golgi localization of rab1a, a key mediator of vesicular transport. Overexpression of rab1a restored Golgi structure, improved hydrolase trafficking and activity, and reduced pathological α-syn in patient neurons. Our work suggests that enhancement of lysosomal hydrolase trafficking may prove beneficial in synucleinopathies and indicates that human midbrain disease models may be useful for identifying critical therapeutic pathways in PD and related disorders.

Technical advance: liposomal alendronate depletes monocytes and macrophages in the nonhuman primate model of human disease.

PubMed

Burwitz, Benjamin J; Reed, Jason S; Hammond, Katherine B; Ohme, Merete A; Planer, Shannon L; Legasse, Alfred W; Ericsen, Adam J; Richter, Yoram; Golomb, Gershon; Sacha, Jonah B

2014-09-01

Nonhuman primates are critical animal models for the study of human disorders and disease and offer a platform to assess the role of immune cells in pathogenesis via depletion of specific cellular subsets. However, this model is currently hindered by the lack of reagents that safely and specifically ablate myeloid cells of the monocyte/macrophage Lin. Given the central importance of macrophages in homeostasis and host immunity, development of a macrophage-depletion technique in nonhuman primates would open new avenues of research. Here, using LA at i.v. doses as low as 0.1 mg/kg, we show a >50% transient depletion of circulating monocytes and tissue-resident macrophages in RMs by an 11-color flow cytometric analysis. Diminution of monocytes was followed rapidly by emigration of monocytes from the bone marrow, leading to a rebound of monocytes to baseline levels. Importantly, LA was well-tolerated, as no adverse effects or changes in gross organ function were observed during depletion. These results advance the ex vivo study of myeloid cells by flow cytometry and pave the way for in vivo studies of monocyte/macrophage biology in nonhuman primate models of human disease. © 2014 Society for Leukocyte Biology.

Technical Advance: Liposomal alendronate depletes monocytes and macrophages in the nonhuman primate model of human disease

PubMed Central

Burwitz, Benjamin J.; Reed, Jason S.; Hammond, Katherine B.; Ohme, Merete A.; Planer, Shannon L.; Legasse, Alfred W.; Ericsen, Adam J.; Richter, Yoram; Golomb, Gershon; Sacha, Jonah B.

2014-01-01

Nonhuman primates are critical animal models for the study of human disorders and disease and offer a platform to assess the role of immune cells in pathogenesis via depletion of specific cellular subsets. However, this model is currently hindered by the lack of reagents that safely and specifically ablate myeloid cells of the monocyte/macrophage Lin. Given the central importance of macrophages in homeostasis and host immunity, development of a macrophage-depletion technique in nonhuman primates would open new avenues of research. Here, using LA at i.v. doses as low as 0.1 mg/kg, we show a >50% transient depletion of circulating monocytes and tissue-resident macrophages in RMs by an 11-color flow cytometric analysis. Diminution of monocytes was followed rapidly by emigration of monocytes from the bone marrow, leading to a rebound of monocytes to baseline levels. Importantly, LA was well-tolerated, as no adverse effects or changes in gross organ function were observed during depletion. These results advance the ex vivo study of myeloid cells by flow cytometry and pave the way for in vivo studies of monocyte/macrophage biology in nonhuman primate models of human disease. PMID:24823811

[Approximation to the dynamics of meningococcal meningitis through dynamic systems and time series].

PubMed

Canals, M

1996-02-01

Meningococcal meningitis is subjected to epidemiological surveillance due to its severity and the occasional presentation of epidemic outbreaks. This work analyses previous disease models, generate new ones and analyses monthly cases using ARIMA time series models. The results show that disease dynamics for closed populations is epidemic and the epidemic size is related to the proportion of carriers and the transmissiveness of the agent. In open populations, disease dynamics depends on the admission rate of susceptible and the relative admission of infected individuals. Our model considers a logistic populational growth and carrier admission proportional to populational size, generating an endemic dynamics. Considering a non-instantaneous system response, a greater realism is obtained establishing that the endemic situation may present a dynamics highly sensitive to initial conditions, depending on the transmissiveness and proportion of susceptible individuals in the population. Time series model showed an adequate predictive capacity in terms no longer than 10 months. The lack of long term predictability was attributed to local changes in the proportion of carriers or on transmissiveness that lead to chaotic dynamics over a seasonal pattern. Predictions for 1995 and 1996 were obtained.

The biomedical model of mental disorder: a critical analysis of its validity, utility, and effects on psychotherapy research.

PubMed

Deacon, Brett J

2013-11-01

The biomedical model posits that mental disorders are brain diseases and emphasizes pharmacological treatment to target presumed biological abnormalities. A biologically-focused approach to science, policy, and practice has dominated the American healthcare system for more than three decades. During this time, the use of psychiatric medications has sharply increased and mental disorders have become commonly regarded as brain diseases caused by chemical imbalances that are corrected with disease-specific drugs. However, despite widespread faith in the potential of neuroscience to revolutionize mental health practice, the biomedical model era has been characterized by a broad lack of clinical innovation and poor mental health outcomes. In addition, the biomedical paradigm has profoundly affected clinical psychology via the adoption of drug trial methodology in psychotherapy research. Although this approach has spurred the development of empirically supported psychological treatments for numerous mental disorders, it has neglected treatment process, inhibited treatment innovation and dissemination, and divided the field along scientist and practitioner lines. The neglected biopsychosocial model represents an appealing alternative to the biomedical approach, and an honest and public dialog about the validity and utility of the biomedical paradigm is urgently needed. Copyright © 2013 Elsevier Ltd. All rights reserved.

Trypanosoma cruzi III from armadillos (Dasypus novemcinctus novemcinctus) from Northeastern Venezuela and its biological behavior in murine model. Risk of emergency of Chagas' disease.

PubMed

Morocoima, Antonio; Carrasco, Hernán J; Boadas, Johanna; Chique, José David; Herrera, Leidi; Urdaneta-Morales, Servio

2012-11-01

Trypanosoma cruzi, etiological agent of Chagas' disease, was isolated from armadillos (Dasypus novemcinctus novemcinctus) captured in rural communities Northeastern Venezuela from Nueva Esparta State (no endemic for Chagas' disease), Monagas and Anzoátegui States (endemics). The isolates, genetically typed by PCR-RFLP as belonging to the TcIII DTU, have demonstrated in murine model heterogenic parasitemia, mortality and histotropism with marked parasitism in cardiac, skeletal, and smooth myocytes that showed correlation with lymphobasophilic inflammatory infiltrates. Our finding of T. cruzi infected armadillos in Isla Margarita (Nueva Esparta State), together with reports of triatomine vectors in this region, the accentuated synanthropy of armadillos, intense economic activity, migration due to tourism and the lack of environmental education programs all of them represent risks that could cause the emergence of Chagas' disease in this area. This is the first report of the TcIII DTU in Northeastern Venezuela, thus widening the geographic distribution of this DTU. Copyright © 2012 Elsevier Inc. All rights reserved.

Human Induced Pluripotent Stem Cell-Derived Macrophages for Unraveling Human Macrophage Biology.

PubMed

Zhang, Hanrui; Reilly, Muredach P

2017-11-01

Despite a substantial appreciation for the critical role of macrophages in cardiometabolic diseases, understanding of human macrophage biology has been hampered by the lack of reliable and scalable models for cellular and genetic studies. Human induced pluripotent stem cell (iPSC)-derived macrophages (IPSDM), as an unlimited source of subject genotype-specific cells, will undoubtedly play an important role in advancing our understanding of the role of macrophages in human diseases. In this review, we summarize current literature in the differentiation and characterization of IPSDM at phenotypic, functional, and transcriptomic levels. We emphasize the progress in differentiating iPSC to tissue resident macrophages, and in understanding the ontogeny of in vitro differentiated IPSDM that resembles primitive hematopoiesis, rather than adult definitive hematopoiesis. We review the application of IPSDM in modeling both Mendelian genetic disorders and host-pathogen interactions. Finally, we highlighted the potential areas of research using IPSDM in functional validation of coronary artery disease loci in genome-wide association studies, functional genomic analyses, drug testing, and cell therapeutics in cardiovascular diseases. © 2017 American Heart Association, Inc.

[Inflammatory pancreatic disease due to enzyme autodigestion: an exceptional model of glandular crinophagy].

PubMed

Sánchez-Fayos Calabuig, P; Martín Relloso, M Jesús; González Guirado, Agustina; Porres Cubero, Juan Carlos

2007-01-01

The exocrine pancreas is a functionally dangerous structure since it is exposed to digestion by its most aggressive enzymes (proteases, etc) despite self-protective measures such as the synthesis of some of these enzymes in the form of inactive zymogens (trypsinogen, etc.). We review inflammatory pancreatic disease by separately analyzing its classical forms of onset: acute and chronic pancreatitis (AP and CP). There is general consensus that the initial pathogenic event in AP is intraacinar activation of trypsinogen into trypsin, followed by that of the remaining proenzymes, giving rise to an unusual model of autophagic inflammation. In contrast, consensus is lacking on the initial pathogenic event in CP (toxic-metabolic lesion, oxidative stress, ductal hypertension, etc.?), although in some cases a sequence due to recurrent episodes of AP seems evident. The pathogenic features shared by both forms of the disease and which justify some recent attempts to formulate an overall explanation of the pathogenesis of pancreatitis are discussed. Such an explanation would place both forms of pancreatitis within the conceptual framework of an .

Contrast-enhanced ultrasound measurement of pancreatic blood flow dynamics predicts type 1 diabetes progression in preclinical models.

PubMed

St Clair, Joshua R; Ramirez, David; Passman, Samantha; Benninger, Richard K P

2018-05-01

In type 1 diabetes (T1D), immune-cell infiltration into the islets of Langerhans (insulitis) and β-cell decline occurs many years before diabetes clinically presents. Non-invasively detecting insulitis and β-cell decline would allow the diagnosis of eventual diabetes, and provide a means to monitor therapeutic intervention. However, there is a lack of validated clinical approaches for specifically and non-invasively imaging disease progression leading to T1D. Islets have a denser microvasculature that reorganizes during diabetes. Here we apply contrast-enhanced ultrasound measurements of pancreatic blood-flow dynamics to non-invasively and predictively assess disease progression in T1D pre-clinical models. STZ-treated mice, NOD mice, and adoptive-transfer mice demonstrate altered islet blood-flow dynamics prior to diabetes onset, consistent with islet microvasculature reorganization. These assessments predict both time to diabetes onset and future responders to antiCD4-mediated disease prevention. Thus contrast-enhanced ultrasound measurements of pancreas blood-flow dynamics may provide a clinically deployable predictive marker for disease progression in pre-symptomatic T1D and therapeutic reversal.

Therapeutic effects of the mitochondrial ROS-redox modulator KH176 in a mammalian model of Leigh Disease.

PubMed

de Haas, Ria; Das, Devashish; Garanto, Alejandro; Renkema, Herma G; Greupink, Rick; van den Broek, Petra; Pertijs, Jeanne; Collin, Rob W J; Willems, Peter; Beyrath, Julien; Heerschap, Arend; Russel, Frans G; Smeitink, Jan A

2017-09-15

Leigh Disease is a progressive neurometabolic disorder for which a clinical effective treatment is currently still lacking. Here, we report on the therapeutic efficacy of KH176, a new chemical entity derivative of Trolox, in Ndufs4 -/- mice, a mammalian model for Leigh Disease. Using in vivo brain diffusion tensor imaging, we show a loss of brain microstructural coherence in Ndufs4 -/- mice in the cerebral cortex, external capsule and cerebral peduncle. These findings are in line with the white matter diffusivity changes described in mitochondrial disease patients. Long-term KH176 treatment retained brain microstructural coherence in the external capsule in Ndufs4 -/- mice and normalized the increased lipid peroxidation in this area and the cerebral cortex. Furthermore, KH176 treatment was able to significantly improve rotarod and gait performance and reduced the degeneration of retinal ganglion cells in Ndufs4 -/- mice. These in vivo findings show that further development of KH176 as a potential treatment for mitochondrial disorders is worthwhile to pursue. Clinical trial studies to explore the potency, safety and efficacy of KH176 are ongoing.

Research gaps for three main tropical diseases in the People’s Republic of China

PubMed Central

2013-01-01

This scoping review analyzes the research gaps of three diseases: schistosomiasis japonica, malaria and echinococcosis. Based on available data in the P.R. China, we highlight the gaps between control capacity and prevalence levels, and between diagnostic/drug development and population need for treatment at different stages of the national control programme. After reviewing the literature from 848 original studies and consultations with experts in the field, the gaps were identified as follows. Firstly, the malaria research gaps include (i) deficiency of active testing in the public community and no appropriate technique to evaluate elimination, (ii) lack of sensitive diagnostic tools for asymptomatic patients, (iii) lack of safe drugs for mass administration. Secondly, gaps in research of schistosomiasis include (i) incongruent policy in the implementation of integrated control strategy for schistosomiasis, (ii) lack of effective tools for Oncomelania sp. snail control, (iii) lack of a more sensitive and cheaper diagnostic test for large population samples, (iv) lack of new drugs in addition to praziquantel. Thirdly, gaps in research of echinococcosis include (i) low capacity in field epidemiology studies, (ii) lack of sanitation improvement studies in epidemic areas, (iii) lack of a sensitivity test for early diagnosis, (iv) lack of more effective drugs for short-term treatment. We believe these three diseases can eventually be eliminated in mainland China if all the research gaps are abridged in a short period of time. PMID:23895635

Testing the Adequacy of a Semi-Markov Process

DTIC Science & Technology

2015-09-17

emphasis on covariate detection. 49 VI. BMI Model Analysis According to the Centers of Disease Control and Prevention (CDC) website [24], childhood obesity ...identified an increasing trend over a span of merely four years. Previous studies have drawn correlations between childhood obesity and various childhood and...started in recent years targeting poor dieting and lack of exercise, two of the primary causal factors in childhood obesity according to the CDC

A Novel Locomotion-based Validation Assay for Candidate Drugs Using Drosophila DYT1 Disease Model

DTIC Science & Technology

2013-11-01

the genome using the same parental fly line, minimizing the effect of surrounding sequences and genetic variations on the ...locomotion and GTPC cyclrohydolase protein levels; (3) supplementation of dopamine can partially rescue the locomotion defects of Drosophila larvae...8217- GCGAACAACCAAAAAATCATTGAGATAATAAACTCCTCCATTAG-3’) to make dtorsin cDNA that lacks GAC (D307) (Fig. 1) respectively. After confirming mutated sequences , the insert was again

Next generation patient-derived prostate cancer xenograft models

PubMed Central

Lin, Dong; Xue, Hui; Wang, Yuwei; Wu, Rebecca; Watahiki, Akira; Dong, Xin; Cheng, Hongwei; Wyatt, Alexander W; Collins, Colin C; Gout, Peter W; Wang, Yuzhuo

2014-01-01

There is a critical need for more effective therapeutic approaches for prostate cancer. Research in this area, however, has been seriously hampered by a lack of clinically relevant, experimental in vivo models of the disease. This review particularly focuses on the development of prostate cancer xenograft models based on subrenal capsule grafting of patients’ tumor tissue into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. This technique allows successful development of transplantable, patient-derived cancer tissue xenograft lines not only from aggressive metastatic, but also from localized prostate cancer tissues. The xenografts have been found to retain key biological properties of the original malignancies, including histopathological and molecular characteristics, tumor heterogeneity, response to androgen ablation and metastatic ability. As such, they are highly clinically relevant and provide valuable tools for studies of prostate cancer progression at cellular and molecular levels, drug screening for personalized cancer therapy and preclinical drug efficacy testing; especially when a panel of models is used to cover a broader spectrum of the disease. These xenograft models could therefore be viewed as next-generation models of prostate cancer. PMID:24589467

A comparison of machine learning and Bayesian modelling for molecular serotyping.

PubMed

Newton, Richard; Wernisch, Lorenz

2017-08-11

Streptococcus pneumoniae is a human pathogen that is a major cause of infant mortality. Identifying the pneumococcal serotype is an important step in monitoring the impact of vaccines used to protect against disease. Genomic microarrays provide an effective method for molecular serotyping. Previously we developed an empirical Bayesian model for the classification of serotypes from a molecular serotyping array. With only few samples available, a model driven approach was the only option. In the meanwhile, several thousand samples have been made available to us, providing an opportunity to investigate serotype classification by machine learning methods, which could complement the Bayesian model. We compare the performance of the original Bayesian model with two machine learning algorithms: Gradient Boosting Machines and Random Forests. We present our results as an example of a generic strategy whereby a preliminary probabilistic model is complemented or replaced by a machine learning classifier once enough data are available. Despite the availability of thousands of serotyping arrays, a problem encountered when applying machine learning methods is the lack of training data containing mixtures of serotypes; due to the large number of possible combinations. Most of the available training data comprises samples with only a single serotype. To overcome the lack of training data we implemented an iterative analysis, creating artificial training data of serotype mixtures by combining raw data from single serotype arrays. With the enhanced training set the machine learning algorithms out perform the original Bayesian model. However, for serotypes currently lacking sufficient training data the best performing implementation was a combination of the results of the Bayesian Model and the Gradient Boosting Machine. As well as being an effective method for classifying biological data, machine learning can also be used as an efficient method for revealing subtle biological insights, which we illustrate with an example.

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.

Dystrophin-deficient large animal models: translational research and exon skipping

PubMed Central

Yu, Xinran; Bao, Bo; Echigoya, Yusuke; Yokota, Toshifumi

2015-01-01

Duchenne muscular dystrophy (DMD) is an X-linked recessive genetic disorder caused by mutations in the dystrophin gene. Affecting approximately 1 in 3,600-9337 boys, DMD patients exhibit progressive muscle degeneration leading to fatality as a result of heart or respiratory failure. Despite the severity and prevalence of the disease, there is no cure available. While murine models have been successfully used in illustrating the mechanisms of DMD, their utility in DMD research is limited due to their mild disease phenotypes such as lack of severe skeletal muscle and cardiac symptoms. To address the discrepancy between the severity of disease displayed by murine models and human DMD patients, dystrophin-deficient dog models with a splice site mutation in intron 6 were established. Examples of these are Golden Retriever muscular dystrophy and beagle-based Canine X-linked muscular dystrophy. These large animal models are widely employed in therapeutic DMD research due to their close resemblance to the severity of human patient symptoms. Recently, genetically tailored porcine models of DMD with deleted exon 52 were developed by our group and others, and can potentially act as a new large animal model. While therapeutic outcomes derived from these large animal models can be more reliably extrapolated to DMD patients, a comprehensive understanding of these models is still needed. This paper will discuss recent progress and future directions of DMD studies with large animal models such as canine and porcine models. PMID:26396664

Fmr-1 as an offspring genetic and a maternal environmental factor in neurodevelopmental disease.

PubMed

Zupan, Bojana; Toth, Miklos

2012-01-01

Since fragile X syndrome (FXS) is a typical X-linked mendelian disorder, the protein product associated with the disease (FMRP) is absent or reduced not only in the affected individuals but, in case of full mutation, also in their mothers. Here, by using the mouse model of the disease, we provide evidence that hyperactivity, a typical symptom of FXS, is not wholly induced by the lack of Fmrp in mice but also occurs as a result of its reduced expression in their mother. Genetically wild-type offspring of mutant mothers also had hyperactivity, albeit less pronounced than the mutant offspring. However, other features of FXS reproduced in the mouse model, such as sensory hyperreactivity and seizure susceptibility, were exclusively associated with the absence of Fmrp in the offspring. These data indicate that fmr-1, the gene encoding Fmrp, can be both an offspring genetic and a maternal environmental factor in producing a neurodevelopmental condition.

A sensitive two-photon probe to selectively detect monoamine oxidase B activity in Parkinson’s disease models

NASA Astrophysics Data System (ADS)

Li, Lin; Zhang, Cheng-Wu; Chen, Grace Y. J.; Zhu, Biwei; Chai, Chou; Xu, Qing-Hua; Tan, Eng-King; Zhu, Qing; Lim, Kah-Leong; Yao, Shao Q.

2014-02-01

The unusually high MAO-B activity consistently observed in Parkinson’s disease (PD) patients has been proposed as a biomarker; however, this has not been realized due to the lack of probes suitable for MAO-B-specific detection in live cells/tissues. Here we report the first two-photon, small molecule fluorogenic probe (U1) that enables highly sensitive/specific and real-time imaging of endogenous MAO-B activities across biological samples. We also used U1 to confirm the reported inverse relationship between parkin and MAO-B in PD models. With no apparent toxicity, U1 may be used to monitor MAO-B activities in small animals during disease development. In clinical samples, we find elevated MAO-B activities only in B lymphocytes (not in fibroblasts), hinting that MAO-B activity in peripheral blood cells might be an accessible biomarker for rapid detection of PD. Our results provide important starting points for using small molecule imaging techniques to explore MAO-B at the organism level.

A framework for the interpretation of de novo mutation in human disease

PubMed Central

Samocha, Kaitlin E.; Robinson, Elise B.; Sanders, Stephan J.; Stevens, Christine; Sabo, Aniko; McGrath, Lauren M.; Kosmicki, Jack A.; Rehnström, Karola; Mallick, Swapan; Kirby, Andrew; Wall, Dennis P.; MacArthur, Daniel G.; Gabriel, Stacey B.; dePristo, Mark; Purcell, Shaun M.; Palotie, Aarno; Boerwinkle, Eric; Buxbaum, Joseph D.; Cook, Edwin H.; Gibbs, Richard A.; Schellenberg, Gerard D.; Sutcliffe, James S.; Devlin, Bernie; Roeder, Kathryn; Neale, Benjamin M.; Daly, Mark J.

2014-01-01

Spontaneously arising (‘de novo’) mutations play an important role in medical genetics. For diseases with extensive locus heterogeneity – such as autism spectrum disorders (ASDs) – the signal from de novo mutations (DNMs) is distributed across many genes, making it difficult to distinguish disease-relevant mutations from background variation. We provide a statistical framework for the analysis of DNM excesses per gene and gene set by calibrating a model of de novo mutation. We applied this framework to DNMs collected from 1,078 ASD trios and – while affirming a significant role for loss-of-function (LoF) mutations – found no excess of de novo LoF mutations in cases with IQ above 100, suggesting that the role of DNMs in ASD may reside in fundamental neurodevelopmental processes. We also used our model to identify ~1,000 genes that are significantly lacking functional coding variation in non-ASD samples and are enriched for de novo LoF mutations identified in ASD cases. PMID:25086666

A sensitive two-photon probe to selectively detect monoamine oxidase B activity in Parkinson's disease models.

PubMed

Li, Lin; Zhang, Cheng-Wu; Chen, Grace Y J; Zhu, Biwei; Chai, Chou; Xu, Qing-Hua; Tan, Eng-King; Zhu, Qing; Lim, Kah-Leong; Yao, Shao Q

2014-01-01

The unusually high MAO-B activity consistently observed in Parkinson's disease (PD) patients has been proposed as a biomarker; however, this has not been realized due to the lack of probes suitable for MAO-B-specific detection in live cells/tissues. Here we report the first two-photon, small molecule fluorogenic probe (U1) that enables highly sensitive/specific and real-time imaging of endogenous MAO-B activities across biological samples. We also used U1 to confirm the reported inverse relationship between parkin and MAO-B in PD models. With no apparent toxicity, U1 may be used to monitor MAO-B activities in small animals during disease development. In clinical samples, we find elevated MAO-B activities only in B lymphocytes (not in fibroblasts), hinting that MAO-B activity in peripheral blood cells might be an accessible biomarker for rapid detection of PD. Our results provide important starting points for using small molecule imaging techniques to explore MAO-B at the organism level.

Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease.

PubMed

El Machhour, Fala; Keuylian, Zela; Kavvadas, Panagiotis; Dussaule, Jean-Claude; Chatziantoniou, Christos

2015-07-01

Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN. Copyright © 2015 by the American Society of Nephrology.

Cardiovascular magnetic resonance imaging: clinical implications in the evaluation of connective tissue diseases

PubMed Central

Mavrogeni, Sophie; Markousis-Mavrogenis, George; Koutsogeorgopoulou, Loukia; Kolovou, Genovefa

2017-01-01

Cardiovascular magnetic resonance imaging is a recently developed noninvasive, nonradiating, operator-independent technique that has been successfully used for the evaluation of congenital heart disease, valvular and pericardial diseases, iron overload, cardiomyopathies, great and coronary vessel diseases, cardiac inflammation, stress–rest myocardial perfusion, and fibrosis. Rheumatoid arthritis and other spondyloarthropathies, systemic lupus erythematosus, inflammatory myopathies, mixed connective tissue diseases (CTDs), systemic sclerosis, vasculitis, and sarcoidosis are among CTDs with serious cardiovascular involvement; this is due to multiple causative factors such as myopericarditis, micro/macrovascular disease, coronary artery disease, myocardial fibrosis, pulmonary hypertension, and finally heart failure. The complicated pathophysiology and the high cardiovascular morbidity and mortality of CTDs demand a versatile, noninvasive, nonradiative diagnostic tool for early cardiovascular diagnosis, risk stratification, and treatment follow-up. Cardiovascular magnetic resonance imaging can detect early silent cardiovascular lesions, assess disease acuteness, and reliably evaluate the effect of both cardiac and rheumatic medication in the cardiovascular system, due to its capability to perform tissue characterization and its high spatial resolution. However, until now, high cost; lack of interaction between cardiologists, radiologists, and rheumatologists; lack of availability; and lack of experts in the field have limited its wider adoption in the clinical practice. PMID:28546762

Mice lacking Faim2 show increased cell death in the MPTP mouse model of Parkinson disease.

PubMed

Komnig, Daniel; Schulz, Jörg B; Reich, Arno; Falkenburger, Björn H

2016-12-01

The death receptor Fas/CD95 mediates apoptotic cell death in response to external stimuli. In neurons, Fas-induced apoptosis is prevented by Fas-apoptotic inhibitory molecule 2 (Faim2). Mice lacking Faim2 showed increased neurodegeneration in animal models of stroke and bacterial meningitis. We therefore tested the relevance of Faim2 in a classical animal model of Parkinson disease and determined the toxicity of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Faim2-deficient mice. Without MPTP treatment, there was no difference in the dopaminergic system between Faim2-deficient mice and control mice. MPTP was applied i.p. in doses of 30 mg per kg on five consecutive days. Fourteen days after the last MPTP injection, the number of dopaminergic neurons in the lateral substantia nigra, assayed by stereological counting, was reduced by 39% in control mice and 53% in Faim2-deficient mice. The density of dopaminergic fibers in the dorsal striatum was reduced by 36% in control mice and 69% in Faim2-deficient mice, in the ventral striatum 44% in control mice and 76% in Faim2-deficient mice. Fiber density recovered at 90 days after MPTP with similar density in both groups. Striatal catecholamine levels were reduced by 81-84% in both groups and recovered at 90 days. Faim2 expression was documented in mouse midbrain using quantitative reverse transcription-PCR (qRT-PCR) and found decreased after MPTP administration. Taken together, our findings demonstrate increased degeneration of dopaminergic neurons with Faim2 deficiency, indicating that Fas-induced apoptosis contributes to cell death in the MPTP mouse model. Along with the decreased expression of Faim2 after MPTP, this finding indicates that boosting Faim2 function might represent a therapeutic strategy for Parkinson disease. © 2016 International Society for Neurochemistry.

Toward developmental models of psychiatric disorders in zebrafish

PubMed Central

Norton, William H. J.

2013-01-01

Psychiatric disorders are a diverse set of diseases that affect all aspects of mental function including social interaction, thinking, feeling, and mood. Although psychiatric disorders place a large economic burden on society, the drugs available to treat them are often palliative with variable efficacy and intolerable side-effects. The development of novel drugs has been hindered by a lack of knowledge about the etiology of these diseases. It is thus necessary to further investigate psychiatric disorders using a combination of human molecular genetics, gene-by-environment studies, in vitro pharmacological and biochemistry experiments, animal models, and investigation of the non-biological basis of these diseases, such as environmental effects. Many psychiatric disorders, including autism spectrum disorder, attention-deficit/hyperactivity disorder, mental retardation, and schizophrenia can be triggered by alterations to neural development. The zebrafish is a popular model for developmental biology that is increasingly used to study human disease. Recent work has extended this approach to examine psychiatric disorders as well. However, since psychiatric disorders affect complex mental functions that might be human specific, it is not possible to fully model them in fish. In this review, I will propose that the suitability of zebrafish for developmental studies, and the genetic tools available to manipulate them, provide a powerful model to study the roles of genes that are linked to psychiatric disorders during neural development. The relative speed and ease of conducting experiments in zebrafish can be used to address two areas of future research: the contribution of environmental factors to disease onset, and screening for novel therapeutic compounds. PMID:23637652

The role of disturbed blood flow in the development of pulmonary arterial hypertension: lessons from preclinical animal models.

PubMed

Dickinson, Michael G; Bartelds, Beatrijs; Borgdorff, Marinus A J; Berger, Rolf M F

2013-07-01

Pulmonary arterial hypertension (PAH) is a progressive pulmonary vasoproliferative disorder characterized by the development of unique neointimal lesions, including concentric laminar intima fibrosis and plexiform lesions. Although the histomorphology of neointimal lesions is well described, the pathogenesis of PAH and neointimal development is largely unknown. After three decades of PAH pathobiology research the focus has shifted from vasoconstriction towards a mechanism of cancer-like angioproliferation. In this concept the role of disturbed blood flow is seen as an important trigger in the development of vascular remodeling. For instance, in PAH associated with congenital heart disease, increased pulmonary blood flow (i.e., systemic-to-pulmonary shunt) is an essential trigger for the occurrence of neointimal lesions and PAH development. Still, questions remain about the exact role of these blood flow characteristics in disease progression. PAH animal models are important for obtaining insight in new pathobiological processes and therapeutical targets. However, as for any preclinical model the pathophysiological mechanism and clinical course has to be comparable to the human disease that it mimics. This means that animal models mimicking human PAH ideally are characterized by: a hit recognized in human disease (e.g., altered pulmonary blood flow), specific vascular remodeling resembling human neointimal lesions, and disease progression that leads to right ventriclular dysfunction and death. A review that underlines the current knowledge of PAH due to disturbed flow is still lacking. In this review we will summarize the current knowledge obtained from PAH animal models associated with disturbed pulmonary blood flow and address questions for future treatment strategies for PAH.

Hospitalizations of the elderly in the United States for non-specific gastrointestinal diseases: A search for etilogical clues

EPA Science Inventory

Nonspecific gastrointestinal (GI) disease is a common cause of GI-related hospitalizations in U.S. elderly (82.9% of all cases) and it peaks concurrently with viral enteritis, suggesting a lack of diagnostic testing. The lack of etiological specificity in the current coding syste...

Improving public health policy through infection transmission modelling: Guidelines for creating a Community of Practice

PubMed Central

Moghadas, Seyed M; Haworth-Brockman, Margaret; Isfeld-Kiely, Harpa; Kettner, Joel

2015-01-01

BACKGROUND: Despite significant research efforts in Canada, real application of modelling in public health decision making and practice has not yet met its full potential. There is still room to better address the diversity of the Canadian population and ensure that research outcomes are translated for use within their relevant contexts. OBJECTIVES: To strengthen connections to public health practice and to broaden its scope, the Pandemic Influenza Outbreak Research Modelling team partnered with the National Collaborating Centre for Infectious Diseases to hold a national workshop. Its objectives were to: understand areas where modelling terms, methods and results are unclear; share information on how modelling can best be used in informing policy and improving practice, particularly regarding the ways to integrate a focus on health equity considerations; and sustain and advance collaborative work in the development and application of modelling in public health. METHOD: The Use of Mathematical Modelling in Public Health Decision Making for Infectious Diseases workshop brought together research modellers, public health professionals, policymakers and other experts from across the country. Invited presentations set the context for topical discussions in three sessions. A final session generated reflections and recommendations for new opportunities and tasks. CONCLUSIONS: Gaps in content and research include the lack of standard frameworks and a glossary for infectious disease modelling. Consistency in terminology, clear articulation of model parameters and assumptions, and sustained collaboration will help to bridge the divide between research and practice. PMID:26361486

Animal models for ebolavirus countermeasures discovery: what defines a useful model?

PubMed

Shurtleff, Amy C; Bavari, Sina

2015-07-01

Ebolaviruses are highly pathogenic filoviruses, which cause disease in humans and nonhuman primates (NHP) in Africa. The Zaire ebolavirus outbreak in 2014, which continues to greatly affect Western Africa and other countries to which the hemorrhagic fever was exported due to travel of unsymptomatic yet infected individuals, was complicated by the lack of available licensed vaccines or therapeutics to combat infection. After almost a year of research at an increased pace to find and test vaccines and therapeutics, there is now a deeper understanding of the available disease models for ebolavirus infection. Demonstration of vaccine or therapeutic efficacy in NHP models of ebolavirus infection is crucial to the development and eventual licensure of ebolavirus medical countermeasures, so that safe and effective countermeasures can be accelerated into human clinical trials. The authors describe ebolavirus hemorrhagic fever (EHF) disease in various animal species: mice, guinea pigs, hamsters, pigs and NHP, to include baboons, marmosets, rhesus and cynomolgus macaques, as well as African green monkeys. Because the NHP models are supremely useful for therapeutics and vaccine testing, emphasis is placed on comparison of these models, and their use as gold-standard models of EHF. Animal models of EHF varying from rodents to NHP species are currently under evaluation for their reproducibility and utility for modeling infection in humans. Complete development and licensure of therapeutic agents and vaccines will require demonstration that mechanisms conferring protection in NHP models of infection are predictive of protective responses in humans, for a given countermeasure.

Climate Predictors of the Spatial Distribution of Human Plague Cases in the West Nile Region of Uganda

PubMed Central

MacMillan, Katherine; Monaghan, Andrew J.; Apangu, Titus; Griffith, Kevin S.; Mead, Paul S.; Acayo, Sarah; Acidri, Rogers; Moore, Sean M.; Mpanga, Joseph Tendo; Enscore, Russel E.; Gage, Kenneth L.; Eisen, Rebecca J.

2012-01-01

East Africa has been identified as a region where vector-borne and zoonotic diseases are most likely to emerge or re-emerge and where morbidity and mortality from these diseases is significant. Understanding when and where humans are most likely to be exposed to vector-borne and zoonotic disease agents in this region can aid in targeting limited prevention and control resources. Often, spatial and temporal distributions of vectors and vector-borne disease agents are predictable based on climatic variables. However, because of coarse meteorological observation networks, appropriately scaled and accurate climate data are often lacking for Africa. Here, we use a recently developed 10-year gridded meteorological dataset from the Advanced Weather Research and Forecasting Model to identify climatic variables predictive of the spatial distribution of human plague cases in the West Nile region of Uganda. Our logistic regression model revealed that within high elevation sites (above 1,300 m), plague risk was positively associated with rainfall during the months of February, October, and November and negatively associated with rainfall during the month of June. These findings suggest that areas that receive increased but not continuous rainfall provide ecologically conducive conditions for Yersinia pestis transmission in this region. This study serves as a foundation for similar modeling efforts of other vector-borne and zoonotic disease in regions with sparse observational meteorologic networks. PMID:22403328

Parkinson's disease in Jordan: Barriers and motivators to exercise.

PubMed

Khalil, Hanan; Nazzal, Mohammad; Al-Sheyab, Nihaya

2016-10-01

Perceived barriers to engaging in exercise in people with Parkinson's disease (PD) are becoming more defined in countries such as the UK and the US. This, however, may vary by culture and environment. This study aimed to explore the perceptions of exercise and barriers that may affect participation in people with PD from Jordan. Two focus groups and seven individual interviews were conducted with people with PD. Additionally, individual interviews were conducted with two neurologists. Conversations were digitally recorded and transcribed. Transcripts were analyzed using thematic analysis and validated via researcher triangulation and peer checking. Most of the PD participants lacked previous participation in any disease-specific exercises. Several barriers were perceived by PD participants for such lack of participation. Barriers included difficulty of diagnosis, lack of informational support provided by neurologists, lack of referral to physiotherapy services, disease-specific issues, and setting-related issues. Neurologists indicated a number of barriers in counseling their PD patients on exercise including lack of time and lack of health system resources. Motivators to participate in future exercise included outcome expectations and family support. Findings of the study shed light into large areas of unmet needs of supporting exercise and physiotherapy for people with PD in developing countries as per Jordan. For better patient outcomes, findings of the study suggest that it is crucial to raise awareness among all PD-related stakeholders on the benefits of early referrals to physiotherapy and early engagement in exercise programs.

Mining heart disease risk factors in clinical text with named entity recognition and distributional semantic models.

PubMed

Urbain, Jay

2015-12-01

We present the design, and analyze the performance of a multi-stage natural language processing system employing named entity recognition, Bayesian statistics, and rule logic to identify and characterize heart disease risk factor events in diabetic patients over time. The system was originally developed for the 2014 i2b2 Challenges in Natural Language in Clinical Data. The system's strengths included a high level of accuracy for identifying named entities associated with heart disease risk factor events. The system's primary weakness was due to inaccuracies when characterizing the attributes of some events. For example, determining the relative time of an event with respect to the record date, whether an event is attributable to the patient's history or the patient's family history, and differentiating between current and prior smoking status. We believe these inaccuracies were due in large part to the lack of an effective approach for integrating context into our event detection model. To address these inaccuracies, we explore the addition of a distributional semantic model for characterizing contextual evidence of heart disease risk factor events. Using this semantic model, we raise our initial 2014 i2b2 Challenges in Natural Language of Clinical data F1 score of 0.838 to 0.890 and increased precision by 10.3% without use of any lexicons that might bias our results. Copyright © 2015 Elsevier Inc. All rights reserved.

Control of Mucosal Candidiasis in the Zebrafish Swim Bladder Depends on Neutrophils That Block Filament Invasion and Drive Extracellular-Trap Production

PubMed Central

Gratacap, Remi L.; Scherer, Allison K.; Seman, Brittany G.

2017-01-01

ABSTRACT Candida albicans is a ubiquitous mucosal commensal that is normally prevented from causing acute or chronic invasive disease. Neutrophils contribute to protection in oral infection but exacerbate vulvovaginal candidiasis. To dissect the role of neutrophils during mucosal candidiasis, we took advantage of a new, transparent zebrafish swim bladder infection model. Intravital microscopic tracking of individual animals revealed that the blocking of neutrophil recruitment leads to rapid mortality in this model through faster disease progression. Conversely, artificial recruitment of neutrophils during early infection reduces disease pressure. Noninvasive longitudinal tracking showed that mortality is a consequence of C. albicans breaching the epithelial barrier and invading surrounding tissues. Accordingly, we found that a hyperfilamentous C. albicans strain breaches the epithelial barrier more frequently and causes mortality in immunocompetent zebrafish. A lack of neutrophils at the infection site is associated with less fungus-associated extracellular DNA and less damage to fungal filaments, suggesting that neutrophil extracellular traps help to protect the epithelial barrier from C. albicans breach. We propose a homeostatic model where C. albicans disease pressure is balanced by neutrophil-mediated damage of fungi, maintaining this organism as a commensal while minimizing the risk of damage to host tissue. The unequaled ability to dissect infection dynamics at a high spatiotemporal resolution makes this zebrafish model a unique tool for understanding mucosal host-pathogen interactions. PMID:28607100

Artificial immune system for diabetes meal plans optimization

NASA Astrophysics Data System (ADS)

Prilianti, K. R.; Callista, P. B.; Setiawan, H.

2017-03-01

Type 2 diabetes mellitus is a disease that occurs because the body lacks of insulin or the insulin produced by the pancreas cannot work effectively such that the glucose level in the blood cannot well controlled. One of the most common causes of diabetes mellitus type 2 is obesity, therefore this disease can be controlled with the appropriate diet regarding to the daily calorie requirement. Hence, the level of blood glucose is maintained. Unfortunately, because the lack of proper diet education and facility, many people cannot work on proper daily healthy diet by their own. In this research Artificial Immune System algorithm was applied to build a model that help diabetes mellitus patient arrange their meal plans. The model can calculate the amount of daily calorie needed and arrange the appropriate daily meal plans based on it. The meal plans vary according to the patient calorie needs. The required input data are age, gender, weight, height, and type of patient daily main activity. The experiments show that this model has a good result. The result is already approaching the patients' daily calorie need, i.e. 97.6% (actual need is not less than 80% and not greater than 100%). Carbohydrate of the meal plan is 55-57% (actual need is not less than 45% and not greater than 60%) whereas the protein approximate 15-18% (actual need is not less than 15% and not greater than 20%) and fat of approximate 22-24% (actual need is not less than 20% and not greater than 25%).

