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Sample records for system diseases preclinical

  1. 1H magnetic resonance spectroscopy in preclinical Huntington disease

    NARCIS (Netherlands)

    van Oostrom, Joost C. H.; Sijens, Paul E.; Roos, Raymund A. C.; Leenders, Klaus L.

    2007-01-01

    Huntington disease (HD) is a hereditary brain disease, causing progressive deterioration after a preclinical phase. The pathophysiology of early brain abnormalities around disease onset is largely unknown. Some preclinical mutation carriers (PMC) show structural or metabolic changes on brain imaging

  2. Preclinical Alzheimer disease and risk of falls.

    Science.gov (United States)

    Stark, Susan L; Roe, Catherine M; Grant, Elizabeth A; Hollingsworth, Holly; Benzinger, Tammie L; Fagan, Anne M; Buckles, Virginia D; Morris, John C

    2013-07-30

    We determined the rate of falls among cognitively normal, community-dwelling older adults, some of whom had presumptive preclinical Alzheimer disease (AD) as detected by in vivo imaging of fibrillar amyloid plaques using Pittsburgh compound B (PiB) and PET and/or by assays of CSF to identify Aβ₄₂, tau, and phosphorylated tau. We conducted a 12-month prospective cohort study to examine the cumulative incidence of falls. Participants were evaluated clinically and underwent PiB PET imaging and lumbar puncture. Falls were reported monthly using an individualized calendar journal returned by mail. A Cox proportional hazards model was used to test whether time to first fall was associated with each biomarker and the ratio of CSF tau/Aβ₄₂ and CSF phosphorylated tau/Aβ₄₂, after adjustment for common fall risk factors. The sample (n = 125) was predominately female (62.4%) and white (96%) with a mean age of 74.4 years. When controlled for ability to perform activities of daily living, higher levels of PiB retention (hazard ratio = 2.95 [95% confidence interval 1.01-6.45], p = 0.05) and of CSF biomarker ratios (p fall. Presumptive preclinical AD is a risk factor for falls in older adults. This study suggests that subtle noncognitive changes that predispose older adults to falls are associated with AD and may precede detectable cognitive changes.

  3. Detection of preclinical Parkinson's disease with PET

    International Nuclear Information System (INIS)

    Brooks, D.J.

    1991-01-01

    Putamen 18F-dopa uptake of patients with Parkinson's disease (PD) is reduced by at least 35% at onset of symptoms; therefore, positron-emission tomography (PET) can be used to detect preclinical disease in clinically unaffected twins and relatives of patients with PD. Three out of 6 monozygotic and 2 out of 3 dizygotic unaffected PD co-twins have shown reduced putamen 18F-dopa uptake to date. In addition, an intact sibling and a daughter of 1 of 4 siblings with PD both had low putamen 18F-dopa uptake. These preliminary findings suggest there may be a familial component to the etiology of PD. PET can also be used to detect underlying nigral pathology in patients with isolated tremor and patients who become rigid taking dopamine-receptor blocking agents (DRBAs). Patients with familial essential tremor have normal, and those with isolated rest tremor have consistently low, putamen 18F-dopa uptake. Drug-induced parkinsonism is infrequently associated with underlying nigral pathology

  4. [Preclinical experience in stem cell therapy for digestive tract diseases].

    Science.gov (United States)

    Jeon, Myung Shin; Hong, Soon Sun

    2011-09-25

    Adult stem cells are multipotent and self-renewing cells that contain several functions; i) migration and homing potential: stem cells can migrate to injured and inflamed tissues. ii) differentiation potential: stem cells which migrated to injured tissues can be differentiated into multiple cell types for repairing and regenerating the tissues. iii) immunomodulatory properties: stem cells, especially mesenchymal stem cells can suppress immune system such as inflammation. All those characteristics might be useful for the treatment of the digestive tract diseases which are complex and encompass a broad spectrum of different pathogenesis. Preclinical stem cell therapy showed some promising results, especially in liver failure, pancreatitis, sepsis, and inflammatory bowel disease. If we can understand more about the mechanism of stem cell action, stem cell therapy can become a promising alternative treatment for refractory digestive disease in the near future. In this review, we summarized current preclinical experiences in diseases of the digestive tract using stem cells. (Korean J Gastroenterol 2011;58:133-138).

  5. Diagnosis of preclinical Alzheimer's disease in a clinical setting.

    Science.gov (United States)

    Visser, P J; Verhey, F R; Ponds, R W; Jolles, J

    2001-12-01

    The aim of the study was to investigate whether the preclinical stage of Alzheimer's disease (AD) can be diagnosed in a clinical setting. To this end we investigated whether subjects with preclinical AD could be differentiated from subjects with nonprogressive mild cognitive impairment and from subjects with very mild AD-type dementia. Twenty-three subjects with preclinical AD, 44 subjects with nonprogressive mild cognitive impairment, and 25 subjects with very mild AD-type dementia were selected from a memory clinic population. Variables that were used to differentiate the groups were demographic variables, the Mini-Mental State Examination score, performance on cognitive tests, measures of functional impairment, and measures of noncognitive symptomatology. Age and the scores for the delayed recall task could best discriminate between subjects with preclinical AD and subjects with nonprogressive mild cognitive impairment. The overall accuracy was 87%. The score on the Global Deterioration Scale and a measure of intelligence could best discriminate between subjects with preclinical AD and subjects with very mild AD-type dementia. The overall accuracy was 85%. Subjects with preclinical AD can be distinguished from subjects with nonprogressive mild cognitive impairment and from subjects with very mild AD-type dementia. This means that preclinical AD is a diagnostic entity for which clinical criteria should be developed.

  6. Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

    Science.gov (United States)

    Dubois, Bruno; Hampel, Harald; Feldman, Howard H; Scheltens, Philip; Aisen, Paul; Andrieu, Sandrine; Bakardjian, Hovagim; Benali, Habib; Bertram, Lars; Blennow, Kaj; Broich, Karl; Cavedo, Enrica; Crutch, Sebastian; Dartigues, Jean-François; Duyckaerts, Charles; Epelbaum, Stéphane; Frisoni, Giovanni B; Gauthier, Serge; Genthon, Remy; Gouw, Alida A; Habert, Marie-Odile; Holtzman, David M; Kivipelto, Miia; Lista, Simone; Molinuevo, José-Luis; O'Bryant, Sid E; Rabinovici, Gil D; Rowe, Christopher; Salloway, Stephen; Schneider, Lon S; Sperling, Reisa; Teichmann, Marc; Carrillo, Maria C; Cummings, Jeffrey; Jack, Cliff R

    2016-03-01

    During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations. Copyright © 2016 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.

  7. Neuropsychiatric symptoms predict hypometabolism in preclinical Alzheimer disease.

    Science.gov (United States)

    Ng, Kok Pin; Pascoal, Tharick A; Mathotaarachchi, Sulantha; Chung, Chang-Oh; Benedet, Andréa L; Shin, Monica; Kang, Min Su; Li, Xiaofeng; Ba, Maowen; Kandiah, Nagaendran; Rosa-Neto, Pedro; Gauthier, Serge

    2017-05-09

    To identify regional brain metabolic dysfunctions associated with neuropsychiatric symptoms (NPS) in preclinical Alzheimer disease (AD). We stratified 115 cognitively normal individuals into preclinical AD (both amyloid and tau pathologies present), asymptomatic at risk for AD (either amyloid or tau pathology present), or healthy controls (no amyloid or tau pathology present) using [ 18 F]florbetapir PET and CSF phosphorylated tau biomarkers. Regression and voxel-based regression models evaluated the relationships between baseline NPS measured by the Neuropsychiatric Inventory (NPI) and baseline and 2-year change in metabolism measured by [ 18 F]fluorodeoxyglucose (FDG) PET. Individuals with preclinical AD with higher NPI scores had higher [ 18 F]FDG uptake in the posterior cingulate cortex (PCC), ventromedial prefrontal cortex, and right anterior insula at baseline. High NPI scores predicted subsequent hypometabolism in the PCC over 2 years only in individuals with preclinical AD. Sleep/nighttime behavior disorders and irritability and lability were the components of the NPI that drove this metabolic dysfunction. The magnitude of NPS in preclinical cases, driven by sleep behavior and irritability domains, is linked to transitory metabolic dysfunctions within limbic networks vulnerable to the AD process and predicts subsequent PCC hypometabolism. These findings support an emerging conceptual framework in which NPS constitute an early clinical manifestation of AD pathophysiology. Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

  8. The basics of preclinical drug development for neurodegenerative disease indications

    Directory of Open Access Journals (Sweden)

    Spack Edward G

    2009-06-01

    Full Text Available Abstract Preclinical development encompasses the activities that link drug discovery in the laboratory to initiation of human clinical trials. Preclinical studies can be designed to identify a lead candidate from several hits; develop the best procedure for new drug scale-up; select the best formulation; determine the route, frequency, and duration of exposure; and ultimately support the intended clinical trial design. The details of each preclinical development package can vary, but all have some common features. Rodent and nonrodent mammalian models are used to delineate the pharmacokinetic profile and general safety, as well as to identify toxicity patterns. One or more species may be used to determine the drug's mean residence time in the body, which depends on inherent absorption, distribution, metabolism, and excretion properties. For drugs intended to treat Alzheimer's disease or other brain-targeted diseases, the ability of a drug to cross the blood brain barrier may be a key issue. Toxicology and safety studies identify potential target organs for adverse effects and define the Therapeutic Index to set the initial starting doses in clinical trials. Pivotal preclinical safety studies generally require regulatory oversight as defined by US Food and Drug Administration (FDA Good Laboratory Practices and international guidelines, including the International Conference on Harmonisation. Concurrent preclinical development activities include developing the Clinical Plan and preparing the new drug product, including the associated documentation to meet stringent FDA Good Manufacturing Practices regulatory guidelines. A wide range of commercial and government contract options are available for investigators seeking to advance their candidate(s. Government programs such as the Small Business Innovative Research and Small Business Technology Transfer grants and the National Institutes of Health Rapid Access to Interventional Development Pilot

  9. USHERING IN THE STUDY AND TREATMENT OF PRECLINICAL ALZHEIMER DISEASE

    Science.gov (United States)

    Langbaum, Jessica B.S.; Fleisher, Adam S.; Chen, Kewei; Ayutyanont, Napatkamon; Lopera, Francisco; Quiroz, Yakeel T.; Caselli, Richard J.; Tariot, Pierre N.; Reiman, Eric M.

    2014-01-01

    Researchers have begun to characterize the subtle biological and cognitive processes that precede the clinical onset of Alzheimer disease (AD), and to set the stage for accelerated evaluation of experimental treatments to delay the onset, reduce the risk of or completely prevent clinical decline. Here, we provide an overview of the experimental strategies, and brain imaging and cerebrospinal fluid biomarker measures that are used in early detection and tracking of AD, highlighting at-risk individuals who could be suitable for preclinical monitoring. We discuss how these advances have contributed to reconceptualization of AD as a sequence of biological changes that occur during progression from preclinical AD, to mild cognitive impairment and finally dementia, and we review recently proposed research criteria for preclinical AD. Advances in the study of preclinical AD have driven the recognition that efficacy of at least some AD therapies may depend on initiation of treatment before clinical manifestation of disease, leading to a new era of AD prevention research. PMID:23752908

  10. Imaging and cerebrospinal fluid biomarkers in early preclinical Alzheimer disease

    Science.gov (United States)

    Vlassenko, Andrei G.; McCue, Lena; Jasielec, Mateusz S; Su, Yi; Gordon, Brian A.; Xiong, Chengjie; Holtzman, David M; Benzinger, Tammie LS; Morris, John C; Fagan, Anne M

    2016-01-01

    Objective Deposition of Aβ-containing plaques as evidenced by amyloid imaging and CSF Aβ42 is an early indicator of preclinical Alzheimer disease (AD). To better understand their relationship during the earliest preclinical stages, we investigated baseline CSF markers in cognitively normal individuals at different stages of amyloid deposition defined by longitudinal amyloid imaging with Pittsburgh Compound B (PIB): 1) PIB-negative at baseline and follow-up (PIB−, normal); 2) PIB− at baseline but PIB-positive at follow-up (PIB converters, early preclinical AD); and 3) PIB-positive at baseline and follow-up (PIB+, preclinical AD). Methods Cognitively normal individuals (n=164) who had undergone baseline PIB scan and CSF collection within one year of each other and at least one additional PIB follow-up were included. Amyloid status was defined dichotomously using an a priori mean cortical cut-off. Results PIB converters (n=20) at baseline exhibited significantly lower CSF Aβ42 compared to those who remained PIB− (n=123), but higher compared to PIB+ group (n=21). A robust negative correlation (r=−0.879, p=0.0001) between CSF Aβ42 and absolute (but sub-threshold) PIB binding was observed during this early preclinical stage. The negative correlation was not as strong once individuals were PIB+ (r=−0.456, p=0.038), and there was no correlation in the stable PIB− group (p=0.905) or in the group (n=10) with early symptomatic AD (p=0.537). Interpretation CSF Ab42 levels are tightly coupled with cortical amyloid load in the earliest stages of preclinical AD, and began to decrease dramatically prior to the point when an abnormal threshold of cortical accumulation is detected with amyloid imaging. PMID:27398953

  11. Preclinical diagnosis of Alzheimer's disease: Prevention or prediction?

    Directory of Open Access Journals (Sweden)

    Ricardo Nitrini

    Full Text Available Abstract The diagnosis of Alzheimer's disease (AD for cases with dementia may be too late to allow effective treatment. Criteria for diagnosis of preclinical AD suggested by the Alzheimer's Association include the use of molecular and structural biomarkers. Preclinical diagnosis will enable testing of new drugs and forms of treatment toward achieving successful preventive treatment. But what are the advantages for the individual? To know that someone who is cognitively normal is probably going to develop AD's dementia when there is no effective preventive treatment is definitely not good news. A research method whereby volunteers are assigned to receive treatment or placebo without knowing whether they are in the control or at-risk arm of a trial would overcome this potential problem. If these new criteria are used wisely they may represent a relevant milestone in the search for a definitive treatment for AD.

  12. Mouse models of neurodegenerative disease: preclinical imaging and neurovascular component.

    Science.gov (United States)

    Albanese, Sandra; Greco, Adelaide; Auletta, Luigi; Mancini, Marcello

    2017-10-26

    Neurodegenerative diseases represent great challenges for basic science and clinical medicine because of their prevalence, pathologies, lack of mechanism-based treatments, and impacts on individuals. Translational research might contribute to the study of neurodegenerative diseases. The mouse has become a key model for studying disease mechanisms that might recapitulate in part some aspects of the corresponding human diseases. Neurodegenerative disorders are very complicated and multifactorial. This has to be taken in account when testing drugs. Most of the drugs screening in mice are very difficult to be interpretated and often useless. Mouse models could be condiderated a 'pathway models', rather than as models for the whole complicated construct that makes a human disease. Non-invasive in vivo imaging in mice has gained increasing interest in preclinical research in the last years thanks to the availability of high-resolution single-photon emission computed tomography (SPECT), positron emission tomography (PET), high field Magnetic resonance, Optical Imaging scanners and of highly specific contrast agents. Behavioral test are useful tool to characterize different animal models of neurodegenerative pathology. Furthermore, many authors have observed vascular pathological features associated to the different neurodegenerative disorders. Aim of this review is to focus on the different existing animal models of neurodegenerative disorders, describe behavioral tests and preclinical imaging techniques used for diagnose and describe the vascular pathological features associated to these diseases.

  13. Pediatric Blood Pressure and Adult Preclinical Markers of Cardiovascular Disease

    Science.gov (United States)

    Magnussen, Costan G.; Smith, Kylie J.

    2016-01-01

    A high blood pressure level in adults is considered the single most important modifiable risk factor for global disease burden, especially those of cardiovascular (CV) origin such as stroke and ischemic heart disease. Because blood pressure levels have been shown to persist from childhood to adulthood, elevations in pediatric levels have been hypothesized to lead to increased CV burden in adulthood and, as such, might provide a window in the life course where primordial and primary prevention could be focused. In the absence of substantive data directly linking childhood blood pressure levels to overt adult CV disease, this review outlines the available literature that examines the association between pediatric blood pressure and adult preclinical markers of CV disease. PMID:27168729

  14. A generalizable pre-clinical research approach for orphan disease therapy

    Directory of Open Access Journals (Sweden)

    Beaulieu Chandree L

    2012-06-01

    Full Text Available Abstract With the advent of next-generation DNA sequencing, the pace of inherited orphan disease gene identification has increased dramatically, a situation that will continue for at least the next several years. At present, the numbers of such identified disease genes significantly outstrips the number of laboratories available to investigate a given disorder, an asymmetry that will only increase over time. The hope for any genetic disorder is, where possible and in addition to accurate diagnostic test formulation, the development of therapeutic approaches. To this end, we propose here the development of a strategic toolbox and preclinical research pathway for inherited orphan disease. Taking much of what has been learned from rare genetic disease research over the past two decades, we propose generalizable methods utilizing transcriptomic, system-wide chemical biology datasets combined with chemical informatics and, where possible, repurposing of FDA approved drugs for pre-clinical orphan disease therapies. It is hoped that this approach may be of utility for the broader orphan disease research community and provide funding organizations and patient advocacy groups with suggestions for the optimal path forward. In addition to enabling academic pre-clinical research, strategies such as this may also aid in seeding startup companies, as well as further engaging the pharmaceutical industry in the treatment of rare genetic disease.

  15. Characteristics and Progression of Preclinical Inflammatory Bowel Disease.

    Science.gov (United States)

    Rodríguez-Lago, Iago; Merino, Olga; Azagra, Irene; Maiz, Ainara; Zapata, Eva; Higuera, Rebeca; Montalvo, Isabel; Fernández-Calderón, María; Arreba, Paz; Carrascosa, Juan; Iriarte, Ainara; Portillo, Isabel; Aguirre, Urko; Barreiro-de Acosta, Manuel; Muñoz-Navas, Miguel; Cabriada, José Luis

    2017-11-11

    Inflammatory bowel disease (IBD) is a chronic disease usually diagnosed after the appearance of gastrointestinal symptoms. Little is known about IBD progression during its early and even preclinical phases. We aimed to determine the number of new incidental diagnoses of IBD in an older population, and evaluate disease progression from its early stages. We performed a retrospective analysis of 31,005 colonoscopies performed during colorectal cancer screening of patients with positive results from fecal immunochemical tests, at 11 centers in the Basque Country (Spain) from 2009 through 2014. We collected clinical and laboratory data from all asymptomatic individuals suspected to have IBD during screening colonoscopies, with histologic confirmation. Colonoscopy screening led to 79 new diagnoses of ulcerative colitis, 24 of Crohn's disease, and 7 of unclassified colitis (average patient age, 57 y; interquartile range, 52-62 y; 57% male). Eleven patients had symptoms before colonoscopy and were excluded from the analysis. Among those patients who were asymptomatic at diagnosis, 36% developed symptoms after a follow-up period of 25 months (interquartile range, 10.5-42 mo), mostly rectal bleeding and diarrhea. Treatment was prescribed for 81 patients (88%), and 2 cases required surgery. We analyzed data from a large cohort of patients with IBD diagnosed at early or even preclinical stages, from an older population. New incidental diagnoses of IBD were made in 0.35% of individuals undergoing a population-based screening colonoscopy-most were classified as ulcerative colitis. Approximately one third of patients developed symptoms during the follow-up period. Copyright © 2018 AGA Institute. Published by Elsevier Inc. All rights reserved.

  16. Subjective memory complaints in preclinical autosomal dominant Alzheimer disease.

    Science.gov (United States)

    Norton, Daniel J; Amariglio, Rebecca; Protas, Hillary; Chen, Kewei; Aguirre-Acevedo, Daniel C; Pulsifer, Brendan; Castrillon, Gabriel; Tirado, Victoria; Munoz, Claudia; Tariot, Pierre; Langbaum, Jessica B; Reiman, Eric M; Lopera, Francisco; Sperling, Reisa A; Quiroz, Yakeel T

    2017-10-03

    To cross-sectionally study subjective memory complaints (SMC) in autosomal dominant Alzheimer disease (ADAD). We examined self-reported and study partner-based SMC in 52 young, cognitively unimpaired individuals from a Colombian kindred with early-onset ADAD. Twenty-six carried the PSEN-1 E280A mutation, averaging 7 years of age younger than the kindred's expected clinical onset. Twenty-six were age-matched noncarriers. Participants also underwent structural MRI and cognitive testing. Self-reported SMC were greater in carriers than noncarriers ( p = 0.02). Study partner-based SMC did not differ between groups ( p = 0.21), but in carriers increased with age ( r = 0.66, p < 0.001) and decreased with hippocampal volume ( r = -0.35, p = 0.08). Cognitively unimpaired PSEN-1 carriers have elevated SMC. Self-reported SMC may be a relatively early indicator of preclinical AD, while partner- reported SMC increases later in preclinical AD, closer to clinical onset. © 2017 American Academy of Neurology.

  17. Preclinical Development of New Therapy for Glycogen Storage Diseases

    Science.gov (United States)

    Sun, Baodong; Brooks, Elizabeth D.; Koeberl, Dwight D.

    2015-01-01

    Glycogen storage disease (GSD) consists of more than 10 discrete conditions for which the biochemical and genetic bases have been determined, and new therapies have been under development for several of these conditions. Gene therapy research has generated proof-of-concept for GSD types I (von Gierke disease) and II (Pompe disease). Key features of these gene therapy strategies include the choice of vector and regulatory cassette, and recently adeno-associated virus (AAV) vectors containing tissue-specific promoters have achieved a high degree of efficacy. Efficacy of gene therapy for Pompe disease depend upon the induction of immune tolerance to the therapeutic enzyme. Efficacy of von Gierke disease is transient, waning gradually over the months following vector administration. Small molecule therapies have been evaluated with the goal of improving standard of care therapy or ameliorating the cellular abnormalities associated with specific GSDs. The receptor-mediated uptake of the therapeutic enzyme in Pompe disease was enhanced by administration of β2 agonists. Rapamycin reduced the liver fibrosis observed in GSD III. Further development of gene therapy could provide curative therapy for patients with GSD, if efficacy from preclinical research is observed in future clinical trials and these treatments become clinically available. PMID:26122079

  18. Preclinical Development of New Therapy for Glycogen Storage Diseases.

    Science.gov (United States)

    Sun, Baodong; Brooks, Elizabeth D; Koeberl, Dwight D

    2015-01-01

    Glycogen storage disease (GSD) consists of more than 10 discrete conditions for which the biochemical and genetic bases have been determined, and new therapies have been under development for several of these conditions. Gene therapy research has generated proof-of-concept for GSD types I (von Gierke disease) and II (Pompe disease). Key features of these gene therapy strategies include the choice of vector and regulatory cassette, and recently adeno-associated virus (AAV) vectors containing tissue-specific promoters have achieved a high degree of efficacy. Efficacy of gene therapy for Pompe disease depend upon the induction of immune tolerance to the therapeutic enzyme. Efficacy of von Gierke disease is transient, waning gradually over the months following vector administration. Small molecule therapies have been evaluated with the goal of improving standard of care therapy or ameliorating the cellular abnormalities associated with specific GSDs. The receptor-mediated uptake of the therapeutic enzyme in Pompe disease was enhanced by administration of β2 agonists. Rapamycin reduced the liver fibrosis observed in GSD III. Further development of gene therapy could provide curative therapy for patients with GSD, if efficacy from preclinical research is observed in future clinical trials and these treatments become clinically available.

  19. Asymptomatic Preclinical Rheumatoid Arthritis-Associated Interstitial Lung Disease

    Directory of Open Access Journals (Sweden)

    Juan Chen

    2013-01-01

    Full Text Available Objective. Interstitial lung disease (ILD is a common extra-articular manifestation of rheumatoid arthritis (RA and a significant cause of morbidity and mortality. The objective of this study was to define high-resolution chest CT (HRCT and pulmonary function test (PFT abnormalities capable of identifying asymptomatic, preclinical forms of RA-ILD that may represent precursors to more severe fibrotic lung disease. Methods. We analyzed chest HRCTs in consecutively enrolled RA patients and subsequently classified these individuals as RA-ILD or RA-no ILD based on the presence/absence of ground glass opacification, septal thickening, reticulation, traction bronchiectasis, and/or honeycombing. Coexisting PFT abnormalities (reductions in percent predicted FEV1, FVC, TLC, and/or DLCO were also used to further characterize occult respiratory defects. Results. 61% (63/103 of RA patients were classified as RA-ILD based on HRCT and PFT abnormalities, while 39% (40/103 were designated as RA-no ILD. 57/63 RA-ILD patients lacked symptoms of significant dyspnea or cough at the time of HRCT and PFT assessment. Compared with RA-no ILD, RA-ILD patients were older and had longer disease duration, higher articular disease activity, and more significant PFT abnormalities. Conclusion. HRCT represents an effective tool to detect occult/asymptomatic ILD that is highly prevalent in our unselected, university-based cohort of RA patients.

  20. Functional network integrity presages cognitive decline in preclinical Alzheimer disease.

    Science.gov (United States)

    Buckley, Rachel F; Schultz, Aaron P; Hedden, Trey; Papp, Kathryn V; Hanseeuw, Bernard J; Marshall, Gad; Sepulcre, Jorge; Smith, Emily E; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A; Chhatwal, Jasmeer P

    2017-07-04

    To examine the utility of resting-state functional connectivity MRI (rs-fcMRI) measurements of network integrity as a predictor of future cognitive decline in preclinical Alzheimer disease (AD). A total of 237 clinically normal older adults (aged 63-90 years, Clinical Dementia Rating 0) underwent baseline β-amyloid (Aβ) imaging with Pittsburgh compound B PET and structural and rs-fcMRI. We identified 7 networks for analysis, including 4 cognitive networks (default, salience, dorsal attention, and frontoparietal control) and 3 noncognitive networks (primary visual, extrastriate visual, motor). Using linear and curvilinear mixed models, we used baseline connectivity in these networks to predict longitudinal changes in preclinical Alzheimer cognitive composite (PACC) performance, both alone and interacting with Aβ burden. Median neuropsychological follow-up was 3 years. Baseline connectivity in the default, salience, and control networks predicted longitudinal PACC decline, unlike connectivity in the dorsal attention and all noncognitive networks. Default, salience, and control network connectivity was also synergistic with Aβ burden in predicting decline, with combined higher Aβ and lower connectivity predicting the steepest curvilinear decline in PACC performance. In clinically normal older adults, lower functional connectivity predicted more rapid decline in PACC scores over time, particularly when coupled with increased Aβ burden. Among examined networks, default, salience, and control networks were the strongest predictors of rate of change in PACC scores, with the inflection point of greatest decline beyond the fourth year of follow-up. These results suggest that rs-fcMRI may be a useful predictor of early, AD-related cognitive decline in clinical research settings. © 2017 American Academy of Neurology.

  1. Personality Change in the Preclinical Phase of Alzheimer Disease.

    Science.gov (United States)

    Terracciano, Antonio; An, Yang; Sutin, Angelina R; Thambisetty, Madhav; Resnick, Susan M

    2017-12-01

    Changes in behavior and personality are 1 criterion for the diagnosis of dementia. It is unclear, however, whether such changes begin before the clinical onset of the disease. To determine whether increases in neuroticism, declines in conscientiousness, and changes in other personality traits occur before the onset of mild cognitive impairment or dementia. A cohort of 2046 community-dwelling older adults who volunteered to participate in the Baltimore Longitudinal Study of Aging were included. The study examined personality and clinical assessments obtained between 1980 and July 13, 2016, from participants with no cognitive impairment at first assessment who were followed up for as long as 36 years (mean [SD], 12.05 [9.54] years). The self-report personality scales were not considered during consensus diagnostic conferences. Change in self-rated personality traits assessed in the preclinical phase of Alzheimer disease and other dementias with the Revised NEO Personality Inventory, a 240-item questionnaire that assesses 30 facets, 6 for each of the 5 major dimensions: neuroticism, extraversion, openness, agreeableness, and conscientiousness. Of the 2046 participants, 931 [45.5%] were women; mean (SD) age at first assessment was 62.56 (14.63) years. During 24 569 person-years, mild cognitive impairment was diagnosed in 104 (5.1%) individuals, and all-cause dementia was diagnosed in 255 (12.5%) participants, including 194 (9.5%) with Alzheimer disease. Multilevel modeling that accounted for age, sex, race, and educational level found significant differences on the intercept of several traits: individuals who developed dementia scored higher on neuroticism (β = 2.83; 95% CI, 1.44 to 4.22; P Alzheimer disease groups (eg, neuroticism: β = 0.00; 95% CI, -0.08 to 0.08; P = .91; conscientiousness: β = -0.06; 95% CI, -0.16 to 0.04; P = .24). Slopes for individuals who developed mild cognitive impairment (eg, neuroticism: β = 0.00; 95% CI, -0

  2. Neuroprotective Surgical Strategies in Parkinson’s Disease: Role of Preclinical Data

    Directory of Open Access Journals (Sweden)

    Napoleon Torres

    2017-10-01

    Full Text Available Although there have been many pharmacological agents considered to be neuroprotective therapy in Parkinson’s disease (PD patients, neurosurgical approaches aimed to neuroprotect or restore the degenerative nigrostriatal system have rarely been the focus of in depth reviews. Here, we explore the neuroprotective strategies involving invasive surgical approaches (NSI using neurotoxic models 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP and 6-hydroxydopamine (6-OHDA, which have led to clinical trials. We focus on several NSI approaches, namely deep brain stimulation of the subthalamic nucleus, glial neurotrophic derived factor (GDNF administration and cell grafting methods. Although most of these interventions have produced positive results in preclinical animal models, either from behavioral or histological studies, they have generally failed to pass randomized clinical trials to validate each approach. We argue that NSI are promising approaches for neurorestoration in PD, but preclinical studies should be planned carefully in order not only to detect benefits but also to detect potential adverse effects. Further, clinical trials should be designed to be able to detect and disentangle neuroprotection from symptomatic effects. In summary, our review study evaluates the pertinence of preclinical models to study NSI for PD and how this affects their efficacy when translated into clinical trials.

  3. Preclinical platform of retinoblastoma xenografts recapitulating human disease and molecular markers of dissemination.

    Science.gov (United States)

    Pascual-Pasto, Guillem; Olaciregui, Nagore G; Vila-Ubach, Monica; Paco, Sonia; Monterrubio, Carles; Rodriguez, Eva; Winter, Ursula; Batalla-Vilacis, Mireia; Catala, Jaume; Salvador, Hector; Parareda, Andreu; Schaiquevich, Paula; Suñol, Mariona; Mora, Jaume; Lavarino, Cinzia; de Torres, Carmen; Chantada, Guillermo L; Carcaboso, Angel M

    2016-09-28

    Translational research in retinoblastoma - a pediatric tumor that originates during the development of the retina - would be improved by the creation of new patient-derived models. Using tumor samples from enucleated eyes we established a new battery of preclinical models that grow in vitro in serum-free medium and in vivo in immunodeficient mice. To examine whether the new xenografts recapitulate human disease and disseminate from the retina to the central nervous system, we evaluated their histology and the presence of molecular markers of dissemination that are used in the clinical setting to detect extraocular metastases. We evaluated GD2 synthase and CRX as such markers and generated a Taqman real-time quantitative PCR method to measure CRX mRNA for rapid, sensitive and specific quantification of local and metastatic tumor burden. This approach was able to detect 1 human retinoblastoma cell in 100.000 mouse brain cells. Our research adds novel preclinical tools for the discovery of new retinoblastoma treatments for clinical translation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Comparative assessment of the diets of healthy individuals, subjects with preclinical coronary heart disease and patients with severe heart diseases

    International Nuclear Information System (INIS)

    Aronov, D.M.; Eganyan, R.A.; Kovaleva, O.F.; Zhidko, N.I.; Danielov, G.Eh.; Rozhnov, A.V.; Shcherbakova, I.A.

    1991-01-01

    92 males aged 26 to 55 (28 healthy individuals, 45 persons with preclinical coronary heart disease and 19 patients with functional class 1-2 coronary heart disease) were examined to study the peculiarities and dietary patterns of persons with a high physical working capacity and having no typical clinical signs of the disease. All persons were subjected to a complex examination which included questionnarire, myocardial scintigraphy with 201 Tl at a maximum physical loading, echocardiography, coronaroangiography. Certain dietary peculiarities are established in persons with preclinical coronary heart disease

  5. An Update of Patents, Preclinical and Clinical Outcomes of Lipid Nanoparticulate Systems.

    Science.gov (United States)

    Pathak, Kamla; Shankar, Ravi; Joshi, Monika

    2017-11-21

    Lipid nanoparticles have attracted increased degree of scientific and commercial attention in the last decade. The lipidic nanoparticles have emerged as a potential alternative to other nano-scale systems due to their various advantages over them and also due to overcoming the shortcomings of the already available colloidal systems like liposomes, niosomes and polymeric nanoparticles. These have been investigated for delivery of macromolecules, genes, siRNA and other therapeutic agents for oral, topical, parenteral administration and target site specific delivery for various diseases like cancer, ocular diseases and brain disorders. The lipid nanoparticles have evolved from SLNs, then NLCs and lipid drug conjugates overcoming any issues related to production and formulation and adding advantages, if any. The current review article focuses on the lipid nanoparticles, their formulation approaches and current advancements in the field through recent clinical trials and patents. This manuscript embodies various patents, preclinical and clinical aspects related to the lipidic nanocarriers. Over the years the lipidic nanoparticulate systems have evolved as significant carriers for improved therapeutics and in diagnostic field. The large number of patents and preclinical trials in the recent years suggests that these systems will find immense potential in near future. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. Striatal dopamine D2 receptors, metabolism, and volume in preclinical Huntington disease

    NARCIS (Netherlands)

    van Oostrom, JCH; Maguire, RP; Verschuuren-Bemelmans, CC; van der Duin, LV; Pruim, J; Roos, RAC; Leenders, KL

    2005-01-01

    Among 27 preclinical carriers of the Huntington disease mutation (PMC), the authors found normal striatal values for MRI volumetry in 88% and for fluorodesoxyglucose PET metabolic index in 67%. Raclopride PET binding potential (RAC-BP) was decreased in 50% and correlated with increases in the

  7. Neuroprotection in Parkinson's disease: A systematic review of the preclinical data

    NARCIS (Netherlands)

    Douna, H.; Bavelaar, B.M.; Pellikaan, H.; Olivier, B.; Pieters, T.

    2012-01-01

    Aim: This study aimed to systematically review the preclinical data of neuroprotective agents for Parkinson's disease (PD) to support the translation of these compounds. Methods: The study consisted of two phases. In phase I, Pubmed and Scopus were systematically searched for neuroprotective agents

  8. Preclinical Development of New Therapy for Glycogen Storage Diseases

    OpenAIRE

    Sun, Baodong; Brooks, Elizabeth D.; Koeberl, Dwight D.

    2015-01-01

    Glycogen storage disease (GSD) consists of more than 10 discrete conditions for which the biochemical and genetic bases have been determined, and new therapies have been under development for several of these conditions. Gene therapy research has generated proof-of-concept for GSD types I (von Gierke disease) and II (Pompe disease). Key features of these gene therapy strategies include the choice of vector and regulatory cassette, and recently adeno-associated virus (AAV) vectors containing t...

  9. Preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular diseases.

    Science.gov (United States)

    Zordoky, Beshay N M; Robertson, Ian M; Dyck, Jason R B

    2015-06-01

    Cardiovascular disease is the leading cause of death worldwide. Despite advancements in diagnosis and treatment of cardiovascular disease, the incidence of cardiovascular disease is still rising. Therefore, new lines of medications are needed to treat the growing population of patients with cardiovascular disease. Although the majority of the existing pharmacotherapies for cardiovascular disease are synthesized molecules, natural compounds, such as resveratrol, are also being tested. Resveratrol is a non-flavonoid polyphenolic compound, which has several biological effects. Preclinical studies have provided convincing evidence that resveratrol has beneficial effects in animal models of hypertension, atherosclerosis, stroke, ischemic heart disease, arrhythmia, chemotherapy-induced cardiotoxicity, diabetic cardiomyopathy, and heart failure. Although not fully delineated, some of the beneficial cardiovascular effects of resveratrol are mediated through activation of silent information regulator 1 (SIRT1), AMP-activated protein kinase (AMPK), and endogenous anti-oxidant enzymes. In addition to these pathways, the anti-inflammatory, anti-platelet, insulin-sensitizing, and lipid-lowering properties of resveratrol contribute to its beneficial cardiovascular effects. Despite the promise of resveratrol as a treatment for numerous cardiovascular diseases, the clinical studies for resveratrol are still limited. In addition, several conflicting results from trials have been reported, which demonstrates the challenges that face the translation of the exciting preclinical findings to humans. Herein, we will review much of the preclinical and clinical evidence for the role of resveratrol in the treatment of cardiovascular disease and provide information about the physiological and molecular signaling mechanisms involved. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes. Copyright © 2014

  10. Mapping preclinical compensation in Parkinson's disease: an imaging genomics approach

    DEFF Research Database (Denmark)

    van Nuenen, Bart F L; van Eimeren, Thilo; van der Vegt, Joyce P M

    2009-01-01

    Mutations in the Parkin (PARK2) and PINK1 gene (PARK 6) can cause recessively inherited Parkinson's disease (PD). The presence of a single Parkin or PINK1 mutation is associated with a dopaminergic nigrostriatal dysfunction and conveys an increased risk to develop PD throughout lifetime. Therefore...... development of overt disease. In two separate experiments, Parkin mutation carriers displayed stronger activation of rostral supplementary motor area (SMA) and right dorsal premotor cortex (PMd) during a simple motor sequence task and anterior cingulate motor area and left rostral PMd during internal movement...

  11. Are sleep disturbances preclinical markers of Parkinson’s disease?

    DEFF Research Database (Denmark)

    Brito dos Santos, Altair; Kohlmeier, Kristi Anne; Barreto, George

    2015-01-01

    Parkinson’s disease (PD) is a neurobehavioral disorder characterized by motor symptoms and signs, and non-motor abnormalities such as olfactory dysfunction, pain, sleep disorders and cognitive impairment. Amongst these alterations, sleep disturbances play an important role in the pathology...

  12. Deep Machine Learning Application to the Detection of Preclinical Neurodegenerative Diseases of Aging

    Directory of Open Access Journals (Sweden)

    Mathew J. Summers

    2017-12-01

    Full Text Available Artificial intelligence (AI deep learning protocols offer solutions to complex data processing and analysis. Increasingly these solutions are being applied in the healthcare field, most commonly in processing complex medical imaging data used for diagnosis. Current models apply AI to screening populations of patients for markers of disease and report detection accuracy rates exceeding those of human data screening. In this paper, we explore an alternate model for AI deployment, that of monitoring and analysing an individual’s level of function over time. In adopting this approach, we propose that AI may provide highly accurate and reliable detection of preclinical disease states associated with aging-related neurodegenerative diseases. One of the key challenges facing clinical detection of preclinical phases of diseases such as dementia is the high degree of inter-individual variability in aging-related changes to cognitive function. AI based monitoring of an individual over time offers the potential for the early detection of change in function for the individual, rather than relying on comparing the individual’s performance to population norms. We explore an approach to developing AI platforms for individual monitoring and preclinical disease detection and examine the potential benefits to the stakeholders in this technological development.

  13. Deleterious Effects of VEGFR2 and RET Inhibition in a Preclinical Model of Parkinson's Disease.

    Science.gov (United States)

    Requejo, C; Ruiz-Ortega, J A; Bengoetxea, H; Bulnes, S; Ugedo, L; Lafuente, J V

    2018-01-01

    Neurotrophic factors (NTFs) are a promising therapeutic option for Parkinson's disease (PD). They exert their function through tyrosine kinase receptors. Our goal was to assess the effects of administering a selective tyrosine kinase inhibitor (vandetanib) that blocks VEGFR2 and RET receptors in a preclinical model of PD. Rats underwent intrastriatal injections of 6-hydroxydopamine (6-OHDA). Two weeks later, the rats received 30 mg/kg vandetanib or saline orally. The effects were assessed using the rotational behavioral test, tyrosine hydroxylase (TH) immunohistochemistry, and western blot. In 6-OHDA-lesioned rats, motor symptoms were almost undetectable, but morphological and biochemical changes were significant. Vandetanib treatment, combined with the presence of 6-OHDA lesions, significantly increased behavioral impairment and morphological and biochemical changes. Therefore, after vandetanib treatment, the TH-immunopositive striatal volume, the percentage of TH+ neurons, and the extent of the axodendritic network in the substantia nigra decreased. Glial fibrillary acidic protein-positivity significantly decreased in the striatum and substantia nigra in the vandetanib-treated group. In addition, p-Akt and p-ERK 1/2 levels were significantly lower and caspase-3 expression significantly increased after vandetanib administration. In conclusion, we demonstrate for the first time the deleterious effect of a tyrosine kinase inhibitor on the dopaminergic system, supporting the beneficial and synergistic effect of NTFs reported in previous papers.

  14. Contextualized Autonomy and Liberalism: Broadening the Lenses on Complementary and Alternative Medicines in Preclinical Alzheimer's Disease.

    Science.gov (United States)

    Racine, Eric; Aspler, John; Forlini, Cynthia; Chandler, Jennifer A

    Given advances in Alzheimer's disease (AD) research, some experts have proposed a state of "preclinical" AD to describe asymptomatic individuals displaying certain biomarkers. The diagnostic accuracy of these biomarkers remains debated; however, given economic pressures, this "diagnosis" may eventually reach consumers. Since evidence-based prevention and treatment options remain only modestly effective, patients may turn to complementary and alternative medicine (CAM). We explore ethical challenges associated with CAM use in preclinical AD. We first consider these issues through the liberal lens, which emphasizes informed choice while occasionally disregarding the complexity of decision making, at least as currently applied to CAM policies. We then broaden the liberal lens with a socio-contextual lens, which describes the impact of social context on choice. Finally, we describe an alternate lens (contextualized liberalism) and its practical health and policy implications while 1) building on the liberal commitment to autonomy and 2) recognizing contextual determinants of choice.

  15. Positron Emission Tomography: Current Challenges and Opportunities for Technological Advances in Clinical and Preclinical Imaging Systems

    Science.gov (United States)

    Vaquero, Juan José; Kinahan, Paul

    2017-01-01

    Positron emission tomography (PET) imaging is based on detecting two time-coincident high-energy photons from the emission of a positron-emitting radioisotope. The physics of the emission, and the detection of the coincident photons, give PET imaging unique capabilities for both very high sensitivity and accurate estimation of the in vivo concentration of the radiotracer. PET imaging has been widely adopted as an important clinical modality for oncological, cardiovascular, and neurological applications. PET imaging has also become an important tool in preclinical studies, particularly for investigating murine models of disease and other small-animal models. However, there are several challenges to using PET imaging systems. These include the fundamental trade-offs between resolution and noise, the quantitative accuracy of the measurements, and integration with X-ray computed tomography and magnetic resonance imaging. In this article, we review how researchers and industry are addressing these challenges. PMID:26643024

  16. Evaluation of Cholinergic Deficiency in Preclinical Alzheimer’s Disease Using Pupillometry

    Directory of Open Access Journals (Sweden)

    Shaun Frost

    2017-01-01

    Full Text Available Cortical cholinergic deficiency is prominent in Alzheimer’s disease (AD, and published findings of diminished pupil flash response in AD suggest that this deficiency may extend to the visual cortical areas and anterior eye. Pupillometry is a low-cost, noninvasive technique that may be useful for monitoring cholinergic deficits which generally lead to memory and cognitive disorders. The aim of the study was to evaluate pupillometry for early detection of AD by comparing the pupil flash response (PFR in AD (N=14 and cognitively normal healthy control (HC, N=115 participants, with the HC group stratified according to high (N=38 and low (N=77 neocortical amyloid burden (NAB. Constriction phase PFR parameters were significantly reduced in AD compared to HC (maximum acceleration p<0.05, maximum velocity p<0.0005, average velocity p<0.005, and constriction amplitude p<0.00005. The high-NAB HC subgroup had reduced PFR response cross-sectionally, and also a greater decline longitudinally, compared to the low-NAB subgroup, suggesting changes to pupil response in preclinical AD. The results suggest that PFR changes may occur in the preclinical phase of AD. Hence, pupillometry has a potential as an adjunct for noninvasive, cost-effective screening for preclinical AD.

  17. Dissociating emotional and cognitive empathy in pre-clinical and clinical Huntington's disease.

    Science.gov (United States)

    Maurage, Pierre; Lahaye, Magali; Grynberg, Delphine; Jeanjean, Anne; Guettat, Lamia; Verellen-Dumoulin, Christine; Halkin, Stéphane; Heeren, Alexandre; Billieux, Joël; Constant, Eric

    2016-03-30

    Huntington's disease (HD) is centrally characterized by motor, neurocognitive and psychiatric symptoms, but impaired emotional decoding abilities have also been reported. However, more complex affective abilities are still to be explored, and particularly empathy, which is essential for social relations and is impaired in various psychiatric conditions. This study evaluates empathic abilities and social skills in pre-clinical and clinical HD, and explores the distinction between two empathy sub-components (emotional-cognitive). Thirty-six HD patients (17 pre-clinical) and 36 matched controls filled in the Empathy Quotient Scale, while controlling for psychopathological comorbidities. At the clinical stage of HD, no global empathy impairment was observed but rather a specific deficit for the cognitive sub-component, while emotional empathy was preserved. A deficit was also observed for social skills. Pre-clinical HD was not associated with any empathy deficit. Emotional deficits in clinical HD are thus not limited to basic emotion decoding but extend towards complex interpersonal abilities. The dissociation between impaired cognitive and preserved emotional empathy in clinical HD reinforces the proposal that empathy subtypes are sustained by distinct processes. Finally, these results underline the extent of distinct affective and social impairments in HD and the need to grasp them in clinical contexts. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  18. Promoting blood vessel growth in ischemic diseases: challenges in translating preclinical potential into clinical success

    Directory of Open Access Journals (Sweden)

    Galina Dragneva

    2013-03-01

    Full Text Available Angiogenic therapy, which involves the use of an exogenous stimulus to promote blood vessel growth, is an attractive approach for the treatment of ischemic diseases. It has been shown in animal models that the stimulation of blood vessel growth leads to the growth of the whole vascular tree, improvement of ischemic tissue perfusion and improved muscle aerobic energy metabolism. However, very few positive results have been gained from Phase 2 and 3 clinical angiogenesis trials. Many reasons have been given for the failures of clinical trials, including poor transgene expression (in gene-therapy trials and instability of the vessels induced by therapy. In this Review, we discuss the selection of preclinical models as one of the main reasons why clinical translation has been unsuccessful thus far. This issue has received little attention, but could have had dramatic implications on the expectations of clinical trials. We highlight crucial differences between human patients and animal models with regards to blood flow and pressure, as well as issues concerning the chronic nature of ischemic diseases in humans. We use these as examples to demonstrate why the results from preclinical trials might have overestimated the efficacy of angiogenic therapies developed to date. We also suggest ways in which currently available animal models of ischemic disease could be improved to better mimic human disease conditions, and offer advice on how to work with existing models to avoid overestimating the efficacy of new angiogenic therapies.

  19. Is your system calibrated? MRI gradient system calibration for pre-clinical, high-resolution imaging.

    Directory of Open Access Journals (Sweden)

    James O'Callaghan

    Full Text Available High-field, pre-clinical MRI systems are widely used to characterise tissue structure and volume in small animals, using high resolution imaging. Both applications rely heavily on the consistent, accurate calibration of imaging gradients, yet such calibrations are typically only performed during maintenance sessions by equipment manufacturers, and potentially with acceptance limits that are inadequate for phenotyping. To overcome this difficulty, we present a protocol for gradient calibration quality assurance testing, based on a 3D-printed, open source, structural phantom that can be customised to the dimensions of individual scanners and RF coils. In trials on a 9.4 T system, the gradient scaling errors were reduced by an order of magnitude, and displacements of greater than 100 µm, caused by gradient non-linearity, were corrected using a post-processing technique. The step-by-step protocol can be integrated into routine pre-clinical MRI quality assurance to measure and correct for these errors. We suggest that this type of quality assurance is essential for robust pre-clinical MRI experiments that rely on accurate imaging gradients, including small animal phenotyping and diffusion MR.

  20. The marmoset monkey: a multi-purpose preclinical and translational model of human biology and disease.

    Science.gov (United States)

    't Hart, Bert A; Abbott, David H; Nakamura, Katsuki; Fuchs, Eberhard

    2012-11-01

    The development of biologic molecules (monoclonal antibodies, cytokines, soluble receptors) as specific therapeutics for human disease creates a need for animal models in which safety and efficacy can be tested. Models in lower animal species are precluded when the reagents fail to recognize their targets, which is often the case in rats and mice. In this Feature article we will highlight the common marmoset, a small-bodied nonhuman primate (NHP), as a useful model in biomedical and preclinical translational research. Copyright © 2012 Elsevier Ltd. All rights reserved.

  1. Preclinical studies of potential amyloid binding PET/SPECT ligands in Alzheimer's disease

    International Nuclear Information System (INIS)

    Svedberg, Marie M.; Rahman, Obaidur; Hall, Håkan

    2012-01-01

    Visualizing the neuropathological hallmarks amyloid plaques and neurofibrillary tangles of Alzheimer's disease in vivo using positron emission tomography (PET) or single photon emission computed tomography will be of great value in diagnosing the individual patient and will also help in our understanding of the disease. The successful introduction of [ 11 C]PIB as a PET tracer for the amyloid plaques less than 10 years ago started an intensive research, and numerous new compounds for use in molecular imaging of the amyloid plaques have been developed. The candidates are based on dyes like thioflavin T, Congo red and chrysamine G, but also on other types such as benzoxazoles, curcumin and stilbenes. In the present review, we present methods of the radiochemistry and preclinical evaluation as well as the main properties of some of these compounds.

  2. Microstructural white matter alterations in preclinical Alzheimer's disease detected using free water elimination diffusion tensor imaging.

    Directory of Open Access Journals (Sweden)

    Andrew R Hoy

    Full Text Available Brain changes associated with Alzheimer's disease (AD begin decades before disease diagnosis. While β-amyloid plaques and neurofibrillary tangles are defining features of AD, neuronal loss and synaptic pathology are closely related to the cognitive dysfunction. Brain imaging methods that are tuned to assess degeneration of myelinated nerve fibers in the brain (collectively called white matter include diffusion tensor imaging (DTI and related techniques, and are expected to shed light on disease-related loss of structural connectivity. Participants (N = 70, ages 47-76 years from the Wisconsin Registry for Alzheimer's Prevention study underwent DTI and hybrid diffusion imaging to determine a free-water elimination (FWE-DTI model. The study assessed the extent to which preclinical AD pathology affects brain white matter. Preclinical AD pathology was determined using cerebrospinal fluid (CSF biomarkers. The sample was enriched for AD risk (APOE ε4 and parental history of AD. AD pathology assessed by CSF analyses was significantly associated with altered microstructure on both DTI and FWE-DTI. Affected regions included frontal, parietal, and especially temporal white matter. The f-value derived from the FWE-DTI model appeared to be the most sensitive to the relationship between the CSF AD biomarkers and microstructural alterations in white matter. These findings suggest that white matter degeneration is an early pathological feature of AD that may have utility both for early disease detection and as outcome measures for clinical trials. More complex models of microstructural diffusion properties including FWE-DTI may provide increased sensitivity to early brain changes associated with AD over standard DTI.

  3. Local and distributed PiB accumulation associated with development of preclinical Alzheimer's disease.

    Science.gov (United States)

    Brier, Matthew R; McCarthy, John E; Benzinger, Tammie L S; Stern, Ari; Su, Yi; Friedrichsen, Karl A; Morris, John C; Ances, Beau M; Vlassenko, Andrei G

    2016-02-01

    Amyloid-beta plaques are a hallmark of Alzheimer's disease (AD) that can be assessed by amyloid imaging (e.g., Pittsburgh B compound [PiB]) and summarized as a scalar value. Summary values may have clinical utility but are an average over many regions of interest, potentially obscuring important topography. This study investigates the longitudinal evolution of amyloid topographies in cognitively normal older adults who had normal (N = 131) or abnormal (N = 26) PiB scans at baseline. At 3 years follow-up, 16 participants with a previously normal PiB scan had conversion to PiB scans consistent with preclinical AD. We investigated the multivariate relationship (canonical correlation) between baseline and follow-up PiB topographies. Furthermore, we used penalized regression to investigate the added information derived from PiB topography compared to summary measures. PiB accumulation can be local, that is, a topography predicting the same topography in the future, and/or distributed, that is, one topography predicting another. Both local and distributed PiB accumulation was associated with conversion of PiB status. Additionally, elements of the multivariate topography, and not the commonly used summary scalar, correlated with future PiB changes. Consideration of the entire multivariate PiB topography provides additional information regarding the development of amyloid-beta pathology in very early preclinical AD. Copyright © 2016 Elsevier Inc. All rights reserved.

  4. Local and distributed PiB accumulation associated with development of preclinical Alzheimer’s disease

    Science.gov (United States)

    Brier, Matthew R.; McCarthy, John E.; Benzinger, Tammie L.S.; Stern, Ari; Su, Yi; Friedrichsen, Karl A.; Morris, John C.; Ances, Beau M.; Vlassenko, Andrei G.

    2017-01-01

    Amyloid-beta plaques are a hallmark of Alzheimer’s disease (AD) that can be assessed by amyloid imaging (e.g., Pittsburgh B compound [PiB]) and summarized as a scalar value. Summary values may have clinical utility but are an average over many regions of interest, potentially obscuring important topography. This study investigates the longitudinal evolution of amyloid topographies in cognitively normal older adults who had normal (N = 131) or abnormal (N = 26) PiB scans at baseline. At 3 years follow-up, 16 participants with a previously normal PiB scan had conversion to PiB scans consistent with preclinical AD. We investigated the multivariate relationship (canonical correlation) between baseline and follow-up PiB topographies. Furthermore, we used penalized regression to investigate the added information derived from PiB topography compared to summary measures. PiB accumulation can be local, that is, a topography predicting the same topography in the future, and/or distributed, that is, one topography predicting another. Both local and distributed PiB accumulation was associated with conversion of PiB status. Additionally, elements of the multivariate topography, and not the commonly used summary scalar, correlated with future PiB changes. Consideration of the entire multivariate PiB topography provides additional information regarding the development of amyloid-beta pathology in very early preclinical AD. PMID:26827648

  5. Commentary: IDSA guidelines for improving the teaching of preclinical medical microbiology and infectious diseases.

    Science.gov (United States)

    Southwick, Frederick; Katona, Peter; Kauffman, Carol; Monroe, Sara; Pirofski, Liise-anne; del Rio, Carlos; Gallis, Harry; Dismukes, William

    2010-01-01

    Preclinical microbiology and infectious diseases courses too often primarily depend on PowerPoint lectures and notes, combined with multiple-choice tests, as their primary teaching tools. This strategy sets low expectations for students, encouraging short-term memory and discouraging understanding and long-term memory. These methods also fail to stimulate active participation, collaborative learning, and two-way communication with the professor, and they do not respect the students' diverse talents and ways of learning. The Infectious Diseases Society of America Preclinical Curriculum Committee proposes a new approach that emphasizes active learning and understanding and that addresses all of these failures. It consists of five components: (1) "Just-in-time" teaching that requires students to e-mail the answers to two general questions as well as any areas of misunderstanding to the instructor several hours before each lecture, (2) peer instruction or large-group sessions consisting of student teams of four who electronically answer a conceptual question before each major section of the lecture, (3) teaching from edited textbooks and Internet sources, (4) small-group discussions that emphasize pathogenesis and differential diagnosis, and (5) essay questions that encourage and test understanding in addition to recognition. A national consensus on factual content is proposed, with the goals of reducing information overload and minimizing requirements for excessive memorization. These strategies promise to enhance learning and rekindle interest in the field of infectious diseases. Other subspecialty organizations should create similar teaching guidelines that will encourage future medical students to bring a richer understanding of clinical and basic science to the bedside.

  6. Cerebrospinal Fluid Prion Disease Biomarkers in Pre-clinical and Clinical Naturally Occurring Scrapie.

    Science.gov (United States)

    Llorens, Franc; Barrio, Tomás; Correia, Ângela; Villar-Piqué, Anna; Thüne, Katrin; Lange, Peter; Badiola, Juan José; Schmitz, Matthias; Lachmann, Ingolf; Bolea, Rosa; Zerr, Inga

    2018-03-23

    The analysis of the cerebrospinal fluid (CSF) biomarkers in patients with suspected prion diseases became a useful tool in diagnostic routine. Prion diseases can only be identified at clinical stages when the disease already spread throughout the brain and massive neuronal damage occurs. Consequently, the accuracy of CSF tests detecting non-symptomatic patients is unknown. Here, we aimed to investigate the usefulness of CSF-based diagnostic tests in pre-clinical and clinical naturally occurring scrapie. While decreased total prion protein (PrP) levels and positive PrP seeding activity were already detectable at pre-symptomatic stages, the surrogate markers of neuronal damage total tau (tau) and 14-3-3 proteins were exclusively increased at clinical stages. The present findings confirm that alterations in PrP levels and conformation are primary events in the pathology of prion diseases preceding neuronal damage. Our work also supports the potential use of these tests in the screening of pre-symptomatic scrapie and human prion disease cases.

  7. Preclinical evaluation of gene delivery methods for the treatment of loco-regional disease in breast cancer.

    LENUS (Irish Health Repository)

    Rajendran, Simon

    2012-01-31

    Preclinical results with various gene therapy strategies indicate significant potential for new cancer treatments. However, many therapeutics fail at clinical trial, often due to differences in tissue physiology between animal models and humans, and tumor phenotype variation. Clinical data relevant to treatment strategies may be generated prior to clinical trial through experimentation using intact patient tissue ex vivo. We developed a novel tumor slice model culture system that is universally applicable to gene delivery methods, using a realtime luminescence detection method to assess gene delivery. Methods investigated include viruses (adenovirus [Ad] and adeno-associated virus), lipofection, ultrasound (US), electroporation and naked DNA. Viability and tumor populations within the slices were well maintained for seven days, and gene delivery was qualitatively and quantitatively examinable for all vectors. Ad was the most efficient gene delivery vector with transduction efficiency >50%. US proved the optimal non-viral gene delivery method in human tumor slices. The nature of the ex vivo culture system permitted examination of specific elements. Parameters shown to diminish Ad gene delivery included blood, regions of low viability and secondary disease. US gene delivery was significantly reduced by blood and skin, while tissue hyperthermia improved gene delivery. US achieved improved efficacy for secondary disease. The ex vivo model was also suitable for examination of tissue-specific effects on vector expression, with Ad expression mediated by the CXCR4 promoter shown to provide a tumor selective advantage over the ubiquitously active cytomegalovirus promoter. In conclusion, this is the first study incorporating patient tissue models in comparing gene delivery from various vectors, providing knowledge on cell-type specificity and examining the crucial biological factors determining successful gene delivery. The results highlight the importance of in

  8. Preclinical evaluation of gene delivery methods for the treatment of loco-regional disease in breast cancer.

    LENUS (Irish Health Repository)

    Rajendran, Simon

    2011-04-01

    Preclinical results with various gene therapy strategies indicate significant potential for new cancer treatments. However, many therapeutics fail at clinical trial, often due to differences in tissue physiology between animal models and humans, and tumor phenotype variation. Clinical data relevant to treatment strategies may be generated prior to clinical trial through experimentation using intact patient tissue ex vivo. We developed a novel tumor slice model culture system that is universally applicable to gene delivery methods, using a realtime luminescence detection method to assess gene delivery. Methods investigated include viruses (adenovirus [Ad] and adeno-associated virus), lipofection, ultrasound (US), electroporation and naked DNA. Viability and tumor populations within the slices were well maintained for seven days, and gene delivery was qualitatively and quantitatively examinable for all vectors. Ad was the most efficient gene delivery vector with transduction efficiency >50%. US proved the optimal non-viral gene delivery method in human tumor slices. The nature of the ex vivo culture system permitted examination of specific elements. Parameters shown to diminish Ad gene delivery included blood, regions of low viability and secondary disease. US gene delivery was significantly reduced by blood and skin, while tissue hyperthermia improved gene delivery. US achieved improved efficacy for secondary disease. The ex vivo model was also suitable for examination of tissue-specific effects on vector expression, with Ad expression mediated by the CXCR4 promoter shown to provide a tumor selective advantage over the ubiquitously active cytomegalovirus promoter. In conclusion, this is the first study incorporating patient tissue models in comparing gene delivery from various vectors, providing knowledge on cell-type specificity and examining the crucial biological factors determining successful gene delivery. The results highlight the importance of in

  9. Long-term preclinical magnetic resonance imaging alterations in sporadic Creutzfeldt-Jakob disease.

    Science.gov (United States)

    Zanusso, Gianluigi; Camporese, Giulia; Ferrari, Sergio; Santelli, Luca; Bongianni, Matilde; Fiorini, Michele; Monaco, Salvatore; Manara, Renzo; Cagnin, Annachiara

    2016-10-01

    An asymptomatic 74-year-old woman, on follow-up for a carotid body tumor, showed magnetic resonance imaging (MRI) focal restricted diffusion confined to the left temporal and occipital cortices. Thirteen months later, diffusion-weighted images revealed a bilateral cortical ribbon sign involving all lobes. After 1 month, the patient developed gait instability and cognitive decline rapidly evolving to severe dementia and death within 3 months. Prion protein gene sequence, molecular, and neuropathological studies confirmed the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 subtype. Here we show the kinetics of MRI changes and prion spreading in preclinical sCJD MM1. Ann Neurol 2016;80:629-632. © 2016 American Neurological Association.

  10. Novel Cognitive Paradigms for the Detection of Memory Impairment in Preclinical Alzheimer's Disease.

    Science.gov (United States)

    Loewenstein, David A; Curiel, Rosie E; Duara, Ranjan; Buschke, Herman

    2018-04-01

    In spite of advances in neuroimaging and other brain biomarkers to assess preclinical Alzheimer's disease (AD), cognitive assessment has relied on traditional memory paradigms developed well over six decades ago. This has led to a growing concern about their effectiveness in the early diagnosis of AD which is essential to develop preventive and early targeted interventions before the occurrence of multisystem brain degeneration. We describe the development of novel tests that are more cognitively challenging, minimize variability in learning strategies, enhance initial acquisition and retrieval using cues, and exploit vulnerabilities in persons with incipient AD such as the susceptibility to proactive semantic interference, and failure to recover from proactive semantic interference. The advantages of various novel memory assessment paradigms are examined as well as how they compare with traditional neuropsychological assessments of memory. Finally, future directions for the development of more effective assessment paradigms are suggested.

  11. Correlates of preclinical cardiovascular disease in Indigenous and Non-Indigenous Australians: a case control study

    Directory of Open Access Journals (Sweden)

    Shaw A Andrew

    2008-07-01

    Full Text Available Abstract Background The high frequency of premature death from cardiovascular disease in indigenous Australians is often attributed to the high prevalence of risk factors, especially type II diabetes mellitus (DM. We evaluated the relationship of ethnicity to atherosclerotic burden, as evidenced by carotid intima-media thickness (IMT, independent of risk factor status. Methods We studied 227 subjects (147 men; 50 ± 13 y: 119 indigenous subjects with (IDM, n = 54, and without DM (InDM, n = 65, 108 Caucasian subjects with (CDM, n = 52, and without DM (CnDM, n = 56. IMT was measured according to standard methods and compared with clinical data and cardiovascular risk factors. Results In subjects both with and without DM, IMT was significantly greater in indigenous subjects. There were no significant differences in gender, body mass index (BMI, systolic blood pressure (SBP, or diastolic blood pressure (DBP between any of the groups, and subjects with DM showed no difference in plasma HbA1c. Cardiovascular risk factors were significantly more prevalent in indigenous subjects. Nonetheless, ethnicity (β = -0.34; p Conclusion Ethnicity appears to be an independent correlate of preclinical cardiovascular disease, even after correction for the high prevalence of cardiovascular risk factors in indigenous Australians. Standard approaches to control currently known risk factors are vital to reduce the burden of cardiovascular disease, but in themselves may be insufficient to fully address the high prevalence in this population.

  12. A semi-automated vascular access system for preclinical models

    Science.gov (United States)

    Berry-Pusey, B. N.; Chang, Y. C.; Prince, S. W.; Chu, K.; David, J.; Taschereau, R.; Silverman, R. W.; Williams, D.; Ladno, W.; Stout, D.; Tsao, T. C.; Chatziioannou, A.

    2013-08-01

    Murine models are used extensively in biological and translational research. For many of these studies it is necessary to access the vasculature for the injection of biologically active agents. Among the possible methods for accessing the mouse vasculature, tail vein injections are a routine but critical step for many experimental protocols. To perform successful tail vein injections, a high skill set and experience is required, leaving most scientists ill-suited to perform this task. This can lead to a high variability between injections, which can impact experimental results. To allow more scientists to perform tail vein injections and to decrease the variability between injections, a vascular access system (VAS) that semi-automatically inserts a needle into the tail vein of a mouse was developed. The VAS uses near infrared light, image processing techniques, computer controlled motors, and a pressure feedback system to insert the needle and to validate its proper placement within the vein. The VAS was tested by injecting a commonly used radiolabeled probe (FDG) into the tail veins of five mice. These mice were then imaged using micro-positron emission tomography to measure the percentage of the injected probe remaining in the tail. These studies showed that, on average, the VAS leaves 3.4% of the injected probe in the tail. With these preliminary results, the VAS system demonstrates the potential for improving the accuracy of tail vein injections in mice.

  13. Cognitive reserve and lifestyle: moving towards preclinical Alzheimer’s disease

    Science.gov (United States)

    Arenaza-Urquijo, Eider M.; Wirth, Miranka; Chételat, Gaël

    2015-01-01

    The large majority of neuroimaging studies in Alzheimer’s disease (AD) patients have supported the idea that lifestyle factors may protect against the clinical manifestations of AD rather than influence AD neuropathological processes (the cognitive reserve hypothesis). This evidence argues in favor of the hypothesis that lifestyle factors act as moderators between AD pathology and cognition, i.e., through indirect compensatory mechanisms. In this review, we identify emerging evidence in cognitively normal older adults that relate lifestyle factors to established AD neuroimaging biomarkers. While some of these investigations are in agreement with the compensatory view of cognitive reserve, other studies have revealed new clues on the neural mechanisms underlying beneficial effects of lifestyle factors on the brain. Specifically, they provide novel evidence suggesting direct effects of lifestyle factors on AD neuropathological processes. We propose a tentative theoretical model where lifestyle factors may act via direct neuroprotective and/or indirect compensatory mechanisms. Importantly, we suggest that neuroprotective mechanisms may have a major role during early stages and compensatory mechanisms in later stages of the disease. In the absence of an effective treatment for AD and considering the potential of lifestyle factors in AD prevention, understanding the neural mechanisms underlying lifestyle effects on the brain seems crucial. We hope to provide an integrative view that may help to better understand the complex effects of lifestyle factors on AD neuropathological processes, starting from the preclinical stage. PMID:26321944

  14. AV-1451 PET imaging of tau pathology in preclinical Alzheimer disease: Defining a summary measure.

    Science.gov (United States)

    Mishra, Shruti; Gordon, Brian A; Su, Yi; Christensen, Jon; Friedrichsen, Karl; Jackson, Kelley; Hornbeck, Russ; Balota, David A; Cairns, Nigel J; Morris, John C; Ances, Beau M; Benzinger, Tammie L S

    2017-11-01

    Utilizing [18F]-AV-1451 tau positron emission tomography (PET) as an Alzheimer disease (AD) biomarker will require identification of brain regions that are most important in detecting elevated tau pathology in preclinical AD. Here, we utilized an unsupervised learning, data-driven approach to identify brain regions whose tau PET is most informative in discriminating low and high levels of [18F]-AV-1451 binding. 84 cognitively normal participants who had undergone AV-1451 PET imaging were used in a sparse k-means clustering with resampling analysis to identify the regions most informative in dividing a cognitively normal population into high tau and low tau groups. The highest-weighted FreeSurfer regions of interest (ROIs) separating these groups were the entorhinal cortex, amygdala, lateral occipital cortex, and inferior temporal cortex, and an average SUVR in these four ROIs was used as a summary metric for AV-1451 uptake. We propose an AV-1451 SUVR cut-off of 1.25 to define high tau as described by imaging. This spatial distribution of tau PET is a more widespread pattern than that predicted by pathological staging schemes. Our data-derived metric was validated first in this cognitively normal cohort by correlating with early measures of cognitive dysfunction, and with disease progression as measured by β-amyloid PET imaging. We additionally validated this summary metric in a cohort of 13 Alzheimer disease patients, and showed that this measure correlates with cognitive dysfunction and β-amyloid PET imaging in a diseased population. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Clinical and preclinical treatment of urologic diseases with phosphodiesterase isoenzymes 5 inhibitors: an update

    Directory of Open Access Journals (Sweden)

    Wen-Hao Zhang

    2016-01-01

    Full Text Available Phosphodiesterase isoenzymes 5 inhibitors (PDE5-Is are the first-line therapy for erectile dysfunction (ED. The constant discoveries of nitric oxide (NO/cyclic guanosine monophosphate (cGMP cell-signaling pathway for smooth muscle (SM control in other urogenital tracts (UGTs make PDE5-Is promising pharmacologic agents against other benign urological diseases. This article reviews the literature and contains some previously unpublished data about characterizations and activities of PDE5 and its inhibitors in treating urological disorders. Scientific discoveries have improved our understanding of cell-signaling pathway in NO/cGMP-mediated SM relaxation in UGTs. Moreover, the clinical applications of PDE5-Is have been widely recognized. On-demand PDE5-Is are efficacious for most cases of ED, while daily-dosing and combination with testosterone are recommended for refractory cases. Soluble guanylate cyclase (sGC stimulators also have promising role in the management of severe ED conditions. PDE5-Is are also the first rehabilitation strategy for postoperation or postradiotherapy ED for prostate cancer patients. PDE5-Is, especially combined with α-adrenoceptor antagonists, are very effective for benign prostatic hyperplasia (BPH except on maximum urinary flow rate (Q max with tadalafil recently proved for BPH with/without ED. Furthermore, PDE5-Is are currently under various phases of clinical or preclinical researches with promising potential for other urinary and genital illnesses, such as priapism, premature ejaculation, urinary tract calculi, overactive bladder, Peyronie′s disease, and female sexual dysfunction. Inhibition of PDE5 is expected to be an effective strategy in treating benign urological diseases. However, further clinical studies and basic researches investigating mechanisms of PDE5-Is in disorders of UGTs are required.

  16. Preclinical study of dimebon on β-amyloid-mediated neuropathology in Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Xie Mathew

    2011-01-01

    Full Text Available Abstract Background Dimebon is a retired non-selective antihistamine drug currently being investigated as a therapeutic agent for the treatment of Alzheimer's disease (AD. Results from several completed clinical trials are mixed and contradictory. Proper interpretations of these clinical observations, as well as future development of dimebon in AD treatment are complicated by the lack of concrete information on the mechanisms by which dimebon might benefit AD. Results The present studies are designed specifically to assess whether dimebon might modulate β-amyloid (Aβ-mediated responses which are central to the development and progression of AD dementia. We found that dimebon is bioavailable in the brains of mice following oral administration. AD mice chronically treated with dimebon exhibited a trend of improvement in spatial memory function without affecting the levels of total Aβ as well as soluble oligomeric Aβ in the brain. The same trend of behavior improvement is also seen in wild type animals chronically treated with dimebon. Conclusion Collectively, our preclinical studies using the TgCRND8 AD mouse model demonstrated that dimebon might have some beneficial effect in improving cognitive function independent of Alzheimer's disease-type Aβ-related mechanisms or global energy metabolism in the brain. Observations from our study and others suggesting dimebon might improve cognition in wild type mice and rats raises the possibility that dimebon might be able to benefit cognitive function in patients with other neurodegenerative disorders, such as Huntington's disease, or in the aging population. Additional studies will be necessary to clarify the mechanisms by which dimebon might directly or indirectly benefit cognitive function.

