WorldWideScience

Sample records for system diseases preclinical

  1. Early, Incomplete, or Preclinical Autoimmune Systemic Rheumatic Diseases and Pregnancy Outcome.

    Science.gov (United States)

    Spinillo, Arsenio; Beneventi, Fausta; Locatelli, Elena; Ramoni, Vèronique; Caporali, Roberto; Alpini, Claudia; Albonico, Giulia; Cavagnoli, Chiara; Montecucco, Carlomaurizio

    2016-10-01

    To evaluate the impact of preclinical systemic autoimmune rheumatic disorders on pregnancy outcome. In this longitudinal cohort study, patients were enrolled during the first trimester of pregnancy if they reported having had connective tissue disorder symptoms, were found to be positive for circulating autoantibodies, and on clinical evaluation were judged to have a preclinical or incomplete rheumatic disorder. The incidence of fetal growth restriction (FGR), preeclampsia, and adverse pregnancy outcomes in patients with preclinical rheumatic disorders was compared with that in selected controls, after adjustment for confounders by penalized logistic regression. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Of 5,232 women screened, 150 (2.9%) were initially diagnosed as having a suspected rheumatic disorder. After a mean ± SD postpartum follow-up of 16.7 ± 5.5 months, 64 of these women (42.7%) had no clinically apparent rheumatic disease and 86 (57.3%) had persistent symptoms and positive autoantibody results, including 10 (6.7%) who developed a definitive rheumatic disease. The incidences of preeclampsia/FGR and of small for gestational age (SGA) infants were 5.1% (23 of 450) and 9.3% (42 of 450), respectively, among controls, 12.5% (8 of 640) (OR 2.7 [95% CI 1.1-6.4]) and 18.8% (12 of 64) (OR 2.2 [95% CI 1.1-4.5]), respectively, among women with no clinically apparent disease, and 16.3% (14 of 86) (OR 3.8 [95% CI 1.9-7.7]) and 18.6% (16 of 86) (OR 2.3 [95% CI 1.2-4.3]), respectively, among those with persisting symptoms at follow-up. Mean ± SD umbilical artery Doppler pulsatility indices were higher among women with no clinically apparent disease (0.95 ± 0.2) and those with persisting symptoms (0.96 ± 0.21) than in controls (0.89 ± 0.12) (P = 0.01 and P rheumatic disorders were associated with an increased risk of FGR/preeclampsia and SGA. The impact of these findings and their utility in screening

  2. 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

  3. 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 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.

  4. Study partners should be required in preclinical Alzheimer's disease trials.

    Science.gov (United States)

    Grill, Joshua D; Karlawish, Jason

    2017-12-06

    In an effort to intervene earlier in Alzheimer's disease (AD), clinical trials are testing promising candidate therapies in preclinical disease. Preclinical AD trial participants are cognitively normal, functionally independent, and autonomous decision-makers. Yet, like AD dementia trials, preclinical trials require dual enrollment of a participant and a knowledgeable informant, or study partner. The requirement of dyadic enrollment is a barrier to recruitment and may present unique ethical challenges. Despite these limitations, the requirement should continue. Study partners may be essential to ensure participant safety and wellbeing, including overcoming distress related to biomarker disclosure and minimizing risk for catastrophic reactions and suicide. The requirement may maximize participant retention and ensure data integrity, including that study partners are the source of data that will ultimately instruct whether a new treatment has a clinical benefit and meaningful impact on the population health burden associated with AD. Finally, study partners are needed to ensure the scientific and clinical value of trials. Preclinical AD will represent a new model of care, in which persons with no symptoms are informed of probable cognitive decline and eventual dementia. The rationale for early diagnosis in symptomatic AD is equally applicable in preclinical AD-to minimize risk, maximize quality of life, and ensure optimal planning and communication. Family members and other sources of support will likely be essential to the goals of this new model of care for preclinical AD patients and trials must instruct this clinical practice.

  5. 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.

  6. 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.

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

    Science.gov (United States)

    Steinmetz, Karen L; Spack, Edward G

    2009-06-12

    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 Harmonization. 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 Program provide funding and

  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. Development and reliability of a multi-modality scoring system for evaluation of disease progression in pre-clinical models of osteoarthritis: celecoxib may possess disease-modifying properties.

    Science.gov (United States)

    Panahifar, A; Jaremko, J L; Tessier, A G; Lambert, R G; Maksymowych, W P; Fallone, B G; Doschak, M R

    2014-10-01

    We sought to develop a comprehensive scoring system for evaluation of pre-clinical models of osteoarthritis (OA) progression, and use this to evaluate two different classes of drugs for management of OA. Post-traumatic OA (PTOA) was surgically induced in skeletally mature rats. Rats were randomly divided in three groups receiving either glucosamine (high dose of 192 mg/kg) or celecoxib (clinical dose) or no treatment. Disease progression was monitored utilizing micro-magnetic resonance imaging (MRI), micro-computed tomography (CT) and histology. Pertinent features such as osteophytes, subchondral sclerosis, joint effusion, bone marrow lesion (BML), cysts, loose bodies and cartilage abnormalities were included in designing a sensitive multi-modality based scoring system, termed the rat arthritis knee scoring system (RAKSS). Overall, an inter-observer correlation coefficient (ICC) of greater than 0.750 was achieved for each scored feature. None of the treatments prevented cartilage loss, synovitis, joint effusion, or sclerosis. However, celecoxib significantly reduced osteophyte development compared to placebo. Although signs of inflammation such as synovitis and joint effusion were readily identified at 4 weeks post-operation, we did not detect any BML. We report the development of a sensitive and reliable multi-modality scoring system, the RAKSS, for evaluation of OA severity in pre-clinical animal models. Using this scoring system, we found that celecoxib prevented enlargement of osteophytes in this animal model of PTOA, and thus it may be useful in preventing OA progression. However, it did not show any chondroprotective effect using the recommended dose. In contrast, high dose glucosamine had no measurable effects. Copyright © 2014 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  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. 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

  13. 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.

  14. 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.

  15. Cued memory decline in biomarker-defined preclinical Alzheimer disease.

    Science.gov (United States)

    Papp, Kathryn V; Rentz, Dorene M; Mormino, Elizabeth C; Schultz, Aaron P; Amariglio, Rebecca E; Quiroz, Yakeel; Johnson, Keith A; Sperling, Reisa A

    2017-04-11

    To determine whether a decline in cued recall is observable in the preclinical stage of Alzheimer disease (AD) in clinically normal older adults with elevated β-amyloid (Aβ) burden on PET imaging. Clinically normal older adults underwent baseline neuroimaging (PET to assess Aβ +/- status and MRI) and annual neuropsychological testing. Cox proportional hazards models were used to assess the relative risk of cued memory decline (drop of 1, 2, 3, or 4 points on the total score of the Free and Cued Selective Reminding Test) in relation to neuroimaging measures, functional status, age, sex, and education. A total of 276 older adults (Clinical Dementia Rating = 0, mean Mini-Mental State Examination score = 29 ± 1.06) were followed up for a mean of 3.6 ± 1.2 years. Despite the infrequency of cued memory decline (only 19% of participants scored ≤46/48 in total recall by year 3), Aβ + participants were 3.55 times (95% confidence interval = 1.77-7.12) more likely to exhibit decline in total recall (≤46/48) compared with their Aβ - peers. Furthermore, Aβ + participants who scored ≤46/48 had smaller hippocampal volumes ( t = 3.37, p = 0.001) and evidence of early functional decline, i.e., greater risk of progression to global Clinical Dementia Rating of 0.5 (χ 2 = 14.30, p recall. Cued memory decline in healthy older adults may be particularly indicative of Aβ-related decline during the preclinical stage of AD and useful for identifying Aβ + clinically normal individuals at greatest risk of short-term clinical progression. © 2017 American Academy of Neurology.

  16. 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.

  17. 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

  18. Alzheimer's disease and age-related memory decline (preclinical).

    Science.gov (United States)

    Terry, Alvin V; Callahan, Patrick M; Hall, Brandon; Webster, Scott J

    2011-08-01

    An unfortunate result of the rapid rise in geriatric populations worldwide is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that is characterized by a profound impairment of cognitive function, marked physical disability, and an enormous economic burden on the afflicted individual, caregivers, and society in general. The rise in elderly populations is also resulting in an increase in individuals with related (potentially treatable) conditions such as "Mild Cognitive Impairment" (MCI) which is characterized by a less severe (but abnormal) level of cognitive impairment and a high-risk for developing dementia. Even in the absence of a diagnosable disorder of cognition (e.g., AD and MCI), the perception of increased forgetfulness and declining mental function is a clear source of apprehension in the elderly. This is a valid concern given that even a modest impairment of cognitive function is likely to be associated with significant disability in a rapidly evolving, technology-based society. Unfortunately, the currently available therapies designed to improve cognition (i.e., for AD and other forms of dementia) are limited by modest efficacy and adverse side effects, and their effects on cognitive function are not sustained over time. Accordingly, it is incumbent on the scientific community to develop safer and more effective therapies that improve and/or sustain cognitive function in the elderly allowing them to remain mentally active and productive for as long as possible. As diagnostic criteria for memory disorders evolve, the demand for pro-cognitive therapeutic agents is likely to surpass AD and dementia to include MCI and potentially even less severe forms of memory decline. The purpose of this review is to provide an overview of the contemporary therapeutic targets and preclinical pharmacologic approaches (with representative drug examples) designed to enhance memory

  19. Preclinical murine models of Chronic Obstructive Pulmonary Disease.

    Science.gov (United States)

    Vlahos, Ross; Bozinovski, Steven

    2015-07-15

    Chronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and is the 4th leading cause of death worldwide. It is believed that an exaggerated inflammatory response to cigarette smoke causes progressive airflow limitation. This inflammation, where macrophages, neutrophils and T lymphocytes are prominent, leads to oxidative stress, emphysema, small airway fibrosis and mucus hypersecretion. Much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities and infectious (viral and bacterial) exacerbations (AECOPD). Comorbidities, defined as other chronic medical conditions, in particular skeletal muscle wasting and cardiovascular disease markedly impact on disease morbidity, progression and mortality. The mechanisms and mediators underlying COPD and its comorbidities are poorly understood and current COPD therapy is relatively ineffective. Thus, there is an obvious need for new therapies that can prevent the induction and progression of COPD and effectively treat AECOPD and comorbidities of COPD. Given that access to COPD patients can be difficult and that clinical samples often represent a "snapshot" at a particular time in the disease process, many researchers have used animal modelling systems to explore the mechanisms underlying COPD, AECOPD and comorbidities of COPD with the goal of identifying novel therapeutic targets. This review highlights the mouse models used to define the cellular, molecular and pathological consequences of cigarette smoke exposure and the recent advances in modelling infectious exacerbations and comorbidities of COPD. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. Preclinical Magnetic Resonance Fingerprinting (MRF) at 7 T: Effective Quantitative Imaging for Rodent Disease Models

    Science.gov (United States)

    Gao, Ying; Chen, Yong; Ma, Dan; Jiang, Yun; Herrmann, Kelsey A.; Vincent, Jason A.; Dell, Katherine M.; Drumm, Mitchell L.; Brady-Kalnay, Susann M.; Griswold, Mark A.; Flask, Chris A.; Lu, Lan

    2015-01-01

    High field, preclinical magnetic resonance imaging (MRI) scanners are now commonly used to quantitatively assess disease status and efficacy of novel therapies in a wide variety of rodent models. Unfortunately, conventional MRI methods are highly susceptible to respiratory and cardiac motion artifacts resulting in potentially inaccurate and misleading data. We have developed an initial preclinical, 7.0 T MRI implementation of the highly novel Magnetic Resonance Fingerprinting (MRF) methodology that has been previously described for clinical imaging applications. The MRF technology combines a priori variation in the MRI acquisition parameters with dictionary-based matching of acquired signal evolution profiles to simultaneously generate quantitative maps of T1 and T2 relaxation times and proton density. This preclinical MRF acquisition was constructed from a Fast Imaging with Steady-state Free Precession (FISP) MRI pulse sequence to acquire 600 MRF images with both evolving T1 and T2 weighting in approximately 30 minutes. This initial high field preclinical MRF investigation demonstrated reproducible and differentiated estimates of in vitro phantoms with different relaxation times. In vivo preclinical MRF results in mouse kidneys and brain tumor models demonstrated an inherent resistance to respiratory motion artifacts as well as sensitivity to known pathology. These results suggest that MRF methodology may offer the opportunity for quantification of numerous MRI parameters for a wide variety of preclinical imaging applications. PMID:25639694