Sarcopenia in the prognosis of cirrhosis: Going beyond the MELD score

PubMed Central

Kim, Hee Yeon; Jang, Jeong Won

2015-01-01

Estimating the prognosis of patients with cirrhosis remains challenging, because the natural history of cirrhosis varies according to the cause, presence of portal hypertension, liver synthetic function, and the reversibility of underlying disease. Conventional prognostic scoring systems, including the Child-Turcotte-Pugh score or model for end-stage liver diseases are widely used; however, revised models have been introduced to improve prognostic performance. Although sarcopenia is one of the most common complications related to survival of patients with cirrhosis, the newly proposed prognostic models lack a nutritional status evaluation of patients. This is reflected by the lack of an optimal index for sarcopenia in terms of objectivity, reproducibility, practicality, and prognostic performance, and of a consensus definition for sarcopenia in patients with cirrhosis in whom ascites and edema may interfere with body composition analysis. Quantifying skeletal muscle mass using cross-sectional abdominal imaging is a promising tool for assessing sarcopenia. As radiological imaging provides direct visualization of body composition, it is useful to evaluate sarcopenia in patients with cirrhosis whose body mass index, anthropometric measurements, or biochemical markers are inaccurate on a nutritional assessment. Sarcopenia defined by cross-sectional imaging-based muscular assessment is prevalent and predicts mortality in patients with cirrhosis. Sarcopenia alone or in combination with conventional prognostic systems shows promise for a cirrhosis prognosis. Including an objective assessment of sarcopenia with conventional scores to optimize the outcome prediction for patients with cirrhosis needs further research. PMID:26167066

Dimer-based model for heptaspanning membrane receptors.

PubMed

Franco, Rafael; Casadó, Vicent; Mallol, Josefa; Ferré, Sergi; Fuxe, Kjell; Cortés, Antonio; Ciruela, Francisco; Lluis, Carmen; Canela, Enric I

2005-07-01

The existence of intramembrane receptor-receptor interactions for heptaspanning membrane receptors is now fully accepted, but a model considering dimers as the basic unit that binds to two ligand molecules is lacking. Here, we propose a two-state-dimer model in which the ligand-induced conformational changes from one component of the dimer are communicated to the other. Our model predicts cooperativity in binding, which is relevant because the other current models fail to address this phenomenon satisfactorily. Our two-state-dimer model also predicts the variety of responses elicited by full or partial agonists, neutral antagonists and inverse agonists. This model can aid our understanding of the operation of heptaspanning receptors and receptor channels, and, potentially, be important for improving the treatment of cardiovascular, neurological and neuropsychyatric diseases.

Development of the first oligonucleotide microarray for global gene expression profiling in guinea pigs: defining the transcription signature of infectious diseases.

PubMed

Jain, Ruchi; Dey, Bappaditya; Tyagi, Anil K

2012-10-02

The Guinea pig (Cavia porcellus) is one of the most extensively used animal models to study infectious diseases. However, despite its tremendous contribution towards understanding the establishment, progression and control of a number of diseases in general and tuberculosis in particular, the lack of fully annotated guinea pig genome sequence as well as appropriate molecular reagents has severely hampered detailed genetic and immunological analysis in this animal model. By employing the cross-species hybridization technique, we have developed an oligonucleotide microarray with 44,000 features assembled from different mammalian species, which to the best of our knowledge is the first attempt to employ microarray to study the global gene expression profile in guinea pigs. To validate and demonstrate the merit of this microarray, we have studied, as an example, the expression profile of guinea pig lungs during the advanced phase of M. tuberculosis infection. A significant upregulation of 1344 genes and a marked down regulation of 1856 genes in the lungs identified a disease signature of pulmonary tuberculosis infection. We report the development of first comprehensive microarray for studying the global gene expression profile in guinea pigs and validation of its usefulness with tuberculosis as a case study. An important gap in the area of infectious diseases has been addressed and a valuable molecular tool is provided to optimally harness the potential of guinea pig model to develop better vaccines and therapies against human diseases.

Association of educational attainment with chronic disease and mortality: the Kidney Early Evaluation Program (KEEP).

PubMed

Choi, Andy I; Weekley, Cristin C; Chen, Shu-Cheng; Li, Suying; Tamura, Manjula Kurella; Norris, Keith C; Shlipak, Michael G

2011-08-01

Recent reports have suggested a close relationship between education and health, including mortality, in the United States. Observational cohort. We studied 61,457 participants enrolled in a national health screening initiative, the National Kidney Foundation's Kidney Early Evaluation Program (KEEP). Self-reported educational attainment. Chronic diseases (hypertension, diabetes, cardiovascular disease, reduced kidney function, and albuminuria) and mortality. We evaluated cross-sectional associations between self-reported educational attainment with the chronic diseases listed using logistic regression models adjusted for demographics, access to care, behaviors, and comorbid conditions. The association of educational attainment with survival was determined using multivariable Cox proportional hazards regression. Higher educational attainment was associated with a lower prevalence of each of the chronic conditions listed. In multivariable models, compared with persons not completing high school, college graduates had a lower risk of each chronic condition, ranging from 11% lower odds of decreased kidney function to 37% lower odds of cardiovascular disease. During a mean follow-up of 3.9 (median, 3.7) years, 2,384 (4%) deaths occurred. In the fully adjusted Cox model, those who had completed college had 24% lower mortality compared with participants who had completed at least some high school. Lack of income data does not allow us to disentangle the independent effects of education from income. In this diverse contemporary cohort, higher educational attainment was associated independently with a lower prevalence of chronic diseases and short-term mortality in all age and race/ethnicity groups. Published by Elsevier Inc.

Understanding Lymphangiogenesis in Knockout Models, the Cornea, and Ocular Diseases for the Development of Therapeutic Interventions

PubMed Central

Yang, Jessica F.; Walia, Amit; Huang, Yu-hui; Han, Kyu-yeon; Rosenblatt, Mark I; Azar, Dimitri T.; Chang, Jin-Hong

2015-01-01

A major focus of cancer research for several decades has been understanding the ability of tumors to induce new blood vessel formation, a process known as angiogenesis. Unfortunately, only limited success has been achieved in the clinical application of angiogenesis inhibitors. We now know that lymphangiogenesis, the growth of lymphatic vessels, likely also plays a major role in tumor progression. Thus, therapeutic strategies targeting lymphangiogenesis or both lymphangiogenesis and angiogenesis may represent promising approaches for treating cancer and other diseases. Importantly, research progress toward understanding lymphangiogenesis is significantly behind that related to angiogenesis. A PubMed search of ‘angiogenesis’ returns nearly 80,000 articles, whereas a search of ‘lymphangiogenesis’ returns approximately 2,635 articles. This stark contrast can be explained by the lack of molecular markers for identifying the invisible lymphatic vasculature that persisted until less than two decades ago combined with the intensity of research interest in angiogenesis during the past half-century. Still, significant strides have been made in developing strategies to modulate lymphangiogenesis, largely using ocular disease models. Here, we review the current knowledge of lymphangiogenesis in the context of knockout models, ocular diseases, the biology of activators and inhibitors, and the potential for therapeutic interventions targeting this process. PMID:26706194

PREDICT: A next generation platform for near real-time prediction of cholera

NASA Astrophysics Data System (ADS)

Jutla, A.; Aziz, S.; Akanda, A. S.; Alam, M.; Ahsan, G. U.; Huq, A.; Colwell, R. R.

2017-12-01

Data on disease prevalence and infectious pathogens is sparingly collected/available in region(s) where climatic variability and extreme natural events intersect with population vulnerability (such as lack of access to water and sanitation infrastructure). Therefore, traditional time series modeling approach of calibration and validation of a model is inadequate. Hence, prediction of diarrheal infections (such as cholera, Shigella etc) remain a challenge even though disease causing pathogens are strongly associated with modalities of regional climate and weather system. Here we present an algorithm that integrates satellite derived data on several hydroclimatic and ecological processes into a framework that can determine high resolution cholera risk on global scales. Cholera outbreaks can be classified in three forms- epidemic (sudden or seasonal outbreaks), endemic (recurrence and persistence of the disease for several consecutive years) and mixed-mode endemic (combination of certain epidemic and endemic conditions) with significant spatial and temporal heterogeneity. Using data from multiple satellites (AVHRR, TRMM, GPM, MODIS, VIIRS, GRACE), we will show examples from Haiti, Yemen, Nepal and several other regions where our algorithm has been successful in capturing risk of outbreak of infection in human population. A spatial model validation algorithm will also be presented that has capabilities to self-calibrate as new hydroclimatic and disease data become available.

Identification of natural products with neuronal and metabolic benefits through autophagy induction.

PubMed

Fan, Yuying; Wang, Nan; Rocchi, Altea; Zhang, Weiran; Vassar, Robert; Zhou, Yifa; He, Congcong

2017-01-02

Autophagy is a housekeeping lysosomal degradation pathway important for cellular survival, homeostasis and function. Various disease models have shown that upregulation of autophagy may be beneficial to combat disease pathogenesis. However, despite several recently reported small-molecule screens for synthetic autophagy inducers, natural chemicals of diverse structures and functions have not been included in the synthetic libraries, and characterization of their roles in autophagy has been lacking. To discover novel autophagy-regulating compounds and study their therapeutic mechanisms, we used analytic chemistry approaches to isolate natural phytochemicals from a reservoir of medicinal plants used in traditional remedies. From this pilot plant metabolite library, we identified several novel autophagy-inducing phytochemicals, including Rg2. Rg2 is a steroid glycoside chemical that activates autophagy in an AMPK-ULK1-dependent and MTOR-independent manner. Induction of autophagy by Rg2 enhances the clearance of protein aggregates in a cell-based model, improves cognitive behaviors in a mouse model of Alzheimer disease, and prevents high-fat diet-induced insulin resistance. Thus, we discovered a series of autophagy-inducing phytochemicals from medicinal plants, and found that one of the compounds Rg2 mediates metabolic and neurotrophic effects dependent on activation of the autophagy pathway. These findings may help explain how medicinal plants exert the therapeutic functions against metabolic diseases.

SOCIAL, HISTORICAL AND CULTURAL DIMENSIONS OF TUBERCULOSIS.

PubMed

Mason, Paul H; Roy, Anupom; Spillane, Jayden; Singh, Puneet

2016-03-01

Tuberculosis (TB) researchers and clinicians, by virtue of the social disease they study, are drawn into an engagement with ways of understanding illness that extend beyond the strictly biomedical model. Primers on social science concepts directly relevant to TB, however, are lacking. The particularities of TB disease mean that certain social science concepts are more relevant than others. Concepts such as structural violence can seem complicated and off-putting. Other concepts, such as gender, can seem so familiar that they are left relatively unexplored. An intimate familiarity with the social dimensions of disease is valuable, particularly for infectious diseases, because the social model is an important complement to the biomedical model. This review article offers an important introduction to a selection of concepts directly relevant to TB from health sociology, medical anthropology and social cognitive theory. The article has pedagogical utility and also serves as a useful refresher for those researchers already engaged in this genre of work. The conceptual tools of health sociology, medical anthropology and social cognitive theory offer insightful ways to examine the social, historical and cultural dimensions of public health. By recognizing cultural experience as a central force shaping human interactions with the world, TB researchers and clinicians develop a more nuanced consideration of how health, illness and medical treatment are understood, interpreted and confronted.

Pathophysiology of hantavirus pulmonary syndrome in rhesus macaques.

PubMed

Safronetz, David; Prescott, Joseph; Feldmann, Friederike; Haddock, Elaine; Rosenke, Rebecca; Okumura, Atsushi; Brining, Douglas; Dahlstrom, Eric; Porcella, Stephen F; Ebihara, Hideki; Scott, Dana P; Hjelle, Brian; Feldmann, Heinz

2014-05-13

The pathophysiology of hantavirus pulmonary syndrome (HPS) remains unclear because of a lack of surrogate disease models with which to perform pathogenesis studies. Nonhuman primates (NHP) are considered the gold standard model for studying the underlying immune activation/suppression associated with immunopathogenic viruses such as hantaviruses; however, to date an NHP model for HPS has not been described. Here we show that rhesus macaques infected with Sin Nombre virus (SNV), the primary etiological agent of HPS in North America, propagated in deer mice develop HPS, which is characterized by thrombocytopenia, leukocytosis, and rapid onset of respiratory distress caused by severe interstitial pneumonia. Despite establishing a systemic infection, SNV differentially activated host responses exclusively in the pulmonary endothelium, potentially the mechanism leading to acute severe respiratory distress. This study presents a unique chronological characterization of SNV infection and provides mechanistic data into the pathophysiology of HPS in a closely related surrogate animal model. We anticipate this model will advance our understanding of HPS pathogenesis and will greatly facilitate research toward the development of effective therapeutics and vaccines against hantaviral diseases.

An object-relational model for structured representation of medical knowledge.

PubMed

Koch, S; Risch, T; Schneider, W; Wagner, I V

2006-07-01

Domain specific knowledge is often not static but continuously evolving. This is especially true for the medical domain. Furthermore, the lack of standardized structures for presenting knowledge makes it difficult or often impossible to assess new knowledge in the context of existing knowledge. Possibilities to compare knowledge easily and directly are often not given. It is therefore of utmost importance to create a model that allows for comparability, consistency and quality assurance of medical knowledge in specific work situations. For this purpose, we have designed on object-relational model based on structured knowledge elements that are dynamically reusable by different multi-media-based tools for case-based documentation, disease course simulation, and decision support. With this model, high-level components, such as patient case reports or simulations of the course of a disease, and low-level components (e.g., diagnoses, symptoms or treatments) as well as the relationships between these components are modeled. The resulting schema has been implemented in AMOS II, on object-relational multi-database system supporting different views with regard to search and analysis depending on different work situations.

Patient-derived orthotopic xenograft models for cancer of unknown primary precisely distinguish chemotherapy, and tumor-targeting S. typhimurium A1-R is superior to first-line chemotherapy.

PubMed

Miyake, Kentaro; Kiyuna, Tasuku; Miyake, Masuyo; Kawaguchi, Kei; Yoon, Sang Nam; Zhang, Zhiying; Igarashi, Kentaro; Razmjooei, Sahar; Wangsiricharoen, Sintawat; Murakami, Takashi; Li, Yunfeng; Nelson, Scott D; Russell, Tara A; Singh, Arun S; Hiroshima, Yukihiko; Momiyama, Masashi; Matsuyama, Ryusei; Chishima, Takashi; Singh, Shree Ram; Endo, Itaru; Eilber, Fritz C; Hoffman, Robert M

2018-01-01

Cancer of unknown primary (CUP) is a recalcitrant disease with poor prognosis because it lacks standard first-line therapy. CUP consists of diverse malignancy groups, making personalized precision therapy essential. The present study aimed to identify an effective therapy for a CUP patient using a patient-derived orthotopic xenograft (PDOX) model. This paper reports the usefulness of the PDOX model to precisely identify effective and ineffective chemotherapy and to compare the efficacy of S. typhimurium A1-R with first-line chemotherapy using the CUP PDOX model. The present study is the first to use a CUP PDOX model, which was able to precisely distinguish the chemotherapeutic course. We found that a carboplatinum (CAR)-based regimen was effective for this CUP patient. We also demonstrated that S. typhimurium A1-R was more effective against the CUP tumor than first-line chemotherapy. Our results indicate that S. typhimurium A1-R has clinical potential for CUP, a resistant disease that requires effective therapy.

Public health program planning logic model for community engaged type 2 diabetes management and prevention.

PubMed

West, Joseph F

2014-02-01

Diabetes remains a growing epidemic with widening health inequity gaps in disease management, self-management knowledge, access to care and outcomes. Yet there is a paucity of evaluation tools for community engaged interventions aimed at closing the gaps and improving health. The Guide to Community Preventive Services (the Community Guide) developed by the Task Force on Community Preventive Services (the Task Force) at the Centers for Disease Control and Prevention (CDC) recommends two healthcare system level interventions, case management interventions and disease management programs, to improve glycemic control. However, as a public health resource guide for diabetes interventions a model for community engagement is a glaringly absent component of the Community Guide recommendations. In large part there are few evidence-based interventions featuring community engagement as a practice and system-level focus of chronic disease and Type 2 diabetes management. The central argument presented in this paper is that the absence of these types of interventions is due to the lack of tools for modeling and evaluating such interventions, especially among disparate and poor populations. A conceptual model emphasizing action-oriented micro-level community engagement is needed to complement the Community Guide and serve as the basis for testing and evaluation of these kinds of interventions. A unique logic model advancing the Community Guide diabetes recommendations toward measureable and sustainable community engagement for improved Type 2 diabetes outcomes is presented. Copyright © 2013 Elsevier Ltd. All rights reserved.

Caffeine, Adenosine Receptors and Estrogen in Toxin Models of Parkinson’s Disease

DTIC Science & Technology

2005-10-01

right). Adjacent coronal brain sections were processed for A2A receptor immunohistochemsitry (B) with a HRP-coupled secondary antibody yielding a...declines steadily with increasing intake of caffeine or of coffee (but not decaffeinated coffee). The mechanisms that underlie this epidemiological...ad Sju - 5261.[7 of decaffeinated coffee was not associated with an Furthermore. A2A knockout mice (lacking function- altered risk of PD). clearly

Production of cattle lacking prion protein

PubMed Central

Richt, Jürgen A; Kasinathan, Poothappillai; Hamir, Amir N; Castilla, Joaquin; Sathiyaseelan, Thillai; Vargas, Francisco; Sathiyaseelan, Janaki; Wu, Hua; Matsushita, Hiroaki; Koster, Julie; Kato, Shinichiro; Ishida, Isao; Soto, Claudio; Robl, James M; Kuroiwa, Yoshimi

2010-01-01

Prion diseases are caused by propagation of misfolded forms of the normal cellular prion protein PrPC, such as PrPBSE in bovine spongiform encephalopathy (BSE) in cattle and PrPCJD in Creutzfeldt-Jakob disease (CJD) in humans1. Disruption of PrPC expression in mice, a species that does not naturally contract prion diseases, results in no apparent developmental abnormalities2–5. However, the impact of ablating PrPC function in natural host species of prion diseases is unknown. Here we report the generation and characterization of PrPC-deficient cattle produced by a sequential gene-targeting system6. At over 20 months of age, the cattle are clinically, physiologically, histopathologically, immunologically and reproductively normal. Brain tissue homogenates are resistant to prion propagation in vitro as assessed by protein misfolding cyclic amplification7. PrPC-deficient cattle may be a useful model for prion research and could provide industrial bovine products free of prion proteins. PMID:17195841

The potential of disease management for neuromuscular hereditary disorders.

PubMed

Chouinard, Maud-Christine; Gagnon, Cynthia; Laberge, Luc; Tremblay, Carmen; Côté, Charlotte; Leclerc, Nadine; Mathieu, Jean

2009-01-01

Neuromuscular hereditary disorders require long-term multidisciplinary rehabilitation management. Although the need for coordinated healthcare management has long been recognized, most neuromuscular disorders are still lacking clinical guidelines about their long-term management and structured evaluation plan with associated services. One of the most prevalent adult-onset neuromuscular disorders, myotonic dystrophy type 1, generally presents several comorbidities and a variable clinical picture, making management a constant challenge. This article presents a healthcare follow-up plan and proposes a nursing case management within a disease management program as an innovative and promising approach. This disease management program and model consists of eight components including population identification processes, evidence-based practice guidelines, collaborative practice, patient self-management education, and process outcomes evaluation (Disease Management Association of America, 2004). It is believed to have the potential to significantly improve healthcare management for neuromuscular hereditary disorders and will prove useful to nurses delivering and organizing services for this population.

Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology

NASA Astrophysics Data System (ADS)

Mederacke, Ingmar; Hsu, Christine C.; Troeger, Juliane S.; Huebener, Peter; Mu, Xueru; Dapito, Dianne H.; Pradere, Jean-Philippe; Schwabe, Robert F.

2013-11-01

Although organ fibrosis causes significant morbidity and mortality in chronic diseases, the lack of detailed knowledge about specific cellular contributors mediating fibrogenesis hampers the design of effective antifibrotic therapies. Different cellular sources, including tissue-resident and bone marrow-derived fibroblasts, pericytes and epithelial cells, have been suggested to give rise to myofibroblasts, but their relative contributions remain controversial, with profound differences between organs and different diseases. Here we employ a novel Cre-transgenic mouse that marks 99% of hepatic stellate cells (HSCs), a liver-specific pericyte population, to demonstrate that HSCs give rise to 82-96% of myofibroblasts in models of toxic, cholestatic and fatty liver disease. Moreover, we exclude that HSCs function as facultative epithelial progenitor cells in the injured liver. On the basis these findings, HSCs should be considered the primary cellular target for antifibrotic therapies across all types of liver disease.

The burden of mental disorders: a comparison of methods between the Australian burden of disease studies and the Global Burden of Disease study.

PubMed Central

Vos, T.; Mathers, C. D.

2000-01-01

The national and Victorian burden of disease studies in Australia set out to examine critically the methods used in the Global Burden of Disease study to estimate the burden of mental disorders. The main differences include the use of a different set of disability weights allowing estimates in greater detail by level of severity, adjustments for comorbidity between mental disorders, a greater number of mental disorders measured, and modelling of substance use disorders, anxiety disorders and bipolar disorder as chronic conditions. Uniform age-weighting in the Australian studies produces considerably lower estimates of the burden due to mental disorders in comparison with age-weighted disability-adjusted life years. A lack of follow-up data on people with mental disorders who are identified in cross-sectional surveys poses the greatest challenge in determining the burden of mental disorders more accurately. PMID:10885161

A situational analysis of training for behaviour change counselling for primary care providers, South Africa.

PubMed

Malan, Zelra; Mash, Bob; Everett-Murphy, Katherine

2015-03-18

Non-communicable diseases and associated risk factors (smoking, alcohol abuse, physical inactivity and unhealthy diet) are a major contributor to primary care morbidity and the burden of disease. The need for healthcare-provider training in evidence-based lifestyle interventions has been acknowledged by the National Department of Health. However, local studies suggest that counselling on lifestyle modification from healthcare providers is inadequate and this may, in part, be attributable to a lack of training. This study aimed to assess the current training courses for primary healthcare providers in the Western Cape. Stellenbosch University and University of Cape Town. Qualitative interviews were conducted with six key informants (trainers of primary care nurses and registrars in family medicine) and two focus groups (nine nurses and eight doctors) from both Stellenbosch University and the University of Cape Town. Trainers lack confidence in the effectiveness of behaviour change counselling and in current approaches to training. Current training is limited by time constraints and is not integrated throughout the curriculum--there is a focus on theory rather than modelling and practice, as well as a lack of both formative and summative assessment. Implementation of training is limited by a lack of patient education materials, poor continuity of care and record keeping, conflicting lifestyle messages and an unsupportive organisational culture. Revising the approach to current training is necessary in order to improve primary care providers' behaviour change counselling skills. Primary care facilities need to create a more conducive environment that is supportive of behaviour change counselling.

A situational analysis of training for behaviour change counselling for primary care providers, South Africa

PubMed Central

Mash, Bob; Everett-Murphy, Katherine

2015-01-01

Abstract Background Non-communicable diseases and associated risk factors (smoking, alcohol abuse, physical inactivity and unhealthy diet) are a major contributor to primary care morbidity and the burden of disease. The need for healthcare-provider training in evidence-based lifestyle interventions has been acknowledged by the National Department of Health. However, local studies suggest that counselling on lifestyle modification from healthcare providers is inadequate and this may, in part, be attributable to a lack of training. Aim This study aimed to assess the current training courses for primary healthcare providers in the Western Cape. Setting Stellenbosch University and University of Cape Town. Methods Qualitative interviews were conducted with six key informants (trainers of primary care nurses and registrars in family medicine) and two focus groups (nine nurses and eight doctors) from both Stellenbosch University and the University of Cape Town. Results Trainers lack confidence in the effectiveness of behaviour change counselling and in current approaches to training. Current training is limited by time constraints and is not integrated throughout the curriculum – there is a focus on theory rather than modelling and practice, as well as a lack of both formative and summative assessment. Implementation of training is limited by a lack of patient education materials, poor continuity of care and record keeping, conflicting lifestyle messages and an unsupportive organisational culture. Conclusion Revising the approach to current training is necessary in order to improve primary care providers’ behaviour change counselling skills. Primary care facilities need to create a more conducive environment that is supportive of behaviour change counselling. PMID:26245589

Appetite and tuberculosis: is the lack of appetite an unidentified risk factor for tuberculosis?

PubMed

Hernández-Garduño, Eduardo; Pérez-Guzmán, Carlos

2007-01-01

Different risk factors have been identified as associated with tuberculosis (TB), an important and common one is malnutrition, however, the causes of malnutrition have not been studied in detail, the lack of food and poverty are among the most frequent in developing countries but others are yet to be identified. We hypothesized that chronic lack of appetite can be one of the causes of malnutrition associated to TB and therefore be a potential independent risk factor for latent tuberculosis infection (LTBI) or TB disease. If this is true, contact subjects with LTBI who have poor appetite will be at higher risk for getting the disease and people with the disease will be at risk for poor treatment outcomes.

Pharmacotherapy of retinal disease with visual cycle modulators.

PubMed

Hussain, Rehan M; Gregori, Ninel Z; Ciulla, Thomas A; Lam, Byron L

2018-04-01

Pharmacotherapy with visual cycle modulators (VCMs) is under investigation for retinitis pigmentosa (RP), Leber congenital amaurosis (LCA), Stargardt macular dystrophy (SMD) and nonexudative age-related macular degeneration (AMD), all blinding diseases that lack effective treatment options. Areas covered: The authors review investigational VCMs, including oral retinoids, 9-cis-retinyl-acetate (zuretinol) and 9-cis-β-carotene, which restore 11-cis-retinal levels in RP and LCA caused by LRAT and RPE65 gene mutations, and may improve visual acuity and visual fields. Therapies for SMD aiming to decrease accumulation of toxic Vitamin A dimers and lipofuscin in the retina and retinal pigment epithelium (RPE) include C20-D3-vitamin A (ALK-001), isotretinoin, VM200, emixustat, and A1120. Mouse models of SMD show promising data for these treatments, though proof of efficacy in humans is currently lacking. Fenretinide and emixustat are investigational VCMs for dry AMD, though neither has been shown to reduce geographic atrophy or improve vision in human trials. A1120 prevents retinol transport into the RPE and may spare the side effects typically seen in VCMs (nyctalopia and chromatopsia) per mouse studies. Expert opinion: Oral VCMs may be feasible treatment options for degenerative retinal diseases based on pre-clinical and some early clinical studies. Further trials are warranted to assess their efficacy and safety in humans.

WONOEP appraisal: Development of epilepsy biomarkers-What we can learn from our patients?

PubMed

Jozwiak, Sergiusz; Becker, Albert; Cepeda, Carlos; Engel, Jerome; Gnatkovsky, Vadym; Huberfeld, Gilles; Kaya, Mehmet; Kobow, Katja; Simonato, Michele; Loeb, Jeffrey A

2017-06-01

Current medications for patients with epilepsy work in only two of three patients. For those medications that do work, they only suppress seizures. They treat the symptoms, but do not modify the underlying disease, forcing patients to take these drugs with significant side effects, often for the rest of their lives. A major limitation in our ability to advance new therapeutics that permanently prevent, reduce the frequency of, or cure epilepsy comes from a lack of understanding of the disease coupled with a lack of reliable biomarkers that can predict who has or who will get epilepsy. The main goal of this report is to present a number of approaches for identifying reliable biomarkers from observing patients with brain disorders that have a high probability of producing epilepsy. A given biomarker, or more likely a profile of biomarkers, will have both a quantity and a time course during epileptogenesis that can be used to predict who will get the disease, to confirm epilepsy as a diagnosis, to identify coexisting pathologies, and to monitor the course of treatments. Additional studies in patients and animal models could identify common and clinically valuable biomarkers to successfully translate animal studies into new and effective clinical trials. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

Pathogen evolution across the agro-ecological interface: implications for disease management.

PubMed

Burdon, Jeremy J; Thrall, Peter H

2008-02-01

Infectious disease is a major causal factor in the demography of human, plant and animal populations. While it is generally accepted in medical, veterinary and agricultural contexts that variation in host resistance and pathogen virulence and aggressiveness is of central importance to understanding patterns of infection, there has been remarkably little effort to directly investigate causal links between population genetic structure and disease dynamics, and even less work on factors influencing host-pathogen coevolution. The lack of empirical evidence is particularly surprising, given the potential for such variation to not only affect disease dynamics and prevalence, but also when or where new diseases or pathotypes emerge. Increasingly, this lack of knowledge has led to calls for an integrated approach to disease management, incorporating both ecological and evolutionary processes. Here, we argue that plant pathogens occurring in agro-ecosystems represent one clear example where the application of evolutionary principles to disease management would be of great benefit, as well as providing model systems for advancing our ability to generalize about the long-term coevolutionary dynamics of host-pathogen systems. We suggest that this is particularly the case given that agro-ecological host-pathogen interactions represent a diversity of situations ranging from those that only involve agricultural crops through to those that also include weedy crop relatives or even unrelated native plant communities. We begin by examining some of the criteria that are important in determining involvement in agricultural pathogen evolution by noncrop plants. Throughout we use empirical examples to illustrate the fact that different processes may dominate in different systems, and suggest that consideration of life history and spatial structure are central to understanding dynamics and direction of the interaction. We then discuss the implications that such interactions have for disease management in agro-ecosystems and how we can influence those outcomes. Finally, we identify several major gaps where future research could increase our ability to utilize evolutionary principles in managing disease in agro-ecosystems.

Economic Models of Preventive Dentistry for Australian Children and Adolescents: A Systematic Review.

PubMed

Tonmukayakul, Utsana; Sia, Kah-Ling; Gold, Lisa; Hegde, Shalika; de Silva, Andrea M; Moodie, Marj

2015-01-01

To identify economic evaluation models and parameters that could be replicated or adapted to construct a generic model to assess cost-effectiveness of and prioritise a wide range of community-based oral disease prevention programmes in an Australian context. The literature search was conducted using MEDLINE, ERIC, PsycINFO, CINHAL (EBSCOhost), EMBASE (Ovid), CRD, DARE, NHSEED, HTA, all databases in the Cochrane library, Scopus and ScienceDirect databases from their inception to November 2012. Thirty-three articles met the criteria for inclusion in this review (7 were Australian studies, 26 articles were international). Existing models focused primarily on dental caries. Periodontal disease, another common oral health problem, was lacking. Among caries prevention studies, there was an absence of clear evidence showing continuous benefits from primary through to permanent dentition and the long-term effects of oral health promotion. No generic model was identified from previous studies that could be immediately adopted or adapted for our purposes of simulating and prioritising a diverse range of oral health interventions for Australian children and adolescents. Nevertheless, data sources specified in the existing Australian-based models will be useful for developing a generic model for such purposes.

Metabolic Differentiation of Early Lyme Disease from Southern Tick-Associated Rash Illness (STARI)

PubMed Central

Molins, C. R.; Ashton, L. V.; Wormser, G. P.; Andre, B. G.; Hess, A. M.; Delorey, M. J.; Pilgard, M. A.; Johnson, B. J.; Webb, K.; Islam, M. N.; Pegalajar-Jurado, A; Molla, I.; Jewett, M. W.; Belisle, J. T.

2017-01-01

Lyme disease, the most commonly reported vector-borne disease in the United States, results from infection with Borrelia burgdorferi. Early clinical diagnosis of this disease is largely based on the presence of an erythematous skin lesion for individuals in high-risk regions. This, however, can be confused with other illnesses including southern tick-associated rash illness (STARI), an illness that lacks a defined etiological agent or laboratory diagnostic test, and is co-prevalent with Lyme disease in portions of the Eastern United States. By applying an unbiased metabolomics approach with sera retrospectively obtained from well-characterized patients we defined biochemical and diagnostic differences between early Lyme disease and STARI. Specifically, a metabolic biosignature consisting of 261 molecular features (MFs) revealed that altered N-acyl ethanolamine and primary fatty acid amide metabolism discriminated early Lyme disease from STARI. More importantly, development of classification models with the 261 MF biosignature and testing against validation samples differentiated early Lyme disease from STARI with an accuracy of 85 to 98%. These findings revealed metabolic dissimilarity between early Lyme disease and STARI, and provide a powerful and new approach to objectively distinguish early Lyme disease from an illness with nearly identical symptoms. PMID:28814545

Lethal Crimean-Congo Hemorrhagic Fever Virus Infection in Interferon α/β Receptor Knockout Mice Is Associated With High Viral Loads, Proinflammatory Responses, and Coagulopathy

PubMed Central

Zivcec, Marko; Safronetz, David; Scott, Dana; Robertson, Shelly; Ebihara, Hideki; Feldmann, Heinz

2013-01-01

Crimean-Congo hemorrhagic fever (CCHF) is a widely distributed viral hemorrhagic fever characterized by rapid onset of flu-like symptoms often followed by hemorrhagic manifestations. CCHF virus (CCHFV), a bunyavirus in the Nairovirus genus, is capable of infecting a wide range of mammalian hosts in nature but so far only causes disease in humans. Recently, immunocompromised mice have been reported as CCHF disease models, but detailed characterization is lacking. Here, we closely followed infection and disease progression in CCHFV-infected interferon α/β receptor knockout (IFNAR−/−) mice and age-matched wild-type (WT) mice. WT mice quickly clear CCHFV without developing any disease signs. In contrast, CCHFV infected IFNAR−/− mice develop an acute fulminant disease with high viral loads leading to organ pathology (liver and lymphoid tissues), marked proinflammatory host responses, severe thrombocytopenia, coagulopathy, and death. Disease progression closely mimics hallmarks of human CCHF disease, making IFNAR−/− mice an excellent choice to assess medical countermeasures. PMID:23417661

Incidence and multivariable correlates of long-term mortality in patients treated with surgical or percutaneous revascularization in the synergy between percutaneous coronary intervention with taxus and cardiac surgery (SYNTAX) trial.

PubMed

Farooq, Vasim; Serruys, Patrick W; Bourantas, Christos; Vranckx, Pascal; Diletti, Roberto; Garcia Garcia, Hector M; Holmes, David R; Kappetein, Arie-Pieter; Mack, Michael; Feldman, Ted; Morice, Marie Claude; Colombo, Antonio; Morel, Marie-angèle; de Vries, Ton; van Es, Gerrit Anne; Steyerberg, Ewout W; Dawkins, Keith D; Mohr, Friedrich W; James, Stefan; Ståhle, Elisabeth

2012-12-01

The aim of this investigation was to determine the incidence and multivariable correlates of long-term (4-year) mortality in patients treated with surgical or percutaneous revascularization in the synergy between percutaneous coronary intervention (PCI) with TAXUS Express and Cardiac Surgery (SYNTAX) trial. A total of 1800 patients were randomized to undergo coronary artery bypass graft (CABG) surgery (n = 897) or PCI (n = 903). Prospectively collected baseline and peri- and post-procedural data were used to determine independent correlates of 4-year all-cause death in the CABG and the PCI arms (Cox proportional hazards model). Four-year mortality rates in the CABG and the PCI arms were 9.0% [74 deaths (12 in-hospital)] and 11.8% [104 deaths (16 in-hospital)], respectively (log-rank P-value = 0.063). Censored data comprised 78 patients (8.7%) in the CABG arm, and 24 patients (2.7%) in the PCI arm (log-rank P-value < 0.001). Within the CABG arm, the strongest independent correlates of 4-year mortality were lack of discharge aspirin [hazard ratio (HR) 3.56; 95% CI: 2.04, 6.21; P < 0.001], peripheral vascular disease (PVD) (HR: 2.65; 95% CI: 1.49, 4.72; P = 0.001), chronic obstructive pulmonary disease, age, and serum creatinine. Within the PCI arm, the strongest independent correlate of 4-year mortality was lack of post-procedural anti-platelet therapy (HR: 152.16; 95% CI: 53.57, 432.22; P < 0.001), with 10 reported early (within 45 days) in-hospital deaths secondary to multifactorial causes precluding administration of anti-platelet therapy. Other independent correlates of mortality in the PCI arm included amiodarone therapy on discharge, pre-procedural poor left ventricular ejection fraction, a 'history of gastrointestinal bleeding or peptic ulcer disease', PVD (HR: 2.13; 95% CI: 1.26, 3.60; P = 0.005), age, female gender (HR: 1.60; 95% CI: 1.01, 2.56; P = 0.048), and the SYNTAX score (Per increase in 10 points: HR: 1.25; 95% CI: 1.06, 1.47; P = 0.007). Independent correlates of 4-year mortality in the SYNTAX trial were multifactorial. Lack of discharge aspirin and lack of post-procedural anti-platelet therapy were the strongest independent correlates of mortality in the CABG and the PCI arms, respectively. Peripheral vascular disease is a common independent correlate of 4-year mortality and may be a marker of the severity of baseline coronary disease and risk of future native coronary disease (and extra-cardiac disease) progression.

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

PubMed Central

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

2015-01-01

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

Development of a Metabolic Biosignature for Detection of Early Lyme Disease

PubMed Central

Molins, Claudia R.; Ashton, Laura V.; Wormser, Gary P.; Hess, Ann M.; Delorey, Mark J.; Mahapatra, Sebabrata; Schriefer, Martin E.; Belisle, John T.

2015-01-01

Background. Early Lyme disease patients often present to the clinic prior to developing a detectable antibody response to Borrelia burgdorferi, the etiologic agent. Thus, existing 2-tier serology-based assays yield low sensitivities (29%–40%) for early infection. The lack of an accurate laboratory test for early Lyme disease contributes to misconceptions about diagnosis and treatment, and underscores the need for new diagnostic approaches. Methods. Retrospective serum samples from patients with early Lyme disease, other diseases, and healthy controls were analyzed for small molecule metabolites by liquid chromatography-mass spectrometry (LC-MS). A metabolomics data workflow was applied to select a biosignature for classifying early Lyme disease and non-Lyme disease patients. A statistical model of the biosignature was trained using the patients' LC-MS data, and subsequently applied as an experimental diagnostic tool with LC-MS data from additional patient sera. The accuracy of this method was compared with standard 2-tier serology. Results. Metabolic biosignature development selected 95 molecular features that distinguished early Lyme disease patients from healthy controls. Statistical modeling reduced the biosignature to 44 molecular features, and correctly classified early Lyme disease patients and healthy controls with a sensitivity of 88% (84%–95%), and a specificity of 95% (90%–100%). Importantly, the metabolic biosignature correctly classified 77%–95% of the of serology negative Lyme disease patients. Conclusions. The data provide proof-of-concept that metabolic profiling for early Lyme disease can achieve significantly greater (P < .0001) diagnostic sensitivity than current 2-tier serology, while retaining high specificity. PMID:25761869

Clinical and Microbiological Aspects of Trichomonas vaginalis

PubMed Central

Petrin, Dino; Delgaty, Kiera; Bhatt, Renuka; Garber, Gary

1998-01-01

Trichomonas vaginalis, a parasitic protozoan, is the etiologic agent of trichomoniasis, a sexually transmitted disease (STD) of worldwide importance. Trichomoniasis is the most common nonviral STD, and it is associated with many perinatal complications, male and female genitourinary tract infections, and an increased incidence of HIV transmission. Diagnosis is difficult, since the symptoms of trichomoniasis mimic those of other STDs and detection methods lack precision. Although current treatment protocols involving nitroimidazoles are curative, metronidazole resistance is on the rise, outlining the need for research into alternative antibiotics. Vaccine development has been limited by a lack of understanding of the role of the host immune response to T. vaginalis infection. The lack of a good animal model has made it difficult to conduct standardized studies in drug and vaccine development and pathogenesis. Current work on pathogenesis has focused on the host-parasite relationship, in particular the initial events required to establish infection. These studies have illustrated that the pathogenesis of T. vaginalis is indeed very complex and involves adhesion, hemolysis, and soluble factors such as cysteine proteinases and cell-detaching factor. T. vaginalis interaction with the members of the resident vaginal flora, an advanced immune evasion strategy, and certain stress responses enable the organism to survive in its changing environment. Clearly, further research and collaboration will help elucidate these pathogenic mechanisms, and with better knowledge will come improved disease control. PMID:9564565

Mapping X-Disease Phytoplasma Resistance in Prunus virginiana

PubMed Central

Lenz, Ryan R.; Dai, Wenhao

2017-01-01

Phytoplasmas such as “Candidatus Phytoplasma pruni,” the causal agent of X-disease of stone fruits, lack detailed biological analysis. This has limited the understanding of plant resistance mechanisms. Chokecherry (Prunus virginiana L.) is a promising model to be used for the plant-phytoplasma interaction due to its documented ability to resist X-disease infection. A consensus chokecherry genetic map “Cho” was developed with JoinMap 4.0 by joining two parental maps. The new map contains a complete set of 16 linkage groups, spanning a genetic distance of 2,172 cM with an average marker density of 3.97 cM. Three significant quantitative trait loci (QTL) associated with X-disease resistance were identified contributing to a total of 45.9% of the phenotypic variation. This updated genetic linkage map and the identified QTL will provide the framework needed to facilitate molecular genetics, genomics, breeding, and biotechnology research concerning X-disease in chokecherry and other Prunus species. PMID:29238359

SpatialEpiApp: A Shiny web application for the analysis of spatial and spatio-temporal disease data.