  17. An olfactory ‘stress test’ may detect preclinical Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Schofield Peter W

    2012-05-01

    Full Text Available Abstract Background The olfactory bulb (OB receives extensive cholinergic input from the basal forebrain and is affected very early in Alzheimer’s disease (AD. We speculated that an olfactory ‘stress test’ (OST, targeting the OB, might be used to unmask incipient AD. We investigated if change in olfactory performance following intranasal atropine was associated with several known antecedents or biomarkers of AD. Methods We measured change in performance on the University of Pennsylvania Smell Identification Test (UPSIT in the left nostril before (20-items and after (remaining 20-items intranasal administration of 1 mg of atropine. We administered cognitive tests, measured hippocampal volume from MRI scans and recorded Apolipoprotein E genotype as indices relevant to underlying AD. Results In a convenience sample of 56 elderly individuals (14 probable AD, 13 cognitive impairment no dementia, 29 cognitively intact the change in UPSIT score after atropine (‘atropine effect’ = AE correlated significantly with demographically scaled episodic memory score (r = 0.57, p Conclusions The OST using atropine as an olfactory probe holds promise as a simple, inexpensive screen for early and preclinical AD and further work, including longitudinal studies, is needed to explore this possibility.

  18. Increased levels of 4-hydroxynonenal and acrolein in the brain in preclinical Alzheimer disease.

    Science.gov (United States)

    Bradley, M A; Markesbery, W R; Lovell, M A

    2010-06-15

    Previous studies demonstrate increased levels of 4-hydroxynonenal (HNE) and acrolein in vulnerable brain regions of subjects with mild cognitive impairment and late-stage Alzheimer disease (LAD). Recently preclinical AD (PCAD) subjects, who demonstrate normal antemortem neuropsychological test scores but abundant AD pathology at autopsy, have become the focus of increased study. Levels of extractable HNE and acrolein were quantified by gas chromatography-mass spectrometry with negative chemical ionization, and protein-bound HNE and acrolein were quantified by dot-blot immunohistochemistry in the hippocampus/parahippocampal gyrus (HPG), superior and middle temporal gyri (SMTG), and cerebellum (CER) of 10 PCAD and 10 age-matched normal control (NC) subjects. Results of the analyses show a significant (Pacrolein in the HPG of PCAD subjects compared to age-matched NC subjects and a significant decrease in extractable acrolein in PCAD CER. Significant increases in protein-bound HNE in HPG and a significant decrease in CER of PCAD subjects compared to NC subjects were observed. No significant alterations were observed in either extractable or protein-bound HNE or acrolein in the SMTG of PCAD subjects. Additionally, no significant differences in levels of protein carbonyls were observed in the HPG, SMTG, or CER of PCAD subjects compared to NC subjects. (c) 2010 Elsevier Inc. All rights reserved.

  19. Prevention approaches in a preclinical canine model of Alzheimer’s disease: Benefits and challenges

    Directory of Open Access Journals (Sweden)

    Paulina R. Davis

    2014-03-01

    Full Text Available Aged dogs spontaneously develop many features of human aging and Alzheimer’s disease (AD including cognitive decline and neuropathology. In this review, we discuss age-dependent learning tasks, memory tasks, and functional measures that can be used in aged dogs for sensitive treatment outcome measures. Neuropathology that is linked to cognitive decline is described along with examples of treatment studies that show reduced neuropathology in aging dogs (dietary manipulations, behavioral enrichment, immunotherapy, and statins. Studies in canine show that multi-targeted approaches may be more beneficial than single pathway manipulations (e.g. antioxidants combined with behavioral enrichment. Aging canine studies show good predictive validity for human clinical trials outcomes (e.g. immunotherapy and several interventions tested in dogs strongly support a prevention approach (e.g. immunotherapy and statins. Further, dogs are ideally suited for prevention studies as they the age because onset of cognitive decline and neuropathology strongly support longitudinal interventions that can be completed within a 3-5 year period. Disadvantages to using the canine model are that they lengthy, use labor-intensive comprehensive cognitive testing, and involve costly housing (almost as high as that of nonhuman primates. However overall, using the dog as a preclinical model for testing preventive approaches for AD may complement work in rodents and nonhuman primates.

  20. Shexiang Baoxin Pills for Coronary Heart Disease in Animal Models: Preclinical Evidence and Promoting Angiogenesis Mechanism

    Directory of Open Access Journals (Sweden)

    Ke-Jian Zhang

    2017-06-01

    Full Text Available Shexiang Baoxin Pill (SBP originated from a classical TCM Fufang Suhexiang Pill for chest pain with dyspnea in the Southern Song Dynasty (1107–110 AD. Here, we aimed to evaluate preclinical evidence and possible mechanism of SBP for experimental coronary heart disease (CHD. Studies of SBP in animal models with CHD were identified from 6 databases until April 2016. Study quality for each included article was evaluated according to the CAMARADES 10-item checklist. Outcome measures were myocardial infarction area, vascular endothelial growth factor (VEGF and microvessel count (MVC. All the data were analyzed by using RevMan 5.1 software. As a consequence, 25 studies with 439 animals were identified. The quality score of studies ranged from 2 to 5, with the median of 3.6. Meta-analysis of seven studies showed more significant effects of SBP on the reduction of the myocardial infarction area than the control (P < 0.01. Meta-analysis of eight studies showed significant effects of SBP for increasing VEGF expression compared with the control (P < 0.01. Meta-analysis of 10 studies indicated that SBP significantly improved MVC compared with the control (P < 0.01. In conclusion, these findings preliminarily demonstrated that SBP can reduce myocardial infarction area, exerting cardioprotective function largely through promoting angiogenesis.

  1. Preclinical models of muscle spasticity: valuable tools in the development of novel treatment for neurological diseases and conditions.

    Science.gov (United States)

    Bespalov, Anton; Mus, Liudmila; Zvartau, Edwin

    2016-05-01

    Poor validity of preclinical animal models is one of the most commonly discussed explanations for the failures to develop novel drugs in general and in neuroscience in particular. However, there are several areas of neuroscience such as injury-induced spasticity where etiological factor can be adequately recreated and models can focus on specific pathophysiological mechanisms that likely contribute to spasticity syndrome in humans (such as motoneuron hyperexcitability and spinal hyperreflexia). Methods used to study spasticity in preclinical models are expected to have a high translational value (e.g., electromyogram (EMG)-based electrophysiological tools) and can efficiently assist clinical development programs. However, validation of these models is not complete yet. First, true predictive validity of these models is not established as clinically efficacious drugs have been used to reverse validate preclinical models while newly discovered mechanisms effective in preclinical models are yet to be fully explored in humans (e.g., 5-HT2C receptor inverse agonists, fatty acid amid hydrolase inhibitors). Second, further efforts need to be invested into cross-laboratory validation of study protocols and tools, adherence to the highest quality standards (blinding, randomization, pre-specified study endpoints, etc.), and systematic efforts to replicate key sets of data. These appear to be readily achievable tasks that will enable development not only of symptomatic but also of disease-modifying therapy of spasticity, an area that seems to be currently not in focus of research efforts.

  2. Cognitive reserve and lifestyle: moving towards preclinical Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Eider M Arenaza-Urquijo

    2015-08-01

    Full Text Available The large majority of neuroimaging studies in Alzheimer’s disease (AD patients have supported the idea that lifestyle factors may protect against the clinical manifestations of AD rather than influence AD neuropathological processes (the cognitive reserve hypothesis. This evidence argues in favor of the hypothesis that lifestyle factors act as moderators between AD pathology and cognition, i.e. through indirect compensatory mechanisms. In this review, we identify emerging evidence in cognitively normal older people that relate lifestyle factors to established AD neuroimaging biomarkers. While some of these investigations are in agreement with the compensatory view of cognitive reserve, other studies have revealed new clues on the neural mechanisms underlying beneficial effects of lifestyle factors on the brain. Specifically, they provide novel evidence suggesting direct effects of lifestyle factors on AD neuropathological processes. Here, we review current findings on the effects of lifestyle factors on AD neuroimaging biomarkers in cognitively normal older people. We propose a tentative theoretical model where lifestyle factors may act via direct neuroprotective and/or indirect compensatory pathways. Importantly, we suggest that neuroprotective mechanisms may have a major role during early stages and compensatory pathways in later stages of the disease. In the absence of an effective treatment for AD and considering the potential of lifestyle factors in AD prevention, understanding the neural mechanisms underlying lifestyle effects on the brain seems crucial. We hope to provide an integrative view that may help to better understand the complex effects of lifestyle factors on AD neuropathological processes, starting from the preclinical stage.

  3. Early Detection of Learning Difficulties when Confronted with Novel Information in Preclinical Alzheimer's Disease Stage 1.

    Science.gov (United States)

    Tort-Merino, Adrià; Valech, Natalia; Peñaloza, Claudia; Grönholm-Nyman, Petra; León, María; Olives, Jaume; Estanga, Ainara; Ecay-Torres, Mirian; Fortea, Juan; Martínez-Lage, Pablo; Molinuevo, José L; Laine, Matti; Rodríguez-Fornells, Antoni; Rami, Lorena

    2017-01-01

    We employed a highly demanding experimental associative learning test (the AFE-T) to explore memory functioning in Preclinical Alzheimer's Disease stage 1 (PreAD-1) and stage 2 (PreAD-2). The task consisted in the learning of unknown object/name pairs and our comprehensive setup allowed the analysis of learning curves, immediate recall, long-term forgetting rates at one week, three months, and six months, and relearning curves. Forty-nine cognitively healthy subjects were included and classified according to the presence or absence of abnormal CSF biomarkers (Control, n = 31; PreAD-1, n = 14; PreAD-2, n = 4). Control and PreAD-1 performances on the experimental test were compared by controlling for age and education. These analyses showed clear learning difficulties in PreAD-1 subjects (F = 6.98; p = 0.01). Between-group differences in long-term forgetting rates were less notable, reaching statistical significance only for the three-month cued forgetting rate (F = 4.83; p = 0.03). Similarly, relearning sessions showed only statistical trends between the groups (F = 3.22; p = 0.08). In the whole sample, significant correlations between CSF Aβ42/tau ratio and the AFE-T were found, both in the total learning score (r = 0.52; p learning and recall difficulties in these subjects when compared with the PreAD-1 group. The present results suggest that explicit learning difficulties when binding information could be one of the earliest signs of the future emergence of episodic memory difficulties on the Alzheimer's disease continuum. Our findings indicate that the AFE-T is a sensitive test, capable of detecting subtle memory difficulties in PreAD-1.

  4. Increased levels of 4-hydroxynonenal and acrolein in the brain in preclinical Alzheimer’s disease (PCAD)

    OpenAIRE

    Bradley, M. A.; Markesbery, W. R.; Lovell, M. A.

    2010-01-01

    Previous studies demonstrate increased levels of 4-hydroxynonenal (HNE) and acrolein in vulnerable brain regions of subjects with mild cognitive impairment (MCI) and late-stage Alzheimer’s disease (AD). Recently preclinical AD (PCAD) subjects, who demonstrate normal antemortem neuropsychological test scores but abundant AD pathology at autopsy, have become the focus of increased study. Levels of extractable HNE and acrolein were quantified by gas chromatography mass spectrometry with negative...

  5. Pre-clinical therapeutic development of a series of metalloporphyrins for Parkinson's disease

    International Nuclear Information System (INIS)

    Liang, Li-Ping; Huang, Jie; Fulton, Ruth; Pearson-Smith, Jennifer N.; Day, Brian J.; Patel, Manisha

    2017-01-01

    Reactive oxygen species are a well-defined therapeutic target for Parkinson's disease (PD) and pharmacological agents that catalytically scavenge reactive species are promising neuroprotective strategies for treatment. Metalloporphyrins are synthetic catalytic antioxidants that mimic the body's own antioxidant enzymes i.e. superoxide dismutases and catalase. The goal of this study was to determine if newly designed metalloporphyrins have enhanced pharmacodynamics including oral bioavailability, longer plasma elimination half-lives, penetrate the blood brain barrier, and show promise for PD treatment. Three metalloporphyrins (AEOL 11216, AEOL 11203 and AEOL 11114) were identified in this study as potential candidates for further pre-clinical development. Each of these compounds demonstrated blood brain barrier permeability by the i.p. route and two of three compounds (AEOL 11203 and AEOL 11114) were orally bioavailable. All of these compounds protected against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity, including dopamine depletion in the striatum, dopaminergic neuronal loss in the substantial nigra, and increased oxidative/nitrative stress indices (glutathione disulfide and 3-nitrotyrosine) in the ventral midbrain of the mice without inhibiting MPTP metabolism. Daily therapeutic dosing of these metalloporphyrins were well tolerated without accumulation of brain manganese levels or behavioral alterations assessed by open field and rotarod tests. The study identified two orally active metalloporphyrins and one injectable metalloporphyrin as clinical candidates for further development in PD. - Highlights: • A series of metalloporphyrins were optimized in a mouse model of parkinsonism. • Two novel orally active, brain permeable antioxidant metalloporphyrins were identified. • The identified metalloporphyrins were well tolerated.

  6. Plasma 24-metabolite panel predicts preclinical transition to clinical stages of Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Massimo S Fiandaca

    2015-11-01

    Full Text Available We recently documented plasma lipid dysregulation in preclinical late-onset Alzheimer’s disease (LOAD. A ten plasma lipid panel, predicted phenoconversion and provided 90% sensitivity and 85% specificity in differentiating an at-risk group from those that would remain cognitively intact. Despite these encouraging results, low positive predictive values limit the clinical usefulness of this panel as a screening tool in subjects aged 70-80 years or younger. In this report we re-examine our metabolomic data, analyzing baseline plasma specimens from our group of phenoconverters (n=28 and a matched set of cognitively normal subjects (n=73, and discover and internally validate a panel of 24 plasma metabolites. The new panel provides a classifier with receiver operating characteristic area under the curve, for the discovery and internal validation cohort, of 1.0 and 0.995 (95% Confidence Intervals of 1.0 to 1.0, and 0.981 to 1.0, respectively. Twenty-two of the 24 metabolites were significantly dysregulated lipids. While positive and negative predictive values were improved compared to our 10-lipid panel, low positive predictive values provide a reality check on the utility of such biomarkers in this age group (or younger. Through inclusion of additional significantly dysregulated analyte species, our new biomarker panel provides greater accuracy in our cohort but remains limited by predictive power. Unfortunately, the novel metabolite panel alone may not provide improvement in counseling and management of at-risk individuals, but, may further improve selection of subjects for LOAD secondary prevention trials. We expect that external validation will remain challenging due to our stringent study design, especially compared with more diverse subject cohorts. We anticipate, however, external validation of reduced plasma lipid species as a predictor of phenoconversion to either prodromal or manifest LOAD.

  7. The role of the endocannabinoid system in eating disorders: neurochemical and behavioural preclinical evidence.

    Science.gov (United States)

    Scherma, Maria; Fattore, Liana; Castelli, Maria Paola; Fratta, Walter; Fadda, Paola

    2014-01-01

    The endocannabinoid system has long been known as a modulator of several physiological functions, among which the homeostatic and hedonic aspects of eating. CB1 receptors are widely expressed in brain regions that control food intake, reward and energy balance. Animal and human studies indicate that CB1 receptor agonists possess orexigenic effects enhancing appetite and increasing the rewarding value of food. Conversely, CB1 antagonists have been shown to inhibit the intake of food. Eating disorders include a range of chronic and disabling related pathological illnesses that are characterized by aberrant patterns of feeding behaviour and weight regulation, and by abnormal attitudes and perceptions toward body shape image. The psychological and biological factors underlying eating disorders are complex and not yet completely understood. However in the last decades, converging evidence have led to hypothesise a link between defects in the endocannabinoid system and eating disorders, including obesity. Here we review the neurochemical and behavioural preclinical evidence supporting the role of the endocannabinoid system in eating disorders to offer the reader an update regarding the state of the art. Despite the recent withdrawal from the market of rimonabant for treating obesity and overweight individuals with metabolic complications due to its psychiatric side effects, preclinical findings support the rationale for the clinical development of drug which modulate the endocannabinoid system in the treatment of eating disorders.

  8. Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo : The EPIC Study

    NARCIS (Netherlands)

    Boswood, A; Gordon-McKeon, Shauna; Häggström, J; Wess, G; Stepien, R L; Oyama, M A; Keene, B W; Bonagura, J; MacDonald, K A; Patteson, M; Smith, S|info:eu-repo/dai/nl/35742574X; Fox, P R; Sanderson, K; Woolley, S.R.; Szatmári, V|info:eu-repo/dai/nl/272734497; Menaut, P; Church, W M; O'Sullivan, M L; Jaudon, J-P; Kresken, J-G; Rush, John; Barrett, A.K.; Rosenthal, S L; Saunders, B.A.C.; Ljungvall, I; Deinert, M; Bomassi, E; Estrada, A H; Fernandez Del Palacio, M J; Moise, N S; Abbott, J A; Fujii, Y; Spier, A; Luethy, M W; Santilli, R A; Uechi, M; Tidholm, A; Schummer, C; Watson, Poppy

    BACKGROUND: Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. OBJECTIVES: To investigate the effect of pimobendan on clinical variables and the relationship between

  9. Associations between white matter microstructure and amyloid burden in preclinical Alzheimer's disease: A multimodal imaging investigation

    Directory of Open Access Journals (Sweden)

    Annie M. Racine

    2014-01-01

    Full Text Available Some cognitively healthy individuals develop brain amyloid accumulation, suggestive of incipient Alzheimer's disease (AD, but the effect of amyloid on other potentially informative imaging modalities, such as Diffusion Tensor Imaging (DTI, in characterizing brain changes in preclinical AD requires further exploration. In this study, a sample (N = 139, mean age 60.6, range 46 to 71 from the Wisconsin Registry for Alzheimer's Prevention (WRAP, a cohort enriched for AD risk factors, was recruited for a multimodal imaging investigation that included DTI and [C-11]Pittsburgh Compound B (PiB positron emission tomography (PET. Participants were grouped as amyloid positive (Aβ+, amyloid indeterminate (Aβi, or amyloid negative (Aβ− based on the amount and pattern of amyloid deposition. Regional voxel-wise analyses of four DTI metrics, fractional anisotropy (FA, mean diffusivity (MD, axial diffusivity (Da, and radial diffusivity (Dr, were performed based on amyloid grouping. Three regions of interest (ROIs, the cingulum adjacent to the corpus callosum, hippocampal cingulum, and lateral fornix, were selected based on their involvement in the early stages of AD. Voxel-wise analysis revealed higher FA among Aβ+ compared to Aβ− in all three ROIs and in Aβi compared to Aβ− in the cingulum adjacent to the corpus callosum. Follow-up exploratory whole-brain analyses were consistent with the ROI findings, revealing multiple regions where higher FA was associated with greater amyloid. Lower fronto-lateral gray matter MD was associated with higher amyloid burden. Further investigation showed a negative correlation between MD and PiB signal, suggesting that Aβ accumulation impairs diffusion. Interestingly, these findings in a largely presymptomatic sample are in contradistinction to relationships reported in the literature in symptomatic disease stages of Mild Cognitive Impairment and AD, which usually show higher MD and lower FA. Together with

  10. Altered whole-brain white matter networks in preclinical Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Florian Udo Fischer

    2015-01-01

    Our results suggest an impairment of WM networks in preclinical AD that is detectable while other structural imaging markers do not yet indicate incipient neurodegeneration. Moreover, these findings are specific to WM networks and cannot be explained by other surrogates of global WM integrity.

  11. Novel Scoring Criteria for the Evaluation of Ocular Graft-versus-Host Disease in a Preclinical Allogeneic Hematopoietic Stem Cell Transplantation Animal Model.

    Science.gov (United States)

    Perez, Victor L; Barsam, Alexander; Duffort, Stephanie; Urbieta, Maitee; Barreras, Henry; Lightbourn, Casey; Komanduri, Krishna V; Levy, Robert B

    2016-10-01

    Ocular complications occur after transplantation in 60% to 90% of chronic graft-versus-host disease (GVHD) patients and significantly impair vision-related quality of life. Ocular surface inflammation and dry eye disease are the most common manifestations of ocular GVHD. Ocular GVHD can be viewed as an excellent preclinical model that can be studied to understand the immune pathogenesis of this common and debilitating disease. A limitation of this is that only a few experimental models mimic the ocular complications after hematopoietic stem cell transplantation (HSCT) and have focused on the acute GVHD process. To address this issue, we used a preclinical animal model developed by our group where ocular involvement was preceded by systemic GVHD to gain insight regarding the contributing immune mechanisms. Employing this "matched unrelated donor" model enabled the development of clinical scoring criteria, which readily identified different degrees of ocular pathology at both the ocular surface and adnexa, dependent on the level of conditioning before HSCT. As far as we are aware, we report for the first time that these clinical and immune responses occur not only on the ocular surface, but they also heavily involve the lid margin region. In total, the present study reports a preclinical scoring model that can be applied to animal models as investigators look to further explore GVHD's immunologic effects at the level of the ocular surface and eyelid adnexa compartments. We speculate that future studies will use this clinical scoring index in combination with what is recognized histologically and correlated with serum biomarkers identified in chronic/ocular GVHD. Copyright © 2016 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.

  12. SPECT and PET imaging of angiogenesis and arteriogenesis in pre-clinical models of myocardial ischemia and peripheral vascular disease

    Energy Technology Data Exchange (ETDEWEB)

    Hendrikx, Geert [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht (Netherlands); Voeoe, Stefan [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Bauwens, Matthias [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); Maastricht University, School of Nutrition and Translational Research in Metabolism (NUTRIM), Maastricht (Netherlands); Post, Mark J. [Maastricht University, Department of Physiology, Maastricht (Netherlands); Maastricht University, Cardiovascular Research Institute Maastricht (CARIM), Maastricht (Netherlands); Mottaghy, Felix M. [Maastricht University Medical Centre MUMC+, Department of Nuclear Medicine, Postbox 5800, Maastricht (Netherlands); University Hospital, RWTH Aachen University, Department of Nuclear Medicine, Aachen (Germany)

    2016-12-15

    The extent of neovascularization determines the clinical outcome of coronary artery disease and other occlusive cardiovascular disorders. Monitoring of neovascularization is therefore highly important. This review article will elaborately discuss preclinical studies aimed at validating new nuclear angiogenesis and arteriogenesis tracers. Additionally, we will briefly address possible obstacles that should be considered when designing an arteriogenesis radiotracer. A structured medline search was the base of this review, which gives an overview on different radiopharmaceuticals that have been evaluated in preclinical models. Neovascularization is a collective term used to indicate different processes such as angiogenesis and arteriogenesis. However, while it is assumed that sensitive detection through nuclear imaging will facilitate translation of successful therapeutic interventions in preclinical models to the bedside, we still lack specific tracers for neovascularization imaging. Most nuclear imaging research to date has focused on angiogenesis, leaving nuclear arteriogenesis imaging largely overlooked. Although angiogenesis is the process which is best understood, there is no scarcity in theoretical targets for arteriogenesis imaging. (orig.)

  13. Development, validation and application of a new fornix template for studies of aging and preclinical Alzheimer's disease.

    Science.gov (United States)

    Brown, Christopher A; Johnson, Nathan F; Anderson-Mooney, Amelia J; Jicha, Gregory A; Shaw, Leslie M; Trojanowski, John Q; Van Eldik, Linda J; Schmitt, Frederick A; Smith, Charles D; Gold, Brian T

    2017-01-01

    We developed a merged younger-older adult template of the fornix and demonstrated its utility for studies of aging and preclinical Alzheimer's disease (AD). In Experiment 1, probabilistic tractography was used to reconstruct the fornix in younger and older adults and successful streamlines were then averaged to create a merged template in standard space. The new template includes the majority of the fornix from the hippocampal formation to the subcallosal region and the thalamus/hypothalamus. In Experiment 2, the merged template was validated as an appropriate measure for studies of aging, with comparisons against manual tracing measures indicating identical spatial coverage in younger and older adult groups. In Experiment 3, the merged template was found to outperform age-specific templates in measures of sensitivity and specificity computed on diffusion tensor imaging data of an independent participant cohort. In Experiment 4, relevance to preclinical AD was demonstrated via associations between fractional anisotropy within the new fornix template and cerebrospinal fluid markers of AD pathology (Aβ 42 and the t-tau/Aβ 42 ratio) in a third independent cohort of cognitively normal older adults. Our new template provides an appropriate measure for use in future studies seeking to characterize microstructural alterations in the fornix associated with aging and preclinical AD.

  14. Periodontal Disease and Systemic Health

    Science.gov (United States)

    ... Gum Disease and Other Diseases Gum Disease and Diabetes Gum Disease and Heart Disease Gum Disease and Other Systemic ... Gum Disease and Other Diseases Gum Disease and Diabetes Gum Disease and Heart Disease Gum Disease and Other Systemic ...

  15. NEMA NU 4-2008 Comparison of Preclinical PET Imaging Systems

    Science.gov (United States)

    Goertzen, Andrew L.; Bao, Qinan; Bergeron, Mélanie; Blankemeyer, Eric; Blinder, Stephan; Cañadas, Mario; Chatziioannou, Arion F.; Dinelle, Katherine; Elhami, Esmat; Jans, Hans-Sonke; Lage, Eduardo; Lecomte, Roger; Sossi, Vesna; Surti, Suleman; Tai, Yuan-Chuan; Vaquero, Juan José; Vicente, Esther; Williams, Darin A.; Laforest, Richard

    2014-01-01

    The National Electrical Manufacturers Association (NEMA) standard NU 4-2008 for performance measurements of small-animal tomographs was recently published. Before this standard, there were no standard testing procedures for preclinical PET systems, and manufacturers could not provide clear specifications similar to those available for clinical systems under NEMA NU 2-1994 and 2-2001. Consequently, performance evaluation papers used methods that were modified ad hoc from the clinical PET NEMA standard, thus making comparisons between systems difficult. Methods We acquired NEMA NU 4-2008 performance data for a collection of commercial animal PET systems manufactured since 2000: micro- PET P4, microPET R4, microPET Focus 120, microPET Focus 220, Inveon, ClearPET, Mosaic HP, Argus (formerly eXplore Vista), VrPET, LabPET 8, and LabPET 12. The data included spatial resolution, counting-rate performance, scatter fraction, sensitivity, and image quality and were acquired using settings for routine PET. Results The data showed a steady improvement in system performance for newer systems as compared with first-generation systems, with notable improvements in spatial resolution and sensitivity. Conclusion Variation in system design makes direct comparisons between systems from different vendors difficult. When considering the results from NEMA testing, one must also consider the suitability of the PET system for the specific imaging task at hand. PMID:22699999

  16. Anti-inflammatory and neuroprotective effects of an orally active apocynin derivative in pre-clinical models of Parkinson’s disease

    Directory of Open Access Journals (Sweden)

    Ghosh Anamitra

    2012-10-01

    Full Text Available Abstract Background Parkinson’s disease (PD is a devastating neurodegenerative disorder characterized by progressive motor debilitation, which affects several million people worldwide. Recent evidence suggests that glial cell activation and its inflammatory response may contribute to the progressive degeneration of dopaminergic neurons in PD. Currently, there are no neuroprotective agents available that can effectively slow the disease progression. Herein, we evaluated the anti-inflammatory and antioxidant efficacy of diapocynin, an oxidative metabolite of the naturally occurring agent apocynin, in a pre-clinical 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of PD. Methods Both pre-treatment and post-treatment of diapocynin were tested in the MPTP mouse model of PD. Diapocynin was administered via oral gavage to MPTP-treated mice. Following the treatment, behavioral, neurochemical and immunohistological studies were performed. Neuroinflammatory markers, such as ionized calcium binding adaptor molecule 1 (Iba-1, glial fibrillary acidic protein (GFAP, gp91phox and inducible nitric oxide synthase (iNOS, were measured in the nigrostriatal system. Nigral tyrosine hydroxylase (TH-positive neurons as well as oxidative markers 3-nitrotyrosine (3-NT, 4-hydroxynonenal (4-HNE and striatal dopamine levels were quantified for assessment of the neuroprotective efficacy of diapocynin. Results Oral administration of diapocynin significantly attenuated MPTP-induced microglial and astroglial cell activation in the substantia nigra (SN. MPTP-induced expression of gp91phox and iNOS activation in the glial cells of SN was also completely blocked by diapocynin. Notably, diapocynin markedly inhibited MPTP-induced oxidative markers including 3-NT and 4-HNE levels in the SN. Treatment with diapocynin also significantly improved locomotor activity, restored dopamine and its metabolites, and protected dopaminergic neurons and their nerve terminals in

  17. Novel Scoring Criteria for the Evaluation of Ocular Graft Versus Host Disease in a Pre-Clinical Allo-HSCT Animal Model

    Science.gov (United States)

    Perez, Victor L.; Barsam, Alexander; Duffort, Stephanie; Urbieta, Maitee; Barreras, Henry; Lightbourn, Casey; Levy, Robert B.

    2017-01-01

    Ocular complications occur after transplant in 60–90% of chronic graft versus host disease (GVHD) patients and significantly impair vision-related quality of life. Ocular surface inflammation and dry eye disease (DED) are the most common manifestations of ocular GVHD (oGVHD). oGVHD can be viewed as an excellent pre- clinical model that can be studied to understand the immune pathogenesis of this common and debilitating disease. A limitation of this is that only a few experimental models mimic the ocular complications following HSCT and have focused on the acute GVHD process. To address this issue, we used a pre-clinical animal model developed by our group where ocular involvement was preceded by systemic GVHD to gain insight regarding the contributing immune mechanisms. Employing this "MUD" model enabled the development of a clinical scoring criterion, which readily identified different degrees of ocular pathology at both the ocular surface and adnexa dependent on the level of conditioning prior to HSCT. As far as we are aware we report that for the first time these clinical and immune responses occur not only on the ocular surface, but also heavily involve the lid margin region. In total, the present study reports a pre-clinical scoring model that can be applied to animal models as investigators look to further explore GVHD's immunologic effects at the level of the ocular surface and eyelid adnexa compartments. We speculate that future studies will use this clinical scoring index in combination with what is recognized histologically and correlated with serum biomarkers being identified in chronic/ocular GVHD. PMID:27492793

  18. Pre-Clinical Tests of an Integrated CMOS Biomolecular Sensor for Cardiac Diseases Diagnosis.

    Science.gov (United States)

    Lee, Jen-Kuang; Wang, I-Shun; Huang, Chi-Hsien; Chen, Yih-Fan; Huang, Nien-Tsu; Lin, Chih-Ting

    2017-11-26

    Coronary artery disease and its related complications pose great threats to human health. In this work, we aim to clinically evaluate a CMOS field-effect biomolecular sensor for cardiac biomarkers, cardiac-specific troponin-I (cTnI), N -terminal prohormone brain natriuretic peptide (NT-proBNP), and interleukin-6 (IL-6). The CMOS biosensor is implemented via a standard commercialized 0.35 μm CMOS process. To validate the sensing characteristics, in buffer conditions, the developed CMOS biosensor has identified the detection limits of IL-6, cTnI, and NT-proBNP as being 45 pM, 32 pM, and 32 pM, respectively. In clinical serum conditions, furthermore, the developed CMOS biosensor performs a good correlation with an enzyme-linked immuno-sorbent assay (ELISA) obtained from a hospital central laboratory. Based on this work, the CMOS field-effect biosensor poses good potential for accomplishing the needs of a point-of-care testing (POCT) system for heart disease diagnosis.

  19. A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles.

    Science.gov (United States)

    Southwell, Amber L; Skotte, Niels H; Villanueva, Erika B; Østergaard, Michael E; Gu, Xiaofeng; Kordasiewicz, Holly B; Kay, Chris; Cheung, Daphne; Xie, Yuanyun; Waltl, Sabine; Dal Cengio, Louisa; Findlay-Black, Hailey; Doty, Crystal N; Petoukhov, Eugenia; Iworima, Diepiriye; Slama, Ramy; Ooi, Jolene; Pouladi, Mahmoud A; Yang, X William; Swayze, Eric E; Seth, Punit P; Hayden, Michael R

    2017-03-15

    Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most global benefit. Thus there is a need for preclinical models of HD recapitulating human HTT genetics. We previously generated a humanized mouse model of HD, Hu97/18, by intercrossing BACHD and YAC18 mice with knockout of the endogenous mouse HD homolog (Hdh). Hu97/18 mice recapitulate the genetics of HD, having two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of Caucasian descent. We have now generated a companion model, Hu128/21, by intercrossing YAC128 and BAC21 mice on the Hdh-/- background. Hu128/21 mice have two full-length, genomic human HTT transgenes heterozygous for the HD mutation and polymorphisms associated with HD in populations of East Asian descent and in a minority of patients from other ethnic groups. Hu128/21 mice display a wide variety of HD-like phenotypes that are similar to YAC128 mice. Additionally, both transgenes in Hu128/21 mice match the human HTT exon 1 reference sequence. Conversely, the BACHD transgene carries a floxed, synthetic exon 1 sequence. Hu128/21 mice will be useful for investigations of human HTT that cannot be addressed in Hu97/18 mice, for developing therapies targeted to exon 1, and for preclinical screening of personalized HTT lowering therapies in HD patients of East Asian descent. © The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Functional compensation or pathology in cortico-subcortical interactions in preclinical Huntington's disease?

    Science.gov (United States)

    Beste, Christian; Saft, Carsten; Yordanova, Juliana; Andrich, Jürgen; Gold, Ralf; Falkenstein, Michael; Kolev, Vasil

    2007-10-01

    Huntington's disease (HD) is an autosomal dominant neurological disorder, with degeneration amongst others affecting the basal ganglia dopaminergic system. Recent findings suggest compensatory as well as pathogenetic mechanisms mediated via the adenosine receptor system in the presymptomatic stage (pHD) of HD. The adenosine receptor system is functionally related to the dopaminergic system. In this study, we assessed error processing, a dopamine-dependent cognitive function, using an event-related potential the error negativity (Ne/ERN) in pHD and controls. This was done by means of a flanker task. The Ne consists of a cognitive and a motor component, expressed via different frequency bands. Time-frequency decomposition of the Ne into delta and theta sub-components was applied to assess if degeneration or compensation predominantly involve cognitive or motor processes. No parameter of the behavioral data (reaction times, error frequency, corrections, post-error slowing) differed between the groups. A selective increase in the power of the cognitive delta-Ne component was found in pHD relative to controls inversely related to the estimated age of onset (eAO). Thus, the increase in the power of the cognitive delta-Ne component was stronger in pHD with an earlier eAO. An earlier eAO implies stronger pathogenetic mechanisms. Due to the behavioral data our results speak for a solely cognitive compensating-mechanism controlling performance monitoring in pHD. In contrast, correlations with eAO suggest that the increase in delta-Ne activity is also related to pathogenesis. It is proposed that compensation is a transient effect of the whole pathogenetic dynamics of HD, with these two processes not foreclosing each other.

  1. Iterative Image Processing for Early Diagnostic of Beta-Amyloid Plaque Deposition in Pre-Clinical Alzheimer's Disease Studies.

    Science.gov (United States)

    Slavine, Nikolai V; Kulkarni, Padmakar V; McColl, Roderick W

    2017-08-01

    To test and evaluate an efficient iterative image processing strategy to improve the quality of sub-optimal pre-clinical PET images. A novel iterative resolution subsets-based method to reduce noise and enhance resolution (RSEMD) has been demonstrated on examples of PET imaging studies of Alzheimer's disease (AD) plaques deposition in mice brains. The RSEMD method was applied to imaging studies of non-invasive detection of beta-amyloid plaque in transgenic mouse models of AD. Data acquisition utilized a Siemens Inveon® micro PET/CT device. Quantitative uptake of the tracer in control and AD mice brains was determined by counting the extent of plaque deposition by histological staining. The pre-clinical imaging software inviCRO ® was used for fitting the recovery PET images to the mouse brain atlas and obtaining the time activity curves (TAC) from different brain areas. In all of the AD studies the post-processed images proved to have higher resolution and lower noise as compared with images reconstructed by conventional OSEM method. In general, the values of SNR reached a plateau at around 10 iterations with an improvement factor of about 2 over sub-optimal PET brain images. A rapidly converging, iterative deconvolution image processing algorithm with a resolution subsets-based approach RSEMD has been used for quantitative studies of changes in Alzheimer's pathology over time. The RSEMD method can be applied to sub-optimal clinical PET brain images to improve image quality to diagnostically acceptable levels and will be crucial in order to facilitate diagnosis of AD progression at the earliest stages.

  2. Infectious prions in pre-clinical deer and transmission of chronic wasting disease solely by environmental exposure.

    Directory of Open Access Journals (Sweden)

    Candace K Mathiason

    Full Text Available Key to understanding the epidemiology and pathogenesis of prion diseases, including chronic wasting disease (CWD of cervids, is determining the mode of transmission from one individual to another. We have previously reported that saliva and blood from CWD-infected deer contain sufficient infectious prions to transmit disease upon passage into naïve deer. Here we again use bioassays in deer to show that blood and saliva of pre-symptomatic deer contain infectious prions capable of infecting naïve deer and that naïve deer exposed only to environmental fomites from the suites of CWD-infected deer acquired CWD infection after a period of 15 months post initial exposure. These results help to further explain the basis for the facile transmission of CWD, highlight the complexities associated with CWD transmission among cervids in their natural environment, emphasize the potential utility of blood-based testing to detect pre-clinical CWD infection, and could augur similar transmission dynamics in other prion infections.

  3. Development of a prototype gantry system for preclinical x-ray phase-contrast computed tomography

    International Nuclear Information System (INIS)

    Tapfer, Arne; Bech, Martin; Pauwels, Bart; Liu Xuan; Bruyndonckx, Peter; Sasov, Alexander; Kenntner, Johannes; Mohr, Juergen; Walter, Marco; Schulz, Joachim; Pfeiffer, Franz

    2011-01-01

    Purpose: To explore the potential of grating-based x-ray phase-contrast imaging for clinical applications, a first compact gantry system was developed. It is designed such that it can be implemented into an in-vivo small-animal phase-contrast computed tomography (PC-CT) scanner. The purpose of the present study is to assess the accuracy and quantitativeness of the described gantry in both absorption and phase-contrast. Methods: A phantom, containing six chemically well-defined liquids, was constructed. A tomography scan with cone-beam reconstruction of this phantom was performed yielding the spatial distribution of the linear attenuation coefficient μ and decrement δ of the complex refractive index. Theoretical values of μ and δ were calculated for each liquid from tabulated data and compared with the experimentally measured values. Additionally, a color-fused image representation is proposed to display the complementary absorption and phase-contrast information in a single image. Results: Experimental and calculated data of the phantom agree well confirming the quantitativeness and accuracy of the reconstructed spatial distributions of μ and δ. The proposed color-fused image representation, which combines the complementary absorption and phase information, considerably helps in distinguishing the individual substances. Conclusions: The concept of grating-based phase-contrast computed tomography (CT) can be implemented into a compact, cone-beam geometry gantry setup. The authors believe that this work represents an important milestone in translating phase-contrast x-ray imaging from previous proof-of-principle experiments to first preclinical biomedical imaging applications on small-animal models.

  4. Concise Review: Review and Perspective of Cell Dosage and Routes of Administration From Preclinical and Clinical Studies of Stem Cell Therapy for Heart Disease.

    Science.gov (United States)

    Golpanian, Samuel; Schulman, Ivonne H; Ebert, Ray F; Heldman, Alan W; DiFede, Darcy L; Yang, Phillip C; Wu, Joseph C; Bolli, Roberto; Perin, Emerson C; Moyé, Lem; Simari, Robert D; Wolf, Ariel; Hare, Joshua M

    2016-02-01

    An important stage in the development of any new therapeutic agent is establishment of the optimal dosage and route of administration. This can be particularly challenging when the treatment is a biologic agent that might exert its therapeutic effects via complex or poorly understood mechanisms. Multiple preclinical and clinical studies have shown paradoxical results, with inconsistent findings regarding the relationship between the cell dose and clinical benefit. Such phenomena can, at least in part, be attributed to variations in cell dosing or concentration and the route of administration (ROA). Although clinical trials of cell-based therapy for cardiovascular disease began more than a decade ago, specification of the optimal dosage and ROA has not been established. The present review summarizes what has been learned regarding the optimal cell dosage and ROA from preclinical and clinical studies of stem cell therapy for heart disease and offers a perspective on future directions. Significance: Preclinical and clinical studies on cell-based therapy for cardiovascular disease have shown inconsistent results, in part because of variations in study-specific dosages and/or routes of administration (ROA). Future preclinical studies and smaller clinical trials implementing cell-dose and ROA comparisons are warranted before proceeding to pivotal trials. ©AlphaMed Press.

  5. Pre-clinical Evaluation of an Adult Extracoproreal Carbon Dioxide Removal System for Pediatric Application

    Directory of Open Access Journals (Sweden)

    Yerbol Mussin

    2014-12-01

    Full Text Available Introduction. Adult extracorporeal carbon dioxide removal (ECCO2R systems and pediatric ECMO share the common objectives of having a low blood flow rate and low priming volume while safely maintaining sufficient respiratory support. The Hemolung is a highly simplified adult ECCO2R system intended for partial respiratory support in adult patients with acute hypercapnic respiratory failure. The objective of this work was to conduct pre-clinical feasibility studies to determine if a highly efficient, active-mixing, adult ECCO2R system can safely be translated to the pediatric population. Methods. 14 healthy nonsedated juvenile sheep were used for acute (2 animals and 7-day chronic (12 animals in-vivo studies to evaluate treatment safety independently of respiratory related injuries. In all evaluations, we hypothesized that gas exchange capabilities of the Hemolung RAS in this model would be equivalent to the adult configuration performance at similar blood flows - minimum CO2 removal of 50 mL/min at a venous partial pressure of CO2 equal to 45 mmHg. Target blood flow rates were set to a minimum of 280 mL/min. Swan Ganz catheters were used under general anesthesia in the two acute subjects to evaluate blood gas status in the pulmonary artery.Results. The Hemolung RAS was found to have adequate gas exchange and pumping capabilities for full respiratory support for subjects weighing 3 – 25 kg. The Hemolung device was estimated to provide a partial respiratory support for subjects weighing 27 – 34 kg. The seven-day studies in juvenile sheep demonstrated that veno-venous extracorporeal support could be provided safely at low flows with no significant adverse reactions related to device operation.Conclusion. The study outcomes suggest the potential use of the Hemolung RAS in a veno-venous pediatric configuration to safely provide respiratory support utilizing a significantly less complex system than traditional pediatric ECMO. 

  6. Relationship of serum osteoprotegerin with arterial stiffness, preclinical atherosclerosis, and disease activity in patients with ankylosing spondylitis.

    Science.gov (United States)

    Serdaroğlu Beyazal, Münevver; Erdoğan, Turan; Türkyılmaz, Aysegül Kücükali; Devrimsel, Gül; Cüre, Medine Cumhur; Beyazal, Mehmet; Sahin, Ismail

    2016-09-01

    Patients with ankylosing spondylitis (AS) reportedly have a higher mortality and morbidity risk. Osteoprotegerin (OPG) was recently defined as an important cardiovascular (CV) marker in the general population. We aimed to assess the relationship of serum OPG levels with arterial stiffness, carotid intima media thickness (CIMT), and clinical and laboratory data in AS patients. We examined 60 AS patients without CV disease or risk factors and 50 healthy controls. Disease activity was evaluated using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and the Ankylosing Spondylitis Disease Activity Score (ASDAS), whereas functional capacity was evaluated using the Bath Ankylosing Spondylitis Functional Index (BASFI). Serum OPG levels were measured with the enzyme-linked immunosorbent assay. Carotid-femoral pulse wave velocity (PWV) was used as an indicator of arterial stiffness, whereas CIMT (examined via carotid ultrasonography) was used to evaluate preclinical atherosclerosis. The mean serum OPG level, PWV, and CIMT were significantly higher in AS patients than in controls (106.7 ± 50.9 vs. 58.1 ± 12.7 pg/mL; 7.4 ± 1.8 vs. 6.2 ± 1.2 m/s; 0.72 ± 0.13 vs. 0.57 ± 0.07 mm, respectively; P < 0.001 for all). In AS patients, the serum OPG levels were not significantly correlated with PWV and CIMT but were significantly correlated with erthrocyte sedimentation rate, BASFI, and ASDAS. AS patients without CV disease or risk exhibited high OPG levels and increased PWV and CIMT values. Although OPG levels were not significantly correlated with PWV or CIMT, future long-term follow-up studies will help define the predictive value of OPG in these patients.

  7. Imaging mass spectrometry (IMS) of cortical lipids from preclinical to severe stages of Alzheimer's disease.

    Science.gov (United States)

    Gónzalez de San Román, E; Manuel, I; Giralt, M T; Ferrer, I; Rodríguez-Puertas, R

    2017-09-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disease affecting millions of patients worldwide. Previous studies have demonstrated alterations in the lipid composition of lipid extracts from plasma and brain samples of AD patients. However, there is no consensus regarding the qualitative and quantitative changes of lipids in brains from AD patients. In addition, the recent developments in imaging mass spectrometry methods are leading to a new stage in the in situ analysis of lipid species in brain tissue slices from human postmortem samples. The present study uses the matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI-IMS), permitting the direct anatomical analysis of lipids in postmortem brain sections from AD patients, which are compared with the intensity of the lipid signal in samples from matched subjects with no neurological diseases. The frontal cortex samples from AD patients were classified in three groups based on Braak's histochemical criteria, ranging from non-cognitively impaired patients to those severely affected. The main results indicate a depletion of different sulfatide lipid species from the earliest stages of the disease in both white and gray matter areas of the frontal cortex. Therefore, the decrease in sulfatides in cortical areas could be considered as a marker of the disease, but may also indicate neurochemical modifications related to the pathogenesis of the disease. This article is part of a Special Issue entitled: Membrane Lipid Therapy: Drugs Targeting Biomembranes edited by Pablo V. Escribá. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Preclinical MRI and NMR Biomarkers of Alzheimer’s Disease: Concepts and Applications

    Directory of Open Access Journals (Sweden)

    Marc Dhenain

    2008-01-01

    Full Text Available Alzheimer’s disease is an important social and economic issue for our societies. The development of therapeutics against this severe dementia requires assessing the effects of new drugs in animal models thanks to dedicated biomarkers. This review first overviews Alzheimer’s disease and its models as well as the concept of biomarkers. It then focuses on MRI and NMR biomarkers of Alzheimer’s disease in animals. Anatomical markers such as atrophy and angiography are useful to phenotype newly developed models of Alzheimer’s disease, even if the alterations in these animals are not as severe as in humans. Amyloid plaques imaging is a promising marker of the pathology in animals, and is a rapidly evolving field of MRI. Functional methods such as perfusion and diffusion imaging or spectroscopy are able to detect alterations in transgenic mice mimicking Alzheimer and also to show similar alterations than in humans. They can thus be good translational markers of the disease. Manganese-Enhanced MRI shows a reduction of neuronal transportation in transgenic models of Alzheimer and it allows monitoring improvements induced by treatments of the disease. It is thus a promising biomarker of the pathology in animals.

  9. Preclinical MRI and NMR Bio-markers of Alzheimer's Disease: Concepts and Applications

    International Nuclear Information System (INIS)

    Dhenain, M.; Dhenain, M.; Dhenain, M.

    2008-01-01

    Alzheimer's disease is an important social and economic issue for our societies. The development of therapeutics against this severe dementia requires assessing the effects of new drugs in animal models thanks to dedicated bio-markers. This review first overviews Alzheimer's disease and its models as well as the concept of bio-markers. It then focuses on MRI and NMR bio-markers of Alzheimer's disease in animals. Anatomical markers such as atrophy and angiography are useful to phenotype newly developed models of Alzheimer's disease, even if the alterations in these animals are not as severe as in humans. Amyloid plaques imaging is a promising marker of the pathology in animals, and is a rapidly evolving field of MRI. Functional methods such as perfusion and diffusion imaging or spectroscopy are able to detect alterations in transgenic mice mimicking Alzheimer and also to show similar alterations than in humans. They can thus be good translational markers of the disease. Manganese-Enhanced MRI shows a reduction of neuronal transportation in transgenic models of Alzheimer and it allows monitoring improvements induced by treatments of the disease. It is thus a promising bio-marker of the pathology in animals. (authors)

  10. Molecular changes underlying reduced pineal melatonin levels in Alzheimer disease: alterations in preclinical and clinical stages

    NARCIS (Netherlands)

    Wu, Ying-Hui; Feenstra, Matthijs G. P.; Zhou, Jiang-Ning; Liu, Rong-Yu; Toranõ, Javier Sastre; van Kan, Hendrikus J. M.; Fischer, David F.; Ravid, Rivka; Swaab, Dick F.

    2003-01-01

    A disturbed sleep-wake rhythm is common in Alzheimer disease (AD) patients and correlated with decreased melatonin levels and a disrupted circadian melatonin rhythm. Melatonin levels in the cerebrospinal fluid are decreased during the progression of AD neuropathology (as determined by the Braak

  11. Evaluating Health Span in Preclinical Models of Aging and Disease: Guidelines, Challenges, and Opportunities for Geroscience

    Science.gov (United States)

    Huffman, Derek M.; Justice, Jamie N.; Stout, Michael B.; Kirkland, James L.; Barzilai, Nir

    2016-01-01

    Life extension is no longer considered sufficient evidence of delayed aging in research animals. It must also be demonstrated that a broad swathe of health indicators have been extended. During a retreat of the Geroscience Network, a consortium of basic and clinical aging researchers, potential measures of mouse health were considered for their potential as easily standardized, highly informative metrics. Major health domains considered were neuromuscular, cognitive, cardiovascular, metabolic, and inflammatory functions as well as body composition and energetics and a multitude of assays interrogating these domains. A particularly sensitive metric of health is the ability to respond to, and recover, from stress. Therefore, the Network also considered stresses of human relevance that could be implemented in mouse models to assess frailty and resilience. Mouse models already exist for responses to forced immobility, cancer chemotherapy, infectious diseases, dietary challenges, and surgical stress, and it was felt that these could be employed to determine whether putative senescence-retarding interventions increased and extended organismal robustness. The Network discussed challenges in modeling age-related human chronic diseases and concluded that more attention needs to be paid to developing disease models with later age of onset, models of co- and multimorbidity, diversifying the strains and sexes commonly used in aging research, and considering additional species. PMID:27535967

  12. Relationship of cognitive reserve and CSF biomarkers to emergence of clinical symptoms in preclinical Alzheimer’s Disease

    Science.gov (United States)

    Soldan, Anja; Pettigrew, Corinne; Li, Shanshan; Wang, Mei-Cheng; Moghekar, Abhay; Selnes, Ola A.; Albert, Marilyn; O’Brien, Richard

    2013-01-01

    Levels of β-amyloid and phosphorylated tau (p-tau), as measured in cerebrospinal fluid (CSF), have been associated with risk of progressing from normal cognition to onset of clinical symptoms during preclinical Alzheimer’s disease (AD). We examined whether cognitive reserve (CR) modifies this association. CSF was obtained at baseline from 239 participants (mean age 57.2 years) who had been followed for up to 17 years with clinical and cognitive assessments (mean follow-up 8 years). A composite score based on the National Adult Reading Test (NART), vocabulary, and years of education at baseline was used as an index of CR. Cox regression models showed that increased risk of progressing from normal cognition to symptom onset was associated with lower CR, lower baseline β-amyloid, and higher baseline p-tau. There was no interaction between CR and β-amyloid, suggesting that the protective effects of higher CR are equivalent across the observed range of amyloid levels. By contrast, both tau and p-tau interacted with CR, indicating that CR was more protective at lower levels of tau and p-tau. PMID:23916061

  13. A test of lens opacity as an indicator of preclinical Alzheimer Disease.

    Science.gov (United States)

    Bei, Ling; Shui, Ying-Bo; Bai, Fang; Nelson, Suzanne K; Van Stavern, Gregory P; Beebe, David C

    2015-11-01

    Previous studies reported that characteristic lens opacities were present in Alzheimer Disease (AD) patients postmortem. We therefore determined whether cataract grade or lens opacity is related to the risk of Alzheimer dementia in participants who have biomarkers that predict a high risk of developing the disease. AD biomarker status was determined by positron emission tomography-Pittsburgh compound B (PET-PiB) imaging and cerebrospinal fluid (CSF) levels of Aβ42. Cognitively normal participants with a clinical dementia rating of zero (CDR = 0; N = 40) or with slight evidence of dementia (CDR = 0.5; N = 2) were recruited from longitudinal studies of memory and aging at the Washington University Knight Alzheimer's Disease Research Center. The age, sex, race, cataract type and cataract grade of all participants were recorded and an objective measure of lens light scattering was obtained for each eye using a Scheimpflug camera. Twenty-seven participants had no biomarkers of Alzheimer dementia and were CDR = 0. Fifteen participants had biomarkers indicating increased risk of AD, two of which were CDR = 0.5. Participants who were biomarker positive were older than those who were biomarker negative. Biomarker positive participants had more advanced cataracts and increased cortical light scattering, none of which reached statistical significance after adjustment for age. We conclude that cataract grade or lens opacity is unlikely to provide a non-invasive measure of the risk of developing Alzheimer dementia. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. The Preclinical Research Progress of Stem Cells Therapy in Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Jun Zhang

    2016-01-01

    Full Text Available Parkinson’s disease (PD is a type of degenerative disorder of the basal ganglia, causing tremor at rest, muscle rigidity hypokinesia, and dementia. The effectiveness of drug treatments gradually diminishes because the conversion to dopamine within the brain is increasingly disrupted by the progressive degeneration of the dopaminergic terminals. After long-term treatment, most patients with PD suffer from disability that cannot be satisfactorily controlled. To solve these issues, stem cells have recently been used for cell therapy of PD. In this review, the characteristics of different stem cells and their therapeutic effects on PD treatment will be discussed.

  15. Local and distributed PiB accumulation associated with development of preclinical Alzheimer’s disease

    OpenAIRE

    Brier, Matthew R.; McCarthy, John E.; Benzinger, Tammie L.S.; Stern, Ari; Su, Yi; Friedrichsen, Karl A.; Morris, John C.; Ances, Beau M.; Vlassenko, Andrei G.

    2015-01-01

    Amyloid-beta plaques are a hallmark of Alzheimer’s disease (AD) that can be assessed by amyloid imaging (e.g., Pittsburgh B compound [PiB]) and summarized as a scalar value. Summary values may have clinical utility but are an average over many regions of interest, potentially obscuring important topography. This study investigates the longitudinal evolution of amyloid topographies in cognitively normal older adults who had normal (N = 131) or abnormal (N = 26) PiB scans at baseline. At 3 year...

  16. Compensation in Preclinical Huntington's Disease: Evidence From the Track-On HD Study

    Science.gov (United States)

    Klöppel, Stefan; Gregory, Sarah; Scheller, Elisa; Minkova, Lora; Razi, Adeel; Durr, Alexandra; Roos, Raymund A.C.; Leavitt, Blair R.; Papoutsi, Marina; Landwehrmeyer, G. Bernhard; Reilmann, Ralf; Borowsky, Beth; Johnson, Hans; Mills, James A.; Owen, Gail; Stout, Julie; Scahill, Rachael I.; Long, Jeffrey D.; Rees, Geraint; Tabrizi, Sarah J.

    2015-01-01

    Background Cognitive and motor task performance in premanifest Huntington's disease (HD) gene-carriers is often within normal ranges prior to clinical diagnosis, despite loss of brain volume in regions involved in these tasks. This indicates ongoing compensation, with the brain maintaining function in the presence of neuronal loss. However, thus far, compensatory processes in HD have not been modeled explicitly. Using a new model, which incorporates individual variability related to structural change and behavior, we sought to identify functional correlates of compensation in premanifest-HD gene-carriers. Methods We investigated the modulatory effects of regional brain atrophy, indexed by structural measures of disease load, on the relationship between performance and brain activity (or connectivity) using task-based and resting-state functional MRI. Findings Consistent with compensation, as atrophy increased performance-related activity increased in the right parietal cortex during a working memory task. Similarly, increased functional coupling between the right dorsolateral prefrontal cortex and a left hemisphere network in the resting-state predicted better cognitive performance as atrophy increased. Such patterns were not detectable for the left hemisphere or for motor tasks. Interpretation Our findings provide evidence for active compensatory processes in premanifest-HD for cognitive demands and suggest a higher vulnerability of the left hemisphere to the effects of regional atrophy. PMID:26629536

  17. ERP-based detection of brain pathology in rat models for preclinical Alzheimer's disease

    Science.gov (United States)

    Nouriziabari, Seyed Berdia

    Early pathological features of Alzheimer's disease (AD) include the accumulation of hyperphosphorylated tau protein (HP-tau) in the entorhinal cortex and progressive loss of basal forebrain (BF) cholinergic neurons. These pathologies are known to remain asymptomatic for many years before AD is clinically diagnosed; however, they may induce aberrant brain processing which can be captured as an abnormality in event-related potentials (ERPs). Here, we examined cortical ERPs while a differential associative learning paradigm was applied to adult male rats with entorhinal HP-tau, pharmacological blockade of muscarinic acetylcholine receptors, or both conditions. Despite no impairment in differential associative and reversal learning, each pathological feature induced distinct abnormality in cortical ERPs to an extent that was sufficient for machine classifiers to accurately detect a specific type of pathology based on these ERP features. These results highlight a potential use of ERPs during differential associative learning as a biomarker for asymptomatic AD pathology.

  18. Fluctuations in Protein Aggregation: Design of Preclinical Screening for Early Diagnosis of Neurodegenerative Disease

    Science.gov (United States)

    Costantini, Giulio; Budrikis, Zoe; Taloni, Alessandro; Buell, Alexander K.; Zapperi, Stefano; La Porta, Caterina A. M.

    2016-09-01

    Autocatalytic fibril nucleation has recently been proposed to be a determining factor for the spread of neurodegenerative diseases, but the same process could also be exploited to amplify minute quantities of protein aggregates in a diagnostic context. Recent advances in microfluidic technology allow the analysis of protein aggregation in micron-scale samples, potentially enabling such diagnostic approaches, but the theoretical foundations for the analysis and interpretation of such data are, so far, lacking. Here, we study computationally the onset of protein aggregation in small volumes and show that the process is ruled by intrinsic fluctuations whose volume-dependent distribution we also estimate theoretically. Based on these results, we develop a strategy to quantify in silico the statistical errors associated with the detection of aggregate-containing samples. Our work explores a different perspective on the forecasting of protein aggregation in asymptomatic subjects.

  19. Quality of Reporting and Adherence to ARRIVE Guidelines in Animal Studies for Chagas Disease Preclinical Drug Research: A Systematic Review.

    Directory of Open Access Journals (Sweden)

    Julián Ernesto Nicolás Gulin

    2015-11-01

    Full Text Available Publication of accurate and detailed descriptions of methods in research articles involving animals is essential for health scientists to accurately interpret published data, evaluate results and replicate findings. Inadequate reporting of key aspects of experimental design may reduce the impact of studies and could act as a barrier to translation of research findings. Reporting of animal use must be as comprehensive as possible in order to take advantage of every study and every animal used. Animal models are essential to understanding and assessing new chemotherapy candidates for Chagas disease pathology, a widespread parasitic disease with few treatment options currently available. A systematic review was carried out to compare ARRIVE guidelines recommendations with information provided in publications of preclinical studies for new anti-Trypanosoma cruzi compounds. A total of 83 publications were reviewed. Before ARRIVE guidelines, 69% of publications failed to report any macroenvironment information, compared to 57% after ARRIVE publication. Similar proportions were observed when evaluating reporting of microenvironmental information (56% vs. 61%. Also, before ARRIVE guidelines publication, only 13% of papers described animal gender, only 18% specified microbiological status and 13% reported randomized treatment assignment, among other essential information missing or incomplete. Unfortunately, publication of ARRIVE guidelines did not seem to enhance reporting quality, compared to papers appeared before ARRIVE publication. Our results suggest that there is a strong need for the scientific community to improve animal use description, animal models employed, transparent reporting and experiment design to facilitate its transfer and application to the affected human population. Full compliance with ARRIVE guidelines, or similar animal research reporting guidelines, would be an excellent start in this direction.

  20. Quality of Reporting and Adherence to ARRIVE Guidelines in Animal Studies for Chagas Disease Preclinical Drug Research: A Systematic Review.

    Science.gov (United States)

    Gulin, Julián Ernesto Nicolás; Rocco, Daniela Marisa; García-Bournissen, Facundo

    2015-11-01

    Publication of accurate and detailed descriptions of methods in research articles involving animals is essential for health scientists to accurately interpret published data, evaluate results and replicate findings. Inadequate reporting of key aspects of experimental design may reduce the impact of studies and could act as a barrier to translation of research findings. Reporting of animal use must be as comprehensive as possible in order to take advantage of every study and every animal used. Animal models are essential to understanding and assessing new chemotherapy candidates for Chagas disease pathology, a widespread parasitic disease with few treatment options currently available. A systematic review was carried out to compare ARRIVE guidelines recommendations with information provided in publications of preclinical studies for new anti-Trypanosoma cruzi compounds. A total of 83 publications were reviewed. Before ARRIVE guidelines, 69% of publications failed to report any macroenvironment information, compared to 57% after ARRIVE publication. Similar proportions were observed when evaluating reporting of microenvironmental information (56% vs. 61%). Also, before ARRIVE guidelines publication, only 13% of papers described animal gender, only 18% specified microbiological status and 13% reported randomized treatment assignment, among other essential information missing or incomplete. Unfortunately, publication of ARRIVE guidelines did not seem to enhance reporting quality, compared to papers appeared before ARRIVE publication. Our results suggest that there is a strong need for the scientific community to improve animal use description, animal models employed, transparent reporting and experiment design to facilitate its transfer and application to the affected human population. Full compliance with ARRIVE guidelines, or similar animal research reporting guidelines, would be an excellent start in this direction.

  1. Quality of Reporting and Adherence to ARRIVE Guidelines in Animal Studies for Chagas Disease Preclinical Drug Research: A Systematic Review

    Science.gov (United States)

    Gulin, Julián Ernesto Nicolás; Rocco, Daniela Marisa; García-Bournissen, Facundo

    2015-01-01

    Publication of accurate and detailed descriptions of methods in research articles involving animals is essential for health scientists to accurately interpret published data, evaluate results and replicate findings. Inadequate reporting of key aspects of experimental design may reduce the impact of studies and could act as a barrier to translation of research findings. Reporting of animal use must be as comprehensive as possible in order to take advantage of every study and every animal used. Animal models are essential to understanding and assessing new chemotherapy candidates for Chagas disease pathology, a widespread parasitic disease with few treatment options currently available. A systematic review was carried out to compare ARRIVE guidelines recommendations with information provided in publications of preclinical studies for new anti-Trypanosoma cruzi compounds. A total of 83 publications were reviewed. Before ARRIVE guidelines, 69% of publications failed to report any macroenvironment information, compared to 57% after ARRIVE publication. Similar proportions were observed when evaluating reporting of microenvironmental information (56% vs. 61%). Also, before ARRIVE guidelines publication, only 13% of papers described animal gender, only 18% specified microbiological status and 13% reported randomized treatment assignment, among other essential information missing or incomplete. Unfortunately, publication of ARRIVE guidelines did not seem to enhance reporting quality, compared to papers appeared before ARRIVE publication. Our results suggest that there is a strong need for the scientific community to improve animal use description, animal models employed, transparent reporting and experiment design to facilitate its transfer and application to the affected human population. Full compliance with ARRIVE guidelines, or similar animal research reporting guidelines, would be an excellent start in this direction. PMID:26587586

  2. Allopregnanolone preclinical acute pharmacokinetic and pharmacodynamic studies to predict tolerability and efficacy for Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Ronald W Irwin

    Full Text Available To develop allopregnanolone as a therapeutic for Alzheimer's disease, we investigated multiple formulations and routes of administration in translationally relevant animal models of both sexes. Subcutaneous, topical (transdermal and intranasal, intramuscular, and intravenous allopregnanolone were bolus-administered. Pharmacokinetic analyses of intravenous allopregnanolone in rabbit and mouse indicated that peak plasma and brain levels (3-fold brain/plasma ratios at 5min were sufficient to activate neuroregenerative responses at sub-sedative doses. Slow-release subcutaneous suspension of allopregnanolone displayed 5-fold brain/plasma ratio at Cmax at 30min. At therapeutic doses by either subcutaneous or intravenous routes, allopregnanolone mouse plasma levels ranged between 34-51ng/ml by 30min, comparable to published endogenous human level in the third trimester of pregnancy. Exposure to subcutaneous, topical, intramuscular, and intravenous allopregnanolone, at safe and tolerable doses, increased hippocampal markers of neurogenesis including BrdU and PCNA in young 3xTgAD and aged wildtype mice. Intravenous allopregnanolone transiently and robustly phosphorylated CREB within 5min and increased levels of neuronal differentiation transcription factor NeuroD within 4h. Neurogenic efficacy was achieved with allopregnanolone brain exposure of 300-500hr*ng/g. Formulations were tested to determine the no observable adverse effect level (NOAEL and maximally tolerated doses (MTD in male and female rats by sedation behavior time course. Sex differences were apparent, males exhibited ≥40% more sedation time compared to females. Allopregnanolone formulated in sulfobutyl-ether-beta-cyclodextrin at optimized complexation ratio maximized allopregnanolone delivery and neurogenic efficacy. To establish the NOAEL and MTD for Allo-induced sedation using a once-per-week intravenous regenerative treatment regimen: In female rats the NOAEL was 0.5mg/kg and MTD 2mg

  3. Cognitive reserve and long-term change in cognition in aging and preclinical Alzheimer's disease.

    Science.gov (United States)

    Soldan, Anja; Pettigrew, Corinne; Cai, Qing; Wang, Jiangxia; Wang, Mei-Cheng; Moghekar, Abhay; Miller, Michael I; Albert, Marilyn

    2017-12-01

    We examined if baseline levels of cognitive reserve (CR) and of Alzheimer's disease (AD) biomarkers modify the rate of change in cognition among individuals with normal cognition at baseline (n = 303, mean baseline age = 57 years, mean follow-up = 12 years); 66 participants subsequently developed mild cognitive impairment (MCI) or dementia due to AD. CR was indexed by years of education, reading, and vocabulary measures. AD biomarkers were measured with a composite score composed of measures of amyloid, phosphorylated tau, and neurodegeneration. Higher CR scores were associated with better cognitive performance but did not modify the rate of change in cognition among those who remained cognitively normal, nor among those who progressed to MCI before symptom onset, independent of baseline biomarker levels. However, higher CR scores were associated with faster cognitive decline after symptom onset of MCI. These results suggest that the mechanism by which CR mediates the relationship between pathology and cognitive function is by delaying the onset of symptoms rather than reducing the rate of cognitive decline. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Neuropsychological measures that detect early impairment and decline in preclinical Alzheimer disease.

    Science.gov (United States)

    Schindler, Suzanne E; Jasielec, Mateusz S; Weng, Hua; Hassenstab, Jason J; Grober, Ellen; McCue, Lena M; Morris, John C; Holtzman, David M; Xiong, Chengjie; Fagan, Anne M

    2017-08-01

    Identifying which neuropsychological measures detect early cognitive changes associated with Alzheimer disease (AD), brain pathology would be helpful clinically for the diagnosis of early AD and for the design of clinical trials. We evaluated which neuropsychological measures in our cognitive battery are most strongly associated with cerebrospinal fluid (CSF) biomarkers of AD brain pathology. We studied a large cohort (n = 233) of middle-to older-aged community-dwelling individuals (mean age 61 years) who had no clinical symptoms of dementia and underwent baseline CSF collection at baseline. Participants completed a battery of 9 neuropsychological measures at baseline and then every 1 to 3 years. CSF tau/Aβ42 was associated with baseline performance on 5/9 neuropsychological measures, especially measures of episodic memory, and longitudinal performance on 7/9 neuropsychological measures, especially measures of global cognition. The free recall portion of the Free and Cued Selective Reminding Task (FCSRT-free) detected declining cognition in the high CSF tau/Aβ42 group the earliest, followed by another measure of episodic memory and a sequencing task. Copyright © 2017 Elsevier Inc. All rights reserved.

  5. Behavioral phenotyping of Parkin-deficient mice: looking for early preclinical features of Parkinson's disease.

    Directory of Open Access Journals (Sweden)

    Daniel Rial

    Full Text Available There is considerable evidence showing that the neurodegenerative processes that lead to sporadic Parkinson's disease (PD begin many years before the appearance of the characteristic motor symptoms. Neuropsychiatric, sensorial and cognitive deficits are recognized as early non-motor manifestations of PD, and are not attenuated by the current anti-parkinsonian therapy. Although loss-of-function mutations in the parkin gene cause early-onset familial PD, Parkin-deficient mice do not display spontaneous degeneration of the nigrostriatal pathway or enhanced vulnerability to dopaminergic neurotoxins such as 6-OHDA and MPTP. Here, we employed adult homozygous C57BL/6 mice with parkin gene deletion on exon 3 (parkin-/- to further investigate the relevance of Parkin in the regulation of non-motor features, namely olfactory, emotional, cognitive and hippocampal synaptic plasticity. Parkin-/- mice displayed normal performance on behavioral tests evaluating olfaction (olfactory discrimination, anxiety (elevated plus-maze, depressive-like behavior (forced swimming and tail suspension and motor function (rotarod, grasping strength and pole. However, parkin-/- mice displayed a poor performance in the open field habituation, object location and modified Y-maze tasks suggestive of procedural and short-term spatial memory deficits. These behavioral impairments were accompanied by impaired hippocampal long-term potentiation (LTP. These findings indicate that the genetic deletion of parkin causes deficiencies in hippocampal synaptic plasticity, resulting in memory deficits with no major olfactory, emotional or motor impairments. Therefore, parkin-/- mice may represent a promising animal model to study the early stages of PD and for testing new therapeutic strategies to restore learning and memory and synaptic plasticity impairments in PD.

  6. Preclinical testing of radiopharmaceuticals for novel applications in HIV, bacterial and fungal infectious diseases

    International Nuclear Information System (INIS)

    Shah, M.; Garg, G.; Dadachova, E.

    2015-01-01

    Antibiotics, antifungal and antiviral medications have traditionally been used in the management of infections. Due to widespread emergence of resistance to antimicrobial medications, and their side effects, there is a growing need for alternative approaches for management of such conditions. Antibiotic resistant bacterial pathogens are on the rise. A cure has not been achieved for viral infections like AIDS, while fungal and parasitic infections are constant threats to the health of general public. The incidence of opportunistic infections in immunocompromised individuals like HIV patients, patients receiving high dose steroids, chemotherapy patients, and organ transplant recipients is on the rise. Radioimmunotherapy (RIT) has the potential to be a suitable and viable therapeutic modality in the arena of infection management. Provided the target-associated antigen is expressed by the target cells and minimally or not expressed by other tissues, selective targeting of radiation to target sites can be theoretically accomplished with relative sparing normal tissues from radiation exposure. In our laboratory we successfully demonstrated the effectiveness of RIT for treating infectious diseases. We targeted murine cryptococcosis with a mAb to the Cryptococcus neoformans capsular glucuronoxylomannan labeled with Bismuth-213 (213Bi) or Rhenium-188 (188Re). We subsequently extended the applicability of RIT for treating bacterial and viral infections. One of the advantages of using RIT to treat infections as opposed to cancer is that, in contrast to tumor cells, cells expressing microbial antigens are antigenically very different from host tissues and thus provide the potential for exquisite specificity and low cross-reactivity. Ever increasing incidence of infectious pathologies, exhaustion of antimicrobial possibilities and rising drug resistance calls for use of alternative and novel therapeutic options and we believe RIT is the need of the hour to combat these

  7. Development of a preclinical 211Rn/211At generator system for targeted alpha therapy research with 211At.

    Science.gov (United States)

    Crawford, Jason R; Yang, Hua; Kunz, Peter; Wilbur, D Scott; Schaffer, Paul; Ruth, Thomas J

    2017-05-01

    The availability of 211 At for targeted alpha therapy research can be increased by the 211 Rn/ 211 At generator system, whereby 211 At is produced by 211 Rn electron capture decay. This study demonstrated the feasibility of using generator-produced 211 At to label monoclonal antibody (BC8, anti-human CD45) for preclinical use, following isolation from the 207 Po contamination also produced by these generators (by 211 Rn α-decay). 211 Rn was produced by 211 Fr electron capture decay following mass separated ion beam implantation and chemically isolated in liquid alkane hydrocarbon (dodecane). 211 At produced by the resulting 211 Rn source was extracted in strong base (2N NaOH) and purified by granular Te columns. BC8-B10 (antibody conjugated with closo-decaborate(2-)) was labeled with generator-produced 211 At and purified by PD-10 columns. Aqueous solutions extracted from the generator were found to contain 211 At and 207 Po, isolated from 211 Rn. High radionuclidic purity was obtained for 211 At eluted from Te columns, from which BC8-B10 monoclonal antibody was successfully labeled. If not removed, 207 Po was found to significantly contaminate the final 211 At-BC8-B10 product. High yield efficiencies (decay-corrected, n=3) were achieved for 211 At extraction from the generator (86%±7%), Te column purification (70%±10%), and antibody labeling (76%±2%). The experimental 211 Rn/ 211 At generator was shown to be well-suited for preclinical 211 At-based research. We believe that these experiments have furthered the knowledge-base for expanding accessibility to 211 At using the 211 Rn/ 211 At generator system. As established by this work, the 211 Rn/ 211 At generator has the capability of facilitating preclinical evaluations of 211 At-based therapies. Copyright © 2017 Elsevier Inc. All rights reserved.