  1. Preclinical magnetic resonance imaging and systems biology in cancer research: current applications and challenges.

    Science.gov (United States)

    Albanese, Chris; Rodriguez, Olga C; VanMeter, John; Fricke, Stanley T; Rood, Brian R; Lee, YiChien; Wang, Sean S; Madhavan, Subha; Gusev, Yuriy; Petricoin, Emanuel F; Wang, Yue

    2013-02-01

    Biologically accurate mouse models of human cancer have become important tools for the study of human disease. The anatomical location of various target organs, such as brain, pancreas, and prostate, makes determination of disease status difficult. Imaging modalities, such as magnetic resonance imaging, can greatly enhance diagnosis, and longitudinal imaging of tumor progression is an important source of experimental data. Even in models where the tumors arise in areas that permit visual determination of tumorigenesis, longitudinal anatomical and functional imaging can enhance the scope of studies by facilitating the assessment of biological alterations, (such as changes in angiogenesis, metabolism, cellular invasion) as well as tissue perfusion and diffusion. One of the challenges in preclinical imaging is the development of infrastructural platforms required for integrating in vivo imaging and therapeutic response data with ex vivo pathological and molecular data using a more systems-based multiscale modeling approach. Further challenges exist in integrating these data for computational modeling to better understand the pathobiology of cancer and to better affect its cure. We review the current applications of preclinical imaging and discuss the implications of applying functional imaging to visualize cancer progression and treatment. Finally, we provide new data from an ongoing preclinical drug study demonstrating how multiscale modeling can lead to a more comprehensive understanding of cancer biology and therapy. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

  2. 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

  3. 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

  4. 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

  5. Pre-clinical cognitive phenotypes for Alzheimer disease: a latent profile approach.

    Science.gov (United States)

    Hayden, Kathleen M; Kuchibhatla, Maragatha; Romero, Heather R; Plassman, Brenda L; Burke, James R; Browndyke, Jeffrey N; Welsh-Bohmer, Kathleen A

    2014-11-01

    Cognitive profiles for pre-clinical Alzheimer disease (AD) can be used to identify groups of individuals at risk for disease and better characterize pre-clinical disease. Profiles or patterns of performance as pre-clinical phenotypes may be more useful than individual test scores or measures of global decline. To evaluate patterns of cognitive performance in cognitively normal individuals to derive latent profiles associated with later onset of disease using a combination of factor analysis and latent profile analysis. The National Alzheimer Coordinating Centers collect data, including a battery of neuropsychological tests, from participants at 29 National Institute on Aging-funded Alzheimer Disease Centers across the United States. Prior factor analyses of this battery demonstrated a four-factor structure comprising memory, attention, language, and executive function. Factor scores from these analyses were used in a latent profile approach to characterize cognition among a group of cognitively normal participants (N = 3,911). Associations between latent profiles and disease outcomes an average of 3 years later were evaluated with multinomial regression models. Similar analyses were used to determine predictors of profile membership. Four groups were identified; each with distinct characteristics and significantly associated with later disease outcomes. Two groups were significantly associated with development of cognitive impairment. In post hoc analyses, both the Trail Making Test Part B, and a contrast score (Delayed Recall - Trails B), significantly predicted group membership and later cognitive impairment. Latent profile analysis is a useful method to evaluate patterns of cognition in large samples for the identification of preclinical AD phenotypes; comparable results, however, can be achieved with very sensitive tests and contrast scores. Copyright © 2014 American Association for Geriatric Psychiatry. Published by Elsevier Inc. All rights reserved.

  6. 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.

  7. 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

    REM sleep behaviour and currently several other disturbances have gained importance as potential markers, such as excessive daytime sleepiness, restless legs syndrome and new evidence also points to changes in circadian rhythms. Here we present a brief review of the major evidence indicating......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......, but presence of disturbed sleep is not currently considered in diagnosis. However, sleeping problems may precede by many years the classic motor abnormalities of PD and should be clinically evaluated as a potential marker before disease onset. The first disturbance reported with this potential was the disorder...

  8. 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

    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....... Extensions of this line of research involve fMRI paradigms probing nonmotor brain functions. Additionally, the same fMRI paradigms should be applied to nonmanifesting mutation carriers in genes linked to autosomal dominant PD. This will help to determine how "generically" the human brain compensates......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...

  9. Anti-Correlated Cerebrospinal Fluid Biomarker Trajectories in Preclinical Alzheimer's Disease.

    Science.gov (United States)

    Gomar, Jesus J; Conejero-Goldberg, Concepcion; Davies, Peter; Goldberg, Terry E

    2016-01-01

    The earliest stage of preclinical Alzheimer's disease (AD) is defined by low levels of cerebrospinal fluid (CSF) amyloid-β (Aβ42). However, covariance in longitudinal dynamic change of Aβ42 and tau in incipient preclinical AD is poorly understood. To examine dynamic interrelationships between Aβ42 and tau in preclinical AD. We followed 47 cognitively intact participants (CI) with available CSF data over four years in ADNI. Based on longitudinal Aβ42 levels in CSF, CI were classified into three groups: 1) Aβ42 stable with normal levels of Aβ42 over time (n = 15); 2) Aβ42 declining with normal Aβ42 levels at baseline but showing decline over time (n = 14); and 3) Aβ42 levels consistently abnormal (n = 18). In the Aβ42 declining group, suggestive of incipient preclinical AD, CSF phosphorylated tau (p-tau) showed a similar longitudinal pattern of increasing abnormality over time (p = 0.0001). Correlation between longitudinal slopes of Aβ42 and p-tau confirmed that both trajectories were anti-correlated (rho = -0.60; p = 0.02). Regression analysis showed that Aβ42 slope (decreasing Aβ42) predicted p-tau slope (increasing p-tau) (R2 = 0.47, p = 0.03). Atrophy in the hippocampus was predicted by the interaction of Aβ42 and p-tau slopes (p anti-correlated trajectory, i.e., as Aβ42 declined, p-tau increased, and thus was suggestive of strong temporal coincidence. Rapid pathogenic cross-talk between Aβ42 and p-tau thus may be evident in very early stages of preclinical AD.

  10. Disclosure of amyloid status is not a barrier to recruitment in preclinical Alzheimer's disease clinical trials.

    Science.gov (United States)

    Grill, Joshua D; Zhou, Yan; Elashoff, David; Karlawish, Jason

    2016-03-01

    Preclinical Alzheimer's disease (AD) clinical trials may require participants to learn if they meet biomarker enrollment criteria. To examine whether this requirement will impact trial recruitment, we presented 132 older community volunteers who self-reported normal cognition with 1 of 2 hypothetical informed consent forms (ICFs) describing an AD prevention clinical trial. Both ICFs described amyloid Positron Emission Tomography scans. One ICF stated that scan results would not be shared with the participants (blinded enrollment); the other stated that only persons with elevated amyloid would be eligible (transparent enrollment). Participants rated their likelihood of enrollment and completed an interview with a research assistant. We found no difference between the groups in willingness to participate. Study risks and the requirement of a study partner were reported as the most important factors in the decision whether to enroll. The requirement of biomarker disclosure may not slow recruitment to preclinical AD trials. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Pre-Clinical Testing of Real-Time PCR Assays for Diarrheal Disease Agents of Genera Escherichia and Shigella

    Science.gov (United States)

    2014-05-16

    FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA May 16, 2014 Reporting Period: October 1, 2010 to September 30, 2013...10-2010 - 30-09-2013 PRE-CLINICAL TESTING OF REAL-TIME PCR ASSAYS FOR DIARRHEAL DISEASE AGENTS OF GENERA ESCHERICHIA AND SHIGELLA ...Texas (MOA 2007 - 2013. Agreement No.: DODI 4000.19; AFI 25-201). Pre-clinical test results qualify ETEC and Shigella real-time PCR assays as lead

  12. 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.

  13. 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

  14. 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

    2015-01-01

    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.

  15. Theory of mind and empathy in preclinical and clinical Huntington's disease.

    Science.gov (United States)

    Adjeroud, Najia; Besnard, Jérémy; El Massioui, Nicole; Verny, Christophe; Prudean, Adriana; Scherer, Clarisse; Gohier, Bénédicte; Bonneau, Dominique; Allain, Philippe

    2016-01-01

    We investigated cognitive and affective Theory of Mind (ToM) and empathy in patients with premanifest and manifest Huntington's disease (HD). The relationship between ToM performance and executive skills was also examined. Sixteen preclinical and 23 clinical HD patients, and 39 healthy subjects divided into 2 control groups were given a French adaptation of the Yoni test (Shamay-Tsoory, S.G., Aharon-Peretz, J. (2007). Dissociable prefrontal networks for cognitive and affective theory of mind: a lesion study. Neuropsychologia, 45(3), 3054-67) that examines first- and second-order cognitive and affective ToM processing in separate conditions with a physical control condition. Participants were also given questionnaires of empathy and cognitive tests which mainly assessed executive functions (inhibition and mental flexibility). Clinical HD patients made significantly more errors than their controls in the first- and second-order cognitive and affective ToM conditions of the Yoni task, but exhibited no empathy deficits. However, there was no evidence that ToM impairment was related to cognitive deficits in these patients. Preclinical HD patients were unimpaired in ToM tasks and empathy measures compared with their controls. Our results are consistent with the idea that impaired affective and cognitive mentalizing emerges with the clinical manifestation of HD, but is not necessarily part of the preclinical stage. Furthermore, these impairments appear independent of executive dysfunction and empathy. © The Author (2015). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

  16. Diagnostic and prognostic role of semantic processing in preclinical Alzheimer's disease.

    Science.gov (United States)

    Venneri, Annalena; Jahn-Carta, Caroline; Marco, Matteo De; Quaranta, Davide; Marra, Camillo

    2018-06-13

    Relatively spared during most of the timeline of normal aging, semantic memory shows a subtle yet measurable decline even during the pre-clinical stage of Alzheimer's disease. This decline is thought to reflect early neurofibrillary changes and impairment is detectable using tests of language relying on lexical-semantic abilities. A promising approach is the characterization of semantic parameters such as typicality and age of acquisition of words, and propositional density from verbal output. Seminal research like the Nun Study or the analysis of the linguistic decline of famous writers and politicians later diagnosed with Alzheimer's disease supports the early diagnostic value of semantic processing and semantic memory. Moreover, measures of these skills may play an important role for the prognosis of patients with mild cognitive impairment.

  17. 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.

  18. 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

  19. 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

  20. 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.

  1. Pituitary tumor with gigantism, acromegaly and preclinical Cushing's disease diagnosed from the 10th row.

    Science.gov (United States)

    Tourtelot, John B; Vesely, David L

    2013-08-01

    A 7'3" basketball player was noted to have 2 to 3 times thicker tissue in his hands than 6'10" players by an endocrinologist sitting 10 rows above the player in a basketball arena. This led to the diagnosis of pituitary gigantism where the history revealed that he was 7'3" at 15 years of age. At age 19 when the acryl enlargement was noted, a diagnostic workup revealed elevated growth hormones and insulin-like growth factor 1 (IGF-1) with a 2 × 1.3 cm pituitary tumor. His history suggested that his epiphyseal plates had closed at age 15, and because he continued to produce IGF-1, he now has acromegaly. His elevated adrenocorticotropic hormone (ACTH) before surgery suggests that he also had preclinical Cushing's disease. After pituitary transsphenoidal surgery, all acryl enlargement in hands and ligaments disappeared. His growth hormone, IGF-1 and ACTH returned to normal 2 weeks after surgery.