PubMed

Moraga, Paula

2017-11-01

During last years, public health surveillance has been facilitated by the existence of several packages implementing statistical methods for the analysis of spatial and spatio-temporal disease data. However, these methods are still inaccesible for many researchers lacking the adequate programming skills to effectively use the required software. In this paper we present SpatialEpiApp, a Shiny web application that integrate two of the most common approaches in health surveillance: disease mapping and detection of clusters. SpatialEpiApp is easy to use and does not require any programming knowledge. Given information about the cases, population and optionally covariates for each of the areas and dates of study, the application allows to fit Bayesian models to obtain disease risk estimates and their uncertainty by using R-INLA, and to detect disease clusters by using SaTScan. The application allows user interaction and the creation of interactive data visualizations and reports showing the analyses performed. Copyright © 2017 Elsevier Ltd. All rights reserved.

Senescent Cells: A Novel Therapeutic Target for Aging and Age-Related Diseases

PubMed Central

Naylor, RM; Baker, DJ; van Deursen, JM

2014-01-01

Aging is the main risk factor for most chronic diseases, disabilities, and declining health. It has been proposed that senescent cells—damaged cells that have lost the ability to divide—drive the deterioration that underlies aging and age-related diseases. However, definitive evidence for this relationship has been lacking. The use of a progeroid mouse model (which expresses low amounts of the mitotic checkpoint protein BubR1) has been instrumental in demonstrating that p16Ink4a-positive senescent cells drive age-related pathologies and that selective elimination of these cells can prevent or delay age-related deterioration. These studies identify senescent cells as potential therapeutic targets in the treatment of aging and age-related diseases. Here, we describe how senescent cells develop, the experimental evidence that causally implicates senescent cells in age-related dysfunction, the chronic diseases and disorders that are characterized by the accumulation of senescent cells at sites of pathology, and the therapeutic approaches that could specifically target senescent cells. PMID:23212104

Endothelial Progenitor Cells and Kidney Diseases.

PubMed

Ozkok, Abdullah; Yildiz, Alaattin

2018-05-10

Endothelial progenitor cells (EPC) are bone marrow derived or tissue-resident cells that play major roles in the maintenance of vascular integrity and repair of endothelial damage. Although EPCs may be capable of directly engrafting and regenerating the endothelium, the most important effects of EPCs seem to be depended on paracrine effects. In recent studies, specific microvesicles and mRNAs have been found to mediate the pro-angiogenic and regenerative effects of EPCs on endothelium. EPC counts have important prognostic implications in cardiovascular diseases (CVD). Uremia and inflammation are associated with lower EPC counts which probably contribute to increased CVD risks in patients with chronic kidney disease. Beneficial effects of the EPC therapies have been shown in studies performed on different models of CVD and kidney diseases such as acute and chronic kidney diseases and glomerulonephritis. However, lack of a clear definition and specific marker of EPCs is the most important problem causing difficulties in interpretation of the results of the studies investigating EPCs. © 2018 The Author(s). Published by S. Karger AG, Basel.

Periodontal disease and the special needs patient.

PubMed

Brown, Louise F; Ford, Pauline J; Symons, Anne L

2017-06-01

Individuals with special needs are at more risk of dental disease, including periodontal diseases, and have a greater prevalence and incidence of periodontal diseases than the rest of the population. Genetic or medical conditions, and/or the use of prescription medication or recreational substances, may further increase the risk for susceptibility to periodontal disease. The success of preventing or controlling periodontal diseases amongst this group of patients has not been established. Even those individuals who access regular and comprehensive dental care appear to develop periodontal diseases as they age, and this development occurs at a rate comparable to the natural history of the disease. The reasons behind the lack of success of interventions in reducing the incidence of periodontal diseases are complex and part of the lack of success may relate to the professional challenges in treating individuals with special needs. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Serotonin System Implication in l-DOPA-Induced Dyskinesia: From Animal Models to Clinical Investigations

PubMed Central

Carta, Manolo; Tronci, Elisabetta

2014-01-01

In the recent years, the serotonin system has emerged as a key player in the induction of l-DOPA-induced dyskinesia (LID) in animal models of Parkinson’s disease. In fact, serotonin neurons possess the enzymatic machinery able to convert exogenous l-DOPA to dopamine (DA), and mediate its vesicular storage and release. However, serotonin neurons lack a feedback control mechanism able to regulate synaptic DA levels. While in a situation of partial DA depletion spared DA terminals can buffer DA released from serotonin neurons, the progression of DA neuron degeneration impairs this protective mechanism, causing swings in synaptic DA levels and pulsatile stimulation of post-synaptic DA receptors. In line with this view, removal of serotonin neurons by selective toxin, or pharmacological silencing of their activity, produced complete suppression of LID in animal models of Parkinson’s disease. In this article, we will revise the experimental evidence pointing to the important role of serotonin neurons in dyskinesia, and we will discuss the clinical implications. PMID:24904522

Modeling Inborn Errors of Hepatic Metabolism Using Induced Pluripotent Stem Cells.

PubMed

Pournasr, Behshad; Duncan, Stephen A

2017-11-01

Inborn errors of hepatic metabolism are because of deficiencies commonly within a single enzyme as a consequence of heritable mutations in the genome. Individually such diseases are rare, but collectively they are common. Advances in genome-wide association studies and DNA sequencing have helped researchers identify the underlying genetic basis of such diseases. Unfortunately, cellular and animal models that accurately recapitulate these inborn errors of hepatic metabolism in the laboratory have been lacking. Recently, investigators have exploited molecular techniques to generate induced pluripotent stem cells from patients' somatic cells. Induced pluripotent stem cells can differentiate into a wide variety of cell types, including hepatocytes, thereby offering an innovative approach to unravel the mechanisms underlying inborn errors of hepatic metabolism. Moreover, such cell models could potentially provide a platform for the discovery of therapeutics. In this mini-review, we present a brief overview of the state-of-the-art in using pluripotent stem cells for such studies. © 2017 American Heart Association, Inc.

Calculating Stress: From Entropy to a Thermodynamic Concept of Health and Disease

PubMed Central

Nečesánek, Ivo; Konečný, David; Vasku, Anna

2016-01-01

To date, contemporary science has lacked a satisfactory tool for the objective expression of stress. This text thus introduces a new–thermodynamically derived–approach to stress measurement, based on entropy production in time and independent of the quality or modality of a given stressor or a combination thereof. Hereto, we propose a novel model of stress response based on thermodynamic modelling of entropy production, both in the tissues/organs and in regulatory feedbacks. Stress response is expressed in our model on the basis of stress entropic load (SEL), a variable we introduced previously; the mathematical expression of SEL, provided here for the first time, now allows us to describe the various states of a living system, including differentiating between states of health and disease. The resulting calculation of stress response regardless of the type of stressor(s) in question is thus poised to become an entirely new tool for predicting the development of a living system. PMID:26771542

Economic Game Theory to Model the Attenuation of Virulence of an Obligate Intracellular Bacterium.

PubMed

Tago, Damian; Meyer, Damien F

2016-01-01

Diseases induced by obligate intracellular pathogens have a large burden on global human and animal health. Understanding the factors involved in the virulence and fitness of these pathogens contributes to the development of control strategies against these diseases. Based on biological observations, a theoretical model using game theory is proposed to explain how obligate intracellular bacteria interact with their host. The equilibrium in such a game shows that the virulence and fitness of the bacterium is host-triggered and by changing the host's defense system to which the bacterium is confronted, an evolutionary process leads to an attenuated strain. Although, the attenuation procedure has already been conducted in practice in order to develop an attenuated vaccine (e.g., with Ehrlichia ruminantium), there was a lack of understanding of the theoretical basis behind this process. Our work provides a model to better comprehend the existence of different phenotypes and some underlying evolutionary mechanisms for the virulence of obligate intracellular bacteria.

Molecular determinants for a cardiovascular collapse in anthrax

PubMed Central

Brojatsch, Jurgen; Casadevall, Arturo; Goldman, David L.

2015-01-01

Bacillus anthracis releases two bipartite proteins, lethal toxin and edema factor, that contribute significantly to the progression of anthrax-associated shock. As blocking the anthrax toxins prevents disease, the toxins are considered the main virulence factors of the bacterium. The anthrax bacterium and the anthrax toxins trigger multiorgan failure associated with enhanced vascular permeability, hemorrhage and cardiac dysfunction in animal challenge models. A recent study using mice that either lacked the anthrax toxin receptor in specific cells and corresponding mice expressing the receptor in specific cell types demonstrated that cardiovascular cells are critical for disease mediated by anthrax lethal toxin. These studies are consistent with involvement of the cardiovascular system, and with an increase of cardiac failure markers observed in human anthrax and in animal models using B. anthracis and anthrax toxins. This review discusses the current state of knowledge regarding the pathophysiology of anthrax and tries to provide a mechanistic model and molecular determinants for the circulatory shock in anthrax. PMID:24389148

Economic Game Theory to Model the Attenuation of Virulence of an Obligate Intracellular Bacterium

PubMed Central

Tago, Damian; Meyer, Damien F.

2016-01-01

Diseases induced by obligate intracellular pathogens have a large burden on global human and animal health. Understanding the factors involved in the virulence and fitness of these pathogens contributes to the development of control strategies against these diseases. Based on biological observations, a theoretical model using game theory is proposed to explain how obligate intracellular bacteria interact with their host. The equilibrium in such a game shows that the virulence and fitness of the bacterium is host-triggered and by changing the host's defense system to which the bacterium is confronted, an evolutionary process leads to an attenuated strain. Although, the attenuation procedure has already been conducted in practice in order to develop an attenuated vaccine (e.g., with Ehrlichia ruminantium), there was a lack of understanding of the theoretical basis behind this process. Our work provides a model to better comprehend the existence of different phenotypes and some underlying evolutionary mechanisms for the virulence of obligate intracellular bacteria. PMID:27610355

The pathophysiology of human obstructive cholestasis is mimicked in cholestatic Gold Syrian hamsters.

PubMed

van Golen, Rowan F; Olthof, Pim B; de Haan, Lianne R; Coelen, Robert J; Pechlivanis, Alexandros; de Keijzer, Mark J; Weijer, Ruud; de Waart, Dirk R; van Kuilenburg, André B P; Roelofsen, Jeroen; Gilijamse, Pim W; Maas, Martinus A; Lewis, Matthew R; Nicholson, Jeremy K; Verheij, Joanne; Heger, Michal

2018-03-01

Obstructive cholestasis causes liver injury via accumulation of toxic bile acids (BAs). Therapeutic options for cholestatic liver disease are limited, partially because the available murine disease models lack translational value. Profiling of time-related changes following bile duct ligation (BDL) in Gold Syrian hamsters revealed a biochemical response similar to cholestatic patients in terms of BA pool composition, alterations in hepatocyte BA transport and signaling, suppression of BA production, and adapted BA metabolism. Hamsters tolerated cholestasis well for up to 28days and progressed relatively slowly to fibrotic liver injury. Hepatocellular necrosis was absent, which coincided with preserved intrahepatic energy levels and only mild oxidative stress. The histological response to cholestasis in hamsters was similar to the changes seen in 17 patients with prolonged obstructive cholestasis caused by cholangiocarcinoma. Hamsters moreover upregulated hepatic fibroblast growth factor 15 (Fgf15) expression in response to BDL, which is a cytoprotective adaptation to cholestasis that hitherto had only been documented in cholestatic human livers. Hamster models should therefore be added to the repertoire of animal models used to study the pathophysiology of cholestatic liver disease. Copyright © 2017 Elsevier B.V. All rights reserved.

[Lack of insight in schizophrenia: a review].

PubMed

Raffard, S; Bayard, S; Capdevielle, D; Garcia, F; Boulenger, J-P; Gely-Nargeot, M-C

2008-10-01

Relative to other psychiatric disorders, patients with schizophrenia are often unaware of the consequences of their disease and their need for treatment. These deficits in awareness referred in general in the English literature as "poor insight", have been the focus of many clinical studies over recent years. This phenomenon, which is considered as fundamental in clinical evaluations of schizophrenia, should be understood as a multidimensional process rather than a dichotomic phenomenon, as is presently the case. The links between insight deficits and responses to vocational rehabilitation efforts represent a major interest in research, including those related to medication compliance and clinical outcome. To conduct such studies, various evaluation tools have been developed, enabling the assessment of insight, of its time-course and of its components in psychosis and schizophrenia spectrum disorders. The Scale to Assess Unawareness of illness in Mental Disorders (SUMD) developed by Amador and Strauss appears to be the most frequently used scale for the evaluation of awareness of the disorder in schizophrenia. Although the model proposed by Amador and Strauss is considered as the privileged model in the multidimensional approach of insight, it corresponds only to a phenomenological analysis of this concept. In the second part of this article, we thus review the current models attempting to explain the lack of insight in schizophrenia. Four current explanatory models of lack of insight will be described as follows: resulting either from adaptation or defence mechanisms to environmental stressors, resulting from cognitive bias of data processing, resulting from neuropsychological functional deficits and resulting from metacognitive deficits. Several hypotheses concerning these deficits arise from clinical studies. Although coping, and defence mechanisms to the consequences and stigmatization of the disease were hardly studied, the fact that poor insight does not appear related to the severity of symptomatology or to the emotional state of the patients argue against this hypothesis. Conversely, a considerable body of literature emphasized how unawareness may result from cognitive deficits. Research in neuropsychology and cognitive psychology has provided consistent results concerning the link between deficit in executive functions, frontal lobe dysfunction and poor insight. Recent studies on bias in cognitive information treatment and social cognition theories currently open new prospects.

A novel mouse model identifies cooperating mutations and therapeutic targets critical for chronic myeloid leukemia progression

PubMed Central

Giotopoulos, George; van der Weyden, Louise; Osaki, Hikari; Rust, Alistair G.; Gallipoli, Paolo; Meduri, Eshwar; Horton, Sarah J.; Chan, Wai-In; Foster, Donna; Prinjha, Rab K.; Pimanda, John E.; Tenen, Daniel G.; Vassiliou, George S.; Koschmieder, Steffen; Adams, David J.

2015-01-01

The introduction of highly selective ABL-tyrosine kinase inhibitors (TKIs) has revolutionized therapy for chronic myeloid leukemia (CML). However, TKIs are only efficacious in the chronic phase of the disease and effective therapies for TKI-refractory CML, or after progression to blast crisis (BC), are lacking. Whereas the chronic phase of CML is dependent on BCR-ABL, additional mutations are required for progression to BC. However, the identity of these mutations and the pathways they affect are poorly understood, hampering our ability to identify therapeutic targets and improve outcomes. Here, we describe a novel mouse model that allows identification of mechanisms of BC progression in an unbiased and tractable manner, using transposon-based insertional mutagenesis on the background of chronic phase CML. Our BC model is the first to faithfully recapitulate the phenotype, cellular and molecular biology of human CML progression. We report a heterogeneous and unique pattern of insertions identifying known and novel candidate genes and demonstrate that these pathways drive disease progression and provide potential targets for novel therapeutic strategies. Our model greatly informs the biology of CML progression and provides a potent resource for the development of candidate therapies to improve the dismal outcomes in this highly aggressive disease. PMID:26304963

Experimental West Nile Virus Infection in Rabbits: An Alternative Model for Studying Induction of Disease and Virus Control

PubMed Central

Suen, Willy W.; Uddin, Muhammad J.; Wang, Wenqi; Brown, Vienna; Adney, Danielle R.; Broad, Nicole; Prow, Natalie A.; Bowen, Richard A.; Hall, Roy A.; Bielefeldt-Ohmann, Helle

2015-01-01

The economic impact of non-lethal human and equine West Nile virus (WNV) disease is substantial, since it is the most common presentation of the infection. Experimental infection with virulent WNV strains in the mouse and hamster models frequently results in severe neural infection and moderate to high mortality, both of which are not representative features of most human and equine infections. We have established a rabbit model for investigating pathogenesis and immune response of non-lethal WNV infection. Two species of rabbits, New Zealand White (Oryctolagus cuniculus) and North American cottontail (Sylvilagus sp.), were experimentally infected with virulent WNV and Murray Valley encephalitis virus strains. Infected rabbits exhibited a consistently resistant phenotype, with evidence of low viremia, minimal-absent neural infection, mild-moderate neuropathology, and the lack of mortality, even though productive virus replication occurred in the draining lymph node. The kinetics of anti-WNV neutralizing antibody response was comparable to that commonly seen in infected horses and humans. This may be explained by the early IFNα/β and/or γ response evident in the draining popliteal lymph node. Given this similarity to the human and equine disease, immunocompetent rabbits are, therefore, a valuable animal model for investigating various aspects of non-lethal WNV infections. PMID:26184326

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

Nipah Virus C and W Proteins Contribute to Respiratory Disease in Ferrets

PubMed Central

Satterfield, Benjamin A.; Cross, Robert W.; Fenton, Karla A.; Borisevich, Viktoriya; Agans, Krystle N.; Deer, Daniel J.; Graber, Jessica; Basler, Christopher F.; Mire, Chad E.

2016-01-01

ABSTRACT Nipah virus (NiV) is a highly lethal paramyxovirus that recently emerged as a causative agent of febrile encephalitis and severe respiratory disease in humans. The ferret model has emerged as the preferred small-animal model with which to study NiV disease, but much is still unknown about the viral determinants of NiV pathogenesis, including the contribution of the C protein in ferrets. Additionally, studies have yet to examine the synergistic effects of the various P gene products on pathogenesis in animal models. Using recombinant NiVs (rNiVs), we examine the sole contribution of the NiV C protein and the combined contributions of the C and W proteins in the ferret model of NiV pathogenesis. We show that an rNiV void of C expression resulted in 100% mortality, though with limited respiratory disease, like our previously reported rNiV void of W expression; this finding is in stark contrast to the attenuated phenotype observed in previous hamster studies utilizing rNiVs void of C expression. We also observed that an rNiV void of both C and W expression resulted in limited respiratory disease; however, there was severe neurological disease leading to 60% mortality, and the surviving ferrets demonstrated sequelae similar to those for human survivors of NiV encephalitis. IMPORTANCE Nipah virus (NiV) is a human pathogen capable of causing lethal respiratory and neurological disease. Many human survivors have long-lasting neurological impairment. Using a ferret model, this study demonstrated the roles of the NiV C and W proteins in pathogenesis, where lack of either the C or the W protein independently decreased the severity of clinical respiratory disease but did not decrease lethality. Abolishing both C and W expression, however, dramatically decreased the severity of respiratory disease and the level of destruction of splenic germinal centers. These ferrets still suffered severe neurological disease: 60% succumbed to disease, and the survivors experienced long-term neurological impairment, such as that seen in human survivors. This new ferret NiV C and W knockout model may allow, for the first time, the examination of interventions to prevent or mitigate the neurological damage and sequelae experienced by human survivors. PMID:27147733

Nipah Virus C and W Proteins Contribute to Respiratory Disease in Ferrets.

PubMed

Satterfield, Benjamin A; Cross, Robert W; Fenton, Karla A; Borisevich, Viktoriya; Agans, Krystle N; Deer, Daniel J; Graber, Jessica; Basler, Christopher F; Geisbert, Thomas W; Mire, Chad E

2016-07-15

Nipah virus (NiV) is a highly lethal paramyxovirus that recently emerged as a causative agent of febrile encephalitis and severe respiratory disease in humans. The ferret model has emerged as the preferred small-animal model with which to study NiV disease, but much is still unknown about the viral determinants of NiV pathogenesis, including the contribution of the C protein in ferrets. Additionally, studies have yet to examine the synergistic effects of the various P gene products on pathogenesis in animal models. Using recombinant NiVs (rNiVs), we examine the sole contribution of the NiV C protein and the combined contributions of the C and W proteins in the ferret model of NiV pathogenesis. We show that an rNiV void of C expression resulted in 100% mortality, though with limited respiratory disease, like our previously reported rNiV void of W expression; this finding is in stark contrast to the attenuated phenotype observed in previous hamster studies utilizing rNiVs void of C expression. We also observed that an rNiV void of both C and W expression resulted in limited respiratory disease; however, there was severe neurological disease leading to 60% mortality, and the surviving ferrets demonstrated sequelae similar to those for human survivors of NiV encephalitis. Nipah virus (NiV) is a human pathogen capable of causing lethal respiratory and neurological disease. Many human survivors have long-lasting neurological impairment. Using a ferret model, this study demonstrated the roles of the NiV C and W proteins in pathogenesis, where lack of either the C or the W protein independently decreased the severity of clinical respiratory disease but did not decrease lethality. Abolishing both C and W expression, however, dramatically decreased the severity of respiratory disease and the level of destruction of splenic germinal centers. These ferrets still suffered severe neurological disease: 60% succumbed to disease, and the survivors experienced long-term neurological impairment, such as that seen in human survivors. This new ferret NiV C and W knockout model may allow, for the first time, the examination of interventions to prevent or mitigate the neurological damage and sequelae experienced by human survivors. Copyright © 2016, American Society for Microbiology. All Rights Reserved.

Fenofibrate, but not ezetimibe, prevents fatty liver disease in mice lacking phosphatidylethanolamine N-methyltransferase.

PubMed

van der Veen, Jelske N; Lingrell, Susanne; Gao, Xia; Takawale, Abhijit; Kassiri, Zamaneh; Vance, Dennis E; Jacobs, René L

2017-04-01

Mice lacking phosphatidylethanolamine N -methyltransferase (PEMT) are protected from high-fat diet (HFD)-induced obesity and insulin resistance. However, these mice develop severe nonalcoholic fatty liver disease (NAFLD) when fed the HFD, which is mainly due to inadequate secretion of VLDL particles. Our aim was to prevent NAFLD development in mice lacking PEMT. We treated Pemt -/- mice with either ezetimibe or fenofibrate to see if either could ameliorate liver disease in these mice. Ezetimibe treatment did not reduce fat accumulation in Pemt -/- livers, nor did it reduce markers for hepatic inflammation or fibrosis. Fenofibrate, conversely, completely prevented the development of NAFLD in Pemt -/- mice: hepatic lipid levels, as well as markers of endoplasmic reticulum stress, inflammation, and fibrosis, in fenofibrate-treated Pemt -/- mice were similar to those in Pemt +/+ mice. Importantly, Pemt -/- mice were still protected against HFD-induced obesity and insulin resistance. Moreover, fenofibrate partially reversed hepatic steatosis and fibrosis in Pemt -/- mice when treatment was initiated after NAFLD had already been established. Increasing hepatic fatty acid oxidation can compensate for the lower VLDL-triacylglycerol secretion rate and prevent/reverse fatty liver disease in mice lacking PEMT. Copyright © 2017 by the American Society for Biochemistry and Molecular Biology, Inc.

Fenofibrate, but not ezetimibe, prevents fatty liver disease in mice lacking phosphatidylethanolamine N-methyltransferase[S

PubMed Central

van der Veen, Jelske N.; Lingrell, Susanne; Gao, Xia; Takawale, Abhijit; Kassiri, Zamaneh; Vance, Dennis E.; Jacobs, René L.

2017-01-01

Mice lacking phosphatidylethanolamine N-methyltransferase (PEMT) are protected from high-fat diet (HFD)-induced obesity and insulin resistance. However, these mice develop severe nonalcoholic fatty liver disease (NAFLD) when fed the HFD, which is mainly due to inadequate secretion of VLDL particles. Our aim was to prevent NAFLD development in mice lacking PEMT. We treated Pemt−/− mice with either ezetimibe or fenofibrate to see if either could ameliorate liver disease in these mice. Ezetimibe treatment did not reduce fat accumulation in Pemt−/− livers, nor did it reduce markers for hepatic inflammation or fibrosis. Fenofibrate, conversely, completely prevented the development of NAFLD in Pemt−/− mice: hepatic lipid levels, as well as markers of endoplasmic reticulum stress, inflammation, and fibrosis, in fenofibrate-treated Pemt−/− mice were similar to those in Pemt+/+ mice. Importantly, Pemt−/− mice were still protected against HFD-induced obesity and insulin resistance. Moreover, fenofibrate partially reversed hepatic steatosis and fibrosis in Pemt−/− mice when treatment was initiated after NAFLD had already been established. Increasing hepatic fatty acid oxidation can compensate for the lower VLDL-triacylglycerol secretion rate and prevent/reverse fatty liver disease in mice lacking PEMT. PMID:28159867

Disease Progression Modeling to Evaluate the Effects of Enzyme Replacement Therapy on Kidney Function in Adult Patients with the Classic Phenotype of Fabry Disease.

PubMed

Nowak, Albina; Koch, Gilbert; Huynh-Do, Uyen; Siegenthaler, Martin; Marti, Hans-Peter; Pfister, Marc

2017-01-01

Fabry disease (FD) is a rare inherited lysosomal storage disease with common and serious kidney complications. Enzyme replacement therapies (ERT) with agalsidase-α and -β were investigated to characterize their therapeutic effect on kidney function in FD patients with Classic phenotype. The prospective FD cohort consisted of 98 genetically confirmed patients (females, n = 61, males, n = 37). The median [interquartile range] follow-up time (time difference from first to last visit) was 9 [6, 12] years. The median age of ERT start was 36 [21 - 54] years for females and 39 [28 - 49] years for males. A disease progression model was developed to (i) characterize the time course of estimated glomerular filtration rate (eGFR) and (ii) evaluate therapeutic effects of ERT on kidney function. Change in eGFR over time was best described by the linear model. Females had stable kidney function with and without ERT (eGFR slopes of -0.07 ml/min/1.73m^2 per year and 0.52 ml/min/1.73m^2 per year, respectively). Males with ERT showed an eGFR decrease of -3.07 ml/min/1.73m^2 per year. Mathematical disease progression modeling indicates that there is no clear therapeutic effect of ERT on kidney function in adult patients with Classic Phenotype of FD. Interpretation of these findings should take into account that the study is not randomized and lacks a placebo controlled group. Further investigations are warranted to clarify whether earlier ERT initiation before 18 years of age, higher ERT dose or more intensive therapies can preserve kidney function. © 2017 The Author(s)Published by S. Karger AG, Basel.

Using handgrip strength to screen for diabetes in developing countries.

PubMed

Eckman, Molly; Gigliotti, Christopher; Sutermaster, Staci; Butler, Peter J; Mehta, Khanjan

2016-01-01

Lack of access to healthcare in the developing world has created a need for locally-based primary and pre-primary healthcare systems. Many regions of the world have adopted Community Health Worker (CHW) programmes, but volunteers in these programmes lack the tools and resources to screen for disease. Because of its simplicity of operation, handgrip strength (HGS) measurements have the potential to be an affordable and effective screening tool for conditions that cause muscle weakness in this context. In the study described in this report, translators were used to collect data on age, gender, height, weight, blood pressure, HGS and key demographic data. HGS was significantly lower for diabetics than patients without diabetes. A simple binary logistic model was created that used HGS, age, blood pressure and BMI to predict a patient's probability of having diabetes. This study develops a predictive model for diabetes using HGS and other basic health measurements and shows that HGS-based screening is a viable method of early detection of diabetes.

Collaborative Drug Therapy Management: Case Studies of Three Community-Based Models of Care

PubMed Central

Snyder, Margie E.; Earl, Tara R.; Greenberg, Michael; Heisler, Holly; Revels, Michelle; Matson-Koffman, Dyann

2015-01-01

Collaborative drug therapy management agreements are a strategy for expanding the role of pharmacists in team-based care with other providers. However, these agreements have not been widely implemented. This study describes the features of existing provider–pharmacist collaborative drug therapy management practices and identifies the facilitators and barriers to implementing such services in community settings. We conducted in-depth, qualitative interviews in 2012 in a federally qualified health center, an independent pharmacy, and a retail pharmacy chain. Facilitators included 1) ensuring pharmacists were adequately trained; 2) obtaining stakeholder (eg, physician) buy-in; and 3) leveraging academic partners. Barriers included 1) lack of pharmacist compensation; 2) hesitation among providers to trust pharmacists; 3) lack of time and resources; and 4) existing informal collaborations that resulted in reduced interest in formal agreements. The models described in this study could be used to strengthen clinical–community linkages through team-based care, particularly for chronic disease prevention and management. PMID:25811494

Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo.

PubMed

Colvin, Stephanie C; Malik, Raleigh E; Showalter, Aaron D; Sloop, Kyle W; Rhodes, Simon J

2011-01-04

The etiology of most pediatric hormone deficiency diseases is poorly understood. Children with combined pituitary hormone deficiency (CPHD) have insufficient levels of multiple anterior pituitary hormones causing short stature, metabolic disease, pubertal failure, and often have associated nervous system symptoms. Mutations in developmental regulatory genes required for the specification of the hormone-secreting cell types of the pituitary gland underlie severe forms of CPHD. To better understand these diseases, we have created a unique mouse model of CPHD with a targeted knockin mutation (Lhx3 W227ter), which is a model for the human LHX3 W224ter disease. The LHX3 gene encodes a LIM-homeodomain transcription factor, which has essential roles in pituitary and nervous system development in mammals. The introduced premature termination codon results in deletion of the carboxyl terminal region of the LHX3 protein, which is critical for pituitary gene activation. Mice that lack all LHX3 function do not survive beyond birth. By contrast, the homozygous Lhx3 W227ter mice survive, but display marked dwarfism, thyroid disease, and female infertility. Importantly, the Lhx3 W227ter mice have no apparent nervous system deficits. The Lhx3 W227ter mouse model provides a unique array of hormone deficits and facilitates experimental approaches that are not feasible with human patients. These experiments demonstrate that the carboxyl terminus of the LHX3 transcription factor is not required for viability. More broadly, this study reveals that the in vivo actions of a transcription factor in different tissues are molecularly separable.

Utility of genetic and non-genetic risk factors in predicting coronary heart disease in Singaporean Chinese.

PubMed

Chang, Xuling; Salim, Agus; Dorajoo, Rajkumar; Han, Yi; Khor, Chiea-Chuen; van Dam, Rob M; Yuan, Jian-Min; Koh, Woon-Puay; Liu, Jianjun; Goh, Daniel Yt; Wang, Xu; Teo, Yik-Ying; Friedlander, Yechiel; Heng, Chew-Kiat

2017-01-01

Background Although numerous phenotype based equations for predicting risk of 'hard' coronary heart disease are available, data on the utility of genetic information for such risk prediction is lacking in Chinese populations. Design Case-control study nested within the Singapore Chinese Health Study. Methods A total of 1306 subjects comprising 836 men (267 incident cases and 569 controls) and 470 women (128 incident cases and 342 controls) were included. A Genetic Risk Score comprising 156 single nucleotide polymorphisms that have been robustly associated with coronary heart disease or its risk factors ( p < 5 × 10 -8 ) in at least two independent cohorts of genome-wide association studies was built. For each gender, three base models were used: recalibrated Adult Treatment Panel III (ATPIII) Model (M 1 ); ATP III model fitted using Singapore Chinese Health Study data (M 2 ) and M 3 : M 2 + C-reactive protein + creatinine. Results The Genetic Risk Score was significantly associated with incident 'hard' coronary heart disease ( p for men: 1.70 × 10 -10 -1.73 × 10 -9 ; p for women: 0.001). The inclusion of the Genetic Risk Score in the prediction models improved discrimination in both genders (c-statistics: 0.706-0.722 vs. 0.663-0.695 from base models for men; 0.788-0.790 vs. 0.765-0.773 for women). In addition, the inclusion of the Genetic Risk Score also improved risk classification with a net gain of cases being reclassified to higher risk categories (men: 12.4%-16.5%; women: 10.2% (M 3 )), while not significantly reducing the classification accuracy in controls. Conclusions The Genetic Risk Score is an independent predictor for incident 'hard' coronary heart disease in our ethnic Chinese population. Inclusion of genetic factors into coronary heart disease prediction models could significantly improve risk prediction performance.

Internet access and use by COPD patients in the National Emphysema/COPD Association Survey

PubMed Central

2014-01-01

Background Technology offers opportunities to improve healthcare, but little is known about Internet use by COPD patients. We tested two hypotheses: Internet access is associated with socio-demographic disparities and frequency of use is related to perceived needs. Methods We analyzed data from a 2007–2008 national convenience sample survey of COPD patients to determine the relationship between Internet access and frequency of use with demographics, socio-economic status, COPD severity, and satisfaction with healthcare. Results Among survey respondents (response rate 7.2%; n = 914, 59.1% women, mean age 71.2 years), 34.2% reported lack of Internet access, and an additional 49% had access but used the Internet less than weekly. Multivariate models showed association between lack of access and older age (OR 1.10, 95% CI 1.07, 1.13), lower income (income below $30,000 OR 2.47, 95% CI 1.63, 3.73), less education (high school highest attainment OR 2.30, 95% CI 1.54, 3.45), comorbid arthritis or mobility-related disease (OR 1.56, 95% CI 1.05, 2.34). More frequent use (at least weekly) was associated with younger age (OR 0.95, 95% CI 0.93, 0.98), absence of cardiovascular disease (OR 0.48, 95% CI 0.29, 0.78), but with perception of needs insufficiently met by the healthcare system, including diagnostic delay (OR 1.72, 95% CI 1.06, 2.78), feeling treated poorly (OR 2.46, 95% CI 1.15, 5.24), insufficient physician time (OR 2.29, 95% CI 1.02, 5.13), and feeling their physician did not listen (OR 3.14, 95% CI 1.42, 6.95). Conclusions An analysis of the characteristics associated with Internet access and use among COPD patients identified two different patient populations. Lack of Internet access was a marker of socioeconomic disparity and mobility-associated diseases, while frequent Internet use was associated with less somatic disease but dissatisfaction with care. PMID:24755090

Childhood asthma: considerations for primary care practice and chronic disease management in the village of care.

PubMed

Rosenthal, Michael P

2012-06-01

Childhood asthma is at historically high levels, with significant morbidity and mortality. Despite more than two decades of improved understanding of childhood asthma care and the evolution of beneficial medications, widespread control remains poor, leading to suboptimal patient outcomes and quality of life. This lack of control results in excessive emergency department use, hospitalizations, and inappropriate and/or unnecessary costs to the health care system. Advanced practice models that incorporate community-based approaches and services for childhood asthma are needed. Innovative, community-included methods of care to address the burden of childhood asthma may provide examples for care of other chronic diseases. Copyright © 2012 Elsevier Inc. All rights reserved.

Biosurveillance Using Clinical Diagnoses and Social Media Indicators in Military Populations

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

Corley, Courtney D.; Volkova, Svitlana; Rounds, Jeremiah

U.S. military influenza surveillance uses electronic reporting of clinical diagnoses to monitor health of military personnel and detect naturally occurring and bioterrorism-related epidemics. While accurate, these systems lack in timeliness. More recently, researchers have used novel data sources to detect influenza in real time and capture nontraditional populations. With data-mining techniques, military social media users are identified and influenza-related discourse is integrated along with medical data into a comprehensive disease model. By leveraging heterogeneous data streams and developing dashboard biosurveillance analytics, the researchers hope to increase the speed at which outbreaks are detected and provide accurate disease forecasting among militarymore » personnel.« less

Immunization against Small Ruminant Lentiviruses

PubMed Central

Reina, Ramsés; de Andrés, Damián; Amorena, Beatriz

2013-01-01

Multisystemic disease caused by Small Ruminant Lentiviruses (SRLV) in sheep and goats leads to production losses, to the detriment of animal health and welfare. This, together with the lack of treatments, has triggered interest in exploring different strategies of immunization to control the widely spread SRLV infection and, also, to provide a useful model for HIV vaccines. These strategies involve inactivated whole virus, subunit vaccines, DNA encoding viral proteins in the presence or absence of plasmids encoding immunological adjuvants and naturally or artificially attenuated viruses. In this review, we revisit, comprehensively, the immunization strategies against SRLV and analyze this double edged tool individually, as it may contribute to either controlling or enhancing virus replication and/or disease. PMID:23917352

Region- and age-dependent alterations of glial-neuronal metabolic interactions correlate with CNS pathology in a mouse model of globoid cell leukodystrophy.

PubMed

Meisingset, Tore Wergeland; Ricca, Alessandra; Neri, Margherita; Sonnewald, Ursula; Gritti, Angela

2013-07-01

Globoid cell leukodystrophy (GLD) or Krabbe disease is a lysosomal storage disorder caused by genetic defects in the expression and activity of galactosylceramidase, a key enzyme in the catabolism of myelin-enriched sphingolipids. While there are several histologic, biochemical, and functional studies on GLD, correlations between morphologic and biochemical alterations in central nervous system (CNS) tissues during disease progression are lacking. Here, we combined immunohistochemistry and metabolic analysis using (1)H and (13)C magnetic resonance (MR) spectra of spinal cord, cerebellum, and forebrain to investigate glial-neuronal metabolic interactions and dysfunction in a GLD murine model that recapitulates the human pathology. In order to assess the temporal- and region-dependent disease progression and the potential metabolic correlates, we investigated CNS tissues at mildly symptomatic and fully symptomatic stages of the disease. When compared with age-matched controls, GLD mice showed glucose hypometabolism, alterations in neurotransmitter content, N-acetylaspartate, N-acetylaspartylglutamate, and osmolytes levels. Notably, age- and region-dependent patterns of metabolic disturbances were in close agreement with the progression of astrogliosis, microglia activation, apoptosis, and neurodegeneration. We suggest that MR spectroscopy could be used in vivo to monitor disease progression, as well as ex vivo and in vivo to provide criteria for the outcome of experimental therapies.

Lessons Learned in Promoting Evidence-Based Public Health: Perspectives from Managers in State Public Health Departments.

PubMed

Allen, Peg; Jacob, Rebekah R; Lakshman, Meenakshi; Best, Leslie A; Bass, Kathryn; Brownson, Ross C

2018-03-02

Evidence-based public health (EBPH) practice, also called evidence-informed public health, can improve population health and reduce disease burden in populations. Organizational structures and processes can facilitate capacity-building for EBPH in public health agencies. This study involved 51 structured interviews with leaders and program managers in 12 state health department chronic disease prevention units to identify factors that facilitate the implementation of EBPH. Verbatim transcripts of the de-identified interviews were consensus coded in NVIVO qualitative software. Content analyses of coded texts were used to identify themes and illustrative quotes. Facilitator themes included leadership support within the chronic disease prevention unit and division, unit processes to enhance information sharing across program areas and recruitment and retention of qualified personnel, training and technical assistance to build skills, and the ability to provide support to external partners. Chronic disease prevention leaders' role modeling of EBPH processes and expectations for staff to justify proposed plans and approaches were key aspects of leadership support. Leaders protected staff time in order to identify and digest evidence to address the common barrier of lack of time for EBPH. Funding uncertainties or budget cuts, lack of political will for EBPH, and staff turnover remained challenges. In conclusion, leadership support is a key facilitator of EBPH capacity building and practice. Section and division leaders in public health agencies with authority and skills can institute management practices to help staff learn and apply EBPH processes and spread EBPH with partners.