  8. Synthesis, characterization, and preclinical validation of a PET radiopharmaceutical for interrogating Aβ (β-amyloid) plaques in Alzheimer's disease.

    Science.gov (United States)

    Sundaram, Guruswami Sm; Dhavale, Dhruva; Prior, Julie L; Sivapackiam, Jothilingam; Laforest, Richard; Kotzbauer, Paul; Sharma, Vijay

    2015-12-01

    PET radiopharmaceuticals capable of imaging β-amyloid (Aβ) plaque burden in the brain could offer highly valuable diagnostic tools for clinical studies of Alzheimer's disease. To further supplement existing armamentarium of FDA-approved agents as well as those under development, and to correlate multiphoton-imaging data reported earlier, herein, we describe preclinical validation of a PET tracer. A novel PET radiopharmaceutical ((18)F-7B) was synthesized and characterized. To assess its affinity for Aβ, binding assays with Aβ1-42 fibrils, Alzheimer's disease (AD) homogenates, and autoradiography studies and their IHC correlations were performed. For assessing its overall pharmacokinetic profiles in general and its ability to cross the blood-brain barrier (BBB) in particular, biodistribution studies in normal mice were performed. Finally, for evaluating potential for (18)F-7B to serve as a targeted Aβ probe, the microPET/CT imaging was performed in age-matched amyloid precursor protein/presenilin-1 (APP/PS1) mice and wild-type (WT) counterparts. The radiotracer (18)F-7B shows saturable binding to autopsy-confirmed AD homogenates (K d = 17.7 nM) and Aβ1-42 fibrils (K d = 61 nM). Preliminary autoradiography studies show binding of (18)F-7B to cortical Aβ plaques in autopsy-confirmed AD tissue sections, inhibition of that binding by unlabeled counterpart 7A-indicating specificity, and a good correlation of tracer binding with Aβ immunostaining. The agent indicates high initial penetration into brains (7.23 ± 0.47%ID/g; 5 min) of normal mice, thus indicating a 5-min/120-min brain uptake clearance ratio of 4.7, a benchmark value (>4) consistent with the ability of agents to traverse the BBB to enable PET brain imaging. Additionally, (18)F-7B demonstrates the presence of parental species in human serum. Preliminary microPET/CT imaging demonstrates significantly higher retention of (18)F-7B in brains of transgenic mice compared with their WT counterparts

  9. Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses

    Directory of Open Access Journals (Sweden)

    Mahmoud Ameri

    2014-05-01

    Full Text Available This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC. Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables.

  10. Human Growth Hormone Delivery with a Microneedle Transdermal System: Preclinical Formulation, Stability, Delivery and PK of Therapeutically Relevant Doses.

    Science.gov (United States)

    Ameri, Mahmoud; Kadkhodayan, Miryam; Nguyen, Joe; Bravo, Joseph A; Su, Rebeca; Chan, Kenneth; Samiee, Ahmad; Daddona, Peter E

    2014-05-15

    This study evaluated the feasibility of coating formulated recombinant human growth hormone (rhGH) on a titanium microneedle transdermal delivery system, Zosano Pharma (ZP)-hGH, and assessed preclinical patch delivery performance. Formulation rheology and surface activity were assessed by viscometry and contact angle measurement. rhGH liquid formulation was coated onto titanium microneedles by dip-coating and drying. The stability of coated rhGH was determined by size exclusion chromatography-high performance liquid chromatography (SEC-HPLC). Preclinical delivery and pharmacokinetic studies were conducted in female hairless guinea pigs (HGP) using rhGH coated microneedle patches at 0.5 and 1 mg doses and compared to Norditropin® a commercially approved rhGH subcutaneous injection. Studies demonstrated successful rhGH formulation development and coating on microneedle arrays. The ZP-hGH patches remained stable at 40 °C for six months with no significant change in % aggregates. Pharmacokinetic studies showed that the rhGH-coated microneedle patches, delivered with high efficiency and the doses delivered indicated linearity with average Tmax of 30 min. The absolute bioavailability of the microneedle rhGH patches was similar to subcutaneous Norditropin® injections. These results suggest that ZP-transdermal microneedle patch delivery of rhGH is feasible and may offer an effective and patient-friendly alternative to currently marketed rhGH injectables.

  11. Performance characterization of a new CZT-based preclinical SPECT system: a comparative study of different collimators

    Science.gov (United States)

    Yu, A. R.; Park, S.-J.; Choi, Y. Y.; Kim, K. M.; Kim, H.-J.

    2015-09-01

    Triumph X-SPECT is a newly released CZT-based preclinical small-animal SPECT system with interchangeable collimators. The purpose of this work was to evaluate and systematically compare the imaging performances of three different collimators in the CZT-based preclinical small-animal system: a single-pinhole collimator (SPH), a multi-pinhole collimator (MPH) and a parallel-hole collimator. We measured the spatial resolutions and sensitivities of the three collimators with 99mTc sources, considering three distinct energy window widths (5, 10, and 20%), and used the NEMA NU4-2008 Image Quality phantom to test the imaging performance of the three collimators in terms of uniformity and spill-over ratio (SOR) for each energy window. With a 10% energy window width at a radius of rotation (ROR) of 30 mm, the system resolution of the SPH, MPH and parallel-hole collimators was 0.715, 0.855 and 3.270 mm FWHM, respectively. For the same energy window, the sensitivity of the system with SPH, MPH and parallel-hole collimators was 32.860, 152.514 and 49.205 counts/sec/MBq at a 100 mm source-to-detector distance and 6.790, 33.376 and 49.038 counts/sec/MBq at a 130 mm source-to-detector distance, respectively. The image noise and SORair for the three collimators were 20.137, 12.278 and 11.232 (%STDunif) and 0.106, 0.140 and 0.161, respectively. Overall, the results show that the SPH had better spatial resolution than the other collimators. The MPH had the highest sensitivity at 100 mm source-to-collimator distance, and the parallel-hole collimator had the highest sensitivity at 130 mm-source-to-detector distance. Therefore, the proper collimator for Triumph X-SPECT system must be determined by the task. These results provide valuable reference data and insight into the imaging performance of various collimators in CZT-based preclinical small-animal SPECT.

  12. DISEASE MANAGEMENT INFORMATION SYSTEM

    OpenAIRE

    Bens Pardamean; Anindito; Anjela Djoeang; Nana Tobing

    2013-01-01

    The study designed an information system model for Disease Management (DisMan) that met the specifications and needs of a consumer electronics manufacturer. The diseases monitored by this study were diabetes, hypertension and tuberculosis. Data were collected through interviews with the companyâs human resources department and occupational health provider. As for the model, literature and online research were conducted to collect health standards and information system standards on existing D...

  13. Fully 3D tomographic reconstruction by Monte Carlo simulation of the system matrix in preclinical PET with iodine 124

    International Nuclear Information System (INIS)

    Moreau, Matthieu

    2014-01-01

    Immuno-PET imaging can be used to assess the pharmacokinetic in radioimmunotherapy. When using iodine-124, PET quantitative imaging is limited by physics-based degrading factors within the detection system and the object, such as the long positron range in water and the complex spectrum of gamma photons. The objective of this thesis was to develop a fully 3D tomographic reconstruction method (S(MC)2PET) using Monte Carlo simulations for estimating the system matrix, in the context of preclinical imaging with iodine-124. The Monte Carlo simulation platform GATE was used for that respect. Several complexities of system matrices were calculated, with at least a model of the PET system response function. Physics processes in the object was either neglected or taken into account using a precise or a simplified object description. The impact of modelling refinement and statistical variance related to the system matrix elements was evaluated on final reconstructed images. These studies showed that a high level of complexity did not always improve qualitative and quantitative results, owing to the high-variance of the associated system matrices. (author)

  14. [Neurophysiology of systemic diseases].

    Science.gov (United States)

    Attarian, S

    2004-01-01

    Connective tissue diseases represent a varied and challenging group of disorders. Neuromuscular structures are highly susceptible targets for damage. In this review, the neurophysiological explorations of the neuromuscular complications are examined with particular attention to the peripheral nerve system. The most common presentations are sensorimotor polyneuropathy, mononeuritis multiplex, distal symmetric neuropathy, compression neuropathy and trigeminal sensory neuropathy.

  15. Cannabinoids and Dementia: A Review of Clinical and Preclinical Data

    Directory of Open Access Journals (Sweden)

    Michael Halpern

    2010-08-01

    Full Text Available The endocannabinoid system has been shown to be associated with neurodegenerative diseases and dementia. We review the preclinical and clinical data on cannabinoids and four neurodegenerative diseases: Alzheimer’s disease (AD, Huntington’s disease (HD, Parkinson’s disease (PD and vascular dementia (VD. Numerous studies have demonstrated an involvement of the cannabinoid system in neurotransmission, neuropathology and neurobiology of dementias. In addition, several candidate compounds have demonstrated efficacy in vitro. However, some of the substances produced inconclusive results in vivo. Therefore, only few trials have aimed to replicate the effects seen in animal studies in patients. Indeed, the literature on cannabinoid administration in patients is scarce. While preclinical findings suggest causal treatment strategies involving cannabinoids, clinical trials have only assessed the suitability of cannabinoid receptor agonists, antagonists and cannabidiol for the symptomatic treatment of dementia. Further research is needed, including in vivo models of dementia and human studies.

  16. [Systemic sclerosis: a multisystem disease

    NARCIS (Netherlands)

    Berrevoets, M.A.; Markhorst, J.; Meek, I.; Ede, A.E. van; Vonk, M.C.

    2014-01-01

    Systemic sclerosis is a rare, systemic autoimmune disease, characterized by inflammation, vasculopathy and fibrosis of the skin and internal organs. The disease is associated with a significantly increased morbidity and mortality, and can be rapidly progressive. Interstitial lung disease, renal

  17. AGRICULTURE DISEASE MITIGATION SYSTEM

    Directory of Open Access Journals (Sweden)

    Sion Hannuna

    2011-06-01

    Full Text Available Around 52% of the population of India rely on farming for their livelihood which accounts for 17% of India’s GDP. Whilst most farmers are familiar with conventional farming practices, they are often ill positioned to promptly deal with diseases and plant infestations affecting their crops. Current advisory systems tend to be generic and are not tailored to specific plots or farms. This work comprises an agriculture advisory call center similar to a modern call center to provide an agriculture disease mitigation system. The information regarding an individual farm is collected using mobile phones. The image of diseased/infected crop is also captured using mobile phones and is made available to the expert to provide the advisory. To scale the advisory, an attempt is also made to automate the disease recognition process using image processing. Unfortunately, the photos taken will be sensitive to a number of factors including camera type and lighting incident on the scene. Ideally, the images would be processed in such a way as to provide the expert with a visual representation of the affected crops that reflects the true nature of the scene. We describe a framework for standardising the colour of plant images taken using both mobile phones and compact cameras within the context of the advisory system.

  18. Does posterior cingulate hypometabolism result from disconnection or local pathology across preclinical and clinical stages of Alzheimer's disease?

    Energy Technology Data Exchange (ETDEWEB)

    Teipel, Stefan [University of Rostock, Department of Psychosomatic Medicine, Rostock (Germany); DZNE, German Center for Neurodegenerative Diseases, Rostock (Germany); Alzheimer' s Disease Neuroimaging Initiative (United States); Grothe, Michel J. [DZNE, German Center for Neurodegenerative Diseases, Rostock (Germany); Alzheimer' s Disease Neuroimaging Initiative (United States)

    2016-03-15

    Posterior cingulate cortex (PCC) hypometabolism as measured by FDG PET is an indicator of Alzheimer's disease (AD) in prodromal stages, such as in mild cognitive impairment (MCI), and has been found to be closely associated with hippocampus atrophy in AD dementia.We studied the effects of local and remote atrophy and of local amyloid load on the PCC metabolic signal in patients with different preclinical and clinical stages of AD. We determined the volume of the hippocampus and PCC grey matter based on volumetric MRI scans, PCC amyloid load based on AV45 PET, and PCC metabolism based on FDG PET in 667 subjects participating in the Alzheimer's Disease Neuroimaging Initiative spanning the range from cognitively normal ageing through prodromal AD to AD dementia. In cognitively normal individuals and those with early MCI, PCC hypometabolism was exclusively associated with hippocampus atrophy, whereas in subjects with late MCI it was associated with both local and remote effects of atrophy as well as local amyloid load. In subjects with AD dementia, PCC hypometabolism was exclusively related to local atrophy. Our findings suggest that the effects of remote pathology on PCC hypometabolism decrease and the effects of local pathology increase from preclinical to clinical stages of AD, consistent with a progressive disconnection of the PCC from downstream cortical and subcortical brain regions. (orig.)

  19. Does posterior cingulate hypometabolism result from disconnection or local pathology across preclinical and clinical stages of Alzheimer's disease?

    International Nuclear Information System (INIS)

    Teipel, Stefan; Grothe, Michel J.

    2016-01-01

    Posterior cingulate cortex (PCC) hypometabolism as measured by FDG PET is an indicator of Alzheimer's disease (AD) in prodromal stages, such as in mild cognitive impairment (MCI), and has been found to be closely associated with hippocampus atrophy in AD dementia.We studied the effects of local and remote atrophy and of local amyloid load on the PCC metabolic signal in patients with different preclinical and clinical stages of AD. We determined the volume of the hippocampus and PCC grey matter based on volumetric MRI scans, PCC amyloid load based on AV45 PET, and PCC metabolism based on FDG PET in 667 subjects participating in the Alzheimer's Disease Neuroimaging Initiative spanning the range from cognitively normal ageing through prodromal AD to AD dementia. In cognitively normal individuals and those with early MCI, PCC hypometabolism was exclusively associated with hippocampus atrophy, whereas in subjects with late MCI it was associated with both local and remote effects of atrophy as well as local amyloid load. In subjects with AD dementia, PCC hypometabolism was exclusively related to local atrophy. Our findings suggest that the effects of remote pathology on PCC hypometabolism decrease and the effects of local pathology increase from preclinical to clinical stages of AD, consistent with a progressive disconnection of the PCC from downstream cortical and subcortical brain regions. (orig.)

  20. SU-E-T-20: A Novel Hybrid CBCT, Bioluminescence and Fluorescence Tomography System for Preclinical Radiation Research

    Energy Technology Data Exchange (ETDEWEB)

    Zhang, B; Eslami, S; Iordachita, I [Johns Hopkins University, Baltimore, Maryland (United States); Yang, Y [University of Miami School of Medicine, Miami, FL (United States); Patterson, M [Hamilton Regional Cancer Ctr., Hamilton, ON (Canada); Wong, J [Johns Hopkins University, Baltimore, MD (United States); Wang, K [Johns Hopkins Hospital, Baltimore, MD (United States)

    2014-06-01

    Purpose: A novel standalone bioluminescence and fluorescence tomography (BLT and FT) system equipped with high resolution CBCT has been built in our group. In this work, we present the system calibration method and validate our system in both phantom and in vivo environment. Methods: The CBCT is acquired by rotating the animal stage while keeping the x-ray source and detector panel static. The optical signal is reflected by the 3-mirror system to a multispectral filter set and then delivered to the CCD camera with f/1.4 lens mounted. Nine fibers passing through the stage and in contact with the mouse skin serve as the light sources for diffuse optical tomography (DOT) and FT. The anatomical information and optical properties acquired from the CBCT and DOT, respectively, are used as the priori information to improve the BLT/FT reconstruction accuracy. Flat field correction for the optical system was acquired at multiple wavelengths. A home-built phantom is used to register the optical and CBCT coordinates. An absolute calibration relating the CCD photon counts rate to the light fluence rate emitted at animal surface was developed to quantify the bioluminescence power or fluorophore concentration. Results: An optical inhomogeneous phantom with 2 light sources (3mm separation) imbedded is used to test the system. The optical signal is mapped onto the mesh generated from CBCT for optical reconstruction. Our preliminary results show that the center of mass can be reconstructed within 2.8mm accuracy. A live mouse with the light source imbedded is also used to validate our system. Liver or lung metastatic luminescence tumor model will be used for further testing. Conclusion: This hybrid system transforms preclinical research to a level that even sub-palpable volume of cells can be imaged rapidly and non-invasively, which largely extends the scope of radiobiological research. The research is supported by the NCI grant R01CA158100-01.

  1. Pre-clinical evaluation of an adult extracorporeal carbon dioxide removal system with active mixing for pediatric respiratory support.

    Science.gov (United States)

    Jeffries, R Garrett; Mussin, Yerbol; Bulanin, Denis S; Lund, Laura W; Kocyildirim, Ergin; Zhumadilov, Zhaksybay Zh; Olzhayev, Farkhad S; Federspiel, William J; Wearden, Peter D

    2014-12-01

    The objective of this work was to conduct pre-clinical feasibility studies to determine if a highly efficient, active-mixing, adult extracorporeal carbon dioxide removal (ECCO2R) system can safely be translated to the pediatric population. The Hemolung Respiratory Assist System (RAS) was tested in vitro and in vivo to evaluate its performance for pediatric veno-venous applications. The Hemolung RAS operates at blood flows of 350-550 ml/min and utilizes an integrated pump-gas exchange cartridge with a membrane surface area of 0.59 m² as the only component of the extracorporeal circuit. Both acute and seven-day chronic in vivo tests were conducted in healthy juvenile sheep using a veno-venous cannulation strategy adapted to the in vivo model. The Hemolung RAS was found to have gas exchange and pumping capabilities relevant to patients weighing 3-25 kg. Seven-day animal studies in juvenile sheep demonstrated that veno-venous extracorporeal support could be used safely and effectively with no significant adverse reactions related to device operation.

  2. Development of a preclinical orthotopic xenograft model of ewing sarcoma and other human malignant bone disease using advanced in vivo imaging.

    Directory of Open Access Journals (Sweden)

    Britta Vormoor

    Full Text Available Ewing sarcoma and osteosarcoma represent the two most common primary bone tumours in childhood and adolescence, with bone metastases being the most adverse prognostic factor. In prostate cancer, osseous metastasis poses a major clinical challenge. We developed a preclinical orthotopic model of Ewing sarcoma, reflecting the biology of the tumour-bone interactions in human disease and allowing in vivo monitoring of disease progression, and compared this with models of osteosarcoma and prostate carcinoma. Human tumour cell lines were transplanted into non-obese diabetic/severe combined immunodeficient (NSG and Rag2(-/-/γc(-/- mice by intrafemoral injection. For Ewing sarcoma, minimal cell numbers (1000-5000 injected in small volumes were able to induce orthotopic tumour growth. Tumour progression was studied using positron emission tomography, computed tomography, magnetic resonance imaging and bioluminescent imaging. Tumours and their interactions with bones were examined by histology. Each tumour induced bone destruction and outgrowth of extramedullary tumour masses, together with characteristic changes in bone that were well visualised by computed tomography, which correlated with post-mortem histology. Ewing sarcoma and, to a lesser extent, osteosarcoma cells induced prominent reactive new bone formation. Osteosarcoma cells produced osteoid and mineralised "malignant" bone within the tumour mass itself. Injection of prostate carcinoma cells led to osteoclast-driven osteolytic lesions. Bioluminescent imaging of Ewing sarcoma xenografts allowed easy and rapid monitoring of tumour growth and detection of tumour dissemination to lungs, liver and bone. Magnetic resonance imaging proved useful for monitoring soft tissue tumour growth and volume. Positron emission tomography proved to be of limited use in this model. Overall, we have developed an orthotopic in vivo model for Ewing sarcoma and other primary and secondary human bone malignancies, which

  3. VECTor: A Preclinical Imaging System for Simultaneous Submillimeter SPECT and PET

    NARCIS (Netherlands)

    Goorden, M.C.; van der Have, F.; Kreuger, R.; Ramakers, R.M.; Vastenhouw, B.; Burbach, J.P.H.; Booij, J.; Molthoff, C.F.M.; Beekman, F.J.

    2013-01-01

    Today, PET and SPECT tracers cannot be imaged simultaneously at high resolutions but require 2 separate imaging systems. This paper introduces a Versatile Emission Computed Tomography system (VECTor) for radionuclides that enables simultaneous submillimeter imaging of single-photon and positron-

  4. System vaccinology for the evaluation of influenza vaccine safety by multiplex gene detection of novel biomarkers in a preclinical study and batch release test.

    Directory of Open Access Journals (Sweden)

    Takuo Mizukami

    Full Text Available Vaccines are beneficial and universal tools to prevent infectious disease. Thus, safety of vaccines is strictly evaluated in the preclinical phase of trials and every vaccine batch must be tested by the National Control Laboratories according to the guidelines published by each country. Despite many vaccine production platforms and methods, animal testing for safety evaluation is unchanged thus far. We recently developed a systems biological approach to vaccine safety evaluation where identification of specific biomarkers in a rat pre-clinical study evaluated the safety of vaccines for pandemic H5N1 influenza including Irf7, Lgals9, Lgalsbp3, Cxcl11, Timp1, Tap2, Psmb9, Psme1, Tapbp, C2, Csf1, Mx2, Zbp1, Ifrd1, Trafd1, Cxcl9, β2m, Npc1, Ngfr and Ifi47. The current study evaluated whether these 20 biomarkers could evaluate the safety, batch-to-batch and manufacturer-to-manufacturer consistency of seasonal trivalent influenza vaccine using a multiplex gene detection system. When we evaluated the influenza HA vaccine (HAv from four different manufactures, the biomarker analysis correlated to findings from conventional animal use tests, such as abnormal toxicity test. In addition, sensitivity of toxicity detection and differences in HAvs were higher and more accurate than with conventional methods. Despite a slight decrease in body weight caused by HAv from manufacturer B that was not statistically significant, our results suggest that HAv from manufacturer B is significantly different than the other HAvs tested with regard to Lgals3bp, Tapbp, Lgals9, Irf7 and C2 gene expression in rat lungs. Using the biomarkers confirmed in this study, we predicted batch-to-batch consistency and safety of influenza vaccines within 2 days compared with the conventional safety test, which takes longer. These biomarkers will facilitate the future development of new influenza vaccines and provide an opportunity to develop in vitro methods of evaluating batch

  5. System vaccinology for the evaluation of influenza vaccine safety by multiplex gene detection of novel biomarkers in a preclinical study and batch release test.

    Science.gov (United States)

    Mizukami, Takuo; Momose, Haruka; Kuramitsu, Madoka; Takizawa, Kazuya; Araki, Kumiko; Furuhata, Keiko; Ishii, Ken J; Hamaguchi, Isao; Yamaguchi, Kazunari

    2014-01-01

    Vaccines are beneficial and universal tools to prevent infectious disease. Thus, safety of vaccines is strictly evaluated in the preclinical phase of trials and every vaccine batch must be tested by the National Control Laboratories according to the guidelines published by each country. Despite many vaccine production platforms and methods, animal testing for safety evaluation is unchanged thus far. We recently developed a systems biological approach to vaccine safety evaluation where identification of specific biomarkers in a rat pre-clinical study evaluated the safety of vaccines for pandemic H5N1 influenza including Irf7, Lgals9, Lgalsbp3, Cxcl11, Timp1, Tap2, Psmb9, Psme1, Tapbp, C2, Csf1, Mx2, Zbp1, Ifrd1, Trafd1, Cxcl9, β2m, Npc1, Ngfr and Ifi47. The current study evaluated whether these 20 biomarkers could evaluate the safety, batch-to-batch and manufacturer-to-manufacturer consistency of seasonal trivalent influenza vaccine using a multiplex gene detection system. When we evaluated the influenza HA vaccine (HAv) from four different manufactures, the biomarker analysis correlated to findings from conventional animal use tests, such as abnormal toxicity test. In addition, sensitivity of toxicity detection and differences in HAvs were higher and more accurate than with conventional methods. Despite a slight decrease in body weight caused by HAv from manufacturer B that was not statistically significant, our results suggest that HAv from manufacturer B is significantly different than the other HAvs tested with regard to Lgals3bp, Tapbp, Lgals9, Irf7 and C2 gene expression in rat lungs. Using the biomarkers confirmed in this study, we predicted batch-to-batch consistency and safety of influenza vaccines within 2 days compared with the conventional safety test, which takes longer. These biomarkers will facilitate the future development of new influenza vaccines and provide an opportunity to develop in vitro methods of evaluating batch-to-batch consistency and

  6. The Leaflex™ Catheter System - a viable treatment option alongside valve replacement? Preclinical feasibility of a novel device designed for fracturing aortic valve.

    Science.gov (United States)

    Jonas, Michael; Rozenman, Yoseph; Moshkovitz, Yaron; Hamdan, Ashraf; Kislev, Yael; Tirosh, Nitzan; Sax, Sharon; Trumer, Dror; Golan, Erez; Raanani, Ehud

    2015-09-01

    To demonstrate the feasibility of the Leaflex™ Catheter System, a novel percutaneous device for fracturing valve calcification using mechanical impact in order to regain leaflet mobility. Radiographic analysis of calcium patterns in 90 ex vivo human aortic valve leaflets demonstrated that 82% of leaflets had a typical "bridge" or "half-bridge" pattern, which formed the basis for the catheter design. The therapeutic effect was quantified in 13 leaflets showing a reduction of 49±16% in leaflet resistance to folding after treatment. A pulsatile flow simulator was then used with 11 ex vivo valves demonstrating an increase in aortic valve area of 35±12%. Using gross pathology and histology on fresh calcified leaflets, we then verified that mechanical impacts do not entail excessive risk of embolisation. In vivo safety and usability were then confirmed in the ovine model. We demonstrated preclinically that it is feasible to improve valve function using the Leaflex™ technology. Once demonstrated clinically, such an approach may have an important role as preparation for or bridging to TAVI, as destination treatment for patients where TAVI is clinically or economically questionable and, in the future, maybe even as a means to slow disease progression in asymptomatic patients.

  7. Systematic calibration of an integrated x-ray and optical tomography system for preclinical radiation research

    International Nuclear Information System (INIS)

    Yang, Yidong; Wang, Ken Kang-Hsin; Wong, John W.; Eslami, Sohrab; Iordachita, Iulian I.; Patterson, Michael S.

    2015-01-01

    Purpose: The cone beam computed tomography (CBCT) guided small animal radiation research platform (SARRP) has been developed for focal tumor irradiation, allowing laboratory researchers to test basic biological hypotheses that can modify radiotherapy outcomes in ways that were not feasible previously. CBCT provides excellent bone to soft tissue contrast, but is incapable of differentiating tumors from surrounding soft tissue. Bioluminescence tomography (BLT), in contrast, allows direct visualization of even subpalpable tumors and quantitative evaluation of tumor response. Integration of BLT with CBCT offers complementary image information, with CBCT delineating anatomic structures and BLT differentiating luminescent tumors. This study is to develop a systematic method to calibrate an integrated CBCT and BLT imaging system which can be adopted onboard the SARRP to guide focal tumor irradiation. Methods: The integrated imaging system consists of CBCT, diffuse optical tomography (DOT), and BLT. The anatomy acquired from CBCT and optical properties acquired from DOT serve as a priori information for the subsequent BLT reconstruction. Phantoms were designed and procedures were developed to calibrate the CBCT, DOT/BLT, and the entire integrated system. Geometrical calibration was performed to calibrate the CBCT system. Flat field correction was performed to correct the nonuniform response of the optical imaging system. Absolute emittance calibration was performed to convert the camera readout to the emittance at the phantom or animal surface, which enabled the direct reconstruction of the bioluminescence source strength. Phantom and mouse imaging were performed to validate the calibration. Results: All calibration procedures were successfully performed. Both CBCT of a thin wire and a euthanized mouse revealed no spatial artifact, validating the accuracy of the CBCT calibration. The absolute emittance calibration was validated with a 650 nm laser source, resulting in a 3

  8. Systematic calibration of an integrated x-ray and optical tomography system for preclinical radiation research

    Energy Technology Data Exchange (ETDEWEB)

    Yang, Yidong, E-mail: yidongyang@med.miami.edu [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231 and Department of Radiation Oncology, University of Miami School of Medicine, Miami, Florida 33136 (United States); Wang, Ken Kang-Hsin; Wong, John W. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231 (United States); Eslami, Sohrab; Iordachita, Iulian I. [Laboratory for Computational Sensing and Robotics, Johns Hopkins University, Baltimore, Maryland 21218 (United States); Patterson, Michael S. [Juravinski Cancer Centre and Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ontario L8S4K1 (Canada)

    2015-04-15

    Purpose: The cone beam computed tomography (CBCT) guided small animal radiation research platform (SARRP) has been developed for focal tumor irradiation, allowing laboratory researchers to test basic biological hypotheses that can modify radiotherapy outcomes in ways that were not feasible previously. CBCT provides excellent bone to soft tissue contrast, but is incapable of differentiating tumors from surrounding soft tissue. Bioluminescence tomography (BLT), in contrast, allows direct visualization of even subpalpable tumors and quantitative evaluation of tumor response. Integration of BLT with CBCT offers complementary image information, with CBCT delineating anatomic structures and BLT differentiating luminescent tumors. This study is to develop a systematic method to calibrate an integrated CBCT and BLT imaging system which can be adopted onboard the SARRP to guide focal tumor irradiation. Methods: The integrated imaging system consists of CBCT, diffuse optical tomography (DOT), and BLT. The anatomy acquired from CBCT and optical properties acquired from DOT serve as a priori information for the subsequent BLT reconstruction. Phantoms were designed and procedures were developed to calibrate the CBCT, DOT/BLT, and the entire integrated system. Geometrical calibration was performed to calibrate the CBCT system. Flat field correction was performed to correct the nonuniform response of the optical imaging system. Absolute emittance calibration was performed to convert the camera readout to the emittance at the phantom or animal surface, which enabled the direct reconstruction of the bioluminescence source strength. Phantom and mouse imaging were performed to validate the calibration. Results: All calibration procedures were successfully performed. Both CBCT of a thin wire and a euthanized mouse revealed no spatial artifact, validating the accuracy of the CBCT calibration. The absolute emittance calibration was validated with a 650 nm laser source, resulting in a 3

  9. Preclinical Absorption, Distribution, Metabolism, and Excretion of an Oral Amide Prodrug of Gemcitabine Designed to Deliver Prolonged Systemic Exposure

    Directory of Open Access Journals (Sweden)

    Shannon Dow

    2013-05-01

    Full Text Available Gemcitabine is an intravenously administered nucleoside analog chemotherapeutic agent. The ability to deliver this agent as an oral drug would allow greater flexibility of administration and patient convenience; however, attempts have been fraught with high first-pass metabolism and potential intestinal toxicity. Alternatively, an amide prodrug of gemcitabine (LY2334737 was discovered, which is able to avoid the extensive first-pass metabolism that occurs following administration of gemcitabine. Preclinical in vitro and in vivo experiments were conducted to evaluate the hydrolysis and pharmacokinetics of LY2334737 and its downstream metabolites. In mice, rats, and dogs, the prodrug is absorbed largely intact across the intestinal epithelium and delivers LY2334737 to systemic circulation. The hydrolysis of LY2334737 is relatively slow, resulting in sustained release of gemcitabine in vivo. In vitro experiments identified carboxylesterase 2 (CES2 as a major enzyme involved in the hydrolysis of LY2334737, but with relatively low intrinsic clearance. Following hydrolysis of the prodrug, gemcitabine is cleared predominantly via the formation of its inactive metabolite dFdU. Both biliary and renal excretion was responsible for the elimination of LY2334737 and its metabolites in both mice and dogs.

  10. A cable-driven soft robot surgical system for cardiothoracic endoscopic surgery: preclinical tests in animals.

    Science.gov (United States)

    Wang, Hesheng; Zhang, Runxi; Chen, Weidong; Wang, Xiaozhou; Pfeifer, Rolf

    2017-08-01

    Minimally invasive surgery attracts more and more attention because of the advantages of minimal trauma, less bleeding and pain and low complication rate. However, minimally invasive surgery for beating hearts is still a challenge. Our goal is to develop a soft robot surgical system for single-port minimally invasive surgery on a beating heart. The soft robot described in this paper is inspired by the octopus arm. Although the octopus arm is soft and has more degrees of freedom (DOFs), it can be controlled flexibly. The soft robot is driven by cables that are embedded into the soft robot manipulator and can control the direction of the end and middle of the soft robot manipulator. The forward, backward and rotation movement of the soft robot is driven by a propulsion plant. The soft robot can move freely by properly controlling the cables and the propulsion plant. The soft surgical robot system can perform different thoracic operations by changing surgical instruments. To evaluate the flexibility, controllability and reachability of the designed soft robot surgical system, some testing experiments have been conducted in vivo on a swine. Through the subxiphoid, the soft robot manipulator could enter into the thoracic cavity and pericardial cavity smoothly and perform some operations such as biopsy, ligation and ablation. The operations were performed successfully and did not cause any damage to the surrounding soft tissues. From the experiments, the flexibility, controllability and reachability of the soft robot surgical system have been verified. Also, it has been shown that this system can be used in the thoracic and pericardial cavity for different operations. Compared with other endoscopy robots, the soft robot surgical system is safer, has more DOFs and is more flexible for control. When performing operations in a beating heart, this system maybe more suitable than traditional endoscopy robots.

  11. Preclinical models in radiation oncology

    International Nuclear Information System (INIS)

    Kahn, Jenna; Tofilon, Philip J; Camphausen, Kevin

    2012-01-01

    As the incidence of cancer continues to rise, the use of radiotherapy has emerged as a leading treatment modality. Preclinical models in radiation oncology are essential tools for cancer research and therapeutics. Various model systems have been used to test radiation therapy, including in vitro cell culture assays as well as in vivo ectopic and orthotopic xenograft models. This review aims to describe such models, their advantages and disadvantages, particularly as they have been employed in the discovery of molecular targets for tumor radiosensitization. Ultimately, any model system must be judged by its utility in developing more effective cancer therapies, which is in turn dependent on its ability to simulate the biology of tumors as they exist in situ. Although every model has its limitations, each has played a significant role in preclinical testing. Continued advances in preclinical models will allow for the identification and application of targets for radiation in the clinic

  12. Performance of two different digital evaluation systems used for assessing pre-clinical dental students' prosthodontic technical skills.

    Science.gov (United States)

    Gratton, D G; Kwon, S R; Blanchette, D R; Aquilino, S A

    2017-11-01

    Proper integration of newly emerging digital assessment tools is a central issue in dental education in an effort to provide more accurate and objective feedback to students. The study examined how the outcomes of students' tooth preparation were correlated when evaluated using traditional faculty assessment and two types of digital assessment approaches. Specifically, incorporation of the Romexis Compare 2.0 (Compare) and Sirona prepCheck 1.1 (prepCheck) systems was evaluated. Additionally, satisfaction of students based on the type of software was evaluated through a survey. Students in a second-year pre-clinical prosthodontics course were allocated to either Compare (n = 42) or prepCheck (n = 37) systems. All students received conventional instruction and used their assigned digital system as an additional evaluation tool to aid in assessing their work. Examinations assessed crown preparations of the maxillary right central incisor (#8) and the mandibular left first molar (#19). All submissions were graded by faculty, Compare and prepCheck. Technical scores did not differ between student groups for any of the assessment approaches. Compare and prepCheck had modest, statistically significant correlations with faculty scores with a minimum correlation of 0.3944 (P = 0.0011) and strong, statistically significant correlations with each other with a minimum correlation of 0.8203 (P < 0.0001). A post-course student survey found that 55.26% of the students felt unfavourably about learning the digital evaluation protocols. A total of 62.31% felt favourably about the integration of these digital tools into the curriculum. Comparison of Compare and prepCheck showed no evidence of significant difference in students' prosthodontics technical performance and perception. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress.

    Science.gov (United States)

    Chow, Matthew; Cao, Michelle

    2016-01-01

    Much of the understanding of the hypocretin/orexin (HCRT/OX) system in sleep-wake regulation came from narcolepsy-cataplexy research. The neuropeptides hypocretin-1 and -2/orexin-A and -B (HCRT-1 and -2/OX-A and -B, respectively), as we know, are intimately involved in the regulation wakefulness. The HCRT/OX system regulates sleep-wake control through complex interactions between monoaminergic/cholinergic (wake-promoting) and gamma-aminobutyric acid-ergic (sleep-promoting) neuronal systems. Deficiency of HCRT/OX results in loss of sleep-wake control or stability with consequent unstable transitions between wakefulness to nonrapid eye movement and rapid eye movement sleep. This manifests clinically as abnormal daytime sleepiness with sleep attacks and cataplexy. Research on the development of HCRT/OX agonists and antagonists for the treatment of sleep disorders has dramatically increased with the US Food and Drug Administration approval of the first-in-class dual HCRT/OX receptor antagonist for the treatment of insomnia. This review focuses on the origin, mechanisms of HCRT/OX receptors, clinical progress, and applications for the treatment of sleep disorders.

  14. The hypocretin/orexin system in sleep disorders: preclinical insights and clinical progress

    Directory of Open Access Journals (Sweden)

    Chow M

    2016-03-01

    Full Text Available Matthew Chow, Michelle CaoDepartment of Psychiatry and Behavioral Sciences, Division of Sleep Medicine, Stanford University School of Medicine, Stanford, CA, USAAbstract: Much of the understanding of the hypocretin/orexin (HCRT/OX system in sleep–wake regulation came from narcolepsy–cataplexy research. The neuropeptides hypocretin-1 and -2/orexin-A and -B (HCRT-1 and -2/OX-A and -B, respectively, as we know, are intimately involved in the regulation wakefulness. The HCRT/OX system regulates sleep–wake control through complex interactions between monoaminergic/cholinergic (wake-promoting and gamma-aminobutyric acid-ergic (sleep-promoting neuronal systems. Deficiency of HCRT/OX results in loss of sleep–wake control or stability with consequent unstable transitions between wakefulness to nonrapid eye movement and rapid eye movement sleep. This manifests clinically as abnormal daytime sleepiness with sleep attacks and cataplexy. Research on the development of HCRT/OX agonists and antagonists for the treatment of sleep disorders has dramatically increased with the US Food and Drug Administration approval of the first-in-class dual HCRT/OX receptor antagonist for the treatment of insomnia. This review focuses on the origin, mechanisms of HCRT/OX receptors, clinical progress, and applications for the treatment of sleep disorders.Keywords: hypocretin, orexin, narcolepsy, insomnia, orexin antagonist, orexin agonist

  15. Inebilizumab, a B Cell-Depleting Anti-CD19 Antibody for the Treatment of Autoimmune Neurological Diseases: Insights from Preclinical Studies

    Directory of Open Access Journals (Sweden)

    Ding Chen

    2016-11-01

    Full Text Available Exaggerated or inappropriate responses by B cells are an important feature in many types of autoimmune neurological diseases. The recent success of B-cell depletion in the treatment of multiple sclerosis (MS has stimulated the development of novel B-cell-targeting therapies with the potential for improved efficacy. CD19 has emerged as a promising target for the depletion of B cells as well as CD19-positive plasmablasts and plasma cells. Inebilizumab (MEDI-551, an anti-CD19 antibody with enhanced antibody-dependent cell-mediated cytotoxicity against B cells, is currently being evaluated in MS and neuromyelitis optica. This review discusses the role of B cells in autoimmune neurological disorders, summarizes the development of inebilizumab, and analyzes the recent results for inebilizumab treatment in an autoimmune encephalitis mouse model. The novel insights obtained from these preclinical studies can potentially guide future investigation of inebilizumab in patients.

  16. Pre-clinical evaluation of a diode-based In vivo dosimetry system

    Energy Technology Data Exchange (ETDEWEB)

    Trujillo, G. [National Oncology Institute, Havana (Cuba)

    1998-12-31

    Diode detector systems are routinely used in a number of departments for the quality assurance of the delivered dose in radiation oncology (1,2,3,4,5). The main advantage of diode detectors for in vivo dosimetry (over TLDs, film dosimetry, ionization chambers) is that results are immediately available in real time, do not need external bias voltage and are more sensitive for the same detection volume than ionization chambers thereby allowing a direct and immediate check of the treatment accuracy. Also, is important to mention that is possible to obtain different accuracy levels. For example, in the case of the measurements designed for evaluating the dosimetric accuracy of a new treatment technique for dose escalation studies the action level should be tighter (the order of 2 % to 4 %, 2 standard deviations) than for routine measurements aiming to discover and correct for errors in the treatment of individual patients ({+-} 5 % - 10 % or to avoid mis administrations (10 % - 15 %). This work describes the calibration method adopted and the evaluation of the accuracy and precision of in vivo dosimetry at Co 60 and 23 MV photon energies. Extensive phantoms measurements were made to determine the influence of physical conditions on the diode response. Parameters investigated included diode linearity, leakage, and measurement reproducibility, as well as the field size, SSD, and angular dependence. the practical consequences of these measurements are reported. There is still some controversy as to whether in vivo (diode) dosemeters are required for routine quality assurance purposes. Our work has shown that while care must be taken in choosing and handling diode detector systems they are able to provide an efficient and effective method of ensuring the dose delivered to the patient during treatment is within acceptable limits. (Author)

  17. Systemic Cat Scratch Disease

    Directory of Open Access Journals (Sweden)

    Hui-Min Liao

    2006-01-01

    Full Text Available Systemic cat scratch disease (CSD is often associated with prolonged fever and microabscesses in the liver and/or spleen. We report a case of systemic CSD with hepatic, splenic and renal involvement in an aboriginal child in Taiwan. A previously healthy 9-year-old girl had an intermittent fever for about 17 days, and complained of abdominal pain, headache and weight loss. Abdominal computed tomography showed multiple tiny hypodense nodular lesions in the spleen and both kidneys. Laparotomy revealed multiple soft, whitishtan lesions on the surface of the liver and spleen. Histopathologic examination of a biopsy specimen of the spleen showed necrotizing granulomatous inflammation with central necrosis surrounded by epithelioid cells and occasional Langhans' giant cells, strongly suggestive of Bartonella henselae infection. History revealed close contact with a cat. B. henselae DNA was detected by polymerase chain reaction in the tissue specimen, and the single antibody titer against B. henselae was greater than 1:2048. These results confirmed the diagnosis of visceral CSD caused by B. henselae. The patient's symptoms resolved after treatment with rifampin and tetracycline. This case illustrates the need for inclusion of systemic CSD in patients with fever of unknown origin and abdominal pain.

  18. Neuromuscular disease classification system

    Science.gov (United States)

    Sáez, Aurora; Acha, Begoña; Montero-Sánchez, Adoración; Rivas, Eloy; Escudero, Luis M.; Serrano, Carmen

    2013-06-01

    Diagnosis of neuromuscular diseases is based on subjective visual assessment of biopsies from patients by the pathologist specialist. A system for objective analysis and classification of muscular dystrophies and neurogenic atrophies through muscle biopsy images of fluorescence microscopy is presented. The procedure starts with an accurate segmentation of the muscle fibers using mathematical morphology and a watershed transform. A feature extraction step is carried out in two parts: 24 features that pathologists take into account to diagnose the diseases and 58 structural features that the human eye cannot see, based on the assumption that the biopsy is considered as a graph, where the nodes are represented by each fiber, and two nodes are connected if two fibers are adjacent. A feature selection using sequential forward selection and sequential backward selection methods, a classification using a Fuzzy ARTMAP neural network, and a study of grading the severity are performed on these two sets of features. A database consisting of 91 images was used: 71 images for the training step and 20 as the test. A classification error of 0% was obtained. It is concluded that the addition of features undetectable by the human visual inspection improves the categorization of atrophic patterns.

  19. Theoretical Exploration of the Neural Bases of Behavioural Disinhibition, Apathy and Executive Dysfunction in Preclinical Alzheimer's Disease in People with Down's Syndrome: Potential Involvement of Multiple Frontal-Subcortical Neuronal Circuits

    Science.gov (United States)

    Ball, S. L.; Holland, A. J.; Watson, P. C.; Huppert, F. A.

    2010-01-01

    Background: Recent research has suggested a specific impairment in frontal-lobe functioning in the preclinical stages of Alzheimer's disease (AD) in people with Down's syndrome (DS), characterised by prominent changes in personality or behaviour. The aim of the current paper is to explore whether particular kinds of change (namely executive…

  20. Relationship of medial temporal lobe atrophy, APOE genotype, and cognitive reserve in preclinical Alzheimer’s disease

    Science.gov (United States)

    Soldan, Anja; Pettigrew, Corinne; Lu, Yi; Wang, Mei-Cheng; Selnes, Ola; Albert, Marilyn; Brown, Timothy; Ratnanather, J. Tilak; Younes, Laurent; Miller, Michael I.

    2015-01-01

    This study evaluated the utility of baseline and longitudinal MRI measures of medial temporal lobe brain regions collected when participants were cognitively normal and largely in middle age (mean age 57 years) to predict the time to onset of clinical symptoms associated with mild cognitive impairment (MCI). Furthermore, we examined whether the relationship between MRI measures and clinical symptom onset was modified by Apolipoprotein E (ApoE) genotype and level of cognitive reserve (CR). MRI scans and measures of CR were obtained at baseline from 245 participants who had been followed for up to 18 years (mean follow-up 11 years). A composite score based on reading, vocabulary, and years of education was used as an index of CR. Cox regression models showed that lower baseline volume of the right hippocampus and smaller baseline thickness of the right entorhinal cortex predicted the time to symptom onset independently of CR and ApoE-ε4 genotype, which also predicted the onset of symptoms. The atrophy rates of bilateral entorhinal cortex and amygdala volumes were also associated with time to symptom onset, independent of CR, ApoE genotype, and baseline volume. Only one measure, the left entorhinal cortex baseline volume, interacted with CR, such that smaller volumes predicted symptom onset only in individuals with lower CR. These results suggest that MRI measures of medial temporal atrophy, ApoE-ε4 genotype, and the protective effects of higher CR all predict the time to onset of symptoms associated with MCI in a largely independent, additive manner during the preclinical phase of AD. PMID:25879865

  1. A Novel Cognitive Stress Test for the Detection of Preclinical Alzheimer Disease: Discriminative Properties and Relation to Amyloid Load.

    Science.gov (United States)

    Loewenstein, David A; Curiel, Rosie E; Greig, Maria T; Bauer, Russell M; Rosado, Marian; Bowers, Dawn; Wicklund, Meredith; Crocco, Elizabeth; Pontecorvo, Michael; Joshi, Abhinay D; Rodriguez, Rosemarie; Barker, Warren W; Hidalgo, Jacqueline; Duara, Ranjan

    2016-10-01

    To examine the utility of a novel "cognitive stress test" to detect subtle cognitive impairments and amyloid load within the brains of neuropsychologically normal community-dwelling elders. Participants diagnosed as cognitively normal (CN), subjective memory impairment (SMI), mild cognitive impairment (MCI), and preclinical mild cognitive impairment (PreMCI) were administered the Loewenstein-Acevedo Scale for Semantic Interference and Learning (LASSI-L), a sensitive test of proactive semantic interference (PSI), retroactive semantic interference, and, uniquely, the ability to recover from the effects of PSI. Ninety-three subjects (31 men and 62 women) were recruited from three academic institutions in a research consortium. A subset of these individuals underwent 18F florbetapir positron emission tomography scanning. Relative percentages of impairment for each diagnostic group on the LASSI-L were calculated by χ(2) and Fisher's exact tests. Spearman's rho was used to examine associations between amyloid load and different cognitive measures. LASSI-L deficits were identified among 89% of those with MCI, 47% with PreMCI, 33% with SMI, and 13% classified as CN. CN subjects had no difficulties with recovery from PSI, whereas SMI, preMCI, and MCI participants evidenced deficits in recovery from PSI effects. Among a subgroup of participants with normal scores on traditional neuropsychological tests, the strong associations were between the failure to recover from the effects of PSI and amyloid load in the brain. Failure to recover or compensate for the effects of PSI on the LASSI-L distinguishes the LASSI-L from other widely used neuropsychological tests and appears to be sensitive to subtle cognitive impairments and increasing amyloid load. Copyright © 2016 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  2. Infectious Prions in Pre-Clinical Deer and Transmission of Chronic Wasting Disease Solely by Environmental Exposure

    OpenAIRE

    Mathiason, Candace K.; Hays, Sheila A.; Powers, Jenny; Hayes-Klug, Jeanette; Langenberg, Julia; Dahmes, Sallie J.; Osborn, David A.; Miller, Karl V.; Warren, Robert J.; Mason, Gary L.; Hoover, Edward A.

    2009-01-01

    Key to understanding the epidemiology and pathogenesis of prion diseases, including chronic wasting disease (CWD) of cervids, is determining the mode of transmission from one individual to another. We have previously reported that saliva and blood from CWD-infected deer contain sufficient infectious prions to transmit disease upon passage into naïve deer. Here we again use bioassays in deer to show that blood and saliva of pre-symptomatic deer contain infectious prions capable of infecting na...

  3. A novel humanized mouse model of Huntington disease for preclinical development of therapeutics targeting mutant huntingtin alleles

    DEFF Research Database (Denmark)

    Southwell, Amber L; Skotte, Niels H; Villanueva, Erika B

    2017-01-01

    Huntington disease (HD) is a neurodegenerative disease caused by a mutation in the huntingtin (HTT) gene. HTT is a large protein, interacts with many partners and is involved in many cellular pathways, which are perturbed in HD. Therapies targeting HTT directly are likely to provide the most glob...

  4. Pre-clinical evaluation of AAV5-miHTT gene therapy of Huntington´s disease

    Czech Academy of Sciences Publication Activity Database

    Konstantinová, P.; Miniarikova, J.; Blits, B.; Zimmer, V.; Spoerl, A.; Southwell, A.; Hayden, M.; van Deventer, S.; Deglon, N.; Motlík, Jan; Juhás, Štefan; Juhásová, Jana; Richard, Ch.; Petry, H.

    2015-01-01

    Roč. 78, Supl 2 (2015), s. 8-8 ISSN 1210-7859. [Conference on Animal Models for neurodegenerative Diseases /3./. 08.11.2015-10.11.2015, Liblice] R&D Projects: GA MŠk ED2.1.00/03.0124 Institutional support: RVO:67985904 Keywords : Huntington´s disease * gene therapy * AAV5-miHTT Subject RIV: EB - Gene tics ; Molecular Biology

  5. Multimodal imaging of bone metastases: From preclinical to clinical applications

    Directory of Open Access Journals (Sweden)

    Stephan Ellmann

    2015-10-01

    Full Text Available Metastases to the skeletal system are commonly observed in cancer patients, highly affecting the patients' quality of life. Imaging plays a major role in detection, follow-up, and molecular characterisation of metastatic disease. Thus, imaging techniques have been optimised and combined in a multimodal and multiparametric manner for assessment of complementary aspects in osseous metastases. This review summarises both application of the most relevant imaging techniques for bone metastasis in preclinical models and the clinical setting.

  6. [Cardiovascular disease and systemic inflammatory diseases].

    Science.gov (United States)

    Cuende, José I; Pérez de Diego, Ignacio J; Godoy, Diego

    2016-01-01

    More than a century of research has shown that atherosclerosis is an inflammatory process more than an infiltrative or thrombogenic process. It has been demonstrated epidemiologically and by imaging techniques, that systemic inflammatory diseases (in particular, but not exclusively, rheumatoid arthritis and systemic lupus erythematosus) increase the atherosclerotic process, and has a demonstrated pathophysiological basis. Furthermore, treatments to control inflammatory diseases can modify the course of the atherosclerotic process. Although there are no specific scales for assessing cardiovascular risk in patients with these diseases, cardiovascular risk is high. A number of specific risk scales are being developed, that take into account specific factors such as the degree of inflammatory activity. Copyright © 2015 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

  7. High affinity radiopharmaceuticals based upon lansoprazole for PET imaging of aggregated tau in Alzheimer's disease and progressive supranuclear palsy: synthesis, preclinical evaluation, and lead selection.

    Science.gov (United States)

    Fawaz, Maria V; Brooks, Allen F; Rodnick, Melissa E; Carpenter, Garrett M; Shao, Xia; Desmond, Timothy J; Sherman, Phillip; Quesada, Carole A; Hockley, Brian G; Kilbourn, Michael R; Albin, Roger L; Frey, Kirk A; Scott, Peter J H

    2014-08-20

    Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [(18)F]lansoprazole, [(11)C]N-methyl lansoprazole, and [(18)F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [(18)F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials.

  8. High Affinity Radiopharmaceuticals Based Upon Lansoprazole for PET Imaging of Aggregated Tau in Alzheimer’s Disease and Progressive Supranuclear Palsy: Synthesis, Preclinical Evaluation, and Lead Selection

    Science.gov (United States)

    2014-01-01

    Abnormally aggregated tau is the hallmark pathology of tauopathy neurodegenerative disorders and is a target for development of both diagnostic tools and therapeutic strategies across the tauopathy disease spectrum. Development of carbon-11- or fluorine-18-labeled radiotracers with appropriate affinity and specificity for tau would allow noninvasive quantification of tau burden using positron emission tomography (PET) imaging. We have synthesized [18F]lansoprazole, [11C]N-methyl lansoprazole, and [18F]N-methyl lansoprazole and identified them as high affinity radiotracers for tau with low to subnanomolar binding affinities. Herein, we report radiosyntheses and extensive preclinical evaluation with the aim of selecting a lead radiotracer for translation into human PET imaging trials. We demonstrate that [18F]N-methyl lansoprazole, on account of the favorable half-life of fluorine-18 and its rapid brain entry in nonhuman primates, favorable kinetics, low white matter binding, and selectivity for binding to tau over amyloid, is the lead compound for progression into clinical trials. PMID:24896980

  9. Longitudinal Analysis of Quality of Life, Clinical, Radiographic, Echocardiographic, and Laboratory Variables in Dogs with Preclinical Myxomatous Mitral Valve Disease Receiving Pimobendan or Placebo: The EPIC Study.

    Science.gov (United States)

    Boswood, A; Gordon, S G; Häggström, J; Wess, G; Stepien, R L; Oyama, M A; Keene, B W; Bonagura, J; MacDonald, K A; Patteson, M; Smith, S; Fox, P R; Sanderson, K; Woolley, R; Szatmári, V; Menaut, P; Church, W M; O'Sullivan, M L; Jaudon, J-P; Kresken, J-G; Rush, J; Barrett, K A; Rosenthal, S L; Saunders, A B; Ljungvall, I; Deinert, M; Bomassi, E; Estrada, A H; Fernandez Del Palacio, M J; Moise, N S; Abbott, J A; Fujii, Y; Spier, A; Luethy, M W; Santilli, R A; Uechi, M; Tidholm, A; Schummer, C; Watson, P

    2018-01-01

    Changes in clinical variables associated with the administration of pimobendan to dogs with preclinical myxomatous mitral valve disease (MMVD) and cardiomegaly have not been described. To investigate the effect of pimobendan on clinical variables and the relationship between a change in heart size and the time to congestive heart failure (CHF) or cardiac-related death (CRD) in dogs with MMVD and cardiomegaly. To determine whether pimobendan-treated dogs differ from dogs receiving placebo at onset of CHF. Three hundred and fifty-four dogs with MMVD and cardiomegaly. Prospective, blinded study with dogs randomized (ratio 1:1) to pimobendan (0.4-0.6 mg/kg/d) or placebo. Clinical, laboratory, and heart-size variables in both groups were measured and compared at different time points (day 35 and onset of CHF) and over the study duration. Relationships between short-term changes in echocardiographic variables and time to CHF or CRD were explored. At day 35, heart size had reduced in the pimobendan group: median change in (Δ) LVIDDN -0.06 (IQR: -0.15 to +0.02), P dogs treated with pimobendan were indistinguishable from those receiving placebo. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  10. Review article: the endocannabinoid system in liver disease, a potential therapeutic target.

    Science.gov (United States)

    Basu, P P; Aloysius, M M; Shah, N J; Brown, R S

    2014-04-01

    Endocannabinoids are a family of potent lipid-soluble molecules, acting on the cannabinoid (CB) receptors that mediate the effects of marijuana. The CB receptors, endocannabinoids and the enzymes involved in their synthesis and degradation are located in the brain and peripheral tissues, including the liver. To review the current understanding of the role of the endocannabinoid system in liver disease-associated pathophysiological conditions, and drugs targeting the endocannabinoid system as therapy for liver disease. Original articles and reviews were used to summarise the relevant pre-clinical and clinical research findings relating to this topic. The endocannabinoid system as a whole plays an important role in liver diseases (i.e. non-alcoholic liver disease, alcoholic liver disease, hepatic encephalopathy and autoimmune hepatitis) and related pathophysiological conditions (i.e. altered hepatic haemodynamics, cirrhotic cardiomyopathy, metabolic syndrome and ischaemia/reperfusion disease). Pharmacological targeting of the endocannabinoid system has had success as treatment for patients with liver disease, but adverse events led to withdrawal of marketing approval. However, there is optimism over novel therapeutics targeting the endocannabinoid system currently in the pre-clinical stage of development. The endocannabinoid system plays an important role in the pathophysiology of liver disease and its associated conditions. While some drugs targeting the endocannabinoid system have deleterious neurological adverse events, there is promise for a newer generation of therapies that do not cross the blood-brain barrier. © 2014 John Wiley & Sons Ltd.

  11. Leukotrienes as Modifiers of Preclinical Atherosclerosis?

    Directory of Open Access Journals (Sweden)

    Graziano Riccioni

    2012-01-01

    Full Text Available Preclinical atherosclerosis represents a crucial period associated with several pathophysiological reactions in the vascular wall. Failure to diagnose preclinical atherosclerosis at this stage misses a major opportunity to prevent the long-term consequences of this disease. Surrogate biological and structural vascular markers are available to determine the presence and the extension of preclinical vascular injury in the general population. Examples of surrogate markers are carotid intima media thickness and biomarkers including high-sensitivity C-reactive protein, cell adhesion molecules and matrix metalloproteinases, and leukotrienes. Recently, leukotrienes have been implicated as mediators, biomarkers, and possible therapeutic targets in the context of subclinical atherosclerosis. The aim of this short paper is to focus on the relation between preclinical atherosclerosis and leukotrienes, with particular attention to the recent development on the use of leukotriene modifiers in the treatment of atherosclerosis.

  12. Time to Amyloid Positivity and Preclinical Changes in Brain Metabolism, Atrophy, and Cognition: Evidence for Emerging Amyloid Pathology in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Philip S. Insel

    2017-05-01

    Full Text Available Background: Aβ pathology is associated with longitudinal changes of brain metabolism, atrophy, and cognition, in cognitively healthy elders. However, Aβ information is usually measured cross-sectionally and dichotomized to classify subjects as Aβ-positive or Aβ-negative, making it difficult to evaluate when brain and cognitive changes occur with respect to emerging Aβ pathology. In this study, we use longitudinal Aβ information to combine the level and rate of change of Aβ to estimate the time to Aβ-positivity for each subject and test this temporal proximity to significant Aβ pathology for associations with brain structure, metabolism, and cognition.Methods: In 89 cognitively healthy elders with up to 10 years of follow-up, we estimated the points at which rates of fluorodeoxyglucose (FDG PET, MRI, and cognitive and functional decline begin to accelerate with respect to the time to Aβ-positivity. Points of initial acceleration in rates of decline were estimated using mixed-effects models with penalized regression splines.Results: Acceleration of rates of FDG PET were observed to occur 20+ years before the conventional threshold for Aβ-positivity. Subtle signs of cognitive dysfunction were observed 10+ years before Aβ-positivity.Conclusions: Aβ may have subtle associations with other hallmarks of Alzheimer's disease before Aβ biomarkers reach conventional thresholds for Aβ-positivity. Therefore, we propose that emerging Aβ pathology occurs many years before cognitively healthy elders reach the current threshold for Aβ positivity (preclinical AD. To allow prevention in the earliest disease stages, AD clinical trials may be designed to also include subjects with Aβ biomarkers in the sub-threshold range.

  13. In vivo pharmacological characterization of a novel selective alpha7 neuronal nicotinic acetylcholine receptor agonist ABT-107: preclinical considerations in Alzheimer's disease.

    Science.gov (United States)

    Bitner, R Scott; Bunnelle, William H; Decker, Michael W; Drescher, Karla U; Kohlhaas, Kathy L; Markosyan, Stella; Marsh, Kennan C; Nikkel, Arthur L; Browman, Kaitlin; Radek, Rich; Anderson, David J; Buccafusco, Jerry; Gopalakrishnan, Murali

    2010-09-01

    We previously reported that alpha7 nicotinic acetylcholine receptor (nAChR) agonism produces efficacy in preclinical cognition models correlating with activation of cognitive and neuroprotective signaling pathways associated with Alzheimer's disease (AD) pathology. In the present studies, the selective and potent alpha7 nAChR agonist 5-(6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy] pyridazin-3-yl)-1H-indole (ABT-107) was evaluated in behavioral assays representing distinct cognitive domains. Studies were also conducted to address potential issues that may be associated with the clinical development of an alpha7 nAChR agonist. Specifically, ABT-107 improved cognition in monkey delayed matching to sample, rat social recognition, and mouse two-trial inhibitory avoidance, and continued to improve cognitive performance at injection times when exposure levels continued to decline. Rats concurrently infused with ABT-107 and donepezil at steady-state levels consistent with clinical exposure showed improved short-term recognition memory. Compared with nicotine, ABT-107 did not produce behavioral sensitization in rats or exhibit psychomotor stimulant activity in mice. Repeated (3 days) daily dosing of ABT-107 increased extracellular cortical acetylcholine in rats, whereas acute administration increased cortical extracellular signal-regulated kinase and cAMP response element-binding protein phosphorylation in mice, neurochemical and biochemical events germane to cognitive function. ABT-107 increased cortical phosphorylation of the inhibitory residue (Ser9) of glycogen synthase kinase-3, a primary tau kinase associated with AD pathology. In addition, continuous infusion of ABT-107 in tau/amyloid precursor protein transgenic AD mice reduced spinal tau hyperphosphorylation. These findings show that targeting alpha7 nAChRs may have potential utility for symptomatic alleviation and slowing of disease progression in the treatment AD, and expand the understanding of the potential

  14. COPD: a multifactorial systemic disease.

    Science.gov (United States)

    Huertas, Alice; Palange, Paolo

    2011-06-01

    Chronic obstructive pulmonary disease (COPD) has traditionally been considered a disease of the lungs secondary to cigarette smoking and characterized by airflow obstruction due to abnormalities of both airway (bronchitis) and lung parenchyma (emphysema). It is now well known that COPD is associated with significant systemic abnormalities, such as renal and hormonal abnormalities, malnutrition, muscle wasting, osteoporosis, and anemia. However, it is still unclear whether they represent consequences of the pulmonary disorder, or whether COPD should be considered as a systemic disease. These systemic abnormalities have been attributed to an increased level of systemic inflammation. Chronic inflammation, however, may not be the only cause of the systemic effects of COPD. Recent data from humans and animal models support the view that emphysema may be a vascular disease. Other studies have highlighted the role of repair failure, bone marrow abnormality, genetic and epigenetic factors, immunological disorders and infections as potential causes of COPD systemic manifestations. Based on this new evidence, it is reasonable to consider COPD, and emphysema in particular, as 'a disease with a significant systemic component' if not a 'systemic disease' per se. The aim of this review is to give an overview of the most relevant and innovative hypothesis about the extrapulmonary manifestations of COPD.

  15. Preclinical Evaluation of miR-15/107 Family Members as Multifactorial Drug Targets for Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Sepideh Parsi

    2015-01-01

    Full Text Available Alzheimer's disease (AD is a multifactorial, fatal neurodegenerative disorder characterized by the abnormal accumulation of Aβ and Tau deposits in the brain. There is no cure for AD, and failure at different clinical trials emphasizes the need for new treatments. In recent years, significant progress has been made toward the development of miRNA-based therapeutics for human disorders. This study was designed to evaluate the efficiency and potential safety of miRNA replacement therapy in AD, using miR-15/107 paralogues as candidate drug targets. We identified miR-16 as a potent inhibitor of amyloid precursor protein (APP and BACE1 expression, Aβ peptide production, and Tau phosphorylation in cells. Brain delivery of miR-16 mimics in mice resulted in a reduction of AD-related genes APP, BACE1, and Tau in a region-dependent manner. We further identified Nicastrin, a γ-secretase component involved in Aβ generation, as a target of miR-16. Proteomics analysis identified a number of additional putative miR-16 targets in vivo, including α-Synuclein and Transferrin receptor 1. Top-ranking biological networks associated with miR-16 delivery included AD and oxidative stress. Collectively, our data suggest that miR-16 is a good candidate for future drug development by targeting simultaneously endogenous regulators of AD biomarkers (i.e., Aβ and Tau, inflammation, and oxidative stress.

  16. Preclinical studies for a phase 1 clinical trial of autologous hematopoietic stem cell gene therapy for sickle cell disease.

    Science.gov (United States)

    Urbinati, Fabrizia; Wherley, Jennifer; Geiger, Sabine; Fernandez, Beatriz Campo; Kaufman, Michael L; Cooper, Aaron; Romero, Zulema; Marchioni, Filippo; Reeves, Lilith; Read, Elizabeth; Nowicki, Barbara; Grassman, Elke; Viswanathan, Shivkumar; Wang, Xiaoyan; Hollis, Roger P; Kohn, Donald B

    2017-09-01

    Gene therapy by autologous hematopoietic stem cell transplantation (HSCT) represents a new approach to treat sickle cell disease (SCD). Optimization of the manufacture, characterization and testing of the transduced hematopoietic stem cell final cell product (FCP), as well as an in depth in vivo toxicology study, are critical for advancing this approach to clinical trials. Data are shown to evaluate and establish the feasibility of isolating, transducing with the Lenti/β AS3 -FB vector and cryopreserving CD34 + cells from human bone marrow (BM) at clinical scale. In vitro and in vivo characterization of the FCP was performed, showing that all the release criteria were successfully met. In vivo toxicology studies were conducted to evaluate potential toxicity of the Lenti/β AS3 -FB LV in the context of a murine BM transplant. Primary and secondary transplantation did not reveal any toxicity from the lentiviral vector. Additionally, vector integration site analysis of murine and human BM cells did not show any clonal skewing caused by insertion of the Lenti/β AS3 -FB vector in cells from primary and secondary transplanted mice. We present here a complete protocol, thoroughly optimized to manufacture, characterize and establish safety of a FCP for gene therapy of SCD. Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

  17. Effects of non-steroidal anti-inflammatory drug treatments on cognitive decline vary by phase of pre-clinical Alzheimer disease: findings from the randomized controlled Alzheimer's Disease Anti-inflammatory Prevention Trial.

    Science.gov (United States)

    Leoutsakos, Jeannie-Marie S; Muthen, Bengt O; Breitner, John C S; Lyketsos, Constantine G

    2012-04-01

    We examined the effects of non-steroidal anti-inflammatory drugs on cognitive decline as a function of phase of pre-clinical Alzheimer disease. Given recent findings that cognitive decline accelerates as clinical diagnosis is approached, we used rate of decline as a proxy for phase of pre-clinical Alzheimer disease. We fit growth mixture models of Modified Mini-Mental State (3MS) Examination trajectories with data from 2388 participants in the Alzheimer's Disease Anti-inflammatory Prevention Trial and included class-specific effects of naproxen and celecoxib. We identified three classes: "no decline", "slow decline", and "fast decline", and examined the effects of celecoxib and naproxen on linear slope and rate of change by class. Inclusion of quadratic terms improved fit of the model (-2 log likelihood difference: 369.23; p < 0.001) but resulted in reversal of effects over time. Over 4 years, participants in the slow-decline class on placebo typically lost 6.6 3MS points, whereas those on naproxen lost 3.1 points (p-value for difference: 0.19). Participants in the fast-decline class on placebo typically lost 11.2 points, but those on celecoxib first declined and then gained points (p-value for difference from placebo: 0.04), whereas those on naproxen showed a typical decline of 24.9 points (p-value for difference from placebo: <0.0001). Our results appeared statistically robust but provided some unexpected contrasts in effects of different treatments at different times. Naproxen may attenuate cognitive decline in slow decliners while accelerating decline in fast decliners. Celecoxib appeared to have similar effects at first but then attenuated change in fast decliners. Copyright © 2011 John Wiley & Sons, Ltd.

  18. Preclinical assessment of dopaminergic system in rats by MicroPET using three positron-emitting radiopharmaceuticals

    Energy Technology Data Exchange (ETDEWEB)

    Lara-Camacho, V. M., E-mail: victormlc13@hotmail.com; Ávila-García, M. C., E-mail: victormlc13@hotmail.com; Ávila-Rodríguez, M. A., E-mail: victormlc13@hotmail.com [Unidad PET, Facultad de Medicina, Universidad Nacional Autónoma de México, 04510, México, D.F. (Mexico)

    2014-11-07

    Different diseases associated with dysfunction of dopaminergic system such as Parkinson, Alzheimer, and Schizophrenia are being widely studied with positron emission tomography (PET) which is a noninvasive method useful to assess the stage of these illnesses. In our facility we have recently implemented the production of [{sup 11}C]-DTBZ, [{sup 11}C]-RAC, and [{sup 18}F]-FDOPA, which are among the most common PET radiopharmaceuticals used in neurology applications to get information about the dopamine pathways. In this study two healthy rats were imaged with each of those radiotracers in order to confirm selective striatum uptake as a proof of principle before to release them for human use.

  19. Preclinical assessment of the distribution of maraviroc to potential human immunodeficiency virus (HIV) sanctuary sites in the central nervous system (CNS) and gut-associated lymphoid tissue (GALT).

    Science.gov (United States)

    Walker, D K; Bowers, S J; Mitchell, R J; Potchoiba, M J; Schroeder, C M; Small, H F

    2008-10-01

    1. Growing knowledge of the pathogenesis of human immunodeficiency virus (HIV)-1 infection has led to the identification of potential virus sanctuary sites within the central nervous system and gut-associated lymphoid tissue. 2. Maraviroc is a novel CCR5 antagonist for the treatment of HIV-1 infection. Disposition studies have been performed within the preclinical testing of maraviroc to determine its distribution to these anatomical sites. 3. Maraviroc, which is a substrate of the efflux transporter P-glycoprotein, shows limited distribution to the central nervous system as evidenced by cerebrospinal fluid concentrations that were 10% of the free plasma concentration following intravenous infusion to rats. Tissue distribution studies also indicated limited distribution of radioactivity into brain tissue of rats. 4. Radioactivity in gut-associated lymphoid tissue lymph nodes exceeded the concentrations in blood and concentrations in the contents of thoracic ducts of the lymphatic system were similar to blood levels following intravenous administration to rats.

  20. The endocannabinoid system and Post Traumatic Stress Disorder (PTSD): From preclinical findings to innovative therapeutic approaches in clinical settings.

    Science.gov (United States)

    Berardi, Andrea; Schelling, Gustav; Campolongo, Patrizia

    2016-09-01

    Post-Traumatic Stress Disorder (PTSD) is a psychiatric chronic disease developing in individuals after the experience of an intense and life-threatening traumatic event. The post-traumatic symptomatology encompasses alterations in memory processes, mood, anxiety and arousal. There is now consensus in considering the disease as an aberrant adaptation to traumatic stress. Pharmacological research, aimed at the discovery of new potential effective treatments, has lately directed its attention towards the "so-called" cognitive enhancers. This class of substances, by modulating cognitive processes involved in the development and/or persistence of the post-traumatic symptomatology, could be of great help in improving the outcome of psychotherapies and patients' prognosis. In this perspective, drugs acting on the endocannabinoid system are receiving great attention due to their dual ability to modulate memory processes on one hand, and to reduce anxiety and depression on the other. The purpose of the present review is to offer a thorough overview of both animal and human studies investigating the effects of cannabinoids on memory processes. First, we will briefly describe the characteristics of the endocannabinoid system and the most commonly used animal models of learning and memory. Then, studies investigating cannabinoid modulatory influences on memory consolidation, retrieval and extinction will be separately presented, and the potential benefits associated with each approach will be discussed. In the final section, we will review literature data reporting beneficial effects of cannabinoid drugs in PTSD patients. Copyright © 2016 Elsevier Ltd. All rights reserved.