  2. Low Cognitive Awareness, but Not Complaint, is a Good Marker of Preclinical Alzheimer's Disease.

    Science.gov (United States)

    Cacciamani, Federica; Tandetnik, Caroline; Gagliardi, Geoffroy; Bertin, Hugo; Habert, Marie-Odile; Hampel, Harald; Boukadida, Laurie; Révillon, Marie; Epelbaum, Stéphane; Dubois, Bruno

    2017-01-01

    Subjective cognitive decline (SCD) may result from many conditions, including Alzheimer's disease (AD). In this study, we searched for a specific pattern of SCD in asymptomatic individuals at risk for AD. Cognitively normal older adults (N = 318) reporting SCD and their informants were enrolled in the INSIGHT-PreAD cohort. We examined the relationship between six SCD measures and both cognitive scores and AD neuroimaging markers (amyloid burden, hippocampal atrophy and brain hypometabolism). An awareness of cognitive decline index (ACDI) has been introduced based on the subject-informant discrepancy in a questionnaire of SCD and participants with low versus high awareness were compared. Scores in the INSIGHT-PreAD SCD questionnaires did not correlate with AD neuroimaging markers. As well, no correlation has been found between SCD measures and cognitive scores. Comparing subjects with a low (n = 19) and high (n = 86) level of awareness, no significant difference in terms of demography, neuropsychiatric symptoms, autonomy, quality of life, cognition, and hippocampal volume was found. However, the "low awareness" group showed greater amyloid burden and lower cortical metabolism, compared to the "high awareness" group. This study provided additional evidence that reporting SCD by itself is not a specific symptom of preclinical AD. Conversely, a low cognitive awareness (namely, when subjects report fewer difficulties than their relatives do) may represent a very early form of anosognosia and serve as a specific indicator of preclinical AD. This finding is of key importance as an enrichment factor to consider in both clinical practice and research trials.

  3. Resistance vs resilience to Alzheimer disease: Clarifying terminology for preclinical studies.

    Science.gov (United States)

    Arenaza-Urquijo, Eider M; Vemuri, Prashanthi

    2018-04-10

    Preventing or delaying Alzheimer disease (AD) through lifestyle interventions will come from a better understanding of the mechanistic underpinnings of (1) why a significant proportion of elderly remain cognitively normal with AD pathologies (ADP), i.e., amyloid or tau; and (2) why some elderly individuals do not have significant ADP. In the last decades, concepts such as brain reserve, cognitive reserve, and more recently brain maintenance have been proposed along with more general notions such as (neuro)protection and compensation. It is currently unclear how to effectively apply these concepts in the new field of preclinical AD specifically separating the 2 distinct mechanisms of coping with pathology vs avoiding pathology. We propose a simplistic conceptual framework that builds on existing concepts using the nomenclature of resistance in the context of avoiding pathology, i.e., remaining cognitively normal without significant ADP, and resilience in the context of coping with pathology, i.e., remaining cognitively normal despite significant ADP. In the context of preclinical AD studies, we (1) define these concepts and provide recommendations (and common scenarios) for their use; (2) discuss how to employ this terminology in the context of investigating mechanisms and factors; (3) highlight the complementarity and clarity they provide to existing concepts; and (4) discuss different study designs and methodologies. The application of the proposed framework for framing hypotheses, study design, and interpretation of results and mechanisms can provide a consistent framework and nomenclature for researchers to reach consensus on identifying factors that may prevent ADP or delay the onset of cognitive impairment. © 2018 American Academy of Neurology.

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

    International Nuclear Information System (INIS)

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

    2013-01-01

    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. (paper)

  5. Allopregnanolone promotes regeneration and reduces β-amyloid burden in a preclinical model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Shuhua Chen

    Full Text Available Previously, we demonstrated that allopregnanolone (APα promoted proliferation of rodent and human neural progenitor cells in vitro. Further, we demonstrated that APα promoted neurogenesis in the hippocampal subgranular zone (SGZ and reversed learning and memory deficits in the male triple transgenic mouse model of Alzheimer's (3xTgAD. In the current study, we determined the efficacy of APα to promote the survival of newly generated neural cells while simultaneously reducing Alzheimer's disease (AD pathology in the 3xTgAD male mouse model. Comparative analyses between three different APα treatment regimens indicated that APα administered 1/week for 6 months was maximally efficacious for simultaneous promotion of neurogenesis and survival of newly generated cells and reduction of AD pathology. We further investigated the efficacy of APα to impact Aβ burden. Treatment was initiated either prior to or post intraneuronal Aβ accumulation. Results indicated that APα administered 1/week for 6 months significantly increased survival of newly generated neurons and simultaneously reduced Aβ pathology with greatest efficacy in the pre-pathology treatment group. APα significantly reduced Aβ generation in hippocampus, cortex, and amygdala, which was paralleled by decreased expression of Aβ-binding-alcohol-dehydrogenase. In addition, APα significantly reduced microglia activation as indicated by reduced expression of OX42 while increasing CNPase, an oligodendrocyte myelin marker. Mechanistic analyses indicated that pre-pathology treatment with APα increased expression of liver-X-receptor, pregnane-X-receptor, and 3-hydroxy-3-methyl-glutaryl-CoA-reductase (HMG-CoA-R, three proteins that regulate cholesterol homeostasis and clearance from brain. Together these findings provide preclinical evidence for the optimal treatment regimen of APα to achieve efficacy as a disease modifying therapeutic to promote regeneration while simultaneously decreasing

  6. 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.

  7. 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.

  8. 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.

  9. 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.

  10. 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.

  11. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Liang, Li-Ping [Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); Huang, Jie [Department of Medicine, National Jewish Health, Denver, CO (United States); Fulton, Ruth; Pearson-Smith, Jennifer N. [Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); Day, Brian J. [Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States); Department of Medicine, National Jewish Health, Denver, CO (United States); Patel, Manisha, E-mail: manisha.patel@ucdenver.edu [Department of Pharmaceutical Sciences, University of Colorado Denver, Aurora, CO (United States)

    2017-07-01

    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.

  13. Disclosure of amyloid status is not a barrier to recruitment in preclinical Alzheimer’s disease clinical trials

    Science.gov (United States)

    Grill, Joshua; Zhou, Yan; Elashoff, David; Karlawish, Jason

    2016-01-01

    Preclinical Alzheimer’s disease (AD) clinical trials may require participants to learn if they meet biomarker enrollment criteria to enroll. To examine whether this requirement will impact trial recruitment, we presented 132 older community volunteers who self-reported normal cognition with one of two hypothetical informed consent forms (ICF) describing an AD prevention clinical trial. Both ICFs described amyloid Positron Emission Tomography (PET) scans. One ICF stated that scan results would not be shared with the participants (blinded enrollment); the other stated that only persons with elevated amyloid would be eligible (transparent enrollment). Participants rated their likelihood of enrollment and completed an interview with a research assistant. We found no difference between the groups in willingness to participate. Study risks and the requirement of a study partner were reported as the most important factors in the decision whether to enroll. The requirement of biomarker disclosure may not slow recruitment to preclinical AD trials. PMID:26923411

  14. 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.

  15. 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.)

  16. The SPOTS System: An Ocular Scoring System Optimized for Use in Modern Preclinical Drug Development and Toxicology.

    Science.gov (United States)

    Eaton, Joshua Seth; Miller, Paul E; Bentley, Ellison; Thomasy, Sara M; Murphy, Christopher J

    2017-12-01

    To present a semiquantitative ocular scoring system comprising elements and criteria that address many of the limitations associated with systems commonly used in preclinical studies, providing enhanced cross-species applicability and predictive value in modern ocular drug and device development. Revisions to the ocular scoring systems of McDonald-Shadduck and Hackett-McDonald were conducted by board-certified veterinary ophthalmologists at Ocular Services On Demand (OSOD) over the execution of hundreds of in vivo preclinical ocular drug and device development studies and general toxicological investigations. This semiquantitative preclinical ocular toxicology scoring (SPOTS) system was driven by limitations of previously published systems identified by our group's recent review of slit lamp-based scoring systems in clinical ophthalmology, toxicology, and vision science. The SPOTS system provides scoring criteria for the anterior segment, posterior segment, and characterization of intravitreal test articles. Key elements include: standardized slit lamp settings; expansion of criteria to enhance applicability to nonrabbit species; refinement and disambiguation of scoring criteria for corneal opacity, fluorescein staining severity, and aqueous flare; introduction of novel criteria for scoring of aqueous and anterior vitreous cell; and introduction of criteria for findings observed with drugs/devices targeting the posterior segment. A modified Standardization of Uveitis Nomenclature (SUN) system is also introduced to facilitate accurate use of SUN's criteria in laboratory species. The SPOTS systems provide criteria that stand to enhance the applicability of semiquantitative scoring criteria to the full range of laboratory species, in the context of modern approaches to ocular therapeutics and drug delivery and drug and device development.

  17. 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

  18. Network Disruption in the Preclinical Stages of Alzheimer's Disease: From Subjective Cognitive Decline to Mild Cognitive Impairment.

    Science.gov (United States)

    López-Sanz, David; Garcés, Pilar; Álvarez, Blanca; Delgado-Losada, María Luisa; López-Higes, Ramón; Maestú, Fernando

    2017-12-01

    Subjective Cognitive Decline (SCD) is a largely unknown state thought to represent a preclinical stage of Alzheimer's Disease (AD) previous to mild cognitive impairment (MCI). However, the course of network disruption in these stages is scarcely characterized. We employed resting state magnetoencephalography in the source space to calculate network smallworldness, clustering, modularity and transitivity. Nodal measures (clustering and node degree) as well as modular partitions were compared between groups. The MCI group exhibited decreased smallworldness, clustering and transitivity and increased modularity in theta and beta bands. SCD showed similar but smaller changes in clustering and transitivity, while exhibiting alterations in the alpha band in opposite direction to those showed by MCI for modularity and transitivity. At the node level, MCI disrupted both clustering and nodal degree while SCD showed minor changes in the latter. Additionally, we observed an increase in modular partition variability in both SCD and MCI in theta and beta bands. SCD elders exhibit a significant network disruption, showing intermediate values between HC and MCI groups in multiple parameters. These results highlight the relevance of cognitive concerns in the clinical setting and suggest that network disorganization in AD could start in the preclinical stages before the onset of cognitive symptoms.

  19. Changes in neural circuitry associated with depression at pre-clinical, pre-motor and early motor phases of Parkinson's disease.

    Science.gov (United States)

    Borgonovo, Janina; Allende-Castro, Camilo; Laliena, Almudena; Guerrero, Néstor; Silva, Hernán; Concha, Miguel L

    2017-02-01

    Although Parkinson's Disease (PD) is mostly considered a motor disorder, it can present at early stages as a non-motor pathology. Among the non-motor clinical manifestations, depression shows a high prevalence and can be one of the first clinical signs to appear, even a decade before the onset of motor symptoms. Here, we review the evidence of early dysfunction in neural circuitry associated with depression in the context of PD, focusing on pre-clinical, pre-motor and early motor phases of the disease. In the pre-clinical phase, structural and functional changes in the substantia nigra, basal ganglia and limbic structures are already observed. Some of these changes are linked to motor compensation mechanisms while others correspond to pathological processes common to PD and depression and thus could underlie the appearance of depressive symptoms during the pre-motor phase. Studies of the early motor phase (less than five years post diagnosis) reveal an association between the extent of damage in different monoaminergic systems and the appearance of emotional disorders. We propose that the limbic loop of the basal ganglia and the lateral habenula play key roles in the early genesis of depression in PD. Alterations in the neural circuitry linked with emotional control might be sensitive markers of the ongoing neurodegenerative process and thus may serve to facilitate an early diagnosis of this disease. To take advantage of this, we need to improve the clinical criteria and develop biomarkers to identify depression, which could be used to determine individuals at risk to develop PD. Copyright © 2016 Elsevier Ltd. All rights reserved.

  20. 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.