Infiltration of CD4+ lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease

PubMed Central

Brochard, Vanessa; Combadière, Béhazine; Prigent, Annick; Laouar, Yasmina; Perrin, Aline; Beray-Berthat, Virginie; Bonduelle, Olivia; Alvarez-Fischer, Daniel; Callebert, Jacques; Launay, Jean-Marie; Duyckaerts, Charles; Flavell, Richard A.; Hirsch, Etienne C.; Hunot, Stéphane

2008-01-01

Parkinson disease (PD) is a neurodegenerative disorder characterized by a loss of dopamine-containing neurons. Mounting evidence suggests that dopaminergic cell death is influenced by the innate immune system. However, the pathogenic role of the adaptive immune system in PD remains enigmatic. Here we showed that CD8+ and CD4+ T cells but not B cells had invaded the brain in both postmortem human PD specimens and in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD during the course of neuronal degeneration. We further demonstrated that MPTP-induced dopaminergic cell death was markedly attenuated in the absence of mature T lymphocytes in 2 different immunodeficient mouse strains (Rag1–/– and Tcrb–/– mice). Importantly, similar attenuation of MPTP-induced dopaminergic cell death was seen in mice lacking CD4 as well as in Rag1–/– mice reconstituted with FasL-deficient splenocytes. However, mice lacking CD8 and Rag1–/– mice reconstituted with IFN-γ–deficient splenocytes were not protected. These data indicate that T cell–mediated dopaminergic toxicity is almost exclusively arbitrated by CD4+ T cells and requires the expression of FasL but not IFNγ. Further, our data may provide a rationale for targeting the adaptive arm of the immune system as a therapeutic strategy in PD. PMID:19104149

Loss of Mitochondrial Ndufs4 in Striatal Medium Spiny Neurons Mediates Progressive Motor Impairment in a Mouse Model of Leigh Syndrome.

PubMed

Chen, Byron; Hui, Jessica; Montgomery, Kelsey S; Gella, Alejandro; Bolea, Irene; Sanz, Elisenda; Palmiter, Richard D; Quintana, Albert

2017-01-01

Inability of mitochondria to generate energy leads to severe and often fatal myoencephalopathies. Among these, Leigh syndrome (LS) is one of the most common childhood mitochondrial diseases; it is characterized by hypotonia, failure to thrive, respiratory insufficiency and progressive mental and motor dysfunction, leading to early death. Basal ganglia nuclei, including the striatum, are affected in LS patients. However, neither the identity of the affected cell types in the striatum nor their contribution to the disease has been established. Here, we used a mouse model of LS lacking Ndufs4 , a mitochondrial complex I subunit, to confirm that loss of complex I, but not complex II, alters respiration in the striatum. To assess the role of striatal dysfunction in the pathology, we selectively inactivated Ndufs4 in the striatal medium spiny neurons (MSNs), which account for over 95% of striatal neurons. Our results show that lack of Ndufs4 in MSNs causes a non-fatal progressive motor impairment without affecting the cognitive function of mice. Furthermore, no inflammatory responses or neuronal loss were observed up to 6 months of age. Hence, complex I deficiency in MSNs contributes to the motor deficits observed in LS, but not to the neural degeneration, suggesting that other neuronal populations drive the plethora of clinical signs in LS.

The role of self-management in designing care for people with osteoarthritis of the hip and knee.

PubMed

Brand, Caroline A

2008-11-17

Osteoarthritis of the hip and knee is an increasingly common condition that is managed principally with lifestyle behaviour changes. Osteoarthritis management can be complex, as it typically affects older patients with multiple comorbidities. There is evidence that opportunities exist to improve uptake of evidence-based recommendations for care, especially for non-pharmacological interventions. The National Chronic Disease Strategy (NCDS) defines key components of programs designed to meet the needs of people with chronic conditions; one component is patient self-management. NCDS principles have been effectively integrated into chronic disease management programs for other conditions, but there is limited evidence of effectiveness for osteoarthritis programs. A comprehensive osteoarthritis management model that reflects NCDS policy is needed. Barriers to implementing such a model include poor integration of decision support, a lack of national infrastructure, workforce constraints and limited funding.

Dopamine-Independent Locomotor Actions of Amphetamines in a Novel Acute Mouse Model of Parkinson Disease

PubMed Central

Sotnikova, Tatyana D; Beaulieu, Jean-Martin; Barak, Larry S; Wetsel, William C; Gainetdinov, Raul R

2005-01-01

Brain dopamine is critically involved in movement control, and its deficiency is the primary cause of motor symptoms in Parkinson disease. Here we report development of an animal model of acute severe dopamine deficiency by using mice lacking the dopamine transporter. In the absence of transporter-mediated recycling mechanisms, dopamine levels become entirely dependent on de novo synthesis. Acute pharmacological inhibition of dopamine synthesis in these mice induces transient elimination of striatal dopamine accompanied by the development of a striking behavioral phenotype manifested as severe akinesia, rigidity, tremor, and ptosis. This phenotype can be reversed by administration of the dopamine precursor, L-DOPA, or by nonselective dopamine agonists. Surprisingly, several amphetamine derivatives were also effective in reversing these behavioral abnormalities in a dopamine-independent manner. Identification of dopamine transporter- and dopamine-independent locomotor actions of amphetamines suggests a novel paradigm in the search for prospective anti-Parkinsonian drugs. PMID:16050778

The lack of a big picture in tuberculosis: the clinical point of view, the problems of experimental modeling and immunomodulation. The factors we should consider when designing novel treatment strategies

PubMed Central

Vilaplana, Cristina; Cardona, Pere-Joan

2014-01-01

This short review explores the large gap between clinical issues and basic science, and suggests why tuberculosis research should focus on redirect the immune system and not only on eradicating Mycobacterium tuberculosis bacillus. Along the manuscript, several concepts involved in human tuberculosis are explored in order to understand the big picture, including infection and disease dynamics, animal modeling, liquefaction, inflammation and immunomodulation. Scientists should take into account all these factors in order to answer questions with clinical relevance. Moreover, the inclusion of the concept of a strong inflammatory response being required in order to develop cavitary tuberculosis disease opens a new field for developing new therapeutic and prophylactic tools in which destruction of the bacilli may not necessarily be the final goal. PMID:24592258

The lack of a big picture in tuberculosis: the clinical point of view, the problems of experimental modeling and immunomodulation. The factors we should consider when designing novel treatment strategies.

PubMed

Vilaplana, Cristina; Cardona, Pere-Joan

2014-01-01

This short review explores the large gap between clinical issues and basic science, and suggests why tuberculosis research should focus on redirect the immune system and not only on eradicating Mycobacterium tuberculosis bacillus. Along the manuscript, several concepts involved in human tuberculosis are explored in order to understand the big picture, including infection and disease dynamics, animal modeling, liquefaction, inflammation and immunomodulation. Scientists should take into account all these factors in order to answer questions with clinical relevance. Moreover, the inclusion of the concept of a strong inflammatory response being required in order to develop cavitary tuberculosis disease opens a new field for developing new therapeutic and prophylactic tools in which destruction of the bacilli may not necessarily be the final goal.

The use of mathematical models to inform influenza pandemic preparedness and response

PubMed Central

Wu, Joseph T; Cowling, Benjamin J

2011-01-01

Summary Influenza pandemics have occurred throughout history and were associated with substantial excess mortality and morbidity. Mathematical models of infectious diseases permit quantitative description of epidemic processes based on the underlying biological mechanisms. Mathematical models have been widely used in the past decade to aid pandemic planning by allowing detailed predictions of the speed of spread of an influenza pandemic and the likely effectiveness of alternative control strategies. During the initial waves of the 2009 influenza pandemic, mathematical models were used to track the spread of the virus, predict the time course of the pandemic and assess the likely impact of large-scale vaccination. While mathematical modeling has made substantial contributions to influenza pandemic preparedness, its use as a real-time tool for pandemic control is currently limited by the lack of essential surveillance information such as serologic data. Mathematical modeling provided a useful framework for analyzing and interpreting surveillance data during the 2009 influenza pandemic, for highlighting limitations in existing pandemic surveillance systems, and for guiding how these systems should be strengthened in order to cope with future epidemics of influenza or other emerging infectious diseases. PMID:21727183

Rational Design of in Vivo Tau Tangle-Selective Near-Infrared Fluorophores: Expanding the BODIPY Universe.

PubMed

Verwilst, Peter; Kim, Hye-Ri; Seo, Jinho; Sohn, Nak-Won; Cha, Seung-Yun; Kim, Yeongmin; Maeng, Sungho; Shin, Jung-Won; Kwak, Jong Hwan; Kang, Chulhun; Kim, Jong Seung

2017-09-27

The elucidation of the cause of Alzheimer's disease remains one of the greatest questions in neurodegenerative research. The lack of highly reliable low-cost sensors to study the structural changes in key proteins during the progression of the disease is a contributing factor to this lack of insight. In the current work, we describe the rational design and synthesis of two fluorescent BODIPY-based probes, named Tau 1 and Tau 2. The probes were evaluated on the molecular surface formed by a fibril of the PHF6 ( 306 VQIVYK 311 ) tau fragment using molecular docking studies to provide a potential molecular model to rationalize the selectivity of the new probes as compared to a homologous Aβ-selective probe. The probes were synthesized in a few steps from commercially available starting products and could thus prove to be highly cost-effective. We demonstrated the excellent photophysical properties of the dyes, such as a large Stokes shift and emission in the near-infrared window of the electromagnetic spectrum. The probes demonstrated a high selectivity for self-assembled microtubule-associated protein tau (Tau protein), in both solution and cell-based experiments. Moreover, the administration to an acute murine model of tauopathy clearly revealed the staining of self-assembled hyperphosphorylated tau protein in pathologically relevant hippocampal brain regions. Tau 1 demonstrated efficient blood-brain barrier penetrability and demonstrated a clear selectivity for tau tangles over Aβ plaques, as well as the capacity for in vivo imaging in a transgenic mouse model. The current work could open up avenues for the cost-effective monitoring of the tau protein aggregation state in animal models as well as tissue staining. Furthermore, these fluorophores could serve as the basis for the development of clinically relevant sensors, for example based on PET imaging.

'Mitochondrial energy imbalance and lipid peroxidation cause cell death in Friedreich's ataxia'.

PubMed

Abeti, R; Parkinson, M H; Hargreaves, I P; Angelova, P R; Sandi, C; Pook, M A; Giunti, P; Abramov, A Y

2016-05-26

Friedreich's ataxia (FRDA) is an inherited neurodegenerative disease. The mutation consists of a GAA repeat expansion within the FXN gene, which downregulates frataxin, leading to abnormal mitochondrial iron accumulation, which may in turn cause changes in mitochondrial function. Although, many studies of FRDA patients and mouse models have been conducted in the past two decades, the role of frataxin in mitochondrial pathophysiology remains elusive. Are the mitochondrial abnormalities only a side effect of the increased accumulation of reactive iron, generating oxidative stress? Or does the progressive lack of iron-sulphur clusters (ISCs), induced by reduced frataxin, cause an inhibition of the electron transport chain complexes (CI, II and III) leading to reactive oxygen species escaping from oxidative phosphorylation reactions? To answer these crucial questions, we have characterised the mitochondrial pathophysiology of a group of disease-relevant and readily accessible neurons, cerebellar granule cells, from a validated FRDA mouse model. By using live cell imaging and biochemical techniques we were able to demonstrate that mitochondria are deregulated in neurons from the YG8R FRDA mouse model, causing a decrease in mitochondrial membrane potential (▵Ψm) due to an inhibition of Complex I, which is partially compensated by an overactivation of Complex II. This complex activity imbalance leads to ROS generation in both mitochondrial matrix and cytosol, which results in glutathione depletion and increased lipid peroxidation. Preventing this increase in lipid peroxidation, in neurons, protects against in cell death. This work describes the pathophysiological properties of the mitochondria in neurons from a FRDA mouse model and shows that lipid peroxidation could be an important target for novel therapeutic strategies in FRDA, which still lacks a cure.

Murine Models for Viral Hemorrhagic Fever.

PubMed

Gonzalez-Quintial, Rosana; Baccala, Roberto

2018-01-01

Hemorrhagic fever (HF) viruses, such as Lassa, Ebola, and dengue viruses, represent major human health risks due to their highly contagious nature, the severity of the clinical manifestations induced, the lack of vaccines, and the very limited therapeutic options currently available. Appropriate animal models are obviously critical to study disease pathogenesis and develop efficient therapies. We recently reported that the clone 13 (Cl13) variant of the lymphocytic choriomeningitis virus (LCMV-Cl13), a prototype arenavirus closely related to Lassa virus, causes in some mouse strains endothelial damage, vascular leakage, platelet loss, and death, mimicking pathological aspects typically observed in Lassa and other HF syndromes. This model has the advantage that the mice used are fully immunocompetent, allowing studies on the contribution of the immune response to disease progression. Moreover, LCMV is very well characterized and exhibits limited pathogenicity in humans, allowing handling in convenient BSL-2 facilities. In this chapter we outline protocols for the induction and analysis of arenavirus-mediated pathogenesis in the NZB/LCMV model, including mouse infection, virus titer determination, platelet counting, phenotypic analysis of virus-specific T cells, and assessment of vascular permeability.

Spontaneous food allergy in Was-/- mice occurs independent of FcεRI-mediated mast cell activation.

PubMed

Lexmond, W S; Goettel, J A; Sallis, B F; McCann, K; Rings, E H H M; Jensen-Jarolim, E; Nurko, S; Snapper, S B; Fiebiger, E

2017-12-01

Food allergies are a growing health problem, and the development of therapies that prevent disease onset is limited by the lack of adjuvant-free experimental animal models. We compared allergic sensitization in patients with food allergy or Wiskott-Aldrich syndrome (WAS) and defined whether spontaneous disease in Was -/- mice recapitulates the pathology of a conventional disease model and/or human food allergy. Comparative ImmunoCAP ISAC microarray was performed in patients with food allergy or WAS. Spontaneous food allergy in Was -/- mice was compared to an adjuvant-based model in wild-type mice (WT-OVA/alum). Intestinal and systemic anaphylaxis was assessed, and the role of the high-affinity IgE Fc receptor (FcεRI) in allergic sensitization was evaluated using Was -/- Fcer1a -/- mice. Polysensitization to food was detected in both WAS and food-allergic patients which was recapitulated in the Was -/- model. Oral administration of ovalbumin (OVA) in Was -/- mice induced low titers of OVA-specific IgE compared to the WT-OVA/alum model. Irrespectively, 79% of Was -/- mice developed allergic diarrhea following oral OVA challenge. Systemic anaphylaxis occurred in Was -/- mice (95%) with a mortality rate >50%. Spontaneous sensitization and intestinal allergy occurred independent of FcεRI expression on mast cells (MCs) and basophils. Was -/- mice provide a model of food allergy with the advantage of mimicking polysensitization and low food-antigen IgE titers as observed in humans with clinical food allergy. This model will facilitate studies on aberrant immune responses during spontaneous disease development. Our results imply that therapeutic targeting of the IgE/FcεRI activation cascade will not affect sensitization to food. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

Evidence for major gene inheritance of Alzheimer disease in families of patients with and without Apolipoprotein E {epsilon}4

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

Rao, V.S.; Auerbach, S.A.; Farrer, L.A.

1996-09-01

Apolipoprotein E (APOE) genotype is the single most important determinant to the common form of Alzheimer disease (AD) yet identified. Several studies show that family history of AD is not entirely accounted for by APOE genotype. Also, there is evidence for an interaction between APOE genotype and gender. We carried out a complex segregation analysis in 636 nuclear families of consecutively ascertained and rigorously diagnosed probands in the Multi-Institutional Research in Alzheimer Genetic Epidemiology study in order to derive models of disease transmission which account for the influences of APOE genotype of the proband and gender. In the total groupmore » of families, models postulating sporadic occurrence, no major gene effect, random environmental transmission, and Mendelian inheritance were rejected. Transmission of AD in families of probands with at least one {epsilon}4 allele best fit a dominant model. Moreover, single gene inheritance best explained clustering of the disorder in families of probands lacking E4, but a more complex genetic model or multiple genetic models may ultimately account for risk in this group of families. Our results also suggest that susceptibility to AD differs between men and women regardless of the proband`s APOE status. Assuming a dominant model, AD appears to be completely penetrant in women, whereas only 62%-65% of men with predisposing genotypes develop AD. However, parameter estimates from the arbitrary major gene model suggests that AD is expressed dominantly in women and additively in men. These observations, taken together with epidemiologic data, are consistent with the hypothesis of an interaction between genes and other biological factors affecting disease susceptibility. 76 refs., 4 tabs.« less

Distal Potassium Handling Based On Flow Modulation of Maxi-K Channel Activity

PubMed Central

Rodan, Aylin R.; Huang, Chou-Long

2011-01-01

Purpose of review Studies on the mechanisms of distal K+ secretion have highlighted the importance of the renal outer-medullary K+ (ROMK) and maxi-K channels. This review considers several human disorders characterized by hypo- and hyperkalemia, as well as mouse models of these disorders, and the mechanisms by which ROMK and maxi-K may be dysregulated. Recent findings Analysis of knockout mice lacking ROMK, a model for type II Bartter’s syndrome, has shown a role for maxi-K in distal K+ secretion. Knockout mice lacking either the α or β1 subunits of maxi-K also show deficits in flow-dependent K+ secretion. Analysis of transgenic and knock-in mouse models of pseudohypoaldsoteronism type II (PHA2), in which mutant forms of with-no-lysine kinase 4 (WNK4) are expressed, suggests ways in which ROMK and maxi-K may be dysregulated to result in hyperkalemia. Modeling studies also provide insights into the role of Na+ delivery versus flow in K+ secretion. Summary The importance of both ROMK and maxi-K to distal K+ secretion is now well-established, but the relative role each of these two channels plays in normal and diseased states has not been definitively established. Analysis of human and animal model data can generate hypotheses for future experiments. PMID:19448535

Response to an emerging vector-borne disease: surveillance and preparedness for Schmallenberg virus.

PubMed

Roberts, H C; Elbers, A R W; Conraths, F J; Holsteg, M; Hoereth-Boentgen, D; Gethmann, J; van Schaik, G

2014-10-15

Surveillance for new emerging animal diseases from a European perspective is complicated by the non-harmonised approach across Member States for data capture, recording livestock populations and case definitions. In the summer of 2011, a new vector-borne Orthobunyavirus emerged in Northern Europe and for the first time, a coordinated approach to horizon scanning, risk communication, data and diagnostic test sharing allowed EU Member States to develop early predictions of the disease, its impact and risk management options. There are many different systems in place across the EU for syndromic and scanning surveillance and the differences in these systems have presented epidemiologists and risk assessors with concerns about their combined use in early identification of an emerging disease. The emergence of a new disease always will raise challenging issues around lack of capability and lack of knowledge; however, Schmallenberg virus (SBV) gave veterinary authorities an additional complex problem: the infection caused few clinical signs in adult animals, with no indication of the possible source and little evidence about its spread or means of transmission. This paper documents the different systems in place in some of the countries (Germany and the Netherlands) which detected disease initially and predicted its spread (to the UK) and how information sharing helped to inform early warning and risk assessment for Member States. Microarray technology was used to identify SBV as a new pathogen and data from the automated cattle milking systems coupled with farmer-derived data on reporting non-specific clinical signs gave the first indications of a widespread issue while the UK used meteorological modelling to map disease incursion. The coordinating role of both EFSA and the European Commission were vital as are the opportunities presented by web-based publishing for disseminating information to industry and the public. The future of detecting emerging disease looks more positive in the light of this combined approach in the EU. Crown Copyright © 2014. Published by Elsevier B.V. All rights reserved.

Clinically Available Medicines Demonstrating Anti-Toxoplasma Activity

PubMed Central

Neville, Andrew J.; Zach, Sydney J.; Wang, Xiaofang; Larson, Joshua J.; Judge, Abigail K.; Davis, Lisa A.; Vennerstrom, Jonathan L.

2015-01-01

Toxoplasma gondii is an apicomplexan parasite of humans and other mammals, including livestock and companion animals. While chemotherapeutic regimens, including pyrimethamine and sulfadiazine regimens, ameliorate acute or recrudescent disease such as toxoplasmic encephalitis or ocular toxoplasmosis, these drugs are often toxic to the host. Moreover, no approved options are available to treat infected women who are pregnant. Lastly, no drug regimen has shown the ability to eradicate the chronic stage of infection, which is characterized by chemoresistant intracellular cysts that persist for the life of the host. In an effort to promote additional chemotherapeutic options, we now evaluate clinically available drugs that have shown efficacy in disease models but which lack clinical case reports. Ideally, less-toxic treatments for the acute disease can be identified and developed, with an additional goal of cyst clearance from human and animal hosts. PMID:26392504

Stem cells for the prevention of neonatal lung disease.

PubMed

O'Reilly, Megan; Thébaud, Bernard

2015-01-01

Preterm birth affects approximately 11% of all newborns worldwide and is a major risk factor for infant mortality and morbidity. A common complication of preterm birth is the chronic lung disease of prematurity called bronchopulmonary dysplasia (BPD). Due to the lack of a specific treatment for BPD, preterm infants surviving with BPD face a lifelong risk of poor lung health. The therapeutic potential of stem cells in regenerative medicine is being harnessed for many diseases, including BPD. Compelling preclinical data using stem cells to prevent/repair lung damage in animal models of experimental BPD has built the basis for its translation into the clinic in preterm infants. This review highlights the exciting translation from bench to bedside that will hopefully lead in the near future to improved pulmonary outcomes in preterm infants. © 2015 S. Karger AG, Basel.

Multiparametric and semiquantitative scoring systems for the evaluation of mouse model histopathology - a systematic review

PubMed Central

2013-01-01

Background Histopathology has initially been and is still used to diagnose infectious, degenerative or neoplastic diseases in humans or animals. In addition to qualitative diagnoses semiquantitative scoring of a lesion`s magnitude on an ordinal scale is a commonly demanded task for histopathologists. Multiparametric, semiquantitative scoring systems for mouse models histopathology are a common approach to handle these questions and to include histopathologic information in biomedical research. Results Inclusion criteria for scoring systems were a first description of a multiparametric, semiquantiative scoring systems which comprehensibly describe an approach to evaluate morphologic lesion. A comprehensive literature search using these criteria identified 153 originally designed semiquantitative scoring systems for the analysis of morphologic changes in mouse models covering almost all organs systems and a wide variety of disease models. Of these, colitis, experimental autoimmune encephalitis, lupus nephritis and collagen induced osteoarthritis colitis were the disease models with the largest number of different scoring systems. Closer analysis of the identified scoring systems revealed a lack of a rationale for the selection of the scoring parameters or a correlation between scoring parameter value and the magnitude of the clinical symptoms in most studies. Conclusion Although a decision for a particular scoring system is clearly dependent on the respective scientific question this review gives an overview on currently available systems and may therefore allow for a better choice for the respective project. PMID:23800279

A mechanistic spatio-temporal framework for modelling individual-to-individual transmission—With an application to the 2014-2015 West Africa Ebola outbreak

PubMed Central

McClelland, Amanda; Zelner, Jon; Streftaris, George; Funk, Sebastian; Metcalf, Jessica; Dalziel, Benjamin D.; Grenfell, Bryan T.

2017-01-01

In recent years there has been growing availability of individual-level spatio-temporal disease data, particularly due to the use of modern communicating devices with GPS tracking functionality. These detailed data have been proven useful for inferring disease transmission to a more refined level than previously. However, there remains a lack of statistically sound frameworks to model the underlying transmission dynamic in a mechanistic manner. Such a development is particularly crucial for enabling a general epidemic predictive framework at the individual level. In this paper we propose a new statistical framework for mechanistically modelling individual-to-individual disease transmission in a landscape with heterogeneous population density. Our methodology is first tested using simulated datasets, validating our inferential machinery. The methodology is subsequently applied to data that describes a regional Ebola outbreak in Western Africa (2014-2015). Our results show that the methods are able to obtain estimates of key epidemiological parameters that are broadly consistent with the literature, while revealing a significantly shorter distance of transmission. More importantly, in contrast to existing approaches, we are able to perform a more general model prediction that takes into account the susceptible population. Finally, our results show that, given reasonable scenarios, the framework can be an effective surrogate for susceptible-explicit individual models which are often computationally challenging. PMID:29084216

A mechanistic spatio-temporal framework for modelling individual-to-individual transmission-With an application to the 2014-2015 West Africa Ebola outbreak.

PubMed

Lau, Max S Y; Gibson, Gavin J; Adrakey, Hola; McClelland, Amanda; Riley, Steven; Zelner, Jon; Streftaris, George; Funk, Sebastian; Metcalf, Jessica; Dalziel, Benjamin D; Grenfell, Bryan T

2017-10-01

In recent years there has been growing availability of individual-level spatio-temporal disease data, particularly due to the use of modern communicating devices with GPS tracking functionality. These detailed data have been proven useful for inferring disease transmission to a more refined level than previously. However, there remains a lack of statistically sound frameworks to model the underlying transmission dynamic in a mechanistic manner. Such a development is particularly crucial for enabling a general epidemic predictive framework at the individual level. In this paper we propose a new statistical framework for mechanistically modelling individual-to-individual disease transmission in a landscape with heterogeneous population density. Our methodology is first tested using simulated datasets, validating our inferential machinery. The methodology is subsequently applied to data that describes a regional Ebola outbreak in Western Africa (2014-2015). Our results show that the methods are able to obtain estimates of key epidemiological parameters that are broadly consistent with the literature, while revealing a significantly shorter distance of transmission. More importantly, in contrast to existing approaches, we are able to perform a more general model prediction that takes into account the susceptible population. Finally, our results show that, given reasonable scenarios, the framework can be an effective surrogate for susceptible-explicit individual models which are often computationally challenging.

An in vitro model of murine middle ear epithelium.

PubMed

Mulay, Apoorva; Akram, Khondoker M; Williams, Debbie; Armes, Hannah; Russell, Catherine; Hood, Derek; Armstrong, Stuart; Stewart, James P; Brown, Steve D M; Bingle, Lynne; Bingle, Colin D

2016-11-01

Otitis media (OM), or middle ear inflammation, is the most common paediatric disease and leads to significant morbidity. Although understanding of underlying disease mechanisms is hampered by complex pathophysiology it is clear that epithelial abnormalities underpin the disease. There is currently a lack of a well-characterised in vitro model of the middle ear (ME) epithelium that replicates the complex cellular composition of the middle ear. Here, we report the development of a novel in vitro model of mouse middle ear epithelial cells (mMECs) at an air-liquid interface (ALI) that recapitulates the characteristics of the native murine ME epithelium. We demonstrate that mMECs undergo differentiation into the varied cell populations seen within the native middle ear. Proteomic analysis confirmed that the cultures secrete a multitude of innate defence proteins from their apical surface. We showed that the mMECs supported the growth of the otopathogen, nontypeable Haemophilus influenzae (NTHi), suggesting that the model can be successfully utilised to study host-pathogen interactions in the middle ear. Overall, our mMEC culture system can help to better understand the cell biology of the middle ear and improve our understanding of the pathophysiology of OM. The model also has the potential to serve as a platform for validation of treatments designed to reverse aspects of epithelial remodelling that underpin OM development. © 2016. Published by The Company of Biologists Ltd.

Merits and complexities of modeling multiple sclerosis in non-human primates: implications for drug discovery.

PubMed

't Hart, Bert A; Laman, Jon D; Kap, Yolanda S

2018-05-01

The translation of scientific discoveries made in animal models into effective treatments for patients often fails, indicating that currently used disease models in preclinical research are insufficiently predictive for clinical success. An often-used model in the preclinical research of autoimmune neurological diseases, multiple sclerosis in particular, is experimental autoimmune encephalomyelitis (EAE). Most EAE models are based on genetically susceptible inbred/SPF mouse strains used at adolescent age (10-12 weeks), which lack exposure to genetic and microbial factors which shape the human immune system. Areas covered: Herein, the authors ask whether an EAE model in adult non-human primates from an outbred conventionally-housed colony could help bridge the translational gap between rodent EAE models and MS patients. Particularly, the authors discuss a novel and translationally relevant EAE model in common marmosets (Callithrix jacchus) that shares remarkable pathological similarity with MS. Expert opinion: The MS-like pathology in this model is caused by the interaction of effector memory T cells with B cells infected with the γ1-herpesvirus (CalHV3), both present in the pathogen-educated marmoset immune repertoire. The authors postulate that depletion of only the small subset (<0.05%) of CalHV3-infected B cells may be sufficient to limit chronic inflammatory demyelination.

Monoamine oxidase-B inhibition in the treatment of Parkinson's disease.

PubMed

Fernandez, Hubert H; Chen, Jack J

2007-12-01

Inhibitors of monoamine oxidase (MAO) with selectivity and specificity for MAO type B prolong the activity of both endogenously and exogenously derived dopamine, making them an option either as monotherapy in early Parkinson's disease or as adjunctive therapy in patients treated with levodopa who are experiencing motor complications. In addition to symptomatic benefits, experimental data suggest that MAO-B inhibitors may be neuroprotective through MAO-B inhibition and other mechanisms that have yet to be clearly defined. The two available MAO-B inhibitors approved for use in the United States, rasagiline and selegiline, each provide symptomatic relief as monotherapy and as adjunctive therapy, and have shown potential disease-modifying effects in experimental models and clinical studies. Selegiline in a conventional tablet formulation is less bioavailable than rasagiline, resulting in limited potency. It also has amphetamine metabolites that may produce adverse effects and interfere with any putative disease-modifying effects. The oral disintegrating tablet formulation of selegiline allows pregastric absorption, minimizing first-pass metabolism, thereby increasing selegiline bioavailability and reducing the concentration of amphetamine metabolites. Rasagiline, more potent than selegiline, exhibits disease-modifying effects in experimental models and lacks amphetamine metabolites. Both the symptomatic and potential disease-modifying effects of rasagiline are under investigation. A third agent with MAO-B inhibition properties, safinamide, is in phase III development. Although not yet approved, safinamide may offer the added advantage of combined MAO-B and dopamine reuptake inhibition.

Inulin and oligofructose in chronic inflammatory bowel disease.

PubMed

Leenen, Celine H M; Dieleman, Levinus A

2007-11-01

Crohn's disease and ulcerative colitis, also called chronic inflammatory bowel diseases (IBD), affect up to 500 per 100,000 persons in the Western world. Recent studies in the etiology of IBD suggest that these diseases are caused by a combination of genetic, environmental, and immunological factors. Results from humans and especially animal models of colitis reported by our group and others have indicated that these diseases result from a lack of tolerance to resident intestinal bacteria in genetically susceptible hosts. Probiotic bacteria have health-promoting effects for the host when ingested and have also shown efficacy in ulcerative colitis and refractory pouchitis. In light of the efficacy of providing probiotic bacteria to patients with IBD, there has been interest in the prophylactic and therapeutic potential of inulin, oligofructose, and other prebiotics for patients with or at risk of IBD. Prebiotics are nondigestible dietary oligosaccharides that affect the host by selectively stimulating growth, activity, or both of selective intestinal (probiotic) bacteria. Prebiotics are easy to administer and, in contrast to probiotic therapy, do not require administration of large amounts of (live) bacteria and are therefore easier to administer. Studies using prebiotics, especially beta-fructan oligosaccharides, for the treatment of chronic intestinal inflammation have shown benefit in animal models of colitis. Studies using these prebiotics alone or in combination with probiotics are emerging and have shown promise. These dietary therapies could lead to novel treatments for these chronic debilitating diseases.

Rift Valley fever virus infection in golden Syrian hamsters.

PubMed

Scharton, Dionna; Van Wettere, Arnaud J; Bailey, Kevin W; Vest, Zachary; Westover, Jonna B; Siddharthan, Venkatraman; Gowen, Brian B

2015-01-01

Rift Valley fever virus (RVFV) is a formidable pathogen that causes severe disease and abortion in a variety of livestock species and a range of disease in humans that includes hemorrhagic fever, fulminant hepatitis, encephalitis and blindness. The natural transmission cycle involves mosquito vectors, but exposure can also occur through contact with infected fluids and tissues. The lack of approved antiviral therapies and vaccines for human use underlies the importance of small animal models for proof-of-concept efficacy studies. Several mouse and rat models of RVFV infection have been well characterized and provide useful systems for the study of certain aspects of pathogenesis, as well as antiviral drug and vaccine development. However, certain host-directed therapeutics may not act on mouse or rat pathways. Here, we describe the natural history of disease in golden Syrian hamsters challenged subcutaneously with the pathogenic ZH501 strain of RVFV. Peracute disease resulted in rapid lethality within 2 to 3 days of RVFV challenge. High titer viremia and substantial viral loads were observed in most tissues examined; however, histopathology and immunostaining for RVFV antigen were largely restricted to the liver. Acute hepatocellular necrosis associated with a strong presence of viral antigen in the hepatocytes indicates that fulminant hepatitis is the likely cause of mortality. Further studies to assess the susceptibility and disease progression following respiratory route exposure are warranted. The use of the hamsters to model RVFV infection is suitable for early stage antiviral drug and vaccine development studies.

Incorporating networks in a probabilistic graphical model to find drivers for complex human diseases.

PubMed

Mezlini, Aziz M; Goldenberg, Anna

2017-10-01

Discovering genetic mechanisms driving complex diseases is a hard problem. Existing methods often lack power to identify the set of responsible genes. Protein-protein interaction networks have been shown to boost power when detecting gene-disease associations. We introduce a Bayesian framework, Conflux, to find disease associated genes from exome sequencing data using networks as a prior. There are two main advantages to using networks within a probabilistic graphical model. First, networks are noisy and incomplete, a substantial impediment to gene discovery. Incorporating networks into the structure of a probabilistic models for gene inference has less impact on the solution than relying on the noisy network structure directly. Second, using a Bayesian framework we can keep track of the uncertainty of each gene being associated with the phenotype rather than returning a fixed list of genes. We first show that using networks clearly improves gene detection compared to individual gene testing. We then show consistently improved performance of Conflux compared to the state-of-the-art diffusion network-based method Hotnet2 and a variety of other network and variant aggregation methods, using randomly generated and literature-reported gene sets. We test Hotnet2 and Conflux on several network configurations to reveal biases and patterns of false positives and false negatives in each case. Our experiments show that our novel Bayesian framework Conflux incorporates many of the advantages of the current state-of-the-art methods, while offering more flexibility and improved power in many gene-disease association scenarios.

A data mining methodology for predicting early stage Parkinson’s disease using non-invasive, high-dimensional gait sensor data

PubMed Central

Tucker, Conrad; Han, Yixiang; Nembhard, Harriet Black; Lewis, Mechelle; Lee, Wang-Chien; Sterling, Nicholas W; Huang, Xuemei

2017-01-01

Parkinson’s disease (PD) is the second most common neurological disorder after Alzheimer’s disease. Key clinical features of PD are motor-related and are typically assessed by healthcare providers based on qualitative visual inspection of a patient’s movement/gait/posture. More advanced diagnostic techniques such as computed tomography scans that measure brain function, can be cost prohibitive and may expose patients to radiation and other harmful effects. To mitigate these challenges, and open a pathway to remote patient-physician assessment, the authors of this work propose a data mining driven methodology that uses low cost, non-invasive sensors to model and predict the presence (or lack therefore) of PD movement abnormalities and model clinical subtypes. The study presented here evaluates the discriminative ability of non-invasive hardware and data mining algorithms to classify PD cases and controls. A 10-fold cross validation approach is used to compare several data mining algorithms in order to determine that which provides the most consistent results when varying the subject gait data. Next, the predictive accuracy of the data mining model is quantified by testing it against unseen data captured from a test pool of subjects. The proposed methodology demonstrates the feasibility of using non-invasive, low cost, hardware and data mining models to monitor the progression of gait features outside of the traditional healthcare facility, which may ultimately lead to earlier diagnosis of emerging neurological diseases. PMID:29541376

Psychometric Properties of the Heart Disease Knowledge Scale: Evidence from Item and Confirmatory Factor Analyses

PubMed Central

Lim, Bee Chiu; Kueh, Yee Cheng; Arifin, Wan Nor; Ng, Kok Huan

2016-01-01

Background Heart disease knowledge is an important concept for health education, yet there is lack of evidence on proper validated instruments used to measure levels of heart disease knowledge in the Malaysian context. Methods A cross-sectional, survey design was conducted to examine the psychometric properties of the adapted English version of the Heart Disease Knowledge Questionnaire (HDKQ). Using proportionate cluster sampling, 788 undergraduate students at Universiti Sains Malaysia, Malaysia, were recruited and completed the HDKQ. Item analysis and confirmatory factor analysis (CFA) were used for the psychometric evaluation. Construct validity of the measurement model was included. Results Most of the students were Malay (48%), female (71%), and from the field of science (51%). An acceptable range was obtained with respect to both the difficulty and discrimination indices in the item analysis results. The difficulty index ranged from 0.12–0.91 and a discrimination index of ≥ 0.20 were reported for the final retained 23 items. The final CFA model showed an adequate fit to the data, yielding a 23-item, one-factor model [weighted least squares mean and variance adjusted scaled chi-square difference = 1.22, degrees of freedom = 2, P-value = 0.544, the root mean square error of approximation = 0.03 (90% confidence interval = 0.03, 0.04); close-fit P-value = > 0.950]. Conclusion Adequate psychometric values were obtained for Malaysian undergraduate university students using the 23-item, one-factor model of the adapted HDKQ. PMID:27660543

Psychometric Properties of the Heart Disease Knowledge Scale: Evidence from Item and Confirmatory Factor Analyses.

PubMed

Lim, Bee Chiu; Kueh, Yee Cheng; Arifin, Wan Nor; Ng, Kok Huan

2016-07-01

Heart disease knowledge is an important concept for health education, yet there is lack of evidence on proper validated instruments used to measure levels of heart disease knowledge in the Malaysian context. A cross-sectional, survey design was conducted to examine the psychometric properties of the adapted English version of the Heart Disease Knowledge Questionnaire (HDKQ). Using proportionate cluster sampling, 788 undergraduate students at Universiti Sains Malaysia, Malaysia, were recruited and completed the HDKQ. Item analysis and confirmatory factor analysis (CFA) were used for the psychometric evaluation. Construct validity of the measurement model was included. Most of the students were Malay (48%), female (71%), and from the field of science (51%). An acceptable range was obtained with respect to both the difficulty and discrimination indices in the item analysis results. The difficulty index ranged from 0.12-0.91 and a discrimination index of ≥ 0.20 were reported for the final retained 23 items. The final CFA model showed an adequate fit to the data, yielding a 23-item, one-factor model [weighted least squares mean and variance adjusted scaled chi-square difference = 1.22, degrees of freedom = 2, P-value = 0.544, the root mean square error of approximation = 0.03 (90% confidence interval = 0.03, 0.04); close-fit P-value = > 0.950]. Adequate psychometric values were obtained for Malaysian undergraduate university students using the 23-item, one-factor model of the adapted HDKQ.

Brucella abortus surveillance of cattle in Fiji, Papua New Guinea, Vanuatu, the Solomon Islands and a case for active disease surveillance as a training tool.

PubMed

Tukana, Andrew; Hedlefs, Robert; Gummow, Bruce

2016-10-01

There have been no surveys of the cattle population for brucellosis in the Pacific Island Countries and Territories (PICTs) for more than 15 years. This study used disease surveillance as a capacity building training tool and to examine some of the constraints that impede surveillance in PICTs. The study also developed and implemented a series of surveys for detecting antibodies to B. abortus in cattle in Fiji, Papua New Guinea, Vanuatu and the Solomon Islands contributing to OIE requirements. The findings indicated lack of funds, lack of technical capacity, shortage of veterinarians, high turnover of in-country officials and lack of awareness on the impacts of animal diseases on public health that were constraining active disease surveillance. During the development and implementation of the surveys, constraints highlighted were outdated census data on farm numbers and cattle population, lack of funds for mobilisation of officials to carry out the surveys, lack of equipment for collecting and processing samples, lack of staff knowledge on blood sampling, geographical difficulties and security in accessing farms. Some of the reasons why these were constraints are discussed with likely solutions presented. The detection surveys had the objectives of building capacity for the country officials and demonstrating freedom from brucellosis in cattle for PNG, Vanuatu and the Solomon Islands. PNG, Vanuatu and the Solomon Islands all demonstrated freedom from bovine brucellosis in the areas surveyed using the indirect ELISA test. Fiji had an outbreak of brucellosis, and the objective was to determine its distribution and prevalence on untested farms. The Muaniweni district surveyed during the training had a 95 % confidence interval for true prevalence between 1.66 and 5.45 %. The study showed that active disease surveillance could be used as a tool for training officials thus, improves surveillance capacity in resource poor countries.

The application of epidemiology in aquatic animal health -opportunities and challenges.