  1. Novel System for Real-Time Integration of 3-D Echocardiography and Fluoroscopy for Image-Guided Cardiac Interventions: Preclinical Validation and Clinical Feasibility Evaluation

    Science.gov (United States)

    Housden, R. James; Ma, Yingliang; Rajani, Ronak; Gao, Gang; Nijhof, Niels; Cathier, Pascal; Bullens, Roland; Gijsbers, Geert; Parish, Victoria; Kapetanakis, Stamatis; Hancock, Jane; Rinaldi, C. Aldo; Cooklin, Michael; Gill, Jaswinder; Thomas, Martyn; O'neill, Mark D.; Razavi, Reza; Rhode, Kawal S.

    2014-01-01

    Real-time imaging is required to guide minimally invasive catheter-based cardiac interventions. While transesophageal echocardiography allows for high-quality visualization of cardiac anatomy, X-ray fluoroscopy provides excellent visualization of devices. We have developed a novel image fusion system that allows real-time integration of 3-D echocardiography and the X-ray fluoroscopy. The system was validated in the following two stages: 1) preclinical to determine function and validate accuracy; and 2) in the clinical setting to assess clinical workflow feasibility and determine overall system accuracy. In the preclinical phase, the system was assessed using both phantom and porcine experimental studies. Median 2-D projection errors of 4.5 and 3.3 mm were found for the phantom and porcine studies, respectively. The clinical phase focused on extending the use of the system to interventions in patients undergoing either atrial fibrillation catheter ablation (CA) or transcatheter aortic valve implantation (TAVI). Eleven patients were studied with nine in the CA group and two in the TAVI group. Successful real-time view synchronization was achieved in all cases with a calculated median distance error of 2.2 mm in the CA group and 3.4 mm in the TAVI group. A standard clinical workflow was established using the image fusion system. These pilot data confirm the technical feasibility of accurate real-time echo-fluoroscopic image overlay in clinical practice, which may be a useful adjunct for real-time guidance during interventional cardiac procedures. PMID:27170872

  2. Systemic Evaluation of Electrical Stimulation for Ischemic Wound Therapy in a PreclinicalIn VivoModel.

    Science.gov (United States)

    Graebert, Jennifer K; Henzel, M Kristi; Honda, Kord S; Bogie, Kath M

    2014-06-01

    Objective: In a systematic preclinical investigation of ischemic wound healing, we investigated the hypothesis that electrical stimulation (ES) promotes the healing of ischemic wounds. Approach: The effects of varying clinically relevant ES variables were evaluated using our modified version of the Gould F344 rat ischemic wound model. Stimulation was delivered using the novel lightweight integrated, single-channel, current-controlled modular surface stimulation (MSS) device. Stepwise variation allowed the effects of five different stimulation paradigms within an appropriate current density range to be studied. Within each group, 8-10 animals were treated for 28 days or until the ischemic wounds were healed and 5 animals were treated for 12 days. Eight rats received sham devices. A quantitative multivariable outcomes assessment procedure was used to evaluate the effects of ES. Results: Ischemic wounds treated with a decreased interpulse interval (IPI) had the highest rate of complete wound closure at 3 weeks. Wounds treated with decreased pulse amplitude (PA) had a lower proportion of closed wounds than sham ischemic wounds and showed sustained inflammation with a lack of wound contraction. Innovation: Our systematic study of varying ES paradigms using the novel MSS device provides preliminary insight into potential mechanisms of ES in ischemic wound healing. Conclusion: Clinically appropriate ES can more than double the proportion of ischemic wounds closed by 3 weeks in this model. Ninety percent of wounds treated with a decreased IPI healed by 21 days compared with only 29% of ischemic wounds treated with decreased PA, which appears to inhibit healing.

  3. Systemic diseases and the elderly.

    LENUS (Irish Health Repository)

    McCreary, Christine

    2010-11-01

    Although systemic diseases can occur at any age, they are more common in older patients. Accurate and detailed medical and drug histories are important in dental practice as many conditions and medications can influence oral health and dental care in patients. Not only can these conditions influence patient care in the surgery and oral hygiene at home, but access to dental services may also be adversely affected. Clinical Relevance: The systemic diseases can impact upon oral care or can have oral manifestations. Many of the pharmacological interventions prescribed for chronic conditions can have multiple and diverse adverse effects on the oral environment.

  4. [Preclinical AD and Biomarker; from J-ADNI to AMED Preclinical Study].

    Science.gov (United States)

    Suzuki, Kazushi

    2017-07-01

    Alzheimer's disease (AD) is most prevalent cause of dementia and no cure has been discovered. Although the framework of AD clinical trials is being established utilizing results of large-scale observational studies such as the AD Neuroimaging Initiative (ADNI) and the Japanese-ADNI (J-ADNI), the development of disease-modifying therapy for Alzheimer's disease (AD) has not yet been achieved. Preclinical AD was recently defined as a new disease stage in which AD is asymptomatic but biomarkers suggest the presence of amyloid pathology. Preclinical AD has been focused as promising therapeutic time window and establishment of reliable biomarkers for preclinical AD is an urgent task. The Japanese Agency for Medical Research and Development (AMED) preclinical study is a nationwide multicenter observational study carried out by public research funding from AMED as a successor to the J-ADNI study. The goal of this study is to establish a biomarker that can quantitatively evaluate the disease progression of preclinical AD and mild cognitive impairment (MCI) or predict the progression to MCI and dementia in the future. To achieve this goal, the following assessments will be conducted over time for three years: clinical evaluations; cognitive tests; genetic testing; body fluid biomarker tests; and imaging biomarker studies such as MRI, FDG-PET, and amyloid PET. The obtained data will eventually be released to the public database.

  5. Oral microbiota and systemic disease.

    Science.gov (United States)

    Kumar, Purnima S

    2013-12-01

    It is well known that bacteria are the primary cause of infectious diseases, however, evidence is emerging that these organisms are also indirectly responsible for several diseases including cancer and rheumatoid arthritis. The oral cavity is home to several million bacteria that can cause two major diseases-periodontitis and caries. The relationship between periodontopathic bacteria and systemic diseases has been explored for several years. The concept of the oral cavity as a source of distant infection has been debated for at least a century. This review will discuss the historic aspects of the development of the focal infection theory, the reasons for its demise, its re-emergence and current status. Copyright © 2013 Elsevier Ltd. All rights reserved.

  6. Three-Dimensional Quantitative Morphometric Analysis (QMA for In Situ Joint and Tissue Assessment of Osteoarthritis in a Preclinical Rabbit Disease Model.

    Directory of Open Access Journals (Sweden)

    Kathryn S Stok

    Full Text Available This work utilises advances in multi-tissue imaging, and incorporates new metrics which define in situ joint changes and individual tissue changes in osteoarthritis (OA. The aims are to (1 demonstrate a protocol for processing intact animal joints for microCT to visualise relevant joint, bone and cartilage structures for understanding OA in a preclinical rabbit model, and (2 introduce a comprehensive three-dimensional (3D quantitative morphometric analysis (QMA, including an assessment of reproducibility. Sixteen rabbit joints with and without transection of the anterior cruciate ligament were scanned with microCT and contrast agents, and processed for histology. Semi-quantitative evaluation was performed on matching two-dimensional (2D histology and microCT images. Subsequently, 3D QMA was performed; including measures of cartilage, subchondral cortical and epiphyseal bone, and novel tibio-femoral joint metrics. Reproducibility of the QMA was tested on seven additional joints. A significant correlation was observed in cartilage thickness from matching histology-microCT pairs. The lateral compartment of operated joints had larger joint space width, thicker femoral cartilage and reduced bone volume, while osteophytes could be detected quantitatively. Measures between the in situ tibia and femur indicated an altered loading scenario. High measurement reproducibility was observed for all new parameters; with ICC ranging from 0.754 to 0.998. In conclusion, this study provides a novel 3D QMA to quantify macro and micro tissue measures in the joint of a rabbit OA model. New metrics were established consisting of: an angle to quantitatively measure osteophytes (σ, an angle to indicate erosion between the lateral and medial femoral condyles (ρ, a vector defining altered angulation (λ, α, β, γ and a twist angle (τ measuring instability and tissue degeneration between the femur and tibia, a length measure of joint space width (JSW, and a slope and

  7. Design Rationale and Preclinical Evaluation of the HeartMate 3 Left Ventricular Assist System for Hemocompatibility.

    Science.gov (United States)

    Bourque, Kevin; Cotter, Christopher; Dague, Charles; Harjes, Daniel; Dur, Onur; Duhamel, Julien; Spink, Kaitlyn; Walsh, Kelly; Burke, Edward

    2016-01-01

    The HeartMate 3 (HM3) left ventricular assist device (LVAD) is designed to support advanced heart failure patients. This centrifugal flow pump has a magnetically levitated rotor, artificial pulse, textured blood-contacting surfaces, optimized fluid dynamics, large blood-flow gaps, and low shear stress. Preclinical tests were conducted to assess hemocompatibility. A computational fluid dynamics (CFD) model guided design for low shear stress and sufficient washing. Hemolysis testing was conducted on six pumps. Plasma-free hemoglobin (PfHb) and modified index of hemolysis (MIH) were compared with HeartMate II (HMII). CFD showed secondary flow path residence times between 27 and 798 min, comparable with main flow residence times between 118 and 587 min; HM3 vs. HMII shear stress exposure above 150 Pa was 3.3 vs. 11 mm within the pump volume and 134 vs. 604 mm on surfaces. In in vitro hemolysis tests at 2, 5, and 10 L/min, average pfHb 6 hours after test initiation was 58, 74, and 157 mg/dl, compared with 112, 123, and 353 mg/dl for HMII. The HM3/HMII ratio of average MIH at 2, 5, and 10 L/min was 0.29, 0.36, and 0.22. Eight 60 day bovine implants were tested with average flow rates from 5.6 to 6.4 L/min with no device failures, thrombosis, or hemolysis. Results support advancing HM3 to clinical trials.

  8. The relation of periodontal diseases to systemic diseases

    Directory of Open Access Journals (Sweden)

    Melanie Sadono Djamil

    2008-12-01

    Full Text Available Background: The relationship between systemic disorders and periodontal disease has been studied extensively. With few exceptions, it is more accurate to consider systemic diseases to be contributing factors in the pathogenesis of periodontal disease rather than the primary etiologic factors. The development of periodontal disease cannot be separated from the weakening of immunologic and immunopathological responses. Periodontal disease may enhance susceptibility to certain systemic diseases in several ways. Lipopolysaccharide (LPS and Gram-positive bacteria in the biofilm and proinflammatory cytokines produced from inflamed periodontal tissues may enter the circulation system causing the development of certain systemic diseases. On the other hand, through immunologic mediators, certain systemic disease may enhance susceptibility to periodontal disease caused by the decrease of immune responses and the increase of proinflammatory cytokines. Purpose: The Purpose of this article is to review the immunologic aspect of two way relationship between systemic diseases and periodontal diseases. Review: This review studied the relationship between general health status, systemic diseases, and periodontal diseases through immunopathological responses and the weakening of the immune system in the periodontal tissue. Conclusion: there is a two-way relationship between periodontal diseases and systemic diseases.

  9. Performance Evaluation of a Dedicated Preclinical PET/CT System for the Assessment of Mineralization Process in a Mouse Model of Atherosclerosis.

    Science.gov (United States)

    Rucher, Guillaume; Cameliere, Lucie; Fendri, Jihene; Abbas, Ahmed; Dupont, Kevin; Kamel, Said; Delcroix, Nicolas; Dupont, Axel; Berger, Ludovic; Manrique, Alain

    2018-04-30

    The purpose of this study was to assess the impact of positron emission tomography/X-ray computed tomography (PET/CT) acquisition and reconstruction parameters on the assessment of mineralization process in a mouse model of atherosclerosis. All experiments were performed on a dedicated preclinical PET/CT system. CT was evaluated using five acquisition configurations using both a tungsten wire phantom for in-plane resolution assessment and a bar pattern phantom for cross-plane resolution. Furthermore, the radiation dose of these acquisition configurations was calculated. The PET system was assessed using longitudinal line sources to determine the optimal reconstruction parameters by measuring central resolution and its coefficient of variation. An in vivo PET study was performed using uremic ApoE -/- , non-uremic ApoE -/- , and control mice to evaluate optimal PET reconstruction parameters for the detection of sodium [ 18 F]fluoride (Na[ 18 F]F) aortic uptake and for quantitative measurement of Na[ 18 F]F bone influx (Ki) with a Patlak analysis. For CT, the use of 1 × 1 and 2 × 2 binning detector mode increased both in-plane and cross-plane resolution. However, resolution improvement (163 to 62 μm for in-plane resolution) was associated with an important radiation dose increase (1.67 to 32.78 Gy). With PET, 3D-ordered subset expectation maximization (3D-OSEM) algorithm increased the central resolution compared to filtered back projection (1.42 ± 0.35 mm vs. 1.91 ± 0.08, p PET resolution for preclinical study (FWHM = 0.98 mm). These PET reconstruction parameters allowed the detection of Na[ 18 F]F aortic uptake in 3/14 ApoE -/- mice and demonstrated a decreased Ki in uremic ApoE -/- compared to non-uremic ApoE -/- and control mice (p PET. In addition, improving the CT resolution was associated with a dramatic radiation dose increase.

  10. Radiological approach to systemic connective tissue diseases

    Energy Technology Data Exchange (ETDEWEB)

    Wiesmann, W.; Schneider, M.

    1988-07-01

    Systemic lupus erythematosus (SLE) and progressive systemic sclerosis (PSS) represent the most frequent manifestations of systemic connective tissue diseases (collagen diseases). Radiological examinations are employed to estimate the extension and degree of the pathological process. In addition, progression of the disease can be verified. In both of the above collagen diseases, specific radiological findings can be observed that permit them to be differentiated from other entities. An algorithm for the adequate radiological work-up of collagen diseases is presented.

  11. Preclinical optimization of a broad-spectrum anti-bladder cancer tri-drug regimen via the Feedback System Control (FSC) platform

    Science.gov (United States)

    Liu, Qi; Zhang, Cheng; Ding, Xianting; Deng, Hui; Zhang, Daming; Cui, Wei; Xu, Hongwei; Wang, Yingwei; Xu, Wanhai; Lv, Lei; Zhang, Hongyu; He, Yinghua; Wu, Qiong; Szyf, Moshe; Ho, Chih-Ming; Zhu, Jingde

    2015-06-01

    Therapeutic outcomes of combination chemotherapy have not significantly advanced during the past decades. This has been attributed to the formidable challenges of optimizing drug combinations. Testing a matrix of all possible combinations of doses and agents in a single cell line is unfeasible due to the virtually infinite number of possibilities. We utilized the Feedback System Control (FSC) platform, a phenotype oriented approach to test 100 options among 15,625 possible combinations in four rounds of assaying to identify an optimal tri-drug combination in eight distinct chemoresistant bladder cancer cell lines. This combination killed between 82.86% and 99.52% of BCa cells, but only 47.47% of the immortalized benign bladder epithelial cells. Preclinical in vivo verification revealed its markedly enhanced anti-tumor efficacy as compared to its bi- or mono-drug components in cell line-derived tumor xenografts. The collective response of these pathways to component drugs was both cell type- and drug type specific. However, the entire spectrum of pathways triggered by the tri-drug regimen was similar in all four cancer cell lines, explaining its broad spectrum killing of BCa lines, which did not occur with its component drugs. Our findings here suggest that the FSC platform holdspromise for optimization of anti-cancer combination chemotherapy.

  12. Multiple stent delivery system Multi-LOC, a new technology for spot-stenting of the femoropopliteal artery - proof of concept study in a preclinical large animal model.

    Science.gov (United States)

    Sigl, Martin; Dudeck, Oliver; Jung, Johannes; Koelble, Heinz; Amendt, Klaus

    2017-10-01

    A new stent system was studied in a porcine model to evaluate its feasibility for spot-stenting of the femoropopliteal artery. In a preliminary study in a single pig, handling and mechanical features of the novel multiple stent delivery system were tested. The Multi-LOC system demonstrated great feasibility regarding its pushability, trackability, and crossability. Excellent visibility of the individual stents allowed exact anatomically controlled implantation. In our main study, four to five short Multi-LOC stents (13 mm long) were implanted into the femoropopliteal arteries of six domestic pigs and long (60 to 100 mm) self-expandable nitinol stents were implanted into the same target vessel contralaterally to allow for intraindividual comparison. After four weeks survival under dual antiplatelet treatment, control angiography was performed. The animals were euthanized, stented vessels were explanted, and histologic sections were examined for the presence of neointimal formation. Multi-LOC stents demonstrated no occlusion of the femoropopliteal axis (0 vs. 1 occlusion distal to a control stent), no stent fractures (0 out of 26 vs. 2 out of 6 control stents), and lower percentage diameter stenosis (0.564 ± 0.056 vs. 0.712 ± 0.089; p = 0.008) and length of stenosis (19.715 ± 5.225 vs. 39.397 ± 11.182; p = 0.007) compared to a standard control stent, which was similar in total length to the multiple stented artery segment. Histological examination confirmed myointimal hyperplasia underlying in-stent stenosis. The multiple stent delivery system was studied in a porcine model, which demonstrated its feasibility. Preclinical experience revealed favourable results concerning stent fracture, restenosis, and patency of spot-stented femoropopliteal arteries.

  13. CO2 laser myringotomy with a hand-held otoscope and fiber optic delivery system: animal experimentation and preclinical trials

    Science.gov (United States)

    DeRowe, Ari; Ophir, Dov; Finkelstein, Y.; Katzir, Abraham

    1993-07-01

    CO2 laser myringotomy has previously been proven effective in patients with serous otitis media for short term aeration of the middle ear. However, the system based on a microscope and a coaxially aligned laser is cumbersome and expensive. Also, conventional optical fibers do not transmit CO2 laser energy ((lambda) equals 10.6 micrometers ). We have developed a silver halide optical fiber of diameter 0.9 mm and lengths of several meters, with high transmission at 10.6 micrometers . Using a hand held otoscope coupled to a fiberoptic delivery system CO2 laser myringotomies were performed first in guinea pigs and then in humans. In the animal model the feasibility of the procedure was proven. Different irradiation parameters were studied and a `dose dependent' relationship was found between the total energy used and the duration of a patent myringotomy. This system was used to perform CO2 laser myringotomies under local anesthesia in five patients with serous otitis media and conductive hearing loss. None of the patients complained of discomfort and no scarring was noted. All patients had subjective and audiometric documentation of hearing improvement. The average duration of a patent myringotomy was 21 days. In two patients the effusion recurred. CO2 laser myringotomy utilizing a hand held otoscope coupled to an optical fiber capable of transmitting CO2 laser energy may prove simple and effective in the treatment of serous otitis media.

  14. Smoking Related Systemic and Oral Diseases

    OpenAIRE

    Sajith Vellappally; Zdeněk Fiala; Jindra Šmejkalová; Vimal Jacob; Rakesh Somanathan

    2007-01-01

    This article reviewed smoking related systemic diseases and oral diseases. Smoking is related to lung cancer, cardiovascular diseases and many other systemic diseases. Cigarette smoke affects the oral cavity first, so it is evident that smoking has many negative influences on oral cavity, for example, staining of teeth and dental restorations, wound healing, reduction of the ability to smell and taste, and development of oral diseases such as oral cancer, periodontitis, smoker’s palate, smoke...

  15. Preclinical deposition of pathological prion protein in muscle of experimentally infected primates.

    Directory of Open Access Journals (Sweden)

    Susanne Krasemann

    Full Text Available Prion diseases are transmissible fatal neurodegenerative disorders affecting humans and animals. A central step in disease progression is the accumulation of a misfolded form (PrP(Sc of the host encoded prion protein (PrP(C in neuronal and non-neuronal tissues. The involvement of peripheral tissues in preclinical states increases the risk of accidental transmission. On the other hand, detection of PrP(Sc in non-neuronal easy-accessible compartments such as muscle may offer a novel diagnostic tool. Primate models have proven invaluable to investigate prion diseases. We have studied the deposition of PrP(Sc in muscle and central nervous system of rhesus monkeys challenged with sporadic Creutzfeldt-Jakob disease (sCJD, variant CJD (vCJD and bovine spongiform encephalopathy (BSE in preclinical and clinical stage using biochemical and morphological methods. Here, we show the preclinical presence of PrP(Sc in muscle and central nervous system of rhesus monkeys experimentally infected with vCJD.

  16. {sup 99m}Tc-HYNIC-spermine for imaging polyamine transport system-positive tumours: preclinical evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Pesnel, Sabrina [Institut de Recherche Pierre Fabre, Centre de Recherche en Oncologie Experimentale, Toulouse (France); UPS TAAM - CIPA, CNRS, Orleans (France); Guminski, Yves; Imbert, Thierry [Institut de Recherche Pierre Fabre, Division de Chimie Medicinale III, Castres (France); Pillon, Arnaud; Guilbaud, Nicolas; Kruczynski, Anna; Bailly, Christian [Institut de Recherche Pierre Fabre, Centre de Recherche en Oncologie Experimentale, Toulouse (France); Lerondel, Stephanie [UPS TAAM - CIPA, CNRS, Orleans (France); Le Pape, Alain [UPS TAAM - CIPA, CNRS, Orleans (France); Universite Francois Rabelais, INSERM U618, Tours (France)

    2011-10-15

    F14512 exploiting the polyamine transport system (PTS) for tumour cell delivery has been described as a potent antitumour agent. The optimal use of this compound will require a probe to identify tumour cells expressing a highly active PTS that might be more sensitive to the treatment. The aim of this study was to design and characterize a scintigraphic probe to evaluate its uptake in cancer cells expressing the PTS. Three polyamines coupled to a hydrazinonicotinamide (HYNIC) moiety were synthesized and labelled with {sup 99m}Tc. Their radiochemical purity was determined by HPLC. The plasma stability of the {sup 99m}Tc-HYNIC-spermine probe and its capacity to accumulate into PTS-active cells were also evaluated. In vitro internalization was tested using murine melanoma B16/F10 cells and human lung carcinoma A549 cells. Biodistribution was determined in healthy mice and tumour uptake was studied in B16/F10 tumour-bearing mice. A HL-60-Luc human leukaemia model was used to confront single photon emission computed tomography (SPECT) images obtained with the {sup 99m}Tc-labelled probe with those obtained by bioluminescence. The {sup 99m}Tc-HYNIC-spermine probe was selected for its capacity to accumulate into PTS-active cells and its stability in plasma. In vitro studies demonstrated that the probe was internalized in the cells via the PTS. In vivo measurements indicated a tumour to muscle scintigraphic ratio of 7.9{+-}2.8. The combined bioluminescence and scintigraphic analyses with the leukaemia model demonstrated that the spermine conjugate accumulates into the tumour cells. The {sup 99m}Tc-HYNIC-spermine scintigraphic probe is potentially useful to characterize the PTS activity of tumours. Additional work is needed to determine if this novel conjugate may be useful to analyse the PTS status of patients with solid tumours. (orig.)

  17. SU-D-304-04: Pre-Clinical Feasibility Study for Intensity Modulated Grid Proton Therapy (IMgPT) Using a Newly Developed Delivery System

    Energy Technology Data Exchange (ETDEWEB)

    Tsiamas, P; Moskvin, V; Shin, J; Axente, M; Pirlepesov, F; Krasin, M; Merchant, T; Farr, J [St. Jude Children’s Research Hospital, Memphis, TN (United States)

    2015-06-15

    Purpose: The purpose of the current study was to characterize and evaluate intensity-modulated proton grid therapy (IMgPT) using a clinical proton beam. Methods: A TOPAS MC model of a new developmental mode (pre-clinical) of the Hitachi proton therapy system (PROBEAT) was used for simulation and characterization of proton grid therapy. TOPAS simulations of different energy ranges, depths and spot separation distances were performed. LET spectra for various energies and depths were produced with FLUKA MC code for evaluation potential interplay between planning parameters and their effect on the characterization of areas (valley) between spots. IMgPT planning aspects (spot spacing, skin dose, peak-to-valley ratios, beam selection, etc.) were evaluated for different phantom and patient cases. Raysearch software (v4.51) was used to perform the evaluation. Results: Calculated beam peak-to-valley ratios scenarios showed strong energy and depth dependence with ratios to be larger for higher energies and shallower depths. Peak-to-valley ratios for R90 range and for spot spacing of 1cm varied from 30% (E = 221.3 MeV, depth 30.6 cm) to 80% (E = 70.3 MeV, depth 4 cm). LET spectra calculations showed spectral hardening with depth, which might potential increase, spot separation distance and improve peak-to-valley ratios. IMgPT optimization, using constant spot spacing, showed skin dose reduction between peak regions of dose due to the irradiation of less skin. Single beam for bulky shallower tumors might be a potential candidate for proton grid therapy. Conclusions: Proton grid therapy using a clinical beam is a promising technique that reduces skin dose between peak regions of dose and may be suitable for the treatment of shallow tumors. IMgPT may be considered for use when bystander effects in off peak regions would be appropriate.

  18. [Mobile computing systems in preclinical care of stroke. Results of the Stroke Angel initiative within the BMBF project PerCoMed].

    Science.gov (United States)

    Ziegler, V; Rashid, A; Müller-Gorchs, M; Kippnich, U; Hiermann, E; Kögerl, C; Holtmann, C; Siebler, M; Griewing, B

    2008-07-01

    steps of evaluation. The system significantly influenced the clinical process of acute stroke management more than the preclinical ones (door-to-CT: 32 min. before and 16 min. at the end of the project). Lysis treatment rose from 6.12% (2005) to 11.17% (2007) of patients with acute stroke. From the set of perspectives taken, the study illustrates that mobile computing technologies offer new and innovative approaches to improve intersectional acute stroke care. It also teaches the participants that interdisciplinary research can significantly deepen the understanding of such technologies and projects, which can lead to better decision making concerning solution implementation, management and improvements. The approach will be brought into daily practice in Bad Neustadt/Saale within the next months.

  19. Discovery and preclinical development of a novel prodrug conjugate of mesalamine with eicosapentaenoic acid and caprylic acid for the treatment of inflammatory bowel diseases.

    Science.gov (United States)

    Kandula, Mahesh; Sunil Kumar, K B; Palanichamy, Sivanesan; Rampal, Ashok

    2016-11-01

    Mesalamine (5-ASA) is one of the drugs indicated as first line therapy in ulcerative colitis for induction and maintenance of remission. Sulfasalazine and formulations of 5-ASA (pH-dependent and controlled release formulations) were developed to minimize the systemic absorption and maximize the delivery of the mesalamine to colon. Although, its efficacy and safety is well documented there are approximately 30% nonresponders to 5-ASA therapy. This necessitates the need for novel therapeutic options to improve the efficacy and safety of the currently available 5-ASA therapy. CLX-103 is a novel, patented prodrug molecular conjugate of mesalamine, eicosapentaenoic acid and caprylic acid designed to offer incremental benefits over the currently approved 5-ASA formulations. Results of in vitro and in vivo studies showed that CLX-103, was stable in simulated gastric fluid, but undergoes enzymatic hydrolysis in the small/large intestines to release the active moiety. Our data also showed that the active moiety is retained in the targeted intestinal tissues (ileum and colon) over a longer period of time in relation to sulfasalazine. The in vitro data supports the observed in vivo plasma kinetics of 5-ASA characterized by longer T max , low C max after the oral administration of CLX-103. Efficacy study of CLX-103 in acute dextran sodium sulfate (DSS) mouse colitis model showed improved potency measured as Disease Activity Index (DAI) and histological scores in the colon as compared to sulfasalazine. These findings indicate that CLX-103 could offer a differentiated drug product which is more efficacious and safer than the currently approved 5-ASA formulations in the treatment of inflammatory bowel diseases. Copyright © 2016 Elsevier B.V. All rights reserved.

  20. Preclinical drug development.

    Science.gov (United States)

    Brodniewicz, Teresa; Grynkiewicz, Grzegorz

    2010-01-01

    Life sciences provide reasonably sound prognosis for a number and nature of therapeutic targets on which drug design could be based, and search for new chemical entities--future new drugs, is now more than ever based on scientific principles. Nevertheless, current very long and incredibly costly drug discovery and development process is very inefficient, with attrition rate spanning from many thousands of new chemical structures, through a handful of validated drug leads, to single successful new drug launches, achieved in average after 13 years, with compounded cost estimates from hundreds of thousands to over one billion US dollars. Since radical pharmaceutical innovation is critically needed, number of new research projects concerning this area is steeply rising outside of big pharma industry--both in academic environment and in small private companies. Their prospective success will critically depend on project management, which requires combined knowledge of scientific, technical and legal matters, comprising regulations concerning admission of new drug candidates to be subjects of clinical studies. This paper attempts to explain basic rules and requirements of drug development within preclinical study period, in case of new chemical entities of natural or synthetic origin, which belong to low molecular weight category.

  1. NOD/scid IL-2Rgnull mice: a preclinical model system to evaluate human dendritic cell-based vaccine strategies in vivo

    Directory of Open Access Journals (Sweden)

    Spranger Stefani

    2012-02-01

    Full Text Available Abstract Background To date very few systems have been described for preclinical investigations of human cellular therapeutics in vivo. However, the ability to carry out comparisons of new cellular vaccines in vivo would be of substantial interest for design of clinical studies. Here we describe a humanized mouse model to assess the efficacy of various human dendritic cell (DC preparations. Two reconstitution regimes of NOD/scid IL2Rgnull (NSG mice with adult human peripheral blood mononuclear cells (PBMC were evaluated for engraftment using 4-week and 9-week schedules. This led to selection of a simple and rapid protocol for engraftment and vaccine evaluation that encompassed 4 weeks. Methods NSG recipients of human PBMC were engrafted over 14 days and then vaccinated twice with autologous DC via intravenous injection. Three DC vaccine formulations were compared that varied generation time in vitro (3 days versus 7 days and signals for maturation (with or without Toll-like receptor (TLR3 and TLR7/8 agonists using MART-1 as a surrogate antigen, by electroporating mature DC with in vitro transcribed RNA encoding full length protein. After two weekly vaccinations, the splenocyte populations containing human lymphocytes were recovered 7 days later and assessed for MART-1-specific immune responses using MHC-multimer-binding assays and functional assessment of specific killing of melanoma tumor cell lines. Results Human monocyte-derived DC generated in vitro in 3 days induced better MART-1-specific immune responses in the autologous donor T cells present in the humanized NSG mice. Moreover, consistent with our in vitro observations, vaccination using mature DC activated with TLR3 and TLR7/8 agonists resulted in enhanced immune responses in vivo. These findings led to a ranking of the DC vaccine effects in vivo that reflected the hierarchy previously found for these mature DC variations in vitro. Conclusions This humanized mouse model system enables

  2. NCI Pediatric Preclinical Testing Consortium

    Science.gov (United States)

    NCI has awarded grants to five research teams to participate in its Pediatric Preclinical Testing Consortium, which is intended to help to prioritize which agents to pursue in pediatric clinical trials.

  3. Smoking Related Systemic and Oral Diseases

    Directory of Open Access Journals (Sweden)

    Sajith Vellappally

    2007-01-01

    Full Text Available This article reviewed smoking related systemic diseases and oral diseases. Smoking is related to lung cancer, cardiovascular diseases and many other systemic diseases. Cigarette smoke affects the oral cavity first, so it is evident that smoking has many negative influences on oral cavity, for example, staining of teeth and dental restorations, wound healing, reduction of the ability to smell and taste, and development of oral diseases such as oral cancer, periodontitis, smoker’s palate, smoker’s melanosis, hairy tongue, leukoplakia, oral candidiasis and implant survival rate. The article also discusses the relationship between smoking and dental caries in detail.

  4. Endocannabinoids and the Endocrine System in Health and Disease.

    Science.gov (United States)

    Hillard, Cecilia J

    2015-01-01

    Some of the earliest reports of the effects of cannabis consumption on humans were related to endocrine system changes. In this review, the effects of cannabinoids and the role of the CB1 cannabinoid receptor in the regulation of the following endocrine systems are discussed: the hypothalamic-pituitary-gonadal axis, prolactin and oxytocin, thyroid hormone and growth hormone, and the hypothalamic-pituitary-adrenal axis. Preclinical and human study results are presented.

  5. Expert System For Diagnosis Of Skin Diseases

    Directory of Open Access Journals (Sweden)

    A.A.L.C. Amarathunga

    2015-01-01

    Full Text Available Abstract Dermatology is a one of major session of medicine that concerned with the diagnosis and treatment of skin diseases. Skin diseases are the most common form of disease in humans. Recently many of researchers have advocated and developed the imaging of human vision or in the loop approach to visual object recognition. This research paper presents a development of a skin diseases diagnosis system which allows user to identify diseases of the human skin and to provide advises or medical treatments in a very short time period. For this purpose user will have to upload an image of skin disease to our system and answer questions based on their skin condition or symptoms. It will be used to detect diseases of the skin and offer a treatment recommendation. This system uses technologies such as image processing and data mining for the diagnosis of the disease of the skin. The image of skin disease is taken and it must be subjected to various preprocessing for noise eliminating and enhancement of the image. This image is immediately segmentation of images using threshold values. Finally data mining techniques are used to identify the skin disease and to suggest medical treatments or advice for users. This expert system exhibits disease identification accuracy of 85 for Eczema 95 for Impetigo and 85 for Melanoma.

  6. Premature atherosclerosis in systemic autoimmune diseases

    NARCIS (Netherlands)

    Leeuw, Karina de

    2008-01-01

    Systemic autoimmune diseases such as systemic lupus erythematosus (SLE) and Wegener’s granulomatosis (WG) are associated with a significantly increased prevalence of cardiovascular disease (CVD) compared to age- and sex-matched controls. Many risk factors are involved in the pathogenesis of

  7. A preclinical mouse model of invasive lobular breast cancer metastasis

    NARCIS (Netherlands)

    Doornebal, Chris W.; Klarenbeek, Sjoerd; Braumuller, Tanya M.; Klijn, Christiaan N.; Ciampricotti, Metamia; Hau, Cheei-Sing; Hollmann, Markus W.; Jonkers, Jos; de Visser, Karin E.

    2013-01-01

    Metastatic disease accounts for more than 90% of cancer-related deaths, but the development of effective antimetastatic agents has been hampered by the paucity of clinically relevant preclinical models of human metastatic disease. Here, we report the development of a mouse model of spontaneous

  8. Application of MultiStem® allogeneic cells for immunomodulatory therapy: clinical progress and pre-clinical challenges in prophylaxis for graft vs host disease

    Directory of Open Access Journals (Sweden)

    Bart eVaes

    2012-11-01

    Full Text Available The last decade has seen much progress in adjunctive cell therapy for immune disorders. Both corporate and institutional Phase III studies have been run using mesenchymal stromal cells (MSC for treatment of Graft vs Host Disease (GvHD, and product approval has been achieved for treatment of pediatric GvHD in Canada and New Zealand (Prochymal®; Osiris Therapeutics. This effectiveness has prompted the prophylactic use of adherent stem cells at the time of allogeneic hematopoietic stem cell transplantation (HSCT to prevent occurrence of GvHD and possibly provide stromal support for hematopoietic recovery. The MultiStem® product is an adult adherent stem cell product derived from bone marrow which has significant clinical exposure. MultiStem cells are currently in phase II clinical studies for treatment of ischemic stroke and ulcerative colitis, with Phase I studies completed in acute myocardial infarction and for GvHD prophylaxis in allogeneic HSCT, demonstrating that MultiStem administration was well tolerated while the incidence and severity of GvHD was reduced. In advancing this clinical approach, it is important to recognize that alternate models exist based on clinical manufacturing strategies. Corporate sponsors exploit the universal donor properties of adherent stem cells and manufacture at large scale, with many products obtained from one or limited donors and used across many patients. In Europe, institutional sponsors often produce allogeneic product in a patient designated context. For this approach, disposable bioreactors producing <10 products per donor in a closed system manner are very well suited. In this review, the use of adherent stem cells for GvHD prophylaxis is summarized and the suitability of disposable bioreactors for MultiStem production is presented, with an emphasis on quality control parameters, which are critical with a multiple donor approach for manufacturing.

  9. Estrogen in Cardiovascular Disease during Systemic Lupus Erythematosus

    Science.gov (United States)

    Gilbert, Emily L.; Ryan, Michael J.

    2015-01-01

    Purpose Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disease that disproportionately affects women during their childbearing years. Cardiovascular disease is the leading cause of mortality in this patient population at an age when women often have low cardiovascular risk. Hypertension is a major cardiovascular disease risk factor, and its prevalence is markedly increased in women with SLE. Estrogen has traditionally been implicated in SLE disease progression because of the prevalence of the disease in women; however, its role in cardiovascular risk factors such as hypertension is unclear. The objective of this review is to discuss evidence for the role of estrogen in both human and murine SLE with emphasis on the effect of estrogen on cardiovascular risk factors, including hypertension. Methods PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed. Findings The potential permissive role of estrogen in SLE development is supported by studies from experimental animal models of lupus in which early removal of estrogen or its effects leads to attenuation of SLE disease parameters, including autoantibody production and renal injury. However, data about the role of estrogens in human SLE are much less clear, with most studies not reaching firm conclusions about positive or negative outcomes after hormonal manipulations involving estrogen during SLE (ie, oral contraceptives, hormone therapy). Significant gaps in knowledge remain about the effect of estrogen on cardiovascular risk factors during SLE. Studies in women with SLE were not designed to determine the effect of estrogen or hormone therapy on blood pressure even though hypertension is highly prevalent, and risk of premature ovarian failure could necessitate use of hormone therapy in women with SLE. Recent evidence from an experimental animal model of lupus found that estrogen may protect against

  10. Challenges for Preclinical Investigations of Human Biofield Modalities

    OpenAIRE

    Gronowicz, Gloria; Bengston, William; Yount, Garret

    2015-01-01

    Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external qigong, Johrei, Reiki, therapeutic touch, healing touch, polarity therapy, pranic healing, and other practices. A short history of Western biofield studies using preclinical models is presented and demonstrates numerous and consistent examples of human biofields significantly affecting biological systems both in vitro and in v...

  11. Oral infections and systemic diseases

    DEFF Research Database (Denmark)

    Holmstrup, Palle; Poulsen, Anne Havemose; Andersen, Lone

    2003-01-01

    An association between periodontal infection and CVD has been revealed in some epidemiologic studies, whereas other studies were unable to demonstrate such an association. A link between the two diseases may be explained by shared established or nonestablished risk factors. Future studies with ex...

  12. Disease severity scoring systems in dermatology

    Directory of Open Access Journals (Sweden)

    Cemal Bilaç

    2016-06-01

    Full Text Available Scoring systems have been developed to interpret the disease severity objectively by evaluating the parameters of the disease. Body surface area, visual analogue scale, and physician global assessment are the most frequently used scoring systems for evaluating the clinical severity of the dermatological diseases. Apart from these scoring systems, many specific scoring systems for many dermatological diseases, including acne (acne vulgaris, acne scars, alopecia (androgenetic alopecia, tractional alopecia, bullous diseases (autoimmune bullous diseases, toxic epidermal necrolysis, dermatitis (atopic dermatitis, contact dermatitis, dyshidrotic eczema, hidradenitis suppurativa, hirsutismus, connective tissue diseases (dermatomyositis, skin involvement of systemic lupus erythematosus (LE, discoid LE, scleroderma, lichen planoplaris, mastocytosis, melanocytic lesions, melasma, onychomycosis, oral lichen planus, pityriasis rosea, psoriasis (psoriasis vulgaris, psoriatic arthritis, nail psoriasis, sarcoidosis, urticaria, and vitiligo, have also been developed. Disease severity scoring methods are ever more extensively used in the field of dermatology for clinical practice to form an opinion about the prognosis by determining the disease severity; to decide on the most suitable treatment modality for the patient; to evaluate the efficacy of the applied medication; and to compare the efficiency of different treatment methods in clinical studies.

  13. Systems medicine advances in interstitial lung disease.

    Science.gov (United States)

    Greiffo, Flavia R; Eickelberg, Oliver; Fernandez, Isis E

    2017-09-30

    Fibrotic lung diseases involve subject-environment interactions, together with dysregulated homeostatic processes, impaired DNA repair and distorted immune functions. Systems medicine-based approaches are used to analyse diseases in a holistic manner, by integrating systems biology platforms along with clinical parameters, for the purpose of understanding disease origin, progression, exacerbation and remission.Interstitial lung diseases (ILDs) refer to a heterogeneous group of complex fibrotic diseases. The increase of systems medicine-based approaches in the understanding of ILDs provides exceptional advantages by improving diagnostics, unravelling phenotypical differences, and stratifying patient populations by predictable outcomes and personalised treatments. This review discusses the state-of-the-art contributions of systems medicine-based approaches in ILDs over the past 5 years. Copyright ©ERS 2017.

  14. Recording and surveillance systems for periodontal diseases

    DEFF Research Database (Denmark)

    Beltrán-Aguilar, Eugenio D; Eke, Paul I; Thornton-Evans, Gina

    2012-01-01

    This paper describes tools used to measure periodontal diseases and the integration of these tools into surveillance systems. Tools to measure periodontal diseases at the surveillance level have focussed on current manifestations of disease (e.g. gingival inflammation) or disease sequelae (e......-report measures, are currently under validation. In this paper, we do not review indices designed to measure plaque or residual accumulation around the tooth, indices focussed only on gingival inflammation or radiographic approaches with limited applicability in surveillance systems. Finally, we review current...

  15. Analyses of critical target cell responses during preclinical phases of evolving chronic radiation-induced myeloproliferative disease-exploitation of a unique canine model

    International Nuclear Information System (INIS)

    Seed, T.M.; Kaspar, L.V.; Tolle, D.V.; Fritz, T.E.; Frazier, M.E.

    1988-01-01

    This document briefly summarizes and highlights ongoing studies on the cellular and molecular processes involved in the induction and progression of myeloid leukemia in dogs chronically exposed to low daily doses of wholebody gamma irradiation. Under such conditions, select groups of dogs exhibit extremely high frequencies of myeloproliferative disease (MPD) (i.e., /congruent/50%) of which myeloid leukemia is most prominent. 2 figs

  16. ORAL BACTERIA AND SYSTEMS DISEASES: A REVIEW

    OpenAIRE

    Moromi Nakata, Hilda

    2014-01-01

    In order to show a global vision of oral bacteria in systemic diseases, it is important to analyze the presence and consequences of these microorganisms in relation with: bacteremia, endocarditis, cardiovascular disease, cerebrovascular disease, bacterial pneumonia, neonatal weight, nefritis, arthritis, dermatitis and diabetes mellitus, reaching conclusions for each one of them. Con el objeto de presentar una visión general de la bacterias orales en los procesos sistémicos, se analiza la p...

  17. Antibody Drug Conjugates: Preclinical Considerations.

    Science.gov (United States)

    Bornstein, Gadi G

    2015-05-01

    The development path for antibody drug conjugates (ADCs) is more complex and challenging than for unmodified antibodies. While many of the preclinical considerations for both unmodified and antibody drug conjugates are shared, special considerations must be taken into account when developing an ADC. Unlike unmodified antibodies, an ADC must preferentially bind to tumor cells, internalize, and traffic to the appropriate intracellular compartment to release the payload. Parameters that can impact the pharmacological properties of this class of therapeutics include the selection of the payload, the type of linker, and the methodology for payload drug conjugation. Despite a plethora of in vitro assays and in vivo models to screen and evaluate ADCs, the challenge remains to develop improved preclinical tools that will be more predictive of clinical outcome. This review will focus on preclinical considerations for clinically validated small molecule ADCs. In addition, the lessons learned from Mylotarg®, the first in class FDA-approved ADC, are highlighted.

  18. Disease Recording Systems and Herd Health Schemes for Production Diseases

    Directory of Open Access Journals (Sweden)

    Østerås O

    2001-03-01

    Full Text Available Disease recording of cattle is compulsory in Sweden and Norway. Sweden and Denmark also have mandatory disease recording for swine, whereas Finland and Norway only have compulsory recording of infectious diseases. Both compulsory and voluntary systems are databased, the first ones developed in the 1970's. Disease recording at pig slaughtering is somewhat older. The veterinary practitioner, and often also the farmer, can report treated cases as well as fertility disturbances to the systems. Disease recording at slaughter is carried out by veterinarians and inspection officers. The databases are handled by the veterinary authorities or the agricultural organisations in each country. Costs are defrayed by the authorities and/or the agricultural industry. The farmers receive periodic reports. Data are stored for three to ten years, often longer. Affiliation to animal health schemes for cattle or swine is voluntary. In Sweden and Denmark (cattle they are run within the scope of government regulations. Affiliation to animal health programmes may also be demanded by organisations within the agricultural industry. These organisations are also responsible for the administration of the programmes. Costs to take part in herd health schemes are covered by the farmers themselves. In certain cases, grants are received from agricultural organisations, authorities, or the European Union. Recording of diseases and the format of animal health schemes in the Nordic countries are described here in order to illustrate the possibilities to compare data between countries.

  19. Lower central serotonergic responsivity is associated with preclinical carotid artery atherosclerosis.

    Science.gov (United States)

    Muldoon, Matthew F; Mackey, Rachel H; Sutton-Tyrrell, Kim; Flory, Janine D; Pollock, Bruce G; Manuck, Stephen B

    2007-08-01

    Central nervous system serotonergic neurotransmission appears to play a role in mood disorders, eating habits, and sleep, and also modulates blood pressure and metabolism. This investigation tested a hypothesized association between central serotonergic functioning and preclinical atherosclerosis. Subjects were 244 adults 30 to 55 years of age and free of clinically evident vascular disease (52% men, 84% white). Central serotonergic responsivity was measured as the rise in serum prolactin concentration (area under the curve) over 2.5 hours, adjusted for baseline prolactin, after citalopram administered intravenously at 0.33 mg/kg lean body weight. Carotid artery morphology served as a marker of preclinical atherosclerosis, and carotid artery intima-media thickness and plaque occurrence were determined by B-mode ultrasonography. In linear regression models including age, gender, race, and citalopram concentration, a 1 SD lower prolactin response was associated with greater maximum intima-media thickness (+0.016 mm; P=0.006) and with greater mean intima-media thickness (+0.009 mm; P=0.03). The odds ratio for carotid artery plaque corresponding to a 1 SD decrease in prolactin response, adjusted for age, race, sex, and citalopram concentration, was 1.47 (95% CI, 0.98 to 2.19; P=0.06). The metabolic syndrome mediated (Pserotonergic responsivity are inversely related to preclinical vascular disease.

  20. Associations of Systemic Diseases with Intermediate Uveitis.

    Science.gov (United States)

    Shoughy, Samir S; Kozak, Igor; Tabbara, Khalid F

    2016-01-01

    To determine the associations of systemic diseases with intermediate uveitis. The medical records of 50 consecutive cases with intermediate uveitis referred to The Eye Center in Riyadh, Saudi Arabia, were reviewed. Age- and sex-matched patients without uveitis served as controls. Patients had complete ophthalmic and medical examinations. There were 27 male and 23 female patients. Mean age was 29 years with a range of 5-62 years. Overall, 21 cases (42%) had systemic disorders associated with intermediate uveitis and 29 cases (58%) had no associated systemic disease. A total of 11 patients (22%) had asthma, 4 (8%) had multiple sclerosis, 3 (6%) had presumed ocular tuberculosis, 1 (2%) had inflammatory bowel disease, 1 (2%) had non-Hodgkin lymphoma and 1 (2%) had sarcoidosis. Evidence of systemic disease was found in 50 (5%) of the 1,000 control subjects. Bronchial asthma was found in 37 patients (3.7 %), multiple sclerosis in 9 patients (0.9%), inflammatory bowel disease in 3 patients (0.3%), and tuberculosis in 1 patient (0.1%). None of the control patients had sarcoidosis or lymphoma. There were statistically significant associations between intermediate uveitis and bronchial asthma (p = 0.0001), multiple sclerosis (p = 0.003) and tuberculosis (p = 0.0005). Bronchial asthma and multiple sclerosis were the most frequently encountered systemic diseases associated with intermediate uveitis in our patient population. Patients with intermediate uveitis should undergo careful history-taking and investigations to rule out associated systemic illness.

  1. Symptoms of a Systemic Disease

    OpenAIRE

    Ernst Gusinskiy; Yuliya Turchaninova

    2007-01-01

    This article considers the workings of the state education system, which is almost the same throughout developed countries. Studies on education that became widely known in the 20th and 21st centuries are analyzed, such as John Deweys Democracy and Education and Experience and Education, Alexander Neills Summerhill, John Ravens The Tragic Illusion: Educational Testing, Ivan Illichs Deschooling Society, and John Goodlads A Place Called School. The practice of the American school is paid specia...

  2. Cutaneous necrotizing vasculitis. Relation to systemic disease.

    Science.gov (United States)

    Lotti, T M; Comacchi, C; Ghersetich, I

    1999-01-01

    Cutaneous necrotizing vasculitis (CNV) is a complex multisystem disease generally involving the skin and mucous membranes, often accompanied by renal, gastrointestinal, pericardial, neurological, and articular signs and symptoms. CNV may be idiopatical or occur in association with a drug, infection, or underlying disease. CNV has been shown in patients with chronic infections (viral, bacterial, protozoa, helminthic), serum sickness, a variety of collagen vascular diseases (systemic lupus erythematous, Sjögren's syndrome, rheumatoid arthritis, Behçet's disease) hyperglobulinemic states, cryoglobulinemia, bowel bypass syndrome, ulcerative colitis, cystic fibrosis, primary biliary cirrhosis and HIV infection. Association with malignancies is not frequent. Lymphoproliferative disorders (Hodgkin's disease, mycosis fungoides, lymphosarcoma, adult T-cell leukemia, multiple mieloma) and solid tumors (lung cancer, colon carcinoma, renal, prostate, head and neck cancer and breast cancer) may be associated with CNV. Whenever possible, treatment is directed at the elimination of the cause. In other cases after adequate laboratory screening local and systemic therapy are recommended.

  3. Lentivector Iterations and Pre-Clinical Scale-Up/Toxicity Testing: Targeting Mobilized CD34+ Cells for Correction of Fabry Disease.

    Science.gov (United States)

    Huang, Ju; Khan, Aneal; Au, Bryan C; Barber, Dwayne L; López-Vásquez, Lucía; Prokopishyn, Nicole L; Boutin, Michel; Rothe, Michael; Rip, Jack W; Abaoui, Mona; Nagree, Murtaza S; Dworski, Shaalee; Schambach, Axel; Keating, Armand; West, Michael L; Klassen, John; Turner, Patricia V; Sirrs, Sandra; Rupar, C Anthony; Auray-Blais, Christiane; Foley, Ronan; Medin, Jeffrey A

    2017-06-16

    Fabry disease is a rare lysosomal storage disorder (LSD). We designed multiple recombinant lentivirus vectors (LVs) and tested their ability to engineer expression of human α-galactosidase A (α-gal A) in transduced Fabry patient CD34 + hematopoietic cells. We further investigated the safety and efficacy of a clinically directed vector, LV/AGA, in both ex vivo cell culture studies and animal models. Fabry mice transplanted with LV/AGA-transduced hematopoietic cells demonstrated α-gal A activity increases and lipid reductions in multiple tissues at 6 months after transplantation. Next we found that LV/AGA-transduced Fabry patient CD34 + hematopoietic cells produced even higher levels of α-gal A activity than normal CD34 + hematopoietic cells. We successfully transduced Fabry patient CD34 + hematopoietic cells with "near-clinical grade" LV/AGA in small-scale cultures and then validated a clinically directed scale-up transduction process in a GMP-compliant cell processing facility. LV-transduced Fabry patient CD34 + hematopoietic cells were subsequently infused into NOD/SCID/Fabry (NSF) mice; α-gal A activity corrections and lipid reductions were observed in several tissues 12 weeks after the xenotransplantation. Additional toxicology studies employing NSF mice xenotransplanted with the therapeutic cell product demonstrated minimal untoward effects. These data supported our successful clinical trial application (CTA) to Health Canada and opening of a "first-in-the-world" gene therapy trial for Fabry disease.

  4. Pulse Wave Velocity as Marker of Preclinical Arterial Disease: Reference Levels in a Uruguayan Population Considering Wave Detection Algorithms, Path Lengths, Aging, and Blood Pressure

    Directory of Open Access Journals (Sweden)

    Ignacio Farro

    2012-01-01

    Full Text Available Carotid-femoral pulse wave velocity (PWV has emerged as the gold standard for non-invasive evaluation of aortic stiffness; absence of standardized methodologies of study and lack of normal and reference values have limited a wider clinical implementation. This work was carried out in a Uruguayan (South American population in order to characterize normal, reference, and threshold levels of PWV considering normal age-related changes in PWV and the prevailing blood pressure level during the study. A conservative approach was used, and we excluded symptomatic subjects; subjects with history of cardiovascular (CV disease, diabetes mellitus or renal failure; subjects with traditional CV risk factors (other than age and gender; asymptomatic subjects with atherosclerotic plaques in carotid arteries; patients taking anti-hypertensives or lipid-lowering medications. The included subjects (n=429 were categorized according to the age decade and the blood pressure levels (at study time. All subjects represented the “reference population”; the group of subjects with optimal/normal blood pressures levels at study time represented the “normal population.” Results. Normal and reference PWV levels were obtained. Differences in PWV levels and aging-associated changes were obtained. The obtained data could be used to define vascular aging and abnormal or disease-related arterial changes.

  5. Lentivector Iterations and Pre-Clinical Scale-Up/Toxicity Testing: Targeting Mobilized CD34+ Cells for Correction of Fabry Disease

    Directory of Open Access Journals (Sweden)

    Ju Huang

    2017-06-01

    Full Text Available Fabry disease is a rare lysosomal storage disorder (LSD. We designed multiple recombinant lentivirus vectors (LVs and tested their ability to engineer expression of human α-galactosidase A (α-gal A in transduced Fabry patient CD34+ hematopoietic cells. We further investigated the safety and efficacy of a clinically directed vector, LV/AGA, in both ex vivo cell culture studies and animal models. Fabry mice transplanted with LV/AGA-transduced hematopoietic cells demonstrated α-gal A activity increases and lipid reductions in multiple tissues at 6 months after transplantation. Next we found that LV/AGA-transduced Fabry patient CD34+ hematopoietic cells produced even higher levels of α-gal A activity than normal CD34+ hematopoietic cells. We successfully transduced Fabry patient CD34+ hematopoietic cells with “near-clinical grade” LV/AGA in small-scale cultures and then validated a clinically directed scale-up transduction process in a GMP-compliant cell processing facility. LV-transduced Fabry patient CD34+ hematopoietic cells were subsequently infused into NOD/SCID/Fabry (NSF mice; α-gal A activity corrections and lipid reductions were observed in several tissues 12 weeks after the xenotransplantation. Additional toxicology studies employing NSF mice xenotransplanted with the therapeutic cell product demonstrated minimal untoward effects. These data supported our successful clinical trial application (CTA to Health Canada and opening of a “first-in-the-world” gene therapy trial for Fabry disease.

  6. Systemic autoimmune disease and Raynaud's phenomonen.

    NARCIS (Netherlands)

    Kallenberg, Cornelis

    1982-01-01

    Systemic autoimmune diseases (AID) are clinically characterized by the involvement of multiple organ systems in the desease process, and immunologically by immune responsiveness against "self". The constitute a heterogenous group of disorders wich are presented to the clinician in a wide variety of

  7. Preclinical Testing of Antihuman CD28 Fab' Antibody in a Novel Nonhuman Primate Small Animal Rodent Model of Xenogenic Graft-Versus-Host Disease.

    Science.gov (United States)

    Hippen, Keli L; Watkins, Benjamin; Tkachev, Victor; Lemire, Amanda M; Lehnen, Charles; Riddle, Megan J; Singh, Karnail; Panoskaltsis-Mortari, Angela; Vanhove, Bernard; Tolar, Jakub; Kean, Leslie S; Blazar, Bruce R

    2016-12-01

    Graft-versus-host disease (GVHD) is a severe complication of hematopoietic stem cell transplantation. Current therapies to prevent alloreactive T cell activation largely cause generalized immunosuppression and may result in adverse drug, antileukemia and antipathogen responses. Recently, several immunomodulatory therapeutics have been developed that show efficacy in maintaining antileukemia responses while inhibiting GVHD in murine models. To analyze efficacy and better understand immunological tolerance, escape mechanisms, and side effects of clinical reagents, testing of species cross-reactive human agents in large animal GVHD models is critical. We have previously developed and refined a nonhuman primate (NHP) large animal GVHD model. However, this model is not readily amenable to semi-high throughput screening of candidate clinical reagents. Here, we report a novel, optimized NHP xenogeneic GVHD (xeno-GVHD) small animal model that recapitulates many aspects of NHP and human GVHD. This model was validated using a clinically available blocking, monovalent anti-CD28 antibody (FR104) whose effects in a human xeno-GVHD rodent model are known. Because human-reactive reagents may not be fully cross-reactive or effective in vivo on NHP immune cells, this NHP xeno-GVHD model provides immunological insights and direct testing on NHP-induced GVHD before committing to the intensive NHP studies that are being increasingly used for detailed evaluation of new immune therapeutic strategies before human trials.

  8. Periodontal disease associated to systemic genetic disorders

    OpenAIRE

    Nualart Grollmus, Zacy Carola; Morales Chávez, Mariana Carolina; Silvestre Donat, Francisco Javier

    2007-01-01

    A number of systemic disorders increase patient susceptibility to periodontal disease, which moreover evolves more rapidly and more aggressively. The underlying factors are mainly related to alterations in immune, endocrine and connective tissue status. These alterations are associated with different pathologies and syndromes that generate periodontal disease either as a primary manifestation or by aggravating a pre-existing condition attributable to local factors. This is where the role ...

  9. Thyroid disease and the cardiovascular system.

    Science.gov (United States)

    Danzi, Sara; Klein, Irwin

    2014-06-01

    Thyroid hormones, specifically triiodothyronine (T3), have significant effects on the heart and cardiovascular system. Hypothyroidism, hyperthyroidism, subclinical thyroid disease, and low T3 syndrome each cause cardiac and cardiovascular abnormalities through both genomic and nongenomic effects on cardiac myocytes and vascular smooth muscle cells. In compromised health, such as occurs in heart disease, alterations in thyroid hormone metabolism may further impair cardiac and cardiovascular function. Diagnosis and treatment of cardiac disease may benefit from including analysis of thyroid hormone status, including serum total T3 levels. Copyright © 2014 Elsevier Inc. All rights reserved.

  10. Preclinical evaluation of an MR-compatible microwave ablation system and comparison with a standard microwave ablation system in an ex vivo bovine liver model.

    Science.gov (United States)

    Hoffmann, Rüdiger; Kessler, David-Emanuel; Weiss, Jakob; Clasen, Stephan; Pereira, Philippe L; Nikolaou, Konstantin; Rempp, Hansjörg

    2017-09-01

    Evaluation of a newly developed MR-compatible microwave ablation system with focus on ablation performance and comparison with a corresponding standard microwave ablation system. A total of 52 ablations were performed with a non-cooled microwave ablation system in an ex vivo bovine liver model using the following settings: [A] 16G-standard antenna, 2 cm active tip, 2.4 m cable; [B] MR-compatible 16G-antenna, 2 cm active tip, 2.4 m cable; [C] MR-compatible 16G-antenna, 2 cm active tip, extended 6 m cable; and [D] MR-compatible 16G-antenna, 4 cm active tip, extended 6 m cable. Ablation durations were 3, 5 and 10 min, and additionally 15 min for [D]. Ablations zones were measured for short-axis diameter (SA) and long-axis diameter (LA). Settings [A]-[C] were compared regarding SA, volume (V) and generator energy output (E) with analysis of variance and Tukey-Kramer post hoc test. Ablation performance of the MR-compatible settings [C] and [D] were compared regarding SA, V, E and sphericity index (SA/LA) with unpaired t-test. p < 0.05 was considered as statistically significant. No significant differences were found between [A], [B] and [C] regarding SA and V (10 min; SA[A] = 25.8 ± 2.4 mm, SA[B] = 25.3 ± 1.9 mm, SA[C] = 25.0 ± 2.0 mm, p = 0.88; V[A] = 17.8 ± 4.4 cm³, V[B] = 16.6 ± 3.0 cm³, V[C] = 17.8 ± 2.7 cm³, p = 0.85); however, the highest energy output was measured for setting [C] (10 min; [A]: 9.9 ± 0.5 kJ, [B]: 10.1 ± 0.5 kJ, [C]: 13.1 ± 0.3 kJ, p < 0.001). SA, V and E were significantly larger with setting [D] than [C] with 10 min ablations (SA[C] = 25.0 ± 2.0 mm, SA[D] = 34.0 ± 2.9 mm, p = 0.003; V[C] = 17.8 ± 2.7 cm³, V[D] = 39.4 ± 7.5 cm³, p = 0.007; E[C] = 13.1 ± 0.3 kJ, E[D] = 16.7 ± 0.8 kJ, p = 0.002) without significant difference in sphericity

  11. Untangling the Web of Systemic Autoinflammatory Diseases

    Directory of Open Access Journals (Sweden)

    Donato Rigante

    2014-01-01

    Full Text Available The innate immune system is involved in the pathophysiology of systemic autoinflammatory diseases (SAIDs, an enlarging group of disorders caused by dysregulated production of proinflammatory cytokines, such as interleukin-1β and tumor necrosis factor-α, in which autoreactive T-lymphocytes and autoantibodies are indeed absent. A widely deranged innate immunity leads to overactivity of proinflammatory cytokines and subsequent multisite inflammatory symptoms depicting various conditions, such as hereditary periodic fevers, granulomatous disorders, and pyogenic diseases, collectively described in this review. Further research should enhance our understanding of the genetics behind SAIDs, unearth triggers of inflammatory attacks, and result in improvement for their diagnosis and treatment.

  12. Challenges for Preclinical Investigations of Human Biofield Modalities.

    Science.gov (United States)

    Gronowicz, Gloria; Bengston, William; Yount, Garret

    2015-11-01

    Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external qigong, Johrei, Reiki, therapeutic touch, healing touch, polarity therapy, pranic healing, and other practices. A short history of Western biofield studies using preclinical models is presented and demonstrates numerous and consistent examples of human biofields significantly affecting biological systems both in vitro and in vivo. Methodological issues arising from these studies and practical solutions in experimental design are presented. Important questions still left unanswered with preclinical models include variable reproducibility, dosing, intentionality of the practitioner, best preclinical systems, and mechanisms. Input from the biofield practitioners in the experimental design is critical to improving experimental outcomes; however, the development of standard criteria for uniformity of practice and for inclusion of multiple practitioners is needed. Research in human biofield studies involving preclinical models promises a better understanding of the mechanisms underlying the efficacy of biofield therapies and will be important in guiding clinical protocols and integrating treatments with conventional medical therapies.

  13. Challenges for Preclinical Investigations of Human Biofield Modalities

    Science.gov (United States)

    Gronowicz, Gloria; Bengston, William

    2015-01-01

    Preclinical models for studying the effects of the human biofield have great potential to advance our understanding of human biofield modalities, which include external qigong, Johrei, Reiki, therapeutic touch, healing touch, polarity therapy, pranic healing, and other practices. A short history of Western biofield studies using preclinical models is presented and demonstrates numerous and consistent examples of human biofields significantly affecting biological systems both in vitro and in vivo. Methodological issues arising from these studies and practical solutions in experimental design are presented. Important questions still left unanswered with preclinical models include variable reproducibility, dosing, intentionality of the practitioner, best preclinical systems, and mechanisms. Input from the biofield practitioners in the experimental design is critical to improving experimental outcomes; however, the development of standard criteria for uniformity of practice and for inclusion of multiple practitioners is needed. Research in human biofield studies involving preclinical models promises a better understanding of the mechanisms underlying the efficacy of biofield therapies and will be important in guiding clinical protocols and integrating treatments with conventional medical therapies. PMID:26665042

  14. Imaging Systemic Dysfunction in Parkinson's Disease.

    Science.gov (United States)

    Borghammer, Per; Knudsen, Karoline; Brooks, David J

    2016-06-01

    Parkinson's disease is now widely recognized to be a multisystem disorder affecting the brain and peripheral autonomic nerves. Extensive pathology is present in both the sympathetic and parasympathetic nervous system and the intrinsic gastrointestinal plexuses in patients. Autonomic pathology and symptoms such as constipation can predate the clinical diagnosis by years or decades. Imaging studies have contributed greatly to our understanding of Parkinson's disease but focused primarily on imaging cerebral pathology. However, given the importance of understanding the nature, chronology, and functional consequences of peripheral pathology, there has been renewed interest in imaging peripheral organs in Parkinson's disease. Suitable imaging tools can be divided into two types: radiotracer studies that directly estimate loss of sympathetic or parasympathetic nerve terminals, and imaging modalities to quantitate dysphagia, gastric emptying, esophageal and intestinal transit times, and anorectal dyssynergia. In this review, we summarize current knowledge about peripheral imaging in Parkinson's disease.

  15. Electronic integrated disease surveillance system and pathogen asset control system.

    Science.gov (United States)

    Wahl, Tom G; Burdakov, Aleksey V; Oukharov, Andrey O; Zhilokov, Azamat K

    2012-06-20

    Electronic Integrated Disease Surveillance System (EIDSS) has been used to strengthen and support monitoring and prevention of dangerous diseases within One Health concept by integrating veterinary and human surveillance, passive and active approaches, case-based records including disease-specific clinical data based on standardised case definitions and aggregated data, laboratory data including sample tracking linked to each case and event with test results and epidemiological investigations. Information was collected and shared in secure way by different means: through the distributed nodes which are continuously synchronised amongst each other, through the web service, through the handheld devices. Electronic Integrated Disease Surveillance System provided near real time information flow that has been then disseminated to the appropriate organisations in a timely manner. It has been used for comprehensive analysis and visualisation capabilities including real time mapping of case events as these unfold enhancing decision making. Electronic Integrated Disease Surveillance System facilitated countries to comply with the IHR 2005 requirements through a data transfer module reporting diseases electronically to the World Health Organisation (WHO) data center as well as establish authorised data exchange with other electronic system using Open Architecture approach. Pathogen Asset Control System (PACS) has been used for accounting, management and control of biological agent stocks. Information on samples and strains of any kind throughout their entire lifecycle has been tracked in a comprehensive and flexible solution PACS.Both systems have been used in a combination and individually. Electronic Integrated Disease Surveillance System and PACS are currently deployed in the Republics of Kazakhstan, Georgia and Azerbaijan as a part of the Cooperative Biological Engagement Program (CBEP) sponsored by the US Defense Threat Reduction Agency (DTRA).

  16. Electronic Integrated Disease Surveillance System and Pathogen Asset Control System

    Directory of Open Access Journals (Sweden)

    Tom G. Wahl

    2012-06-01

    Full Text Available Electronic Integrated Disease Surveillance System (EIDSS has been used to strengthen and support monitoring and prevention of dangerous diseases within One Health concept by integrating veterinary and human surveillance, passive and active approaches, case-based records including disease-specific clinical data based on standardised case definitions and aggregated data, laboratory data including sample tracking linked to each case and event with test results and epidemiological investigations. Information was collected and shared in secure way by different means: through the distributed nodes which are continuously synchronised amongst each other, through the web service, through the handheld devices. Electronic Integrated Disease Surveillance System provided near real time information flow that has been then disseminated to the appropriate organisations in a timely manner. It has been used for comprehensive analysis and visualisation capabilities including real time mapping of case events as these unfold enhancing decision making. Electronic Integrated Disease Surveillance System facilitated countries to comply with the IHR 2005 requirements through a data transfer module reporting diseases electronically to the World Health Organisation (WHO data center as well as establish authorised data exchange with other electronic system using Open Architecture approach. Pathogen Asset Control System (PACS has been used for accounting, management and control of biological agent stocks. Information on samples and strains of any kind throughout their entire lifecycle has been tracked in a comprehensive and flexible solution PACS. Both systems have been used in a combination and individually. Electronic Integrated Disease Surveillance System and PACS are currently deployed in the Republics of Kazakhstan, Georgia and Azerbaijan as a part of the Cooperative Biological Engagement Program (CBEP sponsored by the US Defense Threat Reduction Agency (DTRA.

  17. Integrated Knowledge Based Expert System for Disease Diagnosis System

    Science.gov (United States)

    Arbaiy, Nureize; Sulaiman, Shafiza Eliza; Hassan, Norlida; Afizah Afip, Zehan

    2017-08-01

    The role and importance of healthcare systems to improve quality of life and social welfare in a society have been well recognized. Attention should be given to raise awareness and implementing appropriate measures to improve health care. Therefore, a computer based system is developed to serve as an alternative for people to self-diagnose their health status based on given symptoms. This strategy should be emphasized so that people can utilize the information correctly as a reference to enjoy healthier life. Hence, a Web-based Community Center for Healthcare Diagnosis system is developed based on expert system technique. Expert system reasoning technique is employed in the system to enable information about treatment and prevention of the diseases based on given symptoms. At present, three diseases are included which are arthritis, thalassemia and pneumococcal. Sets of rule and fact are managed in the knowledge based system. Web based technology is used as a platform to disseminate the information to users in order for them to optimize the information appropriately. This system will benefit people who wish to increase health awareness and seek expert knowledge on the diseases by performing self-diagnosis for early disease detection.

  18. [Parasitic diseases of the central nervous system].

    Science.gov (United States)

    Schmutzhard, E

    2010-02-01

    Central nervous system infections and infestations by protozoa and helminths constitute a problem of increasing importance throughout all of central European and northern/western countries. This is partially due to the globalisation of our society, tourists and business people being more frequently exposed to parasitic infection/infestation in tropical countries than in moderate climate countries. On top of that, migrants may import chronic infestations and infections with parasitic pathogens, eventually also--sometimes exclusively--involving the nervous system. Knowledge of epidemiology, initial clinical signs and symptoms, diagnostic procedures as well as specific chemotherapeutic therapies and adjunctive therapeutic strategies is of utmost important in all of these infections and infestations of the nervous systems, be it by protozoa or helminths. This review lists, mainly in the form of tables, all possible infections and infestations of the nervous systems by protozoa and by helminths. Besides differentiating parasitic diseases of the nervous system seen in migrants, tourists etc., it is very important to have in mind that disease-related (e.g. HIV) or iatrogenic immunosuppression has led to the increased occurrence of a wide variety of parasitic infections and infestations of the nervous system (e. g. babesiosis, Chagas disease, Strongyloides stercoralis infestation, toxoplasmosis, etc.).

  19. Immune System and Its Link to Rheumatic Diseases

    Science.gov (United States)

    ... Immune System & Its Link to Rheumatic Disease The Immune System and Its Link to Rheumatic Disease Fast Facts ... of a vessel of the body). What’s the immune system? The immune system allows us to identify and ...

  20. Visual system manifestations of Alzheimer's disease.

    Science.gov (United States)

    Kusne, Yael; Wolf, Andrew B; Townley, Kate; Conway, Mandi; Peyman, Gholam A

    2017-12-01

    Alzheimer's disease (AD) is an increasingly common disease with massive personal and economic costs. While it has long been known that AD impacts the visual system, there has recently been an increased focus on understanding both pathophysiological mechanisms that may be shared between the eye and brain and how related biomarkers could be useful for AD diagnosis. Here, were review pertinent cellular and molecular mechanisms of AD pathophysiology, the presence of AD pathology in the visual system, associated functional changes, and potential development of diagnostic tools based on the visual system. Additionally, we discuss links between AD and visual disorders, including possible pathophysiological mechanisms and their relevance for improving our understanding of AD. © 2016 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  1. Pre-clinical biocompatibility testing of peritoneal dialysis solutions.

    Science.gov (United States)

    Holmes, C J

    2000-01-01

    Pre-clinical biocompatibility testing of peritoneal dialysis (PD) solutions has become an integral part of new solution development. The construction of a pre-clinical screening program for solution biocompatibility should take a hierarchical approach, starting with in vitro cell viability and function assays. The selection of cell types and assay systems for the in vitro studies should be broad enough to permit a balanced interpretation. Whenever possible, animal models are recommended for the next hierarchical level of testing, followed by human ex vivo study designs. Designs of the latter sort provide evidence that a new solution formulation is exerting an altered biological response in vivo; the response is not purely an in vitro artifact or restricted to a given animal species. This article discusses the various approaches available for biocompatibility testing during the pre-clinical phase of solution development, with an emphasis on the advantages and drawbacks of each method.

  2. Analgesia in Amphibians: Preclinical Studies and Clinical Applications

    Science.gov (United States)

    Stevens, Craig W.