  1. Radioiodination of central nerves system dopamine D2 receptor imaging agent. IBZM preparation and preclinical study

    International Nuclear Information System (INIS)

    Lin Yansong; Lin Xiangtong; Hu Mingyang; Pan Shangren; Wang Bocheng

    1996-01-01

    To study preparation of central nerves system dopamine D2 imaging agent 131 I-IBZM and its preclinical investigation, peracetic acid was used as the oxidant for preparing radioiodinated 125 I-IBZM and 131 I-IBZM, D2 binding properties of IBZM were examined by in vitro binding saturation analysis, rat whole body and regional brain biodistribution, rat brain autoradiography and rabbit SPECT static imaging, etc. The results are: 1. The radiolabelling yields of 125 I-IBZM and 131 I-IBZM were 84.18% +- 3.06% and 78.50% +- 3.47%. The radiochemical purity were over 95% after being isolated by HPLC; and were over 90% after being isolated by organic extraction. 2. Scatchard plot of D2 receptor saturation binding analysis showed: K d = 0.53 +- 0.06 nmol/L, B max = 466.45 +- 45.88 fmol/mg protein. 3. The rat brain autoradiography and analysis showed that there was high 125 I-IBZM uptake in striatal area 2 hr after injection, the striatal/cerebellum ratio was 6.22 +- 0.48; the high 125 -IBZM uptake can be blocked by haloperidol--a special dopamine D2 receptor antagonist. 4. 131 I-IBZM rat biodistribution and rabbit SPECT planar imaging showed good initial brain uptake and retention, the initial uptake of rat brain was 1.893 +- 0.147% ID/g at 2 min and 1.044 +- 0.135% ID/g at 60 min. The results showed that the radioiodinated IBZM had high affinity, saturation and specificity to rat's and rabbit's central nerves system dopamine D2 receptors

  2. Radioiodination of central nerves system dopamine D2 receptor imaging agent. IBZM preparation and preclinical study

    Energy Technology Data Exchange (ETDEWEB)

    Yansong, Lin; Xiangtong, Lin; Mingyang, Hu; Shangren, Pan; Bocheng, Wang [Huashan Hospital of Shanghai Medical Univ., Shanghai (China)

    1996-11-01

    To study preparation of central nerves system dopamine D2 imaging agent {sup 131}I-IBZM and its preclinical investigation, peracetic acid was used as the oxidant for preparing radioiodinated {sup 125}I-IBZM and {sup 131}I-IBZM, D2 binding properties of IBZM were examined by in vitro binding saturation analysis, rat whole body and regional brain biodistribution, rat brain autoradiography and rabbit SPECT static imaging, etc. The results are: 1. The radiolabelling yields of {sup 125}I-IBZM and {sup 131}I-IBZM were 84.18% +- 3.06% and 78.50% +- 3.47%. The radiochemical purity were over 95% after being isolated by HPLC; and were over 90% after being isolated by organic extraction. 2. Scatchard plot of D2 receptor saturation binding analysis showed: K{sub d} = 0.53 +- 0.06 nmol/L, B{sub max} = 466.45 +- 45.88 fmol/mg protein. 3. The rat brain autoradiography and analysis showed that there was high {sup 125}I-IBZM uptake in striatal area 2 hr after injection, the striatal/cerebellum ratio was 6.22 +- 0.48; the high {sup 125}-IBZM uptake can be blocked by haloperidol--a special dopamine D2 receptor antagonist. 4. {sup 131}I-IBZM rat biodistribution and rabbit SPECT planar imaging showed good initial brain uptake and retention, the initial uptake of rat brain was 1.893 +- 0.147% ID/g at 2 min and 1.044 +- 0.135% ID/g at 60 min. The results showed that the radioiodinated IBZM had high affinity, saturation and specificity to rat`s and rabbit`s central nerves system dopamine D2 receptors.

  3. 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.

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

    Energy Technology Data Exchange (ETDEWEB)

    Dhenain, M. [CEA, DSV, I2BM, SHFJ, F-91401 Orsay (France); Dhenain, M. [CNRS, URA 2210, F-91401 Orsay (France); Dhenain, M. [CEA, DSV, I2BM, Neurospin, F-91191 Gif sur Yvette(France)

    2008-07-01

    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)

  5. 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)

  6. Improving gastric cancer preclinical studies using diverse in vitro and in vivo model systems

    International Nuclear Information System (INIS)

    Chang, Hae Ryung; Park, Hee Seo; Ahn, Young Zoo; Nam, Seungyoon; Jung, Hae Rim; Park, Sungjin; Lee, Sang Jin; Balch, Curt; Powis, Garth; Ku, Ja-Lok; Kim, Yon Hui

    2016-01-01

    “Biomarker-driven targeted therapy,” the practice of tailoring patients’ treatment to the expression/activity levels of disease-specific genes/proteins, remains challenging. For example, while the anti-ERBB2 monoclonal antibody, trastuzumab, was first developed using well-characterized, diverse in vitro breast cancer models (and is now a standard adjuvant therapy for ERBB2-positive breast cancer patients), trastuzumab approval for ERBB2-positive gastric cancer was largely based on preclinical studies of a single cell line, NCI-N87. Ensuing clinical trials revealed only modest patient efficacy, and many ERBB2-positive gastric cancer (GC) patients failed to respond at all (i.e., were inherently recalcitrant), or succumbed to acquired resistance. To assess mechanisms underlying GC insensitivity to ERBB2 therapies, we established a diverse panel of GC cells, differing in ERBB2 expression levels, for comprehensive in vitro and in vivo characterization. For higher throughput assays of ERBB2 DNA and protein levels, we compared the concordance of various laboratory quantification methods, including those of in vitro and in vivo genetic anomalies (FISH and SISH) and xenograft protein expression (Western blot vs. IHC), of both cell and xenograft (tissue-sectioned) microarrays. The biomarker assessment methods strongly agreed, as did correlation between RNA and protein expression. However, although ERBB2 genomic anomalies showed good in vitro vs. in vivo correlation, we observed striking differences in protein expression between cultured cells and mouse xenografts (even within the same GC cell type). Via our unique pathway analysis, we delineated a signaling network, in addition to specific pathways/biological processes, emanating from the ERBB2 signaling cascade, as a potential useful target of clinical treatment. Integrated analysis of public data from gastric tumors revealed frequent (10 – 20 %) amplification of the genes NFKBIE, PTK2, and PIK3CA, each of which

  7. Amyloid and APOE ε4 interact to influence short-term decline in preclinical Alzheimer disease.

    Science.gov (United States)

    Mormino, Elizabeth C; Betensky, Rebecca A; Hedden, Trey; Schultz, Aaron P; Ward, Andrew; Huijbers, Willem; Rentz, Dorene M; Johnson, Keith A; Sperling, Reisa A

    2014-05-20

    To examine whether β-amyloid (Aβ) and APOE ε4 status independently contribute or interact to influence longitudinal cognitive decline in clinically normal older individuals (CN). Data from 490 CNs were aggregated across 3 observational cohort studies (Harvard Aging Brain Study, Alzheimer's Disease Neuroimaging Initiative, and Australian Imaging Biomarkers and Lifestyle Study of Ageing; median age = 75.0 years, 255 female), and the contributions of APOE ε4 and Aβ on longitudinal change over a median of 1.49 years were examined. Cognitive decline was assessed with the Mini-Mental State Examination (MMSE) and Logical Memory (immediate and delayed recall scores). High Aβ participants were more likely to be APOE ε4+ than low Aβ participants. CNs who were both high Aβ and APOE ε4+ showed greater decline in Logical Memory immediate recall (p Alzheimer disease risk factors on cognitive decline in aging. © 2014 American Academy of Neurology.

  8. 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.

  9. Parkinson's disease and the quest for preclinical diagnosis: an interview with Professor Werner Poewe.

    Science.gov (United States)

    Poewe, Werner

    2017-10-01

    Werner Poewe speaks to Laura Dormer, Editorial Director: Professor Werner Poewe is Professor of Neurology and Director of the Department of Neurology at Innsbruck Medical University in Innsbruck, Austria. He held a Residency in Clinical Neurology and Psychiatry at the University of Innsbruck, Austria, from 1977 to 1984. From 1984 to 1985 he teamed up with Gerald Stern and Andrew Lees as a British Council Research Fellow at University College and Middlesex Hospital's Medical School in London to perform clinical studies into levodopa-induced dystonia and pharmacokinetics of levodopa in naive versus L-Dopa treated Parkinson's disease. Following his return to Austria, he held a position as Senior Lecturer in the Department of Neurology at the University of Innsbruck (1986-1989) after which he took over as Professor of Neurology and Acting Director of the Department of Neurology at Virchow Hospital of the Free University of Berlin (1990-1994). Professor Poewe's main research interests in the field of movement disorders are focused on differential and early diagnosis of Parkinson's disease, its natural history and pharmacological treatment. He has been involved in the steering committees of numerous drug trials in different stages of Parkinson's disease for the past 20 years and has authored and coauthored more than 500 original articles and reviews in the field of movement disorders. Professor Poewe served as President of the Austrian Society of Neurology from 2002 to 2004 as well as President of the Austrian Parkinson's Disease Society from 1996 to 2009. He has been awarded honorary membership of the German Society of Neurology as well as the Japanese Society of Neurology. His awards include the Walther-Birkmayer-Prize of the Austrian PD Society, the Dingebauer-Prize of the German Neurological Society as well as the Research Excellence Award of Innsbruck Medical University. Professor Poewe served as President of the International Movement Disorder Society (MDS) from

  10. 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.

  11. 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.

  12. 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.

  13. 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.

  14. 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

  15. 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

  16. 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.

  17. “End-Stage” Neurofibrillary Tangle Pathology in Preclinical Alzheimer's Disease: Fact or Fiction?

    Science.gov (United States)

    Abner, Erin L.; Kryscio, Richard J.; Schmitt, Frederick A.; SantaCruz, Karen S.; Jicha, Gregory A.; Lin, Yushun; Neltner, Janna M.; Smith, Charles D.; Van Eldik, Linda J.; Nelson, Peter T.

    2011-01-01

    Among individuals who were cognitively intact before death, autopsies may reveal some Alzheimer's disease-type pathology. The presence of end-stage pathology in cognitively intact persons would support the hypothesis that pathological markers are epiphenomena. We assessed advanced neurofibrillary (Braak stages V and VI) pathology focusing on nondemented individuals. Data from the National Alzheimer's Coordinating Center database (n = 4,690 included initially) and from the Nun Study (n = 526 included initially) were analyzed, with antemortem information about global cognition and careful postmortem studies available from each case. Global cognition (final Mini-Mental State Examination scores [MMSE] and clinical ‘dementia’ status) was correlated with neuropathology, including the severity of neurofibrillary pathology (Braak stages and neurofibrillary tangle counts in cerebral neocortex). Analyses support three major findings: 1. Braak stage V cases and Braak VI cases are significantly different from each other in terms of associated antemortem cognition; 2. There is an appreciable range of pathology within the category of Braak stage VI based on tangle counts such that brains with the most neurofibrillary tangles in neocortex always had profound antemortem cognitive impairment; and 3. There was no nondemented case with final MMSE score of 30 within a year of life and Braak stage VI pathology. It may be inappropriate to combine Braak stages V and VI cases, particularly in patients with early cognitive dysfunction, since the two pathological stages appear to differ dramatically in terms of both pathological severity and antemortem cognitive status. There is no documented example of truly end-stage neurofibrillary pathology coexisting with intact cognition. PMID:21471646

  18. Phenomenological characterization of memory complaints in preclinical and prodromal Alzheimer's disease.

    Science.gov (United States)

    Buckley, Rachel F; Ellis, Kathryn A; Ames, David; Rowe, Christopher C; Lautenschlager, Nicola T; Maruff, Paul; Villemagne, Victor L; Macaulay, S Lance; Szoeke, Cassandra; Martins, Ralph N; Masters, Colin L; Savage, Greg; Rainey-Smith, Stephanie R; Rembach, Alan; Saling, Michael M

    2015-07-01

    To explore the subjective experience of memory change in groups at risk of dementia (those with mild cognitive impairment MCI or high β-amyloid (Aβ+) burden) to determine the existence of potential phenomenological typologies. We recruited 123 healthy controls (HC) and individuals with MCI from the Australian Imaging, Biomarker and Lifestyle (AIBL) study. Sixty-7 (HC = 47,MCI = 20) had Aβ scans available for analysis. Semistructured interviews were administered, transcribed, and meaningful phrases extracted from transcripts. Twelve themes were defined and compared across diagnostic status and Aβ status. MCI endorsed more complaints of burdensome coping strategies, increasing frequency, sense of predomination, poor contextualization, progression, dependency, impact on affect, and dismissive attitudes. HCAβ+ acknowledged a progressive memory decline compared to HCAβ-, while MCIAβ+ expressed more burdensome coping strategies, dismissive attitudes, and dependency comparative to either healthy group. Depression was more likely to be related to complaint themes in HCs, while complaint themes were associated with poorer list-learning performance in individuals with MCI. Complaint themes in those with MCI align with the MCI symptom complex, particularly when accompanied with high Aβ load. Healthy Aβ+ individuals acknowledged progressive memory change, suggesting they are aware of memory changes not yet detectable via neuropsychological measures. Depressive symptomatology associated with HC complaints, suggesting certain themes are affect-driven, while complaints in MCI are associated with organically driven functional impairment. Qualitative analysis of SMCs can inform the earliest clinical manifestations of Alzheimer's disease. Our findings can inform diagnostic approaches to the clinical evaluation of memory complaints in the nondemented elderly. (c) 2015 APA, all rights reserved).