PubMed

Peeler, Edmund J; Taylor, Nicholas G H

2011-08-11

Over recent years the growth in aquaculture, accompanied by the emergence of new and transboundary diseases, has stimulated epidemiological studies of aquatic animal diseases. Great potential exists for both observational and theoretical approaches to investigate the processes driving emergence but, to date, compared to terrestrial systems, relatively few studies exist in aquatic animals. Research using risk methods has assessed routes of introduction of aquatic animal pathogens to facilitate safe trade (e.g. import risk analyses) and support biosecurity. Epidemiological studies of risk factors for disease in aquaculture (most notably Atlantic salmon farming) have effectively supported control measures. Methods developed for terrestrial livestock diseases (e.g. risk-based surveillance) could improve the capacity of aquatic animal surveillance systems to detect disease incursions and emergence. The study of disease in wild populations presents many challenges and the judicious use of theoretical models offers some solutions. Models, parameterised from observational studies of host pathogen interactions, have been used to extrapolate estimates of impacts on the individual to the population level. These have proved effective in estimating the likely impact of parasite infections on wild salmonid populations in Switzerland and Canada (where the importance of farmed salmon as a reservoir of infection was investigated). A lack of data is often the key constraint in the application of new approaches to surveillance and modelling. The need for epidemiological approaches to protect aquatic animal health will inevitably increase in the face of the combined challenges of climate change, increasing anthropogenic pressures, limited water sources and the growth in aquaculture.

Pharmacological Interventions to Ameliorate Neuropathological Symptoms in a Mouse Model of Lafora Disease.

PubMed

Berthier, Arnaud; Payá, Miguel; García-Cabrero, Ana M; Ballester, Maria Inmaculada; Heredia, Miguel; Serratosa, José M; Sánchez, Marina P; Sanz, Pascual

2016-03-01

Lafora disease (LD, OMIM 254780) is a rare fatal neurodegenerative disorder that usually occurs during childhood with generalized tonic-clonic seizures, myoclonus, absences, drop attacks, or visual seizures. Unfortunately, at present, available treatments are only palliatives and no curative drugs are available yet. The hallmark of the disease is the accumulation of insoluble polyglucosan inclusions, called Lafora bodies (LBs), within the neurons but also in heart, muscle, and liver cells. Mouse models lacking functional EPM2A or EPM2B genes (the two major loci related to the disease) recapitulate the Lafora disease phenotype: they accumulate polyglucosan inclusions, show signs of neurodegeneration, and have a dysregulation of protein clearance and endoplasmic reticulum stress response. In this study, we have subjected a mouse model of LD (Epm2b-/-) to different pharmacological interventions aimed to alleviate protein clearance and endoplasmic reticulum stress. We have used two chemical chaperones, trehalose and 4-phenylbutyric acid. In addition, we have used metformin, an activator of AMP-activated protein kinase (AMPK), as it has a recognized neuroprotective role in other neurodegenerative diseases. Here, we show that treatment with 4-phenylbutyric acid or metformin decreases the accumulation of Lafora bodies and polyubiquitin protein aggregates in the brain of treated animals. 4-Phenylbutyric acid and metformin also diminish neurodegeneration (measured in terms of neuronal loss and reactive gliosis) and ameliorate neuropsychological tests of Epm2b-/- mice. As these compounds have good safety records and are already approved for clinical uses on different neurological pathologies, we think that the translation of our results to the clinical practice could be straightforward.

Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control of Mycobacterium tuberculosis in the Murine Lung

PubMed Central

Cooper, Andrea M.; Pearl, John E.; Brooks, Jason V.; Ehlers, Stefan; Orme, Ian M.

2000-01-01

The interleukin-12 and gamma interferon (IFN-γ) pathway of macrophage activation plays a pivotal role in controlling tuberculosis. In the murine model, the generation of supplementary nitric oxide by the induction of the nitric oxide synthase 2 (NOS2) gene product is considered the principal antimicrobial mechanism of IFN-γ-activated macrophages. Using a low-dose aerosol-mediated infection model in the mouse, we have investigated the role of nitric oxide in controlling Mycobacterium tuberculosis in the lung. In contrast to the consequences of a systemic infection, a low dose of bacteria introduced directly into the lungs of mice lacking the NOS2 gene is controlled almost as well as in intact animals. This is in contrast to the rapid progression of disease in mice lacking IFN-γ or a key member of the IFN signaling pathway, interferon regulatory factor 1. Thus while IFN-γ is pivotal in early control of bacterial growth in the lung, this control does not completely depend upon the expression of the NOS2 gene. The absence of inducible nitric oxide in the lung does, however, result in increased polymorphonuclear cell involvement and eventual necrosis in the pulmonary granulomas of the infected mice lacking the NOS2 gene. PMID:11083808

Planning for climate change: the need for mechanistic systems-based approaches to study climate change impacts on diarrheal diseases

PubMed Central

Levy, Karen; Zimmerman, Julie; Elliott, Mark; Bartram, Jamie; Carlton, Elizabeth; Clasen, Thomas; Dillingham, Rebecca; Eisenberg, Joseph; Guerrant, Richard; Lantagne, Daniele; Mihelcic, James; Nelson, Kara

2016-01-01

Increased precipitation and temperature variability as well as extreme events related to climate change are predicted to affect the availability and quality of water globally. Already heavily burdened with diarrheal diseases due to poor access to water, sanitation and hygiene facilities, communities throughout the developing world lack the adaptive capacity to sufficiently respond to the additional adversity caused by climate change. Studies suggest that diarrhea rates are positively correlated with increased temperature, and show a complex relationship with precipitation. Although climate change will likely increase rates of diarrheal diseases on average, there is a poor mechanistic understanding of the underlying disease transmission processes and substantial uncertainty surrounding current estimates. This makes it difficult to recommend appropriate adaptation strategies. We review the relevant climate-related mechanisms behind transmission of diarrheal disease pathogens and argue that systems-based mechanistic approaches incorporating human, engineered and environmental components are urgently needed. We then review successful systems-based approaches used in other environmental health fields and detail one modeling framework to predict climate change impacts on diarrheal diseases and design adaptation strategies. PMID:26799810

Comprehensive data resources and analytical tools for pathological association of aminoacyl tRNA synthetases with cancer

PubMed Central

Lee, Ji-Hyun; You, Sungyong; Hyeon, Do Young; Kang, Byeongsoo; Kim, Hyerim; Park, Kyoung Mii; Han, Byungwoo; Hwang, Daehee; Kim, Sunghoon

2015-01-01

Mammalian cells have cytoplasmic and mitochondrial aminoacyl-tRNA synthetases (ARSs) that catalyze aminoacylation of tRNAs during protein synthesis. Despite their housekeeping functions in protein synthesis, recently, ARSs and ARS-interacting multifunctional proteins (AIMPs) have been shown to play important roles in disease pathogenesis through their interactions with disease-related molecules. However, there are lacks of data resources and analytical tools that can be used to examine disease associations of ARS/AIMPs. Here, we developed an Integrated Database for ARSs (IDA), a resource database including cancer genomic/proteomic and interaction data of ARS/AIMPs. IDA includes mRNA expression, somatic mutation, copy number variation and phosphorylation data of ARS/AIMPs and their interacting proteins in various cancers. IDA further includes an array of analytical tools for exploration of disease association of ARS/AIMPs, identification of disease-associated ARS/AIMP interactors and reconstruction of ARS-dependent disease-perturbed network models. Therefore, IDA provides both comprehensive data resources and analytical tools for understanding potential roles of ARS/AIMPs in cancers. Database URL: http://ida.biocon.re.kr/, http://ars.biocon.re.kr/ PMID:25824651

Development of a metabolic biosignature for detection of early Lyme disease.

PubMed

Molins, Claudia R; Ashton, Laura V; Wormser, Gary P; Hess, Ann M; Delorey, Mark J; Mahapatra, Sebabrata; Schriefer, Martin E; Belisle, John T

2015-06-15

Early Lyme disease patients often present to the clinic prior to developing a detectable antibody response to Borrelia burgdorferi, the etiologic agent. Thus, existing 2-tier serology-based assays yield low sensitivities (29%-40%) for early infection. The lack of an accurate laboratory test for early Lyme disease contributes to misconceptions about diagnosis and treatment, and underscores the need for new diagnostic approaches. Retrospective serum samples from patients with early Lyme disease, other diseases, and healthy controls were analyzed for small molecule metabolites by liquid chromatography-mass spectrometry (LC-MS). A metabolomics data workflow was applied to select a biosignature for classifying early Lyme disease and non-Lyme disease patients. A statistical model of the biosignature was trained using the patients' LC-MS data, and subsequently applied as an experimental diagnostic tool with LC-MS data from additional patient sera. The accuracy of this method was compared with standard 2-tier serology. Metabolic biosignature development selected 95 molecular features that distinguished early Lyme disease patients from healthy controls. Statistical modeling reduced the biosignature to 44 molecular features, and correctly classified early Lyme disease patients and healthy controls with a sensitivity of 88% (84%-95%), and a specificity of 95% (90%-100%). Importantly, the metabolic biosignature correctly classified 77%-95% of the of serology negative Lyme disease patients. The data provide proof-of-concept that metabolic profiling for early Lyme disease can achieve significantly greater (P < .0001) diagnostic sensitivity than current 2-tier serology, while retaining high specificity. © The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

You cannot prevent a disease; you only treat diseases when they occur: knowledge, attitudes and practices to water-health in a rural Kenyan community.

PubMed

Levison, M M; Elliott, S J; Karanja, D M S; Schuster-Wallace, C J; Harrington, D W

2011-06-01

Almost 1 billion individuals lack access to improved water supplies, with 2.6 billion lacking adequate sanitation. This leads to the propagation of multiple waterborne diseases. The objective of this study was to explore local knowledge, attitudes and practices to understand the mechanisms and pre-conditions for sustainable uptake and use of these facilities. Data collection took place in a rural Kenyan community in September 2009. A qualitative approach was taken, with 4 focus groups and 25 in-depth interviews conducted. Participant characteristics varied by age, gender, education, marital status, employment and community standing. Few participants reported current access to improved water and sanitation facilities. Though they expressed desire for latrines and water sources, barriers including lack of funds and social capital, decrease the ability for installation. Participants understood that there was a link between the quality of water and their health, however, perceived benefits of current contaminated sources outweigh the potential health impacts and proliferate their continued use. While water-health links are understood to varying degrees within the community, contextual (physical environment), compositional (individual) and collective (community) factors interact to influence health. Community challenges, such as lack of unity, lack of education and lack control were identified as the main barriers to initiating change, despite a desire for increased access to safe water and sanitation.

Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome

PubMed Central

Siegmund, Stephanie E; Yang, Hua; Sharma, Rohit; Javors, Martin; Skinner, Owen; Mootha, Vamsi; Hirano, Michio; Schon, Eric A

2017-01-01

Abstract Mitochondrial disorders affecting oxidative phosphorylation (OxPhos) are caused by mutations in both the nuclear and mitochondrial genomes. One promising candidate for treatment is the drug rapamycin, which has been shown to extend lifespan in multiple animal models, and which was previously shown to ameliorate mitochondrial disease in a knock-out mouse model lacking a nuclear-encoded gene specifying an OxPhos structural subunit (Ndufs4). In that model, relatively high-dose intraperitoneal rapamycin extended lifespan and improved markers of neurological disease, via an unknown mechanism. Here, we administered low-dose oral rapamycin to a knock-in (KI) mouse model of authentic mtDNA disease, specifically, progressive mtDNA depletion syndrome, resulting from a mutation in the mitochondrial nucleotide salvage enzyme thymidine kinase 2 (TK2). Importantly, low-dose oral rapamycin was sufficient to extend Tk2KI/KI mouse lifespan significantly, and did so in the absence of detectable improvements in mitochondrial dysfunction. We found no evidence that rapamycin increased survival by acting through canonical pathways, including mitochondrial autophagy. However, transcriptomics and metabolomics analyses uncovered systemic metabolic changes pointing to a potential ‘rapamycin metabolic signature.’ These changes also implied that rapamycin may have enabled the Tk2KI/KI mice to utilize alternative energy reserves, and possibly triggered indirect signaling events that modified mortality through developmental reprogramming. From a therapeutic standpoint, our results support the possibility that low-dose rapamycin, while not targeting the underlying mtDNA defect, could represent a crucial therapy for the treatment of mtDNA-driven, and some nuclear DNA-driven, mitochondrial diseases. PMID:28973153

GPR84 deficiency reduces microgliosis, but accelerates dendritic degeneration and cognitive decline in a mouse model of Alzheimer's disease.

PubMed

Audoy-Rémus, Julie; Bozoyan, Lusine; Dumas, Aline; Filali, Mohammed; Lecours, Cynthia; Lacroix, Steve; Rivest, Serge; Tremblay, Marie-Eve; Vallières, Luc

2015-05-01

Microglia surrounds the amyloid plaques that form in the brains of patients with Alzheimer's disease (AD), but their role is controversial. Under inflammatory conditions, these cells can express GPR84, an orphan receptor whose pathophysiological role is unknown. Here, we report that GPR84 is upregulated in microglia of APP/PS1 transgenic mice, a model of AD. Without GPR84, these mice display both accelerated cognitive decline and a reduced number of microglia, especially in areas surrounding plaques. The lack of GPR84 affects neither plaque formation nor hippocampal neurogenesis, but promotes dendritic degeneration. Furthermore, GPR84 does not influence the clinical progression of other diseases in which its expression has been reported, i.e., experimental autoimmune encephalomyelitis (EAE) and endotoxic shock. We conclude that GPR84 plays a beneficial role in amyloid pathology by acting as a sensor for a yet unknown ligand that promotes microglia recruitment, a response affecting dendritic degeneration and required to prevent further cognitive decline. Copyright © 2015 Elsevier Inc. All rights reserved.

Detection of Free and Protein-Bound ortho-Quinones by Near-Infrared Fluorescence.

PubMed

Mazzulli, Joseph R; Burbulla, Lena F; Krainc, Dimitri; Ischiropoulos, Harry

2016-02-16

Aging and oxidative stress are two prominent pathological mechanisms for Parkinson's disease (PD) that are strongly associated with the degeneration of dopamine (DA) neurons in the midbrain. DA and other catechols readily oxidize into highly reactive o-quinone species that are precursors of neuromelanin (NM) pigment and under pathological conditions can modify and damage macromolecules. The role of DA oxidation in PD pathogenesis remains unclear in part due to the lack of appropriate disease models and the absence of a simple method for the quantification of DA-derived oxidants. Here, we describe a rapid, simple, and reproducible method for the quantification of o-quinones in cells and tissues that relies on the near-infrared fluorescent properties of these species. Importantly, we demonstrate that catechol-derived oxidants can be quantified in human neuroblastoma cells and midbrain dopamine neurons derived from induced pluripotent stem cells, providing a novel model to study the downstream actions of o-quinones. This method should facilitate further study of oxidative stress and DA oxidation in PD and related diseases that affect the dopaminergic system.

Development of a Novel Rabies Simulation Model for Application in a Non-endemic Environment

PubMed Central

Dürr, Salome; Ward, Michael P.

2015-01-01

Domestic dog rabies is an endemic disease in large parts of the developing world and also epidemic in previously free regions. For example, it continues to spread in eastern Indonesia and currently threatens adjacent rabies-free regions with high densities of free-roaming dogs, including remote northern Australia. Mathematical and simulation disease models are useful tools to provide insights on the most effective control strategies and to inform policy decisions. Existing rabies models typically focus on long-term control programs in endemic countries. However, simulation models describing the dog rabies incursion scenario in regions where rabies is still exotic are lacking. We here describe such a stochastic, spatially explicit rabies simulation model that is based on individual dog information collected in two remote regions in northern Australia. Illustrative simulations produced plausible results with epidemic characteristics expected for rabies outbreaks in disease free regions (mean R0 1.7, epidemic peak 97 days post-incursion, vaccination as the most effective response strategy). Systematic sensitivity analysis identified that model outcomes were most sensitive to seven of the 30 model parameters tested. This model is suitable for exploring rabies spread and control before an incursion in populations of largely free-roaming dogs that live close together with their owners. It can be used for ad-hoc contingency or response planning prior to and shortly after incursion of dog rabies in previously free regions. One challenge that remains is model parameterisation, particularly how dogs’ roaming and contacts and biting behaviours change following a rabies incursion in a previously rabies free population. PMID:26114762

Some findings on zero-inflated and hurdle poisson models for disease mapping.

PubMed

Corpas-Burgos, Francisca; García-Donato, Gonzalo; Martinez-Beneito, Miguel A

2018-05-27

Zero excess in the study of geographically referenced mortality data sets has been the focus of considerable attention in the literature, with zero-inflation being the most common procedure to handle this lack of fit. Although hurdle models have also been used in disease mapping studies, their use is more rare. We show in this paper that models using particular treatments of zero excesses are often required for achieving appropriate fits in regular mortality studies since, otherwise, geographical units with low expected counts are oversmoothed. However, as also shown, an indiscriminate treatment of zero excess may be unnecessary and has a problematic implementation. In this regard, we find that naive zero-inflation and hurdle models, without an explicit modeling of the probabilities of zeroes, do not fix zero excesses problems well enough and are clearly unsatisfactory. Results sharply suggest the need for an explicit modeling of the probabilities that should vary across areal units. Unfortunately, these more flexible modeling strategies can easily lead to improper posterior distributions as we prove in several theoretical results. Those procedures have been repeatedly used in the disease mapping literature, and one should bear these issues in mind in order to propose valid models. We finally propose several valid modeling alternatives according to the results mentioned that are suitable for fitting zero excesses. We show that those proposals fix zero excesses problems and correct the mentioned oversmoothing of risks in low populated units depicting geographic patterns more suited to the data. Copyright © 2018 John Wiley & Sons, Ltd.

Prevention of Alzheimer disease: The roles of nutrition and primary care.

PubMed

Bane, Tabitha J; Cole, Connie

2015-05-15

Risk factors for developing Alzheimer disease include hypercholesterolemia, hypertension, obesity, and diabetes. Due to lack of effective treatments for Alzheimer disease, nutrition and primary prevention becomes important.

Triglycerides and Heart Disease, Still a Hypothesis?

PubMed Central

Goldberg, Ira J.; Eckel, Robert H.; McPherson, Ruth

2011-01-01

The purpose of this article is to review the basic and clinical science relating plasma triglycerides and cardiovascular disease. Although many aspects of the basic physiology of triglyceride production, its plasma transport and tissue uptake have been known for several decades, the relationship of plasma triglyceride levels to vascular disease is uncertain. Are triglyceride rich lipoproteins, their influence on HDL and LDL, or the underlying diseases leading to defects in triglyceride metabolism the culprit? Animal models have failed to confirm that anything other than early fatty lesions can be produced by triglyceride-rich lipoproteins. Metabolic products of triglyceride metabolism can be toxic to arterial cells; however, these studies are primarily in vitro. Correlative studies of fasting and postprandial triglycerides and genetic diseases implicate VLDL and their remnants, and chylomicron remnants in atherosclerosis development; but the concomitant alterations in other lipoproteins and other risk factors obscure any conclusions about direct relationships between disease and triglycerides. Genes that regulate triglyceride levels also correlate with vascular disease. Human intervention trials, however, have lacked an appropriately defined population, and have produced outcomes without definitive conclusions. The time is more than ripe for new and creative approaches to understanding the relationship of triglycerides and heart disease. PMID:21527746

Pharmacodynamics and Systems Pharmacology Approaches to Repurposing Drugs in the Wake of Global Health Burden.

PubMed

Bai, Jane P F

2016-10-01

There are emergent needs for cost-effective treatment worldwide, for which repurposing to develop a drug with existing marketing approval of disease(s) for new disease(s) is a valid option. Although strategic mining of electronic health records has produced real-world evidences to inform drug repurposing, using omics data (drug and disease), knowledge base of protein interactions, and database of transcription factors have been explored. Structured integration of all the existing data under the framework of drug repurposing will facilitate decision making. The ability to foresee the need to integrate new data types produced by emergent technologies and to enable data connectivity in the context of human biology and targeted diseases, as well as to use the existing crucial quality data of all approved drugs will catapult the number of drugs being successfully repurposed. However, translational pharmacodynamics databases for modeling information across human biology in the context of host factors are lacking and are critically needed for drug repurposing to improve global public health, especially for the efforts to combat neglected tropic diseases as well as emergent infectious diseases such as Zika or Ebola virus. Published by Elsevier Inc.

Is diabetes and hypertension screening worthwhile in resource-limited settings? An economic evaluation based on a pilot of a Package of Essential Non-communicable disease interventions in Bhutan.

PubMed

Dukpa, Wangchuk; Teerawattananon, Yot; Rattanavipapong, Waranya; Srinonprasert, Varalak; Tongsri, Watsamon; Kingkaew, Pritaporn; Yothasamut, Jomkwan; Wangchuk, Dorji; Dorji, Tandin; Wangmo, Kinzang

2015-10-01

In response to a lack of cost-effective data on screening and early treatment of diabetes and hypertension in resource-limited settings, a model-based economic evaluation was performed on the World Health Organization (WHO)'s Package of Essential Non-communicable (PEN) disease interventions for primary health care in Bhutan. Both local and international data were applied in the model in order to derive lifetime costs and outcomes resulting from the early treatment of diabetes and hypertension. The results indicate that the current screening option (where people who are overweight, obese or aged 40 years or older who visit primary care facilities are screened for diabetes and hypertension) represents good value for money compared to 'no screening'. The study findings also indicate that expanding opportunistic screening (70% coverage of the target population) to universal screening (where 100% of the target population are screened), is likely to be even more cost-effective. From the sensitivity analysis, the value of the screening options remains the same when disease prevalence varies. Therefore, applying this model to other healthcare settings is warranted, since disease prevalence is one of the major factors in affecting the cost-effectiveness results of screening programs. Published by Oxford University Press in association with The London School of Hygiene and Tropical Medicine © The Author 2014; all rights reserved.

Early efforts in modeling the incubation period of infectious diseases with an acute course of illness.

PubMed

Nishiura, Hiroshi

2007-05-11

The incubation period of infectious diseases, the time from infection with a microorganism to onset of disease, is directly relevant to prevention and control. Since explicit models of the incubation period enhance our understanding of the spread of disease, previous classic studies were revisited, focusing on the modeling methods employed and paying particular attention to relatively unknown historical efforts. The earliest study on the incubation period of pandemic influenza was published in 1919, providing estimates of the incubation period of Spanish flu using the daily incidence on ships departing from several ports in Australia. Although the study explicitly dealt with an unknown time of exposure, the assumed periods of exposure, which had an equal probability of infection, were too long, and thus, likely resulted in slight underestimates of the incubation period. After the suggestion that the incubation period follows lognormal distribution, Japanese epidemiologists extended this assumption to estimates of the time of exposure during a point source outbreak. Although the reason why the incubation period of acute infectious diseases tends to reveal a right-skewed distribution has been explored several times, the validity of the lognormal assumption is yet to be fully clarified. At present, various different distributions are assumed, and the lack of validity in assuming lognormal distribution is particularly apparent in the case of slowly progressing diseases. The present paper indicates that (1) analysis using well-defined short periods of exposure with appropriate statistical methods is critical when the exact time of exposure is unknown, and (2) when assuming a specific distribution for the incubation period, comparisons using different distributions are needed in addition to estimations using different datasets, analyses of the determinants of incubation period, and an understanding of the underlying disease mechanisms.

Health and economic impact of PHiD-CV in Canada and the UK: a Markov modelling exercise.

PubMed

Knerer, Gerhart; Ismaila, Afisi; Pearce, David

2012-01-01

The spectrum of diseases caused by Streptococcus pneumoniae and non-typeable Haemophilus influenzae (NTHi) represents a large burden on healthcare systems around the world. Meningitis, bacteraemia, community-acquired pneumonia (CAP), and acute otitis media (AOM) are vaccine-preventable infectious diseases that can have severe consequences. The health economic model presented here is intended to estimate the clinical and economic impact of vaccinating birth cohorts in Canada and the UK with the 10-valent, pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) compared with the newly licensed 13-valent pneumococcal conjugate vaccine (PCV-13). The model described herein is a Markov cohort model built to simulate the epidemiological burden of pneumococcal- and NTHi-related diseases within birth cohorts in the UK and Canada. Base-case assumptions include estimates of vaccine efficacy and NTHi infection rates that are based on published literature. The model predicts that the two vaccines will provide a broadly similar impact on all-cause invasive disease and CAP under base-case assumptions. However, PHiD-CV is expected to provide a substantially greater reduction in AOM compared with PCV-13, offering additional savings of Canadian $9.0 million and £4.9 million in discounted direct medical costs in Canada and the UK, respectively. The main limitations of the study are the difficulties in modelling indirect vaccine effects (herd effect and serotype replacement), the absence of PHiD-CV- and PCV-13-specific efficacy data and a lack of comprehensive NTHi surveillance data. Additional limitations relate to the fact that the transmission dynamics of pneumococcal serotypes have not been modelled, nor has antibiotic resistance been accounted for in this paper. This cost-effectiveness analysis suggests that, in Canada and the UK, PHiD-CV's potential to protect against NTHi infections could provide a greater impact on overall disease burden than the additional serotypes contained in PCV-13.

Cold temperature improves mobility and survival in Drosophila models of autosomal-dominant hereditary spastic paraplegia (AD-HSP).

PubMed

Baxter, Sally L; Allard, Denise E; Crowl, Christopher; Sherwood, Nina Tang

2014-08-01

Autosomal-dominant hereditary spastic paraplegia (AD-HSP) is a crippling neurodegenerative disease for which effective treatment or cure remains unknown. Victims experience progressive mobility loss due to degeneration of the longest axons in the spinal cord. Over half of AD-HSP cases arise from loss-of-function mutations in spastin, which encodes a microtubule-severing AAA ATPase. In Drosophila models of AD-HSP, larvae lacking Spastin exhibit abnormal motor neuron morphology and function, and most die as pupae. Adult survivors display impaired mobility, reminiscent of the human disease. Here, we show that rearing pupae or adults at reduced temperature (18°C), compared with the standard temperature of 24°C, improves the survival and mobility of adult spastin mutants but leaves wild-type flies unaffected. Flies expressing human spastin with pathogenic mutations are similarly rescued. Additionally, larval cooling partially rescues the larval synaptic phenotype. Cooling thus alleviates known spastin phenotypes for each developmental stage at which it is administered and, notably, is effective even in mature adults. We find further that cold treatment rescues larval synaptic defects in flies with mutations in Flower (a protein with no known relation to Spastin) and mobility defects in flies lacking Kat60-L1, another microtubule-severing protein enriched in the CNS. Together, these data support the hypothesis that the beneficial effects of cold extend beyond specific alleviation of Spastin dysfunction, to at least a subset of cellular and behavioral neuronal defects. Mild hypothermia, a common neuroprotective technique in clinical treatment of acute anoxia, might thus hold additional promise as a therapeutic approach for AD-HSP and, potentially, for other neurodegenerative diseases. © 2014. Published by The Company of Biologists Ltd.

Distinct Endothelial Cell Responses in the Heart and Kidney Microvasculature Characterize the Progression of Heart Failure With Preserved Ejection Fraction in the Obese ZSF1 Rat With Cardiorenal Metabolic Syndrome.

PubMed

van Dijk, Christian G M; Oosterhuis, Nynke R; Xu, Yan Juan; Brandt, Maarten; Paulus, Walter J; van Heerebeek, Loek; Duncker, Dirk J; Verhaar, Marianne C; Fontoura, Dulce; Lourenço, André P; Leite-Moreira, Adelino F; Falcão-Pires, Inês; Joles, Jaap A; Cheng, Caroline

2016-04-01

The combination of cardiac and renal disease driven by metabolic risk factors, referred to as cardiorenal metabolic syndrome (CRMS), is increasingly recognized as a critical pathological entity. The contribution of (micro)vascular injury to CRMS is considered to be substantial. However, mechanistic studies are hampered by lack of in vivo models that mimic the natural onset of the disease. Here, we evaluated the coronary and renal microvasculature during CRMS development in obese diabetic Zucker fatty/Spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats. Echocardiographic, urine, and blood evaluations were conducted in 3 groups (Wistar-Kyoto, lean ZSF1, and obese ZSF1) at 20 and 25 weeks of age. Immunohistological evaluation of renal and cardiac tissues was conducted at both time points. At 20 and 25 weeks, obese ZSF1 rats showed higher body weight, significant left ventricular hypertrophy, and impaired diastolic function compared with all other groups. Indices of systolic function did not differ between groups. Obese ZSF1 rats developed hyperproliferative vascular foci in the subendocardium, which lacked microvascular organization and were predilection sites of inflammation and fibrosis. In the kidney, obese ZSF1 animals showed regression of the peritubular and glomerular microvasculature, accompanied by tubulointerstitial damage, glomerulosclerosis, and proteinuria. The obese ZSF1 rat strain is a suitable in vivo model for CRMS, sharing characteristics with the human syndrome during the earliest onset of disease. In these rats, CRMS induces microvascular fibrotic responses in heart and kidneys, associated with functional impairment of both organs. © 2016 American Heart Association, Inc.

A lethal murine infection model for dengue virus 3 in AG129 mice deficient in type I and II interferon receptors leads to systemic disease.

PubMed

Sarathy, Vanessa V; White, Mellodee; Li, Li; Gorder, Summer R; Pyles, Richard B; Campbell, Gerald A; Milligan, Gregg N; Bourne, Nigel; Barrett, Alan D T

2015-01-15

The mosquito-borne disease dengue (DEN) is caused by four serologically and genetically related viruses, termed DENV-1 to DENV-4. Infection with one DENV usually leads to acute illness and results in lifelong homotypic immunity, but individuals remain susceptible to infection by the other three DENVs. The lack of a small-animal model that mimics systemic DEN disease without neurovirulence has been an obstacle, but DENV-2 models that resemble human disease have been recently developed in AG129 mice (deficient in interferon alpha/beta and interferon gamma receptor signaling). However, comparable DENV-1, -3, and -4 models have not been developed. We utilized a non-mouse-adapted DENV-3 Thai human isolate to develop a lethal infection model in AG129 mice. Intraperitoneal inoculation of six to eight-week-old animals with strain C0360/94 led to rapid, fatal disease. Lethal C0360/94 infection resulted in physical signs of illness, high viral loads in the spleen, liver, and large intestine, histological changes in the liver and spleen tissues, and increased serum cytokine levels. Importantly, the animals developed vascular leakage, thrombocytopenia, and leukopenia. Overall, we have developed a lethal DENV-3 murine infection model, with no evidence of neurotropic disease based on a non-mouse-adapted human isolate, which can be used to investigate DEN pathogenesis and to evaluate candidate vaccines and antivirals. This suggests that murine models utilizing non-mouse-adapted isolates can be obtained for all four DENVs. Dengue (DEN) is a mosquito-borne disease caused by four DENV serotypes (DENV-1, -2, -3, and -4) that have no treatments or vaccines. Primary infection with one DENV usually leads to acute illness followed by lifelong homotypic immunity, but susceptibility to infection by the other three DENVs remains. Therefore, a vaccine needs to protect from all four DENVs simultaneously. To date a suitable animal model to mimic systemic human illness exists only for DENV-2 in immunocompromised mice using passaged viruses; however, models are still needed for the remaining serotypes. This study describes establishment of a lethal systemic DENV-3 infection model with a human isolate in immunocompromised mice and is the first report of lethal infection by a nonadapted clinical DENV isolate without evidence of neurological disease. Our DENV-3 model provides a relevant platform to test DEN vaccines and antivirals. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Intracerebroventricular gene therapy that delays neurological disease progression is associated with selective preservation of retinal ganglion cells in a canine model of CLN2 disease.

PubMed

Whiting, Rebecca E H; Jensen, Cheryl A; Pearce, Jacqueline W; Gillespie, Lauren E; Bristow, Daniel E; Katz, Martin L

2016-05-01

CLN2 disease is one of a group of lysosomal storage disorders called the neuronal ceroid lipofuscinoses (NCLs). The disease results from mutations in the TPP1 gene that cause an insufficiency or complete lack of the soluble lysosomal enzyme tripeptidyl peptidase-1 (TPP1). TPP1 is involved in lysosomal protein degradation, and lack of this enzyme results in the accumulation of protein-rich autofluorescent lysosomal storage bodies in numerous cell types including neurons throughout the central nervous system and the retina. CLN2 disease is characterized primarily by progressive loss of neurological functions and vision as well as generalized neurodegeneration and retinal degeneration. In children the progressive loss of neurological functions typically results in death by the early teenage years. A Dachshund model of CLN2 disease with a null mutation in TPP1 closely recapitulates the human disorder with a progression from disease onset at approximately 4 months of age to end-stage at 10-11 months. Delivery of functional TPP1 to the cerebrospinal fluid (CSF), either by periodic infusion of the recombinant protein or by a single administration of a TPP1 gene therapy vector to the CSF, significantly delays the onset and progression of neurological signs and prolongs life span but does not prevent the loss of vision or modest retinal degeneration that occurs by 11 months of age. In this study we found that in dogs that received the CSF gene therapy treatment, the degeneration of the retina and loss of retinal function continued to progress during the prolonged life spans of the treated dogs. Eventually the normal cell layers of the retina almost completely disappeared. An exception was the ganglion cell layer. In affected dogs that received TPP1 gene therapy to the CSF and survived an average of 80 weeks, ganglion cell axons were present in numbers comparable to those of normal Dachshunds of similar age. The selective preservation of the retinal ganglion cells suggests that while TPP1 protein delivered via the CSF may protect these cells, preservation of the remainder of the retina will require delivery of normal TPP1 more directly to the retina, probably via the vitreous body. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

A systematic review of methodology: time series regression analysis for environmental factors and infectious diseases.

PubMed

Imai, Chisato; Hashizume, Masahiro

2015-03-01

Time series analysis is suitable for investigations of relatively direct and short-term effects of exposures on outcomes. In environmental epidemiology studies, this method has been one of the standard approaches to assess impacts of environmental factors on acute non-infectious diseases (e.g. cardiovascular deaths), with conventionally generalized linear or additive models (GLM and GAM). However, the same analysis practices are often observed with infectious diseases despite of the substantial differences from non-infectious diseases that may result in analytical challenges. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, systematic review was conducted to elucidate important issues in assessing the associations between environmental factors and infectious diseases using time series analysis with GLM and GAM. Published studies on the associations between weather factors and malaria, cholera, dengue, and influenza were targeted. Our review raised issues regarding the estimation of susceptible population and exposure lag times, the adequacy of seasonal adjustments, the presence of strong autocorrelations, and the lack of a smaller observation time unit of outcomes (i.e. daily data). These concerns may be attributable to features specific to infectious diseases, such as transmission among individuals and complicated causal mechanisms. The consequence of not taking adequate measures to address these issues is distortion of the appropriate risk quantifications of exposures factors. Future studies should pay careful attention to details and examine alternative models or methods that improve studies using time series regression analysis for environmental determinants of infectious diseases.

Challenges in the management of chronic noncommunicable diseases by Indonesian community pharmacists.

PubMed

Puspitasari, Hanni P; Aslani, Parisa; Krass, Ines

2015-01-01

We explored factors influencing Indonesian primary care pharmacists' practice in chronic noncommunicable disease management and proposed a model illustrating relationships among factors. We conducted in-depth, semistructured interviews with pharmacists working in community health centers (Puskesmas, n=5) and community pharmacies (apotek, n=15) in East Java Province. We interviewed participating pharmacists using Bahasa Indonesia to explore facilitators and barriers to their practice in chronic disease management. We audiorecorded all interviews, transcribed ad verbatim, translated into English and analyzed the data using an approach informed by "grounded-theory". We extracted five emergent themes/factors: pharmacists' attitudes, Puskesmas/apotek environment, pharmacy education, pharmacy professional associations, and the government. Respondents believed that primary care pharmacists have limited roles in chronic disease management. An unfavourable working environment and perceptions of pharmacists' inadequate knowledge and skills were reported by many as barriers to pharmacy practice. Limited professional standards, guidelines, leadership and government regulations coupled with low expectations of pharmacists among patients and doctors also contributed to their lack of involvement in chronic disease management. We present the interplay of these factors in our model. Pharmacists' attitudes, knowledge, skills and their working environment appeared to influence pharmacists' contribution in chronic disease management. To develop pharmacists' involvement in chronic disease management, support from pharmacy educators, pharmacy owners, professional associations, the government and other stakeholders is required. Our findings highlight a need for systematic coordination between pharmacists and stakeholders to improve primary care pharmacists' practice in Indonesia to achieve continuity of care.

The Yeast Saccharomyces cerevisiae: a versatile model system for the identification and characterization of bacterial virulence proteins.

PubMed

Siggers, Keri A; Lesser, Cammie F

2008-07-17

Microbial pathogens utilize complex secretion systems to deliver proteins into host cells. These effector proteins target and usurp host cell processes to promote infection and cause disease. While secretion systems are conserved, each pathogen delivers its own unique set of effectors. The identification and characterization of these effector proteins has been difficult, often limited by the lack of detectable signal sequences and functional redundancy. Model systems including yeast, worms, flies, and fish are being used to circumvent these issues. This technical review details the versatility and utility of yeast Saccharomyces cerevisiae as a system to identify and characterize bacterial effectors.

Neural dynamics in Parkinsonian brain: The boundary between synchronized and nonsynchronized dynamics

NASA Astrophysics Data System (ADS)

Park, Choongseok; Worth, Robert M.; Rubchinsky, Leonid L.

2011-04-01

Synchronous oscillatory dynamics is frequently observed in the human brain. We analyze the fine temporal structure of phase-locking in a realistic network model and match it with the experimental data from Parkinsonian patients. We show that the experimentally observed intermittent synchrony can be generated just by moderately increased coupling strength in the basal ganglia circuits due to the lack of dopamine. Comparison of the experimental and modeling data suggest that brain activity in Parkinson's disease resides in the large boundary region between synchronized and nonsynchronized dynamics. Being on the edge of synchrony may allow for easy formation of transient neuronal assemblies.

Characterization of Neurofibromas of the Skin and Spinal Roots in a Mouse Model

DTIC Science & Technology

2008-02-01

neoplasms , particularly lymphoma (Figure 5C). The lack of grossly evident PNS tumors in these mice suggested that Ink4a deletion is not sufficient for...of MPNSTs in an Nf1+/ background. In addition to forming MPNSTs, we observed a significant frequency of hematopoietic neoplasms among Nf1+/Ink4a...acute myeloid leukemias as well as some mice with myeloproliferative disease. NCSCs Did Not Persist Postnatally in Nf1+/Ink4a/Arf/ Mice To test

Taking Each Day as It Comes: Staff Experiences of Supporting People with Down Syndrome and Alzheimer's Disease in Group Homes

ERIC Educational Resources Information Center

Iacono, T.; Bigby, C.; Carling-Jenkins, R.; Torr, J.

2014-01-01

Background: Disability staff are being increasingly required to support adults with Down syndrome who develop Alzheimer's disease. They have little understanding of the nature of care required, and may lack input from aged care and dementia services, which lack knowledge of intellectual disability. The aim of this study was to report on the…

Predictive model for falling in Parkinson disease patients.

PubMed

Custodio, Nilton; Lira, David; Herrera-Perez, Eder; Montesinos, Rosa; Castro-Suarez, Sheila; Cuenca-Alfaro, Jose; Cortijo, Patricia

2016-12-01

Falls are a common complication of advancing Parkinson's disease (PD). Although numerous risk factors are known, reliable predictors of future falls are still lacking. The aim of this study was to develop a multivariate model to predict falling in PD patients. Prospective cohort with forty-nine PD patients. The area under the receiver-operating characteristic curve (AUC) was calculated to evaluate predictive performance of the purposed multivariate model. The median of PD duration and UPDRS-III score in the cohort was 6 years and 24 points, respectively. Falls occurred in 18 PD patients (30%). Predictive factors for falling identified by univariate analysis were age, PD duration, physical activity, and scores of UPDRS motor, FOG, ACE, IFS, PFAQ and GDS ( p -value < 0.001), as well as fear of falling score ( p -value = 0.04). The final multivariate model (PD duration, FOG, ACE, and physical activity) showed an AUC = 0.9282 (correctly classified = 89.83%; sensitivity = 92.68%; specificity = 83.33%). This study showed that our multivariate model have a high performance to predict falling in a sample of PD patients.