    2010-01-01

    SYNOPSIS Preclinical studies of analgesia in amphibians or recommendations for clinical use of analgesics in amphibian species are extremely limited. This article briefly reviews the issues surrounding the use of analgesics in amphibians starting with common definitions of pain and analgesia when applied to non-human animals. Nociceptive and endogenous opioid systems in amphibians are reviewed and results of preclinical research on opioid and non-opioid analgesics summarized. Recommended opioid and non-opioid analgesics are summarized and practical recommendations made for their clinical use. PMID:21074701

  3. Peripheral Vestibular System Disease in Vestibular Schwannomas

    DEFF Research Database (Denmark)

    Møller, Martin Nue; Hansen, Søren; Caye-Thomasen, Per

    2015-01-01

    with VS. METHODS: Retrospective analysis of vestibular system histopathology in temporal bones from 17 patients with unilateral VS. The material was obtained from The Copenhagen Temporal Bone Collection. RESULTS: Vestibular schwannomas were associated with atrophy of the vestibular ganglion, loss of fiber...... density of the peripheral vestibular nerve branches, and atrophy of the neuroepithelium of the vestibular end organs. In cases with small tumors, peripheral disease occurred only in the tissue structures innervated by the specific nerve from which the tumor originated. CONCLUSION: Vestibular schwannomas...... are associated with distinctive disease of the peripheral vestibular tissue structures, suggesting anterograde degeneration and that dizziness in these patients may be caused by deficient peripheral vestibular nerve fibers, neurons, and end organs. In smaller tumors, a highly localized disease occurs, which...

  4. [Chronic obstructive pulmonary disease and cardiovascular system].

    Science.gov (United States)

    Gürgün, Alev; Gürgün, Cemil

    2008-01-01

    Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide killing nearly 3 million people annually. Even the most optimistic estimates suggest that COPD mortality rates will increase by 50% over the next 15 years. Individuals with COPD are at increased risk of cardiovascular diseases (CVD), lung cancer, osteoporosis and muscle wasting. Smoking is a well-described risk factor for both COPD and CVD, but CVD in patients with COPD is likely to be due to other factors in addition to smoking. Systemic inflammation may be an important common etiological cause between COPD and CVD, being well described in both diseases. This paper reviews the close relationship between COPD and cardiovascular diseases, principally atherosclerosis. The common pathogenetic mechanisms, relation between cardiovascular comorbidities and pulmonary function parameters, the treatment of pulmonary and systemic inflammation, the role medications in the treatment of both disorders, the effect of cardiovascular comorbidities on the prognosis of COPD and prediction of mortality is discussed. The anti-inflammatory effects of inhaled corticosteroids and statins, their effects on cardiovascular endpoints, all-cause mortality, and survival of COPD patients are reviewed as a new perspective to the treatment.

  5. Infectious disease modeling a hybrid system approach

    CERN Document Server

    Liu, Xinzhi

    2017-01-01

    This volume presents infectious diseases modeled mathematically, taking seasonality and changes in population behavior into account, using a switched and hybrid systems framework. The scope of coverage includes background on mathematical epidemiology, including classical formulations and results; a motivation for seasonal effects and changes in population behavior, an investigation into term-time forced epidemic models with switching parameters, and a detailed account of several different control strategies. The main goal is to study these models theoretically and to establish conditions under which eradication or persistence of the disease is guaranteed. In doing so, the long-term behavior of the models is determined through mathematical techniques from switched systems theory. Numerical simulations are also given to augment and illustrate the theoretical results and to help study the efficacy of the control schemes.

  6. Periodontal disease associated to systemic genetic disorders.

    Science.gov (United States)

    Nualart Grollmus, Zacy Carola; Morales Chávez, Mariana Carolina; Silvestre Donat, Francisco Javier

    2007-05-01

    A number of systemic disorders increase patient susceptibility to periodontal disease, which moreover evolves more rapidly and more aggressively. The underlying factors are mainly related to alterations in immune, endocrine and connective tissue status. These alterations are associated with different pathologies and syndromes that generate periodontal disease either as a primary manifestation or by aggravating a pre-existing condition attributable to local factors. This is where the role of bacterial plaque is subject to debate. In the presence of qualitative or quantitative cellular immune alterations, periodontal disease may manifest early on a severe localized or generalized basis--in some cases related to the presence of plaque and/or specific bacteria (severe congenital neutropenia or infantile genetic agranulocytosis, Chediak-Higiashi syndrome, Down syndrome and Papillon-Lefévre syndrome). In the presence of humoral immune alterations, periodontal damage may result indirectly as a consequence of alterations in other systems. In connective tissue disorders, bacterial plaque and alterations of the periodontal tissues increase patient susceptibility to gingival inflammation and alveolar resorption (Marfan syndrome and Ehler-Danlos syndrome). The management of periodontal disease focuses on the control of infection and bacterial plaque by means of mechanical and chemical methods. Periodontal surgery and even extraction of the most seriously affected teeth have also been suggested. There are variable degrees of consensus regarding the background systemic disorder, as in the case of Chediak-Higiashi syndrome, where antibiotic treatment proves ineffective; in severe congenital neutropenia or infantile genetic agranulocytosis, where antibiotic prophylaxis is suggested; and in Papillon-Lefévre syndrome, where an established treatment protocol is available.

  7. [Corneal ulcers in systemic autoimmunologic diseases].

    Science.gov (United States)

    Augsten, R; Dawczynski, J; Voigt, U; Oelzner, P; Schulze, E; Königsdörffer, E

    2011-01-01

    Keratolysis is a rare severe complication following systemic autoimmunologic diseases. Despite of complex therapeutic treatments, the prognosis is very poor. Ten eyes from seven patients with corneal ulcers were reported (age 45 - 73 years, mean 63 years; 6 women, 1 man). The corneal ulcer was perforated in 7 eyes. Five patients suffered from rheumatoid arthritis, and one patient developed a Sjögren's syndrome. Besides, one patient had shown both autoimmunologic diseases. After clinical attendance, visual acuity in the eyes with nonperforated ulcers was between 0.1 and 0.4, and in the eyes with perforated ulcers between light perception and 0.2. In 7 eyes with perforated corneal ulcers an emergency tectonic conjunctival plasty and, 1 - 2 days later, a keratoplasty had been performed. Postoperatively, local therapies had been initiated with antibiotic and immunosuppressive eyedrops as well as with conventional drops for dry-eye symptoms. Because of the autoimmunologic diseases of the patients, a systemic immunosuppressive therapy had been arranged. Follow-up period had been between 4 weeks and 3,5 years (mean 16 months). In the three eyes with nonperforated ulcers which received an antibiotic and immunosuppressive treatment, visual acuity was found at 1 / 20 and 0.4. However, in spite of stabilized findings in the 5 eyes with perforated ulcers, the visual acuity was in this case only between light perception and 0.05. One patient with a perforated ulcer and one patient with a recurrent corneal perforation after keratoplasty refused further operative procedures. Finally, both eyes had to undergo evisceration. Despite of intensive local and systemic immunosuppressive as well as operative therapies, corneal ulcers associated with autoimmunologic diseases (rheumatoid arthritis, Sjögren's syndrome) may cause a marked decrease of visual acuity or the loss of an eye. With regard to the healthy eye, an immunosuppressive therapy for life is most important.

  8. Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Tanaka, Takuji [Cytopatholgy Division, Tohkai Cytopathology Institute, Cancer Research and Prevention (TCI-CaRP), 5-1-2 Minami-uzura, Gifu 500-8285 (Japan); Department of Tumor Pathology, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu 501-1194 (Japan)

    2012-07-16

    Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described.

  9. Preclinical Cancer Chemoprevention Studies Using Animal Model of Inflammation-Associated Colorectal Carcinogenesis

    International Nuclear Information System (INIS)

    Tanaka, Takuji

    2012-01-01

    Inflammation is involved in all stages of carcinogenesis. Inflammatory bowel disease, such as ulcerative colitis and Crohn’s disease is a longstanding inflammatory disease of intestine with increased risk for colorectal cancer (CRC). Several molecular events involved in chronic inflammatory process are reported to contribute to multi-step carcinogenesis of CRC in the inflamed colon. They include over-production of free radicals, reactive oxygen and nitrogen species, up-regulation of inflammatory enzymes in arachidonic acid biosynthesis pathway, up-regulation of certain cytokines, and intestinal immune system dysfunction. In this article, firstly I briefly introduce our experimental animal models where colorectal neoplasms rapidly develop in the inflamed colorectum. Secondary, data on preclinical cancer chemoprevention studies of inflammation-associated colon carcinogenesis by morin, bezafibrate, and valproic acid, using this novel inflammation-related colorectal carcinogenesis model is described

  10. Diseases and pests in biomass production systems

    International Nuclear Information System (INIS)

    Royle, D.J.; Hunter, Tom; McNabb, H.S. Jr.

    1998-01-01

    The current status of disease and pest problems in willow and poplar biomass systems for energy within Canada, Sweden, the United Kingdom and the United States is described. The IEA Disease and Pest Activities within the recent Task XII (1995-1997), and previous Tasks since 1987, have provided outstanding opportunities for international co-operation which has served substantially to augment national research programmes. Work is described on recognizing different forms of an insect pest or pathogen and understanding the genetic basis of its variability, which is of fundamental importance in developing pest management strategies that exclude inputs of energy-rich materials such as pesticides. Options for more natural pest control are considered including breeding for resistance, plantation designs based on host genotype diversity and biological control 16 refs, 2 figs

  11. [Relationship between periodontitis and systemic diseases].

    Science.gov (United States)

    Jepsen, S; Kebschull, M; Deschner, J

    2011-09-01

    Periodontitis is a biofilm-induced inflammatory disease affecting the periodontium with a high and even increasing prevalence in the German population. During recent years, there is emerging evidence for systemic effects of a periodontal infection, in particular in relation to diabetes and atherosclerosis. There is a bi-directional relationship between periodontitis and diabetes. Diabetes promotes the occurrence, the progression, and the severity of periodontitis. The periodontal infection complicates the glycemic control in diabetes, increases the risk of diabetes-associated complications and possibly even of its onset. As a consequence, the treatment of periodontal infections should become an integral part of the management of diabetes, whereas glycemic control is a prerequisite for successful periodontal therapy. Periodontal infections are considered as independent risk factor for atherosclerosis and their clinical sequelae, e.g., cerebro- and cardiovascular diseases. The positive association is only moderate, however remarkably consistent. Periodontal therapy can result in positive effects on subclinical markers of atherosclerosis.

  12. Epigenetic mechanisms underlying nervous system diseases.

    Science.gov (United States)

    Qureshi, Irfan A; Mehler, Mark F

    2018-01-01

    Epigenetic mechanisms act as control systems for modulating genomic structure and activity in response to evolving profiles of cell-extrinsic, cell-cell, and cell-intrinsic signals. These dynamic processes are responsible for mediating cell- and tissue-specific gene expression and function and gene-gene and gene-environmental interactions. The major epigenetic mechanisms include DNA methylation and hydroxymethylation; histone protein posttranslational modifications, nucleosome remodeling/repositioning, and higher-order chromatin reorganization; noncoding RNA regulation; and RNA editing. These mechanisms are intimately involved in executing fundamental genomic programs, including gene transcription, posttranscriptional RNA processing and transport, translation, X-chromosome inactivation, genomic imprinting, retrotransposon regulation, DNA replication, and DNA repair and the maintenance of genomic stability. For the nervous system, epigenetics offers a novel and robust framework for explaining how brain development and aging occur, neural cellular diversity is generated, synaptic and neural network connectivity and plasticity are mediated, and complex cognitive and behavioral phenotypes are inherited transgenerationally. Epigenetic factors and processes are, not surprisingly, implicated in nervous system disease pathophysiology through several emerging paradigms - mutations and genetic variation in genes encoding epigenetic factors; impairments in epigenetic factor expression, localization, and function; epigenetic mechanisms modulating disease-associated factors and pathways; and the presence of deregulated epigenetic profiles in central and peripheral tissues. Copyright © 2018 Elsevier B.V. All rights reserved.

  13. Lung involvement in systemic connective tissue diseases

    Directory of Open Access Journals (Sweden)

    Plavec Goran

    2008-01-01

    Full Text Available Background/Aim. Systemic connective tissue diseases (SCTD are chronic inflammatory autoimmune disorders of unknown cause that can involve different organs and systems. Their course and prognosis are different. All of them can, more or less, involve the respiratory system. The aim of this study was to find out the frequency of respiratory symptoms, lung function disorders, radiography and high-resolution computerized tomography (HRCT abnormalities, and their correlation with the duration of the disease and the applied treatment. Methods. In 47 non-randomized consecutive patients standard chest radiography, HRCT, and lung function tests were done. Results. Hypoxemia was present in nine of the patients with respiratory symptoms (20%. In all of them chest radiography was normal. In five of these patients lung fibrosis was established using HRCT. Half of all the patients with SCTD had symptoms of lung involvement. Lung function tests disorders of various degrees were found in 40% of the patients. The outcome and the degree of lung function disorders were neither in correlation with the duration of SCTD nor with therapy used (p > 0.05 Spearmans Ro. Conclusion. Pulmonary fibrosis occurs in about 10% of the patients with SCTD, and possibly not due to the applied treatment regimens. Hypoxemia could be a sing of existing pulmonary fibrosis in the absence of disorders on standard chest radiography.

  14. Potential large animal models for gene therapy of human genetic diseases of immune and blood cell systems.

    Science.gov (United States)

    Bauer, Thomas R; Adler, Rima L; Hickstein, Dennis D

    2009-01-01

    Genetic mutations involving the cellular components of the hematopoietic system--red blood cells, white blood cells, and platelets--manifest clinically as anemia, infection, and bleeding. Although gene targeting has recapitulated many of these diseases in mice, these murine homologues are limited as translational models by their small size and brief life span as well as the fact that mutations induced by gene targeting do not always faithfully reflect the clinical manifestations of such mutations in humans. Many of these limitations can be overcome by identifying large animals with genetic diseases of the hematopoietic system corresponding to their human disease counterparts. In this article, we describe human diseases of the cellular components of the hematopoietic system that have counterparts in large animal species, in most cases carrying mutations in the same gene (CD18 in leukocyte adhesion deficiency) or genes in interacting proteins (DNA cross-link repair 1C protein and protein kinase, DNA-activated catalytic polypeptide in radiation-sensitive severe combined immunodeficiency). Furthermore, we describe the potential of these animal models to serve as disease-specific preclinical models for testing the efficacy and safety of clinical interventions such as hematopoietic stem cell transplantation or gene therapy before their use in humans with the corresponding disease.

  15. The respiratory neuromuscular system in Pompe disease.

    Science.gov (United States)

    Fuller, David D; ElMallah, Mai K; Smith, Barbara K; Corti, Manuela; Lawson, Lee Ann; Falk, Darin J; Byrne, Barry J

    2013-11-01

    Pompe disease is due to mutations in the gene encoding the lysosomal enzyme acid α-glucosidase (GAA). Absence of functional GAA typically results in cardiorespiratory failure in the first year; reduced GAA activity is associated with progressive respiratory failure later in life. While skeletal muscle pathology contributes to respiratory insufficiency in Pompe disease, emerging evidence indicates that respiratory neuron dysfunction is also a significant part of dysfunction in motor units. Animal models show profound glycogen accumulation in spinal and medullary respiratory neurons and altered neural activity. Tissues from Pompe patients show central nervous system glycogen accumulation and motoneuron pathology. A neural mechanism raises considerations about the current clinical approach of enzyme replacement since the recombinant protein does not cross the blood-brain-barrier. Indeed, clinical data suggest that enzyme replacement therapy delays symptom progression, but many patients eventually require ventilatory assistance, especially during sleep. We propose that treatments which restore GAA activity to respiratory muscles, neurons and networks will be required to fully correct ventilatory insufficiency in Pompe disease. Copyright © 2013. Published by Elsevier B.V.

  16. MIDG-Emerging grid technologies for multi-site preclinical molecular imaging research communities.

    Science.gov (United States)

    Lee, Jasper; Documet, Jorge; Liu, Brent; Park, Ryan; Tank, Archana; Huang, H K

    2011-03-01

    Molecular imaging is the visualization and identification of specific molecules in anatomy for insight into metabolic pathways, tissue consistency, and tracing of solute transport mechanisms. This paper presents the Molecular Imaging Data Grid (MIDG) which utilizes emerging grid technologies in preclinical molecular imaging to facilitate data sharing and discovery between preclinical molecular imaging facilities and their collaborating investigator institutions to expedite translational sciences research. Grid-enabled archiving, management, and distribution of animal-model imaging datasets help preclinical investigators to monitor, access and share their imaging data remotely, and promote preclinical imaging facilities to share published imaging datasets as resources for new investigators. The system architecture of the Molecular Imaging Data Grid is described in a four layer diagram. A data model for preclinical molecular imaging datasets is also presented based on imaging modalities currently used in a molecular imaging center. The MIDG system components and connectivity are presented. And finally, the workflow steps for grid-based archiving, management, and retrieval of preclincial molecular imaging data are described. Initial performance tests of the Molecular Imaging Data Grid system have been conducted at the USC IPILab using dedicated VMware servers. System connectivity, evaluated datasets, and preliminary results are presented. The results show the system's feasibility, limitations, direction of future research. Translational and interdisciplinary research in medicine is increasingly interested in cellular and molecular biology activity at the preclinical levels, utilizing molecular imaging methods on animal models. The task of integrated archiving, management, and distribution of these preclinical molecular imaging datasets at preclinical molecular imaging facilities is challenging due to disparate imaging systems and multiple off-site investigators. A

  17. The Alzheimer’s Prevention Initiative composite cognitive test score: Sample size estimates for the evaluation of preclinical Alzheimer’s disease treatments in presenilin 1 E280A mutation carriers

    Science.gov (United States)

    Ayutyanont, Napatkamon; Langbaum, Jessica B.; Hendrix, Suzanne B.; Chen, Kewei; Fleisher, Adam S.; Friesenhahn, Michel; Ward, Michael; Aguirre, Camilo; Acosta-Baena, Natalia; Madrigal, Lucìa; Muñoz, Claudia; Tirado, Victoria; Moreno, Sonia; Tariot, Pierre N.; Lopera, Francisco; Reiman, Eric M.

    2014-01-01

    Objective There is a need to identify a cognitive composite that is sensitive to tracking preclinical AD decline to be used as a primary endpoint in treatment trials. Method We capitalized on longitudinal data, collected from 1995 to 2010, from cognitively unimpaired presenilin 1 (PSEN1) E280A mutation carriers from the world’s largest known early-onset autosomal dominant AD (ADAD) kindred to identify a composite cognitive test with the greatest statistical power to track preclinical AD decline and estimate the number of carriers age 30 and older needed to detect a treatment effect in the Alzheimer’s Prevention Initiative’s (API) preclinical AD treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of one to seven cognitive tests/sub-tests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a two and five year follow-up period, using data from non-carriers during the same time period to correct for aging and practice effects. Combinations that performed well were then evaluated for robustness across follow-up years, occurrence of selected items within top performing combinations and representation of relevant cognitive domains. Results This optimal test combination included CERAD Word List Recall, CERAD Boston Naming Test (high frequency items), MMSE Orientation to Time, CERAD Constructional Praxis and Ravens Progressive Matrices (Set A) with an MSDR of 1.62. This composite is more sensitive than using either the CERAD Word List Recall (MSDR=0.38) or the entire CERAD-Col battery (MSDR=0.76). A sample size of 75 cognitively normal PSEN1-E280A mutation carriers age 30 and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, p=0.05). Conclusions We have identified a composite cognitive test score representing multiple cognitive domains that has improved power compared to the most

  18. Targeting BAFF and APRIL in systemic lupus erythematosus and other antibody-associated diseases.

    Science.gov (United States)

    Samy, Eileen; Wax, Stephen; Huard, Bertrand; Hess, Henry; Schneider, Pascal

    2017-01-02

    The B cell-stimulating molecules, BAFF (B cell activating factor) and APRIL (a proliferation-inducing ligand), are critical factors in the maintenance of the B cell pool and humoral immunity. In addition, BAFF and APRIL are involved in the pathogenesis of a number of human autoimmune diseases, with elevated levels of these cytokines detected in the sera of patients with systemic lupus erythematosus (SLE), IgA nephropathy, Sjögren's syndrome, and rheumatoid arthritis. As such, both molecules are rational targets for new therapies in B cell-driven autoimmune diseases, and several inhibitors of BAFF or BAFF and APRIL together have been investigated in clinical trials. These include the BAFF/APRIL dual inhibitor, atacicept, and the BAFF inhibitor, belimumab, which is approved as an add-on therapy for patients with active SLE. Post hoc analyses of these trials indicate that baseline serum levels of BAFF and BAFF/APRIL correlate with treatment response to belimumab and atacicept, respectively, suggesting a role for the two molecules as predictive biomarkers. It will, however, be important to refine future testing to identify active forms of BAFF and APRIL in the circulation, as well as to distinguish between homotrimer and heteromer configurations. In this review, we discuss the rationale for dual BAFF/APRIL inhibition versus single BAFF inhibition in autoimmune disease, by focusing on the similarities and differences between the physiological and pathogenic roles of the two molecules. A summary of the preclinical and clinical data currently available is also presented.

  19. Stress, Burnout and Coping Strategies in Preclinical Medical Students.

    Science.gov (United States)

    Fares, Jawad; Al Tabosh, Hayat; Saadeddin, Zein; El Mouhayyar, Christopher; Aridi, Hussam

    2016-02-01

    It is acknowledged that physicians do not seek the same expert aid for themselves as they would offer their patients. In their preclinical years, medical students appear to espouse comparable behavior. To many, medicine is described as a never-ending path that places the student under heavy stress and burnout from the beginning, leaving him/her vulnerable and with insufficient coping methods. Hence, the objective of this study is to 1) explore the prevalence of stress and burnout among preclinical medical students, and 2) propose solutions to decrease stress and burnout and improve medical education in the preclinical years. A detailed scholarly research strategy using Google Scholar, Scopus, Embase, MEDLINE and PubMed was implemented to highlight key themes that are relevant to preclinical medical students' stress and burnout. Stress varied among different samples of medical students and ranged between 20.9% and 90%. Conversely, burnout ranged between 27% and 75%. Methods that help in reducing the incidence of stress and burnout by promoting strategies that focus on personal engagement, extracurricular activities, positive reinterpretation and expression of emotion, student-led mentorship programs, evaluation systems, career counseling and life coaching should be adopted.

  20. Preclinical QSP Modeling in the Pharmaceutical Industry: An IQ Consortium Survey Examining the Current Landscape.

    Science.gov (United States)

    Nijsen, Marjoleen J M A; Wu, Fan; Bansal, Loveleena; Bradshaw-Pierce, Erica; Chan, Jason R; Liederer, Bianca M; Mettetal, Jerome T; Schroeder, Patricia; Schuck, Edgar; Tsai, Alice; Xu, Christine; Chimalakonda, Anjaneya; Le, Kha; Penney, Mark; Topp, Brian; Yamada, Akihiro; Spilker, Mary E

    2018-03-01

    A cross-industry survey was conducted to assess the landscape of preclinical quantitative systems pharmacology (QSP) modeling within pharmaceutical companies. This article presents the survey results, which provide insights on the current state of preclinical QSP modeling in addition to future opportunities. Our results call attention to the need for an aligned definition and consistent terminology around QSP, yet highlight the broad applicability and benefits preclinical QSP modeling is currently delivering. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  1. Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

    International Nuclear Information System (INIS)

    England, Christopher G.; Rui, Lixin; Cai, Weibo

    2017-01-01

    Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future. (orig.)

  2. Lymphoma: current status of clinical and preclinical imaging with radiolabeled antibodies

    Energy Technology Data Exchange (ETDEWEB)

    England, Christopher G. [University of Wisconsin School of Medicine and Public Health, Department of Medical Physics, Madison, WI (United States); Rui, Lixin [University of Wisconsin School of Medicine and Public Health, Department of Medicine, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, WI (United States); Cai, Weibo [University of Wisconsin School of Medicine and Public Health, Department of Medical Physics, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Carbone Cancer Center, Madison, WI (United States); University of Wisconsin School of Medicine and Public Health, Department of Radiology, Madison, WI (United States)

    2017-03-15

    Lymphoma is a complex disease that arises from cells of the immune system with an intricate pathology. While lymphoma may be classified as Hodgkin or non-Hodgkin, each type of tumor is genetically and phenotypically different and highly invasive tissue biopsies are the only method to investigate these differences. Noninvasive imaging strategies, such as immunoPET, can provide a vital insight into disease staging, monitoring treatment response in patients, and dose planning in radioimmunotherapy. ImmunoPET imaging with radiolabeled antibody-based tracers may also assist physicians in optimizing treatment strategies and enhancing patient stratification. Currently, there are two common biomarkers for molecular imaging of lymphoma, CD20 and CD30, both of which have been considered for investigation in preclinical imaging studies. In this review, we examine the current status of both preclinical and clinical imaging of lymphoma using radiolabeled antibodies. Additionally, we briefly investigate the role of radiolabeled antibodies in lymphoma therapy. As radiolabeled antibodies play critical roles in both imaging and therapy of lymphoma, the development of novel antibodies and the discovery of new biomarkers may greatly affect lymphoma imaging and therapy in the future. (orig.)

  3. DNA nanomaterials for preclinical imaging and drug delivery.

    Science.gov (United States)

    Jiang, Dawei; England, Christopher G; Cai, Weibo

    2016-10-10

    Besides being the carrier of genetic information, DNA is also an excellent biological organizer to establish well-designed nanostructures in the fields of material engineering, nanotechnology, and biomedicine. DNA-based materials represent a diverse nanoscale system primarily due to their predictable base pairing and highly regulated conformations, which greatly facilitate the construction of DNA nanostructures with distinct shapes and sizes. Integrating the emerging advancements in bioconjugation techniques, DNA nanostructures can be readily functionalized with high precision for many purposes ranging from biosensors to imaging to drug delivery. Recent progress in the field of DNA nanotechnology has exhibited collective efforts to employ DNA nanostructures as smart imaging agents or delivery platforms within living organisms. Despite significant improvements in the development of DNA nanostructures, there is limited knowledge regarding the in vivo biological fate of these intriguing nanomaterials. In this review, we summarize the current strategies for designing and purifying highly-versatile DNA nanostructures for biological applications, including molecular imaging and drug delivery. Since DNA nanostructures may elicit an immune response in vivo, we also present a short discussion of their potential toxicities in biomedical applications. Lastly, we discuss future perspectives and potential challenges that may limit the effective preclinical and clinical employment of DNA nanostructures. Due to their unique properties, we predict that DNA nanomaterials will make excellent agents for effective diagnostic imaging and drug delivery, improving patient outcome in cancer and other related diseases in the near future. Copyright © 2016 Elsevier B.V. All rights reserved.

  4. Chagas disease and systemic autoimmune diseases among Bolivian patients in Switzerland

    Directory of Open Access Journals (Sweden)

    Yves Jackson

    2018-02-01

    Full Text Available BACKGROUND Chronic cardiomyopathy occurs in 20-40% of the patients with Chagas disease. Autoimmune mechanisms may contribute to its pathogenesis. We diagnosed several cases of systemic autoimmune diseases among Bolivian migrants in Geneva with a high prevalence of Chagas disease. OBJECTIVES We tested the hypothesis of a clinical association between systemic autoimmune diseases and Chagas disease, particularly with the development of cardiomyopathy. METHODS We retrospectively searched the medical records of all Bolivian patients visiting Geneva University Hospitals between 2012 and 2015 for diagnosis of Chagas disease or systemic autoimmune diseases. FINDINGS Of the 2,189 eligible patients, 28 [1.3%; 95% confidence interval (CI = 0.9-1.9%] presented with systemic autoimmune disease. The Chagas status was known in 903 (41.3% patient, of whom 244 (27.0%; 95% CI = 24.2-30.0% were positive. Eight (28.6%; 95% CI = 15.3-47.1% of the 28 cases of systemic autoimmune disease had Chagas disease. We found no association between both entities (p = 1.000 or with Chagasic cardiomyopathy (p = 0.729. Moreover, there was no evidence of a temporal relationship between antiparasitic chemotherapy and the development of systemic autoimmune diseases. CONCLUSIONS Our results do not support a clinical association between chronic Chagas disease and systemic autoimmune diseases. However, prospective studies in areas endemic for Chagas disease should better assess the prevalence of systemic autoimmune diseases and thus a possible relationship with this infection.

  5. Chagas disease and systemic autoimmune diseases among Bolivian patients in Switzerland.

    Science.gov (United States)

    Jackson, Yves; Pula, Drenusha Vieira de Mello; Finckh, Axel; Chizzolini, Carlo; Chappuis, François

    2018-02-05

    Chronic cardiomyopathy occurs in 20-40% of the patients with Chagas disease. Autoimmune mechanisms may contribute to its pathogenesis. We diagnosed several cases of systemic autoimmune diseases among Bolivian migrants in Geneva with a high prevalence of Chagas disease. We tested the hypothesis of a clinical association between systemic autoimmune diseases and Chagas disease, particularly with the development of cardiomyopathy. We retrospectively searched the medical records of all Bolivian patients visiting Geneva University Hospitals between 2012 and 2015 for diagnosis of Chagas disease or systemic autoimmune diseases. Of the 2,189 eligible patients, 28 [1.3%; 95% confidence interval (CI) = 0.9-1.9%] presented with systemic autoimmune disease. The Chagas status was known in 903 (41.3%) patient, of whom 244 (27.0%; 95% CI = 24.2-30.0%) were positive. Eight (28.6%; 95% CI = 15.3-47.1%) of the 28 cases of systemic autoimmune disease had Chagas disease. We found no association between both entities (p = 1.000) or with Chagasic cardiomyopathy (p = 0.729). Moreover, there was no evidence of a temporal relationship between antiparasitic chemotherapy and the development of systemic autoimmune diseases. Our results do not support a clinical association between chronic Chagas disease and systemic autoimmune diseases. However, prospective studies in areas endemic for Chagas disease should better assess the prevalence of systemic autoimmune diseases and thus a possible relationship with this infection.

  6. Cardiovascular Imaging Techniques in Systemic Rheumatic Diseases

    Directory of Open Access Journals (Sweden)

    Fabiola Atzeni

    2018-02-01

    Full Text Available The risk of cardiovascular (CV events and mortality is significantly higher in patients with systemic rheumatic diseases than in the general population. Although CV involvement in such patients is highly heterogeneous and may affect various structures of the heart, it can now be diagnosed earlier and promptly treated. Various types of assessments are employed for the evaluation of CV risk such as transthoracic or transesophageal echocardiography, magnetic resonance imaging (MRI, and computed tomography (CT to investigate valve abnormalities, pericardial disease, and ventricular wall motion defects. The diameter of coronary arteries can be assessed using invasive quantitative coronarography or intravascular ultrasound, and coronary flow reserve can be assessed using non-invasive transesophageal or transthoracic ultrasonography (US, MRI, CT, or positron emission tomography (PET after endothelium-dependent vasodilation. Finally, peripheral circulation can be measured invasively using strain-gauge plethysmography in an arm after the arterial infusion of an endothelium-dependent vasodilator or non-invasively by means of US or MRI measurements of flow-mediated vasodilation of the brachial artery. All of the above are reliable methods of investigating CV involvement, but more recently, introduced use of speckle tracking echocardiography and 3-dimensional US are diagnostically more accurate.

  7. Effects of Dental 3D Multimedia System on the Performance of Junior Dental Students in Preclinical Practice: A Report from China

    Science.gov (United States)

    Hu, Jian; Yu, Hao; Shao, Jun; Li, Zhiyong; Wang, Jiawei; Wang, Yining

    2009-01-01

    Background: Computer-assisted tools are rarely adopted for dental education in China. In China, 3D digital technology, such as Virtual Reality Systems, are often rejected in the dental field due to prohibitive pricing. There is also a reluctance to move away from traditional patterns of dental education. Objective: The current study is one of a…

  8. Preclinical models for obesity research

    Directory of Open Access Journals (Sweden)

    Perry Barrett

    2016-11-01

    Full Text Available A multi-dimensional strategy to tackle the global obesity epidemic requires an in-depth understanding of the mechanisms that underlie this complex condition. Much of the current mechanistic knowledge has arisen from preclinical research performed mostly, but not exclusively, in laboratory mouse and rat strains. These experimental models mimic certain aspects of the human condition and its root causes, particularly the over-consumption of calories and unbalanced diets. As with human obesity, obesity in rodents is the result of complex gene–environment interactions. Here, we review the traditional monogenic models of obesity, their contemporary optogenetic and chemogenetic successors, and the use of dietary manipulations and meal-feeding regimes to recapitulate the complexity of human obesity. We critically appraise the strengths and weaknesses of these different models to explore the underlying mechanisms, including the neural circuits that drive behaviours such as appetite control. We also discuss the use of these models for testing and screening anti-obesity drugs, beneficial bio-actives, and nutritional strategies, with the goal of ultimately translating these findings for the treatment of human obesity.

  9. Microbiota and immunity: from preclinical data to clinical practice

    Directory of Open Access Journals (Sweden)

    Eleonora Giannetti

    2015-10-01

    Full Text Available The intestinal microbiota is composed of 1013-1014 microorganisms, with at least 100 times as many genes as our genome, the microbiome. Its composition is specific for each individual, changes among individuals and also shows an intra-individual variability during life. Although the gastrointestinal microbial communities of adults are often believed to be stable, there is evidence that, even though at lower rates than in childhood, they change with time, and effects of this variability on health have not been determined yet. The interaction between microbiota and environment is close and widely demonstrated. Gut flora composition is deeply influenced by a number of factors, including diet, age, medications, illness, stress and lifestyle. Intestinal microflora has protective, metabolic and trophic functions. Commensal microbiota can deeply influence the development of the gut mucosal immune system, modulating the maturation of the gut-associated lymphoid tissue and preventing exogenous pathogen intrusion, by stimulation of the immune system and by direct interaction with pathogenic bacteria. The increasing amount of preclinical studies regarding the interaction between intestinal microbiota and immune system and the multiple observations of altered microbiota in human diseases have paved the way for a number of clinical trials aimed at verifying the potential benefits deriving from the manipulation of the microbial ensemble. Several probiotic bacteria have been assessed for their potential applicability in human diseases, albeit with different levels of success. In conclusion, the gut microbiota codevelops with the immune system beginning at birth. The development of the microbiota and its interactions with the cellular populations of the bowel provide a substantial contribution to shaping the structure and dynamic operations of the innate and adaptive immune systems. Manipulation of the microbiota, particularly through the administration of

  10. Novel temporary left ventricular assist system with hydrodynamically levitated bearing pump for bridge to decision: initial preclinical assessment in a goat model.

    Science.gov (United States)

    Kishimoto, Satoru; Takewa, Yoshiaki; Tsukiya, Tomonori; Mizuno, Toshihide; Date, Kazuma; Sumikura, Hirohito; Fujii, Yutaka; Ohnuma, Kentaro; Togo, Konomi; Katagiri, Nobumasa; Naito, Noritsugu; Kishimoto, Yuichiro; Nakamura, Yoshinobu; Nishimura, Motonobu; Tatsumi, Eisuke

    2018-03-01

    The management of heart failure patients presenting in a moribund state remains challenging, despite significant advances in the field of ventricular assist systems. Bridge to decision involves using temporary devices to stabilize the hemodynamic state of such patients while further assessment is performed and a decision can be made regarding patient management. We developed a new temporary left ventricular assist system employing a disposable centrifugal pump with a hydrodynamically levitated bearing. We used three adult goats (body weight, 58-68 kg) to investigate the 30-day performance and hemocompatibility of the newly developed left ventricular assist system, which included the pump, inflow and outflow cannulas, the extracorporeal circuit, and connectors. Hemodynamic, hematologic, and blood chemistry measurements were investigated as well as end-organ effect on necropsy. All goats survived for 30 days in good general condition. The blood pump was operated at a rotational speed of 3000-4500 rpm and a mean pump flow of 3.2 ± 0.6 L min. Excess hemolysis, observed in one goat, was due to the inadequate increase in pump rotational speed in response to drainage insufficiency caused by continuous contact of the inflow cannula tip with the left ventricular septal wall in the early days after surgery. At necropsy, no thrombus was noted in the pump, and no damage caused by mechanical contact was found on the bearing. The newly developed temporary left ventricular assist system using a disposable centrifugal pump with hydrodynamic bearing demonstrated consistent and satisfactory hemodynamic performance and hemocompatibility in the goat model.

  11. Autonomic nervous system function in Huntington's disease.

    Science.gov (United States)

    Andrich, J; Schmitz, T; Saft, C; Postert, T; Kraus, P; Epplen, J T; Przuntek, H; Agelink, M W

    2002-06-01

    To investigate whether Huntington's disease (HD) affects autonomic nervous system (ANS) functioning. Twenty patients with HD who had positive genetic test results underwent standardised ANS function tests including sympathetic skin responses (SSRs) of the hands and feet, measurements of heart rate variability (HRV), both during five minutes of resting and deep respiration, and an orthostatic blood pressure test. Patients were classified according to the motor subscale of the unified Huntington's disease rating scale (UHDRS; mean (SD) score 26.4 (13.6)) and divided into two subgroups: UHDRS or =25 points (mid stages, M-HD). Autonomic indices were compared with those obtained for a group of well matched healthy controls (n=60). Overall, patients showed lower HRV indices than controls. Multivariate analysis with the independent factor of "group" (controls, E-HD, M-HD) showed a significant group effect on both the high frequency power (F=4.32, p=0.017) and the coefficient of variation (F=4.23, p=0.018), indicating a significant reduction in vagal modulation in the M-HD group. There was a shift in autonomic neurocardiac balance towards sympathetic predominance in the M-HD group compared with controls (F=2.89, p=0.062). Moreover, we found an inverse correlation between the severity of clinical HD symptoms (assessed by the UHDRS) and the modulation of cardiovagal activity (p=0.028). Vagal dysregulation was present in two patients; one of them also showed a pathological blood pressure test and a latency prolongation in the SSRs of the hands. Two other patients had pathologically reduced SSR amplitudes. Only patients of the M-HD group were affected. Autonomic dysfunction is present even in the middle stages of HD and affects both the sympathetic and parasympathetic branch of the ANS.

  12. Nitric oxide in the pathophysiology of retinopathy: evidences from preclinical and clinical researches.

    Science.gov (United States)

    Opatrilova, Radka; Kubatka, Peter; Caprnda, Martin; Büsselberg, Dietrich; Krasnik, Vladimir; Vesely, Pavol; Saxena, Sandeep; Ruia, Surabhi; Mozos, Ioana; Rodrigo, Luis; Kruzliak, Peter; Dos Santos, Katia Goncalves

    2017-04-08

    Retinopathy is the leading cause of blindness and visual disability in working-aged people. The pathogenesis of retinopathy is an actual and still open query. Alterations contributing to oxidative and nitrosative stress, including elevated nitric oxide and superoxide production, changes in the expression of different isoforms of nitric oxide synthase or endogenous antioxidant system, have been implicated in the mechanisms how this ocular disease develops. In addition, it was documented that renin-angiotensin system has been implicated in the progression of retinopathy. Based on comprehensive preclinical and clinical researches in this area, the role of above-mentioned factors in the pathogenesis of diabetic retinopathy, hypertensive retinopathy and ischaemic proliferative retinopathy is reviewed in this study. Moreover, the genetic susceptibility factors involved in the development of the retinopathy and possible strategies that utilize antioxidants as additive therapy are also highlighted here. © 2017 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  13. Identification of new treatments for epilepsy: issues in preclinical methodology

    Science.gov (United States)

    Galanopoulou, Aristea S.; Buckmaster, Paul S.; Staley, Kevin J.; Moshé, Solomon L.; Perucca, Emilio; Engel, Jerome; Löscher, Wolfgang; Noebels, Jeffrey L.; Pitkänen, Asla; Stables, James; White, Steve H.; O’Brien, Terence J.; Simonato, Michele

    2013-01-01

    Summary Preclinical research has facilitated the discovery of valuable drugs for the symptomatic treatment of epilepsy. Yet, despite these therapies, seizures are not adequately controlled in a third of all affected individuals, and comorbidities still impose a major burden on quality of life. The introduction of multiple new therapies into clinical use over the past two decades has done little to change this. There is an urgent demand to address the unmet clinical needs for: (a) new symptomatic anti-seizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (b) disease modifying treatments that prevent or ameliorate the epileptogenic state, and (c) treatments for the common comorbidities that contribute to disability in people with epilepsy. New therapies also need to address the special needs of certain subpopulations, i.e. age- or gender-specific treatments. Preclinical development in these treatment areas is complex due to heterogeneity in presentation and etiology, and may need to be formulated with a specific seizure, epilepsy syndrome or comorbidity in mind. The aim of this report is to provide a framework that will help define future guidelines that improve and standardize the design, reporting, and validation of data across preclinical anti-epilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis and comorbidities. PMID:22292566

  14. Spectacular manifestations of systemic diseases of the snake

    DEFF Research Database (Denmark)

    Da Silva, Mari-Ann Otkjær; Bertelsen, Mads Frost; Heegaard, Steffen

    2015-01-01

    This paper reports histopathological findings in the spectacles of four snakes diagnosed with systemic gout, inclusion body disease, disseminated lymphoma and myeloproliferative disease, respectively. Gout was characterised by urate ghost tophi in the stroma and outer epithelium of the spectacle....

  15. A Fuzzy Petri Nets System for Heart Disease Diagnosis

    Directory of Open Access Journals (Sweden)

    Hussin Attya Lafta

    2017-02-01

    Full Text Available In this paper we have proposed a Fuzzy Petri Nets Expert System for heart disease diagnosis. The aim of the proposed system is simulating experience of experts in Diagnosis Heart Disease stage, based on Fuzzy Rule System and modeling reasoning operation by using Fuzzy Petri Nets. The database taken from Machine Learning Repository Center for machine learning and intelligent system. The system has 11 input fields and one output field. The accuracy of proposed system is 75%.

  16. Quantification of Liver Proton-Density Fat Fraction in an 7.1 Tesla preclinical MR Systems: Impact of the Fitting Technique

    Science.gov (United States)

    Mahlke, C; Hernando, D; Jahn, C; Cigliano, A; Ittermann, T; Mössler, A; Kromrey, ML; Domaska, G; Reeder, SB; Kühn, JP

    2016-01-01

    Purpose To investigate the feasibility of estimating the proton-density fat fraction (PDFF) using a 7.1 Tesla magnetic resonance imaging (MRI) system and to compare the accuracy of liver fat quantification using different fitting approaches. Materials and Methods Fourteen leptin-deficient ob/ob mice and eight intact controls were examined in a 7.1 Tesla animal scanner using a 3-dimensional six-echo chemical shift-encoded pulse sequence. Confounder-corrected PDFF was calculated using magnitude (magnitude data alone) and combined fitting (complex and magnitude data). Differences between fitting techniques were compared using Bland-Altman analysis. In addition, PDFFs derived with both reconstructions were correlated with histopathological fat content and triglyceride mass fraction using linear regression analysis. Results The PDFFs determined with use of both reconstructions correlated very strongly (r=0.91). However, small mean bias between reconstructions demonstrated divergent results (3.9%; CI 2.7%-5.1%). For both reconstructions, there was linear correlation with histopathology (combined fitting: r=0.61; magnitude fitting: r=0.64) and triglyceride content (combined fitting: r=0.79; magnitude fitting: r=0.70). Conclusion Liver fat quantification using the PDFF derived from MRI performed at 7.1 Tesla is feasible. PDFF has strong correlations with histopathologically determined fat and with triglyceride content. However, small differences between PDFF reconstruction techniques may impair the robustness and reliability of the biomarker at 7.1 Tesla. PMID:27197806

  17. Prevalence of periodontal disease, its association with systemic diseases and prevention

    Science.gov (United States)

    Nazir, Muhammad Ashraf

    2017-01-01

    Periodontal diseases are prevalent both in developed and developing countries and affect about 20-50% of global population. High prevalence of periodontal disease in adolescents, adults, and older individuals makes it a public health concern. Several risk factors such as smoking, poor oral hygiene, diabetes, medication, age, hereditary, and stress are related to periodontal diseases. Robust evidence shows the association of periodontal diseases with systemic diseases such as cardiovascular disease, diabetes, and adverse pregnancy outcomes. Periodontal disease is likely to cause 19% increase in the risk of cardiovascular disease, and this increase in relative risk reaches to 44% among individuals aged 65 years and over. Type 2 diabetic individuals with severe form of periodontal disease have 3.2 times greater mortality risk compared with individuals with no or mild periodontitis. Periodontal therapy has been shown to improve glycemic control in type 2 diabetic subjects. Periodontitis is related to maternal infection, preterm birth, low birth weight, and preeclampsia. Oral disease prevention strategies should be incorporated in chronic systemic disease preventive initiatives to curtail the burden of disease in populations. The reduction in the incidence and prevalence of periodontal disease can reduce its associated systemic diseases and can also minimize their financial impact on the health-care systems. It is hoped that medical, dental practitioners, and other health-care professionals will get familiar with perio-systemic link and risk factors, and need to refer to the specialized dental or periodontal care. PMID:28539867

  18. Prevalence of periodontal disease, its association with systemic diseases and prevention.

    Science.gov (United States)

    Nazir, Muhammad Ashraf

    2017-01-01

    Periodontal diseases are prevalent both in developed and developing countries and affect about 20-50% of global population. High prevalence of periodontal disease in adolescents, adults, and older individuals makes it a public health concern. Several risk factors such as smoking, poor oral hygiene, diabetes, medication, age, hereditary, and stress are related to periodontal diseases. Robust evidence shows the association of periodontal diseases with systemic diseases such as cardiovascular disease, diabetes, and adverse pregnancy outcomes. Periodontal disease is likely to cause 19% increase in the risk of cardiovascular disease, and this increase in relative risk reaches to 44% among individuals aged 65 years and over. Type 2 diabetic individuals with severe form of periodontal disease have 3.2 times greater mortality risk compared with individuals with no or mild periodontitis. Periodontal therapy has been shown to improve glycemic control in type 2 diabetic subjects. Periodontitis is related to maternal infection, preterm birth, low birth weight, and preeclampsia. Oral disease prevention strategies should be incorporated in chronic systemic disease preventive initiatives to curtail the burden of disease in populations. The reduction in the incidence and prevalence of periodontal disease can reduce its associated systemic diseases and can also minimize their financial impact on the health-care systems. It is hoped that medical, dental practitioners, and other health-care professionals will get familiar with perio-systemic link and risk factors, and need to refer to the specialized dental or periodontal care.

  19. Associations between Systemic Sclerosis and Thyroid Diseases

    Directory of Open Access Journals (Sweden)

    Poupak Fallahi

    2017-10-01

    Full Text Available We have reviewed scientific literature about the association of systemic sclerosis (SSc and thyroid disorders. A high incidence, and prevalence, of new cases of autoimmune thyroiditis (AT and/or hypothyroidism have been shown in sclerodermic patients (overall in the female gender. An association among a Th1 immune-predominance, low vitamin D levels, and AT have been also shown in SSc patients. Cases of Graves’ disease (GD have been described in SSc patients, too, according with the higher prevalence of thyroid autoimmunity. It has been also shown a higher prevalence of papillary thyroid cancer (PTC, in association with AT, in SSc patients. However, in order to confirm results about GD and thyroid cancer, studies in larger number of patients with SSc are needed. During the follow-up of SSc patients it would be appropriate to monitor carefully their thyroid status. The abovementioned data strongly suggest a periodic thyroid function follow-up in female SSc patients [showing a borderline high (although in the normal range thyroid-stimulating hormone level, antithyroid peroxidase antibody positivity, and a small thyroid with a hypoechoic pattern], and, when necessary, appropriate treatments. In conclusion, most of the studies show an association among SSc, AT, and hypothyroidism, such as an increased prevalence of TC overall in SSc patients with AT. Only few cases of GD have been also described in SSc.

  20. A novel preclinical murine model of immune-mediated metastatic dormancy

    OpenAIRE

    Romero, Irene; Garrido, Federico; Garcia-Lora, Angel M

    2014-01-01

    The mechanisms underlying cancer dormancy are poorly understood. We have developed a preclinical murine model in which immunosurveillance restrains spontaneous metastases in permanent dormancy. The model faithfully recapitulates human metastatic dormancy and may be useful to decipher the immune mechanisms constraining disease progression, thereby facilitating the development of novel immunotherapeutic approaches to control metastatic disease.

  1. The preclinical data forum network: A new ECNP initiative to improve data quality and robustness for (preclinical) neuroscience.

    Science.gov (United States)

    Steckler, Thomas; Brose, Katja; Haas, Magali; Kas, Martien J; Koustova, Elena; Bespalov, Anton

    2015-10-01

    Current limitations impeding on data reproducibility are often poor statistical design, underpowered studies, lack of robust data, lack of methodological detail, biased reporting and lack of open data sharing, coupled with wrong research incentives. To improve data reproducibility, robustness and quality for brain disease research, a Preclinical Data Forum Network was formed under the umbrella of the European College of Neuropsychopharmacology (ECNP). The goal of this network, members of which met for the first time in October 2014, is to establish a forum to collaborate in precompetitive space, to exchange and develop best practices, and to bring together the members from academia, pharmaceutical industry, publishers, journal editors, funding organizations, public/private partnerships and non-profit advocacy organizations. To address the most pertinent issues identified by the Network, it was decided to establish a data sharing platform that allows open exchange of information in the area of preclinical neuroscience and to develop an educational scientific program. It is also planned to reach out to other organizations to align initiatives to enhance efficiency, and to initiate activities to improve the clinical relevance of preclinical data. Those Network activities should contribute to scientific rigor and lead to robust and relevant translational data. Here we provide a synopsis of the proceedings from the inaugural meeting. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

  2. The eye in systemic disease | Lenake | South African Family Practice

    African Journals Online (AJOL)

    The eye is a unique organ which is often involved in systemic disease. Patients with systemic disease may first present with eye pathology, and patients with known systemic illnesses may need to have their eyes specifically checked for ocular complications. It is thus useful for the physician to be familiar with the ocular ...

  3. Quetiapine: recent developments in preclinical research

    Directory of Open Access Journals (Sweden)

    Marco Orsetti

    2010-03-01

    Full Text Available Quetiapine (QTP is an atypical antipsychotic labelled for the treatment of patients with schizophrenia, bipolar mania and bipolar depression. Nevertheless, QTP has been tried across multiple diagnosis categories and seems to be used, among other atypical antipsychotics, in clinical practice for an expanding range of disorders such as major depression, substance abuse disorders, anxiety disorders, and borderline personality disorders. The present review focuses on papers which investigated the molecular mechanism(s of QTP antidepressant effect. In particular, preclinical studies performed by coupling the chronic mild stress, an animal model of human depression with Affymetrix microarray technology, revealed that chronic QTP administration prevented the stress-induced up- or down-regulation of 42 genes involved in the central nervous system development or having a crucial role for viability of neural cells, like regulation of signal transduction, inorganic ion transport, membrane organisation, and neurite morphogenesis. Among these, Ptgs2, Hes5, Plcb1, Senp2, Gad1, and Marcks are presumably the effectors of the QTP clinical efficacy.

  4. Preclinical studies of alcohol binge drinking

    Science.gov (United States)

    Crabbe, John C.; Harris, R. Adron; Koob, George F.

    2011-01-01

    Binge drinking is prevalent and has serious biomedical consequences. In children, adolescents, and young adults, it is a prominent risk factor for later development of alcohol-use disorders. Many preclinical models have been employed to study the genetic risks for and biomedical consequences of alcohol drinking. However, these models historically did not result in blood-alcohol concentrations (BACs) exceding 80 mg%; this relatively modest level is the threshold that currently defines a binge session, according to the NIAAA and CDC. Nevertheless, in alcohol-dependent rodents, binge drinking has been well documented. Key neurobiological substrates localized to brain reward and stress systems have been identified. Studies of newer models of binge drinking without dependence are reviewed here. In these models, rodents, non-human primates, and flies will drink enough to reach high BACs. They often display observable signs of intoxication. The neurobiological consequences of these episodes of binge drinking without dependence are reviewed, preliminary evidence for roles for GABA, glutamate, opioid peptides, and corticotropin releasing factor are discussed, as is the need for more work to identify the antecedents and consequences of binge drinking in both animal models and humans. PMID:21272009

  5. Evaluation of an automated connective tissue disease screening assay in Korean patients with systemic rheumatic diseases.

    Directory of Open Access Journals (Sweden)

    Seri Jeong

    Full Text Available This study aimed to evaluate the diagnostic utilities of the automated connective tissues disease screening assay, CTD screen, in patients with systemic rheumatic diseases. A total of 1093 serum samples were assayed using CTD screen and indirect immunofluorescent (IIF methods. Among them, 162 were diagnosed with systemic rheumatic disease, including rheumatoid arthritis (RA, systemic lupus erythematosus (SLE, and mixed connective tissue disease (MCT. The remaining 931 with non-systemic rheumatic disease were assigned to the control group. The median ratios of CTD screen tests were significantly higher in the systemic rheumatic disease group than in the control group. The positive likelihood ratios of the CTD screen were higher than those of IIF in patients with total rheumatic diseases (4.1 vs. 1.6, including SLE (24.3 vs. 10.7. The areas under the receiver operating characteristic curves (ROC-AUCs of the CTD screen for discriminating total rheumatic diseases, RA, SLE, and MCT from controls were 0.68, 0.56, 0.92 and 0.80, respectively. The ROC-AUCs of the combinations with IIF were significantly higher in patients with total rheumatic diseases (0.72 and MCT (0.85 than in those of the CTD screen alone. Multivariate analysis indicated that both the CTD screen and IIF were independent variables for predicting systemic rheumatic disease. CTD screen alone and in combination with IIF were a valuable diagnostic tool for predicting systemic rheumatic diseases, particularly for SLE.

  6. Interstitial Lung disease in Systemic Sclerosis

    International Nuclear Information System (INIS)

    Ooi, G.C.; Mok, M.Y.; Tsang, K.W.T.; Khong, P.L.; Fung, P.C.W.; Chan, S.; Tse, H.F.; Wong, R.W.S.; Lam, W.K.; Lau, C.S.; Wong, Y.

    2003-01-01

    Purpose: To evaluate high-resolution CT (HRCT) parameters of inflammation and fibrosis in systemic sclerosis (SSc), for correlation with lung function, skin scores and exercise tolerance. Material and Methods: : 45 SSc patients (40 women, 48.5±13.4 years), underwent thoracic HRCT, lung function assessment, and modified Rodnan skin scores. Exercise tolerance was also graded. HRCT were scored for extent of 4 HRCT patterns of interstitial lung disease (ILD): ground glass opacification (GGO), reticular, mixed and honeycomb pattern in each lobe. Total HRCT score, inflammation index (GGO and mixed score) and fibrosis index (reticular and honeycomb scores) were correlated with lung function and clinical parameters. Results: ILD was present in 39/45 (86.7%) patients. Abnormal (<80% predicted) forced vital capacity (FVC), total lung capacity (TLC) and carbon monoxide diffusion factor (DLco) were detected in 30%, 22% and 46% of patients. Total HRCT score correlated with FVC (r=0.43, p=0.008), FEV1 (forced expiratory volume) (r=-0.37, p=0.03), TLC (r=-0.47, p=0.003), and DLCO (r=-0.43, p=0.008); inflammatory index with DLCO (r=-0.43, p=0.008) and exercise tolerance (r=-0.39, p < 0.05); and fibrosis index with FVC (r=-0.31, p=0.05) and TLC (r=-0.38, p=0.02). Higher total HRCT score, and inflammation and fibrosis indices were found in patients with abnormal lung function. Conclusion: Qualitative HRCT is able to evaluate inflammation and fibrosis, showing important relationships with diffusion capacity and lung volume, respectively

  7. Disease Compass- a navigation system for disease knowledge based on ontology and linked data techniques.

    Science.gov (United States)

    Kozaki, Kouji; Yamagata, Yuki; Mizoguchi, Riichiro; Imai, Takeshi; Ohe, Kazuhiko

    2017-06-19

    Medical ontologies are expected to contribute to the effective use of medical information resources that store considerable amount of data. In this study, we focused on disease ontology because the complicated mechanisms of diseases are related to concepts across various medical domains. The authors developed a River Flow Model (RFM) of diseases, which captures diseases as the causal chains of abnormal states. It represents causes of diseases, disease progression, and downstream consequences of diseases, which is compliant with the intuition of medical experts. In this paper, we discuss a fact repository for causal chains of disease based on the disease ontology. It could be a valuable knowledge base for advanced medical information systems. We developed the fact repository for causal chains of diseases based on our disease ontology and abnormality ontology. This section summarizes these two ontologies. It is developed as linked data so that information scientists can access it using SPARQL queries through an Resource Description Framework (RDF) model for causal chain of diseases. We designed the RDF model as an implementation of the RFM for the fact repository based on the ontological definitions of the RFM. 1554 diseases and 7080 abnormal states in six major clinical areas, which are extracted from the disease ontology, are published as linked data (RDF) with SPARQL endpoint (accessible API). Furthermore, the authors developed Disease Compass, a navigation system for disease knowledge. Disease Compass can browse the causal chains of a disease and obtain related information, including abnormal states, through two web services that provide general information from linked data, such as DBpedia, and 3D anatomical images. Disease Compass can provide a complete picture of disease-associated processes in such a way that fits with a clinician's understanding of diseases. Therefore, it supports user exploration of disease knowledge with access to pertinent information

  8. Endocannabinoids and the Cardiovascular System in Health and Disease.

    Science.gov (United States)

    O'Sullivan, Saoirse Elizabeth

    2015-01-01

    The endocannabinoid system is widely distributed throughout the cardiovascular system. Endocannabinoids play a minimal role in the regulation of cardiovascular function in normal conditions, but are altered in most cardiovascular disorders. In shock, endocannabinoids released within blood mediate the associated hypotension through CB(1) activation. In hypertension, there is evidence for changes in the expression of CB(1), and CB(1) antagonism reduces blood pressure in obese hypertensive and diabetic patients. The endocannabinoid system is also upregulated in cardiac pathologies. This is likely to be cardioprotective, via CB(2) and CB(1) (lesser extent). In the vasculature, endocannabinoids cause vasorelaxation through activation of multiple target sites, inhibition of calcium channels, activation of potassium channels, NO production and the release of vasoactive substances. Changes in the expression or function of any of these pathways alter the vascular effect of endocannabinoids. Endocannabinoids have positive (CB(2)) and negative effects (CB(1)) on the progression of atherosclerosis. However, any negative effects of CB(1) may not be consequential, as chronic CB(1) antagonism in large scale human trials was not associated with significant reductions in atheroma. In neurovascular disorders such as stroke, endocannabinoids are upregulated and protective, involving activation of CB(1), CB(2), TRPV1 and PPARα. Although most of this evidence is from preclinical studies, it seems likely that cannabinoid-based therapies could be beneficial in a range of cardiovascular disorders.

  9. Improvement of preclinical animal models for autoimmune-mediated disorders via reverse translation of failed therapies.

    Science.gov (United States)

    't Hart, Bert A; Jagessar, S Anwar; Kap, Yolanda S; Haanstra, Krista G; Philippens, Ingrid H C H M; Serguera, Che; Langermans, Jan; Vierboom, Michel

    2014-09-01

    The poor translational validity of autoimmune-mediated inflammatory disease (AIMID) models in inbred and specific pathogen-free (SPF) rodents underlies the high attrition of new treatments for the corresponding human disease. Experimental autoimmune encephalomyelitis (EAE) is a frequently used preclinical AIMID model. We discuss here how crucial information needed for the innovation of current preclinical models can be obtained from postclinical analysis of the nonhuman primate EAE model, highlighting the mechanistic reasons why some therapies fail and others succeed. These new insights can also help identify new targets for treatment. Copyright © 2014 Elsevier Ltd. All rights reserved.

  10. Chapter 15. Plant pathology and managing wildland plant disease systems

    Science.gov (United States)

    David L. Nelson

    2004-01-01

    Obtaining specific, reliable knowledge on plant diseases is essential in wildland shrub resource management. However, plant disease is one of the most neglected areas of wildland resources experimental research. This section is a discussion of plant pathology and how to use it in managing plant disease systems.

  11. Oral biofilms, oral and periodontal infections, and systemic disease.

    Science.gov (United States)

    Maddi, Abhiram; Scannapieco, Frank A

    2013-10-01

    Oral biofilms harbor several hundreds of species of bacteria as well as spirochetes, protozoa, fungi and viruses. The composition of the oral biofilm varies from health to disease. It is the source of microorganisms that cause dental and periodontal infections. Oral infections and periodontal disease have been implicated in the etiopathogenesis of several important chronic systemic diseases.

  12. Corneal manifestations of selected systemic diseases: A review

    Directory of Open Access Journals (Sweden)

    Wayne D.H. Gillan

    2015-03-01

    Full Text Available The corneal manifestations of several selected systemic diseases are reviewed. Metabolic, immunologic and inflammatory and infectious diseases are included. A brief overview of each disease and how it manifests in the cornea is discussed. The importance of conducting a slit-lamp examination on every patient is emphasised.

  13. Corneal manifestations of selected systemic diseases: A review

    Directory of Open Access Journals (Sweden)

    Wayne D.H. Gillan

    2015-08-01

    Full Text Available The corneal manifestations of several selected systemic diseases are reviewed. Metabolic, immunologic and inflammatory and infectious diseases are included. A brief overview of each disease and how it manifests in the cornea is discussed. The importance of conducting a slit-lamp examination on every patient is emphasised.

  14. Contribution of Large Pig for Renal Ischemia-Reperfusion and Transplantation Studies: The Preclinical Model

    Directory of Open Access Journals (Sweden)

    S. Giraud

    2011-01-01

    Full Text Available Animal experimentation is necessary to characterize human diseases and design adequate therapeutic interventions. In renal transplantation research, the limited number of in vitro models involves a crucial role for in vivo models and particularly for the porcine model. Pig and human kidneys are anatomically similar (characterized by multilobular structure in contrast to rodent and dog kidneys unilobular. The human proximity of porcine physiology and immune systems provides a basic knowledge of graft recovery and inflammatory physiopathology through in vivo studies. In addition, pig large body size allows surgical procedures similar to humans, repeated collections of peripheral blood or renal biopsies making pigs ideal for medical training and for the assessment of preclinical technologies. However, its size is also its main drawback implying expensive housing. Nevertheless, pig models are relevant alternatives to primate models, offering promising perspectives with developments of transgenic modulation and marginal donor models facilitating data extrapolation to human conditions.

  15. Metabolic Syndrome: Systems Thinking in Heart Disease.

    Science.gov (United States)

    Dommermuth, Ron; Ewing, Kristine

    2018-03-01

    Metabolic syndrome (MetS) is a cluster of cardiometabolic risk factors. MetS is associated with approximately 4-fold increase in the likelihood of developing type 2 diabetes mellitus (T2DM) and a 2-fold increase in the incidence of cardiovascular disease complications. MetS is a progressive, proinflammatory, prothrombotic condition that manifests itself along a broad spectrum of disease. It is associated with hypertension, obstructive sleep apnea, fatty liver disease, gout, and polycystic ovarian syndrome. Intervening in and reversing the pathologic process become more difficult as the disease progresses, highlighting the needs for increased individual and community surveillance and primary prevention. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Monogenic autoimmune diseases of the endocrine system.

    Science.gov (United States)

    Johnson, Matthew B; Hattersley, Andrew T; Flanagan, Sarah E

    2016-10-01

    The most common endocrine diseases, type 1 diabetes, hyperthyroidism, and hypothyroidism, are the result of autoimmunity. Clustering of autoimmune endocrinopathies can result from polygenic predisposition, or more rarely, may present as part of a wider syndrome due to a mutation within one of seven genes. These monogenic autoimmune diseases show highly variable phenotypes both within and between families with the same mutations. The average age of onset of the monogenic forms of autoimmune endocrine disease is younger than that of the common polygenic forms, and this feature combined with the manifestation of other autoimmune diseases, specific hallmark features, or both, can inform clinicians as to the relevance of genetic testing. A genetic diagnosis can guide medical management, give an insight into prognosis, inform families of recurrence risk, and facilitate prenatal diagnoses. Copyright © 2016 Elsevier Ltd. All rights reserved.

  17. Hansen's disease mimicking a systemic vasculitis.

    Science.gov (United States)

    Sampaio, L; Silva, L; Terroso, G; Pimenta, S; Brandão, F; Pinto, J; Prisca, A; Brito, J; Ventura, F

    2011-01-01

    Hansen's disease, caused by Mycobacterium leprae, classically presents with cutaneous and neurological manifestations. Rheumatologic manifestations present in 1 to 5% of the patients, and include arthritis, arthralgias, Charcot arthropathy, erythema nodosum and vasculitis. We report a case of a 86 year old woman with polyarthritis, subcutaneous nodules and leg ulcers whose differential diagnosis included primary vasculitis and diffuse connective tissue diseases and ended to be leprosy in a non endemic country.

  18. Resveratrol as a potential therapeutic drug for respiratory system diseases.

    Science.gov (United States)

    Zhu, Xiao-Dan; Lei, Xiao-Ping; Dong, Wen-Bin

    2017-01-01

    Respiratory system diseases are common and major ailments that seriously endanger human health. Resveratrol, a polyphenolic phytoalexin, is considered an anti-inflammatory, antioxidant, and anticancer agent. Thanks to its wide range of biological activities, resveratrol has become a hotspot in many fields, including respiratory system diseases. Indeed, research has demonstrated that resveratrol is helpful to relieve pulmonary function in the general population. Meanwhile, growing evidence indicates that resveratrol plays a protective role in respiratory system diseases. This review aimed to summarize the main protective effects of resveratrol in respiratory system diseases, including its anti-inflammatory, antiapoptotic, antioxidant, antifibrotic, antihypertensive, and anticancer activities. We found that resveratrol plays a protective role in the respiratory system through a variety of mechanisms, and so it may become a new drug for the treatment of respiratory system diseases.

  19. The Diagnostic Value of Skin Disease Diagnosis Expert System.

    Science.gov (United States)

    Jeddi, Fatemeh Rangraz; Arabfard, Masoud; Arabkermany, Zahra; Gilasi, Hamidreza

    2016-02-01

    Evaluation is a necessary measure to ensure the effectiveness and efficiency of all systems, including expert systems. The aim of this study was to determine the diagnostic value of expert system for diagnosis of complex skin diseases. A case-control study was conducted in 2015 to determine the diagnostic value of an expert system. The study population included patients who were referred to Razi Specialized Hospital, affiliated to Tehran University of Medical Sciences. The control group was selected from patients without the selected skin diseases. Data collection tool was a checklist of clinical signs of diseases including pemphigus vulgaris, lichen planus, basal cell carcinoma, melanoma, and scabies. The sample size formula estimated 400 patients with skin diseases selected by experts and 200 patients without the selected skin diseases. Patient selection was undertaken with randomized stratified sampling and their sign and symptoms were logged into the system. Physician's diagnosis was determined as the gold standard and was compared with the diagnosis of expert system by SPSS software version 16 and STATA. Kappa statistics, indicators of sensitivity, specificity, accuracy and confidence intervals were calculated for each disease. An accuracy of 90% was considered appropriate. Comparing the results of expert system and physician's diagnosis at the evaluation stage showed an accuracy of 97.1%, sensitivity of 97.5% and specificity of 96.5% The Kappa test indicated a high agreement of 93.6%. The expert system can diagnose complex skin diseases. Development of such systems is recommended to identify all skin diseases.

  20. ACUTE RESPIRATORY DISEASE AS THE DEBUT OF SYSTEMIC LUPUS ERYTHEMATOSUS

    Directory of Open Access Journals (Sweden)

    A. Yu. Ischenko

    2015-01-01

    Full Text Available Systemic lupus erythematosus — a chronic autoimmune disease that is often associated with infectious processes. The paper presents two clinical cases of systemic lupus erythematosus , debuted with acute respiratory infection.

  1. Dysregulation of Ubiquitin-Proteasome System in Neurodegenerative Diseases

    Science.gov (United States)

    Zheng, Qiuyang; Huang, Timothy; Zhang, Lishan; Zhou, Ying; Luo, Hong; Xu, Huaxi; Wang, Xin

    2016-01-01

    The ubiquitin-proteasome system (UPS) is one of the major protein degradation pathways, where abnormal UPS function has been observed in cancer and neurological diseases. Many neurodegenerative diseases share a common pathological feature, namely intracellular ubiquitin-positive inclusions formed by aggregate-prone neurotoxic proteins. This suggests that dysfunction of the UPS in neurodegenerative diseases contributes to the accumulation of neurotoxic proteins and to instigate neurodegeneration. Here, we review recent findings describing various aspects of UPS dysregulation in neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease. PMID:28018215

  2. A complete categorization of multiscale models of infectious disease systems.

    Science.gov (United States)

    Garira, Winston

    2017-12-01

    Modelling of infectious disease systems has entered a new era in which disease modellers are increasingly turning to multiscale modelling to extend traditional modelling frameworks into new application areas and to achieve higher levels of detail and accuracy in characterizing infectious disease systems. In this paper we present a categorization framework for categorizing multiscale models of infectious disease systems. The categorization framework consists of five integration frameworks and five criteria. We use the categorization framework to give a complete categorization of host-level immuno-epidemiological models (HL-IEMs). This categorization framework is also shown to be applicable in categorizing other types of multiscale models of infectious diseases beyond HL-IEMs through modifying the initial categorization framework presented in this study. Categorization of multiscale models of infectious disease systems in this way is useful in bringing some order to the discussion on the structure of these multiscale models.

  3. Epidemiologic Insights into Stone Disease as a Systemic Disorder

    Science.gov (United States)

    Curhan, Gary C.

    2007-04-01

    Examining the epidemiology of stone disease can provide insight into etiology. There is a growing body of evidence that stone disease is not simply a disorder of the kidney. In fact, nephrolithiasis is clearly a systemic disorder. Conditions associated with stone disease include the classic ones such as inflammatory bowel disease and primary hyperparathyroidism. More recent studies have demonstrated strong associations with obesity, gout, diabetes and hypertension. Future studies will help uncover the underlying common pathophysiologic abnormalities.

  4. An intervertebral disc whole organ culture system to investigate proinflammatory and degenerative disc disease condition.

    Science.gov (United States)

    Lang, Gernot; Liu, Yishan; Geries, Janna; Zhou, Zhiyu; Kubosch, David; Südkamp, Norbert; Richards, R Geoff; Alini, Mauro; Grad, Sibylle; Li, Zhen

    2018-04-01

    The aim of this study was to compare the effect of different disease initiators of degenerative disc disease (DDD) within an intervertebral disc (IVD) organ culture system and to understand the interplay between inflammation and degeneration in the early stage of DDD. Bovine caudal IVDs were cultured within a bioreactor for up to 11 days. Control group was cultured under physiological loading (0.02-0.2 MPa; 0.2 Hz; 2 hr/day) and high glucose (4.5 g/L) medium. Detrimental loading (0.32-0.5 MPa, 5 Hz; 2 hr/day) and low glucose (2 g/L) medium were applied to mimic the condition of abnormal mechanical stress and limited nutrition supply. Tumour necrosis factor alpha (TNF-α) was injected into the nucleus pulposus (100 ng per IVD) as a proinflammatory trigger. TNF-α combined with detrimental loading and low glucose medium up-regulated interleukin 1β (IL-1β), IL-6, and IL-8 gene expression in disc tissue, nitric oxide, and IL-8 release from IVD, which indicate a proinflammatory effect. The combined initiators up-regulated matrix metalloproteinase 1 gene expression, down-regulated gene expression of Type I collagen in annulus fibrosus and Type II collagen in nucleus pulposus, and reduced the cell viability. Furthermore, the combined initiators induced a degradative effect, as indicated by markedly higher glycosaminoglycan release into conditioned medium. The combination of detrimental dynamic loading, nutrient deficiency, and TNF-α intradiscal injection can synergistically simulate the proinflammatory and degenerative disease condition within DDD. This model will be of high interest to screen therapeutic agents in further preclinical studies for early intervention and treatment of DDD. Copyright © 2018 John Wiley & Sons, Ltd.

  5. Prototype of Information System for Horticulture Pest and Disease Distribution

    OpenAIRE

    Susanti, Erni -

    2015-01-01

    The impact of climate change on the outbreak plant pest and disease seems to be likely increased in the future. However, operational information system on the outbreak of pest and disease on horticulture crops which can provide an overview of outbreak and distribution pest both in space and time is still very limited. The objective of the study is to developed prototype information system for providing information regarding area of horticulture pest and disease outbreak both space and time pu...

  6. [Development of expert diagnostic system for common respiratory diseases].

    Science.gov (United States)

    Xu, Wei-hua; Chen, You-ling; Yan, Zheng

    2014-03-01

    To develop an internet-based expert diagnostic system for common respiratory diseases. SaaS system was used to build architecture; pattern of forward reasoning was applied for inference engine design; ASP.NET with C# from the tool pack of Microsoft Visual Studio 2005 was used for website-interview medical expert system.The database of the system was constructed with Microsoft SQL Server 2005. The developed expert system contained large data memory and high efficient function of data interview and data analysis for diagnosis of various diseases.The users were able to perform this system to obtain diagnosis for common respiratory diseases via internet. The developed expert system may be used for internet-based diagnosis of various respiratory diseases,particularly in telemedicine setting.