  19. Quantitative pre-clinical screening of therapeutics for joint diseases using contrast enhanced micro-computed tomography.

    Science.gov (United States)

    Willett, N J; Thote, T; Hart, M; Moran, S; Guldberg, R E; Kamath, R V

    2016-09-01

    The development of effective therapies for cartilage protection has been limited by a lack of efficient quantitative cartilage imaging modalities in pre-clinical in vivo models. Our objectives were two-fold: first, to validate a new contrast-enhanced 3D imaging analysis technique, equilibrium partitioning of an ionic contrast agent-micro computed tomography (EPIC-μCT), in a rat medial meniscal transection (MMT) osteoarthritis (OA) model; and second, to quantitatively assess the sensitivity of EPIC-μCT to detect the effects of matrix metalloproteinase inhibitor (MMPi) therapy on cartilage degeneration. Rats underwent MMT surgery and tissues were harvested at 1, 2, and 3 weeks post-surgery or rats received an MMPi or vehicle treatment and tissues harvested 3 weeks post-surgery. Parameters of disease progression were evaluated using histopathology and EPIC-μCT. Correlations and power analyses were performed to compare the techniques. EPIC-μCT was shown to provide simultaneous 3D quantification of multiple parameters, including cartilage degeneration and osteophyte formation. In MMT animals treated with MMPi, OA progression was attenuated, as measured by 3D parameters such as lesion volume and osteophyte size. A post-hoc power analysis showed that 3D parameters for EPIC-μCT were more sensitive than 2D parameters requiring fewer animals to detect a therapeutic effect of MMPi. 2D parameters were comparable between EPIC-μCT and histopathology. This study demonstrated that EPIC-μCT has high sensitivity to provide 3D structural and compositional measurements of cartilage and bone in the joint. EPIC-μCT can be used in combination with histology to provide a comprehensive analysis to screen new potential therapies. Copyright © 2016 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  20. Process dissociation analyses of memory changes in healthy aging, preclinical, and very mild Alzheimer disease: Evidence for isolated recollection deficits.

    Science.gov (United States)

    Millar, Peter R; Balota, David A; Maddox, Geoffrey B; Duchek, Janet M; Aschenbrenner, Andrew J; Fagan, Anne M; Benzinger, Tammie L S; Morris, John C

    2017-10-01

    Recollection and familiarity are independent processes that contribute to memory performance. Recollection is dependent on attentional control, which has been shown to be disrupted in early stage Alzheimer's disease (AD), whereas familiarity is independent of attention. The present longitudinal study examines the sensitivity of recollection estimates based on Jacoby's (1991) process dissociation procedure to AD-related biomarkers in a large sample of well-characterized cognitively normal middle-aged and older adults (N = 519) and the extent to which recollection discriminates these individuals from individuals with very mild symptomatic AD (N = 64). Participants studied word pairs (e.g., knee bone), then completed a primed, explicit, cued fragment-completion memory task (e.g., knee b_n_). Primes were either congruent with the correct response (e.g., bone), incongruent (e.g., bend), or neutral (e.g., &). This design allowed for the estimation of independent contributions of recollection and familiarity processes, using the process dissociation procedure. Recollection, but not familiarity, was impaired in healthy aging and in very mild AD. Recollection discriminated cognitively normal individuals from the earliest detectable stage of symptomatic AD above and beyond standard psychometric tests. In cognitively normal individuals, baseline CSF measures indicative of AD pathology were related to lower initial recollection and less practice-related improvement in recollection over time. Finally, presence of amyloid plaques, as imaged by PIB-PET, was also related to less improvement in recollection over time. These findings suggest that attention-demanding memory processes, such as recollection, may be particularly sensitive to both symptomatic and preclinical AD pathology. (PsycINFO Database Record (c) 2017 APA, all rights reserved).

  1. Gene and protein patterns of potential prion-related markers in the central nervous system of clinical and preclinical infected sheep

    Science.gov (United States)

    2013-01-01

    The molecular pathogenic mechanisms of prion diseases are far from clear. Genomic analyses have revealed genetic biomarkers potentially involved in prion neuropathology in naturally scrapie-infected sheep, a good animal model of infectious prionopathies. However, these biomarkers must be validated in independent studies at different stages of the disease. The gene and protein expression profiles and protein distribution of six potential genetic biomarkers (i.e., CAPN6, COL1A2, COL3A1, GALA1, MT2A and MTNR1B) are presented here for both the early and terminal stages of scrapie in five different brain regions. Gene transcription changes were confirmed in the medulla oblongata, and the expression profiles were generally similar in other central nervous system regions. The changes were more substantial in clinical animals compared to preclinical animals. The expression of the CAPN6 protein increased in the spinal cord and cerebellum of the clinical and preclinical brains. The distribution of the GALA1 was identified in glial cells from the cerebellum of scrapie-infected animals, GALA1 protein expression was increased in clinical animals in the majority of regions, and the increase of MT2A was in agreement with previous reports. The downregulation of MTNR1B was especially marked in the Purkinje cells. Finally, although collagen genes were downregulated the protein immunostaining did not reveal significant changes between the scrapie-infected and control animals. In conclusion, this study of gene transcription and protein expression and distribution confirm CAPN6, GALA1, MTNR1B and MT2A as potential targets for further prion disease research. PMID:23497022

  2. 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.

  3. 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...

  4. 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.

  5. 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.

  6. 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 S; 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

    2014-06-01

    To identify a cognitive composite that is sensitive to tracking preclinical Alzheimer's disease decline to be used as a primary end point in treatment trials. 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 Alzheimer's disease kindred to identify a composite cognitive test with the greatest statistical power to track preclinical Alzheimer's disease decline and estimate the number of carriers age 30 years and older needed to detect a treatment effect in the Alzheimer's Prevention Initiative's (API) preclinical Alzheimer's disease treatment trial. The mean-to-standard-deviation ratios (MSDRs) of change over time were calculated in a search for the optimal combination of 1 to 7 cognitive tests/subtests drawn from the neuropsychological test battery in cognitively unimpaired mutation carriers during a 2- and 5-year follow-up period (n = 78 and 57), using data from noncarriers (n = 31 and 56) 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. The optimal test combination included Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Recall, CERAD Boston Naming Test (high frequency items), Mini-Mental State Examination (MMSE) Orientation to Time, CERAD Constructional Praxis, and Raven's 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 aged 30 years and older per treatment arm allows for a detectable treatment effect of 29% in a 60-month trial (80% power, P = .05). We

  7. Association between periodontal diseases and systemic diseases

    Directory of Open Access Journals (Sweden)

    Patrícia Weidlich

    2008-08-01

    Full Text Available Current evidence suggests that periodontal disease may be associated with systemic diseases. This paper reviewed the published data about the relationship between periodontal disease and cardiovascular diseases, adverse pregnancy outcomes, diabetes and respiratory diseases, focusing on studies conducted in the Brazilian population. Only a few studies were found in the literature focusing on Brazilians (3 concerning cardiovascular disease, 7 about pregnancy outcomes, 9 about diabetes and one regarding pneumonia. Although the majority of them observed an association between periodontitis and systemic conditions, a causal relationship still needs to be demonstrated. Further studies, particularly interventional well-designed investigations, with larger sample sizes, need to be conducted in Brazilian populations.

  8. [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.

  9. 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.)

  10. 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.)

  11. 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)

  12. 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

  13. 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.

  14. A Grading System To Evaluate Objectively the Strength of Pre-Clinical Data of Acute Neuroprotective Therapies for Clinical Translation in Spinal Cord Injury

    Science.gov (United States)

    Okon, Elena B.; Tsai, Eve; Beattie, Michael S.; Bresnahan, Jacqueline C.; Magnuson, David K.; Reier, Paul J.; McTigue, Dana M.; Popovich, Phillip G.; Blight, Andrew R.; Oudega, Martin; Guest, James D.; Weaver, Lynne C.; Fehlings, Michael G.; Tetzlaff, Wolfram

    2011-01-01

    Abstract The past three decades have seen an explosion of research interest in spinal cord injury (SCI) and the development of hundreds of potential therapies that have demonstrated some promise in pre-clinical experimental animal models. A growing number of these treatments are seeking to be translated into human clinical trials. Conducting such a clinical trial, however, is extremely costly, not only for the time and money required to execute it, but also for the limited resources that will then no longer be available to evaluate other promising therapies. The decision about what therapies have sufficient pre-clinical evidence of efficacy to justify testing in humans is therefore of utmost importance. Here, we have developed a scoring system for objectively grading the body of pre-clinical literature on neuroprotective treatments for acute SCI. The components of the system include an evaluation of a number of factors that are thought to be important in considering the “robustness” of a therapy's efficacy, including the animal species and injury models that have been used to test it, the time window of efficacy, the types of functional improvements effected by it, and whether efficacy has been independently replicated. The selection of these factors was based on the results of a questionnaire that was performed within the SCI research community. A modified Delphi consensus-building exercise was then conducted with experts in pre-clinical SCI research to refine the criteria and decide upon how to score them. Finally, the grading system was applied to a series of potential neuroprotective treatments for acute SCI. This represents a systematic approach to developing an objective method of evaluating the extent to which the pre-clinical literature supports the translation of a particular experimental treatment into human trials. PMID:20507235

  15. Preclinical models in radiation oncology

    Directory of Open Access Journals (Sweden)

    Kahn Jenna

    2012-12-01

    Full Text Available Abstract 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.

  16. Retinal Electrophysiology Is a Viable Preclinical Biomarker for Drug Penetrance into the Central Nervous System

    Directory of Open Access Journals (Sweden)

    Jason Charng

    2016-01-01

    Full Text Available Objective. To examine whether retinal electrophysiology is a useful surrogate marker of drug penetrance into the central nervous system (CNS. Materials and Methods. Brain and retinal electrophysiology were assessed with full-field visually evoked potentials and electroretinograms in conscious and anaesthetised rats following systemic or local administrations of centrally penetrant (muscimol or nonpenetrant (isoguvacine compounds. Results. Local injections into the eye/brain bypassed the blood neural barriers and produced changes in retinal/brain responses for both drugs. In conscious animals, systemic administration of muscimol resulted in retinal and brain biopotential changes, whereas systemic delivery of isoguvacine did not. General anaesthesia confounded these outcomes. Conclusions. Retinal electrophysiology, when recorded in conscious animals, shows promise as a viable biomarker of drug penetration into the CNS. In contrast, when conducted under anaesthetised conditions confounds can be induced in both cortical and retinal electrophysiological recordings.

  17. 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

  18. 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

  19. A novel navigation system for maxillary positioning in orthognathic surgery: Preclinical evaluation.

    Science.gov (United States)

    Lutz, Jean-Christophe; Nicolau, Stéphane; Agnus, Vincent; Bodin, Frédéric; Wilk, Astrid; Bruant-Rodier, Catherine; Rémond, Yves; Soler, Luc

    2015-11-01

    Appropriate positioning of the maxilla is critical in orthognathic surgery. As opposed to splint-based positioning, navigation systems are versatile and appropriate in assessing the vertical dimension. Bulk and disruption to the line of sight are drawbacks of optical navigation systems. Our aim was to develop and assess a novel navigation system based on electromagnetic tracking of the maxilla, including real-time registration of head movements. Since the software interface has proved to greatly influence the accuracy of the procedure, we purposely designed and evaluated an original, user-friendly interface. A sample of 12 surgeons had to navigate the phantom osteotomized maxilla to eight given target positions using the software we have developed. Time and accuracy (translational error and angular error) were compared between a conventional and a navigated session. A questionnaire provided qualitative evaluation. Our system definitely allows a reduction in variability of time and accuracy among different operators. Accuracy was improved in all surgeons (mean terror difference = 1.11 mm, mean aerror difference = 1.32°). Operative time was decreased in trainees. Therefore, they would benefit from such a system that could also serve for educational purposes. The majority of surgeons who strongly agreed that such a navigation system would prove very helpful in complex deformities, also stated that it would be helpful in everyday orthognathic procedures. Copyright © 2015 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.