New Challenges for Intervertebral Disc Treatment Using Regenerative Medicine

PubMed Central

Masuda, Koichi

2010-01-01

The development of tissue engineering therapies for the intervertebral disc is challenging due to ambiguities of disease and pain mechanisms in patients, and lack of consensus on preclinical models for safety and efficacy testing. Although the issues associated with model selection for studying orthopedic diseases or treatments have been discussed often, the multifaceted challenges associated with developing intervertebral disc tissue engineering therapies require special discussion. This review covers topics relevant to the clinical translation of tissue-engineered technologies: (1) the unmet clinical need, (2) appropriate models for safety and efficacy testing, (3) the need for standardized model systems, and (4) the translational pathways leading to a clinical trial. For preclinical evaluation of new therapies, we recommend establishing biologic plausibility of efficacy and safety using models of increasing complexity, starting with cell culture, small animals (rats and rabbits), and then large animals (goat and minipig) that more closely mimic nutritional, biomechanical, and surgical realities of human application. The use of standardized and reproducible experimental procedures and outcome measures is critical for judging relative efficacy. Finally, success will hinge on carefully designed clinical trials with well-defined patient selection criteria, gold-standard controls, and objective outcome metrics to assess performance in the early postoperative period. PMID:19903086

Assessment of health impacts of decreased smoking prevalence in Copenhagen: Application of the DYNAMO-HIA model.

PubMed

Holm, Astrid Ledgaard; Brønnum-Hansen, Henrik; Robinson, Kirstine Magtengaard; Diderichsen, Finn

2014-07-01

Tobacco smoking is among the leading risk factors for chronic disease and early death in developed countries, including Denmark, where smoking causes 14% of the disease burden. In Denmark, many public health interventions, including smoking prevention, are undertaken by the municipalities, but models to estimate potential health effects of local interventions are lacking. The aim of the current study was to model the effects of decreased smoking prevalence in Copenhagen, Denmark. The DYNAMO-HIA model was applied to the population of Copenhagen, by using health survey data and data from Danish population registers. We modelled the effects of four intervention scenarios aimed at different target groups, compared to a reference scenario. The potential effects of each scenario were modelled until 2040. A combined scenario affecting both initiation rates among youth, and cessation and re-initiation rates among adults, which reduced the smoking prevalence to 4% by 2025, would have large beneficial effects on incidence and prevalence of smoking-related diseases and mortality. Health benefits could also be obtained through interventions targeting only cessation or re-initiation rates, whereas an intervention targeting only initiation among youth had marginal effects on morbidity and mortality within the modelled time frame. By modifying the DYNAMO-HIA model, we were able to estimate the potential health effects of four interventions to reduce smoking prevalence in the population of Copenhagen. The effect of the interventions on future public health depended on population subgroup(s) targeted, duration of implementation and intervention reach. © 2014 the Nordic Societies of Public Health.

WONOEP Appraisal: Development of epilepsy biomarkers - What we can learn from our patients?

PubMed Central

Jozwiak, Sergiusz; Becker, Albert; Cepeda, Carlos; Engel, Jerome; Gnatkovsky, Vadym; Huberfeld, Gilles; Kaya, Mehmet; Kobow, Katja; Simonato, Michele; Loeb, Jeffrey A.

2017-01-01

Summary Objective Current medications for patients with epilepsy work in only two out of three patients. For those medications that do work, they only suppress seizures. They treat the symptoms, but do not modify the underlying disease forcing patients to take these drugs with significant side effects often for the rest of their lives. A major limitation in our ability to advance new therapeutics that permanently prevent, reduce the frequency of, or cure epilepsy comes from a lack of understanding of the disease coupled with a lack of reliable biomarkers that can predict who has or who will get epilepsy. Methods The main goal of this report is to present a number of approaches on how we may be able to identify reliable biomarkers from observing patients with brain disorders that have a high probability of producing epilepsy. Results A given biomarker, or more likely a profile of biomarkers, will have both a quantity and a time course during epileptogenesis that can be used to predict who will get the disease, to confirm epilepsy as a diagnosis, to identify co-existing pathologies, and monitor the course of treatments. Significance Additional studies in patients and animal models could identify common and clinically valuable biomarkers as a means to successfully translate animal studies into new and effective clinical trials. PMID:28387933

REM Sleep Behaviour Disorder in Older Individuals: Epidemiology, Pathophysiology, and Management

PubMed Central

Trotti, Lynn Marie

2010-01-01

Rapid eye movement (REM) sleep behavior disorder (RBD) is a sleep disorder that predominantly affects older adults, in which patients appear to be enacting their dreams while in REM sleep. The behaviors are typically violent, in association with violent dream content, so serious harm can be done to the patient or the bed-partner. The estimated prevalence in adults is 0.4–0.5%, but the frequency is much higher in certain neurodegenerative diseases, especially Parkinson's disease, Dementia with Lewy bodies, and multiple systems atrophy. RBD can occur in the absence of diagnosed neurologic diseases (the “idiopathic” form), although patients with this form of RBD may have subtle neurologic abnormalities and often ultimately develop a neurodegenerative disorder. Animal models and cases of RBD developing after brainstem lesions (pontine tegmentum, medulla) have led to the understanding that RBD is caused by a lack of normal REM muscle atonia and a lack of normal suppression of locomotor generators during REM. Clonazepam is used as first-line therapy for RBD and melatonin for second-line therapy, although evidence for both of these interventions comes from uncontrolled case series. Because the risk of injury to the patient or the bed-partner is high, interventions to improve the safety of the sleep environment are also often necessary. This review describes the epidemiology, pathophysiology, and treatment of RBD. PMID:20524706

A systematic review of qualitative research on the contributory factors leading to medicine-related problems from the perspectives of adult patients with cardiovascular diseases and diabetes mellitus

PubMed Central

Al Hamid, A; Ghaleb, M; Aljadhey, H; Aslanpour, Z

2014-01-01

Objectives To synthesise contributing factors leading to medicine-related problems (MRPs) in adult patients with cardiovascular diseases and/or diabetes mellitus from their perspectives. Design A systematic literature review of qualitative studies regarding the contributory factors leading to MRPs, medication errors and non-adherence, followed by a thematic synthesis of the studies. Data sources We screened Pubmed, EMBASE, ISI Web of Knowledge, PsycInfo, International Pharmaceutical Abstract and PsycExtra for qualitative studies (interviews, focus groups and questionnaires of a qualitative nature). Review methods Thematic synthesis was achieved by coding and developing themes from the findings of qualitative studies. Results The synthesis yielded 21 studies that satisfied the inclusion and exclusion criteria. Three themes emerged that involved contributing factors to MRPs: patient-related factors including socioeconomic factors (beliefs, feeling victimised, history of the condition, lack of finance, lack of motivation and low self-esteem) and lifestyle factors (diet, lack of exercise/time to see the doctor, obesity, smoking and stress), medicine-related factors (belief in natural remedies, fear of medicine, lack of belief in medicines, lack of knowledge, non-adherence and polypharmacy) and condition-related factors (lack of knowledge/understanding, fear of condition and its complications, and lack of control). Conclusions MRPs represent a major health threat, especially among adult patients with cardiovascular diseases and/or diabetes mellitus. The patients’ perspectives uncovered hidden factors that could cause and/or contribute to MRPs in these groups of patients. PMID:25239295

Combined N-of-1 trials to investigate mexiletine in non-dystrophic myotonia using a Bayesian approach; study rationale and protocol.

PubMed

Stunnenberg, Bas C; Woertman, Willem; Raaphorst, Joost; Statland, Jeffrey M; Griggs, Robert C; Timmermans, Janneke; Saris, Christiaan G; Schouwenberg, Bas J; Groenewoud, Hans M; Stegeman, Dick F; van Engelen, Baziel G M; Drost, Gea; van der Wilt, Gert Jan

2015-03-25

To obtain evidence for the clinical and cost-effectiveness of treatments for patients with rare diseases is a challenge. Non-dystrophic myotonia (NDM) is a group of inherited, rare muscle diseases characterized by muscle stiffness. The reimbursement of mexiletine, the expert opinion drug for NDM, has been discontinued in some countries due to a lack of independent randomized controlled trials (RCTs). It remains unclear however, which concessions can be accepted towards the level 1 evidence needed for coverage decisions, in rare diseases. Considering the large number of rare diseases with a lack of treatment evidence, more experience with innovative trial designs is needed. Both NDM and mexiletine are well suited for an N-of-1 trial design. A Bayesian approach allows for the combination of N-of-1 trials, which enables the assessment of outcomes on the patient and group level simultaneously. We will combine 30 individual, double-blind, randomized, placebo-controlled N-of-1 trials of mexiletine (600 mg daily) vs. placebo in genetically confirmed NDM patients using hierarchical Bayesian modeling. Our results will be compared and combined with the main results of an international cross-over RCT (mexiletine vs. placebo in NDM) published in 2012 that will be used as an informative prior. Similar criteria of eligibility, treatment regimen, end-points and measurement instruments are employed as used in the international cross-over RCT. The treatment of patients with NDM with mexiletine offers a unique opportunity to compare outcomes and efficiency of novel N-of-1 trial-based designs and conventional approaches in producing evidence of clinical and cost-effectiveness of treatments for patients with rare diseases. ClinicalTrials.gov Identifier: NCT02045667.

A New Classification System for IgG4 Autoantibodies

PubMed Central

Koneczny, Inga

2018-01-01

IgG4 autoimmune diseases are characterized by the presence of antigen-specific autoantibodies of the IgG4 subclass and contain well-characterized diseases such as muscle-specific kinase myasthenia gravis, pemphigus, and thrombotic thrombocytopenic purpura. In recent years, several new diseases were identified, and by now 14 antigens targeted by IgG4 autoantibodies have been described. The IgG4 subclass is considered immunologically inert and functionally monovalent due to structural differences compared to other IgG subclasses. IgG4 usually arises after chronic exposure to antigen and competes with other antibody species, thus “blocking” their pathogenic effector mechanisms. Accordingly, in the context of IgG4 autoimmunity, the pathogenicity of IgG4 is associated with blocking of enzymatic activity or protein–protein interactions of the target antigen. Pathogenicity of IgG4 autoantibodies has not yet been systematically analyzed in IgG4 autoimmune diseases. Here, we establish a modified classification system based on Witebsky’s postulates to determine IgG4 pathogenicity in IgG4 autoimmune diseases, review characteristics and pathogenic mechanisms of IgG4 in these disorders, and also investigate the contribution of other antibody entities to pathophysiology by additional mechanisms. As a result, three classes of IgG4 autoimmune diseases emerge: class I where IgG4 pathogenicity is validated by the use of subclass-specific autoantibodies in animal models and/or in vitro models of pathogenicity; class II where IgG4 pathogenicity is highly suspected but lack validation by the use of subclass specific antibodies in in vitro models of pathogenicity or animal models; and class III with insufficient data or a pathogenic mechanism associated with multivalent antigen binding. Five out of the 14 IgG4 antigens were validated as class I, five as class II, and four as class III. Antibodies of other IgG subclasses or immunoglobulin classes were present in several diseases and could contribute additional pathogenic mechanisms. PMID:29483905

Scabies: important clinical consequences explained by new molecular studies.

PubMed

Fischer, Katja; Holt, Deborah; Currie, Bart; Kemp, David

2012-01-01

In 2004, we reviewed the status of disease caused by the scabies mite Sarcoptes scabiei at the time and pointed out that very little basic research had ever been done. The reason for this was largely the lack of availability of mites for experimental purposes and, to a degree, a consequent lack of understanding of its importance, resulting in the trivial name 'itch mite'. Scabies is responsible for major morbidity in disadvantaged communities and immunocompromised patients worldwide. In addition to the physical discomfort caused by the disease, scabies infestations facilitate infection by bacterial pathogens such as Streptococcus pyogenes and Staphylococcus aureus via skin lesions, resulting in severe downstream disease such as in a high prevalence of rheumatic fever/heart disease in affected communities. We now have further evidence that in disadvantaged populations living in tropical climates, scabies rather than 'Strep throat' is an important source of S. pyogenes causing rheumatic fever and eventually rheumatic heart disease. In addition, our work has resulted in two fundamental research tools that facilitate much of the current biomedical research efforts on scabies, namely a public database containing ~45,000 scabies mite expressed sequence tags and a porcine in vivo model. Here we will discuss novel and unexpected proteins encountered in the database that appear crucial to mite survival with regard to digestion and evasion of host defence. The mode(s) of action of some of these have been at least partially revealed. Further, newly discovered molecules that may well have a similar role, such as a family of inactivated cysteine proteases, are yet to be investigated. Hence, there are now whole families of potential targets for chemical inhibitors of S. scabiei. These efforts put today's scabies research in a unique position to design and test small molecules that may specifically interfere with mite-derived molecules, such as digestive proteases and mite complement inhibitors. The porcine scabies model will be available to trial in vivo treatment with potential inhibitors. New therapies for scabies may be developed from these studies and may contribute to reduce the spread of scabies and the subsequent prevalence of bacterial skin infections and their devastating sequelae in the community. Copyright © 2012 Elsevier Ltd. All rights reserved.

Dynamic, spatial models of parasite transmission in wildlife: Their structure, applications and remaining challenges.

PubMed

White, Lauren A; Forester, James D; Craft, Meggan E

2018-05-01

Individual differences in contact rate can arise from host, group and landscape heterogeneity and can result in different patterns of spatial spread for diseases in wildlife populations with concomitant implications for disease control in wildlife of conservation concern, livestock and humans. While dynamic disease models can provide a better understanding of the drivers of spatial spread, the effects of landscape heterogeneity have only been modelled in a few well-studied wildlife systems such as rabies and bovine tuberculosis. Such spatial models tend to be either purely theoretical with intrinsic limiting assumptions or individual-based models that are often highly species- and system-specific, limiting the breadth of their utility. Our goal was to review studies that have utilized dynamic, spatial models to answer questions about pathogen transmission in wildlife and identify key gaps in the literature. We begin by providing an overview of the main types of dynamic, spatial models (e.g., metapopulation, network, lattice, cellular automata, individual-based and continuous-space) and their relation to each other. We investigate different types of ecological questions that these models have been used to explore: pathogen invasion dynamics and range expansion, spatial heterogeneity and pathogen persistence, the implications of management and intervention strategies and the role of evolution in host-pathogen dynamics. We reviewed 168 studies that consider pathogen transmission in free-ranging wildlife and classify them by the model type employed, the focal host-pathogen system, and their overall research themes and motivation. We observed a significant focus on mammalian hosts, a few well-studied or purely theoretical pathogen systems, and a lack of studies occurring at the wildlife-public health or wildlife-livestock interfaces. Finally, we discuss challenges and future directions in the context of unprecedented human-mediated environmental change. Spatial models may provide new insights into understanding, for example, how global warming and habitat disturbance contribute to disease maintenance and emergence. Moving forward, better integration of dynamic, spatial disease models with approaches from movement ecology, landscape genetics/genomics and ecoimmunology may provide new avenues for investigation and aid in the control of zoonotic and emerging infectious diseases. © 2017 The Authors. Journal of Animal Ecology published by John Wiley & Sons Ltd on behalf of British Ecological Society.

Clinicopathological correlation of psychosis and brain vascular changes in Alzheimer's disease.

PubMed

Ting, Simon Kang Seng; Hao, Ying; Chia, Pei Shi; Tan, Eng-King; Hameed, Shahul

2016-02-12

Psychosis is common in Alzheimer's disease (AD). However, studies on neuropathology in vascular etiology contributing to psychosis in AD is lacking to date. The aim of this study was to investigate neuropathological vascular related changes in Alzheimer's disease with psychosis. Data of patients with AD from the National Alzheimer's Coordinating Center between 2005 to September 2013 was accessed and reviewed. Presence of psychosis was determined based on Neuropsychiatric Inventory Questionnaire taken from the last visit within one year prior to death, and patients were divided into psychosis positive and negative group. Comparison of clinical details and neuropathological vascular changes between the groups was performed using Wilcoxon rank sum test and Chi-square/ Fisher's exact test. Significant variables were further included in a multivariate logistic model. Overall, 145 patients was included. Of these, 50 patients were psychosis positive. Presence of one or more cortical microinfarcts and moderate to severe arteriosclerosis was found to be positively associated with psychosis. Our results suggest vascular changes correlate with psychosis in Alzheimer's disease.

Tendinopathy: Investigating the Intersection of Clinical and Animal Research to Identify Progress and Hurdles in the Field

PubMed Central

Titan, Ashley; Andarawis-Puri, Nelly

2017-01-01

Biological treatments, surgical interventions, and rehabilitation exercises have been successfully used to treat tendinopathy, but the development of effective treatments has been hindered by the lack of mechanistic data regarding the pathogenesis of the disease.While insightful, clinical studies are limited in their capacity to provide data regarding the pathogenesis of tendinopathies, emphasizing the value of animal models and cell culture studies to fill this essential gap in knowledge.Clinical pathological findings from imaging studies or histological analysis are not universal across patients with tendinopathy and have not been clearly associated with the onset of symptoms.There are several unresolved controversies, including the cellular changes that accompany the tendinopathic disease state and the role of inflammation.Additional research is needed to correlate the manifestations of the disease with its pathogenesis, with the goal of reaching a field-wide consensus on the pathology of the disease state. Such a consensus will allow standardized clinical practices to more effectively diagnose and treat tendinopathy. PMID:27792676

[Risk of contamination from exposure to Rio Doce water: a case study on the population's perceptions in Tumiritinga, Minas Gerais State, Brazil].

PubMed

Guedes, Gilvan Ramalho; Simão, Andréa Branco; Dias, Carlos Alberto; Braga, Eliza de Oliveira

2015-06-01

The close relationship between local residents and the Rio Doce and the river's recurrent flooding lead to continuous exposure of the population to waterborne diseases. Given the epidemiological importance of such diseases in the region, this study analyzes the association between risk perception of contamination and river water use, as well as the heuristic mechanisms used by individuals to shape their personal perception of risk. Regression models coupled with thematic network analysis were applied to primary data from 352 households in 2012. The data are representative of urban residents of Tumiritinga, Minas Gerais State, Brazil. The results show that while 92.6% of respondents perceived high risk of waterborne diseases, only 11.4% reported not making direct use of the river. This apparent paradox is explained by the lack of information on transmission mechanisms, underestimating the perception of contamination. Public campaigns to promote preventive behavior should stress how waterborne diseases are transmitted, using simple examples to reach a wider local audience.

"Touching Triton": Building Student Understanding of Complex Disease Risk.

PubMed

Loftin, Madelene; East, Kelly; Hott, Adam; Lamb, Neil

2016-01-01

Life science classrooms often emphasize the exception to the rule when it comes to teaching genetics, focusing heavily on rare single-gene and Mendelian traits. By contrast, the vast majority of human traits and diseases are caused by more complicated interactions between genetic and environmental factors. Research indicates that students have a deterministic view of genetics, generalize Mendelian inheritance patterns to all traits, and have unrealistic expectations of genetic technologies. The challenge lies in how to help students analyze complex disease risk with a lack of curriculum materials. Providing open access to both content resources and an engaging storyline can be achieved using a "serious game" model. "Touching Triton" was developed as a serious game in which students are asked to analyze data from a medical record, family history, and genomic report in order to develop an overall lifetime risk estimate of six common, complex diseases. Evaluation of student performance shows significant learning gains in key content areas along with a high level of engagement.

The effects of invasive pests and pathogens on strategies for forest diversification.

PubMed

Macpherson, Morag F; Kleczkowski, Adam; Healey, John R; Quine, Christopher P; Hanley, Nick

2017-04-24

Diversification of the tree species composition of production forests is a frequently advocated strategy to increase resilience to pests and pathogens; however, there is a lack of a general framework to analyse the impact of economic and biological conditions on the optimal planting strategy in the presence of tree disease. To meet this need we use a novel bioeconomic model to quantitatively assess the effect of tree disease on the optimal planting proportion of two tree species. We find that diversifying the species composition can reduce the economic loss from disease even when the benefit from the resistant species is small. However, this key result is sensitive to a pathogen's characteristics (probability of arrival, time of arrival, rate of spread of infection) and the losses (damage of the disease to the susceptible species and reduced benefit of planting the resistant species). This study provides an exemplar framework which can be used to help understand the effect of a pathogen on forest management strategies.

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

PubMed Central

Mora, Ana L.; Rojas, Mauricio; Pardo, Annie; Selman, Moises

2018-01-01

Idiopathic pulmonary fibrosis (IPF) is a fatal age-associated disease that is characterized by progressive and irreversible scarring of the lung. The pathogenesis of IPF is not completely understood and current therapies are limited to those that reduce the rate of functional decline in patients with mild-to-moderate disease. In this context, new therapeutic approaches that substantially improve the survival time and quality of life of these patients are urgently needed. Our incomplete understanding of the pathogenic mechanisms of IPF and the lack of appropriate experimental models that reproduce the key characteristics of the human disease are major challenges. As ageing is a major risk factor for IPF, age-related cell perturbations such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis and mitochondrial dysfunction are becoming targets of interest for IPF therapy. In this Review, we discuss current and emerging therapies for IPF, particularly those targeting age-related mechanisms, and discuss future therapeutic approaches. PMID:29081515

Neutrophil extracellular traps enriched in oxidized mitochondrial DNA are interferogenic and contribute to lupus-like disease

PubMed Central

Lood, Christian; Blanco, Luz P.; Purmalek, Monica M.; Carmona-Rivera, Carmelo; De Ravin, Suk S.; Smith, Carolyne K.; Malech, Harry L.; Ledbetter, Jeffrey A.; Elkon, Keith B.; Kaplan, Mariana J.

2015-01-01

Neutrophil extracellular traps (NETs) are implicated in autoimmunity but how they are generated and their roles in sterile inflammation remain unclear. Ribonucleoprotein immune complexes, inducers of NETosis, require mitochondrial ROS for maximal NET stimulation. During this process, mitochondria become hypopolarized and translocate to the cell surface. Extracellular release of oxidized mitochondrial DNA is proinflammatory in vitro and, when injected into mice, stimulates type-I interferon (IFN) signaling through a pathway dependent on the DNA sensor, STING. Mitochondrial ROS is also necessary for spontaneous NETosis of low-density granulocytes from individuals with systemic lupus erythematosus (SLE). This was also observed in individuals with chronic granulomatous disease (CGD), which lack NADPH-oxidase activity, but still develop autoimmunity and type I-IFN signatures. Mitochondrial ROS inhibition in vivo reduces disease severity and type-I IFN responses in a mouse model of lupus. These findings highlight a role for mitochondria in the generation not only of NETs but also of pro-inflammatory oxidized mitochondrial DNA in autoimmune diseases. PMID:26779811

Machine Learning Meta-analysis of Large Metagenomic Datasets: Tools and Biological Insights.

PubMed

Pasolli, Edoardo; Truong, Duy Tin; Malik, Faizan; Waldron, Levi; Segata, Nicola

2016-07-01

Shotgun metagenomic analysis of the human associated microbiome provides a rich set of microbial features for prediction and biomarker discovery in the context of human diseases and health conditions. However, the use of such high-resolution microbial features presents new challenges, and validated computational tools for learning tasks are lacking. Moreover, classification rules have scarcely been validated in independent studies, posing questions about the generality and generalization of disease-predictive models across cohorts. In this paper, we comprehensively assess approaches to metagenomics-based prediction tasks and for quantitative assessment of the strength of potential microbiome-phenotype associations. We develop a computational framework for prediction tasks using quantitative microbiome profiles, including species-level relative abundances and presence of strain-specific markers. A comprehensive meta-analysis, with particular emphasis on generalization across cohorts, was performed in a collection of 2424 publicly available metagenomic samples from eight large-scale studies. Cross-validation revealed good disease-prediction capabilities, which were in general improved by feature selection and use of strain-specific markers instead of species-level taxonomic abundance. In cross-study analysis, models transferred between studies were in some cases less accurate than models tested by within-study cross-validation. Interestingly, the addition of healthy (control) samples from other studies to training sets improved disease prediction capabilities. Some microbial species (most notably Streptococcus anginosus) seem to characterize general dysbiotic states of the microbiome rather than connections with a specific disease. Our results in modelling features of the "healthy" microbiome can be considered a first step toward defining general microbial dysbiosis. The software framework, microbiome profiles, and metadata for thousands of samples are publicly available at http://segatalab.cibio.unitn.it/tools/metaml.

Model of pediatric pituitary hormone deficiency separates the endocrine and neural functions of the LHX3 transcription factor in vivo

PubMed Central

Colvin, Stephanie C.; Malik, Raleigh E.; Showalter, Aaron D.; Sloop, Kyle W.; Rhodes, Simon J.

2011-01-01

The etiology of most pediatric hormone deficiency diseases is poorly understood. Children with combined pituitary hormone deficiency (CPHD) have insufficient levels of multiple anterior pituitary hormones causing short stature, metabolic disease, pubertal failure, and often have associated nervous system symptoms. Mutations in developmental regulatory genes required for the specification of the hormone-secreting cell types of the pituitary gland underlie severe forms of CPHD. To better understand these diseases, we have created a unique mouse model of CPHD with a targeted knockin mutation (Lhx3 W227ter), which is a model for the human LHX3 W224ter disease. The LHX3 gene encodes a LIM-homeodomain transcription factor, which has essential roles in pituitary and nervous system development in mammals. The introduced premature termination codon results in deletion of the carboxyl terminal region of the LHX3 protein, which is critical for pituitary gene activation. Mice that lack all LHX3 function do not survive beyond birth. By contrast, the homozygous Lhx3 W227ter mice survive, but display marked dwarfism, thyroid disease, and female infertility. Importantly, the Lhx3 W227ter mice have no apparent nervous system deficits. The Lhx3 W227ter mouse model provides a unique array of hormone deficits and facilitates experimental approaches that are not feasible with human patients. These experiments demonstrate that the carboxyl terminus of the LHX3 transcription factor is not required for viability. More broadly, this study reveals that the in vivo actions of a transcription factor in different tissues are molecularly separable. PMID:21149718

Quantifying the vascular response to ischemia with speckle variance optical coherence tomography

PubMed Central

Poole, Kristin M.; McCormack, Devin R.; Patil, Chetan A.; Duvall, Craig L.; Skala, Melissa C.

2014-01-01

Longitudinal monitoring techniques for preclinical models of vascular remodeling are critical to the development of new therapies for pathological conditions such as ischemia and cancer. In models of skeletal muscle ischemia in particular, there is a lack of quantitative, non-invasive and long term assessment of vessel morphology. Here, we have applied speckle variance optical coherence tomography (OCT) methods to quantitatively assess vascular remodeling and growth in a mouse model of peripheral arterial disease. This approach was validated on two different mouse strains known to have disparate rates and abilities of recovering following induction of hind limb ischemia. These results establish the potential for speckle variance OCT as a tool for quantitative, preclinical screening of pro- and anti-angiogenic therapies. PMID:25574425

Shaking Out Clues to Autoimmune Disease

MedlinePlus

... include type 1 diabetes, inflammatory bowel diseases and multiple sclerosis. Researchers have found many genetic variants that affect ... they examined a mouse disease that resembles human multiple sclerosis. Mice lacking SGK1 had less severe symptoms and ...

Prospects of Pluripotent and Adult Stem Cells for Rare Diseases.

PubMed

García-Castro, Javier; Singeç, Ilyas

2017-01-01

Rare diseases are highly diverse and complex regarding molecular underpinning and clinical manifestation and afflict millions of patients worldwide. The lack of appropriate model systems with face and construct validity and the limited availability of live tissues and cells from patients has largely hampered the understanding of underlying disease mechanisms. As a consequence, there are no adequate treatment options available for the vast majority of rare diseases. Over the last decade, remarkable progress in pluripotent and adult stem cell biology and the advent of powerful genomic technologies opened up exciting new avenues for the investigation, diagnosis, and personalized therapy of intractable human diseases. Utilizing the entire range of available stem cell types will continue to cross-fertilize different research areas and leverage the investigation of rare diseases based on evidence-based medicine. Standardized cell engineering and manufacturing from inexhaustible stem cell sources should lay the foundation for next-generation drug discovery and cell therapies that are broadly applicable in regenerative medicine. In this chapter we discuss how patient- and disease-specific iPS cells as well as adult stem cells are changing the pace of biomedical research and the translational landscape.

Rare bone diseases and their dental, oral, and craniofacial manifestations.

PubMed

Foster, B L; Ramnitz, M S; Gafni, R I; Burke, A B; Boyce, A M; Lee, J S; Wright, J T; Akintoye, S O; Somerman, M J; Collins, M T

2014-07-01

Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease. © International & American Associations for Dental Research.

Rare Bone Diseases and Their Dental, Oral, and Craniofacial Manifestations

PubMed Central

Foster, B.L.; Ramnitz, M.S.; Gafni, R.I.; Burke, A.B.; Boyce, A.M.; Lee, J.S.; Wright, J.T.; Akintoye, S.O.; Somerman, M.J.; Collins, M.T.

2014-01-01

Hereditary diseases affecting the skeleton are heterogeneous in etiology and severity. Though many of these conditions are individually rare, the total number of people affected is great. These disorders often include dental-oral-craniofacial (DOC) manifestations, but the combination of the rarity and lack of in-depth reporting often limit our understanding and ability to diagnose and treat affected individuals. In this review, we focus on dental, oral, and craniofacial manifestations of rare bone diseases. Discussed are defects in 4 key physiologic processes in bone/tooth formation that serve as models for the understanding of other diseases in the skeleton and DOC complex: progenitor cell differentiation (fibrous dysplasia), extracellular matrix production (osteogenesis imperfecta), mineralization (familial tumoral calcinosis/hyperostosis hyperphosphatemia syndrome, hypophosphatemic rickets, and hypophosphatasia), and bone resorption (Gorham-Stout disease). For each condition, we highlight causative mutations (when known), etiopathology in the skeleton and DOC complex, and treatments. By understanding how these 4 foci are subverted to cause disease, we aim to improve the identification of genetic, molecular, and/or biologic causes, diagnoses, and treatment of these and other rare bone conditions that may share underlying mechanisms of disease. PMID:24700690

Progress, Prospects, and Problems in Epstein-Barr Virus Vaccine Development

PubMed Central

Balfour, Henry H.

2014-01-01

Epstein-Barr virus (EBV) is responsible for a farrago of acute and chronic human diseases including cancer. A prophylactic vaccine could reduce this disease burden. Several EBV vaccines have been given to humans but none has been sufficiently studied to establish safety and efficacy. EBV vaccine development has been hampered by the lack of an animal model other than subhuman primates, proprietary issues, selection of an appropriate adjuvant, and failure to reach consensus on what an EBV vaccine could or should actually achieve. A recent conference at the U.S. National Institutes of Health emphasizing the global importance of EBV vaccine and advocating a phase 3 trial to prevent infectious mononucleosis should encourage research that could eventually lead to its licensure. PMID:24632197

A Potential Role of the Curry Spice Curcumin in Alzheimer’s Disease

PubMed Central

Ringman, John M.; Frautschy, Sally A.; Cole, Gregory M.; Masterman, Donna L.; Cummings, Jeffrey L.

2005-01-01

There is substantial in-vitro data indicating that curcumin has antioxidant, anti-inflammatory, and anti-amyloid activity. In addition, studies in animal models of Alzheimer’s disease (AD) indicate a direct effect of curcumin in decreasing the amyloid pathology of AD. As the widespread use of curcumin as a food additive and relatively small short-term studies in humans suggest safety, curcumin is a promising agent in the treatment and/or prevention of AD. Nonetheless, important information regarding curcumin bioavailability, safety and tolerability, particularly in an elderly population is lacking. We are therefore performing a study of curcumin in patients with AD to gather this information in addition to data on the effect of curcumin on biomarkers of AD pathology. PMID:15974909

Movement impairment: Focus on the brain.

PubMed

Adami, Raffaella; Bottai, Daniele

2016-04-01

The saying "mens sana in corpore sano" has a particular resonance these days because, for the majority who have a very sedentary occupation, the everyday rhythms of life do not compel us to do much physical exercise. Recently published data indicate that exercise can counteract the effects of neurological diseases such as Alzheimer's disease and have prompted research on the beneficial effects of movement on the brain and brain neurogenesis. This might lead us to hypothesize that the absence or reduction of movements, especially those with antigravity effects, could induce a deterioration of the brain. This Review discusses current knowledge of the relationship between neurogenic capacity and the lack of motor activity in human and animal models. © 2016 Wiley Periodicals, Inc.

Patterns of Dupuytren disease in fingers: studying correlations with a multivariate ordinal logit model.

PubMed

Lanting, Rosanne; Nooraee, Nazanin; Werker, Paul M N; van den Heuvel, Edwin R

2014-09-01

Dupuytren disease affects fingers in a variable fashion. Knowledge about specific disease patterns (phenotype) based on location and severity of the disease is lacking. In this cross-sectional study, 344 primary affected hands with Dupuytren disease were physically examined. The Pearson correlation coefficient between the coexistence of Dupuytren disease in pairs of fingers was calculated, and agglomerative hierarchical clustering was applied to identify possible clusters of affected fingers. With a multivariate ordinal logit model, the authors studied the correlation on severity, taking into account age and sex, and tested hypotheses on independence between groups of fingers. The ring finger was most frequently affected by Dupuytren disease, and contractures were seen in 15.1 percent of affected rays. The severity of thumb and index finger, middle and ring fingers, and middle and little fingers was significantly correlated. Occurrences in pairs of fingers were highest in the middle and ring fingers and lowest in the thumb and index finger. Correlation between the ring and little fingers and a correlation between fingers from the ulnar and radial sides could not be demonstrated. Rays on the ulnar side of the hand are predominantly affected. The middle finger is substantially correlated with other fingers on the ulnar side, and the thumb and index finger are correlated; however, there was no evidence that the ulnar side and the radial side were correlated in any way, which suggests that occurrence on one side of the hand does not predict Dupuytren disease on the other side of the hand. Risk, III.

MUC1 enhances tumor progression and contributes toward immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma.

PubMed

Tinder, Teresa L; Subramani, Durai B; Basu, Gargi D; Bradley, Judy M; Schettini, Jorge; Million, Arefayene; Skaar, Todd; Mukherjee, Pinku

2008-09-01

MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune-competent host. Significant enhancement in the development of pancreatic intraepithelial preneoplastic lesions and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and IDO compared with PDA mice lacking MUC1, especially during early stages of tumor development. The increased proinflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease, which in turn regulate the immune responses. Thus, the mouse model is ideally suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer.

MUC1 enhances tumor progression and contributes towards immunosuppression in a mouse model of spontaneous pancreatic adenocarcinoma

PubMed Central

Tinder, Teresa L.; Subramani, Durai B.; Basu, Gargi D.; Bradley, Judy M.; Schettini, Jorge; Million, Arefayene; Skaar, Todd

2008-01-01

MUC1, a membrane tethered mucin glycoprotein, is overexpressed and aberrantly glycosylated in >80% of human ductal pancreatic adenocarcinoma. However, the role of MUC1 in pancreatic cancer has been elusive, partly due to the lack of an appropriate model. We report the characterization of a novel mouse model that expresses human MUC1 as a self molecule (PDA.MUC1 mice). Pancreatic tumors arise in an appropriate MUC1-tolerant background within an immune competent host. Significant enhancement in the development of pancreatic intraepithelial pre-neoplastic lesions (PanINs) and progression to adenocarcinoma is observed in PDA.MUC1 mice, possibly due to increased proliferation. Tumors from PDA.MUC1 mice express higher levels of cyclooxygenase-2 and indoleamine 2,3, dioxygenase compared to PDA mice lacking MUC1, especially during early stages of tumor development. The increased pro-inflammatory milieu correlates with an increased percentage of regulatory T cells and myeloid suppressor cells in the pancreatic tumor and tumor draining lymph nodes. Data shows that during pancreatic cancer progression, MUC1-mediated mechanisms enhance the onset and progression of the disease which in turn regulate the immune responses. Thus, the mouse model is ideally-suited for testing novel chemopreventive and therapeutic strategies against pancreatic cancer. PMID:18713982

Myths in the Diagnosis and Management of Orbital Tumors

PubMed Central

Gündüz, Kaan; Yanık, Özge

2015-01-01

Orbital tumors constitute a group of diverse lesions with a low incidence in the population. Tumors affecting the eye and ocular adnexa may also secondarily invade the orbit. Lack of accumulation of a sufficient number of cases with a specific diagnosis at various orbital centers, the paucity of prospective randomized studies, animal model studies, tissue bank, and genetic studies led to the development of various myths regarding the diagnosis and treatment of orbital lesions in the past. These myths continue to influence the diagnosis and treatment of orbital lesions by orbital specialists. This manuscript discusses some of the more common myths through case summaries and a review of the literature. Detailed genotypic analysis and genetic classification will provide further insight into the pathogenesis of many orbital diseases in the future. This will enable targeted treatments even for diseases with the same histopathologic diagnosis. Phenotypic variability within the same disease will be addressed using targeted treatments. PMID:26692710

Deep Integration: Letting the Epigenome Out of the Bottle Without Losing Sight of the Structural Origins of Population Health

PubMed Central

2013-01-01

Advances in stress physiology and molecular dynamics can illuminate population health inequality. The “weathering” hypothesis posits that socially structured, repeated stress process activation can accumulate and increase disease vulnerability across the life course in marginalized groups. The developmental origins of health and disease (DOHaD) hypothesis focuses on youthful programming for later life disease via epigenetic modifications to limiting uterine or early environments. Weathering and DOHaD are overlapping biopsychosocial models; yet, their emphases and implications vary. Evidence for the primacy of early development over experiences in young through middle adulthood for explaining population health inequality is lacking. By considering weathering and DOHaD together, we call for biomedical researchers to be more cautious in their claims about the social world and for a broader range of social researchers—including qualitative ones—to collaborate with them. PMID:23927509

Antiphospholipase A2 Receptor Autoantibodies: A Step Forward in the Management of Primary Membranous Nephropathy

PubMed Central

Obrisca, Bogdan; Ismail, Gener; Jurubita, Roxana; Baston, Catalin; Andronesi, Andreea; Mircescu, Gabriel

2015-01-01

Since the identification of PLA2R (M-type phospholipase A2 receptor) as the first human antigenic target in primary membranous nephropathy (MN), perpetual progress has been made in understanding the pathogenesis of this disease. Accumulating clinical data support a pathogenic role for the anti-PLA2R antibodies (PLA2R ABs), but confirmation in an animal model is still lacking. However, PLA2R ABs were related to disease activity and outcome, as well as to response therapy. Accordingly, PLA2R ABs assay seems to be promising tool not only to diagnose MN but also to predict the course of the disease and could open the way to personalize therapy. Nevertheless, validation of a universal assay with high precision and definition of cut-off levels, followed by larger studies with a prolonged follow-up period, are needed to confirm these prospects. PMID:26576418

Antiphospholipase A2 Receptor Autoantibodies: A Step Forward in the Management of Primary Membranous Nephropathy.

PubMed

Obrisca, Bogdan; Ismail, Gener; Jurubita, Roxana; Baston, Catalin; Andronesi, Andreea; Mircescu, Gabriel

2015-01-01

Since the identification of PLA2R (M-type phospholipase A2 receptor) as the first human antigenic target in primary membranous nephropathy (MN), perpetual progress has been made in understanding the pathogenesis of this disease. Accumulating clinical data support a pathogenic role for the anti-PLA2R antibodies (PLA2R ABs), but confirmation in an animal model is still lacking. However, PLA2R ABs were related to disease activity and outcome, as well as to response therapy. Accordingly, PLA2R ABs assay seems to be promising tool not only to diagnose MN but also to predict the course of the disease and could open the way to personalize therapy. Nevertheless, validation of a universal assay with high precision and definition of cut-off levels, followed by larger studies with a prolonged follow-up period, are needed to confirm these prospects.

Words matter: Recommendations for clarifying coral disease nomenclature and terminology

USGS Publications Warehouse

Rogers, Caroline S.

2010-01-01

Coral diseases have caused significant losses on Caribbean reefs and are becoming a greater concern in the Pacific. Progress in coral disease research requires collaboration and communication among experts from many different disciplines. The lack of consistency in the use of terms and names in the recent scientific literature reflects the absence of an authority for naming coral diseases, a lack of consensus on the meaning of even some of the most basic terms as they apply to corals, and imprecision in the use of descriptive words. The lack of consensus partly reflects the complexity of this newly emerging field of research. Establishment of a nomenclature committee under the Coral Disease and Health Consortium (CDHC) could lead to more standardized definitions and could promote use of appropriate medical terminology for describing and communicating disease conditions in corals. This committee could also help to define disease terminology unique to corals where existing medical terminology is not applicable. These efforts will help scientists communicate with one another and with the general public more effectively. Scientists can immediately begin to reduce some of the confusion simply by explicitly defining the words they are using. In addition, digital photographs can be posted on the CDHC website and included in publications to document the macroscopic (gross) signs of the conditions observed on coral colonies along with precisely written characterizations and descriptions.