  7. [Odontogenic foci and systemic diseases. A review].

    Science.gov (United States)

    Párkányi, László; Vályi, Péter; Nagy, Katalin; Fráter, Márk

    2018-03-01

    The aim of the present review is to provide an up-to-date picture of what we know about the connection between odontogenic foci and non-oral diseases. After a brief historical summary, we give an overview on how the odontogenic focus causes disease in distant areas of the body in general, and then we start the discussion of the particular conditions, such as cardiovascular diseases, pneumonia, diabetes mellitus, metabolic syndrome, rheumatoid arthritis and adverse pregnancy outcomes. The review is centered around the two main odontogenic foci: periodontitis and periapical periodontitis, the latter being a widely recognized but rarely discussed oral focus. Finally, we offer a few considerations that the practicing dentist may find useful when dealing with odontogenic foci. Orv Hetil. 2018; 159(11): 415-422.

  8. Lipid Involvement in Neurodegenerative Diseases of the Motor System: Insights from Lysosomal Storage Diseases.

    Science.gov (United States)

    Dodge, James C

    2017-01-01

    Lysosomal storage diseases (LSDs) are a heterogeneous group of rare inherited metabolic diseases that are frequently triggered by the accumulation of lipids inside organelles of the endosomal-autophagic-lysosomal system (EALS). There is now a growing realization that disrupted lysosomal homeostasis (i.e., lysosomal cacostasis) also contributes to more common neurodegenerative disorders such as Parkinson disease (PD). Lipid deposition within the EALS may also participate in the pathogenesis of some additional neurodegenerative diseases of the motor system. Here, I will highlight the lipid abnormalities and clinical manifestations that are common to LSDs and several diseases of the motor system, including amyotrophic lateral sclerosis (ALS), atypical forms of spinal muscular atrophy, Charcot-Marie-Tooth disease (CMT), hereditary spastic paraplegia (HSP), multiple system atrophy (MSA), PD and spinocerebellar ataxia (SCA). Elucidating the underlying basis of intracellular lipid mislocalization as well as its consequences in each of these disorders will likely provide innovative targets for therapeutic research.

  9. The Economics of Reproducibility in Preclinical Research.

    Directory of Open Access Journals (Sweden)

    Leonard P Freedman

    2015-06-01

    Full Text Available Low reproducibility rates within life science research undermine cumulative knowledge production and contribute to both delays and costs of therapeutic drug development. An analysis of past studies indicates that the cumulative (total prevalence of irreproducible preclinical research exceeds 50%, resulting in approximately US$28,000,000,000 (US$28B/year spent on preclinical research that is not reproducible-in the United States alone. We outline a framework for solutions and a plan for long-term improvements in reproducibility rates that will help to accelerate the discovery of life-saving therapies and cures.

  10. Expert System For Diagnosis Pest And Disease In Fruit Plants

    Science.gov (United States)

    Dewanto, Satrio; Lukas, Jonathan

    2014-03-01

    This paper discussed the development of an expert system to diagnose pests and diseases on fruit plants. Rule base method was used to store the knowledge from experts and literatures. Control technique using backward chain and started from the symptoms to get conclusions about the pests and diseases that occur. Development of the system has been performed using software Corvid Exsys developed by Exsys company. Results showed that the development of this expert system can be used to assist users in identifying the type of pests and diseases on fruit plants. Further development and possibility of using internet for this system are proposed.

  11. Disease management in soilless culture systems

    NARCIS (Netherlands)

    Os, van E.A.

    2010-01-01

    EU legislation, laid down in the Water Framework Directive, demands to minimize emissions of nitrogen, phosphate and crop protection products to achieve an excellent chemical and ecological quality in 2015. The aim is to force growers to a better water and disease management. Supply water of

  12. Renin-angiotensin system gene expression and neurodegenerative diseases.

    Science.gov (United States)

    Goldstein, Benjamin; Speth, Robert C; Trivedi, Malav

    2016-07-01

    Single nucleotide polymorphisms and altered gene expression of components of the renin-angiotensin system (RAS) are associated with neurodegenerative diseases. Drugs that interact with the RAS have been shown to affect the course of neurodegenerative disease, suggesting that abnormalities in the RAS may contribute to neurodegenerative disease. A meta-analysis of genome-wide association studies and gene expression data for 14 RAS-related proteins was carried out for five neurodegenerative diseases: Alzheimer's disease, Parkinson's disease, narcolepsy, amyotrophic lateral sclerosis and multiple sclerosis. No single nucleotide polymorphisms in any of the 14 RAS-related protein genes were significantly associated with the five neurodegenerative diseases investigated. There was an inverse association between expression of ATP6AP2, which encodes the (pro)renin receptor, and multiple sclerosis, Alzheimer's disease and Parkinson's disease. An association of AGTR, which encodes the AT1 angiotensin II receptor, and Parkinson's disease and Alzheimer's disease was also observed. To date, no single nucleotide polymorphisms in components of the RAS can be definitively linked to the neurodegenerative diseases evaluated in this study. However, altered gene expression of several components of the RAS is associated with several neurodegenerative diseases, which may indicate that the RAS contributes to the pathology of these diseases. © The Author(s) 2016.

  13. Preclinical pharmacokinetic/pharmacodynamic modeling and simulation in the pharmaceutical industry: an IQ consortium survey examining the current landscape.

    Science.gov (United States)

    Schuck, Edgar; Bohnert, Tonika; Chakravarty, Arijit; Damian-Iordache, Valeriu; Gibson, Christopher; Hsu, Cheng-Pang; Heimbach, Tycho; Krishnatry, Anu Shilpa; Liederer, Bianca M; Lin, Jing; Maurer, Tristan; Mettetal, Jerome T; Mudra, Daniel R; Nijsen, Marjoleen Jma; Raybon, Joseph; Schroeder, Patricia; Schuck, Virna; Suryawanshi, Satyendra; Su, Yaming; Trapa, Patrick; Tsai, Alice; Vakilynejad, Majid; Wang, Shining; Wong, Harvey

    2015-03-01

    The application of modeling and simulation techniques is increasingly common in preclinical stages of the drug discovery and development process. A survey focusing on preclinical pharmacokinetic/pharmacodynamics (PK/PD) analysis was conducted across pharmaceutical companies that are members of the International Consortium for Quality and Innovation in Pharmaceutical Development. Based on survey responses, ~68% of companies use preclinical PK/PD analysis in all therapeutic areas indicating its broad application. An important goal of preclinical PK/PD analysis in all pharmaceutical companies is for the selection/optimization of doses and/or dose regimens, including prediction of human efficacious doses. Oncology was the therapeutic area with the most PK/PD analysis support and where it showed the most impact. Consistent use of more complex systems pharmacology models and hybrid physiologically based pharmacokinetic models with PK/PD components was less common compared to traditional PK/PD models. Preclinical PK/PD analysis is increasingly being included in regulatory submissions with ~73% of companies including these data to some degree. Most companies (~86%) have seen impact of preclinical PK/PD analyses in drug development. Finally, ~59% of pharmaceutical companies have plans to expand their PK/PD modeling groups over the next 2 years indicating continued growth. The growth of preclinical PK/PD modeling groups in pharmaceutical industry is necessary to establish required resources and skills to further expand use of preclinical PK/PD modeling in a meaningful and impactful manner.

  14. PERIODONTAL INFECTION AS A POTENTIAL RISK FACTOR FOR SYSTEMIC DISEASE

    Directory of Open Access Journals (Sweden)

    Sumintarti Sumintarti

    2015-06-01

    Full Text Available Oral infection can have an adverse effect on other organs of the body. Oral infections, especially periodontitis, may affect the course and pathogenesis of a number of systemic diseases, such as diabetes mellitus, cardiovascular disease, pre-term low birth weight infant and respiratory disease. The purpose of this article is to evaluate the current status of oral infection especially periodontitis as a potential risk factor of systemic diseases. Three main pathways linking oral infection to secondary systemic effects have been proposed: metastatic infection, metastatic injury and metastatic inflammation. Periodontitis can cause bacteria to enter the blood stream and activate immune cells. These activated cells produce inflammatory cytokines that have a destructive effect throughout the entire body. Therefore, periodontitis as a major oral infection may affect the host’s susceptibility to systemic disease.

  15. Preclinical Evaluation of a Lentiviral Vector for Huntingtin Silencing

    Directory of Open Access Journals (Sweden)

    Karine Cambon

    2017-06-01

    Full Text Available Huntington’s disease (HD is an autosomal dominant neurodegenerative disorder resulting from a polyglutamine expansion in the huntingtin (HTT protein. There is currently no cure for this disease, but recent studies suggest that RNAi to downregulate the expression of both normal and mutant HTT is a promising therapeutic approach. We previously developed a small hairpin RNA (shRNA, vectorized in an HIV-1-derived lentiviral vector (LV, that reduced pathology in an HD rodent model. Here, we modified this vector for preclinical development by using a tat-independent third-generation LV (pCCL backbone and removing the original reporter genes. We demonstrate that this novel vector efficiently downregulated HTT expression in vitro in striatal neurons derived from induced pluripotent stem cells (iPSCs of HD patients. It reduced two major pathological HD hallmarks while triggering a minimal inflammatory response, up to 6 weeks after injection, when administered by stereotaxic surgery in the striatum of an in vivo rodent HD model. Further assessment of this shRNA vector in vitro showed proper processing by the endogenous silencing machinery, and we analyzed gene expression changes to identify potential off-targets. These preclinical data suggest that this new shRNA vector fulfills primary biosafety and efficiency requirements for further development in the clinic as a cure for HD.

  16. The effect of liver disease on the cardiovascular system

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik; Møller, Søren

    2007-01-01

    THE encyclopedic guide to hepatology - for consultation by clinicians and basic scientistsPreviously the Oxford Textbook of Clinical Hepatology, this two-volume textbook is now with Blackwell Publishing. It covers basic, clinical and translational science (converting basic science discoveries...... and clinical practice discussed by the best authors.It includes unique sections on: Symptoms and signs in liver diseaseIndustrial diseases affecting the liverThe effects of diseases of other systems on the liverThe effects of liver diseases on other systemsIt 's bigger and more extensive than other books...

  17. Linking the microbiota, chronic disease and the immune system

    Science.gov (United States)

    Hand, Timothy W.; Vujkovic-Cvijin, Ivan; Ridaura, Vanessa K.; Belkaid, Yasmine

    2016-01-01

    Chronic inflammatory diseases are the most important causes of mortality in the world today and are on the rise. We now know that immune-driven inflammation is critical in the etiology of these diseases, though the environmental triggers and cellular mechanisms that lead to their development are still mysterious. Many chronic inflammatory diseases are associated with significant shifts in the microbiota towards inflammatory configurations, which can affect the host both by inducing local and systemic inflammation and by alterations in microbiota-derived metabolites. This review discusses recent findings suggesting that shifts in the microbiota may contribute to chronic disease via effects on the immune system. PMID:27623245

  18. Automated system for periodontal disease diagnosis

    Science.gov (United States)

    Albalat, Salvador E.; Alcaniz-Raya, Mariano L.; Juan, M. Carmen; Grau Colomer, Vincente; Monserrat, Carlos

    1997-04-01

    Evolution of periodontal disease is one of the most important data for the clinicians in order to achieve correct planning and treatment. Clinical measure of the periodontal sulcus depth is the most important datum to know the exact state of periodontal disease. These measures must be done periodically study bone resorption evolution around teeth. Time factor of resorption indicates aggressiveness of periodontitis. Manual probes are commonly used with direct reading. Mechanical probes give automatic signal but this method uses complicated and heavy probes that are only limited for University researchers. Probe position must be the same to have right diagnosis. Digital image analysis of periodontal probing provides practical, accurate and easy tool. Gum and plaque index could also be digitally measured with this method.

  19. POSSIBILITYIES OF PHYTOTHERAPY AT DIGESTIVE SYSTEM DISEASES

    Directory of Open Access Journals (Sweden)

    A. V. Kurkina

    2016-01-01

    Full Text Available In the present paper the modern approaches to the reasonable using of phytopharmaceuticals for diseases of gastrointestinal tract were discussed. Substantiates using groups of medicinal plants for the treatment of diseases of gastrointestinal tract based on important relationship «biologically active substance-pharmacological effect». According modern data of chemical composition and pharmacological activity in the attitude to this pathology the most important species of medicinal plants are considered. The importance of principle of phytotherapy’s safety as a main approach of evidential medicine was highlighted. This scientific paper will help experts to make an evidence-based decision of medicinal plants and phytopreparations based on them in clinical practice.

  20. Electrocardiographic changes in central nervous system disease.

    Science.gov (United States)

    Valeriano, J; Elson, J

    1993-05-01

    This article gives a basic description of neurophysiologic control of cardiac function. Specific electrocardiographic abnormalities related to various central nervous system insults are discussed also.

  1. Disease management in soilless culture systems

    OpenAIRE

    Os, van, E.A.

    2010-01-01

    EU legislation, laid down in the Water Framework Directive, demands to minimize emissions of nitrogen, phosphate and crop protection products to achieve an excellent chemical and ecological quality in 2015. The aim is to force growers to a better water and disease management. Supply water of excellent chemical quality will have to be recirculated as long as possible, for which adequate disinfection equipment have to be used. Several sources of water are used as supply water. Rainwater is chem...

  2. The microbiome-systemic diseases connection

    NARCIS (Netherlands)

    van der Meulen, T. A.; Harmsen, H. J. M.; Bootsma, H.; Spijkervet, F. K. L.; Kroese, F. G. M.; Vissink, A.

    2016-01-01

    The human microbiome consists of all microorganisms occupying the skin, mucous membranes and intestinal tract of the human body. The contact of the mucosal immune system with the human microbiome is a balanced interplay between defence mechanisms of the immune system and symbiotic or pathogenic

  3. The role of the immune system in kidney disease.

    Science.gov (United States)

    Tecklenborg, J; Clayton, D; Siebert, S; Coley, S M

    2018-05-01

    The immune system and the kidneys are closely linked. In health the kidneys contribute to immune homeostasis, while components of the immune system mediate many acute forms of renal disease and play a central role in progression of chronic kidney disease. A dysregulated immune system can have either direct or indirect renal effects. Direct immune-mediated kidney diseases are usually a consequence of autoantibodies directed against a constituent renal antigen, such as collagen IV in anti-glomerular basement membrane disease. Indirect immune-mediated renal disease often follows systemic autoimmunity with immune complex formation, but can also be due to uncontrolled activation of the complement pathways. Although the range of mechanisms of immune dysregulation leading to renal disease is broad, the pathways leading to injury are similar. Loss of immune homeostasis in renal disease results in perpetual immune cell recruitment and worsening damage to the kidney. Uncoordinated attempts at tissue repair, after immune-mediated disease or non-immune mediated injury, result in fibrosis of structures important for renal function, leading eventually to kidney failure. As renal disease often manifests clinically only when substantial damage has already occurred, new diagnostic methods and indeed treatments must be identified to inhibit further progression and promote appropriate tissue repair. Studying cases in which immune homeostasis is re-established may reveal new treatment possibilities. © 2018 British Society for Immunology.

  4. Role of fluorographic examinations in diagnosis of respiratory system diseases

    International Nuclear Information System (INIS)

    Vil'derman, A.M.; Tsurkan, E.P.; Moskovchuk, A.F.

    1984-01-01

    Materials are considered on the role of fluorography in diagnosis of posttuberculous changes and chromic respiratory system diseases during total epidemiologic examination of 7791 adults from urban and rural population. A scheme is developed that characterize diagnosed pathology of respiratory organs with references to medical establishments rendering medical supervision and forms of supervision. It is shown that fluorograhic examination of the population provide an early diagnosis of both tuberculosis, neoplastic diseases and nonspecific pulmonary diseases that have no visible clinical symptomatology

  5. Preclinical Science Regarding Cannabinoids as Analgesics: An Overview

    Directory of Open Access Journals (Sweden)

    ME Lynch

    2005-01-01

    Full Text Available Modern pharmacology of cannabinoids began in 1964 with the isolation and partial synthesis of delta-9-tetrahydrocannabinol, the main psychoactive agent in herbal cannabis. Since then, potent antinociceptive and antihyperalgesic effects of cannabinoid agonists in animal models of acute and chronic pain; the presence of cannabinoid receptors in pain-processing areas of the brain, spinal cord and periphery; and evidence supporting endogenous modulation of pain systems by cannabinoids has provided support that cannabinoids exhibit significant potential as analgesics. The present article presents an overview of the preclinical science.

  6. [Mental disorders in digestive system diseases - internist's and psychiatrist's insight].

    Science.gov (United States)

    Kukla, Urszula; Łabuzek, Krzysztof; Chronowska, Justyna; Krzystanek, Marek; Okopień, BogusŁaw

    2015-05-01

    Mental disorders accompanying digestive system diseases constitute interdisciplinary yet scarcely acknowledged both diagnostic and therapeutic problem. One of the mostly recognized examples is coeliac disease where patients endure the large spectrum of psychopathological symptoms, starting with attention deficit all the way down to the intellectual disability in extreme cases. It has not been fully explained how the pathomechanism of digestive system diseases affects patient's mental health, however one of the hypothesis suggests that it is due to serotonergic or opioid neurotransmission imbalance caused by gluten and gluten metabolites effect on central nervous system. Behavioral changes can also be invoked by liver or pancreatic diseases, which causes life-threatening abnormalities within a brain. It occurs that these abnormalities reflexively exacerbate the symptoms of primary somatic disease and aggravate its course, which worsens prognosis. The dominant mental disease mentioned in this article is depression which because of its effect on a hypothalamuspituitary- adrenal axis and on an autonomic nervous system, not only aggravates the symptoms of inflammatory bowel diseases but may accelerate their onset in genetically predisposed patients. Depression is known to negatively affects patients' ability to function in a society and a quality of their lives. Moreover, as far as children are concerned, the occurrence of digestive system diseases accompanied by mental disorders, may adversely affect their further physical and psychological development, which merely results in worse school performance. All those aspects of mental disorders indicate the desirability of the psychological care for patients with recognized digestive system disease. The psychological assistance should be provided immediately after diagnosis of a primary disease and be continued throughout the whole course of treatment. © 2015 MEDPRESS.

  7. Absence of high-affinity calreticulin autoantibodies in patients with systemic rheumatic diseases and coeliac disease

    DEFF Research Database (Denmark)

    Jørgensen, C S; Hansen, K B; Jacobsen, Søren

    2005-01-01

    Calreticulin has been reported to be an autoantigen in various autoimmune connective tissue diseases and in coeliac disease. Previous studies have used incubation buffers with low salt and low detergent concentrations (low stringency conditions) with serum albumin or other proteins as a blocking...... binding (high stringency conditions). Using the high stringency conditions, we screened sera from 107 patients with systemic lupus erythematosus, sera from patients with other systemic autoimmune diseases and from children with coeliac disease for the presence of high-affinity calreticulin autoantibodies...... by immunoblotting and ELISA. None of the sera contained high-affinity calreticulin antibodies. It is concluded that calreticulin is not a common autoantigen in patients with autoimmune connective tissue diseases or coeliac disease....

  8. Forest Insect and Disease Tally System (FINDIT) user manual

    Science.gov (United States)

    Barbara J. Bentz

    2000-01-01

    FINDIT, the Forest Insect and Disease Tally System, is an easy-to-use tool for analyzing insect and disease population information taken during stand surveys. Incidence of insects, pathogens, and other biotic and abiotic influences on forest ecosystems are summarized using traditional mensurational measurements. Information is summarized by diameter class, tree species...

  9. Information Supply Chain System for Managing Rare Infectious Diseases

    Science.gov (United States)

    Gopalakrishna-Remani, Venugopal

    2012-01-01

    Timely identification and reporting of rare infectious diseases has important economic, social and health implications. In this study, we investigate how different stakeholders in the existing reporting system influence the timeliness in identification and reporting of rare infectious diseases. Building on the vision of the information supply…

  10. The burden of diverticular disease on patients and healthcare systems.

    Science.gov (United States)

    Reddy, Vikram B; Longo, Walter E

    2013-01-01

    Diverticulitis is a debilitating complication of diverticular disease that affects approximately 2.5 million individuals in the United States. Compared to many other gastrointestinal conditions, diverticular disease is poorly understood in terms of its burden on patients and healthcare systems. This review examines the existing literature and discusses the current knowledge of the burden of diverticular disease. Literature confirmed that bothersome symptoms (such as abdominal pain and bloating) and potentially serious, disease-related complications (such as diverticulitis and diverticular bleeding) place a significant burden on patients. Broad-spectrum antibiotic therapy and surgery are the generally accepted mainstays of treatment for acute complications of diverticular disease. Despite these options, patients frequently experience substantially reduced quality of life (particularly in terms of social and emotional functioning) and increased mortality (predominantly due to disease-related complications) compared to healthy controls. Furthermore, diverticular disease accounted for 254,179 inpatient discharges and 1,493,865 outpatient clinic visits in the United States in 2002, at an estimated cost per hospitalization of $9,742-$11,729. Enhancing the quality of life of patients with diverticular disease and reducing disease exacerbations and complications will substantially benefit patients and healthcare systems. However, long-established treatment algorithms fall short of these therapeutic goals. Research into new treatment options for patients with diverticular disease should therefore be pursued.

  11. Nocturia as a manifestation of systemic disease.

    Science.gov (United States)

    Gulur, Dev Mohan; Mevcha, Amit M; Drake, Marcus J

    2011-03-01

    Nocturia is commonly referred to urologists, but the mechanisms underlying the problem, together with the appropriate clinical assessment and management, may lie outside the ordinary scope of the specialty. Some serious conditions may manifest nocturia as an early feature, often as a consequence of nocturnal polyuria (NP). Voiding frequency is influenced by rate of urine output, reservoir capacity of the bladder, lower urinary tract (LUT) sensation and psychological response. Polyuria can result from polydipsia or endocrine dysfunction. NP can result from endogenous fluid and solute shifts, cardiovascular and autonomic disease, obstructive sleep apnoea, and chronic kidney disease. Nocturia without polyuria occurs in the presence of LUT pathology, pelvic masses and sleep disturbance. Drug intake can contribute to, or counteract, each of these problems. In assessing nocturia, clinicians need to consider an undiagnosed serious condition that may manifest nocturia as an early feature, or suboptimal management of a known condition. The frequency-volume chart is a key tool in categorizing the basis of nocturia, identifying those patients with global polyuria or NP, for whom involvement of other specialties is often necessary for assessment and management. Treatment should be directed at the cause of the problem, with a view to improving long-term health and health-related quality of life. Simple steps should be undertaken by all patients, including improvement of the sleep environment and behaviour modification. Evaluation of treatment response requires objective data to corroborate subjective impressions. Some mechanisms of nocturia do not reliably improve with treatment, leading to refractory symptoms. © 2010 THE AUTHORS. BJU INTERNATIONAL © 2010 BJU INTERNATIONAL.

  12. Progress of radionuclide diagnostic methods in central nervous system diseases

    International Nuclear Information System (INIS)

    Badmaev, K.N.; Zen'kovich, S.G.

    1982-01-01

    A summarry on modern radionuclide diagnosis achivements of central nervous system diseases is presented. Most optimal tumorotropic preparations and compounds in the view of decreasing irradiation does and optimazing image are given

  13. Next generation dengue vaccines: a review of candidates in preclinical development.

    Science.gov (United States)

    Schmitz, Julia; Roehrig, John; Barrett, Alan; Hombach, Joachim

    2011-09-23

    Dengue represents a major public health problem of growing global importance. In the absence of specific dengue therapeutics, strategies for disease control have increasingly focused on the development of dengue vaccines. While a licensed dengue vaccine is not yet available, several vaccine candidates are currently being evaluated in clinical trials and are described in detail in accompanying articles. In addition, there are a large variety of candidates in preclinical development, which are based on diverse technologies, ensuring a continued influx of innovation into the development pipeline. Potentially, some of the current preclinical candidates may become next generation dengue vaccines with superior product profiles. This review provides an overview of the various technological approaches to dengue vaccine development and specifically focuses on candidates in preclinical development. Copyright © 2011 World Health Organization. Published by Elsevier Ltd.. All rights reserved.

  14. Aberrant and alternative splicing in skeletal system disease.

    Science.gov (United States)

    Fan, Xin; Tang, Liling

    2013-10-01

    The main function of skeletal system is to support the body and help movement. A variety of factors can lead to skeletal system disease, including age, exercise, and of course genetic makeup and expression. Pre-mRNA splicing plays a crucial role in gene expression, by creating multiple protein variants with different biological functions. The recent studies show that several skeletal system diseases are related to pre-mRNA splicing. This review focuses on the relationship between pre-mRNA splicing and skeletal system disease. On the one hand, splice site mutation that leads to aberrant splicing often causes genetic skeletal system disease, like COL1A1, SEDL and LRP5. On the other hand, alternative splicing without genomic mutation may generate some marker protein isoforms, for example, FN, VEGF and CD44. Therefore, understanding the relationship between pre-mRNA splicing and skeletal system disease will aid in uncovering the mechanism of disease and contribute to the future development of gene therapy. © 2013 Elsevier B.V. All rights reserved.

  15. Preclinical disability as a risk factor for falls in community-dwelling older adults.

    Science.gov (United States)

    Clough-Gorr, Kerri M; Erpen, Thomas; Gillmann, Gerhard; von Renteln-Kruse, Wolfgang; Iliffe, Steve; Beck, John C; Stuck, Andreas E

    2008-03-01

    Falls are common and serious problems in older adults. The goal of this study was to examine whether preclinical disability predicts incident falls in a European population of community-dwelling older adults. Secondary data analysis was performed on a population-based longitudinal study of 1644 community-dwelling older adults living in London, U.K.; Hamburg, Germany; Solothurn, Switzerland. Data were collected at baseline and 1-year follow-up using a self-administered multidimensional health risk appraisal questionnaire, including validated questions on falls, mobility disability status (high function, preclinical disability, task difficulty), and demographic and health-related characteristics. Associations were evaluated using bivariate and multivariate logistic regression analyses. Overall incidence of falls was 24%, and increased by worsening mobility disability status: high function (17%), preclinical disability (32%), task difficulty (40%), test-of-trend p fall risk factors, preclinical disability (odds ratio [OR] = 1.7, 95% confidence interval [CI], 1.1-2.5), task difficulty (OR = 1.7, 95% CI, 1.1-2.6) and history of falls (OR = 4.7, 95% CI, 3.5-6.3) were the strongest significant predictors of falls. In stratified multivariate analyses, preclinical disability equally predicted falls in participants with (OR = 1.7, 95% CI, 1.0-3.0) and without history of falls (OR = 1.8, 95% CI, 1.1-3.0). This study provides longitudinal evidence that self-reported preclinical disability predicts incident falls at 1-year follow-up independent of other self-reported fall risk factors. Multidimensional geriatric assessment that includes preclinical disability may provide a unique early warning system as well as potential targets for intervention.

  16. [Pregnancy in systemic autoimmune diseases: Myths, certainties and doubts].

    Science.gov (United States)

    Danza, Álvaro; Ruiz-Irastorza, Guillermo; Khamashta, Munther

    2016-10-07

    Systemic autoimmune diseases especially affect young women during childbearing age. The aim of this review is to update systemic lupus erythematosus, antiphospholipid syndrome and systemic sclerosis management during pregnancy. These diseases present variable maternal and fetal risks. Studies show that an appropriate disease control and a reasonable remission period prior to pregnancy are associated with satisfactory obstetric outcomes. Antiphospholipid autoantibodies profile, anti-Ro/anti-La antibodies, pulmonary pressure and activity evaluation are crucial to assess the pregnancy risk. Monitoring requires a multidisciplinary team, serial analytic controls and Doppler ultrasound of maternal and fetal circulation. Evaluation of the activity of the disease is essential. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

  17. An architecture model for multiple disease management information systems.

    Science.gov (United States)

    Chen, Lichin; Yu, Hui-Chu; Li, Hao-Chun; Wang, Yi-Van; Chen, Huang-Jen; Wang, I-Ching; Wang, Chiou-Shiang; Peng, Hui-Yu; Hsu, Yu-Ling; Chen, Chi-Huang; Chuang, Lee-Ming; Lee, Hung-Chang; Chung, Yufang; Lai, Feipei

    2013-04-01

    Disease management is a program which attempts to overcome the fragmentation of healthcare system and improve the quality of care. Many studies have proven the effectiveness of disease management. However, the case managers were spending the majority of time in documentation, coordinating the members of the care team. They need a tool to support them with daily practice and optimizing the inefficient workflow. Several discussions have indicated that information technology plays an important role in the era of disease management. Whereas applications have been developed, it is inefficient to develop information system for each disease management program individually. The aim of this research is to support the work of disease management, reform the inefficient workflow, and propose an architecture model that enhance on the reusability and time saving of information system development. The proposed architecture model had been successfully implemented into two disease management information system, and the result was evaluated through reusability analysis, time consumed analysis, pre- and post-implement workflow analysis, and user questionnaire survey. The reusability of the proposed model was high, less than half of the time was consumed, and the workflow had been improved. The overall user aspect is positive. The supportiveness during daily workflow is high. The system empowers the case managers with better information and leads to better decision making.

  18. Overview of fish immune system and infectious diseases

    Science.gov (United States)

    A brief overview of the fish immune system and the emerging or re-emerging bacterial, viral, parasitic and fungal diseases considered to currently have a negative impact on aquaculture is presented. The fish immune system has evolved with both innate (natural resistance) and adaptive (acquired) immu...

  19. Determination of autoantibodies to annexin XI in systemic autoimmune diseases

    DEFF Research Database (Denmark)

    Jorgensen, C S; Levantino, G; Houen, Gunnar

    2000-01-01

    of 282 sera from patients with systemic rheumatic diseases. The highest number of annexin XI positive sera were found in primary antiphospholipid syndrome (3/17), and in subacute lupus erythematosus (1/6), while lower frequencies of positive sera were found in patients with systemic sclerosis (5...

  20. The use and role of predictive systems in disease management

    Science.gov (United States)

    Disease predictive systems are intended to be management aids. With a few exceptions, these systems typically do not have sustained use directly by growers. Rather, their impact is mostly pedagogic and indirect, improving recommendations from farm advisers and shaping management concepts. The degree...

  1. Commentary on Special Issue : CNS Diseases and the Immune System

    NARCIS (Netherlands)

    't Hart, Bert A.; den Dunnen, Wilfred F.

    In an increasing number of central nervous system (CNS) diseases a pathogenic contribution of the immune system is proposed. However, the exact underlying mechanisms are often poorly understood. The collection of articles in this special issue presents a state-of-the-art review of adaptive and

  2. Role of Helicobacter pylori infection in autoimmune systemic rheumatic diseases.

    Science.gov (United States)

    Radić, Mislav

    2014-09-28

    The relationship between infection and autoimmunity has been increasingly defined over the last 20 years. The systemic rheumatic diseases are characterized by dysregulation of the immune system resulting in a loss of tolerance to self-antigen. The exact etiology for the majority of these diseases is unknown; however, a complex combination of host and environmental factors are believed to play a pivotal role. Helicobacter pylori (H. pylori) is one of the most widely studied infectious agents proposed as agents triggering autoimmune response. The persistent presence of H. pylori in the gastric mucosa results in chronic immune system activation with ongoing cytokine signaling, infiltration of gastric mucosa by neutrophils, macrophages, lymphocytes, as well as production of antibodies and effector T-cells. Various mechanisms have been proposed in an attempt to explain the extra-intestinal manifestations of H. pylori infections. These include: molecular mimicry, endothelial cell damage, superantigens and microchimerism. I performed a systematic literature review using the keywords "rheumatoid arthritis", "Sjögren's syndrome", "systemic sclerosis", "systemic lupus erythematosus", "Helicobacter pylori" and "pathogenesis". A systematic literature search was carried out in MEDLINE; EMBASE; Cochrane Library and ACR/EULAR meeting abstracts. In systemic rheumatic diseases H. pylori infection prevalence alone should not be expected to provide sufficient evidence for or against a pathologic role in the disease. In this article I review studies examining the potential involvement of H. pylori infection in autoimmune systemic rheumatic diseases. Further studies of the immunological response to H. pylori and its role in the pathogenesis of systemic rheumatic diseases are warranted.

  3. Integrating Ultrasound Teaching into Preclinical Problem-based Learning

    Directory of Open Access Journals (Sweden)

    Eli Tumba Tshibwabwa

    2016-01-01

    Full Text Available Objectives: The aim is to provide students in the preclinical with ultrasound image interpretation skills. Research question: Are students in smaller groups with access to a combination of lectures and hands-on patient contact most likely to have better ultrasound image interpretation skills, than students in larger groups with only interactive didactic lectures? Methodology: First-year students at the preclinical Program of the College of Medicine, participated in two 2-h introductory interactive ultrasound sessions. The study comprised two cohorts: 2012/2013 students, who were offered large group teaching (LGT sessions (control group, and 2013/2014 students, who received the intervention in small group learning problem-based learning (PBL sessions (experimental group. The overall learning objectives were identical for both groups. The success of the module was evaluated using pre- and post-tests as well as students′ feedback. Results: The students in the experimental group showed significantly higher scores in interpretations of images than those in the control group. The experimental group showed achievement of learning outcomes along with higher levels of satisfaction with the module compared to the latter. Conclusion: Posttest knowledge of the basics of ultrasound improved significantly over the pretest in the experimental group. In addition, students′ overall satisfaction of the ultrasound module was shown to be higher for the PBL compared to the LGT groups. Small groups in an interactive and PBL setting along with opportunities for hands-on practice and simultaneous visualization of findings on a high definition screen should enhance preclinical student learning of the basics of ultrasound. Despite the potential of ultrasound as a clinical, teaching and learning tool for students in the preclinical years, standardized recommendations have yet to be created regarding its integration into the curricula within academic institutions and

  4. Berberine: metabolic and cardiovascular effects in preclinical and clinical trials

    Directory of Open Access Journals (Sweden)

    Arrigo FG Cicero

    2009-09-01

    Full Text Available Arrigo FG Cicero1, Sibel Ertek21Internal Medicine, Aging and Kidney Diseases Department, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy; 2Ufuk University, Medical Faculty, Dr Ridvan Ege Hospital, Department of Endocrinology and Metabolic Diseases, Ankara, TurkeyAbstract: Berberine is a plant alkaloid with numerous biological activities. A large body of preclinical in vitro and in vivo studies support different pharmacological actions of berberine that could be potentially useful in the management of metabolic diseases associated with high cardiovascular disease risk, such as mixed hyperlipidemia, insulin resistance, metabolic syndrome, and type 2 diabetes. Moreover, it seems that berberine also exerts anti-inflammatory and antiproliferative effects that could play a role in the development of atherosclerosis and its clinical consequences. Recently, the metabolic effects of berberine have been demonstrated in humans, opening new perspectives for the use of this molecule in patient therapy. Larger and longer clinical studies need to be carried out to implement the definition of the therapeutic role of berberine in humans.Keywords: berberine, cardiovascular disease, diabetes, cholesterol

  5. Internet-based surveillance systems for monitoring emerging infectious diseases.

    Science.gov (United States)

    Milinovich, Gabriel J; Williams, Gail M; Clements, Archie C A; Hu, Wenbiao

    2014-02-01

    Emerging infectious diseases present a complex challenge to public health officials and governments; these challenges have been compounded by rapidly shifting patterns of human behaviour and globalisation. The increase in emerging infectious diseases has led to calls for new technologies and approaches for detection, tracking, reporting, and response. Internet-based surveillance systems offer a novel and developing means of monitoring conditions of public health concern, including emerging infectious diseases. We review studies that have exploited internet use and search trends to monitor two such diseases: influenza and dengue. Internet-based surveillance systems have good congruence with traditional surveillance approaches. Additionally, internet-based approaches are logistically and economically appealing. However, they do not have the capacity to replace traditional surveillance systems; they should not be viewed as an alternative, but rather an extension. Future research should focus on using data generated through internet-based surveillance and response systems to bolster the capacity of traditional surveillance systems for emerging infectious diseases. Copyright © 2014 Elsevier Ltd. All rights reserved.

  6. Development of a classification system for periodontal diseases and conditions.

    Science.gov (United States)

    Armitage, G C

    2000-01-01

    Classification systems are necessary in order to provide a framework in which to scientifically study the etiology, pathogenesis, and treatment of diseases in an orderly fashion. In addition, such systems give clinicians a way to organize the health care needs of their patients. The last time scientists and clinicians in the field of periodontology and related areas agreed upon a classification system for periodontal diseases was in 1989 at the World Workshop in Clinical Periodontics. Subsequently, a simpler classification was agreed upon at the 1st European Workshop in Periodontology. These classification systems have been widely used by clinicians and research scientists throughout the world. Unfortunately, the 1989 classification had many shortcomings, including: (1) considerable overlap in disease categories, (2) absence of a gingival disease component, (3) inappropriate emphasis on age of onset of disease and rates of progression, and (4) inadequate or unclear classification criteria. The 1993 European classification lacked the detail necessary for adequate characterization of the broad spectrum of periodontal diseases encountered in clinical practice. The need for a revised classification system for periodontal diseases was emphasized during the 1996 World Workshop in Periodontics. In 1997 the American Academy of Periodontology responded to this need and formed a committee to plan and organize an international workshop to revise the classification system for periodontal diseases. The proceedings in this volume are the result of this reclassification effort. The process involved development by the Organizing Committee of an outline for a new classification and identification of individuals to write state-of-the-science reviews for each of the items on the outline. The reviewers were encouraged to depart from the preliminary outline if there were data to support any modifications. On October 30-November 2, 1999, the International Workshop for a Classification

  7. A LabVIEW Platform for Preclinical Imaging Using Digital Subtraction Angiography and Micro-CT

    Directory of Open Access Journals (Sweden)

    Cristian T. Badea

    2013-01-01

    Full Text Available CT and digital subtraction angiography (DSA are ubiquitous in the clinic. Their preclinical equivalents are valuable imaging methods for studying disease models and treatment. We have developed a dual source/detector X-ray imaging system that we have used for both micro-CT and DSA studies in rodents. The control of such a complex imaging system requires substantial software development for which we use the graphical language LabVIEW (National Instruments, Austin, TX, USA. This paper focuses on a LabVIEW platform that we have developed to enable anatomical and functional imaging with micro-CT and DSA. Our LabVIEW applications integrate and control all the elements of our system including a dual source/detector X-ray system, a mechanical ventilator, a physiological monitor, and a power microinjector for the vascular delivery of X-ray contrast agents. Various applications allow cardiac- and respiratory-gated acquisitions for both DSA and micro-CT studies. Our results illustrate the application of DSA for cardiopulmonary studies and vascular imaging of the liver and coronary arteries. We also show how DSA can be used for functional imaging of the kidney. Finally, the power of 4D micro-CT imaging using both prospective and retrospective gating is shown for cardiac imaging.

  8. A LabVIEW Platform for Preclinical Imaging Using Digital Subtraction Angiography and Micro-CT.

    Science.gov (United States)

    Badea, Cristian T; Hedlund, Laurence W; Johnson, G Allan

    2013-01-01

    CT and digital subtraction angiography (DSA) are ubiquitous in the clinic. Their preclinical equivalents are valuable imaging methods for studying disease models and treatment. We have developed a dual source/detector X-ray imaging system that we have used for both micro-CT and DSA studies in rodents. The control of such a complex imaging system requires substantial software development for which we use the graphical language LabVIEW (National Instruments, Austin, TX, USA). This paper focuses on a LabVIEW platform that we have developed to enable anatomical and functional imaging with micro-CT and DSA. Our LabVIEW applications integrate and control all the elements of our system including a dual source/detector X-ray system, a mechanical ventilator, a physiological monitor, and a power microinjector for the vascular delivery of X-ray contrast agents. Various applications allow cardiac- and respiratory-gated acquisitions for both DSA and micro-CT studies. Our results illustrate the application of DSA for cardiopulmonary studies and vascular imaging of the liver and coronary arteries. We also show how DSA can be used for functional imaging of the kidney. Finally, the power of 4D micro-CT imaging using both prospective and retrospective gating is shown for cardiac imaging.

  9. [Ageing and Alzheimer disease - system dynamics model prediction].

    Science.gov (United States)

    Tomášková, Hana; Kühnová, Jitka; Kuča, Kamil

    The aim of the paper is to describe asystem dynamics model applied on aprediction of the number of patients with Alzheimers disease in the EU in the future and related financial impacts. Dementia resulting from Alzheimers disease is the most widely spread type of dementia and is highly connected with the age of the person - the patient. Most people are diagnosed with Alzheimers disease when they are older than 64. The ageing of population will be an ongoing problem in the next few decades due to alow birth rate and increasing life expectancy. This is areason to focus on prediction models of Alzheimers disease and its impact on economy. The paper presents adynamic modelling approach of system dynamics. The created model of the EU population and patients with AD is expanded by afinancial submodel at the end. This submodel estimates the cost on patients from three available cost studies.Key words: systém dynamic Alzhimers disease population ageing.

  10. METHODOLOGICAL APPROACHES TO EXPERT EVALUATION OF PRECLINICAL AND CLINICAL TRIALS OF HUMAN IMMUNOGLOBULIN PRODUCTS

    Directory of Open Access Journals (Sweden)

    V. B. Ivanov

    2017-01-01

    Full Text Available The article considers the experience of Russian and leading foreign regulatory agencies in organisation and conduction of preclinical and clinical trials of human immunoglobulin products. The authors suggest a classification of human immunoglobulins and provide updated information on authorization of these products in Russia. The article summarizes methodological approaches, basic scientific principles and criteria relating to expert evaluation of preclinical and clinical trials of blood products. The authors further define the expert body’s requirements for data on preclinical and clinical trials of human normal immuniglobulins and human specific immunoglobulins for the prevention and/or treatment of infectious and non-infectious diseases which are submitted as part of applications for marketing authorization or marketing authorization variation. The article suggests programs of preclinical and clinical trials for human normal immunoglobulins and human specific immunoglobulins for the prevention and/or treatment of infectious and non-infectious diseases that are aligned with the Russian legislation and Eurasian Economic Union’s regulations on medicines circulation, and have been elaborated with respect to the guidelines of the European Medicines Agency.

  11. An advanced preclinical mouse model for acute myeloid leukemia using patients' cells of various genetic subgroups and in vivo bioluminescence imaging.

    Directory of Open Access Journals (Sweden)

    Binje Vick

    Full Text Available Acute myeloid leukemia (AML is a clinically and molecularly heterogeneous disease with poor outcome. Adequate model systems are required for preclinical studies to improve understanding of AML biology and to develop novel, rational treatment approaches. Xenografts in immunodeficient mice allow performing functional studies on patient-derived AML cells. We have established an improved model system that integrates serial retransplantation of patient-derived xenograft (PDX cells in mice, genetic manipulation by lentiviral transduction, and essential quality controls by immunophenotyping and targeted resequencing of driver genes. 17/29 samples showed primary engraftment, 10/17 samples could be retransplanted and some of them allowed virtually indefinite serial transplantation. 5/6 samples were successfully transduced using lentiviruses. Neither serial transplantation nor genetic engineering markedly altered sample characteristics analyzed. Transgene expression was stable in PDX AML cells. Example given, recombinant luciferase enabled bioluminescence in vivo imaging and highly sensitive and reliable disease monitoring; imaging visualized minimal disease at 1 PDX cell in 10000 mouse bone marrow cells and facilitated quantifying leukemia initiating cells. We conclude that serial expansion, genetic engineering and imaging represent valuable tools to improve the individualized xenograft mouse model of AML. Prospectively, these advancements enable repetitive, clinically relevant studies on AML biology and preclinical treatment trials on genetically defined and heterogeneous subgroups.

  12. Preclinical imaging and translational animal models of cancer for accelerated clinical implementation of nanotechnologies and macromolecular agents.

    Science.gov (United States)

    De Souza, Raquel; Spence, Tara; Huang, Huang; Allen, Christine

    2015-12-10

    The majority of animal models of cancer have performed poorly in terms of predicting clinical performance of new therapeutics, which are most often first evaluated in patients with advanced, metastatic disease. The development and use of metastatic models of cancer may enhance clinical translatability of preclinical studies focused on the development of nanotechnology-based drug delivery systems and macromolecular therapeutics, potentially accelerating their clinical implementation. It is recognized that the development and use of such models are not without challenge. Preclinical imaging tools offer a solution by allowing temporal and spatial characterization of metastatic lesions. This paper provides a review of imaging methods applicable for evaluation of novel therapeutics in clinically relevant models of advanced cancer. An overview of currently utilized models of oncology in small animals is followed by image-based development and characterization of visceral metastatic cancer models. Examples of imaging tools employed for metastatic lesion detection, evaluation of anti-tumor and anti-metastatic potential and biodistribution of novel therapies, as well as the co-development and/or use of imageable surrogates of response, are also discussed. While the focus is on development of macromolecular and nanotechnology-based therapeutics, examples with small molecules are included in some cases to illustrate concepts and approaches that can be applied in the assessment of nanotechnologies or macromolecules. Copyright © 2015 Elsevier B.V. All rights reserved.

  13. [Evaluation on application of China Disease Prevention and Control Information System of Hydatid Disease II System integration and simulation tests].

    Science.gov (United States)

    Qing, Yu; Shuai, Han; Qiang, Wang; Jing-Bo, Xue

    2017-06-08

    To report the integrated progress of the hydatid disease information management system, and to provide the reference for further system improvements by analysis of results on simulation test feedback. The work of institutional code matching by collecting fundamental and integrated information of the system in epidemic areas of hydatid disease was carried out, and professional control agencies were selected to carry out the simulation test. The results of agencies code matching at stage indicated the average completion rate was 94.30% on administrative agencies, 69.94% on registered professional agencies and 56.40% on professional institutions matching related to hydatid disease prevention and control implements in seven provinces (autonomous regions) and Xinjiang Production and Construction Corps. Meanwhile, the response rate of open-ended proposals was 93.33% on fifteen feedbacks, and the statistics showed 21.43% believed the system was low fluency, 64.29% considered the system was inconvenience for data inputs and 42.86% considered it would be improved on system statistics functions, of which 27.78% were provincial users, 22.22% were the city users and 50.00% were the county users. The hydatid disease prevention information management system meets the fundamental needs of the majority agencies in hyperendemic areas of echinococcosis, it needs to develop the further test with more agencies joining after the work of the institutional code matching completion and the system service improvement in the next stage.

  14. Magnetic particle imaging: from proof of principle to preclinical applications

    Science.gov (United States)

    Knopp, T.; Gdaniec, N.; Möddel, M.

    2017-07-01

    Tomographic imaging has become a mandatory tool for the diagnosis of a majority of diseases in clinical routine. Since each method has its pros and cons, a variety of them is regularly used in clinics to satisfy all application needs. Magnetic particle imaging (MPI) is a relatively new tomographic imaging technique that images magnetic nanoparticles with a high spatiotemporal resolution in a quantitative way, and in turn is highly suited for vascular and targeted imaging. MPI was introduced in 2005 and now enters the preclinical research phase, where medical researchers get access to this new technology and exploit its potential under physiological conditions. Within this paper, we review the development of MPI since its introduction in 2005. Besides an in-depth description of the basic principles, we provide detailed discussions on imaging sequences, reconstruction algorithms, scanner instrumentation and potential medical applications.

  15. Respiratory system anatomy, physiology, and disease: Guinea pigs and chinchillas.

    Science.gov (United States)

    Yarto-Jaramillo, Enrique

    2011-05-01

    Respiratory diseases are common in guinea pigs and chinchillas. There are multifactorial causes of respiratory involvement in these species of rodents, from infectious (bacterial, viral, and fungal) to neoplastic causes. Toxicoses and diseases affecting other systems may also induce respiratory signs. Knowledge of biology, including husbandry, nutritional requirements, and behavior, are important clues for the clinician to determine the role these issues may play in the development, progression, and prognosis of respiratory clinical cases in rodents. Current approaches in the diagnosis and therapy for respiratory disease in small mammals warrant more research concerning response-to-treatment reports. Copyright © 2011 Elsevier Inc. All rights reserved.

  16. For better or worse: Immune system involvement in Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Emma L. Walton

    2018-02-01

    Full Text Available In this issue of the Biomedical Journal, we explore the key role of the immune system in the development of Alzheimer's disease. We also learn more about the link between two disorders related to metabolic imbalances, with findings that could help to inform future screening programs. Finally, we would like to highlight some big news for our journal: the Biomedical Journal will be indexed in the Science Citation Index and receive its first official impact factor from this year. Keywords: Alzheimer's disease, Tau, Immune responses, Subclinical hypothyroidism, Metabolic disease

  17. Management of cardiovascular diseases with micro systems and nanotechnology.

    Science.gov (United States)

    Kong, L X; Peng, Z; Sugumar, D

    2006-01-01

    Cardiovascular diseases are the leading cause of death and morbidity in industrialized nations and are becoming an urgent health problem for all nations due to the unstoppable trend of an ageing and obese population. Due to the rapid development of micro total analysis systems (microTAS) and nanotechnology in recent years, they will play an important role in the diagnosis, management, and therapy of cardiovascular diseases. It is envisaged that the micro and nanotechnologies developed for treating other diseases shall be explored for cardiovascular applications to reduce the research effort required for commercializing the devices and drugs to meet the increasing demand of the cardiovascular patients.

  18. [An evaluation of the surveillance system of mandatory disease reporting].

    Science.gov (United States)

    Peñuelas Ruiz, J A; Manrique Blázquez, R R; Diestro Contreras, A; Pastor Ortega, M C; Leal Fernández, A

    1998-06-30

    Study of the exhaustibility and reliability of the recording of obligatory notifiable diseases (EDO) and the accumulated incidence of the EDO in a health area. Descriptive study. Community setting. Epidemiological surveillance. People who have suffered in 1996 some EDO (excluded measles, rubella, mumps, chickenpox and influenza). They have been selected a total of 205 EDO-disease cases starting from the two recording systems: laboratory and obligatory surveillance diseases system. The exhaustibility of the laboratory has been 82%, 95% confidence interval (76-87%) and that of the EDO system 45%, 95% confidence interval (38-52%). The rate kappa for the diseases global is 0.42 95%, confidence interval (0.4-0.43) and the specific accordance proportion 0.27, 95% confidence interval (0.21-0.34). The cases search in the recording of the laboratory increases the incidence declared to the EDO system in all the diseases. The diseases with greater incidence are the hepatitis (73.59 x 10(5)), the pulmonary tuberculosis (27.07 x 10(5)) and the syphilis (18.05 x 10(5)). The EDO system presents a clear understatement, variable according to the different diseases and being maximum for the hepatitis B and C. The laboratory quantifies a high exhaustibility, and it can increase between 55 and 30% the EDO recording cases, increasing the knowledge of the morbidity caused by EDO in the Area 11. The valuation of the EDO in addition to improving the information for the assumptions of decisions in sanitary planning, optimizes the necessary elements when it is compared the EDO incidence among different geographical areas or within a same area at a different time.

  19. Comparing national infectious disease surveillance systems: China and the Netherlands.

    Science.gov (United States)

    Vlieg, Willemijn L; Fanoy, Ewout B; van Asten, Liselotte; Liu, Xiaobo; Yang, Jun; Pilot, Eva; Bijkerk, Paul; van der Hoek, Wim; Krafft, Thomas; van der Sande, Marianne A; Liu, Qi-Yong

    2017-05-08

    Risk assessment and early warning (RAEW) are essential components of any infectious disease surveillance system. In light of the International Health Regulations (IHR)(2005), this study compares the organisation of RAEW in China and the Netherlands. The respective approaches towards surveillance of arboviral disease and unexplained pneumonia were analysed to gain a better understanding of the RAEW mode of operation. This study may be used to explore options for further strengthening of global collaboration and timely detection and surveillance of infectious disease outbreaks. A qualitative study design was used, combining data retrieved from the literature and from semi-structured interviews with Chinese (5 national-level and 6 provincial-level) and Dutch (5 national-level) experts. The results show that some differences exist such as in the use of automated electronic components of the early warning system in China ('CIDARS'), compared to a more limited automated component in the Netherlands ('barometer'). Moreover, RAEW units in the Netherlands focus exclusively on infectious diseases, while China has a broader 'all hazard' approach (including for example chemical incidents). In the Netherlands, veterinary specialists take part at the RAEW meetings, to enable a structured exchange/assessment of zoonotic signals. Despite these differences, the main conclusion is that for the two infections studied, the early warning system in China and the Netherlands are remarkably similar considering their large differences in infectious disease history, population size and geographical setting. Our main recommendations are continued emphasis on international corporation that requires insight into national infectious disease surveillance systems, the usage of a One Health approach in infectious disease surveillance, and further exploration/strengthening of a combined syndromic and laboratory surveillance system.

  20. Effect of biodiversity changes in disease risk: exploring disease emergence in a plant-virus system.

    Directory of Open Access Journals (Sweden)

    Israel Pagán

    Full Text Available The effect of biodiversity on the ability of parasites to infect their host and cause disease (i.e. disease risk is a major question in pathology, which is central to understand the emergence of infectious diseases, and to develop strategies for their management. Two hypotheses, which can be considered as extremes of a continuum, relate biodiversity to disease risk: One states that biodiversity is positively correlated with disease risk (Amplification Effect, and the second predicts a negative correlation between biodiversity and disease risk (Dilution Effect. Which of them applies better to different host-parasite systems is still a source of debate, due to limited experimental or empirical data. This is especially the case for viral diseases of plants. To address this subject, we have monitored for three years the prevalence of several viruses, and virus-associated symptoms, in populations of wild pepper (chiltepin under different levels of human management. For each population, we also measured the habitat species diversity, host plant genetic diversity and host plant density. Results indicate that disease and infection risk increased with the level of human management, which was associated with decreased species diversity and host genetic diversity, and with increased host plant density. Importantly, species diversity of the habitat was the primary predictor of disease risk for wild chiltepin populations. This changed in managed populations where host genetic diversity was the primary predictor. Host density was generally a poorer predictor of disease and infection risk. These results support the dilution effect hypothesis, and underline the relevance of different ecological factors in determining disease/infection risk in host plant populations under different levels of anthropic influence. These results are relevant for managing plant diseases and for establishing conservation policies for endangered plant species.

  1. A heart disease recognition embedded system with fuzzy cluster algorithm.

    Science.gov (United States)

    de Carvalho, Helton Hugo; Moreno, Robson Luiz; Pimenta, Tales Cleber; Crepaldi, Paulo C; Cintra, Evaldo

    2013-06-01

    This article presents the viability analysis and the development of heart disease identification embedded system. It offers a time reduction on electrocardiogram - ECG signal processing by reducing the amount of data samples, without any significant loss. The goal of the developed system is the analysis of heart signals. The ECG signals are applied into the system that performs an initial filtering, and then uses a Gustafson-Kessel fuzzy clustering algorithm for the signal classification and correlation. The classification indicated common heart diseases such as angina, myocardial infarction and coronary artery diseases. The system uses the European electrocardiogram ST-T Database (EDB) as a reference for tests and evaluation. The results prove the system can perform the heart disease detection on a data set reduced from 213 to just 20 samples, thus providing a reduction to just 9.4% of the original set, while maintaining the same effectiveness. This system is validated in a Xilinx Spartan(®)-3A FPGA. The field programmable gate array (FPGA) implemented a Xilinx Microblaze(®) Soft-Core Processor running at a 50MHz clock rate. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

  2. The CDD system in computed tomographic diagnosis of diverticular disease

    International Nuclear Information System (INIS)

    Pustelnik, Daniel; Elsholtz, Fabian Henry Juergen; Hamm, Bernd; Niehues, Stefan Markus; Bojarski, Christian

    2017-01-01

    Purpose cation in computed tomographic diagnosis and briefly recapitulates its targeted advantages over preliminary systems. Primarily, application of the CDD in computed tomography diagnostics is described. Differences with respect to the categories of the older systems are pointed out on the level of each CDD type using imaging examples. The presented images are derived from our institute according to the S2k criteria. Literature was researched on PubMed. Results The CDD constitutes an improvement compared to older systems for categorizing the stages of diverticular disease. It provides more discriminatory power on the descriptive-morphological level and defines as well as differentiates more courses of the disease. Furthermore, the categories translate more directly into state-of-the-art decision-making concerning hospitalization and therapy. The CDD should be applied routinely in the computed tomographic diagnosis of diverticular disease. Typical imaging patterns are presented.

  3. Applications of systems approaches in the study of rheumatic diseases.

    Science.gov (United States)

    Kim, Ki-Jo; Lee, Saseong; Kim, Wan-Uk

    2015-03-01

    The complex interaction of molecules within a biological system constitutes a functional module. These modules are then acted upon by both internal and external factors, such as genetic and environmental stresses, which under certain conditions can manifest as complex disease phenotypes. Recent advances in high-throughput biological analyses, in combination with improved computational methods for data enrichment, functional annotation, and network visualization, have enabled a much deeper understanding of the mechanisms underlying important biological processes by identifying functional modules that are temporally and spatially perturbed in the context of disease development. Systems biology approaches such as these have produced compelling observations that would be impossible to replicate using classical methodologies, with greater insights expected as both the technology and methods improve in the coming years. Here, we examine the use of systems biology and network analysis in the study of a wide range of rheumatic diseases to better understand the underlying molecular and clinical features.

  4. Implementation of compressive sensing for preclinical cine-MRI

    Science.gov (United States)

    Tan, Elliot; Yang, Ming; Ma, Lixin; Zheng, Yahong Rosa

    2014-03-01

    This paper presents a practical implementation of Compressive Sensing (CS) for a preclinical MRI machine to acquire randomly undersampled k-space data in cardiac function imaging applications. First, random undersampling masks were generated based on Gaussian, Cauchy, wrapped Cauchy and von Mises probability distribution functions by the inverse transform method. The best masks for undersampling ratios of 0.3, 0.4 and 0.5 were chosen for animal experimentation, and were programmed into a Bruker Avance III BioSpec 7.0T MRI system through method programming in ParaVision. Three undersampled mouse heart datasets were obtained using a fast low angle shot (FLASH) sequence, along with a control undersampled phantom dataset. ECG and respiratory gating was used to obtain high quality images. After CS reconstructions were applied to all acquired data, resulting images were quantitatively analyzed using the performance metrics of reconstruction error and Structural Similarity Index (SSIM). The comparative analysis indicated that CS reconstructed images from MRI machine undersampled data were indeed comparable to CS reconstructed images from retrospective undersampled data, and that CS techniques are practical in a preclinical setting. The implementation achieved 2 to 4 times acceleration for image acquisition and satisfactory quality of image reconstruction.

  5. [Preclinical and intrahospital management of mass casualties and terrorist incidents].

    Science.gov (United States)

    Franke, A; Bieler, D; Friemert, B; Kollig, E; Flohe, S

    2017-10-01

    Due to the recent terrorist attacks in Paris, Brussels, Ansbach, Munich, Berlin and more recently Manchester and London, terrorism is realized as a present threat to our society and social life, as well as a challenge for the health care system. Without fueling anxiety, there is a need for sensitization to this subject and to familiarize all concerned with the special kind of terrorist attack-related injuries, the operational priorities and tactics and the individual basic principles of preclinical and hospital care. There is a need to adapt the known established medical structure for a conventional mass casualty situation to the special requirements that are raised by this new kind of terrorist threat to our social life. It is the aim of this article, from a surgical point of view, to depict the tactics and challenges of preclinical care of the special kind of terrorist attack-related injuries from the site of the incident, via the advanced medical post or casualty collecting point, to the triage point at the hospital. The special needs of medical care and organizational aspects of the primary treatment in the hospital are highlighted and possible decisional options and different approaches are discussed.

  6. Preclinical MRI experience in imaging angiogenesis.

    Science.gov (United States)

    Neeman, M

    2000-01-01

    Magnetic resonance imaging (MRI) provides a range of non-invasive measures for visualization of tumor angiogenesis in the clinic as well as in experimental tumor models. MRI methods were developed for assessment of spatial and temporal changes in perfusion, blood volume fraction, vascular permeability, vascular function, vascular maturation, vessel diameter and tortuosity. Molecular targeted contrast agents were used for mapping specific markers of neovasculature. These approaches were applied for analysis of a number of regulatory mechanisms controlling tumor angiogenesis and for preclinical evaluation of tumor response to antiangiogenic agents.

  7. Recent Developments in Preclinical DNA Vaccination

    Directory of Open Access Journals (Sweden)

    Kenji Okuda

    2014-01-01

    Full Text Available The advantages of genetic immunization of the new vaccine using plasmid DNAs are multifold. For example, it is easy to generate plasmid DNAs, increase their dose during the manufacturing process, and sterilize them. Furthermore, they can be stored for a long period of time upon stabilization, and their protein encoding sequences can be easily modified by employing various DNA-manipulation techniques. Although DNA vaccinations strongly increase Th1-mediated immune responses in animals, several problems persist. One is about their weak immunogenicity in humans. To overcome this problem, various genetic adjuvants, electroporation, and prime-boost methods have been developed preclinically, which are reviewed here.

  8. An intelligent medical system for diagnosis of bone diseases

    International Nuclear Information System (INIS)

    Hatzilygeroudis, I.; Vassilakos, P.J.; Tsakalidis, A.

    1994-01-01

    In this paper, aspects of the design of an intelligent medical system for diagnosis of bone diseases that can be detected by scintigraphic images are presented. The system comprises three major parts: a user interface (UI), a database management system (DBMS), and an expert system (ES). The DBMS is used for manipulation of various patient data. A number of patient cases are selected as prototype and stored in separate database. Diagnosis is performed via the ES, called XBONE, based on patient data. Knowledge is represented via an integrated formalism that combines production rules and a neural network. This results in better representation, and facilitates knowledge acquisition and maintenance. (authors)

  9. Manufacture of Third-Generation Lentivirus for Preclinical Use, with Process Development Considerations for Translation to Good Manufacturing Practice.

    Science.gov (United States)

    Gándara, Carolina; Affleck, Valerie; Stoll, Elizabeth Ann

    2018-02-01

    Lentiviral vectors are used in laboratories around the world for in vivo and ex vivo delivery of gene therapies, and increasingly clinical investigation as well as preclinical applications. The third-generation lentiviral vector system has many advantages, including high packaging capacity, stable gene expression in both dividing and post-mitotic cells, and low immunogenicity in the recipient organism. Yet, the manufacture of these vectors is challenging, especially at high titers required for direct use in vivo, and further challenges are presented by the process of translating preclinical gene therapies toward manufacture of products for clinical investigation. The goals of this paper are to report the protocol for manufacturing high-titer third-generation lentivirus for preclinical testing and to provide detailed information on considerations for translating preclinical viral vector manufacture toward scaled-up platforms and processes in order to make gene therapies under Good Manufacturing Practice that are suitable for clinical trials.

  10. Parkinson's disease Assessment using Fuzzy Expert System and Nonlinear Dynamics

    Directory of Open Access Journals (Sweden)

    GEMAN, O.

    2013-02-01

    Full Text Available This paper proposes a new screening system for quantitative evaluation and analysis, designed for the early stage detection of Parkinson disease. This has been carried out in the view of improving the diagnosis currently established upon a basis of subjective scores. Parkinson?s disease (PD appears as a result of dopamine loss, a chemical mediator that is responsible for the body?s ability to control movements. The symptoms reflect the loss of nerve cells, due to an unknown. The input parameters of the system are represented by amplitude, frequency, the spectral characteristic and trembling localization. The main symptoms include trembling of hand, arms, movement difficulties, postural instability, disturbance of coordination and equilibrium, sleep disturbance, difficulties in speaking, reducing of voice volume. The medical knowledge in PD field is characterized by imprecision, uncertainty and vagueness. The proposed system (fuzzy expert systems is non-invasive and, easy to use by both physicians and patients at home.

  11. An amalgam tattoo causing local and systemic disease?

    Science.gov (United States)

    Weaver, T; Auclair, P L; Taybos, G M

    1987-01-01

    Amalgam tattoos are common oral lesions. The case presented here involved a 33-year-old woman who had had an amalgam tattoo for 2 years and complained of localized soreness and occasional swelling as well as systemic symptoms of weight loss, fatigue, sinusitis, and headaches. After excisional biopsy of the lesion, the patient's complaints ceased dramatically. It is suggested that alterations in healing due to the presence of amalgam particles led to systemic as well as local disease.

  12. Microculture system for detection of Newcastle disease virus antibodies.

    Science.gov (United States)

    Wooley, R E; Brown, J; Gratzek, J B; Kleven, S H; Scott, T A

    1974-05-01

    A microculture system utilizing cytopathic effect (CPE) and hemadsorption (HAd) end points was effective in determining the level of Newcastle disease virus (NDV) antibodies. The microculture system was of comparable sensitivity to the plaque reduction test for the detection of NDV antibodies. The standards by which the CPE and HAd microculture tests would be considered reproducible were defined. The results indicate that the CPE and HAd microculture tests are reproducible within one twofold dilution.

  13. Modelling the impacts of pests and diseases on agricultural systems.

    Science.gov (United States)

    Donatelli, M; Magarey, R D; Bregaglio, S; Willocquet, L; Whish, J P M; Savary, S

    2017-07-01

    The improvement and application of pest and disease models to analyse and predict yield losses including those due to climate change is still a challenge for the scientific community. Applied modelling of crop diseases and pests has mostly targeted the development of support capabilities to schedule scouting or pesticide applications. There is a need for research to both broaden the scope and evaluate the capabilities of pest and disease models. Key research questions not only involve the assessment of the potential effects of climate change on known pathosystems, but also on new pathogens which could alter the (still incompletely documented) impacts of pests and diseases on agricultural systems. Yield loss data collected in various current environments may no longer represent a adequate reference to develop tactical, decision-oriented, models for plant diseases and pests and their impacts, because of the ongoing changes in climate patterns. Process-based agricultural simulation modelling, on the other hand, appears to represent a viable methodology to estimate the impacts of these potential effects. A new generation of tools based on state-of-the-art knowledge and technologies is needed to allow systems analysis including key processes and their dynamics over appropriate suitable range of environmental variables. This paper offers a brief overview of the current state of development in coupling pest and disease models to crop models, and discusses technical and scientific challenges. We propose a five-stage roadmap to improve the simulation of the impacts caused by plant diseases and pests; i) improve the quality and availability of data for model inputs; ii) improve the quality and availability of data for model evaluation; iii) improve the integration with crop models; iv) improve the processes for model evaluation; and v) develop a community of plant pest and disease modelers.

  14. Evaluation of the integrated disease surveillance and response system for infectious diseases control in northern Ghana.

    Science.gov (United States)

    Adokiya, Martin Nyaaba; Awoonor-Williams, John Koku; Barau, Inuwa Yau; Beiersmann, Claudia; Mueller, Olaf

    2015-02-04

    Well-functioning surveillance systems are crucial for effective disease control programs. The Integrated Disease Surveillance and Response (IDSR) strategy was developed and adopted in 1998 for Africa as a comprehensive public health approach and subsequently, Ghana adopted the IDSR technical guidelines in 2002. Since 2012, the IDSR data is reported through the new District Health Information Management System II (DHIMS2) network. The objective was to evaluate the Integrated Disease Surveillance and Response (IDSR) system in northern Ghana. This was an observational study using mixed methods. Weekly and monthly IDSR data on selected infectious diseases were downloaded and analyzed for 2011, 2012 and 2013 (the years before, of and after DHIMS2 implementation) from the DHIMS2 databank for the Upper East Region (UER) and for two districts of UER. In addition, key informant interviews were conducted among local and regional health officers on the functioning of the IDSR. Clinically diagnosed malaria was the most prevalent disease in UER, with an annual incidence rate close to 1. Around 500 suspected HIV/AIDS cases were reported each year. The highest incidence of cholera and meningitis was reported in 2012 (257 and 392 cases respectively). Three suspected cases of polio and one suspected case of guinea worm were reported in 2013. None of the polio and guinea worm cases and only a fraction of the reported cases of the other diseases were confirmed. A major observation was the large and inconclusive difference in reported cases when comparing weekly and monthly reports. This can be explained by the different reporting practice for the sub-systems. Other challenges were low priority for surveillance, ill-equipped laboratories, rare supervision and missing feedback. The DHIMS2 has improved the availability of IDSR reports, but the quality of data reported is not sufficient. Particularly the inconsistencies between weekly and monthly data need to be addressed. Moreover

  15. Human Threat Management Systems: Self-Protection and Disease Avoidance

    Science.gov (United States)

    Neuberg, Steven L.; Kenrick, Douglas T.; Schaller, Mark

    2010-01-01

    Humans likely evolved precautionary systems designed to minimize the threats to reproductive fitness posed by highly interdependent ultrasociality. A review of research on the self-protection and disease avoidance systems reveals that each system is functionally distinct and domain-specific: Each is attuned to different cues; engages different emotions, inferences, and behavioral inclinations; and is rooted in somewhat different neurobiological substrates. These systems share important features, however. Each system is functionally coherent, in that perceptual, affective, cognitive, and behavioral processes work in concert to reduce fitness costs of potential threats. Each system is biased in a risk-averse manner, erring toward precautionary responses even when available cues only heuristically imply threat. And each system is functionally flexible, being highly sensitive to specific ecological and dispositional cues that signal greater vulnerability to the relevant threat. These features characterize a general template useful for understanding not only the self-protection and disease avoidance systems, but also a broader set of evolved, domain-specific precautionary systems. PMID:20833199

  16. Disease scoring systems for oral lichen planus; a critical appraisal

    NARCIS (Netherlands)

    Wang, J.; van der Waal, I.

    2015-01-01

    The aim of the present study has been to critically review 22 disease scoring systems (DSSs) on oral lichen planus (OLP) that have been reported in the literature during the past decades. Although the presently available DSSs may all have some merit, particularly for research purposes, the diversity

  17. COPD is a systemic disease – the ex trapulmonary manifestations ...

    African Journals Online (AJOL)

    COPD is a systemic disease – the ex trapulmonary manifestations. C Smith. Abstract. No Abstract. Full Text: EMAIL FREE FULL TEXT EMAIL FREE FULL TEXT · DOWNLOAD FULL TEXT DOWNLOAD FULL TEXT · AJOL African Journals Online. HOW TO USE AJOL... for Researchers · for Librarians · for Authors · FAQ's ...

  18. Systems medicine and integrated care to combat chronic noncommunicable diseases

    NARCIS (Netherlands)

    Bousquet, Jean; Anto, Josep M.; Sterk, Peter J.; Adcock, Ian M.; Chung, Kian Fan; Roca, Josep; Agusti, Alvar; Brightling, Chris; Cambon-Thomsen, Anne; Cesario, Alfredo; Abdelhak, Sonia; Antonarakis, Stylianos E.; Avignon, Antoine; Ballabio, Andrea; Baraldi, Eugenio; Baranov, Alexander; Bieber, Thomas; Bockaert, Joël; Brahmachari, Samir; Brambilla, Christian; Bringer, Jacques; Dauzat, Michel; Ernberg, Ingemar; Fabbri, Leonardo; Froguel, Philippe; Galas, David; Gojobori, Takashi; Hunter, Peter; Jorgensen, Christian; Kauffmann, Francine; Kourilsky, Philippe; Kowalski, Marek L.; Lancet, Doron; Pen, Claude Le; Mallet, Jacques; Mayosi, Bongani; Mercier, Jacques; Metspalu, Andres; Nadeau, Joseph H.; Ninot, Grégory; Noble, Denis; Oztürk, Mehmet; Palkonen, Susanna; Préfaut, Christian; Rabe, Klaus; Renard, Eric; Roberts, Richard G.; Samolinski, Boleslav; Schünemann, Holger J.; Simon, Hans-Uwe; Soares, Marcelo Bento; Superti-Furga, Giulio; Tegner, Jesper; Verjovski-Almeida, Sergio; Wellstead, Peter; Wolkenhauer, Olaf; Wouters, Emiel; Balling, Rudi; Brookes, Anthony J.; Charron, Dominique; Pison, Christophe; Chen, Zhu; Hood, Leroy; Auffray, Charles

    2011-01-01

    ABSTRACT: We propose an innovative, integrated, cost-effective health system to combat major non-communicable diseases (NCDs), including cardiovascular, chronic respiratory, metabolic, rheumatologic and neurologic disorders and cancers, which together are the predominant health problem of the 21st

  19. SECONDARY PULMONARY ARTERIAL HYPERTENSION IN SYSTEMIC DISEASES OF CONNECTIVE TISSUE

    Directory of Open Access Journals (Sweden)

    N. A. Shostak

    2016-01-01

    Full Text Available Modern definition of pulmonary arterial hypertension (PAH as well as data on prevalence and incidence of secondary PAH in systemic disease of connective tissue is presented,  including data of USA, France and Scotland registers. The main chains of pathogenesis, classification approaches, clinical features and diagnostics are described. 