  20. 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.

  1. Molecular and cellular profiling of systemic sclerosis and its preclinical stages

    NARCIS (Netherlands)

    Cossu, Marta

    2017-01-01

    The development of unrestrained fibrosis in the skin and internal organs is the hallmark of systemic sclerosis (SSc). Nevertheless, it is known that fibrosis is preceded by vascular and immune modifications. On the basis of SSc-specific autoantibodies and nailfold capillary lesions it is possible to

  2. Dose-on-demand production of diverse 18F-radiotracers for preclinical applications using a continuous flow microfluidic system.

    Science.gov (United States)

    Matesic, Lidia; Kallinen, Annukka; Greguric, Ivan; Pascali, Giancarlo

    2017-09-01

    The production of 18 F-radiotracers using continuous flow microfluidics is under-utilized due to perceived equipment limitations. We describe the dose-on-demand principle, whereby the back-to-back production of multiple, diverse 18 F-radiotracers can be prepared on the same day, on the same microfluidic system using the same batch of [ 18 F]fluoride, the same microreactor, the same HPLC column and SPE cartridge to obtain a useful production yield. [ 18 F]MEL050, [ 18 F]Fallypride and [ 18 F]PBR111 were radiolabeled with [ 18 F]fluoride using the Advion NanoTek Microfluidic Synthesis System. The outlet of the microreactor was connected to an automated HPLC injector and following the collection of the product, SPE reformulation produced the 18 F-radiotracer in productions for [ 18 F]MEL050 and [ 18 F]Fallypride were performed at total flow rates of 20μL/min, resulting in 40±13% and 25±13% RCY respectively. [ 18 F]PBR111 was performed at 200μL/min to obtain 27±8% RCY. Molar activities for each 18 F-radiotracer were >100GBq/μmol and radiochemical purities were >97%, implying that the cleaning procedure was effective. Using the same initial solution of [ 18 F]fluoride, microreactor, HPLC column and SPE cartridge, three diverse 18 F-radiotracers could be produced in yields sufficient for preclinical studies in a back-to-back fashion using a microfluidic system with no detectable cross-contamination. Crown Copyright © 2017. Published by Elsevier Inc. All rights reserved.

  3. 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.

  4. 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.

  5. 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.

  6. 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

  7. 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.

  8. 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…

  9. BDNF Val66Met in preclinical Alzheimer's disease is associated with short-term changes in episodic memory and hippocampal volume but not serum mBDNF.

    Science.gov (United States)

    Lim, Yen Ying; Rainey-Smith, Stephanie; Lim, Yoon; Laws, Simon M; Gupta, Veer; Porter, Tenielle; Bourgeat, Pierrick; Ames, David; Fowler, Christopher; Salvado, Olivier; Villemagne, Victor L; Rowe, Christopher C; Masters, Colin L; Zhou, Xin Fu; Martins, Ralph N; Maruff, Paul

    2017-11-01

    The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism Met allele exacerbates amyloid (Aβ) related decline in episodic memory (EM) and hippocampal volume (HV) over 36-54 months in preclinical Alzheimer's disease (AD). However, the extent to which Aβ+ and BDNF Val66Met is related to circulating markers of BDNF (e.g. serum) is unknown. We aimed to determine the effect of Aβ and the BDNF Val66Met polymorphism on levels of serum mBDNF, EM, and HV at baseline and over 18-months. Non-demented older adults (n = 446) underwent Aβ neuroimaging and BDNF Val66Met genotyping. EM and HV were assessed at baseline and 18 months later. Fasted blood samples were obtained from each participant at baseline and at 18-month follow-up. Aβ PET neuroimaging was used to classify participants as Aβ- or Aβ+. At baseline, Aβ+ adults showed worse EM impairment and lower serum mBDNF levels relative to Aβ- adults. BDNF Val66Met polymorphism did not affect serum mBDNF, EM, or HV at baseline. When considered over 18-months, compared to Aβ- Val homozygotes, Aβ+ Val homozygotes showed significant decline in EM and HV but not serum mBDNF. Similarly, compared to Aβ+ Val homozygotes, Aβ+ Met carriers showed significant decline in EM and HV over 18-months but showed no change in serum mBDNF. While allelic variation in BDNF Val66Met may influence Aβ+ related neurodegeneration and memory loss over the short term, this is not related to serum mBDNF. Longer follow-up intervals may be required to further determine any relationships between serum mBDNF, EM, and HV in preclinical AD.

  10. Preclinical safety assessments of nano-sized constructs on cardiovascular system toxicity: A case for telemetry.

    Science.gov (United States)

    Cheah, Hoay Yan; Kiew, Lik Voon; Lee, Hong Boon; Japundžić-Žigon, Nina; Vicent, Marίa J; Hoe, See Ziau; Chung, Lip Yong

    2017-11-01

    While nano-sized construct (NSC) use in medicine has grown significantly in recent years, reported unwanted side effects have raised safety concerns. However, the toxicity of NSCs to the cardiovascular system (CVS) and the relative merits of the associated evaluation methods have not been thoroughly studied. This review discusses the toxicological profiles of selected NSCs and provides an overview of the assessment methods, including in silico, in vitro, ex vivo and in vivo models and how they are related to CVS toxicity. We conclude the review by outlining the merits of telemetry coupled with spectral analysis, baroreceptor reflex sensitivity analysis and echocardiography as an appropriate integrated strategy for the assessment of the acute and chronic impact of NSCs on the CVS. Copyright © 2017 John Wiley & Sons, Ltd. Copyright © 2017 John Wiley & Sons, Ltd.

  11. The radioimmunoassay in revealing preclinical disorders of the pituitary-thyroid system functioning

    International Nuclear Information System (INIS)

    Piven', N.V.; Pilatova, N.L.; Lukhverchik, L.N.; Kuz'menkova, E.I.; Solovej, V.V.; Mokhort, T.V.

    2001-01-01

    The main purpose of this research was to study the value of radioimmunoassay (RIA) for assessing the pituitary - thyroid function in healthy persons (aged 18-45). Quantitative criteria have been worked put for estimation of thyroid gland function for the population of Belarus in accordance with regional ecological situation. On this basis, concentrations of thyrotropin, thyroxine, triiodothyronine, thyroglobulin, thyroxine binding globulin were determined by RIA in blood samples. The analysis of the data obtained revealed latent forms of hyperthyroidism (42%) and hypothyroidism (21%), regarded by the authors as late medical consequences of Chernobyl accident. Subclinical stages were diagnosed in most cases. Thus RIA has proved useful for studying the functional state of the regulatory 'pituitary-thyroid gland' system and revealing prenosological disorders in it

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

    International Nuclear Information System (INIS)

    Trujillo, G.

    1998-01-01

    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)

  13. Renal Sympathetic Denervation System via Intraluminal Ultrasonic Ablation: Therapeutic Intravascular Ultrasound Design and Preclinical Evaluation.

    Science.gov (United States)

    Chernin, Gil; Szwarcfiter, Iris; Bausback, Yvonne; Jonas, Michael

    2017-05-01

    To assess the safety and performance of a nonfocused and nonballooned ultrasonic (US) catheter-based renal sympathetic denervation (RDN) system in normotensive swine. RDN with the therapeutic intravascular US catheter was evaluated in 3 experiments: (i) therapeutic intravascular US RDN vs a control group of untreated animals with follow-up of 30, 45, and 90 days (n = 6; n = 12 renal arteries for each group); (ii) therapeutic intravascular US RDN vs radiofrequency (RF) RDN in the contralateral artery in the same animal (n = 2; n = 4 renal arteries); and (iii) therapeutic intravascular US RDN in a recently stent-implanted renal artery (n = 2; n = 4 renal arteries). In the first experiment, therapeutic intravascular US RDN was safe, without angiographic evidence of dissection or renal artery stenosis. Neuronal tissue vacuolization, nuclei pyknosis, and perineuronal inflammation were evident after RDN, without renal artery wall damage. Norepinephrine levels were significantly lower after therapeutic intravascular US RDN after 30, 45, and 90 days compared with the control group (200.17 pg/mg ± 63.35, 184.75 pg/mg ± 44.51, and 203.43 pg/mg ± 58.54, respectively, vs 342.42 pg/mg ± 79.97). In the second experiment, deeper neuronal ablation penetrance was found with therapeutic intravascular US RDN vs RF RDN (maximal penetrance from endothelium of 7.0 mm vs 3.5 mm, respectively). There was less damage to the artery wall after therapeutic intravascular US RDN than with RF RDN, after which edema and injured endothelium were seen. In the third experiment, denervation inside the stent-implanted segments was feasible without damage to the renal artery wall or stent. The therapeutic intravascular US system performed safely and reduced norepinephrine levels. Deeper penetrance and better preservation of vessel wall were observed with therapeutic intravascular US RDN vs RF RDN. Neuronal ablations were observed in stent-implanted renal arteries. Copyright © 2017 SIR. Published

  14. [Applicability of the da Vinci robotic system in the skull base surgical approach. Preclinical investigation].

    Science.gov (United States)

    Fernandez-Nogueras Jimenez, Francisco J; Segura Fernandez-Nogueras, Miguel; Jouma Katati, Majed; Arraez Sanchez, Miguel Ángel; Roda Murillo, Olga; Sánchez Montesinos, Indalecio

    2015-01-01

    The role of robotic surgery is well established in various specialties such as urology and general surgery, but not in others such as neurosurgery and otolaryngology. In the case of surgery of the skull base, it has just emerged from an experimental phase. To investigate possible applications of the da Vinci surgical robot in transoral skull base surgery, comparing it with the authors' experience using conventional endoscopic transnasal surgery in the same region. A transoral transpalatal approach to the nasopharynx and medial skull base was performed on 4 cryopreserved cadaver heads. We used the da Vinci robot, a 30° standard endoscope 12mm thick, dual camera and dual illumination, Maryland forceps on the left terminal and curved scissors on the right, both 8mm thick. Bone drilling was performed manually. For the anatomical study of this region, we used 0.5cm axial slices from a plastinated cadaver head. Various skull base structures at different depths were reached with relative ease with the robot terminals Transoral robotic surgery with the da Vinci system provides potential advantages over conventional endoscopic transnasal surgery in the surgical approach to this region. Copyright © 2014 Sociedad Española de Neurocirugía. Published by Elsevier España. All rights reserved.

  15. MO-G-17A-01: Innovative High-Performance PET Imaging System for Preclinical Imaging and Translational Researches

    Energy Technology Data Exchange (ETDEWEB)

    Sun, X [University of Texas MD Anderson Cancer Center, Houston, TX (United States); Lou, K [University of Texas MD Anderson Cancer Center, Houston, TX (United States); Rice University, Houston, TX (United States); Deng, Z [Tsinghua University, Beijing (China); Shao, Y

    2014-06-15

    Purpose: To develop a practical and compact preclinical PET with innovative technologies for substantially improved imaging performance required for the advanced imaging applications. Methods: Several key components of detector, readout electronics and data acquisition have been developed and evaluated for achieving leapfrogged imaging performance over a prototype animal PET we had developed. The new detector module consists of an 8×8 array of 1.5×1.5×30 mm{sup 3} LYSO scintillators with each end coupled to a latest 4×4 array of 3×3 mm{sup 2} Silicon Photomultipliers (with ∼0.2 mm insensitive gap between pixels) through a 2.0 mm thick transparent light spreader. Scintillator surface and reflector/coupling were designed and fabricated to reserve air-gap to achieve higher depth-of-interaction (DOI) resolution and other detector performance. Front-end readout electronics with upgraded 16-ch ASIC was newly developed and tested, so as the compact and high density FPGA based data acquisition and transfer system targeting 10M/s coincidence counting rate with low power consumption. The new detector module performance of energy, timing and DOI resolutions with the data acquisition system were evaluated. Initial Na-22 point source image was acquired with 2 rotating detectors to assess the system imaging capability. Results: No insensitive gaps at the detector edge and thus it is capable for tiling to a large-scale detector panel. All 64 crystals inside the detector were clearly separated from a flood-source image. Measured energy, timing, and DOI resolutions are around 17%, 2.7 ns and 1.96 mm (mean value). Point source image is acquired successfully without detector/electronics calibration and data correction. Conclusion: Newly developed advanced detector and readout electronics will be enable achieving targeted scalable and compact PET system in stationary configuration with >15% sensitivity, ∼1.3 mm uniform imaging resolution, and fast acquisition counting rate