A new neuroinformatics approach to personalized medicine in neurology: The Virtual Brain

PubMed Central

Falcon, Maria I.; Jirsa, Viktor; Solodkin, Ana

2017-01-01

Purpose of review An exciting advance in the field of neuroimaging is the acquisition and processing of very large data sets (so called ‘big data’), permitting large-scale inferences that foster a greater understanding of brain function in health and disease. Yet what we are clearly lacking are quantitative integrative tools to translate this understanding to the individual level to lay the basis for personalized medicine. Recent findings Here we address this challenge through a review on how the relatively new field of neuroinformatics modeling has the capacity to track brain network function at different levels of inquiry, from microscopic to macroscopic and from the localized to the distributed. In this context, we introduce a new and unique multiscale approach, The Virtual Brain (TVB), that effectively models individualized brain activity, linking large-scale (macroscopic) brain dynamics with biophysical parameters at the microscopic level. We also show how TVB modeling provides unique biological interpretable data in epilepsy and stroke. Summary These results establish the basis for a deliberate integration of computational biology and neuroscience into clinical approaches for elucidating cellular mechanisms of disease. In the future, this can provide the means to create a collection of disease-specific models that can be applied on the individual level to personalize therapeutic interventions. Video abstract http://links.lww.com/CONR/A41 PMID:27224088

Fetal Origins of Life Stage Disease: A Zebrafish Model for the ...

EPA Pesticide Factsheets

In the U.S., childhood obesity has more than doubled in children and quadrupled in adolescents in the past 30 years, affects 35% of adults, and costs the U.S. healthcare industry >$200 billion annually. The chemical environment in the womb may cause susceptibility to different life-stage and life-long metabolic diseases including obesity. The challenge is to understand if exposures during developmentally sensitive windows impact life-stage disease, such as obesity, by increasing adipose tissue mass. In vitro models lack the integrated systems approach needed to assess adipose development, while mammalian models are impractical in a screen of thousands of chemicals. Therefore, an obesogen screening method was developed to interrogate bioactivity using a full systems approach, in a vertebrate zebrafish model with complete metabolic activity, at a time when the full signaling repertoire is expressed and active, to optimally examine how chemical dose and duration impact life-stage adipose mass. A time-line for adipose depot formation was mapped in zebrafish 6−14 days post fertilization (dpf) using the lipophilic dye, Nile Red, in combination with fluorescent microscopy. Those time points were then used to investigate the impact of embryonic tributyltin chloride (TBT, a known obesogen) exposure (10nM daily renewal, 0−5dpf) on adipose mass. Fluorescent microscopy revealed adipose depots that were larger and appeared 2 days earlier in TBT treated compared to contro

Micro-CT Imaging Reveals Mekk3 Heterozygosity Prevents Cerebral Cavernous Malformations in Ccm2-Deficient Mice

PubMed Central

Choi, Jaesung P.; Foley, Matthew; Zhou, Zinan; Wong, Weng-Yew; Gokoolparsadh, Naveena; Arthur, J. Simon C.; Li, Dean Y.; Zheng, Xiangjian

2016-01-01

Mutations in CCM1 (aka KRIT1), CCM2, or CCM3 (aka PDCD10) gene cause cerebral cavernous malformation in humans. Mouse models of CCM disease have been established by deleting Ccm genes in postnatal animals. These mouse models provide invaluable tools to investigate molecular mechanism and therapeutic approaches for CCM disease. However, the full value of these animal models is limited by the lack of an accurate and quantitative method to assess lesion burden and progression. In the present study we have established a refined and detailed contrast enhanced X-ray micro-CT method to measure CCM lesion burden in mouse brains. As this study utilized a voxel dimension of 9.5μm (leading to a minimum feature size of approximately 25μm), it is therefore sufficient to measure CCM lesion volume and number globally and accurately, and provide high-resolution 3-D mapping of CCM lesions in mouse brains. Using this method, we found loss of Ccm1 or Ccm2 in neonatal endothelium confers CCM lesions in the mouse hindbrain with similar total volume and number. This quantitative approach also demonstrated a rescue of CCM lesions with simultaneous deletion of one allele of Mekk3. This method would enhance the value of the established mouse models to study the molecular basis and potential therapies for CCM and other cerebrovascular diseases. PMID:27513872

Disease prevention policy under Medicare: a historical and political analysis.

PubMed

Schauffler, H H

1993-01-01

I review the history and politics of Medicare disease prevention policy and identify factors associated with the success or failure of legislative initiatives to add preventive services benefits to Medicare. Between 1965 and 1990, 453 bills for Medicare preventive services were introduced in the U.S. Congress, but not until 1980, after 350 bills had failed, was the first preventive service added to the Medicare program. Medicare currently pays for only four of the 44 preventive services recommended for the elderly by the U.S. Preventive Services Task Force (pneumococcal and hepatitis B vaccinations, Pap smears, and mammography). In addition, Congress has funded demonstration programs for the influenza vaccine and comprehensive preventive services. The preventive services added to Medicare reflect the bias of the biomedical model toward screening and immunizations. Counseling services have received the least legislative attention. Factors associated with successful enactment include single-benefit bills, incorporation into budget-deficit reduction legislation, documented evidence of cost-effectiveness, public hearings, sponsorship by chairs of key congressional committees, and persistent congressional leadership. Factors associated with failure include lack of support from Medicare beneficiaries, lack of professional support, impact on total Medicare expenditures, disagreement over or failure to address payment and financing mechanisms, and competing congressional priorities.

An Update on Host-Pathogen Interplay and Modulation of Immune Responses during Orientia tsutsugamushi Infection.

PubMed

Díaz, Fabián E; Abarca, Katia; Kalergis, Alexis M

2018-04-01

The obligate intracellular bacterium Orientia tsutsugamushi is the causative agent of scrub typhus in humans, a serious mite-borne disease present in a widespread area of endemicity, which affects an estimated 1 million people every year. This disease may exhibit a broad range of presentations, ranging from asymptomatic to fatal conditions, with the latter being due to disseminated endothelial infection and organ injury. Unique characteristics of the biology and host-pathogen interactions of O. tsutsugamushi , including the high antigenic diversity among strains and the highly variable, short-lived memory responses developed by the host, underlie difficulties faced in the pursuit of an effective vaccine, which is an imperative need. Other factors that have hindered scientific progress relative to the infectious mechanisms of and the immune response triggered by this bacterium in vertebrate hosts include the limited number of mechanistic studies performed on animal models and the lack of genetic tools currently available for this pathogen. However, recent advances in animal model development are promising to improve our understanding of host-pathogen interactions. Here, we comprehensively discuss the recent advances in and future perspectives on host-pathogen interactions and the modulation of immune responses related to this reemerging disease, highlighting the role of animal models. Copyright © 2018 American Society for Microbiology.

Molecular biology of anal squamous cell carcinoma: implications for future research and clinical intervention.

PubMed

Bernardi, Maria-Pia; Ngan, Samuel Y; Michael, Michael; Lynch, A Craig; Heriot, Alexander G; Ramsay, Robert G; Phillips, Wayne A

2015-12-01

Anal squamous cell carcinoma is a human papillomavirus-related disease, in which no substantial advances in treatment have been made in over 40 years, especially for those patients who develop disease relapse and for whom no surgical options exist. HPV can evade the immune system and its role in disease progression can be exploited in novel immunotherapy platforms. Although several studies have investigated the expression and inactivation (through loss of heterozygosity) of tumour suppressor genes in the pathways to cancer, no clinically valuable biomarkers have emerged. Regulators of apoptosis, including survivin, and agents targeting the PI3K/AKT pathway, offer opportunities for targeted therapy, although robust data are scarce. Additionally, antibody therapy targeting EGFR may prove effective, although its safety profile in combination with standard chemoradiotherapy has proven to be suboptimal. Finally, progress in the treatment of anal cancer has remained stagnant due to a lack of preclinical models, including cell lines and mouse models. In this Review, we discuss the molecular biology of anal squamous cell carcinoma, clinical trials in progress, and implications for novel therapeutic targets. Future work should focus on preclinical models to provide a resource for investigation of new molecular pathways and for testing novel targets. Copyright © 2015 Elsevier Ltd. All rights reserved.

Sustainable and tenable renal health model: a Latin American proposal of classification, programming, and evaluation.

PubMed

Calderón, Rafael Burgos; Depine, Santos

2005-08-01

End-stage renal disease (ESRD) presents a major problem to public health, with complex implications for social and economic structures in every nation of the world. Clearly, Latin American and Caribbean countries are not able to meet the needs of every patient requiring dialysis treatment at ESRD. Consequently, a considerable number of patients die every year as a result of lack of resources. Aware of this serious social, ethical, and economic problem, the Latin American Society of Nephrology and Hypertension proposed a new renal health concept in the region. In December 2002, at the workshop in Valdivia, Chile, a modification to the National Kidney Foundation Classification of Chronic Kidney Disease was approved. According to modifications to the concept of chronic kidney disease approved in the Declaration of Valdivia, a new Renal Health Model was proposed. It consists of including orderly follow-up in patients' charts, starting from the earliest stage, and a model establishing a guideline for the reallocation of financial resources to guarantee continuity of treatment to patients with ESRD. The implementation of the Renal Health Program in health ministries of Latin American and Caribbean countries would allow for a substantial improvement in renal health prevention and management, as a result of better distribution of financial and human resources.

Trichomoniasis - are we giving the deserved attention to the most common non-viral sexually transmitted disease worldwide?

PubMed Central

Menezes, Camila Braz; Frasson, Amanda Piccoli; Tasca, Tiana

2016-01-01

Etiology: Trichomonas vaginalis is the etiologic agent of trichomoniasis, the most common non-viral sexually transmitted disease (STD) in the world. Transmission: Trichomoniasis is transmitted by sexual intercourse and transmission via fomites is rare. Epidemiology, incidence and prevalence: The WHO estimates an incidence of 276 million new cases each year and prevalence of 187 million of infected individuals. However, the infection is not notifiable. Pathology/Symptomatology: The T. vaginalis infection results in a variety of clinical manifestations - in most cases the patients are asymptomatic, but some may develop signs typically associated to the disease. Importantly, the main issue concerning trichomoniasis is its relationship with serious health consequences such as cancer, adverse pregnancy outcomes, infertility, and HIV acquisition. Molecular mechanisms of infection: To achieve success in parasitism trichomonads develop a complex process against the host cells that includes dependent- and independent-contact mechanisms. This multifactorial pathogenesis includes molecules such as soluble factors, secreted proteinases, adhesins, lipophosphoglycan that culminate in cytoadherence and cytotoxicity against the host cells. Treatment and curability: The treatment with metronidazole or tinidazole is recommended; however, cure failures remain problematic due to noncompliance, reinfection and/or lack of treatment of sexual partners, inaccurate diagnosis, or drug resistance. Therefore, new therapeutic alternatives are urgently needed. Protection: Strategies for protection including sexual behavior, condom usage, and therapy have not contributed to the decrease on disease prevalence, pointing to the need for innovative approaches. Vaccine development has been hampered by the lack of long-lasting humoral immunity associated to the absence of good animal models. PMID:28357378

Systems Pharmacology Dissecting Holistic Medicine for Treatment of Complex Diseases: An Example Using Cardiocerebrovascular Diseases Treated by TCM.

PubMed

Wang, Yonghua; Zheng, Chunli; Huang, Chao; Li, Yan; Chen, Xuetong; Wu, Ziyin; Wang, Zhenzhong; Xiao, Wei; Zhang, Boli

2015-01-01

Holistic medicine is an interdisciplinary field of study that integrates all types of biological information (protein, small molecules, tissues, organs, external environmental signals, etc.) to lead to predictive and actionable models for health care and disease treatment. Despite the global and integrative character of this discipline, a comprehensive picture of holistic medicine for the treatment of complex diseases is still lacking. In this study, we develop a novel systems pharmacology approach to dissect holistic medicine in treating cardiocerebrovascular diseases (CCDs) by TCM (traditional Chinese medicine). Firstly, by applying the TCM active ingredients screened out by a systems-ADME process, we explored and experimentalized the signed drug-target interactions for revealing the pharmacological actions of drugs at a molecule level. Then, at a/an tissue/organ level, the drug therapeutic mechanisms were further investigated by a target-organ location method. Finally, a translational integrating pathway approach was applied to extract the diseases-therapeutic modules for understanding the complex disease and its therapy at systems level. For the first time, the feature of the drug-target-pathway-organ-cooperations for treatment of multiple organ diseases in holistic medicine was revealed, facilitating the development of novel treatment paradigm for complex diseases in the future.

Systems Pharmacology Dissecting Holistic Medicine for Treatment of Complex Diseases: An Example Using Cardiocerebrovascular Diseases Treated by TCM

PubMed Central

Wang, Yonghua; Zheng, Chunli; Huang, Chao; Li, Yan; Chen, Xuetong; Wu, Ziyin; Wang, Zhenzhong; Xiao, Wei; Zhang, Boli

2015-01-01

Holistic medicine is an interdisciplinary field of study that integrates all types of biological information (protein, small molecules, tissues, organs, external environmental signals, etc.) to lead to predictive and actionable models for health care and disease treatment. Despite the global and integrative character of this discipline, a comprehensive picture of holistic medicine for the treatment of complex diseases is still lacking. In this study, we develop a novel systems pharmacology approach to dissect holistic medicine in treating cardiocerebrovascular diseases (CCDs) by TCM (traditional Chinese medicine). Firstly, by applying the TCM active ingredients screened out by a systems-ADME process, we explored and experimentalized the signed drug-target interactions for revealing the pharmacological actions of drugs at a molecule level. Then, at a/an tissue/organ level, the drug therapeutic mechanisms were further investigated by a target-organ location method. Finally, a translational integrating pathway approach was applied to extract the diseases-therapeutic modules for understanding the complex disease and its therapy at systems level. For the first time, the feature of the drug-target-pathway-organ-cooperations for treatment of multiple organ diseases in holistic medicine was revealed, facilitating the development of novel treatment paradigm for complex diseases in the future. PMID:26101539

Surveying the landscape of Huntington's disease mechanisms, measurements, and medicines.

PubMed

Crook, Zachary R; Housman, David E

2013-01-01

Though 20 years have now passed since the cloning of the huntingtin gene (HTT), there remains no treatment for Huntington's Disease (HD) that alters the course of disease or lifespan of patients. The reasons for this are manifold, and likely have to do with the diverse cellular pathways disrupted by mutant HTT (mHTT) protein expression. Furthermore, the evaluation of efficacy using a putative intervention is complex, largely due to the slow course of disease and variability in the classic techniques for evaluating patient symptoms and quality of life, which make the patient populations and duration of trials particularly imposing. However, there are signs for hope both in the clinic and at the bench. This review serves three purposes. It discusses the known cellular pathologies in HD, the current and upcoming methods for clinical evaluation of disease progress, and the tested and untested interventions proposed to counter the progression in animal models and patients. With the vast knowledge of pathology accumulated over two decades of modeling HD in animals and following it in patients, as well as the advances in intervention techniques both pharmaceutical and genetic, there is reason for optimism in the field. Such optimism can only be tempered by the lack of success in the clinic to this point, though patients, scientists, and clinicians all remain enthusiastic about each new trial, and progress can only continue until an effective treatment is found.

How to treat Parkinson's disease in 2013.

PubMed

Worth, Paul F

2013-02-01

Parkinson's disease is a common, progressive, debilitating disease with substantial physical, psychological and social implications. Pharmacological management is complex and should be individualised according to the needs of the patient. In early disease, treatment is generally highly effective, but medication becomes increasingly inadequate in controlling motor fluctuations and dyskinesias as the disease progresses. Non-motor symptoms, especially depression and dementia, require a holistic, multidisciplinary approach to maximise quality of life for patients and their carers. For the future, the ideal solution remains neuroprotection and restoration. Progress has been hampered by the lack of animal models that reflect the widespread brain pathology presumed to cause both motor and non-motor symptoms of PD in humans. Currently, agents are undergoing clinical trials in early, mildly affected patients, such as the plant-derived substance PYM50028 (Cogane), which promotes expression of endogenous neural growth factors and has shown promise in vitro and in animal models. Gene-therapy trials in progress rely on the viral vectors used to deliver the enzymatic machinery required for dopamine synthesis to the striatum. As PD progresses, adequate control of motor symptoms depends increasingly on continuous drug delivery, and greater physiological stimulation of dopamine receptors may help to prevent the development of LIDs and motor fluctuations. Efforts thus are afoot to develop better delivery systems for levodopa, and a new sustained-release formulation is in development.

Cerebrospinal fluid biomarkers profile of idiopathic normal pressure hydrocephalus.

PubMed

Schirinzi, Tommaso; Sancesario, Giulia Maria; Di Lazzaro, Giulia; D'Elia, Alessio; Imbriani, Paola; Scalise, Simona; Pisani, Antonio

2018-04-01

Idiopathic normal pressure hydrocephalus (iNPH) is a disabling neurological disorder whose potential treatability is significantly limited by diagnostic uncertainty. In fact, typical clinical presentation occurs at late phases of disease, when CSF shunting could be ineffective. In recent years, measurement of different CSF proteins, whose concentration directly reflects neuropathological changes of CNS, has significantly improved both diagnostic timing and accuracy of neurodegenerative disease. Unfortunately iNPH lacks neuropathological hallmarks allowing the identification of specific disease biomarkers. However, neuropathology of iNPH is so rich and heterogeneous that many processes can be tracked in CSF, including Alzheimer's disease core pathology, subcortical degeneration, neuroinflammation and vascular dysfunction. Indeed, a huge number of CSF biomarkers have been analyzed in iNPH patients, but a unifying profile has not been provided yet. In this brief survey, we thus attempted to summarize the main findings in the field of iNPH CSF biomarkers, aimed at outlining a synthetic model. Although defined cut-off values for biomarkers are not available, a better knowledge of CSF characteristics may definitely assist in diagnosing the disease.

[Work-related rhinitis - Is it always an occupational disease?

PubMed

Salski, Witold; Wiszniewska, Marta; Salska, Agata; Tymoszuk, Diana; Walusiak-Skorupa, Jolanta

2016-12-22

Rhinitis is a chronic inflammatory disease of the upper respiratory tract, characterized by a high prevalence and a complex pathogenesis. Work-related rhinitis (WRR) can be divided into occupational rhinitis (OR) and work-exacerbated rhinitis (WER). It is not only considered as a disease entity but also in the context of medical certification as the allergic disease associated with occupational exposure. Epidemiology of work-related rhinitis has been found to vary depending on the occupation and specific exposure, on the other hand the prevalence data may be underestimated due to the lack of uniform diagnostic criteria. This paper reviews the issues comprising the pathogenesis, epidemiology, diagnosis and treatment of patients with work-related rhinitis. It also discusses the significance of the disease in occupational medicine, particularly in terms of preventive worker care, general principles of good practice in primary and secondary WRR prevention and the necessary directions of changes in medical certification in the cases of occupational rhinitis. Med Pr 2016;67(6):801-815. This work is available in Open Access model and licensed under a CC BY-NC 3.0 PL license.

Zebrafish: an animal model for research in veterinary medicine.

PubMed

Nowik, N; Podlasz, P; Jakimiuk, A; Kasica, N; Sienkiewicz, W; Kaleczyc, J

2015-01-01

The zebrafish (Danio rerio) has become known as an excellent model organism for studies of vertebrate biology, vertebrate genetics, embryonal development, diseases and drug screening. Nevertheless, there is still lack of detailed reports about usage of the zebrafish as a model in veterinary medicine. Comparing to other vertebrates, they can lay hundreds of eggs at weekly intervals, externally fertilized zebrafish embryos are accessible to observation and manipulation at all stages of their development, which makes possible to simplify the research techniques such as fate mapping, fluorescent tracer time-lapse lineage analysis and single cell transplantation. Although zebrafish are only 2.5 cm long, they are easy to maintain. Intraperitoneal and intracerebroventricular injections, blood sampling and measurement of food intake are possible to be carry out in adult zebrafish. Danio rerio is a useful animal model for neurobiology, developmental biology, drug research, virology, microbiology and genetics. A lot of diseases, for which the zebrafish is a perfect model organism, affect aquatic animals. For a part of them, like those caused by Mycobacterium marinum or Pseudoloma neutrophila, Danio rerio is a natural host, but the zebrafish is also susceptible to the most of fish diseases including Itch, Spring viraemia of carp and Infectious spleen and kidney necrosis. The zebrafish is commonly used in research of bacterial virulence. The zebrafish embryo allows for rapid, non-invasive and real time analysis of bacterial infections in a vertebrate host. Plenty of common pathogens can be examined using zebrafish model: Streptococcus iniae, Vibrio anguillarum or Listeria monocytogenes. The steps are taken to use the zebrafish also in fungal research, especially that dealing with Candida albicans and Cryptococcus neoformans. Although, the zebrafish is used commonly as an animal model to study diseases caused by external agents, it is also useful in studies of metabolic disorders including fatty liver disease and diabetes. The zebrafish is also a valuable tool as a model in behavioral studies connected with feeding, predator evasion, habituation and memory or lateralized control of behavior. The aim of the present article is to familiarize the reader with the possibilities of Danio rerio as an experimental model for veterinary medicine.

Glomerular disease: why is there a dearth of high quality clinical trials?

PubMed

Leaf, David E; Appel, Gerald B; Radhakrishnan, Jai

2010-08-01

There is a paucity of high quality clinical trials in glomerular disease, particularly in non-diabetic kidney disease. The aims of this review include quantifying the extent of this problem and exploring reasons for the scarcity of such trials in primary glomerular disease, with an emphasis on immunoglobulin A nephropathy, minimal change disease, focal segmental glomerulosclerosis, and membranous nephropathy in comparison with the more common diseases of diabetic nephropathy and lupus nephritis. Reasons for the dearth of high quality clinical trials in primary glomerular disease include (1) low prevalence of disease; (2) variability in clinical presentation; (3) variability in treatment response; (4) lack of consensus in definitions; (5) difficulty in recruiting patients; (6) high costs of randomized controlled trials; and (7) lack of collaborative efforts. To facilitate greater numbers of high quality clinical trials in glomerular disease, practice guidelines should establish common classification systems of disease and common clinical end points, industry and non-industry sponsored research should find common ground and work together toward advancing science, and national registries should be created to encourage collaborations across institutions and across nations.

Spdef Null Mice Lack Conjunctival Goblet Cells and Provide a Model of Dry Eye

PubMed Central

Marko, Christina K.; Menon, Balaraj B.; Chen, Gang; Whitsett, Jeffrey A.; Clevers, Hans; Gipson, Ilene K.

2014-01-01

Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (Spdef) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using Spdef−/− mice, we determined that Spdef is required for conjunctival goblet cell differentiation and that Spdef−/− mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in Spdef−/− mice revealed down-regulation of goblet cell–specific genes (Muc5ac, Tff1, Gcnt3). Up-regulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and proinflammatory genes (Il1-α, Il-1β, Tnf-α), all of which are up-regulated in dry eye. Interestingly, four Wnt pathway genes were down-regulated. SPDEF expression was significantly decreased in the conjunctival epithelium of Sjögren syndrome patients with dry eye and decreased goblet cell mucin expression. These data demonstrate that Spdef is required for conjunctival goblet cell differentiation and down-regulation of SPDEF may play a role in human dry eye with goblet cell loss. Spdef−/− mice have an ocular surface phenotype similar to that in moderate dry eye, providing a new, more convenient model for the disease. PMID:23665202

Lack of Neuropathy-Related Phenotypes in Hint1 Knockout Mice

PubMed Central

Seburn, Kevin L.; Morelli, Kathryn H.; Jordanova, Albena; Burgess, Robert W.

2014-01-01

Mutations in HINT1, the gene encoding histidine triad nucleotide-binding protein 1 (HINT1), cause a recessively inherited peripheral neuropathy that involves primarily motor dysfunction and is usually associated with neuromyotonia, i.e. prolonged muscle contraction resulting from hyperexcitability of the peripheral nerve. Because these mutations are hypothesized to cause loss of function, we analyzed Hint1 knockout mice for their relevance as a disease model. Mice lacking Hint1 were normal in appearance and in behavioral tests or motor performance, although they moved slower and for a smaller fraction of time than wild-type (WT) mice in an open field arena. Muscles, neuromuscular junctions, and nodes of Ranvier are anatomically normal and did not show evidence of degeneration or regeneration. Axon numbers and myelination in peripheral nerves were normal at 4 and 13 months of age. Axons were slightly smaller than those in WT mice at 4 months of age, but this did not cause a decrease in conduction velocity, and no differences in axon diameters were detected at 13 months. Using electromyography, we were unable to detect neuromyotonia, even using supra-physiological stimuli and stressors such as reduced temperature or 3,4 diaminopyridine to block potassium channels. Therefore, we conclude that Hint1 knockout mice may be useful for studying the biochemical activities of HINT1, but these mice do not provide a disease model or a means for investigating the basis of HINT1-associated neuropathy and neuromyotonia. PMID:24918641

Spdef null mice lack conjunctival goblet cells and provide a model of dry eye.

PubMed

Marko, Christina K; Menon, Balaraj B; Chen, Gang; Whitsett, Jeffrey A; Clevers, Hans; Gipson, Ilene K

2013-07-01

Goblet cell numbers decrease within the conjunctival epithelium in drying and cicatrizing ocular surface diseases. Factors regulating goblet cell differentiation in conjunctival epithelium are unknown. Recent data indicate that the transcription factor SAM-pointed domain epithelial-specific transcription factor (Spdef) is essential for goblet cell differentiation in tracheobronchial and gastrointestinal epithelium of mice. Using Spdef(-/-) mice, we determined that Spdef is required for conjunctival goblet cell differentiation and that Spdef(-/-) mice, which lack conjunctival goblet cells, have significantly increased corneal surface fluorescein staining and tear volume, a phenotype consistent with dry eye. Microarray analysis of conjunctival epithelium in Spdef(-/-) mice revealed down-regulation of goblet cell-specific genes (Muc5ac, Tff1, Gcnt3). Up-regulated genes included epithelial cell differentiation/keratinization genes (Sprr2h, Tgm1) and proinflammatory genes (Il1-α, Il-1β, Tnf-α), all of which are up-regulated in dry eye. Interestingly, four Wnt pathway genes were down-regulated. SPDEF expression was significantly decreased in the conjunctival epithelium of Sjögren syndrome patients with dry eye and decreased goblet cell mucin expression. These data demonstrate that Spdef is required for conjunctival goblet cell differentiation and down-regulation of SPDEF may play a role in human dry eye with goblet cell loss. Spdef(-/-) mice have an ocular surface phenotype similar to that in moderate dry eye, providing a new, more convenient model for the disease. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Guinea Pig as a Model to Study the Carotid Body Mediated Chronic Intermittent Hypoxia Effects.

PubMed

Docio, Inmaculada; Olea, Elena; Prieto-LLoret, Jesus; Gallego-Martin, Teresa; Obeso, Ana; Gomez-Niño, Angela; Rocher, Asuncion

2018-01-01

Clinical and experimental evidence indicates a positive correlation between chronic intermittent hypoxia (CIH), increased carotid body (CB) chemosensitivity, enhanced sympatho-respiratory coupling and arterial hypertension and cardiovascular disease. Several groups have reported that both the afferent and efferent arms of the CB chemo-reflex are enhanced in CIH animal models through the oscillatory CB activation by recurrent hypoxia/reoxygenation episodes. Accordingly, CB ablation or denervation results in the reduction of these effects. To date, no studies have determined the effects of CIH treatment in chemo-reflex sensitization in guinea pig, a rodent with a hypofunctional CB and lacking ventilatory responses to hypoxia. We hypothesized that the lack of CB hypoxia response in guinea pig would suppress chemo-reflex sensitization and thereby would attenuate or eliminate respiratory, sympathetic and cardiovascular effects of CIH treatment. The main purpose of this study was to assess if guinea pig CB undergoes overactivation by CIH and to correlate CIH effects on CB chemoreceptors with cardiovascular and respiratory responses to hypoxia. We measured CB secretory activity, ventilatory parameters, systemic arterial pressure and sympathetic activity, basal and in response to acute hypoxia in two groups of animals: control and 30 days CIH exposed male guinea pigs. Our results indicated that CIH guinea pig CB lacks activity elicited by acute hypoxia measured as catecholamine (CA) secretory response or intracellular calcium transients. Plethysmography data showed that only severe hypoxia (7% O 2 ) and hypercapnia (5% CO 2 ) induced a significant increased ventilatory response in CIH animals, together with higher oxygen consumption. Therefore, CIH exposure blunted hyperventilation to hypoxia and hypercapnia normalized to oxygen consumption. Increase in plasma CA and superior cervical ganglion CA content was found, implying a CIH induced sympathetic hyperactivity. CIH promoted cardiovascular adjustments by increasing heart rate and mean arterial blood pressure without cardiac ventricle hypertrophy. In conclusion, CIH does not sensitize CB chemoreceptor response to hypoxia but promotes cardiovascular adjustments probably not mediated by the CB. Guinea pigs could represent an interesting model to elucidate the mechanisms that underlie the long-term effects of CIH exposure to provide evidence for the role of the CB mediating pathological effects in sleep apnea diseases.

Development and antigenic characterization of three recombinant proteins with potential for Glässer's disease prevention.

PubMed

Li, Miao; Li, Chunling; Song, Shuai; Kang, Huahua; Yang, Dongxia; Li, Guoqing

2016-04-27

Haemophilus parasuis is the causative agent of Glässer's disease, which causes high morbidity and mortality in piglets, leading to severe economic losses. The lack of a commercial vaccine against a broad spectrum of strains has limited the disease control. H. parasuis outer membrane proteins (OMPs) are potentially essential components for vaccine formulation. In this study, seven putative OMPs were selected from the annotated H. parasuis serovar 5 genome; they were predicted by bioinformatics and annotated as potential virulence-related factors. These proteins were cloned, expressed, and purified as His-tagged proteins. Antigenicity of the candidate proteins was assessed using Western blotting with convalescent sera against H. parasuis serovar 5. The immunogenicity of the seven OMPs was assessed in a guinea pig model. Except VacJ, all the other six recombinant proteins elicited a detectable antibody response. Antisera against four of the selected proteins effectively killed the bacteria in vitro. Three proteins (Omp26, VacJ, and HAPS_0742) were found to confer significant protection against challenge with a lethal dose of H. parasuis in a guinea pig model. The results suggest that these three proteins have a strong potential to be vaccine candidates against Glässer's disease. Copyright © 2016 Elsevier Ltd. All rights reserved.

A Liquid Chromatography-Quadrupole-Time-of-Flight Mass Spectrometric Assay for the Quantification of Fabry Disease Biomarker Globotriaosylceramide (GB3) in Fabry Model Mouse.

PubMed

Shin, Seok-Ho; Park, Min-Ho; Byeon, Jin-Ju; Lee, Byeong Ill; Park, Yuri; Ko, Ah-Ra; Seong, Mi-Ran; Lee, Soyeon; Kim, Mi Ra; Seo, Jinwook; Jung, Myung Eun; Jin, Dong-Kyu; Shin, Young G

2018-06-07

Fabry disease is a rare lysosomal storage disorder resulting from the lack of α-Gal A gene activity. Globotriaosylceramide (GB3, ceramide trihexoside) is a novel endogenous biomarker which predicts the incidence of Fabry disease. At the early stage efficacy/biomarker study, a rapid method to determine this biomarker in plasma and in all relevant tissues related to this disease simultaneously is required. However, the limited sample volume, as well as the various levels of GB3 in different matrices makes the GB3 quantitation very challenging. Hereby we developed a rapid method to identify GB3 in mouse plasma and various tissues. Preliminary stability tests were also performed in three different conditions: short-term, freeze-thaw, long-term. The calibration curve was well fitted over the concentration range of 0.042⁻10 μg/mL for GB3 in plasma and 0.082⁻20 μg/g for GB3 in various tissues. This method was successfully applied for the comparison of GB3 levels in Fabry model mice (B6;129-Gla tm1Kul /J), which has not been performed previously to the best of our knowledge.

Inhibition of amyloid oligomerization into different supramolecular architectures by small molecules: mechanistic insights and design rules.

PubMed

Brahmachari, Sayanti; Paul, Ashim; Segal, Daniel; Gazit, Ehud

2017-05-01

Protein misfolding and aggregation have been associated with several human disorders, including Alzheimer's, Parkinson's and Huntington's diseases, as well as senile systemic amyloidosis and Type II diabetes. However, there is no current disease-modifying therapy available for the treatment of these disorders. In spite of extensive academic, pharmaceutical, medicinal and clinical research, a complete mechanistic model for this family of diseases is still lacking. In this review, we primarily discuss the different types of small molecular entities which have been used for the inhibition of the aggregation process of different amyloidogenic proteins under diseased conditions. These include small peptides, polyphenols, inositols, quinones and their derivatives, and metal chelator molecules. In recent years, these groups of molecules have been extensively studied using in vitro, in vivo and computational models to understand their mechanism of action and common structural features underlying the process of inhibition. A salient feature found to be instrumental in the process of inhibition is the balance between the aromatic unit that functions as the amyloid recognition unit and the hydrophilic amyloid breaker unit. The establishment of structure-function relationship for amyloid-modifying therapies by the various functional entities should serve as an important step toward the development of efficient therapeutics.

Alcoholic hepatitis: Translational approaches to develop targeted therapies.

PubMed

Mandrekar, Pranoti; Bataller, Ramon; Tsukamoto, Hidekazu; Gao, Bin

2016-10-01

Alcoholic liver disease is a leading cause of liver-related mortality worldwide. In contrast to recent advances in therapeutic strategies for patients with viral hepatitis, there is a significant lack of novel therapeutic options for patients with alcoholic liver disease. In particular, there is an urgent need to focus our efforts on effective therapeutic interventions for alcoholic hepatitis (AH), the most severe form of alcoholic liver disease. AH is characterized by an abrupt development of jaundice and complications related to liver insufficiency and portal hypertension in patients with heavy alcohol intake. The mortality of patients with AH is very high (20%-50% at 3 months). Available therapies are not effective in many patients, and targeted approaches are imminently needed. The development of such therapies requires translational studies in human samples and suitable animal models that reproduce the clinical and histological features of AH. In recent years, new animal models that simulate some of the features of human AH have been developed, and translational studies using human samples have identified potential pathogenic factors and histological parameters that predict survival. This review summarizes the unmet needs for translational studies on the pathogenesis of AH, preclinical translational tools, and emerging drug targets to benefit the AH patient. (Hepatology 2016;64:1343-1355). © 2016 by the American Association for the Study of Liver Diseases.

Alzheimer's disease with cerebrovascular disease: current status in the Asia-Pacific region.

PubMed

Chen, C; Homma, A; Mok, V C T; Krishnamoorthy, E; Alladi, S; Meguro, K; Abe, K; Dominguez, J; Marasigan, S; Kandiah, N; Kim, S Y; Lee, D Y; De Silva, H A; Yang, Y-H; Pai, M-C; Senanarong, V; Dash, A

2016-10-01

There is growing awareness of the coexistence of Alzheimer's disease and cerebrovascular disease (AD+CVD), however, due to lack of well-defined criteria and treatment guidelines AD+CVD may be underdiagnosed in Asia. Sixteen dementia specialists from nine Asia Pacific countries completed a survey in September 2014 and met in November 2014 to review the epidemiology, diagnosis and treatment of AD+CVD in Asia. A consensus was reached by discussion, with evidence provided by published studies when available. AD accounts for up to 60% and AD+CVD accounts for 10-20% of all dementia cases in Asia. The reasons for underdiagnosis of AD+CVD include lack of awareness as a result of a lack of diagnostic criteria, misdiagnosis as vascular dementia or AD, lack of diagnostic facilities, resource constraints and cost of investigations. There is variability in the tools used to diagnose AD+CVD in clinical practice. Diagnosis of AD+CVD should be performed in a stepwise manner of clinical evaluation followed by neuroimaging. Dementia patients should be assessed for cognition, behavioural and psychological symptoms, functional staging and instrumental activities of daily living. Neuroimaging should be performed using computed tomography or magnetic resonance imaging. The treatment goals are to stabilize or slow progression as well as to reduce behavioural and psychological symptoms, improve quality of life and reduce disease burden. First-line therapy is usually an acetylcholinesterase inhibitor such as donepezil. AD+CVD is likely to be under-recognised in Asia. Further research is needed to establish the true prevalence of this treatable and potentially preventable disease. © 2016 The Association for the Publication of the Journal of Internal Medicine.

Generating induced pluripotent stem cell derived endothelial cells and induced endothelial cells for cardiovascular disease modelling and therapeutic angiogenesis.

PubMed

Clayton, Z E; Sadeghipour, S; Patel, S

2015-10-15

Standard therapy for atherosclerotic coronary and peripheral arterial disease is insufficient in a significant number of patients because extensive disease often precludes effective revascularization. Stem cell therapy holds promise as a supplementary treatment for these patients, as pre-clinical and clinical research has shown transplanted cells can promote angiogenesis via direct and paracrine mechanisms. Induced pluripotent stem cells (iPSCs) are a novel cell type obtained by reprogramming somatic cells using exogenous transcription factor cocktails, which have been introduced to somatic cells via viral or plasmid constructs, modified mRNA or small molecules. IPSCs are now being used in disease modelling and drug testing and are undergoing their first clinical trial, but despite recent advances, the inefficiency of the reprogramming process remains a major limitation, as does the lack of consensus regarding the optimum transcription factor combination and delivery method and the uncertainty surrounding the genetic and epigenetic stability of iPSCs. IPSCs have been successfully differentiated into vascular endothelial cells (iPSC-ECs) and, more recently, induced endothelial cells (iECs) have also been generated by direct differentiation, which bypasses the pluripotent intermediate. IPSC-ECs and iECs demonstrate endothelial functionality in vitro and have been shown to promote neovessel growth and enhance blood flow recovery in animal models of myocardial infarction and peripheral arterial disease. Challenges remain in optimising the efficiency, safety and fidelity of the reprogramming and endothelial differentiation processes and establishing protocols for large-scale production of clinical-grade, patient-derived cells. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Fat-soluble vitamins as disease modulators in multiple sclerosis.

PubMed

Torkildsen, Ø; Løken-Amsrud, K I; Wergeland, S; Myhr, K-M; Holmøy, T

2013-01-01

Fat-soluble vitamins (A, D, E and K) have properties that could be relevant as modulators of disease activity in multiple sclerosis (MS). We performed a systematic search on PubMed and Medline up to May 2012, using the search strings 'vitamin A', 'retinol', 'retinal', 'carotenoids', 'vitamin D', 'vitamin E', 'alpha-tocopherol', 'vitamin K' in conjunction with 'multiple sclerosis', 'animal model' and 'experimental autoimmune encephalitis (EAE)'. In addition, the reference lists of the publications identified were examined for further citations of relevance. There is comprehensive evidence from epidemiological, observational, and experimental studies that vitamin D may be beneficial in MS. Results from small-scale clinical studies are inconclusive, and large-scale, adequately powered, randomized, controlled trials are still lacking. For vitamin D, Oxford Centre for Evidence-Based Medicine level 2c evidence exists for a positive therapeutic effect. Evidence from animal models indicates that all the examined fat-soluble vitamins could have potential as modulators of disease activity in MS. For vitamin A and E, level 4 and 5 evidence exists for a modulatory effect in MS; for vitamin K, too few studies have been conducted to indicate an effect in humans. Vitamin D is a promising candidate as modulator of disease activity in MS, and controlled studies are currently being conducted. All the fat-soluble vitamins have, however, been demonstrated to be effective in different animal models for the disease, and vitamin A and E have biological properties that could be relevant for MS pathogenesis. Thus, vitamin A and E seem to be promising candidates for future case-control and cohort studies. © 2012 John Wiley & Sons A/S.

Moderator's view: Predictive models: a prelude to precision nephrology.

PubMed

Zoccali, Carmine

2017-05-01

Appropriate diagnosis is fundamental in medicine because it sets the basis for the prediction of disease outcome at the single patient level (prognosis) and decisions regarding the most appropriate therapy. However, given the large series of social, clinical and biological factors that determine the likelihood of an individual's future outcome, prognosis only partly depends on diagnosis and aetiology and treatment is not decided solely on the basis of the underlying diagnosis. This issue is crucial in multifactorial diseases like atherosclerosis, where the use of statins has now shifted from 'treating hypercholesterolaemia' to 'treating the risk of adverse cardiovascular events'. Approaches that take due account of prognosis limit the lingering risk of over-diagnosis and maximize the value of prognostic information in the clinical decision process. In the nephrology realm, the application of a well-validated risk equation for kidney failure in Canada led to a 35% reduction in new referrals. Prognostic models based on simple clinical data extractable from clinical files have recently been developed to predict all-cause and cardiovascular mortality in end-stage kidney disease patients. However, research on predictive models in renal diseases remains suboptimal and non-accounting for competing events and measurement errors, and a lack of calibration analyses and external validation are common fallacies in currently available studies. More focus on this blossoming research area is desirable. The nephrology community may now start to apply the best validated risk scores and further test their potential usefulness in chronic kidney disease patients in diverse clinical situations and geographical areas. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

Deficient copper concentrations in dried-defatted hepatic tissue from ob/ob mice: A potential model for study of defective copper regulation in metabolic liver disease.