  20. SECONDARY PULMONARY ARTERIAL HYPERTENSION IN SYSTEMIC DISEASES OF CONNECTIVE TISSUE

    Directory of Open Access Journals (Sweden)

    N. A. Shostak

    2009-01-01

    Full Text Available Modern definition of pulmonary arterial hypertension (PAH as well as data on prevalence and incidence of secondary PAH in systemic disease of connective tissue is presented,  including data of USA, France and Scotland registers. The main chains of pathogenesis, classification approaches, clinical features and diagnostics are described. 

  1. Prostate cancer: correlation between local and systemic disease.

    Science.gov (United States)

    Marzi, M; Rosi, P; Mearini, E; Bracarda, S; Cesaroni, S; Porena, M

    1999-12-01

    Prostate cancer is in Italian men the second neoplasm for incidence. Transrectal ultrasonography (TRUS) is still today a cheap test, not very invasive, well accepted by the motivated patient and sufficiently accurate for the valuation of the local status disease. We proposed our data to verify if a careful local ultrasonographic study of prostatic carcinoma could or not predict its systemic course. We have valued 136 out patients affected by prostate cancer and treated with either palliative medical therapy or radiotherapy. The follow-up varies from 12 to 132 months. The local, evaluation of the disease done through TRUS in longitudinal and/or axial scan (the dimension of the gland, the volume and ultrasonographic characteristics of the lesion, capsular involvement and estimation of the surrounding structures: seminal vesicles, vesica, rectum). In the long run, considering the local and systemic course of the disease, we have noticed accordance globally in 116 patients (85.3%); 13 patients showed only systematic progression (9.5%) while in 7 patients, we have noticed a local but not a systemic variation. We can deduce that periodical carrying-out of the TRUS (twice a year) constitute a reliable index not only of local procedure of the pt. but also predicting the systemic course of the disease, making the routine carrying out of the other check-up unnecessary, that could be reserved for cases with precise clinical indication.

  2. Familial systemic autoimmune rheumatic disease in Nigerians: a ...

    African Journals Online (AJOL)

    Systemic Autoimmune Rheumatic Diseases (SARD) are chronic disorders affecting multiple organs. Most SARDs have a female preponderance. SARDs have rarely been reported in African blacks, although there is increasing reportage of recent. Different SARDs are believed to have genetic predisposition and familial ...

  3. Role of systemic markers in periodontal diseases: a possible ...

    African Journals Online (AJOL)

    Background: Periodontitis is a local inflammatory process mediating destruction of periodontium triggered by bacterial insult leading to systemic inflammatory mayhem in the host. Epidemiologically, it has been modestly associated with cardiovascular diseases (CVD) with elevated acute‑phase reactant C‑reactive protein ...

  4. A review of targeted therapies evaluated by the Pediatric Preclinical Testing Program for osteosarcoma

    Directory of Open Access Journals (Sweden)

    Valerie eSampson

    2013-05-01

    Full Text Available Osteosarcoma, the most common malignant bone tumor of childhood, is a high grade primary bone sarcoma that occurs mostly in adolescence. Standard treatment consists of surgery in combination with multi-agent chemotherapy regimens. The development and approval of imatinib for Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL in children and the fully human monoclonal antibody, anti-GD2, as part of an immune therapy for high-risk neuroblastoma patients have established the precedent for use of targeted inhibitors along with standard chemotherapy backbones. However, few targeted agents tested have achieved traditional clinical end points for osteosarcoma. Many biological agents demonstrating anti-tumor responses in preclinical and early phase clinical testing have failed to reach response thresholds to justify randomized trials with large numbers of patients. The development of targeted therapies for pediatric cancer remains a significant challenge. To aid in the prioritization of new agents for clinical testing, the Pediatric Preclinical Testing Program (PPTP has developed reliable and robust preclinical pediatric cancer models to rapidly screen agents for activity in multiple childhood cancers and establish pharmacological parameters and effective drug concentrations for clinical trials. In this article, we examine a range of standard and novel agents that have been evaluated by the PPTP, and we discuss the preclinical and clinical development of these for the treatment of osteosarcoma. We further demonstrate that committed resources for hypothesis-driven drug discovery and development are needed to yield clinical successes in the search for new therapies for this pediatric disease.

  5. Periodontitis and systemic diseases : a record of discussions of working group 4 of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases

    NARCIS (Netherlands)

    Linden, Gerry J; Herzberg, Mark C; van Winkelhoff, Arie

    BACKGROUND: There has been an explosion in research into possible associations between periodontitis and various systemic diseases and conditions. AIM: To review the evidence for associations between periodontitis and various systemic diseases and conditions, including chronic obstructive pulmonary

  6. Involvement of the autonomic nervous system in Chagas heart disease

    Directory of Open Access Journals (Sweden)

    Edison Reis Lopes

    1983-12-01

    Full Text Available The autonomic nervous system and especially the intracardiac autonomic nervous system is involved in Chagas' disease. Ganglionitis and periganglionitis were noted in three groups ofpatients dying with Chagas'disease: 1 Those in heart failure; 2 Those dying a sudden, non violent death and; 3 Those dying as a consequence ofaccidents or homicide. Hearts in the threegroups also revealed myocarditis and scattered involvement of intramyocardial ganglion cells as well as lesions of myelinic and unmyelinic fibers ascribable to Chagas'disease. In mice with experimentally induced Chagas' disease weobserved more intensive neuronal lesions of the cardiac ganglia in the acute phase of infection. Perhaps neuronal loss has a role in the pathogenesis of Chagas cardiomyopathy. However based on our own experience and on other data from the literature we conclude that the loss of neurones is not the main factor responsible for the manifestations exhibited by chronic chagasic patients. On the other hand the neuronal lesions may have played a role in the sudden death ofone group of patients with Chagas'disease but is difficult to explain the group of patients who did not die sudderly but instead progressed to cardiac failure.

  7. Epstein-Barr Virus in Systemic Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Anette Holck Draborg

    2013-01-01

    Full Text Available Systemic autoimmune diseases (SADs are a group of connective tissue diseases with diverse, yet overlapping, symptoms and autoantibody development. The etiology behind SADs is not fully elucidated, but a number of genetic and environmental factors are known to influence the incidence of SADs. Recent findings link dysregulation of Epstein-Barr virus (EBV with SAD development. EBV causes a persistent infection with a tight latency programme in memory B-cells, which enables evasion of the immune defence. A number of immune escape mechanisms and immune-modulating proteins have been described for EBV. These immune modulating functions make EBV a good candidate for initiation of autoimmune diseases and exacerbation of disease progression. This review focuses on systemic lupus erythematosus (SLE, rheumatoid arthritis (RA, and Sjögren’s syndrome (SS and sum up the existing data linking EBV with these diseases including elevated titres of EBV antibodies, reduced T-cell defence against EBV, and elevated EBV viral load. Together, these data suggest that uncontrolled EBV infection can develop diverse autoreactivities in genetic susceptible individuals with different manifestations depending on the genetic background and the site of reactivation.

  8. Methodological aspects in quantitative translational neuroimaging in central nervous system diseases with Positron Emission Tomography

    International Nuclear Information System (INIS)

    Müllauer, J.

    2013-01-01

    Patients suffering from central nervous system (CNS) diseases crucially depend on a sufficient supply with CNS active drugs that help them to control and endure their illness. As the site of action of CNS drugs is in the brain, these substances need to pass the blood-brain barrier (BBB), a physiological barrier seperating the blood circulation and the brain. However, CNS drug treatment is often accompanied by pharmacoresistance (drug resistance). Multidrug transporters, such as permeable glycoprotein (Pgp) are responsible for a gradient dependent transport of substances over the BBB. Drug resistance is hypothesised as a result of overactivity of multidrug transporters at the BBB, with the result of insufficient and poor CNS drug levels in the brain. In the case of epilepsy in up to 20 - 40% of patients drug resistance is observed. The influence of Ppg overexpression on drug resistance in epilepsy was studied using positron emission tomography (PET), a novel non-invasive nuclear imaging method, together with radioligands that interact with Pgp. Radiolabeled Pgp-substrates ((R)-[11C]verapamil), and inhibitors ([11C]elacridar and [11C]tariquidar) were developed and used to study the influence of Pgp and other transporters at the BBB in a translational research approach; in animal models of epilepsy and in humans. The aim in translational PET research is a direct comparision of gathered animal and human data. Consequently diverse methodological challenges arise, that need to be addressed and observed in order to enable a translation between species. To achieve full quantification of the function and density of drug transporters at the BBB in both, humans and rodents, kinetic modeling (compartmental modeling) was applied to the PET pharmacokinetic data. Estimated modeling parameters were in succession used to estimate biological and physiological processes of Pgp at the BBB. Subsequently, nonlinear mixed effects modeling was deployed to increase the mechanistic

  9. Chronotherapeutic drug delivery systems: an approach to circadian rhythms diseases.

    Science.gov (United States)

    Sunil, S A; Srikanth, M V; Rao, N Sreenivasa; Uhumwangho, M U; Latha, K; Murthy, K V Ramana

    2011-11-01

    The purpose of writing this review on chronotherapeutic drug delivery systems (ChrDDs) is to review the literatures with special focus on ChrDDs and the various dosage forms, techniques that are used to target the circadian rhythms (CR) of various diseases. Many functions of the human body vary considerably in a day. ChrDDs refers to a treatment method in which in vivo drug availability is timed to match circadian rhythms of disease in order to optimize therapeutic outcomes and minimize side effects. Several techniques have been developed but not many dosage forms for all the diseases are available in the market. ChrDDs are gaining importance in the field of pharmaceutical technology as these systems reduce dosing frequency, toxicity and deliver the drug that matches the CR of that particular disease when the symptoms are maximum to worse. Finally, the ultimate benefit goes to the patient due the compliance and convenience of the dosage form. Some diseases that follow circadian rhythms include cardiovascular diseases, asthma, arthritis, ulcers, diabetes etc. ChrDDs in the market were also discussed and the current technologies used to formulate were also stated. These technologies include Contin® , Chronotopic®, Pulsincaps®, Ceform®, Timerx®, Oros®, Codas®, Diffucaps®, Egalet®, Tablet in capsule device, Core-in-cup tablet technology. A coated drug-core tablet matrix, A bi-layered tablet, Multiparticulate-based chronotherapeutic drug delivery systems, Chronoset and Controlled release microchips.

  10. Osteoporotic Vertebral Fractures as Part of Systemic Disease.

    Science.gov (United States)

    Oei, Ling; Zillikens, M Carola; Rivadeneira, Fernando; Oei, Edwin H G

    2016-01-01

    Our understanding of the genetic control of skeletogenesis and bone remodeling is expanding, and normally, bone resorption and bone formation are well balanced through regulation by hormones, growth factors, and cytokines. Osteoporosis is considered a systemic disease characterized by low bone mass and microarchitectural deterioration of bone tissue. Consequent increased bone fragility results in higher fracture risk. The most common osteoporotic fractures are located in the spine, and they form a significant health issue. A large variety of systemic diseases are associated with risk of osteoporotic vertebral fractures, illustrating its multifactorial etiology. Prevalences of these conditions vary from common to extremely rare, and incidence peaks differ according to etiology. This review appreciates different aspects of osteoporotic vertebral fractures as part of systemic disease, including genetic, immunologic, inflammatory, metabolic, and endocrine pathways. It seems impossible to be all-comprehensive on this topic; nevertheless, we hope to provide a reasonably thorough overview. Plenty remains to be elucidated in this field, identifying even more associated diseases and further exposing pathophysiological mechanisms underlying osteoporotic vertebral fractures. Copyright © 2016 The International Society for Clinical Densitometry. Published by Elsevier Inc. All rights reserved.

  11. Preclinical and Clinical Assessment of Cannabinoids as Anti-Cancer Agents

    Directory of Open Access Journals (Sweden)

    Daniel A. Ladin

    2016-10-01

    Full Text Available Cancer is the second leading cause of death in the United States with 1.7 million new cases estimated to be diagnosed in 2016. This disease remains a formidable clinical challenge and represents a substantial financial burden to the US health care system. Therefore, research and development of novel therapeutics for the treatment of cancer is of high priority. Cannabinoids and their derivatives have been utilized for their medicinal and therapeutic properties throughout history. Cannabinoid activity is regulated through the endocannabinoid system, which is comprised of cannabinoid receptors, transporters, and enzymes involved in cannabinoid synthesis and breakdown. More recently, cannabinoids have gained special attention for their role in cancer development and reduction. However, many studies investigated these roles using in vitro models which may not adequately mimic tumor growth and metastasis. As such, this article aims to review study results which evaluated effects of cannabinoids from plant, synthetic and endogenous origins on cancer development in preclinical models and to examine the current standing of cannabinoids currently being tested in human cancer patients.

  12. Chagas' disease and the involvement of the autonomic nervous system.

    Science.gov (United States)

    da Cunha, Ademir Batista

    2003-06-01

    Chagas' disease is a major endemic disease in Latin America and a great cause for concern due to its high incidence: it afflicts 16 to 18 million individuals and places over 90 million people at risk of infection. At present, five mechanisms can be proposed to explain the pathogenesis of chronic Chagas cardiopathy: 1. direct lesion of the tissue by Trypanosoma cruzi; 2. dysfunction of the autonomic nervous system (neurogenic concept); 3. microvascular disease; 4. immunologic reaction; 5. alterations in the extracellular matrix. The neurogenic concept is the most attractive explanation for the pathogenesis of chronic Chagas cardiopathy through the involvement of the autonomic nervous system, an issue that has been prominent ever since Chagas first initiated research in the field. Köberle, in his pioneering studies on the role of the autonomic nervous system in Chagas patients in the 1950s, adopted the technique of neuron counts, whereby he registered a reduction in parasympathetic nerve cells, and thus considered Chagas cardiopathy a "parasympathetic reduction" with predominance of the sympathetic. In the 1960s, systematic studies on autonomic function, organized by Professor Dalmo Amorim, were initiated in the School of Medicine in Ribeirão Preto. Several aspects of cardiac autonomic control were later described independently by teams in Brazil (Ribeirão Preto and Brasília), Argentina (Cordoba) and Venezuela (Mérida). In general, the studies performed in Ribeirăo Preto by Amorim and Marin Neto and in Brasília by Junqueira Jr. reflected the functional involvement of the parasympathetic system, while the studies performed in Córdoba were linked with the view of cardiovascular sympathetic dysfunction. In Brazil, the involvement of the sympathetic system, with relation to the functional aspect of sympathetic denervation, is well characterized by Marin Neto through the assessment of heart rate using the tilt test in both Chagas and control groups. Further

  13. Disease severity staging system for idiopathic pulmonary fibrosis in Japan.

    Science.gov (United States)

    Kondoh, Yasuhiro; Taniguchi, Hiroyuki; Kataoka, Kensuke; Furukawa, Taiki; Ando, Masahiko; Murotani, Kenta; Mishima, Michiaki; Inoue, Yoshikazu; Ogura, Takashi; Bando, Masashi; Hagiwara, Koichi; Suda, Takafumi; Chiba, Hirofumi; Takahashi, Hiroki; Sugiyama, Yukihiko; Homma, Sakae

    2017-11-01

    In Japan, the classification of disease severity of idiopathic pulmonary fibrosis (IPF) (J-system) has been used in making decisions on medical care subsidies. The present J-system consists of arterial partial pressure of oxygen (PaO 2 ) and exercise desaturation in stages of I-IV. It provides a good prognostic classification in stages III and IV, but not in stages I and II. Therefore, we propose a revised system to improve discriminative ability in stages I and II. We compared the revised J-system with the present J-system using Cox proportional hazards model to predict mortality rate. We also evaluated the recently proposed GAP (Gender, Age and Physiology) system in comparison to both J-systems. Two-hundred and fifteen IPF patients were studied retrospectively. A univariate model showed that the present and revised J-systems and a modified GAP system were all significant prognostic factors. The C-statistic for discriminating prognosis was higher in the revised J-system than the modified GAP system and the present J-system (0.677, 0.652 and 0.659, respectively). The C-statistics of these models produced from the 10 000 bootstrap samples were similar to those of the original models, suggesting good internal validation (0.665 (95% CI: 0.621-0.705), 0.645 (0.600-0.686) and 0.659 (0.616-0.700), respectively). Multivariate analysis revealed that the revised J-system (P = 0.0038) and the modified GAP system (P = 0.0029) were independent prognostic factors. The revised J-system can provide a better mortality prediction than the present one. Both the revised J-system and the modified GAP system are independent and valuable tools for prognostication and clinical management for IPF. © 2017 Asian Pacific Society of Respirology.

  14. Mitochondrial protein quality control systems in aging and disease.

    Science.gov (United States)

    Luce, Karin; Weil, Andrea C; Osiewacz, Heinz D

    2010-01-01

    Preserving the integrity of proteins, biomolecules prone to molecular damage, is a fundamental function of all biological systems. Impairments in protein quality control (PQC) may lead to degenerative processes, such as aging and various disorders and diseases. Fortunately, cells contain a hierarchical system of pathways coping protein damage. Specific molecular pathways detect misfolded proteins and act either to unfold or degrade them. Degradation of proteins generates peptides and amino acids that can be used for remodelling of impaired pathways and cellular functions. At increased levels of cellular damage whole organelles can be removed via autophagy, a process that depends on the activity oflysosomes. In addition, cells may undergo apoptosis, a form of programmed cell death, which in single-cellular and lower multicellular organisms can lead to death of the individual. Molecular damage of cellular compartments is mainly caused by reactive oxygen species (ROS). ROS is generated via different cellular pathways and frequently arises in the mitochondrial electron transport chain as a by-product of oxygenic energy transduction. Consequently, mitochondrial proteins are under high risk to become damaged. Perhaps for this reason mitochondria contain a very efficient PQC system that keeps mitochondrial proteins functional as long as damage does not reach a certain threshold and the components of this system themselves are not excessively damaged. The mitochondrial PQC system consists of chaperones that counteract protein aggregation through binding and refolding misfolded polypeptides and of membrane-bound and soluble ATP-dependent proteases that are involved in degradation of damaged proteins. During aging and in neurodegenerative diseases components of this PQC system, including Lon protease present in the mitochondrial matrix, become functionally impaired. In this chapter we summarise the current knowledge of cellular quality control systems with special emphasis

  15. Microglial priming and Alzheimer’s disease: a possible role for (early) immune challenges and epigenetics?

    NARCIS (Netherlands)

    Hoeijmakers, L.; Heinen, Y.; van Dam, A-M.; Lucassen, P.J.; Korosi, A.

    2016-01-01

    Neuroinflammation is thought to contribute to Alzheimer’s disease (AD) pathogenesis that is, to a large extent, mediated by microglia. Given the tight interaction between the immune system and the brain, peripheral immune challenges can profoundly affect brain function. Indeed, both preclinical and

  16. Topical and systemic antibiotics in the management of periodontal diseases.

    Science.gov (United States)

    Mombelli, Andrea; Samaranayake, Lakshman P

    2004-02-01

    Both systemic and topical antibiotics are increasingly used in the management of periodontal infections. Whilst these drugs are used mostly on an empirical basis, some contend that rational use of antibiotics should be the norm due to their wide abuse and consequential global emergence of antibiotic resistance organisms. Here we review the rationale and principles of antimicrobial therapy, treatment goals, drug delivery routes and various antibiotics that are used in the management of periodontal diseases. The pros and cons of systemic and local antibiotic therapy are described together with practical guidelines for their delivery. The available data indicate, in general, that mechanical periodontal treatment alone is adequate to ameliorate or resolve the clinical condition in most cases, but adjunctive antimicrobial agents, delivered either locally or systemically, can enhance the effect of therapy in specific situations. This is particularly true for aggressive (early onset) periodontitis, in patients with generalised systemic disease that may affect host resistance and in case of poor response to conventional mechanical therapy. Locally delivered antibiotics together with mechanical debridement are indicated for non-responding sites of focal infection or in localised recurrent disease. After resolution of the periodontal infection, the patient should be placed on an individually tailored maintenance care programme. Optimal plaque control by the patient is of paramount importance for a favourable clinical and microbiological response to any form of periodontal therapy.

  17. Design of Knowledge Management System for Diabetic Complication Diseases

    Science.gov (United States)

    Fiarni, Cut

    2017-01-01

    This paper examines how to develop a Model for Knowledge Management System (KMS) for diabetes complication diseases. People with diabetes have a higher risk of developing a series of serious health problems. Each patient has different condition that could lead to different disease and health problem. But, with the right information, patient could have early detection so the health risk could be minimized and avoided. Hence, the objective of this research is to propose a conceptual framework that integrates social network model, Knowledge Management activities, and content based reasoning (CBR) for designing such a diabetes health and complication disease KMS. The framework indicates that the critical knowledge management activities are in the process to find similar case and the index table for algorithm to fit the framework for the social media. With this framework, KMS developers can work with healthcare provider to easily identify the suitable IT associated with the CBR process when developing a diabetes KMS.

  18. Genetic prion disease: no role for the immune system in disease pathogenesis?

    Science.gov (United States)

    Friedman-Levi, Yael; Binyamin, Orli; Frid, Kati; Ovadia, Haim; Gabizon, Ruth

    2014-08-01

    Prion diseases, which can manifest by transmissible, sporadic or genetic etiologies, share several common features, such as a fatal neurodegenerative outcome and the aberrant accumulation of proteinase K (PK)-resistant PrP forms in the CNS. In infectious prion diseases, such as scrapie in mice, prions first replicate in immune organs, then invade the CNS via ascending peripheral tracts, finally causing death. Accelerated neuroinvasion and death occurs when activated prion-infected immune cells infiltrate into the CNS, as is the case for scrapie-infected mice induced for experimental autoimmune encephalomyelitis (EAE), a CNS inflammatory insult. To establish whether the immune system plays such a central role also in genetic prion diseases, we induced EAE in TgMHu2ME199K mice, a line mimicking for late onset genetic Creutzfeldt Jacob disease (gCJD), a human prion disease. We show here that EAE induction of TgMHu2ME199K mice neither accelerated nor aggravated prion disease manifestation. Concomitantly, we present evidence that PK-resistant PrP forms were absent from CNS immune infiltrates, and most surprisingly also from lymph nodes and spleens of TgMHu2ME199K mice at all ages and stages of disease. These results imply that the mechanism of genetic prion disease differs widely from that of the infectious presentation, and that the conversion of mutant PrPs into PK resistant forms occurs mostly/only in the CNS. If the absence of pathogenic PrP forms form immune organs is also true for gCJD patients, it may suggest their blood is devoid of prion infectivity. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. Model systems of human papillomavirus-associated disease.

    Science.gov (United States)

    Doorbar, John

    2016-01-01

    Human papillomaviruses (HPVs) cause a range of serious diseases, including the vast majority of cervical cancers, most anal cancers and around half of head and neck cancers. They are also responsible for troublesome benign epithelial lesions, including genital warts and laryngeal papillomas, and in some individuals HPVs lead to recurrent respiratory papillomatosis and other difficult-to-manage diseases. As a result, there is a great need for model systems that accurately mimic papillomavirus infections in humans. This is complicated by the diverse variety of HPVs, which now number over 200 types, and the different strategies they have evolved to persist in the population. The most well-developed models involve the culture of HPV-containing keratinocytes in organotypic raft culture, an approach which appears to accurately mimic the life cycle of several of the high-risk cancer-associated HPV types. Included amongst these are HPV16 and 18, which cause the majority of cervical cancers. The low-risk HPV types persist less well in tissue-culture models, and our ability to study the productive life cycle of these viruses is more limited. Although ongoing research is likely to improve this situation, animal models of papillomavirus disease can provide considerable basic information as to how lesions form, regress and can be controlled by the immune system. The best studied are cottontail rabbit papillomavirus, rabbit oral papillomavirus and, more recently, mouse papillomavirus (MmuPV), the last of which is providing exciting new insights into viral tropisms and immune control. In addition, transgenic models of disease have helped us to understand the consequences of persistent viral gene expression and the importance of co-factors such as hormones and UV irradiation in the development of neoplasia and cancer. It is hoped that such disease models will eventually lead us to better understanding and better treatments for human disease. Copyright © 2015 Pathological Society

  20. Preliminary study for small animal preclinical hadrontherapy facility

    Energy Technology Data Exchange (ETDEWEB)

    Russo, G. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Pisciotta, P., E-mail: pietro.pisciotta@ibfm.cnr.it [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy); Cirrone, G.A.P.; Romano, F. [National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy); Cammarata, F.; Marchese, V.; Forte, G.I.; Lamia, D.; Minafra, L.; Bravatá, V. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Acquaviva, R. [University of Catania, Catania (Italy); Gilardi, M.C. [Institute of Molecular Bioimaging and Physiology, IBFM CNR-LATO, Cefalú (Italy); Cuttone, G. [National Institute for Nuclear Physics, Laboratori Nazionali del Sud, INFN-LNS, Catania (Italy)

    2017-02-21

    Aim of this work is the study of the preliminary steps to perform a particle treatment of cancer cells inoculated in small animals and to realize a preclinical hadrontherapy facility. A well-defined dosimetric protocol was developed to explicate the steps needed in order to perform a precise proton irradiation in small animals and achieve a highly conformal dose into the target. A precise homemade positioning and holding system for small animals was designed and developed at INFN-LNS in Catania (Italy), where an accurate Monte Carlo simulation was developed, using Geant4 code to simulate the treatment in order to choose the best animal position and perform accurately all the necessary dosimetric evaluations. The Geant4 application can also be used to realize dosimetric studies and its peculiarity consists in the possibility to introduce the real target composition in the simulation using the DICOM micro-CT image. This application was fully validated comparing the results with the experimental measurements. The latter ones were performed at the CATANA (Centro di AdroTerapia e Applicazioni Nucleari Avanzate) facility at INFN-LNS by irradiating both PMMA and water solid phantom. Dosimetric measurements were performed using previously calibrated EBT3 Gafchromic films as a detector and the results were compared with the Geant4 simulation ones. In particular, two different types of dosimetric studies were performed: the first one involved irradiation of a phantom made up of water solid slabs where a layer of EBT3 was alternated with two different slabs in a sandwich configuration, in order to validate the dosimetric distribution. The second one involved irradiation of a PMMA phantom made up of a half hemisphere and some PMMA slabs in order to simulate a subcutaneous tumour configuration, normally used in preclinical studies. In order to evaluate the accordance between experimental and simulation results, two different statistical tests were made: Kolmogorov test and

  1. Preclinical and clinical safety studies on DNA vaccines.

    NARCIS (Netherlands)

    Schalk, Johanna A C; Mooi, Frits R; Berbers, Guy A M; Aerts, Leon A G J M van; Ovelgönne, Hans; Kimman, Tjeerd G

    2007-01-01

    DNA vaccines are based on the transfer of genetic material, encoding an antigen, to the cells of the vaccine recipient. Despite high expectations of DNA vaccines as a result of promising preclinical data their clinical utility remains unproven. However, much data is gathered in preclinical and

  2. Preclinical Testing of Novel Radiotracers for Positron Emission Tomography (PET)

    NARCIS (Netherlands)

    van Waarde, Aren; Sijbesma, Jurgen; Doorduin, Janine; Elsinga, Philippus; de Vries, Erik; Glaudemans, Andor; Medema, Jitze; van Zanten, Annie K; Dierckx, Rudi; Ahaus, Cees T B

    2017-01-01

    Preclinical tests of novel radiotracers in experimental animals are required to move tracer candidates from the stage of in vitro testing to the stage of toxicity testing and finally studies in human volunteers. Such preclinical tests are aimed at demonstrating: (1) specific in vivo interaction of

  3. Preclinical imaging: an essential ally in modern biosciences.

    Science.gov (United States)

    Cunha, Lídia; Horvath, Ildiko; Ferreira, Sara; Lemos, Joana; Costa, Pedro; Vieira, Domingos; Veres, Dániel S; Szigeti, Krisztián; Summavielle, Teresa; Máthé, Domokos; Metello, Luís F

    2014-04-01

    Translational research is changing the practice of modern medicine and the way in which health problems are approached and solved. The use of small-animal models in basic and preclinical sciences is a major keystone for these kinds of research and development strategies, representing a bridge between discoveries at the molecular level and clinical implementation in diagnostics and/or therapeutics. The development of high-resolution in vivo imaging technologies provides a unique opportunity for studying disease in real time, in a quantitative way, at the molecular level, along with the ability to repeatedly and non-invasively monitor disease progression or response to treatment. The greatest advantages of preclinical imaging techniques include the reduction of biological variability and the opportunity to acquire, in continuity, an impressive amount of unique information (without interfering with the biological process under study) in distinct forms, repeated or modulated as needed, along with the substantial reduction in the number of animals required for a particular study, fully complying with 3R (Replacement, Reduction and Refinement) policies. The most suitable modalities for small-animal in vivo imaging applications are based on nuclear medicine techniques (essentially, positron emission tomography [PET] and single photon emission computed tomography [SPECT]), optical imaging (OI), computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance spectroscopy imaging (MRSI), and ultrasound. Each modality has intrinsic advantages and limitations. More recently, aiming to overcome the inherent limitations of each imaging modality, multimodality devices designed to provide complementary information upon the pathophysiological process under study have gained popularity. The combination of high-resolution modalities, like micro-CT or micro-MRI, with highly sensitive techniques providing functional information, such as micro-PET or micro-SPECT, will

  4. Visual System Involvement in Patients with Newly Diagnosed Parkinson Disease.

    Science.gov (United States)

    Arrigo, Alessandro; Calamuneri, Alessandro; Milardi, Demetrio; Mormina, Enricomaria; Rania, Laura; Postorino, Elisa; Marino, Silvia; Di Lorenzo, Giuseppe; Anastasi, Giuseppe Pio; Ghilardi, Maria Felice; Aragona, Pasquale; Quartarone, Angelo; Gaeta, Michele

    2017-12-01

    Purpose To assess intracranial visual system changes of newly diagnosed Parkinson disease in drug-naïve patients. Materials and Methods Twenty patients with newly diagnosed Parkinson disease and 20 age-matched control subjects were recruited. Magnetic resonance (MR) imaging (T1-weighted and diffusion-weighted imaging) was performed with a 3-T MR imager. White matter changes were assessed by exploring a white matter diffusion profile by means of diffusion-tensor imaging-based parameters and constrained spherical deconvolution-based connectivity analysis and by means of white matter voxel-based morphometry (VBM). Alterations in occipital gray matter were investigated by means of gray matter VBM. Morphologic analysis of the optic chiasm was based on manual measurement of regions of interest. Statistical testing included analysis of variance, t tests, and permutation tests. Results In the patients with Parkinson disease, significant alterations were found in optic radiation connectivity distribution, with decreased lateral geniculate nucleus V2 density (F, -8.28; P Parkinson disease and that the entire intracranial visual system can be involved. © RSNA, 2017 Online supplemental material is available for this article.

  5. Disease-related nutritional risk and mortality in systemic sclerosis.

    Science.gov (United States)

    Cereda, Emanuele; Codullo, Veronica; Klersy, Catherine; Breda, Silvia; Crippa, Anna; Rava, Maria Luisa; Orlandi, Margherita; Bonardi, Chiara; Fiorentini, Maria Lina; Caporali, Roberto; Caccialanza, Riccardo

    2014-06-01

    To evaluate the relationship between mortality and nutritional risk associated with disease activity in Systemic Sclerosis (SSc). A single-centre prospective cohort study involving 160 SSc outpatients (median age, 62 years [25th-75th, 54-68]). Nutritional risk was assessed by the Malnutrition Universal Screening Tool (MUST), a screening tool that combines anthropometric parameters of nutritional status (body mass index [BMI] and percentage of unintentional weight loss [WL]) with the presence of an "acute disease" (as defined by a disease activity score ≥3 according to Valentini's criteria). Prevalence of high nutritional risk (MUST score ≥2) was 24.4% [95%CI, 17.4-31.3]. A low nutritional risk (MUST = 1) was detected in 30% of our study sample. In hazard analysis (median follow-up duration = 46 months [25th-75th percentile, 31-54]), high nutritional risk was significantly associated with mortality (HR = 8.3 [95%CI, 2.1-32.1]). The performance of the model based on nutritional risk including disease activity (Harrell's c = 0.74 [95%CI, 0.59-0.89]) was superior to that based on active disease alone (HR = 6.3 [95%CI, 1.8-21.7]; Harrell's c = 0.68 [95%CI, 0.53-0.84]). Risk scored only by anthropometric parameters (prevalence, 9.4% [95%CI, 4.6-14.2]) was not associated with mortality: HR = 2.8 [95%CI, 0.6-13.2]. In SSc outpatients MUST significantly predicts mortality. The combined assessment of nutritional parameters and disease activity significantly improves the evaluation of mortality risk. Disease-related nutritional risk screening should be systematically included in the clinical workup of every SSc patient. Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  6. Roles of oral bacteria in cardiovascular diseases--from molecular mechanisms to clinical cases: Implication of periodontal diseases in development of systemic diseases.

    Science.gov (United States)

    Inaba, Hiroaki; Amano, Atsuo

    2010-01-01

    Periodontal diseases, some of the most common infectious diseases seen in humans, are characterized by gingival inflammation, as well as loss of connective tissue and bone from around the roots of the teeth, which leads to eventual tooth exfoliation. In the past decade, the association of periodontal diseases with the development of systemic diseases has received increasing attention. Although a number of studies have presented evidence of close relationships between periodontal and systemic diseases, the majority of findings are limited to epidemiological studies, while the etiological details remain unclear. Nevertheless, a variety of recent hypothesis driven investigations have compiled various results showing that periodontal infection and subsequent direct oral-hematogenous spread of bacteria are implicated in the development of various systemic diseases. Herein, we present current understanding in regard to the relationship between periodontal and systemic diseases, including cardiovascular diseases, preterm delivery of low birth weight, diabetes mellitus, respiratory diseases, and osteoporosis.

  7. Role of the Immune System in Diabetic Kidney Disease.

    Science.gov (United States)

    Hickey, Fionnuala B; Martin, Finian

    2018-03-12

    The purpose of this review is to examine the proposed role of immune modulation in the development and progression of diabetic kidney disease (DKD). Diabetic kidney disease has not historically been considered an immune-mediated disease; however, increasing evidence is emerging in support of an immune role in its pathophysiology. Both systemic and local renal inflammation have been associated with DKD. Infiltration of immune cells, predominantly macrophages, into the kidney has been reported in a number of both experimental and clinical studies. In addition, increased levels of circulating pro-inflammatory cytokines have been linked to disease progression. Consequently, a variety of therapeutic strategies involving modulation of the immune response are currently being investigated in diabetic kidney disease. Although no current therapies for DKD are directly based on immune modulation many of the therapies in clinical use have anti-inflammatory effects along with their primary actions. Macrophages emerge as the most likely beneficial immune cell target and compounds which reduce macrophage infiltration to the kidney have shown potential in both animal models and clinical trials.

  8. Enhancement on infectious diseases nursing plan information system.

    Science.gov (United States)

    Yeh, Mei-Lin; Hao, Te-Hui; Hsu, Chien-Yeh

    2009-01-01

    Based on researches, the most time-consuming nursing activities, in teaching hospital, are: room patrols, the blood pressure survey, the body temperature pulse breath survey, the nursing record maintenance. The nursing record is one way to communicate data. It can allow the medical service team to understand what measures the nursing staff once did for sickness, as well as responses from sickness. Nevertheless, it is the key component to utilize the record with a clinical nursing plan, so as to provide a proficient health management. Since the maintenance of nursing plan is costly and time-consuming, therefore, it is essential to establish the nursing plan information system, which can effectively promote the nursing quality. This research main body comes from one infectious disease division nursing plan information system, which was developed in 1992, and its data base covers entire courtyard compatibility and various faculties characteristic nursing plan. The nursing staff often complained that this system is not user-friendly, its contents are not comprehensive, and sometimes it does not let staff choose the right diagnosis. Therefore this research is based on history analysis and the questionnaire survey procedure first, the infectious disease nursing plan use number of times, the frequency and the project content, then by the literature scientific theory and result of the improvement group discussion together. The original 38 infectious disease division nursing plan will be expanded to 45 nursing plans. Moreover, the common 38 infectious disease code (ICD-9), and its corresponding diagnosis items, shall automatically appear in the disease diagnose code field, so it would be better off for the nursing staff to set up the nursing plan efficiently. Infectious disease division nursing plan information system utilization ratio is promoted 9.6-folds, according to research outcome. Each task consumes 3.68 minutes beforehand-including computer program operation, the

  9. Preclinical study design for rAAV.

    Science.gov (United States)

    Flotte, Terence R; Conlon, Thomas J; Mueller, Christian

    2011-01-01

    The process of moving a novel drug such as an adeno-associated viral vector from the bench top to bedside is an arduous process requiring coordination and skill from multiple laboratories and regulatory agencies. Proceeding to a phase I safety trial in humans after most of the proof-of-concept data have been acquired may take several years. During this time, agencies including the FDA, NIH Office of Biotechnology Activities (OBA), and Recombinant DNA Advisory Committee (RAC) along with the investigator's team will develop a series of preclinical toxicology and biodistribution studies in order to develop a safety profile for the intended novel drug. In this chapter, key features of the pharm-tox study design and conduct will be discussed. Highlighted features include choosing a sufficient animal number and species to use in testing, dose determination, typical toxicological assays performed, the use of Standard Operating Procedures in respect to good laboratory practices compliancy, and role of the Quality Assurance Unit.

  10. Developing Potential Candidates of Preclinical Preeclampsia

    Science.gov (United States)

    Founds, Sandra; Zeng, Xuemei; Lykins, David; Roberts, James M.

    2015-01-01

    The potential for developing molecules of interest in preclinical preeclampsia from candidate genes that were discovered on gene expression microarray analysis has been challenged by limited access to additional first trimester trophoblast and decidual tissues. The question of whether these candidates encode secreted proteins that may be detected in maternal circulation early in pregnancy has been investigated using various proteomic methods. Pilot studies utilizing mass spectrometry based proteomic assays, along with enzyme linked immunosorbent assays (ELISAs), and Western immunoblotting in first trimester samples are reported. The novel targeted mass spectrometry methods led to robust multiple reaction monitoring assays. Despite detection of several candidates in early gestation, challenges persist. Future antibody-based studies may lead to a novel multiplex protein panel for screening or detection to prevent or mitigate preeclampsia. PMID:26580600

  11. Developing Potential Candidates of Preclinical Preeclampsia

    Directory of Open Access Journals (Sweden)

    Sandra Founds

    2015-11-01

    Full Text Available The potential for developing molecules of interest in preclinical preeclampsia from candidate genes that were discovered on gene expression microarray analysis has been challenged by limited access to additional first trimester trophoblast and decidual tissues. The question of whether these candidates encode secreted proteins that may be detected in maternal circulation early in pregnancy has been investigated using various proteomic methods. Pilot studies utilizing mass spectrometry based proteomic assays, along with enzyme linked immunosorbent assays (ELISAs, and Western immunoblotting in first trimester samples are reported. The novel targeted mass spectrometry methods led to robust multiple reaction monitoring assays. Despite detection of several candidates in early gestation, challenges persist. Future antibody-based studies may lead to a novel multiplex protein panel for screening or detection to prevent or mitigate preeclampsia.

  12. Preclinical antitoxic properties of Spirulina (Arthrospira).

    Science.gov (United States)

    Martínez-Galero, Elizdath; Pérez-Pastén, Ricardo; Perez-Juarez, Angélica; Fabila-Castillo, Luis; Gutiérrez-Salmeán, Gabriela; Chamorro, German

    2016-08-01

    Spirulina (Arthrospira) exerts a wide spectrum of pharmacological activities which are mainly attributed to its antioxidant effect. However, Spirulina has also been reported (both in preclinical and in clinical scenarios) to exhibit other bioactive effects, including an antitoxic potential. We performed a systematic review of the literature, conducted in TOXNET, PubMed/MEDLINE, and Science Direct-Scopus; all available years were included. Searching criteria included the effects of Spirulina on experimental poisonings from arsenic, cadmium, carbon tetrachloride, deltamethrin, fluoride, hexachlorocyclohexane, iron, lead, lindane, and mercury. In all cases, it was established that the blue-green alga, and its isolated compounds, effectively counteracted these pollutants toxic effects on the exposed organisms. Some molecular mechanisms are proposed, although they have not been fully elucidated yet. Spirulina could be a useful coadjuvant agent within clinical practice for treatment of these or other pollutants poisonings.

  13. Case management and adherence to an online disease management system.

    Science.gov (United States)

    Robertson, Lucy; Smith, Michael; Tannenbaum, Dennis

    2005-01-01

    Non-adherence to treatment presents a significant obstacle to achieving favourable health outcomes. We have studied consumers' adherence to an online disease management system for depression, called Recovery Road. Recovery Road was implemented on a pilot basis for mental health care in Western Australia. Recovery Road was available for use by consumers and clinicians to augment usual treatment. One hundred and thirty consumers who had been diagnosed with major depression were enrolled. Consumers who used Recovery Road (n = 98) were provided with education, progress monitoring, e-consultation, e-diary and online evidenced-based therapy. Consumers received either standard, automated adherence reminders by email (n = 69), or case management, which included personalized email and telephone follow-up in response to non-adherence (n = 29). After the first eight sessions, the adherence was 84% in the case management group and 55% in the automatic reminders group. The results suggest that case management increases adherence to online disease management systems.

  14. Peripheral modulation of the endocannabinoid system in metabolic disease.

    Science.gov (United States)

    Shrestha, Nirajan; Cuffe, James S M; Hutchinson, Dana S; Headrick, John P; Perkins, Anthony V; McAinch, Andrew J; Hryciw, Deanne H

    2018-03-01

    Dysfunction of the endocannabinoid system (ECS) has been identified in metabolic disease. Cannabinoid receptor 1 (CB 1 ) is abundantly expressed in the brain but also expressed in the periphery. Cannabinoid receptor 2 (CB 2 ) is more abundant in the periphery, including the immune cells. In obesity, global antagonism of overexpressed CB 1 reduces bodyweight but leads to centrally mediated adverse psychological outcomes. Emerging research in isolated cultured cells or tissues has demonstrated that targeting the endocannabinoid system in the periphery alleviates the pathologies associated with metabolic disease. Further, peripheral specific cannabinoid ligands can reverse aspects of the metabolic phenotype. This Keynote review will focus on current research on the functionality of peripheral modulation of the ECS for the treatment of obesity. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

  15. Statin Induced Myopathy a Patient with Multiple Systemic Diseases

    Directory of Open Access Journals (Sweden)

    Özgül Uçar

    2011-04-01

    Full Text Available Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins are the most successful class of drugs for the treatment of hypercholesterolaemia and dyslipidaemia. However, the popular profile of statins in terms of efficacy has been maligned by theiradverse effects. Statin induced myopathy, which can be seen at any time during the course of therapy, is a clinically important cause of statin intolerance and discontinuation. When a patient with multiple systemic diseases who use numerous medications represent with myalgia and muscle cramps, statin induced myopathy may not be remembered at first. We present a patient with multiple systemic diseases, alcohol and morphine abuse in whom myopathy developed. After exclusion of other etiologies, we concluded that myopathy was related to statin therapy.

  16. Systems genetics of complex diseases using RNA-sequencing methods

    DEFF Research Database (Denmark)

    Mazzoni, Gianluca; Kogelman, Lisette; Suravajhala, Prashanth

    2015-01-01

    non-coding RNAs (ncRNAs). The integration of transcriptomics data with genomic data in a systems genetics context represents a valuable possibility to go deep into the causal and regulatory mechanisms that generate complex traits and diseases. However RNA-Seq data have to be treated carefully......Next generation sequencing technologies have enabled the generation of huge quantities of biological data, and nowadays extensive datasets at different ‘omics levels have been generated. Systems genetics is a powerful approach that allows to integrate different ‘omics level and understand...... the biological mechanisms behind complex diseases or traits. In the recent past, transcriptomic studies with microarrays have been replaced with the new powerful RNA-seq technologies. This has led to detection of novel gene transcripts, novel regulatory mechanisms, allele specific gene expression and numerous...

  17. Adult neurogenesis and neurodegenerative diseases: A systems biology perspective.

    Science.gov (United States)

    Horgusluoglu, Emrin; Nudelman, Kelly; Nho, Kwangsik; Saykin, Andrew J

    2017-01-01

    New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

  18. Prevalence of Systemic Diseases in Patients with Dental Infections

    OpenAIRE

    Seyed Mohsen Khoshniat Nikoo; Mohammad Bayat; Fatemeh Afshar Hezarkhani

    2013-01-01

    Background and Aims: The aim of this study was to investigate the prevalence of diabetes and other risk factors in patients with dental infections.Materials and Methods: A cross-sectional study was conducted among 50 patients who preferred in maxillofacial word of shariaty hospital with acute dental infections in 9 months. A self-administered questionnaire was administered during a dental appointment in order to gather demographic information and recorded past history of systemic disease, OPG...

  19. Adult Neurogenesis and Neurodegenerative Diseases: A Systems Biology Perspective

    Science.gov (United States)

    Horgusluoglu, Emrin; Nudelman, Kelly; Nho, Kwangsik; Saykin, Andrew J.

    2016-01-01

    New neurons are generated throughout adulthood in two regions of the brain, the olfactory bulb and dentate gyrus of the hippocampus, and are incorporated into the hippocampal network circuitry; disruption of this process has been postulated to contribute to neurodegenerative diseases including Alzheimer’s disease and Parkinson’s disease. Known modulators of adult neurogenesis include signal transduction pathways, the vascular and immune systems, metabolic factors, and epigenetic regulation. Multiple intrinsic and extrinsic factors such as neurotrophic factors, transcription factors, and cell cycle regulators control neural stem cell proliferation, maintenance in the adult neurogenic niche, and differentiation into mature neurons; these factors act in networks of signaling molecules that influence each other during construction and maintenance of neural circuits, and in turn contribute to learning and memory. The immune system and vascular system are necessary for neuronal formation and neural stem cell fate determination. Inflammatory cytokines regulate adult neurogenesis in response to immune system activation, whereas the vasculature regulates the neural stem cell niche. Vasculature, immune/support cell populations (microglia/astrocytes), adhesion molecules, growth factors, and the extracellular matrix also provide a homing environment for neural stem cells. Epigenetic changes during hippocampal neurogenesis also impact memory and learning. Some genetic variations in neurogenesis related genes may play important roles in the alteration of neural stem cells differentiation into new born neurons during adult neurogenesis, with important therapeutic implications. In this review, we discuss mechanisms of and interactions between these modulators of adult neurogenesis, as well as implications for neurodegenerative disease and current therapeutic research. PMID:26879907

  20. Resveratrol as a potential therapeutic drug for respiratory system diseases

    OpenAIRE

    Zhu, Xiao-dan; Lei, Xiao-ping; Dong, Wen-bin

    2017-01-01

    Xiao-dan Zhu, Xiao-ping Lei, Wen-bin Dong Department of Newborn Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China Abstract: Respiratory system diseases are common and major ailments that seriously endanger human health. Resveratrol, a polyphenolic phytoalexin, is considered an anti-inflammatory, antioxidant, and anticancer agent. Thanks to its wide range of biological activities, resveratrol has become a hotspot in many ...

  1. Pervasive mobile healthcare systems for chronic disease monitoring.

    Science.gov (United States)

    Huzooree, Geshwaree; Kumar Khedo, Kavi; Joonas, Noorjehan

    2017-05-01

    Pervasive mobile healthcare system has the potential to improve healthcare and the quality of life of chronic disease patients through continuous monitoring. Recently, many articles related to pervasive mobile healthcare system focusing on health monitoring using wireless technologies have been published. The main aim of this review is to evaluate the state-of-the-art pervasive mobile healthcare systems to identify major technical requirements and design challenges associated with the realization of a pervasive mobile healthcare system. A systematic literature review was conducted over IEEE Xplore Digital Library to evaluate 20 pervasive mobile healthcare systems out of 683 articles from 2011 to 2016. The classification of the pervasive mobile healthcare systems and other important factors are discussed. Potential opportunities and challenges are pointed out for the further deployment of effective pervasive mobile healthcare systems. This article helps researchers in health informatics to have a holistic view toward understanding pervasive mobile healthcare systems and points out new technological trends and design challenges that researchers have to consider when designing such systems for better adoption, usability, and seamless integration.

  2. Clinical and biochemical landmarks in systemic autoinflammatory diseases.

    Science.gov (United States)

    Cantarini, Luca; Rigante, Donato; Brizi, Maria Giuseppina; Lucherini, Orso Maria; Sebastiani, Gian Domenico; Vitale, Antonio; Gianneramo, Valentina; Galeazzi, Mauro

    2012-11-01

    Systemic autoinflammatory diseases are a group of inherited disorders of the innate immune system characterized by seemingly unprovoked inflammation recurring at variable intervals and involving skin, serosal membranes, joints, and gastrointestinal apparatus, with reactive amyloidosis as a possible severe long-term complication. Recent advances in genetics and molecular biology have improved our understanding of the pathogenesis of these diseases, including familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, and hereditary pyogenic and granulomatous disorders: the vast majority of these conditions are related to the activation of the interleukin-1 pathway, which results in (or from?) a common unifying pathogenetic mechanism. Their diagnostic identification derives from the combination of clinical data, evaluation of acute phase reactants, clinical efficacy in response to specific drugs, and recognition of specific mutations in the relevant genes, although genetic tests may be unconstructive in some cases. This review will discuss clinical and laboratory clues useful for a diagnostic approach to systemic autoinflammatory diseases.

  3. The Promise of Systems Biology for Diabetic Kidney Disease.

    Science.gov (United States)

    Brosius, Frank C; Ju, Wenjun

    2018-03-01

    Diabetic kidney disease (DKD) has a complex and prolonged pathogenesis involving many cell types in the kidney as well as extrarenal factors. It is clinically silent for many years after the onset of diabetes and usually progresses over decades. Given this complexity, a comprehensive and unbiased molecular approach is best suited to help identify the most critical mechanisms responsible for progression of DKD and those most suited for targeted intervention. Systems biological investigations provide such an approach since they examine the entire network of molecular changes that occur in a disease process in a comprehensive way instead of focusing on a single abnormal molecule or pathway. Systems biological studies can also start with analysis of the disease in humans, not in animal or cell culture models that often poorly reproduce the changes in human DKD. Indeed, in the last decade, systems biological approaches have led to the identification of critical molecular abnormalities in DKD and have directly led to development of new biomarkers and potential treatments for DKD. Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.

  4. Elevated Adiponectin Serum Levels in Women with Systemic Autoimmune Diseases

    Directory of Open Access Journals (Sweden)

    Éric Toussirot

    2010-01-01

    Full Text Available Adipose tissue produces a wide range of proteins that may influence the immune system. In this study, we assessed the serum levels of leptin, adiponectin, and ghrelin, in association with the measurements of body composition, in 15 female patients with various autoimmune diseases (systemic lupus erythematosus, primary Sjögren's syndrome, sarcoidosis, mixed connective tissue disease, vasculitis, CREST syndrome, and polymyositis and in 15 healthy female controls. There were no statistically significant differences between the patients and controls with regard to serum leptin, serum ghrelin, global fat mass, adiposity, and fat mass in the android or gynoid regions, whereas serum adiponectin levels were higher in patients than controls (16.3±1.6 μg/mL versus 9.7±0.6 μg/mL; =.01. As adiponectin is known to exhibit potent anti-inflammatory properties, a high adiponectinemia in patients with systemic autoimmune disease may mitigate the inflammatory response. However, the precise consequences of these elevated serum adiponectin levels on the metabolic syndrome development and atherosclerotic cardiovascular risk in this patient population still needs to be determined.

  5. Sex Differences in Circadian Timing Systems: Implications for Disease

    Science.gov (United States)

    Bailey, Matthew; Silver, Rae

    2014-01-01

    Virtually every eukaryotic cell has an endogenous circadian clock and a biological sex. These cell-based clocks have been conceptualized as oscillators whose phase can be reset by internal signals such as hormones, and external cues such as light. The present review highlights the inter-relationship between circadian clocks and sex differences. In mammals, the suprachiasmatic nucleus (SCN) serves as a master clock synchronizing the phase of clocks throughout the body. Gonadal steroid receptors are expressed in almost every site that receives direct SCN input. Here we review sex differences in the circadian timing system in the hypothalamic-pituitary-gonadal axis (HPG), the hypothalamicadrenal-pituitary (HPA) axis, and sleep-arousal systems. We also point to ways in which disruption of circadian rhythms within these systems differs in the sexes and is associated with dysfunction and disease. Understanding sex differentiated circadian timing systems can lead to improved treatment strategies for these conditions. PMID:24287074

  6. Adapting Preclinical Benchmarks for First-in-Human Trials of Human Embryonic Stem Cell-Based Therapies.

    Science.gov (United States)

    Barazzetti, Gaia; Hurst, Samia A; Mauron, Alexandre

    2016-08-01

    : As research on human embryonic stem cell (hESC)-based therapies is moving from the laboratory to the clinic, there is an urgent need to assess when it can be ethically justified to make the step from preclinical studies to the first protocols involving human subjects. We examined existing regulatory frameworks stating preclinical requirements relevant to the move to first-in-human (FIH) trials and assessed how they may be applied in the context of hESC-based interventions to best protect research participants. Our findings show that some preclinical benchmarks require rethinking (i.e., identity, purity), while others need to be specified (i.e., potency, viability), owing to the distinctive dynamic heterogeneity of hESC-based products, which increases uncertainty and persistence of safety risks and allows for limited predictions of effects in vivo. Rethinking or adaptation of how to apply preclinical benchmarks in specific cases will be required repeatedly for different hESC-based products. This process would benefit from mutual learning if researchers included these components in the description of their methods in publications. To design translational research with an eye to protecting human participants in early trials, researchers and regulators need to start their efforts at the preclinical stage. Existing regulatory frameworks for preclinical research, however, are not really adapted to this in the case of stem cell translational medicine. This article reviews existing regulatory frameworks for preclinical requirements and assesses how their underlying principles may best be applied in the context of human embryonic stem cell-based interventions for the therapy of Parkinson's disease. This research will help to address the question of when it is ethically justified to start first-in-human trials in stem cell translational medicine. ©AlphaMed Press.

  7. Preclinical in vivo research in implant dentistry. Consensus of the eighth European workshop on periodontology.

    Science.gov (United States)

    Berglundh, Tord; Stavropoulos, Andreas

    2012-02-01

    Guidelines for improving the reporting in preclinical in vivo research (ARRIVE) have been recently proposed. The aim was to assess to what extent the ARRIVE guidelines were considered in preclinical in vivo studies in implant dentistry. Four comprehensive systematic reviews evaluated to what extent the ARRIVE guidelines were considered in preclinical in vivo studies in implant dentistry. Studies on the influence of implant material, surface and design on tissue integration to implants placed in pristine bone, in locally compromised sites and/or systemically compromised animals, as well as on peri-implant mucositis and peri-implantitis were evaluated. The four reviews introduced different modifications to the ARRIVE guidelines dedicated to the specific assignment of the review. A large variation in the frequency of reporting with regard to the items of the modified ARRIVE guidelines was observed. The reviews revealed that relevant information, e.g. sample size calculation, blinding of the assessor etc., was often not reported. It was also identified that several items in the ARRIVE guidelines may be less--if at all--applicable to research in implant dentistry. It is suggested that researchers implement, whenever relevant, the ARRIVE guidelines during planning and reporting of preclinical in vivo studies related to dental implants. © 2012 John Wiley & Sons A/S.

  8. Moving toward a system genetics view of disease.

    Science.gov (United States)

    Sieberts, Solveig K; Schadt, Eric E

    2007-07-01

    Testing hundreds of thousands of DNA markers in human, mouse, and other species for association to complex traits like disease is now a reality. However, information on how variations in DNA impact complex physiologic processes flows through transcriptional and other molecular networks. In other words, DNA variations impact complex diseases through the perturbations they cause to transcriptional and other biological networks, and these molecular phenotypes are intermediate to clinically defined disease. Because it is also now possible to monitor transcript levels in a comprehensive fashion, integrating DNA variation, transcription, and phenotypic data has the potential to enhance identification of the associations between DNA variation and diseases like obesity and diabetes, as well as characterize those parts of the molecular networks that drive these diseases. Toward that end, we review methods for integrating expression quantitative trait loci (eQTLs), gene expression, and clinical data to infer causal relationships among gene expression traits and between expression and clinical traits. We further describe methods to integrate these data in a more comprehensive manner by constructing coexpression gene networks that leverage pairwise gene interaction data to represent more general relationships. To infer gene networks that capture causal information, we describe a Bayesian algorithm that further integrates eQTLs, expression, and clinical phenotype data to reconstruct whole-gene networks capable of representing causal relationships among genes and traits in the network. These emerging network approaches, aimed at processing high-dimensional biological data by integrating data from multiple sources, represent some of the first steps in statistical genetics to identify multiple genetic perturbations that alter the states of molecular networks and that in turn push systems into disease states. Evolving statistical procedures that operate on networks will be critical

  9. Chronic obstructive pulmonary disease and obstructive sleep apnea: overlaps in pathophysiology, systemic inflammation, and cardiovascular disease.

    LENUS (Irish Health Repository)

    McNicholas, Walter T

    2012-02-01

    Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome represent two of the most prevalent chronic respiratory disorders in clinical practice, and cardiovascular diseases represent a major comorbidity in each disorder. The two disorders coexist (overlap syndrome) in approximately 1% of adults but asymptomatic lower airway obstruction together with sleep-disordered breathing is more prevalent. Although obstructive sleep apnea syndrome has similar prevalence in COPD as the general population, and vice versa, factors such as body mass index and smoking influence relationships. Nocturnal oxygen desaturation develops in COPD, independent of apnea\\/hypopnea, and is more severe in the overlap syndrome, thus predisposing to pulmonary hypertension. Furthermore, upper airway flow limitation contributes to nocturnal desaturation in COPD without apnea\\/hypopnea. Evidence of systemic inflammation in COPD and sleep apnea, involving C-reactive protein and IL-6, in addition to nuclear factor-kappaB-dependent pathways involving tumor necrosis factor-alpha and IL-8, provides insight into potential basic interactions between both disorders. Furthermore, oxidative stress develops in each disorder, in addition to activation and\\/or dysfunction of circulating leukocytes. These findings are clinically relevant because systemic inflammation may contribute to the pathogenesis of cardiovascular diseases and the cell\\/molecular pathways involved are similar to those identified in COPD and sleep apnea. However, the pathophysiological and clinical significance of systemic inflammation in COPD and sleep apnea is not proven, and thus, studies of patients with the overlap syndrome should provide insight into the mechanisms of systemic inflammation in COPD and sleep apnea, in addition to potential relationships with cardiovascular disease.

  10. Neuropsychiatric systemic lupus erythematosus: association with global disease activity.

    Science.gov (United States)

    Morrison, E; Carpentier, S; Shaw, E; Doucette, S; Hanly, J G

    2014-04-01

    To determine whether patients with neuropsychiatric (NP) events attributed to systemic lupus erythematosus (SLE) have more global disease activity than patients with NP events not attributed to SLE. Patients were recruited from an academic lupus clinic. Global disease activity was measured with the SLE Disease Activity Index 2000 (SLEDAI-2K) and organ damage with the Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology (ACR) damage index (SDI). NP disease was defined using the ACR case definitions and decision rules for attribution of NP events to SLE and non-SLE causes. There were 68 patients (age (mean ± SD) 40.8 ± 15.2 years, 85% female, 94% Caucasians) with 126 NP events. SLEDAI-2K scores in patients with NP events attributed to SLE were higher than in patients with NP events attributed to non-SLE causes even when NP variables were removed from the SLEDAI-2K (mean ± SD: SLE NP = 7.36 ± 5.42 vs non-SLE NP = 5.53 ± 4.57, P = 0.042). Patients with CNS and diffuse NP events, rather that PNS and focal events, accounted for the group differences in SLEDAI-2K scores. There were no significant differences in total SDI scores comparing NP events due to SLE vs. non-SLE causes (mean ± SD: 2.1 ± 1.8 vs. 1.7 ± 1.7; p = 0.28) even when NP variables were omitted. Increased global SLE disease activity is associated with concurrent NP events attributed to SLE, particularly for diffuse NP and CNS NP events. The findings have diagnostic and therapeutic implications for SLE patients with NP events and inform pathogenetic mechanisms underlying NPSLE.

  11. Ebinformatics: Ebola fuzzy informatics systems on the diagnosis, prediction and recommendation of appropriate treatments for Ebola virus disease (EVD

    Directory of Open Access Journals (Sweden)

    Olugbenga Oluwagbemi

    Full Text Available Ebola Virus Disease (EVD also known as the Ebola hemorrhagic fever is a very deadly infectious disease to humankind. Therefore, a safer and complementary method of diagnosis is to employ the use of an expert system in order to initiate a platform for pre-clinical treatments, thus acting as a precursor to comprehensive medical diagnosis and treatments. This work presents a design and implementation of informatics software and a knowledge-based expert system for the diagnosis, and provision of recommendations on the appropriate type of recommended treatment to the Ebola Virus Disease (EVD.In this research an Ebola fuzzy informatics system was developed for the purpose of diagnosing and providing useful recommendations to the management of the EVD in West Africa and other affected regions of the world. It also acts as a supplementary resource in providing medical advice to individuals in Ebola – ravaged countries. This aim was achieved through the following objectives: (i gathering of facts through the conduct of a comprehensive continental survey to determine the knowledge and perception level of the public about factors responsible for the transmission of the Ebola Virus Disease (ii develop an informatics software based on information collated from health institutions on basic diagnosis of the Ebola Virus Disease-related symptoms (iii adopting and marrying the knowledge of fuzzy logic and expert systems in developing the informatics software. Necessary requirements were collated from the review of existing expert systems, consultation of journals and articles, and internet sources. Online survey was conducted to determine the level at which individuals are aware of the factors responsible for the transmission of the Ebola Virus Disease (EVD. The expert system developed, was designed to use fuzzy logic as its inference mechanism along with a set of rules. A knowledge base was created to help provide diagnosis on the Ebola Virus Disease (EVD

  12. Prevalence of systemic diseases among patients requesting dental consultation in the public and private systems

    Science.gov (United States)

    Garea-Gorís, Rafael; Fernández-Varela, Marta; Tomás-Carmona, Inmaculada; Diniz-Freitas, Marcio; Limeres-Posse, Jacobo

    2012-01-01

    Objectives: To determine the prevalence and aetiology of systemic disease among patients requesting dental treatment in public and private practice. Study Design: A retrospective analysis was performed of the medical histories of 2000 patients requesting dental treatment during the year 2009. One thousand patients came from the Fontiñas Primary Care Oral and Dental Health Unit of the Galician Health Service (SERGAS), Spain, and the other thousand from a private clinic; both clinics were situated in Santiago de Compostela, La Coruña, Spain. The data collected were the following: demographic data (age and sex), presence or absence of systemic diseases and the nosologic categories, and drug history (type and number of drugs). Results: The prevalence of systemic disease was significantly higher among patients seen in the public system (35.2% in the public system versus 28.1% in the private system; p= 0.003). The differences between the two systems were more marked when considering patients aged under 65 years, particularly with respect to rheumatic and endocrine-metabolic (diabetes) disorders. The prevalence of patients receiving polypharmacy (>4 drugs/day) was significantly higher among patients seen in the public system (5.7% in the public system versus 2.7% in the private system; p= 0.009). Conclusions: There is a high prevalence of medical disorders and of patients receiving polypharmacy among individuals requesting dental care, particularly in the public health system. Dentists must have adequate training in medical disease and must be fully integrated into primary care health teams in order to prevent or adequately resolve complications. Key words: Dentistry, medical history, systemic disease, polypharmacy. PMID:22157672

  13. Cerebrospinal fluid interleukin-6 in central nervous system inflammatory diseases.

    Directory of Open Access Journals (Sweden)

    Alexandre Wullschleger

    Full Text Available BACKGROUND: Interleukin (IL-6 is recognised as an important cytokine involved in inflammatory diseases of the central nervous system (CNS. OBJECTIVE: To perform a large retrospective study designed to test cerebrospinal fluid (CSF IL-6 levels in the context of neurological diseases, and evaluate its usefulness as a biomarker to help discriminate multiple sclerosis (MS from other inflammatory neurological diseases (OIND. PATIENTS AND METHODS: We analyzed 374 CSF samples for IL-6 using a quantitative enzyme-linked immunosorbent assay. Groups tested were composed of demyelinating diseases of the CNS (DD, n = 117, including relapsing-remitting MS (RRMS, n = 65, primary progressive MS (PPMS, n = 11, clinically isolated syndrome (CIS, n = 11, optic neuritis (ON, n = 30; idiopathic transverse myelitis (ITM, n = 10; other inflammatory neurological diseases (OIND, n = 35; and non-inflammatory neurological diseases (NIND, n = 212. Differences between groups were analysed using Kruskal-Wallis test and Mann-Whitney U-test. RESULTS: CSF IL-6 levels exceeded the positivity cut-off of 10 pg/ml in 18 (51.4% of the 35 OIND samples, but in only three (3.9% of the 76 MS samples collected. CSF IL-6 was negative for all NIND samples tested (0/212. IL-6 cut-off of 10 pg/ml offers 96% sensitivity to exclude MS. CONCLUSION: CSF IL-6 may help to differentiate MS from its major differential diagnosis group, OIND.

  14. Ubiquitin-proteasome system involvement in Huntington’s disease

    Directory of Open Access Journals (Sweden)

    Zaira eOrtega

    2014-09-01

    Full Text Available Huntington’s disease (HD is a genetic autosomal dominant neurodegenerative disease caused by the expansion of a CAG repeat in the huntingtin (htt gene. This triplet expansion encodes a polyglutamine stretch (polyQ in the N-terminus of the high molecular weight (348-kDa and ubiquitously expressed protein huntingtin (htt. Normal individuals have between 6 and 35 CAG triplets, while expansions longer than 40 repeats lead to HD. The onset and severity of the disease depend on the length of the polyQ tract: the longer the polyQ is, the earlier the disease begins and the more severe the symptoms are. One of the main histopathological hallmarks of HD is the presence of intraneuronal proteinaceous inclusion bodies (IBs, whose prominent and invariant feature is the presence of Ubiquitin (Ub; therefore, they can be detected with anti-ubiquitin and anti-proteasome antibodies. This, together with the observation that mutations in components of the Ubiquitin Proteasome system (UPS give rise to some neurodegenerative diseases, suggests that UPS impairment may be causative of HD. Even though the link between disrupted Ub homeostasis and protein aggregation to HD is undisputed, the functional significance of these correlations and their mechanistic implications remains unresolved. Moreover, there is no consistent evidence documenting an accompanying decrease in levels of free Ub or disruption of Ub pool dynamics in neurodegenerative disease or models thus suggesting that the Ub-conjugate accumulation may be benign and just underlie lesion in 26S function. In this chapter we will elaborate on the different studies that have been performed using different experimental approaches, in order to shed light to this matter.

  15. Estimating multimorbidity prevalence with the Canadian Chronic Disease Surveillance System

    Directory of Open Access Journals (Sweden)

    Allison Feely

    2017-07-01

    Full Text Available Introduction: The Public Health Agency of Canada’s Canadian Chronic Disease Surveillance System (CCDSS uses a validated, standardized methodology to estimate prevalence of individual chronic diseases, such as diabetes. Expansion of the CCDSS for surveillance of multimorbidity, the co-occurrence of two or more chronic diseases, could better inform health promotion and disease prevention. The objective of this study was to assess the feasibility of using the CCDSS to estimate multimorbidity prevalence. Methods: We used administrative health data from seven provinces and three territories and five validated chronic conditions (i.e. cardiovascular disease, respiratory disease, mental illness, hypertension and diabetes to estimate multimorbidity prevalence. We produced age-standardized (using Canada’s 1991 population and age-specific estimates for two multimorbidity definitions: (1 two or more conditions, and (2 three or more conditions from the five validated conditions, by sex, fiscal year and geography. Results: Among Canadians aged 40 years and over in the fiscal year 2011/12, the prevalence of two or more and three or more chronic conditions was 26.5% and 10.2%, respectively, which is comparable to other estimates based on administrative health data. The increase in multimorbidity prevalence with increasing age was similar across provinces. The difference in prevalence for males and females varied by province and territory. We observed substantial variation in estimates over time. Results were consistent for the two definitions of multimorbidity. Conclusion: The CCDSS methodology can produce comparative estimates of multimorbidity prevalence across provinces and territories, but there are challenges in using it to estimate temporal trends. Further expansion of the CCDSS in the number and breadth of validated case definitions will improve the accuracy of multimorbidity surveillance for the Canadian population.

  16. Preclinical safety study of a recombinant Streptococcus pyogenes vaccine formulated with aluminum adjuvant.

    Science.gov (United States)

    HogenEsch, Harm; Dunham, Anisa; Burlet, Elodie; Lu, Fangjia; Mosley, Yung-Yi C; Morefield, Garry

    2017-02-01

    A recombinant vaccine composed of a fusion protein formulated with aluminum hydroxide adjuvant is under development for protection against diseases caused by Streptococcus pyogenes. The safety and local reactogenicity of the vaccine was assessed by a comprehensive series of clinical, pathologic and immunologic tests in preclinical experiments. Outbred mice received three intramuscular injections of 1/5th of the human dose (0.1 ml) and rabbits received two injections of the full human dose. Control groups received adjuvant or protein antigen. The vaccine did not cause clinical evidence of systemic toxicity in mice or rabbits. There was a transient increase of peripheral blood neutrophils after the third vaccination of mice. In addition, the concentration of acute phase proteins serum amyloid A and haptoglobin was significantly increased 1 day after injection of the vaccine in mice. There was mild transient swelling and erythema of the injection site in both mice and rabbits. Treatment-related pathology was limited to inflammation at the injection site and accumulation of adjuvant-containing macrophages in the draining lymph nodes. In conclusion, the absence of clinical toxicity in two animal species suggest that the vaccine is safe for use in a phase I human clinical trial. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

  17. Preclinical aspects of anti-VEGF agents for the treatment of wet AMD: ranibizumab and bevacizumab

    Science.gov (United States)

    Meyer, C H; Holz, F G

    2011-01-01

    Three anti-vascular endothelial growth factor (VEGF) therapies are currently used for the treatment of patients with wet age-related macular degeneration (AMD): pegaptanib, ranibizumab, and bevacizumab. Ranibizumab is an antibody fragment approved for the treatment of wet AMD. Bevacizumab is a full-length antibody registered for use in oncology but unlicensed for wet AMD. However, it is used off-label worldwide not only for wet AMD but also for various other ocular diseases associated with macular edema and abnormal vessel growth. We consider aspects of ranibizumab and bevacizumab in relation to their molecular characteristics, in vitro and in vivo properties, and preclinical safety data. Before 2009, most studies described the short-term toxicity of bevacizumab in multiple cell types of the eye. Since 2009, an increasing number of studies have compared the properties of ranibizumab and bevacizumab and investigated their impact on retinal cell functioning. Compared with bevacizumab, ranibizumab neutralizes VEGF better at low concentrations, maintains efficacy for longer, and has a higher retinal penetration and potency. Studies in animals demonstrate ranibizumab to be better localized to the injected eye, whereas bevacizumab appears to have a greater effect in the fellow eye. In humans, a localized and systemic effect has been reported for both molecules. In conclusion, overlapping yet distinct pharmacological properties of ranibizumab and bevacizumab indicate that safety or efficacy data from one cannot be extrapolated to the other. PMID:21455242

  18. Preclinical tools in PET-tracer development : automatisation and biopharmaceutical evaluation with special emphasis on the adenosine A3 receptor

    International Nuclear Information System (INIS)

    Haeusler, D. I. B.