  16. MO-G-17A-01: Innovative High-Performance PET Imaging System for Preclinical Imaging and Translational Researches

    International Nuclear Information System (INIS)

    Sun, X; Lou, K; Deng, Z; Shao, Y

    2014-01-01

    Purpose: To develop a practical and compact preclinical PET with innovative technologies for substantially improved imaging performance required for the advanced imaging applications. Methods: Several key components of detector, readout electronics and data acquisition have been developed and evaluated for achieving leapfrogged imaging performance over a prototype animal PET we had developed. The new detector module consists of an 8×8 array of 1.5×1.5×30 mm 3 LYSO scintillators with each end coupled to a latest 4×4 array of 3×3 mm 2 Silicon Photomultipliers (with ∼0.2 mm insensitive gap between pixels) through a 2.0 mm thick transparent light spreader. Scintillator surface and reflector/coupling were designed and fabricated to reserve air-gap to achieve higher depth-of-interaction (DOI) resolution and other detector performance. Front-end readout electronics with upgraded 16-ch ASIC was newly developed and tested, so as the compact and high density FPGA based data acquisition and transfer system targeting 10M/s coincidence counting rate with low power consumption. The new detector module performance of energy, timing and DOI resolutions with the data acquisition system were evaluated. Initial Na-22 point source image was acquired with 2 rotating detectors to assess the system imaging capability. Results: No insensitive gaps at the detector edge and thus it is capable for tiling to a large-scale detector panel. All 64 crystals inside the detector were clearly separated from a flood-source image. Measured energy, timing, and DOI resolutions are around 17%, 2.7 ns and 1.96 mm (mean value). Point source image is acquired successfully without detector/electronics calibration and data correction. Conclusion: Newly developed advanced detector and readout electronics will be enable achieving targeted scalable and compact PET system in stationary configuration with >15% sensitivity, ∼1.3 mm uniform imaging resolution, and fast acquisition counting rate capability

  17. 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 - Genetics ; Molecular Biology

  18. Blood responses under chronic low daily dose gamma irradiation: Pt. 2; Differential preclinical responses of irradiated female dogs in progression to either aplastic anemia or myeloproliferative disease

    Energy Technology Data Exchange (ETDEWEB)

    Seed, T.; Carnes, B.; Tolle, D.; Fritz, T. (Argonne National Lab., IL (United States). Biological and Medical Research Div.)

    1993-05-01

    Female beagle dogs were chronically exposed to low daily doses of [sup 60]Co gamma rays and responded in one of three distinct hemopathological patterns. These patterns, reflective of distinct subgroups, were characterized by (a) low radioresistance resulting in progressive hematopoietic suppression, terminal aplastic anemia (AA), and relatively short (<400 days) survival ([sup -]S-AA subgroups); (b) high radioresistance, initially coupled with strong but aberrant regenerative hematopoiesis, and later with the development of myeloproliferative disease (MPD) ([sup +]-R-MPD subgroup); and (c) high radioresistance, coupled with an early phase of strong regenerative hematopoiesis, but later with no myeloproliferative disease ([sup +]R-nonMPD subgroup). In this study, the changes in circulating blood cells levels (granulocytes, monotcytes, erythrocytes, lymphocytes and platelets) were sequentially assessed in time and fitted to a flexible, quadratic-linear-type response model previously developed. The results are consistent with our earlier observations of blood responses of chronically irradiated male dogs, in the subgroups of female dogs prone to specific radiogenic hematopathologies (i.e. AA and MPD) can be readily identified and staged in specific preclinical periods by a series of marked differential blood responses. (Author).

  19. 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.

  20. 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

    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......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......-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...

  1. Pramipexole but not imipramine or fluoxetine reverses the "depressive-like" behaviour in a rat model of preclinical stages of Parkinson's disease.

    Science.gov (United States)

    Berghauzen-Maciejewska, Klemencja; Kuter, Katarzyna; Kolasiewicz, Wacław; Głowacka, Urszula; Dziubina, Anna; Ossowska, Krystyna; Wardas, Jadwiga

    2014-09-01

    Depression is a frequent comorbid disorder in Parkinson's disease and may antedate its motor symptoms. However, mechanisms underlying Parkinson's disease-associated depression are unknown and its current medication is insufficient. The aim of the present study was to compare antidepressant-like effects of imipramine, fluoxetine and pramipexole in a model of preclinical stages of Parkinson's disease in rats. 6-Hydroxydopamine was bilaterally injected into the ventrolateral region of the caudate-putamen in rats. This treatment induced moderate decreases in the levels of dopamine and its metabolites in the caudate-putamen, nucleus accumbens and frontal cortex and reduced the density of tyrosine hydroxylase-immunoreactive neurons in the substantia nigra pars compacta and ventral tegmental area. The lesion increased immobility measured in the forced swimming test without influencing locomotor activity. Chronic (13 days) administration of pramipexole (1mg/kg sc/twice a day) reversed prolongation of the immobility time in lesioned animals but did not stimulate their locomotion. Chronic pramipexole activated dopaminergic transmission in the brain structures which might contribute to its effectiveness in the forced swimming test. In contrast, the 13-day administration of imipramine (10mg/kg ip/day) and fluoxetine (10mg/kg ip/day) did not shorten the immobility time in lesioned rats but reduced their locomotion. The present study indicates that already a moderate lesion of dopaminergic neurons induces "depressive-like" behaviour in animals which is reversed by chronic administration of the antiparkinsonian drug, pramipexole. Copyright © 2014 Elsevier B.V. All rights reserved.

  2. CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease.

    Science.gov (United States)

    Kosovec, Juliann E; Zaidi, Ali H; Omstead, Ashten N; Matsui, Daisuke; Biedka, Mark J; Cox, Erin J; Campbell, Patrick T; Biederman, Robert W W; Kelly, Ronan J; Jobe, Blair A

    2017-11-21

    Esophageal adenocarcinoma (EAC) is a deadly disease with limited therapeutic options. In the present study, we determined the preclinical efficacy of CDK4/6 inhibitor abemaciclib for treatment of EAC. In vitro , apoptosis, proliferation, and pathway regulation were evaluated in OE19, OE33, and FLO1 EAC cell lines. In vivo , esophagojejunostomy was performed on rats to induce EAC. At 36 weeks post-surgery, MRI and endoscopic biopsy established baseline tumor volume and molecular correlates, respectively. Next, the study animals were randomized to 26mg/kg intraperitoneal abemaciclib treatment or vehicle control for 28 days. Pre and post treatment MRIs, histopathology, and qRT-PCR were utilized to determine response. Our results demonstrated treatment with abemaciclib lead to increased apoptosis, and decreased proliferation in OE19 (p=0.185), OE33 (p=0.048), and FLO1 (p=0.043) with anticipated downstream molecular inhibition. In vivo , 78.9% of treatment animals demonstrated >20% tumor volume decrease (placebo 0%). Mean tumor volume changed in the treatment arm by -65.5% (placebo +133.5%) (p<0.01), and prevalence changed by -37.5% (placebo +16.7%) (p<0.01). Pre vs post treatment qRT-PCR demonstrated significant inhibition of all downstream molecular correlates. Overall our findings suggest potent antitumor efficacy of abemaciclib against EAC with evident molecular pathway inhibition and reasonable safety, establishing the rationale for future clinical development.

  3. 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.

  4. 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

  5. A short-term increase in cancer risk associated with daytime napping is likely to reflect pre-clinical disease: prospective cohort study.

    Science.gov (United States)

    Cairns, B J; Travis, R C; Wang, X-S; Reeves, G K; Green, J; Beral, V

    2012-07-24

    Sleep disturbance, a correlate of which is daytime napping, has been hypothesised to be associated with risk of breast and other cancers. We estimated relative risks (RR) of breast and other invasive cancers by the reported frequency of daytime napping in a large prospective cohort of middle-aged women in the UK. During an average of 7.4 years of follow-up, 20 058 breast cancers and 31 856 other cancers were diagnosed. Over the first 4 years of follow-up, daytime napping (sometimes/usually vs rarely/never) was associated with slightly increased risks of breast cancer (RR=1.10, 95% CI 1.06-1.15) and of other cancers (RR=1.12, 1.08-1.15), but the RRs decreased significantly with increasing follow-up time (P=0.001 and P=0.01, respectively, for trend). Four or more years after baseline, there was no elevated risk of breast cancer (RR=1.00, 0.96-1.05), and only marginally greater risk of other cancers (RR=1.04, 1.01-1.07). The effect of pre-clinical disease is a likely explanation for the short-term increased risk of breast and other cancers associated with daytime napping. © 2012 Cancer Research UK

  6. Periodontal disease and systemic complications

    Directory of Open Access Journals (Sweden)

    Rui Vicente Oppermann

    2012-01-01

    Full Text Available Periodontal diseases comprise a number of infectious and inflammatory conditions brought about by the interaction between supragingival and subgingival biofilms and the host inflammatory response. Periodontal diseases should be considered systemic conditions. This means that they are both modulated by the body's systems and play a role as a risk factor for systemic derangements. The current evidence supports some of these interactions, such as smoking as a risk factor for periodontal disease and diabetes mellitus, as both influenced by and influencing inflammatory changes in the periodontal tissue. Other potential associations are still being researched, such as obesity, hormonal changes, cardiovascular disease, and adverse outcomes in pregnancy. These, and others, still require further investigation before the repercussions of periodontal disease can be fully elucidated. Nevertheless, at the present time, the treatment of periodontal diseases-and, most importantly, their prevention-enables adequate intervention as a means of ensuring periodontal health.

  7. [Corneal manifestations in systemic diseases].

    Science.gov (United States)

    Zarranz Ventura, J; De Nova, E; Moreno-Montañés, J

    2008-01-01

    Systemic diseases affecting the cornea have a wide range of manifestations. The detailed study of all pathologies that cause corneal alteration is unapproachable, so we have centered our interest in the most prevalent or characteristic of them. In this paper we have divided these pathologies in sections to facilitate their study. Pulmonar and conective tissue (like colagen, rheumatologic and idiopathic inflamatory diseases), dermatologic, cardiovascular, hematologic, digestive and hepatopancreatic diseases with corneal alteration are described. Endocrine and metabolic diseases, malnutrition and carential states are also studied, as well as some otorhinolaryngologic and genetic diseases that affect the cornea. Finally, a brief report of ocular toxicity induced by drugs is referred.

  8. Ophthalmologic complications of systemic disease.

    Science.gov (United States)

    Klig, Jean E

    2008-02-01

    The human eye, as an organ, can offer critical clues to the presence of systemic disease. This article discusses the various ophthalmologic manifestations of systemic disease that can be evident on examination by an emergency department provider, as well as some findings that can be discerned with specialty consultation. The following topics are reviewed with respect to potential ocular signs and complications: syphilis, herpes zoster, Lyme disease, acquired immunodeficiency syndrome, Reiter's syndrome, Kawasaki's disease, temporal arteritis, endocarditis, hypertension, and diabetes mellitus. Indications for emergent ophthalmologic consultation are also emphasized.

  9. 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.

  10. 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.

  11. Preclinical study of diagnostic performances of contrast-enhanced spectral mammography versus MRI for breast diseases in China.

    Science.gov (United States)

    Wang, Qingguo; Li, Kangan; Wang, Lihui; Zhang, Jianbing; Zhou, Zhiguo; Feng, Yan

    2016-01-01

    To evaluate diagnostic performances of CESM for breast diseases with comparison to breast MRI in China. Sixty-eight patients with 77 breast lesions underwent MR and CESM. Two radiologists interpreted either MRI or CESM images, separately and independently. BI-RADS 1-3 and BI-RADS 4-5 were classified into the suspicious benign and suspicious malignant groups. Diagnostic accuracy parameters were calculated. Receiver operating characteristic (ROC) curves were constructed for the two modalities. The agreement and correlation between maximum lesion diameter based on CESM and MRI, or CESM and pathology were analyzed. Diagnostic accuracy parameters for CESM were sensitivity 95.8 %, specificity 65.5 %, PPV 82.1 %, NPV 90.5 % and accuracy 84.4 %. The diagnostic accuracy parameters for breast MRI were sensitivity 93.8 %, specificity 82.8 %, PPV 88.2 %, NPV 92.3 %and accuracy 89.6 %. Area under the curve (AUC) of ROC was 0.96 for breast MRI and 0.88 for CESM. The Bland-Altman plots showed a mean difference of 0.7 mm with 95 % limits of agreement of 11.4 mm in tumor diameter measured using CESM and breast MRI. The differences of size measurement between CESM and breast MRI were significant, whereas no difference was observed between CESM and pathology as well as between breast MRI and pathology. The better correlation with pathological results was found in CESM than breast MRI. Our study demonstrates that CESM possesses better diagnostic performances than breast MRI in terms of diagnostic sensitivity and lesion size assessment. And CESM is a good alternative method of screening breast cancer in high-risk people.