PubMed

Church, Stephanie J; Begley, Paul; Kureishy, Nina; McHarg, Selina; Bishop, Paul N; Bechtold, David A; Unwin, Richard D; Cooper, Garth J S

2015-05-08

Ob/ob mice provide an animal model for non-alcoholic fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH) in patients with obesity and type-2 diabetes. Low liver copper has been linked to hepatic lipid build-up (steatosis) in animals with systemic copper deficiency caused by low-copper diets. However, hepatic copper status in patients with NAFLD or NASH is uncertain, and a validated animal model useful for the study of hepatic copper regulation in common forms of metabolic liver disease is lacking. Here, we report parallel measurements of essential metal levels in whole-liver tissue and defatted-dried liver tissue from ob/ob and non-obese control mice. Measurements in whole-liver tissue from ob/ob mice at an age when they have developed NAFLD/NASH, provide compelling evidence for factitious lowering of copper and all other essential metals by steatosis, and so cannot be used to study hepatic metal regulation in this model. By marked contrast, metal measurements in defatted-dried liver samples reveal that most essential metals were actually normal and indicate specific lowering of copper in ob/ob mice, consistent with hepatic copper deficiency. Thus ob/ob mice can provide a model useful for the study of copper regulation in NAFLD and NASH, provided levels are measured in defatted-dried liver tissue. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

A Pilot Study on Integrating Videography and Environmental Microbial Sampling to Model Fecal Bacterial Exposures in Peri-Urban Tanzania.

PubMed

Julian, Timothy R; Pickering, Amy J

2015-01-01

Diarrheal diseases are a leading cause of under-five mortality and morbidity in sub-Saharan Africa. Quantitative exposure modeling provides opportunities to investigate the relative importance of fecal-oral transmission routes (e.g. hands, water, food) responsible for diarrheal disease. Modeling, however, requires accurate descriptions of individuals' interactions with the environment (i.e., activity data). Such activity data are largely lacking for people in low-income settings. In the present study, we collected activity data and microbiological sampling data to develop a quantitative microbial exposure model for two female caretakers in peri-urban Tanzania. Activity data were combined with microbiological data of contacted surfaces and fomites (e.g. broom handle, soil, clothing) to develop example exposure profiles describing second-by-second estimates of fecal indicator bacteria (E. coli and enterococci) concentrations on the caretaker's hands. The study demonstrates the application and utility of video activity data to quantify exposure factors for people in low-income countries and apply these factors to understand fecal contamination exposure pathways. This study provides both a methodological approach for the design and implementation of larger studies, and preliminary data suggesting contacts with dirt and sand may be important mechanisms of hand contamination. Increasing the scale of activity data collection and modeling to investigate individual-level exposure profiles within target populations for specific exposure scenarios would provide opportunities to identify the relative importance of fecal-oral disease transmission routes.

Genetically modified mouse models to investigate thyroid development, function and growth.

PubMed

Löf, C; Patyra, K; Kero, A; Kero, J

2018-06-01

The thyroid gland produces thyroid hormones (TH), which are essential regulators for growth, development and metabolism. The thyroid is mainly controlled by the thyroid-stimulating hormone (TSH) that binds to its receptor (TSHR) on thyrocytes and mediates its action via different G protein-mediated signaling pathways. TSH primarily activates the G s -pathway, and at higher concentrations also the G q/11 -pathway, leading to an increase of intracellular cAMP and Ca 2+ , respectively. To date, the physiological importance of other G protein-mediated signaling pathways in thyrocytes is unclear. Congenital hypothyroidism (CH) is defined as the lack of TH at birth. In familial cases, high-throughput sequencing methods have facilitated the identification of novel mutations. Nevertheless, the precise etiology of CH yet remains unraveled in a proportion of cases. Genetically modified mouse models can reveal new pathophysiological mechanisms of thyroid diseases. Here, we will present an overview of genetic mouse models for thyroid diseases, which have provided crucial insights into thyroid gland development, function, and growth with a special focus on TSHR and microRNA signaling. Copyright © 2018 Elsevier Ltd. All rights reserved.

Chimeric Mice with Competent Hematopoietic Immunity Reproduce Key Features of Severe Lassa Fever.

PubMed

Oestereich, Lisa; Lüdtke, Anja; Ruibal, Paula; Pallasch, Elisa; Kerber, Romy; Rieger, Toni; Wurr, Stephanie; Bockholt, Sabrina; Pérez-Girón, José V; Krasemann, Susanne; Günther, Stephan; Muñoz-Fontela, César

2016-05-01

Lassa fever (LASF) is a highly severe viral syndrome endemic to West African countries. Despite the annual high morbidity and mortality caused by LASF, very little is known about the pathophysiology of the disease. Basic research on LASF has been precluded due to the lack of relevant small animal models that reproduce the human disease. Immunocompetent laboratory mice are resistant to infection with Lassa virus (LASV) and, to date, only immunodeficient mice, or mice expressing human HLA, have shown some degree of susceptibility to experimental infection. Here, transplantation of wild-type bone marrow cells into irradiated type I interferon receptor knockout mice (IFNAR-/-) was used to generate chimeric mice that reproduced important features of severe LASF in humans. This included high lethality, liver damage, vascular leakage and systemic virus dissemination. In addition, this model indicated that T cell-mediated immunopathology was an important component of LASF pathogenesis that was directly correlated with vascular leakage. Our strategy allows easy generation of a suitable small animal model to test new vaccines and antivirals and to dissect the basic components of LASF pathophysiology.

Item Response Theory to Quantify Longitudinal Placebo and Paliperidone Effects on PANSS Scores in Schizophrenia.

PubMed

Krekels, Ehj; Novakovic, A M; Vermeulen, A M; Friberg, L E; Karlsson, M O

2017-08-01

As biomarkers are lacking, multi-item questionnaire-based tools like the Positive and Negative Syndrome Scale (PANSS) are used to quantify disease severity in schizophrenia. Analyzing composite PANSS scores as continuous data discards information and violates the numerical nature of the scale. Here a longitudinal analysis based on Item Response Theory is presented using PANSS data from phase III clinical trials. Latent disease severity variables were derived from item-level data on the positive, negative, and general PANSS subscales each. On all subscales, the time course of placebo responses were best described with Weibull models, and dose-independent functions with exponential models to describe the onset of the full effect were used to describe paliperidone's effect. Placebo and drug effect were most pronounced on the positive subscale. The final model successfully describes the time course of treatment effects on the individual PANSS item-levels, on all PANSS subscale levels, and on the total score level. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Blockade of PI3Kgamma suppresses joint inflammation and damage in mouse models of rheumatoid arthritis.

PubMed

Camps, Montserrat; Rückle, Thomas; Ji, Hong; Ardissone, Vittoria; Rintelen, Felix; Shaw, Jeffrey; Ferrandi, Chiara; Chabert, Christian; Gillieron, Corine; Françon, Bernard; Martin, Thierry; Gretener, Denise; Perrin, Dominique; Leroy, Didier; Vitte, Pierre-Alain; Hirsch, Emilio; Wymann, Matthias P; Cirillo, Rocco; Schwarz, Matthias K; Rommel, Christian

2005-09-01

Phosphoinositide 3-kinases (PI3K) have long been considered promising drug targets for the treatment of inflammatory and autoimmune disorders as well as cancer and cardiovascular diseases. But the lack of specificity, isoform selectivity and poor biopharmaceutical profile of PI3K inhibitors have so far hampered rigorous disease-relevant target validation. Here we describe the identification and development of specific, selective and orally active small-molecule inhibitors of PI3Kgamma (encoded by Pik3cg). We show that Pik3cg(-/-) mice are largely protected in mouse models of rheumatoid arthritis; this protection correlates with defective neutrophil migration, further validating PI3Kgamma as a therapeutic target. We also describe that oral treatment with a PI3Kgamma inhibitor suppresses the progression of joint inflammation and damage in two distinct mouse models of rheumatoid arthritis, reproducing the protective effects shown by Pik3cg(-/-) mice. Our results identify selective PI3Kgamma inhibitors as potential therapeutic molecules for the treatment of chronic inflammatory disorders such as rheumatoid arthritis.

Saccharomyces cerevisiae-derived virus-like particle parvovirus B19 vaccine elicits binding and neutralizing antibodies in a mouse model for sickle cell disease.

PubMed

Penkert, Rhiannon R; Young, Neal S; Surman, Sherri L; Sealy, Robert E; Rosch, Jason; Dormitzer, Philip R; Settembre, Ethan C; Chandramouli, Sumana; Wong, Susan; Hankins, Jane S; Hurwitz, Julia L

2017-06-22

Parvovirus B19 infections are typically mild in healthy individuals, but can be life threatening in individuals with sickle cell disease (SCD). A Saccharomyces cerevisiae-derived B19 VLP vaccine, now in pre-clinical development, is immunogenic in wild type mice when administered with the adjuvant MF59. Because SCD alters the immune response, we evaluated the efficacy of this vaccine in a mouse model for SCD. Vaccinated mice with SCD demonstrated similar binding and neutralizing antibody responses to those of heterozygous littermate controls following a prime-boost-boost regimen. Due to the lack of a mouse parvovirus B19 challenge model, we employed a natural mouse pathogen, Sendai virus, to evaluate SCD respiratory tract responses to infection. Normal mucosal and systemic antibody responses were observed in these mice. Results demonstrate that mice with SCD can respond to a VLP vaccine and to a respiratory virus challenge, encouraging rapid development of the B19 vaccine for patients with SCD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Periodontal bacterial invasion and infection: contribution to atherosclerotic pathology.

PubMed

Reyes, Leticia; Herrera, David; Kozarov, Emil; Roldán, Silvia; Progulske-Fox, Ann

2013-04-01

The objective of this review was to perform a systematic evaluation of the literature reporting current scientific evidence for periodontal bacteria as contributors to atherosclerosis. Literature from epidemiological, clinical and experimental studies concerning periodontal bacteria and atherosclerosis were reviewed. Gathered data were categorized into seven "proofs" of evidence that periodontal bacteria: 1) disseminate from the oral cavity and reach systemic vascular tissues; 2) can be found in the affected tissues; 3) live within the affected site; 4) invade affected cell types in vitro; 5) induce atherosclerosis in animal models of disease; 6) non-invasive mutants of periodontal bacteria cause significantly reduced pathology in vitro and in vivo; and 7) periodontal isolates from human atheromas can cause disease in animal models of infection. Substantial evidence for proofs 1 to 6 was found. However, proof 7 has not yet been fulfilled. Despite the lack of evidence that periodontal bacteria obtained from human atheromas can cause atherosclerosis in animal models of infection, attainment of proofs 1 to 6 provides support that periodontal pathogens can contribute to atherosclerosis. © 2013 European Federation of Periodontology and American Academy of Periodontology.

Quantifying the Contribution of the Liver to Glucose Homeostasis: A Detailed Kinetic Model of Human Hepatic Glucose Metabolism

PubMed Central

König, Matthias; Bulik, Sascha; Holzhütter, Hermann-Georg

2012-01-01

Despite the crucial role of the liver in glucose homeostasis, a detailed mathematical model of human hepatic glucose metabolism is lacking so far. Here we present a detailed kinetic model of glycolysis, gluconeogenesis and glycogen metabolism in human hepatocytes integrated with the hormonal control of these pathways by insulin, glucagon and epinephrine. Model simulations are in good agreement with experimental data on (i) the quantitative contributions of glycolysis, gluconeogenesis, and glycogen metabolism to hepatic glucose production and hepatic glucose utilization under varying physiological states. (ii) the time courses of postprandial glycogen storage as well as glycogen depletion in overnight fasting and short term fasting (iii) the switch from net hepatic glucose production under hypoglycemia to net hepatic glucose utilization under hyperglycemia essential for glucose homeostasis (iv) hormone perturbations of hepatic glucose metabolism. Response analysis reveals an extra high capacity of the liver to counteract changes of plasma glucose level below 5 mM (hypoglycemia) and above 7.5 mM (hyperglycemia). Our model may serve as an important module of a whole-body model of human glucose metabolism and as a valuable tool for understanding the role of the liver in glucose homeostasis under normal conditions and in diseases like diabetes or glycogen storage diseases. PMID:22761565

Stem Cell Technology for (Epi)genetic Brain Disorders.

PubMed

Riemens, Renzo J M; Soares, Edilene S; Esteller, Manel; Delgado-Morales, Raul

2017-01-01

Despite the enormous efforts of the scientific community over the years, effective therapeutics for many (epi)genetic brain disorders remain unidentified. The common and persistent failures to translate preclinical findings into clinical success are partially attributed to the limited efficiency of current disease models. Although animal and cellular models have substantially improved our knowledge of the pathological processes involved in these disorders, human brain research has generally been hampered by a lack of satisfactory humanized model systems. This, together with our incomplete knowledge of the multifactorial causes in the majority of these disorders, as well as a thorough understanding of associated (epi)genetic alterations, has been impeding progress in gaining more mechanistic insights from translational studies. Over the last years, however, stem cell technology has been offering an alternative approach to study and treat human brain disorders. Owing to this technology, we are now able to obtain a theoretically inexhaustible source of human neural cells and precursors in vitro that offer a platform for disease modeling and the establishment of therapeutic interventions. In addition to the potential to increase our general understanding of how (epi)genetic alterations contribute to the pathology of brain disorders, stem cells and derivatives allow for high-throughput drugs and toxicity testing, and provide a cell source for transplant therapies in regenerative medicine. In the current chapter, we will demonstrate the validity of human stem cell-based models and address the utility of other stem cell-based applications for several human brain disorders with multifactorial and (epi)genetic bases, including Parkinson's disease (PD), Alzheimer's disease (AD), fragile X syndrome (FXS), Angelman syndrome (AS), Prader-Willi syndrome (PWS), and Rett syndrome (RTT).

Staphylococcus aureus infection dynamics.

PubMed

Pollitt, Eric J G; Szkuta, Piotr T; Burns, Nicola; Foster, Simon J

2018-06-01

Staphylococcus aureus is a human commensal that can also cause systemic infections. This transition requires evasion of the immune response and the ability to exploit different niches within the host. However, the disease mechanisms and the dominant immune mediators against infection are poorly understood. Previously it has been shown that the infecting S. aureus population goes through a population bottleneck, from which very few bacteria escape to establish the abscesses that are characteristic of many infections. Here we examine the host factors underlying the population bottleneck and subsequent clonal expansion in S. aureus infection models, to identify underpinning principles of infection. The bottleneck is a common feature between models and is independent of S. aureus strain. Interestingly, the high doses of S. aureus required for the widely used "survival" model results in a reduced population bottleneck, suggesting that host defences have been simply overloaded. This brings into question the applicability of the survival model. Depletion of immune mediators revealed key breakpoints and the dynamics of systemic infection. Loss of macrophages, including the liver Kupffer cells, led to increased sensitivity to infection as expected but also loss of the population bottleneck and the spread to other organs still occurred. Conversely, neutrophil depletion led to greater susceptibility to disease but with a concomitant maintenance of the bottleneck and lack of systemic spread. We also used a novel microscopy approach to examine abscess architecture and distribution within organs. From these observations we developed a conceptual model for S. aureus disease from initial infection to mature abscess. This work highlights the need to understand the complexities of the infectious process to be able to assign functions for host and bacterial components, and why S. aureus disease requires a seemingly high infectious dose and how interventions such as a vaccine may be more rationally developed.

Low-dose rapamycin extends lifespan in a mouse model of mtDNA depletion syndrome.

PubMed

Siegmund, Stephanie E; Yang, Hua; Sharma, Rohit; Javors, Martin; Skinner, Owen; Mootha, Vamsi; Hirano, Michio; Schon, Eric A

2017-12-01

Mitochondrial disorders affecting oxidative phosphorylation (OxPhos) are caused by mutations in both the nuclear and mitochondrial genomes. One promising candidate for treatment is the drug rapamycin, which has been shown to extend lifespan in multiple animal models, and which was previously shown to ameliorate mitochondrial disease in a knock-out mouse model lacking a nuclear-encoded gene specifying an OxPhos structural subunit (Ndufs4). In that model, relatively high-dose intraperitoneal rapamycin extended lifespan and improved markers of neurological disease, via an unknown mechanism. Here, we administered low-dose oral rapamycin to a knock-in (KI) mouse model of authentic mtDNA disease, specifically, progressive mtDNA depletion syndrome, resulting from a mutation in the mitochondrial nucleotide salvage enzyme thymidine kinase 2 (TK2). Importantly, low-dose oral rapamycin was sufficient to extend Tk2KI/KI mouse lifespan significantly, and did so in the absence of detectable improvements in mitochondrial dysfunction. We found no evidence that rapamycin increased survival by acting through canonical pathways, including mitochondrial autophagy. However, transcriptomics and metabolomics analyses uncovered systemic metabolic changes pointing to a potential 'rapamycin metabolic signature.' These changes also implied that rapamycin may have enabled the Tk2KI/KI mice to utilize alternative energy reserves, and possibly triggered indirect signaling events that modified mortality through developmental reprogramming. From a therapeutic standpoint, our results support the possibility that low-dose rapamycin, while not targeting the underlying mtDNA defect, could represent a crucial therapy for the treatment of mtDNA-driven, and some nuclear DNA-driven, mitochondrial diseases. © The Author 2017. Published by Oxford University Press.

A systematic review of qualitative research on the contributory factors leading to medicine-related problems from the perspectives of adult patients with cardiovascular diseases and diabetes mellitus.

PubMed

Al Hamid, A; Ghaleb, M; Aljadhey, H; Aslanpour, Z

2014-09-19

To synthesise contributing factors leading to medicine-related problems (MRPs) in adult patients with cardiovascular diseases and/or diabetes mellitus from their perspectives. A systematic literature review of qualitative studies regarding the contributory factors leading to MRPs, medication errors and non-adherence, followed by a thematic synthesis of the studies. We screened Pubmed, EMBASE, ISI Web of Knowledge, PsycInfo, International Pharmaceutical Abstract and PsycExtra for qualitative studies (interviews, focus groups and questionnaires of a qualitative nature). Thematic synthesis was achieved by coding and developing themes from the findings of qualitative studies. The synthesis yielded 21 studies that satisfied the inclusion and exclusion criteria. Three themes emerged that involved contributing factors to MRPs: patient-related factors including socioeconomic factors (beliefs, feeling victimised, history of the condition, lack of finance, lack of motivation and low self-esteem) and lifestyle factors (diet, lack of exercise/time to see the doctor, obesity, smoking and stress), medicine-related factors (belief in natural remedies, fear of medicine, lack of belief in medicines, lack of knowledge, non-adherence and polypharmacy) and condition-related factors (lack of knowledge/understanding, fear of condition and its complications, and lack of control). MRPs represent a major health threat, especially among adult patients with cardiovascular diseases and/or diabetes mellitus. The patients' perspectives uncovered hidden factors that could cause and/or contribute to MRPs in these groups of patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Sexual dimorphism of liver metastasis by murine pancreatic neuroendocrine tumors is affected by expression of complement C5.

PubMed

Contractor, Tanupriya; Kobayashi, Shinta; da Silva, Edaise; Clausen, Richard; Chan, Chang; Vosburgh, Evan; Tang, Laura H; Levine, Arnold J; Harris, Chris R

2016-05-24

In a mouse model for neuroendocrine tumors of the pancreas (PanNETs), liver metastasis occurred at a higher frequency in males. Male mice also had higher serum and intratumoral levels of the innate immunity protein complement C5. In mice that lost the ability to express complement C5, there was a lower frequency of metastasis, and males no longer had a higher frequency of metastasis than females. Treatment with PMX53, a small molecule antagonist of C5aR1/CD88, the receptor for complement C5a, also reduced metastasis. Mice lacking a functional gene for complement C5 had smaller primary tumors, which were less invasive and lacked the CD68+ macrophages that have previously been associated with metastasis in this type of tumor. This is the first report of a gene that causes sexual dimorphism of metastasis in a mouse model. In the human disease, which also shows sexual dimorphism for metastasis, clinically advanced tumors expressed more complement C5 than less advanced tumors.

Kawasaki disease and immunisation: A systematic review.

PubMed

Phuong, Linny Kimly; Bonetto, Caterina; Buttery, Jim; Pernus, Yolanda Brauchli; Chandler, Rebecca; Felicetti, Patrizia; Goldenthal, Karen L; Kucuku, Merita; Monaco, Giuseppe; Pahud, Barbara; Shulman, Stanford T; Top, Karina A; Trotta, Francesco; Ulloa-Gutierrez, Rolando; Varricchio, Frederick; de Ferranti, Sarah; Newburger, Jane W; Dahdah, Nagib; Singh, Surjit; Bonhoeffer, Jan; Burgner, David

2017-03-27

Kawasaki disease is a complex and potentially serious condition. It has been observed in temporal relation to immunisation. We conducted a systematic literature review using various reference sources to review the available evidence published in the literature. We identified twenty seven publications reporting a temporal association between immunisation and Kawasaki disease. We present a systematic review of data drawn from randomised controlled trials, observational studies, case series and reports, and reviews. Overall there was a lack of standardised case definitions, making data interpretation and comparability challenging. Although a temporal relationship between immunisation and Kawasaki disease is suggested, evidence for an increased risk or a causal association is lacking. Implementation of a standardised Kawasaki disease case definition would increase confidence in the findings and add value to future studies of pre- or post-licensure vaccine safety studies. Copyright © 2016. Published by Elsevier Ltd.

Comparing deep learning models for population screening using chest radiography

NASA Astrophysics Data System (ADS)

Sivaramakrishnan, R.; Antani, Sameer; Candemir, Sema; Xue, Zhiyun; Abuya, Joseph; Kohli, Marc; Alderson, Philip; Thoma, George

2018-02-01

According to the World Health Organization (WHO), tuberculosis (TB) remains the most deadly infectious disease in the world. In a 2015 global annual TB report, 1.5 million TB related deaths were reported. The conditions worsened in 2016 with 1.7 million reported deaths and more than 10 million people infected with the disease. Analysis of frontal chest X-rays (CXR) is one of the most popular methods for initial TB screening, however, the method is impacted by the lack of experts for screening chest radiographs. Computer-aided diagnosis (CADx) tools have gained significance because they reduce the human burden in screening and diagnosis, particularly in countries that lack substantial radiology services. State-of-the-art CADx software typically is based on machine learning (ML) approaches that use hand-engineered features, demanding expertise in analyzing the input variances and accounting for the changes in size, background, angle, and position of the region of interest (ROI) on the underlying medical imagery. More automatic Deep Learning (DL) tools have demonstrated promising results in a wide range of ML applications. Convolutional Neural Networks (CNN), a class of DL models, have gained research prominence in image classification, detection, and localization tasks because they are highly scalable and deliver superior results with end-to-end feature extraction and classification. In this study, we evaluated the performance of CNN based DL models for population screening using frontal CXRs. The results demonstrate that pre-trained CNNs are a promising feature extracting tool for medical imagery including the automated diagnosis of TB from chest radiographs but emphasize the importance of large data sets for the most accurate classification.

Stakeholders' perception on the organization of chronic care: a SWOT analysis to draft avenues for health care reforms.

PubMed

Van Durme, Thérèse; Macq, Jean; Anthierens, Sibyl; Symons, Linda; Schmitz, Olivier; Paulus, Dominique; Van den Heede, Koen; Remmen, Roy

2014-04-18

Adequate care for individuals living with chronic illnesses calls for a healthcare system redesign, moving from acute, disease-centered to patient-centered models. The aim of this study was to identify Belgian stakeholders' perceptions on the strengths, weaknesses, opportunities and threats of the healthcare system for people with chronic diseases in Belgium. Four focus groups were held with stakeholders from the micro and meso level, in addition to two interviews with stakeholders who could not attend the focus group sessions. Data collection and the discussion were based on the Chronic Care model. Thematic analysis of the transcripts allowed for the identification of the strengths, weaknesses, opportunities and threats of the current health care system with focus on chronic care. Informants stressed the overall good quality of the acute health care system and the level of reimbursement of care as an important strength of the current system. In contrast, the lack of integration of care was identified as one of the biggest weaknesses of today's health care system, along with the unclear definitions of the roles and functions of health professionals involved in care processes. Patient education to support self-management exists for patients with diabetes and/or terminal kidney failure but not for those living with other or multiple chronic conditions. The current overall fee-for-service system is a barrier to integrated care, as are the lack of incentives for integrated care. Attending multidisciplinary meetings, for example, is underfinanced to date. Finally, clinical information systems lack interoperability, which further impedes the information flow across settings and disciplines. Our study's methods allowed for the identification of problematic domains in the health system for people living with chronic conditions. These findings provided useful insights surrounding perceived priorities. This methodology may inspire other countries faced with the challenge of drafting reforms to tackle the issue of chronic care.

Stakeholders’ perception on the organization of chronic care: a SWOT analysis to draft avenues for health care reforms

PubMed Central

2014-01-01

Background Adequate care for individuals living with chronic illnesses calls for a healthcare system redesign, moving from acute, disease-centered to patient-centered models. The aim of this study was to identify Belgian stakeholders’ perceptions on the strengths, weaknesses, opportunities and threats of the healthcare system for people with chronic diseases in Belgium. Methods Four focus groups were held with stakeholders from the micro and meso level, in addition to two interviews with stakeholders who could not attend the focus group sessions. Data collection and the discussion were based on the Chronic Care model. Thematic analysis of the transcripts allowed for the identification of the strengths, weaknesses, opportunities and threats of the current health care system with focus on chronic care. Results Informants stressed the overall good quality of the acute health care system and the level of reimbursement of care as an important strength of the current system. In contrast, the lack of integration of care was identified as one of the biggest weaknesses of today’s health care system, along with the unclear definitions of the roles and functions of health professionals involved in care processes. Patient education to support self-management exists for patients with diabetes and/or terminal kidney failure but not for those living with other or multiple chronic conditions. The current overall fee-for-service system is a barrier to integrated care, as are the lack of incentives for integrated care. Attending multidisciplinary meetings, for example, is underfinanced to date. Finally, clinical information systems lack interoperability, which further impedes the information flow across settings and disciplines. Conclusion Our study’s methods allowed for the identification of problematic domains in the health system for people living with chronic conditions. These findings provided useful insights surrounding perceived priorities. This methodology may inspire other countries faced with the challenge of drafting reforms to tackle the issue of chronic care. PMID:24742204

Role of pharmacist in cardiovascular disease-related health promotion and in hypertension and dyslipidemia management: a cross-sectional study in the State of Qatar.

PubMed

El Hajj, Maguy Saffouh; Mahfoud, Ziyad R; Al Suwaidi, Jassim; Alkhiyami, Dania; Alasmar, Aya Riyad

2016-06-01

In Qatar, cardiovascular diseases (CVD) have recently become the leading cause of morbidity and mortality. Prevention, detection and management of CVD risk factors reduce CVD chance. The study objectives were to assess Qatar pharmacists' involvement in CVD health promotion, to identify the activities that they currently provide to patients with CVD risk factors, to describe their attitudes towards their involvement in CVD prevention and to assess their perceived barriers for provision of CVD prevention services We conducted a cross-sectional survey of community and ambulatory pharmacists in Qatar. Pharmacist characteristics, involvement in CVD-related activities along with their attitudes and perceived barriers were analysed using frequency distributions. Bivariate linear regression models were used to test for associations between CVD health promotion activity score and each variable. Variables with a P-value of 0.20 or less were included in the multivariate model. A total of 141 pharmacists completed the survey (response rate 60%). More than 70% responded with rarely or never to 6 out of the 10 CVD health promotion activities. Eighty-four per cent and 68% always or often describe to patients the appropriate time to take antihypertensive medications and the common medication adverse effects, respectively. Yet, 50% rarely or never review the medication refill history or provide adherence interventions. Lack of CVD educational materials was the top perceived barrier (55%) in addition to lack of having private counselling area (44.6%), and lack of time (38.3%). Females and community pharmacists were more involved in CVD health promotion (P = 0.046 and P = 0.017, respectively) than their counterparts. Health promotion practice increased with increasing attitudes score and decreased with increased barriers score (P = 0.012 and P = 0.001). The scope of pharmacy practice in CVD prevention is limited in Qatar. Efforts need to be exerted to increase pharmacists' involvement in CVD prevention. © 2015 John Wiley & Sons, Ltd.

Efficiency of circulant diallels via mixed models in the selection of papaya genotypes resistant to foliar fungal diseases.

PubMed

Vivas, M; Silveira, S F; Viana, A P; Amaral, A T; Cardoso, D L; Pereira, M G

2014-07-02

Diallel crossing methods provide information regarding the performance of genitors between themselves and their hybrid combinations. However, with a large number of parents, the number of hybrid combinations that can be obtained and evaluated become limited. One option regarding the number of parents involved is the adoption of circulant diallels. However, information is lacking regarding diallel analysis using mixed models. This study aimed to evaluate the efficacy of the method of linear mixed models to estimate, for variable resistance to foliar fungal diseases, components of general and specific combining ability in a circulant table with different s values. Subsequently, 50 diallels were simulated for each s value, and the correlations and estimates of the combining abilities of the different diallel combinations were analyzed. The circulant diallel method using mixed modeling was effective in the classification of genitors regarding their combining abilities relative to the complete diallels. The numbers of crosses in which each genitor(s) will compose the circulant diallel and the estimated heritability affect the combining ability estimates. With three crosses per parent, it is possible to obtain good concordance (correlation above 0.8) between the combining ability estimates.

[Neglected infectious diseases: an ongoing challenge for public health and equity in Peru].

PubMed

Cabezas-Sánchez, César

2014-04-01

Neglected Infectious Diseases (NID) affect more than one billion people worldwide, and are associated with poverty, geographic isolation of populations, social stigma, lack of precise data on estimates on both the global and local burden of disease (underreporting of the diseases), inadequate financial and political resources to effective control measures, lack of lobbying on behalf of the most vulnerable population, as well as scarce drug and diagnostic methods development. In this article we describe the relationship between NID, poverty and inequality, we propose a new concept of disease in the tropics, expanding the list of diseases that share characteristics with NID in the Peruvian context, discuss the limited availability of drugs and diagnostic tests to properly deal with these diseases, as well as highlight the contributions by the Peruvian National Institute of Health, and as final thoughts, we state that the solution for the prevention and control of NID must include an integrated approach, including the social determinants of health in the context of the fight against poverty and inequality.

Experimental endometriosis: the nude mouse as a xenographic host.

PubMed

Bruner-Tran, Kaylon L; Webster-Clair, Deborah; Osteen, Kevin G

2002-03-01

Endometriosis is a complex disease that can develop as a consequence of retrograde menstruation, occurring in association with the cyclic loss of endometrial tissue in primates and humans. In addition, progression of disease parallels a woman's exposure to ovarian steroids, rarely occurring prior to menarche and generally resolving following menopause. Because of the cost of developing primate models to study endometriosis, numerous small animal models have been established to approach various elements related to the pathophysiology of this disease. Our laboratory has developed an experimental endometriosis model using nude mice as a xenographic host for human tissues. Our goal is to approach the basic cellular mechanisms of estrogen and progesterone action that link these hormones to the development or prevention of endometriosis. In our initial studies, we have sought to understand steroid-associated regulation of matrix metalloproteinases (MMPs) with regard to the development of experimental endometriosis. Using both short-term organ cultures and nude mice as xenographic hosts of human tissue, we have demonstrated a critical role of progesterone and progesterone-associated cytokines in preventing the initial establishment of experimental disease. Women with endometriosis appear to lack normal endometrial responsiveness to progesterone, resulting in altered expression of several MMPs and an enhanced ability of these tissues to establish ectopic lesions in nude mice. Developing a better understanding of the impairments in the normal endometrial physiology of women with endometriosis should aid in the development of better treatment or diagnostic strategies.

Detecting and Responding to a Dengue Outbreak: Evaluation of Existing Strategies in Country Outbreak Response Planning

PubMed Central

Kroeger, Axel; Runge-Ranzinger, Silvia; O'Dempsey, Tim

2013-01-01

Background. Dengue outbreaks are occurring with increasing frequency and intensity. Evidence-based epidemic preparedness and effective response are now a matter of urgency. Therefore, we have analysed national and municipal dengue outbreak response plans. Methods. Thirteen country plans from Asia, Latin America and Australia, and one international plan were obtained from the World Health Organization. The information was transferred to a data analysis matrix where information was extracted according to predefined and emerging themes and analysed for scope, inconsistencies, omissions, and usefulness. Findings. Outbreak response planning currently has a considerable number of flaws. Outbreak governance was weak with a lack of clarity of stakeholder roles. Late timing of responses due to poor surveillance, a lack of combining routine data with additional alerts, and lack of triggers for initiating the response weakened the functionality of plans. Frequently an outbreak was not defined, and early response mechanisms based on alert signals were neglected. There was a distinct lack of consideration of contextual influences which can affect how an outbreak detection and response is managed. Conclusion. A model contingency plan for dengue outbreak prediction, detection, and response may help national disease control authorities to develop their own more detailed and functional context specific plans. PMID:24222774

Challenges in the management of chronic noncommunicable diseases by Indonesian community pharmacists

PubMed Central

Puspitasari, Hanni P.; Aslani, Parisa; Krass, Ines

2015-01-01

Objectives: We explored factors influencing Indonesian primary care pharmacists’ practice in chronic noncommunicable disease management and proposed a model illustrating relationships among factors. Methods: We conducted in-depth, semistructured interviews with pharmacists working in community health centers (Puskesmas, n=5) and community pharmacies (apotek, n=15) in East Java Province. We interviewed participating pharmacists using Bahasa Indonesia to explore facilitators and barriers to their practice in chronic disease management. We audiorecorded all interviews, transcribed ad verbatim, translated into English and analyzed the data using an approach informed by “grounded-theory”. Results: We extracted five emergent themes/factors: pharmacists’ attitudes, Puskesmas/apotek environment, pharmacy education, pharmacy professional associations, and the government. Respondents believed that primary care pharmacists have limited roles in chronic disease management. An unfavourable working environment and perceptions of pharmacists’ inadequate knowledge and skills were reported by many as barriers to pharmacy practice. Limited professional standards, guidelines, leadership and government regulations coupled with low expectations of pharmacists among patients and doctors also contributed to their lack of involvement in chronic disease management. We present the interplay of these factors in our model. Conclusion: Pharmacists’ attitudes, knowledge, skills and their working environment appeared to influence pharmacists’ contribution in chronic disease management. To develop pharmacists’ involvement in chronic disease management, support from pharmacy educators, pharmacy owners, professional associations, the government and other stakeholders is required. Our findings highlight a need for systematic coordination between pharmacists and stakeholders to improve primary care pharmacists’ practice in Indonesia to achieve continuity of care. PMID:26445618

A Systematic Review of Methodology: Time Series Regression Analysis for Environmental Factors and Infectious Diseases

PubMed Central

Imai, Chisato; Hashizume, Masahiro

2015-01-01

Background: Time series analysis is suitable for investigations of relatively direct and short-term effects of exposures on outcomes. In environmental epidemiology studies, this method has been one of the standard approaches to assess impacts of environmental factors on acute non-infectious diseases (e.g. cardiovascular deaths), with conventionally generalized linear or additive models (GLM and GAM). However, the same analysis practices are often observed with infectious diseases despite of the substantial differences from non-infectious diseases that may result in analytical challenges. Methods: Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, systematic review was conducted to elucidate important issues in assessing the associations between environmental factors and infectious diseases using time series analysis with GLM and GAM. Published studies on the associations between weather factors and malaria, cholera, dengue, and influenza were targeted. Findings: Our review raised issues regarding the estimation of susceptible population and exposure lag times, the adequacy of seasonal adjustments, the presence of strong autocorrelations, and the lack of a smaller observation time unit of outcomes (i.e. daily data). These concerns may be attributable to features specific to infectious diseases, such as transmission among individuals and complicated causal mechanisms. Conclusion: The consequence of not taking adequate measures to address these issues is distortion of the appropriate risk quantifications of exposures factors. Future studies should pay careful attention to details and examine alternative models or methods that improve studies using time series regression analysis for environmental determinants of infectious diseases. PMID:25859149

Planning for climate change: The need for mechanistic systems-based approaches to study climate change impacts on diarrheal diseases.

PubMed

Mellor, Jonathan E; Levy, Karen; Zimmerman, Julie; Elliott, Mark; Bartram, Jamie; Carlton, Elizabeth; Clasen, Thomas; Dillingham, Rebecca; Eisenberg, Joseph; Guerrant, Richard; Lantagne, Daniele; Mihelcic, James; Nelson, Kara

2016-04-01

Increased precipitation and temperature variability as well as extreme events related to climate change are predicted to affect the availability and quality of water globally. Already heavily burdened with diarrheal diseases due to poor access to water, sanitation and hygiene facilities, communities throughout the developing world lack the adaptive capacity to sufficiently respond to the additional adversity caused by climate change. Studies suggest that diarrhea rates are positively correlated with increased temperature, and show a complex relationship with precipitation. Although climate change will likely increase rates of diarrheal diseases on average, there is a poor mechanistic understanding of the underlying disease transmission processes and substantial uncertainty surrounding current estimates. This makes it difficult to recommend appropriate adaptation strategies. We review the relevant climate-related mechanisms behind transmission of diarrheal disease pathogens and argue that systems-based mechanistic approaches incorporating human, engineered and environmental components are urgently needed. We then review successful systems-based approaches used in other environmental health fields and detail one modeling framework to predict climate change impacts on diarrheal diseases and design adaptation strategies. Copyright © 2016 Elsevier B.V. All rights reserved.

Identification of novel mRNAs and lncRNAs associated with mouse experimental colitis and human inflammatory bowel disease.

PubMed

Rankin, Carl Robert; Theodorou, Evangelos; Law, Ivy Ka Man; Rowe, Lorraine; Kokkotou, Efi; Pekow, Joel; Wang, Jiafang; Martin, Martin G; Pothoulakis, Charalabos; Padua, David Miguel

2018-06-28

Inflammatory bowel disease (IBD) is a complex disorder that is associated with significant morbidity. While many recent advances have been made with new diagnostic and therapeutic tools, a deeper understanding of its basic pathophysiology is needed to continue this trend towards improving treatments. By utilizing an unbiased, high-throughput transcriptomic analysis of two well-established mouse models of colitis, we set out to uncover novel coding and non-coding RNAs that are differentially expressed in the setting of colonic inflammation. RNA-seq analysis was performed using colonic tissue from two mouse models of colitis, a dextran sodium sulfate induced model and a genetic-induced model in mice lacking IL-10. We identified 81 coding RNAs that were commonly altered in both experimental models. Of these coding RNAs, 12 of the human orthologs were differentially expressed in a transcriptomic analysis of IBD patients. Interestingly, 5 of the 12 of human differentially expressed genes have not been previously identified as IBD-associated genes, including ubiquitin D. Our analysis also identified 15 non-coding RNAs that were differentially expressed in either mouse model. Surprisingly, only three non-coding RNAs were commonly dysregulated in both of these models. The discovery of these new coding and non-coding RNAs expands our transcriptional knowledge of mouse models of IBD and offers additional targets to deepen our understanding of the pathophysiology of IBD.

Reproducibility Issues: Avoiding Pitfalls in Animal Inflammation Models.

PubMed

Laman, Jon D; Kooistra, Susanne M; Clausen, Björn E

2017-01-01

In light of an enhanced awareness of ethical questions and ever increasing costs when working with animals in biomedical research, there is a dedicated and sometimes fierce debate concerning the (lack of) reproducibility of animal models and their relevance for human inflammatory diseases. Despite evident advancements in searching for alternatives, that is, replacing, reducing, and refining animal experiments-the three R's of Russel and Burch (1959)-understanding the complex interactions of the cells of the immune system, the nervous system and the affected tissue/organ during inflammation critically relies on in vivo models. Consequently, scientific advancement and ultimately novel therapeutic interventions depend on improving the reproducibility of animal inflammation models. As a prelude to the remaining hands-on protocols described in this volume, here, we summarize potential pitfalls of preclinical animal research and provide resources and background reading on how to avoid them.