    2010-01-01

    introduced as the first A3R PET-tracer recently. The adenosine A3 receptor is expressed in high levels in tumor cells, but not in the majority of normal cells. Potential application of a tracer for the A3R will be inflammation processes, oncological diseases as solid tumors; breast-, colon-, lung-, pancreas-, prostate-, melanoma- and brain metastases, as well as ischemia (brain and heart) and neurological pathologies as glaucoma and epilepsy. [18F]FE SUPPY:2, a completely new potential 18F-fluoroethylated radiotracer for the A3R, is presented in the thesis. The thesis covers the radiochemical preparation of [18F]FE SUPPY:2 and the automation of the radiosyntheses of both radiotracers in manuscript 2 and 3. Moreover, preclinical evaluations (affinity, selectivity, unspecific binding, biodistribution, logP, autoradiography and in-vitro and ex-vivo metabolic stability) of the two tracers were conducted, and also a comparison of these parameters are given in manuscripts 3 and 4. [18F]FE CIT, a potential new tracer for imaging of the DAT for e.g. Parkinson patients, was successfully further evaluated in terms of metabolic stability against CES and autoradiographic distribution on rat brain slices. The high selectivity of [18F]FE CIT over SERT and NET was confirmed in this study, and furthermore, it was even significantly higher than the selectivity of the well known tracers [123I]ß-CIT and [123I]FP-CIT. Based on these results, we aim for the future diagnostic application of [18F]FE CIT in humans with neurological and psychiatric diseases caused by changes in the dopaminergic system (e.g. Parkinson s disease, depression, drug abuse). (author) [de

  19. A novel method for preclinical detection of PrPSc in blood.

    Science.gov (United States)

    Rubenstein, Richard; Chang, Binggong; Gray, Perry; Piltch, Martin; Bulgin, Marie S; Sorensen-Melson, Sharon; Miller, Michael W

    2010-07-01

    In this study, we demonstrate that a moderate amount of protein misfolding cyclic amplification (PMCA) coupled to a novel surround optical fibre immunoassay (SOFIA) detection scheme can be used to detect the disease-associated form of the prion protein (PrP(Sc)) in protease-untreated plasma from preclinical and clinical scrapie sheep, and white-tailed deer with chronic wasting disease, following natural and experimental infection. PrP(Sc), resulting from a conformational change of the normal (cellular) form of prion protein (PrP(C)), is considered central to neuropathogenesis and serves as the only reliable molecular marker for prion disease diagnosis. While the highest levels of PrP(Sc) are present in the central nervous system, the development of a reasonable diagnostic assay requires the use of body fluids that characteristically contain exceedingly low levels of PrP(Sc). PrP(Sc) has been detected in the blood of sick animals by means of PMCA technology. However, repeated cycling over several days, which is necessary for PMCA of blood material, has been reported to result in decreased specificity (false positives). To generate an assay for PrP(Sc) in blood that is both highly sensitive and specific, we have utilized limited serial PMCA (sPMCA) with SOFIA. We did not find any enhancement of sPMCA with the addition of polyadenylic acid nor was it necessary to match the genotypes of the PrP(C) and PrP(Sc) sources for efficient amplification.

  20. Glial biomarkers in human central nervous system disease.

    Science.gov (United States)

    Garden, Gwenn A; Campbell, Brian M

    2016-10-01

    There is a growing understanding that aberrant GLIA function is an underlying factor in psychiatric and neurological disorders. As drug discovery efforts begin to focus on glia-related targets, a key gap in knowledge includes the availability of validated biomarkers to help determine which patients suffer from dysfunction of glial cells or who may best respond by targeting glia-related drug mechanisms. Biomarkers are biological variables with a significant relationship to parameters of disease states and can be used as surrogate markers of disease pathology, progression, and/or responses to drug treatment. For example, imaging studies of the CNS enable localization and characterization of anatomical lesions without the need to isolate tissue for biopsy. Many biomarkers of disease pathology in the CNS involve assays of glial cell function and/or response to injury. Each major glia subtype (oligodendroglia, astroglia and microglia) are connected to a number of important and useful biomarkers. Here, we describe current and emerging glial based biomarker approaches for acute CNS injury and the major categories of chronic nervous system dysfunction including neurodegenerative, neuropsychiatric, neoplastic, and autoimmune disorders of the CNS. These descriptions are highlighted in the context of how biomarkers are employed to better understand the role of glia in human CNS disease and in the development of novel therapeutic treatments. GLIA 2016;64:1755-1771. © 2016 Wiley Periodicals, Inc.

  1. Modular cervical plate system for adjacent segment disease.

    Science.gov (United States)

    Hawasli, Ammar H; Cashin, John L; Wright, Neill M

    2018-02-23

    Adjacent-level disease after anterior cervical discectomy and fusion (ACDF) occurs in a significant proportion of patients and frequently requires revision operation. Methods using traditional plates typically require removal of the plate with anecdotally increased operative-time and morbidity. We review our experience in treating symptomatic adjacent-segment disease using both traditional plate removal and modular- plate system which allows for add-on plate components rather than removal of the entire plate. Authors compared 64 patients with revision surgery using modular-plate system for adjacent- segment disease compared to 2-cohorts: (1) patients with traditional plate-removal and (2) patients with no prior plate. Clinical data included demographics, original surgery, presentation, current surgery, use of modular system, need for preoperative computed-topography, operative-time, blood loss, hospital stay, complications, length of dysphagia, neck disability index and time-until-fusion. Modular cervical plate system was utilized to prevent exposure and removal of the entire plate. The terminal portion of the plate was exposed and the distal module was removed. Following the discectomy/arthrodesis, a module-plate extension was added onto the previous plate for extension of the prior instrumentation. Preoperative planning computed-topography was required in 26% of plate-removal and 17% of modular-plate cases. Revision surgery with no prior plate had reduced operative-time (77.0±18.1 min) when compared with plate removal (103.8±46.2 min; p<0.01). Blood-loss was lower for modular-plate system (38.3±20.4 mL) and no prior plate (38.4±12.6 mL) versus plate removal (78.2±65.9 mL, p<0.01). Hospital stay was similar for all groups. No complications were experienced with modular-plate revision but plate removal and revision after no prior plate carried 7.7% and 10.5% complication rates, respectively. There was a trend towards lower dysphagia and neck disability index

  2. Lung cancer, intracellular signaling pathways, and preclinical models

    International Nuclear Information System (INIS)

    Mordant, P.

    2012-01-01

    Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide. Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced anti-tumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the anti-tumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing anti-tumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. We then focus on animal models. Preclinical models of NSCLC require better clinical relevance to study disease mechanisms and innovative

  3. Cognitive reserve and cortical thickness in preclinical Alzheimer's disease.

    Science.gov (United States)

    Pettigrew, Corinne; Soldan, Anja; Zhu, Yuxin; Wang, Mei-Cheng; Brown, Timothy; Miller, Michael; Albert, Marilyn

    2017-04-01

    This study examined whether cognitive reserve (CR) alters the relationship between magnetic resonance imaging (MRI) measures of cortical thickness and risk of progression from normal cognition to the onset of clinical symptoms associated with mild cognitive impairment (MCI). The analyses included 232 participants from the BIOCARD study. Participants were cognitively normal and largely middle aged (M age = 56.5) at their baseline MRI scan. After an average of 11.8 years of longitudinal follow-up, 48 have developed clinical symptoms of MCI or dementia (M time from baseline to clinical symptom onset = 7.0 years). Mean thickness was measured over eight 'AD vulnerable' cortical regions, and cognitive reserve was indexed by a composite score consisting of years of education, reading, and vocabulary measures. Using Cox regression models, CR and cortical thickness were each independently associated with risk of clinical symptom onset within 7 years of baseline, suggesting that the neuronal injury occurring proximal to symptom onset has a direct association with clinical outcomes, regardless of CR. In contrast, there was a significant interaction between CR and mean cortical thickness for risk of progression more than 7 years from baseline, suggesting that individuals with high CR are better able to compensate for cortical thinning that is beginning to occur at the very earliest phase of AD.

  4. Tuberculosis disease diagnosis using artificial immune recognition system.

    Science.gov (United States)

    Shamshirband, Shahaboddin; Hessam, Somayeh; Javidnia, Hossein; Amiribesheli, Mohsen; Vahdat, Shaghayegh; Petković, Dalibor; Gani, Abdullah; Kiah, Miss Laiha Mat

    2014-01-01

    There is a high risk of tuberculosis (TB) disease diagnosis among conventional methods. This study is aimed at diagnosing TB using hybrid machine learning approaches. Patient epicrisis reports obtained from the Pasteur Laboratory in the north of Iran were used. All 175 samples have twenty features. The features are classified based on incorporating a fuzzy logic controller and artificial immune recognition system. The features are normalized through a fuzzy rule based on a labeling system. The labeled features are categorized into normal and tuberculosis classes using the Artificial Immune Recognition Algorithm. Overall, the highest classification accuracy reached was for the 0.8 learning rate (α) values. The artificial immune recognition system (AIRS) classification approaches using fuzzy logic also yielded better diagnosis results in terms of detection accuracy compared to other empirical methods. Classification accuracy was 99.14%, sensitivity 87.00%, and specificity 86.12%.

  5. DISEASES

    DEFF Research Database (Denmark)

    Pletscher-Frankild, Sune; Pallejà, Albert; Tsafou, Kalliopi

    2015-01-01

    Text mining is a flexible technology that can be applied to numerous different tasks in biology and medicine. We present a system for extracting disease-gene associations from biomedical abstracts. The system consists of a highly efficient dictionary-based tagger for named entity recognition...... of human genes and diseases, which we combine with a scoring scheme that takes into account co-occurrences both within and between sentences. We show that this approach is able to extract half of all manually curated associations with a false positive rate of only 0.16%. Nonetheless, text mining should...... not stand alone, but be combined with other types of evidence. For this reason, we have developed the DISEASES resource, which integrates the results from text mining with manually curated disease-gene associations, cancer mutation data, and genome-wide association studies from existing databases...

  6. Effects of Probiotics on the Immune System and Allergic Diseases

    Directory of Open Access Journals (Sweden)

    Naoki Shimojo

    2005-01-01

    Full Text Available Intestinal microbiota play a crucial role in the development of mucosal tolerance and adaptation. Perturbations in microbiota composition are strongly associated with allergies and asthma in westernized countries. There has been accumulating evidence that the administration of probiotics, “live microbial supplements that exert a beneficial effect on human health,” may be effective in the treatment and/or prevention of allergic diseases. Although it has been shown that part of the effect of probiotics arises from its interaction with the host immune system, the precise mechanisms remain to be determined. In addition, future studies are necessary to define appropriate species and strains, optimum dose, frequency, and duration for the treatment of allergic diseases.

  7. Linking Microbiota to Human Diseases: A Systems Biology Perspective.

    Science.gov (United States)

    Wu, Hao; Tremaroli, Valentina; Bäckhed, Fredrik

    2015-12-01

    The human gut microbiota encompasses a densely populated ecosystem that provides essential functions for host development, immune maturation, and metabolism. Alterations to the gut microbiota have been observed in numerous diseases, including human metabolic diseases such as obesity, type 2 diabetes (T2D), and irritable bowel syndrome, and some animal experiments have suggested causality. However, few studies have validated causality in humans and the underlying mechanisms remain largely to be elucidated. We discuss how systems biology approaches combined with new experimental technologies may disentangle some of the mechanistic details in the complex interactions of diet, microbiota, and host metabolism and may provide testable hypotheses for advancing our current understanding of human-microbiota interaction. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. The Thalamostriatal System in Normal and Diseased States

    Directory of Open Access Journals (Sweden)

    Yoland eSmith

    2014-01-01

    Full Text Available Because of our limited knowledge of the functional role of the thalamostriatal system, this massive network is often ignored in models of the pathophysiology of brain disorders of basal ganglia origin, such as Parkinson’s disease. However, over the past decade, significant advances have led to a deeper understanding of the anatomical, electrophysiological, behavioral and pathological aspects of the thalamostriatal system. The cloning of the vesicular glutamate transporters 1 and 2 (vGluT1 and vGluT2 has provided powerful tools to differentiate thalamostriatal from corticostriatal glutamatergic terminals, allowing us to carry out comparative studies of the synaptology and plasticity of these two systems in normal and pathological conditions. Findings from these studies have led to the recognition of two thalamostriatal systems, based on their differential origin from the caudal intralaminar nuclear group, the centre median/parafascicular (CM/Pf complex, or other thalamic nuclei. The recent use of optogenetic methods supports this model of the organization of the thalamostriatal systems, showing differences in functionality and glutamate receptor localization at thalamostriatal synapses from Pf and other thalamic nuclei. At the functional level, evidence largely gathered from thalamic recordings in awake monkeys strongly suggests that the thalamostriatal system from the CM/Pf is involved in regulating alertness and switching behaviors. Importantly, there is evidence that the caudal intralaminar nuclei and their axonal projections to the striatum partly degenerate in Parkinson’s disease and that CM/Pf deep brain stimulation may be therapeutically useful in several movement disorders.

  9. IgG4-related Disease - A Systemic Disease that Deserves Attention Regardless of One's Subspecialty.

    Science.gov (United States)

    Hamano, Hideaki; Tanaka, Eiji; Ishizaka, Nobukazu; Kawa, Shigeyuki

    2017-12-27

    IgG4-related disease (IgG4-RD) is an inflammatory condition characterized by a high serum IgG4 concentration and the abundant infiltration of lymphocytes and IgG4-positive plasma cells in the tissue, as well as spatial (diverse clinical manifestations) and temporal (the possibility of recurrence) multiplicities. Since the initial documentation of IgG4-related disease in patients with autoimmune pancreatitis in 2001, a growing body of evidence has been accumulating to suggest that various-virtually all-organs can be affected by IgG4-RD. In general, steroid therapy is effective and is considered to be the first-line treatment for IgG4-RD. The precise mechanism underlying this systemic disorder has remained unknown. Considering that IgG4-RD was specified as being an intractable disease in 2015, further studies are needed to clarify whether IgG4-RD is indeed a distinct disease entity or a complex of disorders of different etiologies and clinical conditions.

  10. Novel systems biology insights using antifibrotic approaches for diabetic kidney disease

    KAUST Repository

    RamachandraRao, Satish Posettihalli

    2010-01-01

    Although several interventions slow the progression of diabetic nephropathy, current therapies do not halt progression completely. Recent preclinical studies suggested that pirfenidone (PFD) prevents fibrosis in various diseases, but the mechanisms underlying its antifibrotic action are incompletely understood. To explore the therapeutic potential of PFD, we studied the PFD-treated db/db diabetic mouse kidney by liquid chromatography-tandem mass spectrometry proteomics. A total of 21 proteins unique to PFD-treated diabetic kidneys were identified. Analysis of gene ontology and protein-protein interactions of these proteins suggested that PFD may regulate RNA translation. Two key proteins involved in mRNA translation initiation and elongation were further evaluated and found to be regulated by PFD at the level of phosphorylation. In conclusion, insights from combining proteomics and bioinformatics improve the likelihood of rapid advancement of novel clinical therapies focused on reducing inflammation and fibrosis for diabetic complications. © 2010 Expert Reviews Ltd.

  11. Therapeutic potential of systemic brain rejuvenation strategies for neurodegenerative disease.

    Science.gov (United States)

    Horowitz, Alana M; Villeda, Saul A

    2017-01-01

    Neurodegenerative diseases are a devastating group of conditions that cause progressive loss of neuronal integrity, affecting cognitive and motor functioning in an ever-increasing number of older individuals. Attempts to slow neurodegenerative disease advancement have met with little success in the clinic; however, a new therapeutic approach may stem from classic interventions, such as caloric restriction, exercise, and parabiosis. For decades, researchers have reported that these systemic-level manipulations can promote major functional changes that extend organismal lifespan and healthspan. Only recently, however, have the functional effects of these interventions on the brain begun to be appreciated at a molecular and cellular level. The potential to counteract the effects of aging in the brain, in effect rejuvenating the aged brain, could offer broad therapeutic potential to combat dementia-related neurodegenerative disease in the elderly. In particular, results from heterochronic parabiosis and young plasma administration studies indicate that pro-aging and rejuvenating factors exist in the circulation that can independently promote or reverse age-related phenotypes. The recent demonstration that human umbilical cord blood similarly functions to rejuvenate the aged brain further advances this work to clinical translation. In this review, we focus on these blood-based rejuvenation strategies and their capacity to delay age-related molecular and functional decline in the aging brain. We discuss new findings that extend the beneficial effects of young blood to neurodegenerative disease models. Lastly, we explore the translational potential of blood-based interventions, highlighting current clinical trials aimed at addressing therapeutic applications for the treatment of dementia-related neurodegenerative disease in humans.

  12. Whole Blood Gene Expression Profiling in Preclinical and Clinical Cattle Infected with Atypical Bovine Spongiform Encephalopathy.

    Directory of Open Access Journals (Sweden)

    Elena Xerxa

    Full Text Available Prion diseases, such as bovine spongiform encephalopathies (BSE, are transmissible neurodegenerative disorders affecting humans and a wide variety of mammals. Variant Creutzfeldt-Jakob disease (vCJD, a prion disease in humans, has been linked to exposure to BSE prions. This classical BSE (cBSE is now rapidly disappearing as a result of appropriate measures to control animal feeding. Besides cBSE, two atypical forms (named H- and L-type BSE have recently been described in Europe, Japan, and North America. Here we describe the first wide-spectrum microarray analysis in whole blood of atypical BSE-infected cattle. Transcriptome changes in infected animals were analyzed prior to and after the onset of clinical signs. The microarray analysis revealed gene expression changes in blood prior to the appearance of the clinical signs and during the progression of the disease. A set of 32 differentially expressed genes was found to be in common between clinical and preclinical stages and showed a very similar expression pattern in the two phases. A 22-gene signature showed an oscillating pattern of expression, being differentially expressed in the preclinical stage and then going back to control levels in the symptomatic phase. One gene, SEL1L3, was downregulated during the progression of the disease. Most of the studies performed up to date utilized various tissues, which are not suitable for a rapid analysis of infected animals and patients. Our findings suggest the intriguing possibility to take advantage of whole blood RNA transcriptional profiling for the preclinical identification of prion infection. Further, this study highlighted several pathways, such as immune response and metabolism that may play an important role in peripheral prion pathogenesis. Finally, the gene expression changes identified in the present study may be further investigated as a fingerprint for monitoring the progression of disease and for developing targeted therapeutic

  13. Computer-aided diagnosis expert system for cerebrovascular diseases.

    Science.gov (United States)

    Chen, Xu; Wang, Zhijun; Sy, Chrisopher; Liu, Xiaokun; Qian, Jinwu; Zheng, Jia; Dong, Zhiqiang; Cao, Limei; Geng, Xiang; Xu, Shuye; Liu, Xueyuan

    2014-05-01

    To establish an expert diagnosis system for cerebrovascular diseases (CVDs) and assess accuracy of the diagnosis system. An expert diagnosis system for CVDs was established and evaluated using actual clinical cases. An expert diagnosis system for CVDs was established and tested in 319 clinical patients. Diagnosis accordance was obtained in 307 patients (the diagnosis accordance rate was 96.2%). Involved were 223, 7, 23, 54 and 12 patients with cerebral thrombosis, cerebral embolism, transient ischemic attack, cerebral hemorrhage and subarachnoid hemorrhage, respectively; and diagnosis accordance was obtained in 219 (98.2%), 6 (85.7%), 23 (100%), 48 (88.9%) and 11 (91.7%), respectively. Overall, the case analysis results support and demonstrate the diagnostic reasoning accuracy of the expert diagnosis system for CVDs. With the expert diagnosis system, medical experts' diagnosis of CVDs can be effectively mimicked and auxiliary diagnosis of CVDs has been preliminarily realized, laying a foundation for increasing the diagnostic accuracy of clinical diagnoses as it pertains to CVDs.

  14. Effects of migraine disease on the vestibulocochlear system

    Directory of Open Access Journals (Sweden)

    Murat Zaim

    2015-03-01

    Full Text Available Objective: Migraine patients have tendency to have vestibular and auditory system problems. The aim of this study is to evaluate vestibule cochlear system of patients with migraine with Transient-evoked otoacoustic emissions (TEOAE video-nystagmography (VNG and caloric test. Methods:39 patients diagnosed with migraine and control group of 21 healthy volunteers were included in this study. Before they were included in the study, all of them were examined and those who has acute otitis media, chronic otitis media, tympanic membrane perforation, external otitis, ear surgery history and head trauma were excluded from the study. All patients and volunteers were tested by TEOAE, VNG and caloric tests. In evaluating the statistical data, SPSS 15.0 was utilized. Results: When TEOAE values for the migraine group and for the control group are compared, it is found statistically significant that the TEOAE values for the migraine group is lower than those for the control group. This result shows that there can be a pathology that is able to affect cochlear functions in migraine disease. As for VNG test results, a statistically significant difference cannot be determined between migraine and control groups. More over, the identification of canal paresis in caloric test indicates that peripheral vestibular problems accompany migraine disease. Conclusion:Evaluating vestibulocochlear system of migraine patients with TEOAE, VNG and caloric tests has been an important task for identifying vestibular imperfections accompanying these patients and for predicting potential auricular pathologies. J Clin Exp Invest 2015; 6(1: 1-4

  15. [Environmental pollutants as adjuvant factors of immune system derived diseases].

    Science.gov (United States)

    Lehmann, Irina

    2017-06-01

    The main task of the immune system is to protect the body against invading pathogens. To be able to do so, immune cells must be able to recognize and combat exogenous challenges and at the same time tolerate body-borne structures. A complex regulatory network controls the sensitive balance between defense and tolerance. Perturbation of this network ultimately leads to the development of chronic inflammation, such as allergies, autoimmune reactions, and infections, because the immune system is no longer able to efficiently eliminate invading pathogens. Environmental pollutants can cause such perturbations by affecting the function of immune cells in such a way that they would react hypersensitively against allergens and the body's own structures, respectively, or that they would be no longer able to adequately combat pathogens. This indirect effect is also known as adjuvant effect. For pesticides, heavy metals, wood preservatives, or volatile organic compounds such adjuvant effects are well known. Examples of the mechanism by which environmental toxins contribute to chronic inflammatory diseases are manifold and will be discussed along asthma and allergies.While the immune system of healthy adults is typically well able to distinguish between foreign and endogenous substances even under adverse environmental conditions, that of children would react much more sensible upon comparable environmental challenges. To prevent priming for diseases by environmental cues during that highly sensitive period of early childhood children are to be particularly protected.

  16. Kikuchi-Fujimoto disease and systemic lupus erythematosus

    Directory of Open Access Journals (Sweden)

    Baenas DF

    2016-06-01

    Full Text Available Diego F Baenas,1 Fernando A Diehl,1 María J Haye Salinas,2 Verónica Riva,3 Ana Diller,3 Pablo A Lemos1,4 1Clinical Medicine Department, 2Rheumatology Department, 3Pathology Department, Hospital Privado Universitario de Córdoba Medical Center, 4Instituto Universitario de Ciencias Biomédicas, Universitary Institute, Córdoba, Argentina Abstract: Kikuchi–Fujimoto disease, or histiocytic necrotizing lymphadenitis, is an infrequent idiopathic disorder. It has been associated with autoimmune disorders, of which systemic lupus erythematosus is the most outstanding. The basis of its diagnosis relies on the histological examination of lymph nodes, which typically reveals necrosis surrounded by histiocytes with crescentic nucleus, immunoblasts and plasma cells, and absence of neutrophils. We report the case of a 27-year-old Argentinian female patient without any relevant past medical history to demonstrate the correlation between Kikuchi–Fujimoto disease and systemic lupus erythematosus. Keywords: histiocytic necrotizing lymphadenitis, systemic lupus erythematosus, autoimmune disorders, febrile syndrome

  17. Preclinical Mouse Cancer Models: A Maze of Opportunities and Challenges

    Science.gov (United States)

    Day, Chi-Ping; Merlino, Glenn; Van Dyke, Terry

    2015-01-01

    Significant advances have been made in developing novel therapeutics for cancer treatment, and targeted therapies have revolutionized the treatment of some cancers. Despite the promise, only about five percent of new cancer drugs are approved, and most fail due to lack of efficacy. The indication is that current preclinical methods are limited in predicting successful outcomes. Such failure exacts enormous cost, both financial and in the quality of human life. This primer explores the current status, promise and challenges of preclinical evaluation in advanced mouse cancer models and briefly addresses emerging models for early-stage preclinical development. PMID:26406370

  18. Oral Dysbiotic Communities and Their Implications in Systemic Diseases

    Directory of Open Access Journals (Sweden)

    Preethi Sudhakara

    2018-04-01

    Full Text Available The human body supports the growth of a wide array of microbial communities in various niches such as the oral cavity, gastro-intestinal and urogenital tracts, and on the surface of the skin. These host associated microbial communities include yet-un-cultivable bacteria and are influenced by various factors. Together, these communities of bacteria are referred to as the human microbiome. Human oral microbiome consists of both symbionts and pathobionts. Deviation from symbiosis among the bacterial community leads to “dysbiosis”, a state of community disturbance. Dysbiosis occurs due to many confounding factors that predispose a shift in the composition and relative abundance of microbial communities. Dysbiotic communities have been a major cause for many microbiome related systemic infections. Such dysbiosis is directed by certain important pathogens called the “keystone pathogens”, which can modulate community microbiome variations. One such persistent infection is oral infection, mainly periodontitis, where a wide array of causal organisms have been implied to systemic infections such as cardio vascular disease, diabetes mellitus, rheumatoid arthritis, and Alzheimer’s disease. The keystone pathogens co-occur with many yet-cultivable bacteria and their interactions lead to dysbiosis. This has been the focus of recent research. While immune evasion is one of the major modes that leads to dysbiosis, new processes and new virulence factors of bacteria have been shown to be involved in this important process that determines a disease or health state. This review focuses on such dysbiotic communities, their interactions, and their virulence factors that predispose the host to other systemic implications.

  19. Bridging the gap between basic and applied biology: towards preclinical translation

    Directory of Open Access Journals (Sweden)

    Ross L. Cagan

    2013-05-01

    To better translate basic research findings into the clinic, we are moving away from the traditional one-gene–one-phenotype model towards the discovery of complex mechanisms. In this Editorial, the new Editor-in-Chief and Senior Editors of Disease Models & Mechanisms (DMM discuss the role that the journal will play in this transition. DMM will continue to provide a platform for studies that bridge basic and applied science, and, by demanding the rigorous assessment of animal models of disease, will help drive the establishment of robust standards of preclinical testing for drug development.

  20. Current approach for urinary system stone disease in pregnant women

    Directory of Open Access Journals (Sweden)

    Orcun Celik

    2016-01-01

    Full Text Available Urinary system stones can be classified according to size, location, X-ray characteristics, aetiology of formation, composition, and risk of recurrence. Especially urolithiasis during pregnancy is a diagnostic and therapeutic challenge. In most cases, it becomes symptomatic in the second or third trimester. Diagnostic options in pregnant women are limited due to the possible teratogenic, carcinogenic, and mutagenic risk of foetal radiation exposure. Clinical management of a pregnant urolithiasis patient is complex and demands close collaboration between patient, obstetrician and urologist. We would like to review current diagnosis and treatment modalities of stone disease of pregnant woman.

  1. The Equine Neonatal Cardiovascular System in Health and Disease.

    Science.gov (United States)

    Marr, Celia M

    2015-12-01

    The neonatal foal is in a transitional state from prenatal to postnatal circulation. Healthy newborn foals often have cardiac murmurs and dysrhythmias, which are usually transient and of little clinical significance. The neonatal foal is prone to infection and cardiac trauma. Echocardiography is the main tool used for valuation of the cardiovascular system. With prompt identification and appropriate action, dysrhythmias and other sequel to cardiac trauma can be corrected. With infection, the management and prognosis are driven by concurrent sepsis. Congenital disease represents an interesting diagnostic challenge for the neonatologist, but surgical correction is not appropriate for most equids. Copyright © 2015 Elsevier Inc. All rights reserved.

  2. Prototype learning and dissociable categorization systems in Alzheimer's disease.

    Science.gov (United States)

    Heindel, William C; Festa, Elena K; Ott, Brian R; Landy, Kelly M; Salmon, David P

    2013-08-01

    Recent neuroimaging studies suggest that prototype learning may be mediated by at least two dissociable memory systems depending on the mode of acquisition, with A/Not-A prototype learning dependent upon a perceptual representation system located within posterior visual cortex and A/B prototype learning dependent upon a declarative memory system associated with medial temporal and frontal regions. The degree to which patients with Alzheimer's disease (AD) can acquire new categorical information may therefore critically depend upon the mode of acquisition. The present study examined A/Not-A and A/B prototype learning in AD patients using procedures that allowed direct comparison of learning across tasks. Despite impaired explicit recall of category features in all tasks, patients showed differential patterns of category acquisition across tasks. First, AD patients demonstrated impaired prototype induction along with intact exemplar classification under incidental A/Not-A conditions, suggesting that the loss of functional connectivity within visual cortical areas disrupted the integration processes supporting prototype induction within the perceptual representation system. Second, AD patients demonstrated intact prototype induction but impaired exemplar classification during A/B learning under observational conditions, suggesting that this form of prototype learning is dependent on a declarative memory system that is disrupted in AD. Third, the surprisingly intact classification of both prototypes and exemplars during A/B learning under trial-and-error feedback conditions suggests that AD patients shifted control from their deficient declarative memory system to a feedback-dependent procedural memory system when training conditions allowed. Taken together, these findings serve to not only increase our understanding of category learning in AD, but to also provide new insights into the ways in which different memory systems interact to support the acquisition of

  3. Primary immunodeficiency diseases: dissectors of the immune system.

    Science.gov (United States)

    Buckley, Rebecca H

    2002-07-01

    The past 50 years have seen enormous progress in this field. An unknown concept until 1952, there are now more than 100 different primary immunodeficiency syndromes in the world's literature. Each novel syndrome has shed new insight into the workings of the immune system, dissecting its multiple parts into unique functioning components. This has been especially true over the past decade, as the molecular bases of approximately 40 of these diseases have been identified in rapid succession. Advances in the treatment of these diseases have also been impressive. Antibody replacement has been improved greatly by the development of human immunoglobulin preparations that can be safely administered by the intravenous route, and cytokine and humanized anticytokine therapies are now possible through recombinant technologies. The ability to achieve life-saving immune reconstitution of patients with lethal severe combined immunodeficiency by administering rigorously T-cell-depleted allogeneic related haploidentical bone marrow stem cells has extended this option to virtually all such infants, if diagnosed before untreatable infections develop. Finally, the past 3 years have witnessed the first truly successful gene therapy. The impressive results in X-linked severe combined immunodeficiency offer hope that this approach can be extended to many more diseases in the future.

  4. Imaging Assessment of Cardiovascular Disease in Systemic Lupus Erythematosus

    Directory of Open Access Journals (Sweden)

    Sara C. Croca

    2012-01-01

    Full Text Available Systemic lupus erythematosus is a multisystem, autoimmune disease known to be one of the strongest risk factors for atherosclerosis. Patients with SLE have an excess cardiovascular risk compared with the general population, leading to increased cardiovascular morbidity and mortality. Although the precise explanation for this is yet to be established, it seems to be associated with the presence of an accelerated atherosclerotic process, arising from the combination of traditional and lupus-specific risk factors. Moreover, cardiovascular-disease associated mortality in patients with SLE has not improved over time. One of the main reasons for this is the poor performance of standard risk stratification tools on assessing the cardiovascular risk of patients with SLE. Therefore, establishing alternative ways to identify patients at increased risk efficiently is essential. With recent developments in several imaging techniques, the ultimate goal of cardiovascular assessment will shift from assessing symptomatic patients to diagnosing early cardiovascular disease in asymptomatic patients which will hopefully help us to prevent its progression. This review will focus on the current status of the imaging tools available to assess cardiac and vascular function in patients with SLE.

  5. Extensive preclinical evaluation of an infliximab biosimilar candidate.

    Science.gov (United States)

    Velasco-Velázquez, M A; Salinas-Jazmín, N; Hisaki-Itaya, E; Cobos-Puc, L; Xolalpa, W; González, G; Tenorio-Calvo, A; Piña-Lara, N; Juárez-Bayardo, L C; Flores-Ortiz, L F; Medina-Rivero, E; Pérez, N O; Pérez-Tapia, S M

    2017-05-01

    Infliximab is therapeutic monoclonal antibody (mAb) against TNF-α employed in the treatment of immunoinflammatory diseases. The development of biosimilar mAbs is a global strategy to increase drug accessibility and reduce therapy-associated costs. Herein we compared key physicochemical characteristics and biological activities produced by infliximab and infliximab-Probiomed in order to identify functionally relevant differences between the mAbs. Binding of infliximab-Probiomed to TNF-α was specific and had kinetics comparable to that of the reference product. Both mAbs had highly similar neutralizing efficacy in HUVEC cell cultures stimulated with TNF-α. In vitro induction of CDC and ADCC were also similar between the evaluated products. In vivo comparability was assessed using a transgenic mouse model of arthritis that expresses human TNF-α in a 13-week multiple-administration study. Infliximab and infliximab-Probiomed showed comparable efficacy, safety, and pharmacokinetic profiles. Our results indicate that infliximab-Probiomed has highly similar activities to infliximab in preclinical models, warranting a clinical evaluation of its biosimilarity. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. Tomography patterns of lung disease in systemic sclerosis

    Energy Technology Data Exchange (ETDEWEB)

    Bastos, Andrea de Lima; Correa, Ricardo de Amorim; Ferreira, Gilda Aparecida, E-mail: andrealb@ufmg.br [Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, MG (Brazil). Faculdade de Medicina

    2016-09-15

    Currently, lung impairment is the leading factor responsible for the morbidity and mortality associated with systemic sclerosis. Therefore, the recognition of the various tomography patterns becomes decisive in the clinical management of these patients. In high-resolution computed tomography studies, the most common pattern is that of nonspecific interstitial pneumonia. However, there are other forms of lung involvement that must also be recognized. The aim of this study was to review the literature on the main changes resulting from pulmonary involvement in systemic sclerosis and the corresponding radiological findings, considering the current classification of interstitial diseases. We searched the Medline (PubMed), Lilacs, and SciELO databases in order to select articles related to pulmonary changes in systemic sclerosis and published in English between 2000 and 2015. The pulmonary changes seen on computed tomography in systemic sclerosis are varied and are divided into three main categories: interstitial, alveolar, and vascular. Interstitial changes constitute the most common type of pulmonary involvement in systemic sclerosis. However, alveolar and vascular manifestations must also be recognized and considered in the presence of atypical clinical presentations and inadequate treatment responses. (author)

  7. Tomography patterns of lung disease in systemic sclerosis

    Directory of Open Access Journals (Sweden)

    Andréa de Lima Bastos

    Full Text Available Abstract Currently, lung impairment is the leading factor responsible for the morbidity and mortality associated with systemic sclerosis. Therefore, the recognition of the various tomography patterns becomes decisive in the clinical management of these patients. In high-resolution computed tomography studies, the most common pattern is that of nonspecific interstitial pneumonia. However, there are other forms of lung involvement that must also be recognized. The aim of this study was to review the literature on the main changes resulting from pulmonary involvement in systemic sclerosis and the corresponding radiological findings, considering the current classification of interstitial diseases. We searched the Medline (PubMed, Lilacs, and SciELO databases in order to select articles related to pulmonary changes in systemic sclerosis and published in English between 2000 and 2015. The pulmonary changes seen on computed tomography in systemic sclerosis are varied and are divided into three main categories: interstitial, alveolar, and vascular. Interstitial changes constitute the most common type of pulmonary involvement in systemic sclerosis. However, alveolar and vascular manifestations must also be recognized and considered in the presence of atypical clinical presentations and inadequate treatment responses.

  8. Hyperspectral imaging system for disease scanning on banana plants

    Science.gov (United States)

    Ochoa, Daniel; Cevallos, Juan; Vargas, German; Criollo, Ronald; Romero, Dennis; Castro, Rodrigo; Bayona, Oswaldo

    2016-05-01

    Black Sigatoka (BS) is a banana plant disease caused by the fungus Mycosphaerella fijiensis. BS symptoms can be observed at late infection stages. By that time, BS has probably spread to other plants. In this paper, we present our current work on building an hyper-spectral (HS) imaging system aimed at in-vivo detection of BS pre-symptomatic responses in banana leaves. The proposed imaging system comprises a motorized stage, a high-sensitivity VIS-NIR camera and an optical spectrograph. To capture images of the banana leaf, the stage's speed and camera's frame rate must be computed to reduce motion blur and to obtain the same resolution along both spatial dimensions of the resulting HS cube. Our continuous leaf scanning approach allows imaging leaves of arbitrary length with minimum frame loss. Once the images are captured, a denoising step is performed to improve HS image quality and spectral profile extraction.

  9. In vivo imaging enables high resolution preclinical trials on patients' leukemia cells growing in mice.

    Directory of Open Access Journals (Sweden)

    Nadia Terziyska

    Full Text Available Xenograft mouse models represent helpful tools for preclinical studies on human tumors. For modeling the complexity of the human disease, primary tumor cells are by far superior to established cell lines. As qualified exemplary model, patients' acute lymphoblastic leukemia cells reliably engraft in mice inducing orthotopic disseminated leukemia closely resembling the disease in men. Unfortunately, disease monitoring of acute lymphoblastic leukemia in mice is hampered by lack of a suitable readout parameter.Patients' acute lymphoblastic leukemia cells were lentivirally transduced to express the membrane-bound form of Gaussia luciferase. In vivo imaging was established in individual patients' leukemias and extensively validated.Bioluminescence in vivo imaging enabled reliable and continuous follow-up of individual mice. Light emission strictly correlated to post mortem quantification of leukemic burden and revealed a logarithmic, time and cell number dependent growth pattern. Imaging conveniently quantified frequencies of leukemia initiating cells in limiting dilution transplantation assays. Upon detecting a single leukemia cell within more than 10,000 bone marrow cells, imaging enabled monitoring minimal residual disease, time to tumor re-growth and relapse. Imaging quantified therapy effects precisely and with low variances, discriminating treatment failure from partial and complete responses.For the first time, we characterized in detail how in vivo imaging reforms preclinical studies on patient-derived tumors upon increasing monitoring resolution. In the future, in vivo imaging will enable performing precise preclinical studies on a broad range of highly demanding clinical challenges, such as treatment failure, resistance in leukemia initiating cells, minimal residual disease and relapse.

  10. Encapsulated living choroid plexus cells: potential long-term treatments for central nervous system disease and trauma

    Science.gov (United States)

    Skinner, S. J. M.; Geaney, M. S.; Lin, H.; Muzina, M.; Anal, A. K.; Elliott, R. B.; Tan, P. L. J.

    2009-12-01

    In neurodegenerative disease and in acute brain injury, there is often local up-regulation of neurotrophin production close to the site of the lesion. Treatment by direct injection of neurotrophins and growth factors close to these lesion sites has repeatedly been demonstrated to improve recovery. It has therefore been proposed that transplanting viable neurotrophin-producing cells close to the trauma lesion, or site of degenerative disease, might provide a novel means for continuous delivery of these molecules directly to the site of injury or to a degenerative region. The aim of this paper is to summarize recent published information and present new experimental data that indicate that long-lasting therapeutic implants of choroid plexus (CP) neuroepithelium may be used to treat brain disease. CP produces and secretes numerous biologically active neurotrophic factors (NT). New gene microarray and proteomics data presented here indicate that many other anti-oxidant, anti-toxin and neuronal support proteins are also produced and secreted by CP cells. In the healthy brain, these circulate in the cerebrospinal fluid through the brain and spinal cord, maintaining neuronal networks and associated cells. Recent publications describe how transplanted CP cells and tissue, either free or in an immunoprotected encapsulated form, can effectively deliver therapeutic molecules when placed near the lesion or site of degenerative disease in animal models. Using simple techniques, CP neuroepithelial cell clusters in suspension culture were very durable, remaining viable for 6 months or more in vitro. The cell culture conditions had little effect on the wide range and activity of genes expressed and proteins secreted. Recently, completed experiments show that implanting CP within alginate-poly-ornithine capsules effectively protected these xenogeneic cells from the host immune system and allowed their survival for 6 months or more in the brains of rats, causing no adverse effects

  11. Prevalence of Systemic Diseases in Patients with Dental Infections

    Directory of Open Access Journals (Sweden)

    Seyed Mohsen Khoshniat Nikoo

    2013-02-01

    Full Text Available Background and Aims: The aim of this study was to investigate the prevalence of diabetes and other risk factors in patients with dental infections.Materials and Methods: A cross-sectional study was conducted among 50 patients who preferred in maxillofacial word of shariaty hospital with acute dental infections in 9 months. A self-administered questionnaire was administered during a dental appointment in order to gather demographic information and recorded past history of systemic disease, OPG radiography, gingival examination, and the result of lab tests such as CBC , FBS, PT, Bilirubin , Creat, T3, T4, TSH, HIVAb and HBSAg.Results: 28% of the subjects and diabetes, 28% Anemia, 4% Hepatitis and 4% suffered from thyroid deficiency.28% were smokers and 18% declared using alcohol. 6% of this population was addicted to narcotic substances.There was a significant correlation between age, education, diabetes and dental infections (P<0.05. DMFT forpeople with dental infections without any systemic disease were 8, for diabetic patients, smokers and alcohol users were respectively 17.16, 17 and 14.Conclusion: Diabetes found highly prevalent in patients with dental infection and high DMFT.It indicates a need to establish a comprehensive oral health promotion program based on whole examination and blood glucose control in diabetic patients who have acute dental infection by collaboration between dental and general health care professionals. Moreover, it is recommended that all patients should be educated in dental and oral health forprevention of dental infections.

  12. Histiocytoid Sweet Syndrome in a Child without Underlying Systemic Disease.

    Science.gov (United States)

    Yeom, Seung Dohn; Ko, Hye Soo; Moon, Jong Hyuk; Kang, Min Ji; Byun, Ji Won; Choi, Gwang Seong; Shin, Jeonghyun

    2017-10-01

    Sweet syndrome (acute, febrile, neutrophilic dermatosis) is characterized by the acute onset of an eruption of painful nodules or erythematous or violaceous plaques on the limbs, face and neck. These symptoms are accompanied by fever. The diagnostic features include histopathological findings of dermal neutrophilic infiltration without leukocytoclastic vasculitis or peripheral blood leukocytosis. Sweet syndrome is associated with infection, malignancies, autoimmune disease, pregnancy, and drugs. Patients with Sweet syndrome demonstrate a complete and rapid response to systemic steroid administration. Recently, a distinct variant of Sweet syndrome was reported, termed "histiocytoid Sweet syndrome", in which the infiltration of myeloperoxidase-positive histiocytoid mononuclear cells are observed (in contrast to the infiltration of neutrophils). The other clinical features are similar to those of classic Sweet syndrome. Pediatric Sweet syndrome is uncommon, and the histiocytoid type is even rarer. To date, four cases of histiocytoid Sweet syndrome have been reported in children. Herein, we describe a case of histiocytoid Sweet syndrome in an otherwise healthy 10-year-old boy with no underlying systemic disease in whom non-steroidal, anti-inflammatory drug treatment was successful.

  13. Adipokines and the cardiovascular system: mechanisms mediating health and disease.

    Science.gov (United States)

    Northcott, Josette M; Yeganeh, Azadeh; Taylor, Carla G; Zahradka, Peter; Wigle, Jeffrey T

    2012-08-01

    This review focuses on the role of adipokines in the maintenance of a healthy cardiovascular system, and the mechanisms by which these factors mediate the development of cardiovascular disease in obesity. Adipocytes are the major cell type comprising the adipose tissue. These cells secrete numerous factors, termed adipokines, into the blood, including adiponectin, leptin, resistin, chemerin, omentin, vaspin, and visfatin. Adipose tissue is a highly vascularised endocrine organ, and different adipose depots have distinct adipokine secretion profiles, which are altered with obesity. The ability of many adipokines to stimulate angiogenesis is crucial for adipose tissue expansion; however, excessive blood vessel growth is deleterious. As well, some adipokines induce inflammation, which promotes cardiovascular disease progression. We discuss how these 7 aforementioned adipokines act upon the various cardiovascular cell types (endothelial progenitor cells, endothelial cells, vascular smooth muscle cells, pericytes, cardiomyocytes, and cardiac fibroblasts), the direct effects of these actions, and their overall impact on the cardiovascular system. These were chosen, as these adipokines are secreted predominantly from adipocytes and have known effects on cardiovascular cells.

  14. Vitamin D endocrine system involvement in autoimmune rheumatic diseases.

    Science.gov (United States)

    Cutolo, Maurizio; Pizzorni, Carmen; Sulli, Alberto

    2011-12-01

    Vitamin D is synthesized from cholesterol in the skin (80-90%) under the sunlight and then metabolized into an active D hormone in liver, kidney and peripheral immune/inflammatory cells. These endocrine-immune effects include also the coordinated activities of the vitamin D-activating enzyme, 1alpha-hydroxylase (CYP27B1), and the vitamin D receptor (VDR) on cells of the immune system in mediating intracrine and paracrine actions. Vitamin D is implicated in prevention and protection from chronic infections (i.e. tubercolosis), cancer (i.e. breast cancer) and autoimmune rheumatic diseases since regulates both innate and adaptive immunity potentiating the innate response (monocytes/macrophages with antimicrobial activity and antigen presentation), but suppressing the adaptive immunity (T and B lymphocyte functions). Vitamin D has modulatory effects on B lymphocytes and Ig production and recent reports have demonstrated that 1,25(OH)2D3 does indeed exert direct effects on B cell homeostasis. A circannual rhythm of trough vitamin D levels in winter and peaks in summer time showed negative correlation with clinical status at least in rheumatoid arthritis and systemic lupus erythematosus. Recently, the onset of symptoms of early arthritis during winter or spring have been associated with greater radiographic evidence of disease progression at 12 months possibly are also related to seasonal lower vitamin D serum levels. Copyright © 2011 Elsevier B.V. All rights reserved.

  15. Fatal evolution of systemic lupus erythematosus associated with Crohn's disease

    Directory of Open Access Journals (Sweden)

    CHEBLI Júlio M. Fonseca

    2000-01-01

    Full Text Available The authors describe the case of a young Brazilian woman who was treated of ileocolonic Crohn's disease sparing rectum, as confirmed by colonoscopy and histopathological examination. After a 4-year course of sulfasalazine treatment, she presented with skin facial lesions in vespertilio, fever, arthralgias and high titers of anti-ANA and LE cells. A sulfasalazine-induced lupus syndrome was diagnosed, because after sulfasalazine withdrawal and a short course of prednisone, the clinical symptoms disappeared and the laboratory tests returned to normal. Mesalazine 3 g/day was started and the patient remained well for the next 3 years, when she was again admitted with fever, weakness, arthralgias, diplopy, strabismus and hypoaesthesia in both hands and feet, microhematuria, haematic casts, hypocomplementemia and high titers of autoimmune antibodies. A diagnosis of associated systemic lupus erythematosus was made. Although a pulsotherapy with methylprednisolone was started, no improvement was noticed. A cyclophosphamide trial was tried and again no positive results occurred. The patient evolved to severe clinical manifestations of general vasculitis affecting the central and peripheral nervous system and lungs, having a fatal evolution after 2 weeks. Although uncommon, the association of both disease may occur, and the authors call attention to this possibility, making a brief review of literature.

  16. Comparison and Prediction of Preclinical Students' Performance in ...

    African Journals Online (AJOL)

    olayemitoyin

    four preclinical students who took the. Bachelor of Medicine and Bachelor of Surgery (MBBS) Stage I Examination in Anatomy, Biochemistry, Physiology,. Social and Preventive Medicine, and Pharmacology between December1997 and May ...

  17. The role of radiolabelled compounds in preclinical drug development

    International Nuclear Information System (INIS)

    Hawkins, D.R.

    1988-01-01

    The role of radiolabelled compounds in the development of new drugs is discussed, with particular reference to their use in toxicological, metabolic and pharmacokinetic studies for the pre-clinical safety evaluation of new drugs. (U.K.)

  18. Comparison and Prediction of Preclinical Students' Performance in ...

    African Journals Online (AJOL)

    four preclinical students who took the Bachelor of Medicine and Bachelor of Surgery (MBBS) Stage I Examination in Anatomy, Biochemistry, Physiology, Social and Preventive Medicine, and Pharmacology between December1997 and May ...

  19. Pre-clinical functional magnetic resonance imaging. Pt. I. The kidney

    International Nuclear Information System (INIS)

    Zoellner, Frank G.; Kalayciyan, Raffi; Chacon-Caldera, Jorge; Zimmer, Fabian; Schad, Lothar R.

    2014-01-01

    The prevalence of chronic kidney disease (CKD) is increasing worldwide. In Europe alone, at least 8% of the population currently has some degree of CKD. CKD is associated with serious comorbidity, reduced life expectancy, and high economic costs; hence, the early detection and adequate treatment of kidney disease is important. Pre-clinical research can not only give insights into the mechanisms of the various kidney diseases but it also allows for investigating the outcome of new drugs developed to treat kidney disease. Functional magnetic resonance imaging provides non-invasive access to tissue and organ function in animal models. Advantages over classical animal research approaches are numerous: the same animal might be repeatedly imaged to investigate a progress or a treatment of disease over time. This has also a direct impact on animal welfare and the refinement of classical animal experiments as the number of animals in the studies might be reduced. In this paper, we review current state of the art in functional magnetic resonance imaging with a focus on pre-clinical kidney imaging.

  20. Pre-clinical functional magnetic resonance imaging. Pt. I. The kidney

    Energy Technology Data Exchange (ETDEWEB)

    Zoellner, Frank G.; Kalayciyan, Raffi; Chacon-Caldera, Jorge; Zimmer, Fabian; Schad, Lothar R. [Heidelberg Univ., Mannheim (Germany). Computer Assisted Clinical Medicine

    2014-07-01

    The prevalence of chronic kidney disease (CKD) is increasing worldwide. In Europe alone, at least 8% of the population currently has some degree of CKD. CKD is associated with serious comorbidity, reduced life expectancy, and high economic costs; hence, the early detection and adequate treatment of kidney disease is important. Pre-clinical research can not only give insights into the mechanisms of the various kidney diseases but it also allows for investigating the outcome of new drugs developed to treat kidney disease. Functional magnetic resonance imaging provides non-invasive access to tissue and organ function in animal models. Advantages over classical animal research approaches are numerous: the same animal might be repeatedly imaged to investigate a progress or a treatment of disease over time. This has also a direct impact on animal welfare and the refinement of classical animal experiments as the number of animals in the studies might be reduced. In this paper, we review current state of the art in functional magnetic resonance imaging with a focus on pre-clinical kidney imaging.

  1. Phasic Dopaminergic Signaling and the Presymptomatic Phase of Parkinson's Disease

    National Research Council Canada - National Science Library

    Garris, Paul A; Schallert, Tim; Heldenreich, Byron A

    2005-01-01

    .... The overall hypothesis is that, in rats with partial dopamine lesions mimicking the preclinical phase of Parkinson's disease, deficits in phasic dopaminergic signaling are associated with behavioral deficits...

  2. An Automated Home-Cage System to Assess Learning and Performance of a Skilled Motor Task in a Mouse Model of Huntington's Disease.

    Science.gov (United States)

    Woodard, Cameron L; Bolaños, Federico; Boyd, James D; Silasi, Gergely; Murphy, Timothy H; Raymond, Lynn A

    2017-01-01

    Behavioral testing is a critical step in assessing the validity of rodent models of neurodegenerative disease, as well as evaluating the efficacy of pharmacological interventions. In models of Huntington's disease (HD), a gradual progression of impairments is observed across ages, increasing the need for sensitive, high-throughput and longitudinal assessments. Recently, a number of automated systems have been developed to perform behavioral profiling of animals within their own home-cage, allowing for 24-h monitoring and minimizing experimenter interaction. However, as of yet, few of these have had functionality for the assessment of skilled motor learning, a relevant behavior for movement disorders such as HD. To address this, we assess a lever positioning task within the mouse home-cage. Animals first acquire a simple operant response, before moving to a second phase where they must learn to hold the lever for progressively longer in a rewarded position range. Testing with this paradigm has revealed the presence of distinct phenotypes in the YAC128 mouse model of HD at three early symptomatic time points. YAC128 mice at two months old, but not older, had a motor learning deficit when required to adapt their response to changes in task requirements. In contrast, six-month-old YAC128 mice had disruptions of normal circadian activity and displayed kinematic abnormalities during performance of the task, suggesting an impairment in motor control. This system holds promise for facilitating high throughput behavioral assessment of HD mouse models for preclinical therapeutic screening.

  3. Guidance for Methods Descriptions Used in Preclinical Imaging Papers

    Directory of Open Access Journals (Sweden)

    David Stout

    2013-10-01

    Full Text Available Preclinical molecular imaging is a rapidly growing field, where new imaging systems, methods, and biological findings are constantly being developed or discovered. Imaging systems and the associated software usually have multiple options for generating data, which is often overlooked but is essential when reporting the methods used to create and analyze data. Similarly, the ways in which animals are housed, handled, and treated to create physiologically based data must be well described in order that the findings be relevant, useful, and reproducible. There are frequently new developments for metabolic imaging methods. Thus, specific reporting requirements are difficult to establish; however, it remains essential to adequately report how the data have been collected, processed, and analyzed. To assist with future manuscript submissions, this article aims to provide guidelines of what details to report for several of the most common imaging modalities. Examples are provided in an attempt to give comprehensive, succinct descriptions of the essential items to report about the experimental process.

  4. Preclinical dosimetry of magnetic fluid hyperthermia for bladder cancer

    Science.gov (United States)

    Oliveira, Tiago R.; Stauffer, Paul R.; Lee, Chen-Ting; Landon, Chelsea; Etienne, Wiguins; Maccarini, Paolo F.; Inman, Brant; Dewhirst, Mark W.

    2013-02-01

    Background Despite positive efficacy, thermotherapy is not widely used in clinical oncology. Difficulties associated with field penetration and controlling power deposition patterns in heterogeneous tissue have limited its use for heating deep in the body. Heat generation using iron-oxide super-paramagnetic nanoparticles excited with magnetic fields has been demonstrated to overcome some of these limitations. The objective of this preclinical study is to investigate the feasibility of treating bladder cancer with magnetic fluid hyperthermia (MFH) by analyzing the thermal dosimetry of nanoparticle heating in a rat bladder model. Methods The bladders of 25 female rats were injected with 0.4 ml of Actium Biosystems magnetite-based nanoparticles (Actium Biosystems, Boulder CO) via catheters inserted in the urethra. To assess the distribution of nanoparticles in the rat after injection we used the 7 T small animal MRI system (Bruker ClinScan, Bruker BioSpin MRI GmbH, Ettlingen, Germany). Heat treatments were performed with a small animal magnetic field applicator (Actium Biosystems, Boulder CO) with a goal of raising bladder temperature to 42°C in 1°C/min to a steady-state of 42°C. Conclusion Our data demonstrate that a MFH system provides well-localized heating of rat bladder with effective control of temperature in the bladder and minimal heating of surrounding tissues.

  5. Intelligence system based classification approach for medical disease diagnosis

    Science.gov (United States)

    Sagir, Abdu Masanawa; Sathasivam, Saratha

    2017-08-01

    The prediction of breast cancer in women who have no signs or symptoms of the disease as well as survivability after undergone certain surgery has been a challenging problem for medical researchers. The decision about presence or absence of diseases depends on the physician's intuition, experience and skill for comparing current indicators with previous one than on knowledge rich data hidden in a database. This measure is a very crucial and challenging task. The goal is to predict patient condition by using an adaptive neuro fuzzy inference system (ANFIS) pre-processed by grid partitioning. To achieve an accurate diagnosis at this complex stage of symptom analysis, the physician may need efficient diagnosis system. A framework describes methodology for designing and evaluation of classification performances of two discrete ANFIS systems of hybrid learning algorithms least square estimates with Modified Levenberg-Marquardt and Gradient descent algorithms that can be used by physicians to accelerate diagnosis process. The proposed method's performance was evaluated based on training and test datasets with mammographic mass and Haberman's survival Datasets obtained from benchmarked datasets of University of California at Irvine's (UCI) machine learning repository. The robustness of the performance measuring total accuracy, sensitivity and specificity is examined. In comparison, the proposed method achieves superior performance when compared to conventional ANFIS based gradient descent algorithm and some related existing methods. The software used for the implementation is MATLAB R2014a (version 8.3) and executed in PC Intel Pentium IV E7400 processor with 2.80 GHz speed and 2.0 GB of RAM.

  6. Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

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    Carlo Abbate

    2014-01-01

    Full Text Available Objective. We describe a case of dementia with Lewy bodies (DLB that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI- DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS. The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder.

  7. Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

    Science.gov (United States)

    Abbate, Carlo; Trimarchi, Pietro Davide; Inglese, Silvia; Viti, Niccolò; Cantatore, Alessandra; De Agostini, Lisa; Pirri, Federico; Marino, Lorenza; Bagarolo, Renzo

    2014-01-01

    Objective. We describe a case of dementia with Lewy bodies (DLB) that presented long-lasting preclinical complex polymodal hallucinations. Background. Few studies have deeply investigated the characteristics of hallucinations in DLB, especially in the preclinical phase. Moreover, the clinical phenotype of mild cognitive impairment-(MCI-) DLB is poorly understood. Methods. The patient was followed for 4 years and a selective phenomenological and cognitive study was performed at the predementia stage. Results. The phenomenological study showed the presence of hypnagogic and hypnopompic hallucinations that allowed us to make a differential diagnosis between DLB and Charles Bonnet syndrome (CBS). The neuropsychological evaluation showed a multiple domain without amnesia MCI subtype with prefrontal dysexecutive, visuoperceptual, and visuospatial impairments and simultanagnosia, which has not previously been reported in MCI-DLB. Conclusions. This study extends the prognostic value of hallucinations for DLB to the preclinical phases. It supports and refines the MCI-DLB concept and identifies simultanagnosia as a possible early cognitive marker. Finally, it confirms an association between hallucinations and visuoperceptual impairments at an intermediate stage of the disease course and strongly supports the hypothesis that hallucinations in the earliest stages of DLB may reflect a narcolepsy-like REM-sleep disorder. PMID:24868122

  8. Oral immune therapy: targeting the systemic immune system via the gut immune system for the treatment of inflammatory bowel disease.

    Science.gov (United States)

    Ilan, Yaron

    2016-01-01

    Inflammatory bowel diseases (IBD) are associated with an altered systemic immune response leading to inflammation-mediated damage to the gut and other organs. Oral immune therapy is a method of systemic immune modulation via alteration of the gut immune system. It uses the inherit ability of the innate system of the gut to redirect the systemic innate and adaptive immune responses. Oral immune therapy is an attractive clinical approach to treat autoimmune and inflammatory disorders. It can induce immune modulation without immune suppression, has minimal toxicity and is easily administered. Targeting the systemic immune system via the gut immune system can serve as an attractive novel therapeutic method for IBD. This review summarizes the current data and discusses several examples of oral immune therapeutic methods for using the gut immune system to generate signals to reset systemic immunity as a treatment for IBD.

  9. The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia

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    Martins-de-Souza Daniel

    2012-03-01

    Full Text Available Abstract Background Establishing preclinical models is essential for novel drug discovery in schizophrenia. Most existing models are characterized by abnormalities in behavioral readouts, which are informative, but do not necessarily translate to the symptoms of the human disease. Therefore, there is a necessity of characterizing the preclinical models from a molecular point of view. Selective reaction monitoring (SRM has already shown promise in preclinical and clinical studies for multiplex measurement of diagnostic, prognostic and treatment-related biomarkers. Methods We have established an SRM assay for multiplex analysis of 7 enzymes of the glycolysis pathway which is already known to be affected in human schizophrenia and in the widely-used acute PCP rat model of schizophrenia. The selected enzymes were hexokinase 1 (Hk1, aldolase C (Aldoc, triosephosphate isomerase (Tpi1, glyceraldehyde-3-phosphate dehydrogenase (Gapdh, phosphoglycerate mutase 1 (Pgam1, phosphoglycerate kinase 1 (Pgk1 and enolase 2 (Eno2. The levels of these enzymes were analyzed using SRM in frontal cortex from brain tissue of PCP treated rats. Results Univariate analyses showed statistically significant altered levels of Tpi1 and alteration of Hk1, Aldoc, Pgam1 and Gapdh with borderline significance in PCP rats compared to controls. Most interestingly, multivariate analysis which considered the levels of all 7 enzymes simultaneously resulted in generation of a bi-dimensional chart that can distinguish the PCP rats from the controls. Conclusions This study not only supports PCP treated rats as a useful preclinical model of schizophrenia, but it also establishes that SRM mass spectrometry could be used in the development of multiplex classification tools for complex psychiatric disorders such as schizophrenia.

  10. Skin as a marker of general feline health: Cutaneous manifestations of systemic disease.

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    Vogelnest, Linda J

    2017-09-01

    Practical relevance: Although most skin lesions occur due to diseases primarily affecting the skin, some reflect important systemic diseases. Such lesions may relate directly to the systemic disease, or may occur due to secondary skin diseases that develop because of immunosuppression. Early recognition of skin changes as a marker of systemic disease will maximise patient outcomes. Clinical challenges: In older or clearly debilitated cats presenting with skin disease, the potential for underlying systemic disease is often readily apparent. Similarly, cats presenting with severe ulcerative or multifocal nodular skin lesions, or with concurrent signs of systemic illness, will more instinctively prompt systemic evaluation. More challenging is the cat presenting with alopecic, scaling, erythemic and/or mildly crusted skin disease, with or without pruritus; hypersensitivities and infectious dermatoses are the most common considerations, but occasionally systemic disease underlies the skin changes. Knowing when screening laboratory testing, body imaging or other systemic diagnostics are indicated is not always straightforward. Evidence base: This article reviews cutaneous presentations of systemic diseases reported in the veterinary literature, and discusses important differential diagnoses. The author draws on clinical experience, published data on disease prevalence and case evaluations, and expert opinions on approach to common systemic problems to provide guidance on when investigation for underlying systemic disease is most appropriate.

  11. Prospects of multidisciplinary research for development of new therapeutic modalities in India: preclinical research on brain tumors as an illustrative example

    International Nuclear Information System (INIS)

    Kalia, Vijay K.; Kalyani Kumari; George, Jennifer; Shobha, A.G.

    2012-01-01

    Preclinical research is an essential prerequisite for the development of new therapeutic modalities for different diseases. Close interactions between basic scientists and clinicians are important for rapid progress with optimum input of resources. Cancer is emerging as a very important health hazard in India. Brain tumors, particularly malignant gliomas present a unique challenge, because of their location within the limited space of skull compartment. Conventional adjuvant radiotherapy after surgery is ineffective in killing the residual tumour, and also leads to radiation necrosis in patients with prolonged survival. Therefore, several agents and their combinations are being investigated to enhance the radiation sensitivity of brain tumor cells. Malignant brain tumors are known to have significantly elevated glycolytic activity as compared to the corresponding normal tissues. Our earlier preclinical studies combining 2-deoxy-D-glucose (2-DG) with radiation showed that manifestation of damage was increased in several tumor cell systems, whereas it was reduced in the normal cells. These studies lead to clinical trials using radiation plus 2-DG on malignant gliomas. Lonidamine (LND), a selective inhibitor of glycolytic pathway in cancer cells has been used in clinical trials on patients with brain and several other types of malignant tumors. Recent studies from this laboratory on the combination of LND and 2-DG with other anticancer agents on malignant human glioma cell lines as well as cells derived from glioma biopsies will be described in this presentation. The role of multidisciplinary collaborations between basic scientists and clinicians in such studies will also be discussed. (author)

  12. Antemortem detection of PrP-CWD in preclinical, ranch-raised Rocky Mountain elk (Cervus elaphus nelsoni) by biopsy of the rectal mucosa

    Science.gov (United States)

    Chronic wasting disease is a transmissible spongiform encephalopathy or TSE of deer and elk in North America. All diseases in this family are characterized by long preclinical incubation periods following by a relatively short clinical course. The abnormal isoform of the normal cellular prion prot...

  13. Areca nut chewing and systemic inflammation: evidence of a common pathway for systemic diseases

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    Shafique Kashif

    2012-06-01

    Full Text Available Abstract Background Areca nut, the seed of fruit of an oriental palm, known as Areca catechu, is commonly chewed in many countries. Diabetes, hypertension, cardiovascular diseases, oropharyngeal and oesophageal cancers have been associated with areca nut chewing and the mechanism by which areca nut chewing increases the risk of systemic diseases remains elusive. We hypothesize that systemic inflammation may be elevated among areca nut users, which is linked with many systemic diseases. Therefore, this present study was conducted to examine the systemic inflammation among areca nut chewers and healthy controls. Methods This was an observational cross sectional study carried out on areca nut chewers and healthy individuals in Karachi, Pakistan. Participants were selected from a region of the city by invitation request sent from door to door. Information was collected regarding the socio-demographic profile and the pattern of use, and a blood sample was obtained to measure the level of C-reactive protein (CRP. We carried out multiple logistic regressions to investigate the association between socio-demographic profile, areca nut chewing and CRP levels. Results We carried out final analysis on 1112 individuals of which 556 were areca nut chewers and 556 were the age, gender and area matched controls. Areca nut chewers had a significantly higher proportion of men (15.1%, n = 84 who had an elevated CRP (>10 mg/dl as compared to controls (5.2%, n = 29. Multivariate analyses showed that areca nut chewers had significantly higher odds of an elevated CRP (OR = 3.23, 95% CI 2.08-5.02, p value Conclusions Areca nut chewing has a significant association with systemic inflammation. Further work is required to confirm that systemic inflammation is the main pathway by which areca nut use increases the risk of systemic diseases.

  14. Microtubules in health and degenerative disease of the nervous system.

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    Matamoros, Andrew J; Baas, Peter W

    2016-09-01

    Microtubules are essential for the development and maintenance of axons and dendrites throughout the life of the neuron, and are vulnerable to degradation and disorganization in a variety of neurodegenerative diseases. Microtubules, polymers of tubulin heterodimers, are intrinsically polar structures with a plus end favored for assembly and disassembly and a minus end less favored for these dynamics. In the axon, microtubules are nearly uniformly oriented with plus ends out, whereas in dendrites, microtubules have mixed orientations. Microtubules in developing neurons typically have a stable domain toward the minus end and a labile domain toward the plus end. This domain structure becomes more complex during neuronal maturation when especially stable patches of polyaminated tubulin become more prominent within the microtubule. Microtubules are the substrates for molecular motor proteins that transport cargoes toward the plus or minus end of the microtubule, with motor-driven forces also responsible for organizing microtubules into their distinctive polarity patterns in axons and dendrites. A vast array of microtubule-regulatory proteins impart direct and indirect changes upon the microtubule arrays of the neuron, and these include microtubule-severing proteins as well as proteins responsible for the stability properties of the microtubules. During neurodegenerative diseases, microtubule mass is commonly diminished, and the potential exists for corruption of the microtubule polarity patterns and microtubule-mediated transport. These ill effects may be a primary causative factor in the disease or may be secondary effects, but regardless, therapeutics capable of correcting these microtubule abnormalities have great potential to improve the status of the degenerating nervous system. Copyright © 2016 Elsevier Inc. All rights reserved.

  15. Sexually transmitted disease and the evolution of mating systems.

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    Kokko, Hanna; Ranta, Esa; Ruxton, Graeme; Lundberg, Per

    2002-06-01

    Sexually transmitted diseases (STDs) have been shown to increase the costs of multiple mating and therefore favor relatively monogamous mating strategies. We examine another way in which STDs can influence mating systems in species in which female choice is important. Because more popular males are more likely to become infected, STDs can counteract any selective pressure that generates strong mating skews. We build two models to investigate female mate choice when the sexual behavior of females determines the prevalence of infection in the population. The first model has no explicit social structure. The second model considers the spatial distribution of matings under social monogamy, when females mated to unattractive males seek extrapair fertilizations from attractive males. In both cases, the STD has the potential to drastically reduce the mating skew. However, this reduction does not always happen. If the per contact transmission probability is low, the disease dies out and is of no consequence. In contrast, if the transmission probability is very high, males are likely to be infected regardless of their attractiveness, and mating with the most attractive males imposes again no extra cost for the female. We also show that optimal female responses to the risk of STDs can buffer the prevalence of infection to remain constant, or even decrease, with increasing per contact transmission probabilities. In all cases considered, the feedback between mate choice strategies and STD prevalence creates frequency-dependent fitness benefits for the two alternative female phenotypes considered (choosy vs. randomly mating females or faithful vs. unfaithful females). This maintains mixed evolutionarily stable strategies or polymorphisms in female behavior. In this way, a sexually transmitted disease can stabilize the populationwide proportion of females that mate with the most attractive males or that seek extrapair copulations.

  16. Citation classics in central nervous system inflammatory demyelinating disease.

    Science.gov (United States)

    Kim, Jee-Eun; Park, Kang M; Kim, Yerim; Yoon, Dae Y; Bae, Jong S

    2017-06-01

    To identify and analyze the characteristics of the most influential articles about central nervous system (CNS) inflammatory demyelinating disease. The Institute for Scientific Information (ISI) Web of Science database and the 2014 Journal Citation Reports Science Edition were used to retrieve the top 100 cited articles on CNS inflammatory demyelinating disease. The citation numbers, journals, years of publication, authorships, article types, subjects and main issues were analyzed. For neuromyelitis optica (NMO), articles that were cited more than 100 times were regarded as a citation classic and described separately. The top 100 cited articles were published between 1972 and 2011 in 13 journals. The highest number of articles ( n  = 24) was published in Brain, followed by The New England Journal of Medicine ( n  = 21). The average number of citations was 664 (range 330-3,897), and 64% of the articles were from the United States and the United Kingdom. The majority of the top 100 cited articles were related to multiple sclerosis ( n  = 87), and only a few articles reported on other topics such as NMO ( n  = 9), acute disseminated encephalomyelitis ( n  = 2) and optic neuritis ( n  = 2). Among the top 100 cited articles, 77% were original articles. Forty-one citation classics were found for NMO. Our study provides a historical perspective on the research progress on CNS inflammatory demyelinating disease and may serve as a guide for important advances and trends in the field for associated researchers.

  17. Cardiovascular disease and cognitive dysfunction in systemic lupus erythematosus.

    Science.gov (United States)

    Murray, Sara G; Yazdany, Jinoos; Kaiser, Rachel; Criswell, Lindsey A; Trupin, Laura; Yelin, Edward H; Katz, Patricia P; Julian, Laura J

    2012-09-01

    Cognitive dysfunction and cardiovascular disease are common and debilitating manifestations of systemic lupus erythematosus (SLE). In this study, we evaluated the relationship between cardiovascular events, traditional cardiovascular risk factors, and SLE-specific risk factors as predictors of cognitive dysfunction in a large cohort of participants with SLE. Subjects included 694 participants from the Lupus Outcomes Study (LOS), a longitudinal study of SLE outcomes based on an annual telephone survey querying demographic and clinical variables. The Hopkins Verbal Learning Test-Revised and the Controlled Oral Word Association Test were administered to assess cognitive function. Multiple logistic regression was used to identify cardiovascular events (myocardial infarction, stroke), traditional cardiovascular risk factors (hypertension, hyperlipidemia, diabetes mellitus, obesity, smoking), and SLE-specific risk factors (antiphospholipid antibodies [aPL], disease activity, disease duration) associated with cognitive impairment in year 7 of the LOS. The prevalence of cognitive impairment as measured by verbal memory and verbal fluency metrics was 15%. In adjusted multiple logistic regression analyses, aPL (odds ratio [OR] 2.10, 95% confidence interval [95% CI] 1.3-3.41), hypertension (OR 2.06, 95% CI 1.19-3.56), and a history of stroke (OR 2.27, 95% CI 1.16-4.43) were significantly associated with cognitive dysfunction. In additional analyses evaluating the association between these predictors and severity of cognitive impairment, stroke was significantly more prevalent in participants with severe impairment when compared to those with mild or moderate impairment (P = 0.036). These results suggest that the presence of aPL, hypertension, and stroke are key variables associated with cognitive impairment, which may aid in identification of patients at greatest risk. Copyright © 2012 by the American College of Rheumatology.

  18. Bioluminescence Tomography–Guided Radiation Therapy for Preclinical Research

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    Zhang, Bin [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Wang, Ken Kang-Hsin, E-mail: kwang27@jhmi.edu [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Yu, Jingjing [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); School of Physics and Information Technology, Shaanxi Normal University, Shaanxi (China); Eslami, Sohrab; Iordachita, Iulian [Laboratory for Computational Sensing and Robotics, Johns Hopkins University, Baltimore, Maryland (United States); Reyes, Juvenal; Malek, Reem [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Tran, Phuoc T. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States); Department of Oncology and Urology, Brady Urological Institute, Johns Hopkins University, Baltimore, Maryland (United States); Patterson, Michael S. [Department of Medical Physics and Applied Radiation Sciences, McMaster University, Hamilton, Ontario (Canada); Wong, John W. [Department of Radiation Oncology and Molecular Radiation Sciences, Johns Hopkins School of Medicine, Baltimore, Maryland (United States)

    2016-04-01

    Purpose: In preclinical radiation resear