  12. 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.

  13. 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.

  14. Periodontal Disease and Systemic Diseases: An Update for the Clinician.

    Science.gov (United States)

    John, Vanchit; Alqallaf, Hawra; De Bedout, Tatiana

    2016-01-01

    A link between periodontal disease and various systemic diseases has been investigated for several years. Interest in unearthing such a link has grown as the health care profession is looking for a better understanding of disease processes and their relationships to periodontal and other oral diseases. The article aims to provide recent information on the relationship between periodontal disease and systemic diseases such as; cardiovascular, respiratory, endocrine, musculoskeletal, and reproductive system related abnormalities.

  15. 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.

  16. 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

  17. 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.

  18. Breast manifestations of systemic diseases

    Directory of Open Access Journals (Sweden)

    Dilaveri CA

    2012-02-01

    Full Text Available Christina A Dilaveri, Maire Brid Mac Bride, Nicole P Sandhu, Lonzetta Neal, Karthik Ghosh, Dietlind L Wahner-RoedlerDivision of General Internal Medicine, Mayo Clinic, Rochester, MN, USAAbstract: Although much emphasis has been placed on the primary presentations of breast cancer, little focus has been placed on how systemic illnesses may affect the breast. In this article, we discuss systemic illnesses that can manifest in the breast. We summarize the clinical features, imaging, histopathology, and treatment recommendations for endocrine, vascular, systemic inflammatory, infectious, and hematologic diseases, as well as for the extramammary malignancies that can present in the breast. Despite the rarity of these manifestations of systemic disease, knowledge of these conditions is critical to the appropriate evaluation and treatment of patients presenting with breast symptoms.Keywords: breast, endocrine, hematologic, infectious, vascular

  19. Radiological approach to systemic connective tissue diseases

    International Nuclear Information System (INIS)

    Wiesmann, W.; Schneider, M.

    1988-01-01

    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. (orig.) [de

  20. 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.

  1. 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.

  2. Preclinical studies of dendrimer prodrugs.

    Science.gov (United States)

    Kojima, Chie

    2015-01-01

    Dendrimers are synthetic macromolecules with well-defined structures bearing a wide variety of functional groups on their periphery. These groups can be used to conjugate bioactive molecules such as drugs, ligands and imaging agents. Dendrimer prodrugs can be used to improve the water solubility and pharmacokinetic properties of the corresponding free drugs. This article summarizes preclinical studies pertaining to the use of drug-dendrimer conjugates as dendrimer prodrugs for the treatments of various diseases, including cancer and inflammatory diseases. A wide range of anticancer drugs have been conjugated to dendrimers via biodegradable linkers. The side effects of the parent drugs can be markedly reduced using dendrimer prodrugs, with some drugs showing improved efficacy. Anti-inflammatory agents have also been conjugated to dendrimers and used to treat a number of inflammatory diseases. Drug-dendrimer conjugates are preferable to drug-dendrimer complexes, where the use of degradable linkers is critical to the release of the drug. Polyethylene glycol and/or ligands can be added to a dendrimer prodrug, which is useful for the targeting of affected tissues. Imaging probes can also be incorporated into dendrimer prodrugs for the simultaneous delivery of therapeutic and diagnostic agents as 'theranostics.'

  3. 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.

  4. TOWARDS MODELING DISEASE OUTBREAK NOTIFICATION SYSTEMS

    OpenAIRE

    Farag Azzedin; Jaweed Yazdani,; Salahadin Adam; Mustafa Ghaleb

    2014-01-01

    Disease outbreak detection, monitoring and notification systems play an important role in assessing threats to public health since disease outbreaks are becoming increasingly common world-wide. There are several systems in use around the world, with coverage of national, international and global disease outbreaks. These systems use different taxonomies and classifications for the detection and prioritization of potential disease outbreaks. In this paper, we study and analyze th...

  5. Performance characterization of the Inveon preclinical small-animal PET/SPECT/CT system for multimodality imaging

    International Nuclear Information System (INIS)

    Magota, Keiichi; Kubo, Naoki; Kuge, Yuji; Nishijima, Ken-ichi; Zhao, Songji; Tamaki, Nagara

    2011-01-01

    We investigated the performance of the Inveon small-animal PET/SPECT/CT system and compared the imaging capabilities of the SPECT and PET components. For SPECT, the energy resolution, tomographic spatial resolution and system sensitivity were evaluated with a 99m Tc solution using a single pinhole collimator. For PET, the spatial resolution, absolute sensitivity, scatter fraction and peak noise equivalent count were evaluated. Phantoms and a normal rat were scanned to compare the imaging capabilities of SPECT and PET. The SPECT spatial resolution was 0.84 mm full-width at half-maximum (FWHM) at a radius of rotation of 25 mm using a 0.5-mm pinhole aperture collimator, while the PET spatial resolution was 1.63 mm FWHM at the centre. The SPECT system sensitivity at a radius of rotation of 25 mm was 35.3 cps/MBq (4 x 10 -3 %) using the 0.5-mm pinhole aperture, while the PET absolute sensitivity was 3.2% for 350-650 keV and 3.432 ns. Accordingly, the volume sensitivity of PET was three orders of magnitude higher than that of SPECT. This integrated PET/SPECT/CT system showed high performance with excellent spatial resolution for SPECT and sensitivity for PET. Based on the tracer availability and system performance, SPECT and PET have complementary roles in multimodality small-animal imaging. (orig.)

  6. Modeling the Western Diet for Preclinical Investigations.

    Science.gov (United States)

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

    2018-05-01

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

  7. Initial performance evaluation of a preclinical PET scanner available as a clip-on assembly in a sequential PET/MRI system.

    Science.gov (United States)

    Vrigneaud, Jean-Marc; McGrath, John; Courteau, Alan; Pegg, Rosie; Sanchez-Pastor Gomis, Alberto; Camacho, Angela; Martin, Gary; Schramm, Nils; Brunotte, François

    2018-05-15

    We evaluated the performance characteristics of a prototype preclinical PET scanner available as an easy clippable assembly that can dock to an MRI system. The single ring version of the PET system consists of 8 detectors, each of which comprises a 12 × 12 silicon photomultipliers (SiPMs) array coupled with a dual layer of offset scintillation crystals to measure depth of interaction. The crystal arrays have 29 × 29 (30 × 30 for the outer layer) 4 mm long LYSO crystals (6 mm for the outer layer). The ring diameter is 119.2 mm and the axial field of view is 50.4 mm. The NEMA NU-4-2008 protocol was followed for studying the PET performance. Temperature stability of SiPMs was also investigated. The peak system absolute sensitivity was 4.70% with an energy window of 250-750 keV. The spatial resolution was 1.28/1.88/1.85 mm FWHM (radial/tangential/axial) at a distance of 5 mm from the center. Peak noise equivalent counting rate (NECR) and scatter fraction for mouse phantom were 61.9 kcps at 14.9 MBq and 21.0%, respectively. The uniformity was 6.3% and the spill-over ratios in the images of the water- and air-filled chambers were 0.07 and 0.17, respectively. Recovery coefficients ranged from 0.13 to 0.96. Change in sensitivity as a function of ambient temperature was 0.3%/°C. These first results indicate excellent spatial resolution performance for use with animal studies. Moreover, the clippable assembly can be upgraded to accept a second ring of SiPMs modules, leading to improved sensitivity and axial coverage. © 2018 Institute of Physics and Engineering in Medicine.

  8. 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.

  9. Preclinical Evaluation of 18F-RO6958948, 11C-RO6931643, and 11C-RO6924963 as Novel PET Radiotracers for Imaging Tau Aggregates in Alzheimer Disease.

    Science.gov (United States)

    Honer, Michael; Gobbi, Luca; Knust, Henner; Kuwabara, Hiroto; Muri, Dieter; Koerner, Matthias; Valentine, Heather; Dannals, Robert F; Wong, Dean F; Borroni, Edilio

    2018-04-01

    Tau aggregates and amyloid-β (Aβ) plaques are key histopathologic features in Alzheimer disease (AD) and are considered targets for therapeutic intervention as well as biomarkers for diagnostic in vivo imaging agents. This article describes the preclinical in vitro and in vivo characterization of 3 novel compounds-RO6958948, RO6931643, and RO6924963-that bind specifically to tau aggregates and have the potential to become PET tracers for future human use. Methods: RO6958948, RO6931643, and RO6924963 were identified as high-affinity competitors at the 3 H-T808 binding site on native tau aggregates in human late-stage AD brain tissue. Binding of tritiated compounds to brain tissue sections of AD patients and healthy controls was analyzed by macro- and microautoradiography and by costaining of tau aggregates and Aβ plaques on the same tissue section using specific antibodies. All 3 tracer candidates were radiolabeled with a PET nuclide and tested in vivo in tau-naïve baboons to assess brain uptake, distribution, clearance, and metabolism. Results: 3 H-RO6958948, 3 H-RO6931643, and 3 H-RO6924963 bound with high affinity and specificity to tau aggregates, clearly lacking affinity for concomitant Aβ plaques in human AD Braak V tissue sections. The specificity of all 3 radioligands for tau aggregates was supported, first, by binding patterns in AD sections comparable to the tau-specific radioligand 3 H-T808; second, by very low nonspecific binding in brain tissue devoid of tau pathology, excluding significant radioligand binding to any other central nervous system target; and third, by macroscopic and microscopic colocalization and quantitative correlation of radioligand binding and tau antibody staining on the same tissue section. RO6958948, RO6931643, and RO6924963 were successfully radiolabeled with a PET nuclide at high specific activity, radiochemical purity, and yield. After intravenous administration of 18 F-RO6958948, 11 C-RO6931643, and 11 C-RO6924963 to

  10. Periodontal Disease and Systemic Health

    Science.gov (United States)

    ... Club Program Perio Store Education & Careers Careers in Periodontics Perio Exam for Dental Licensure Recommended Competencies Periodontal ... may also help with the management of other chronic inflammatory conditions. Diabetes heart Disease Other Diseases Members ...

  11. Recommendations for Benchmarking Preclinical Studies of Nanomedicines.

    Science.gov (United States)

    Dawidczyk, Charlene M; Russell, Luisa M; Searson, Peter C

    2015-10-01

    Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small-molecule drug therapy for cancer and to achieve both therapeutic and diagnostic functions in the same platform. Preclinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of preclinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of preclinical trials and propose a protocol for benchmarking that we recommend be included in in vivo preclinical studies of drug-delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. ©2015 American Association for Cancer Research.

  12. Blood responses under chronic low daily dose gamma irradiation: Pt. 1; Differential preclinical responses of irradiated male dogs in progression to either aplastic anemia or myeloproliferative disease

    Energy Technology Data Exchange (ETDEWEB)

    Seed, T.M.; Carnes, B.A.; Tolle, D.V.; Fritz, T.E. (Argonne National Lab., IL (USA))

    1989-01-01

    Male beagles chronically exposed to low daily doses of {sup 60}Co {gamma} rays show one of three hematopoietic patterns, which reflect three different distinctly responding subgroups: (1) low radioresistance with progressing aplastic anemia and shortened survival ({sup -S}-AA subgroup); (2) high radioresistance with a complex of progressing myeloproliferative disorders ({sup +}R-MPD group); or (3) high radioresistance with other nonMPD syndromes ({sup +}R-nonMPD group). Blood cell levels (granulocytes, monocytes, erythrocytes, lymphocytes, and platelets) were assessed and fitted to a flexible polynomial spline model. Results showed that relative to the overall magnitude of blood cell loss as well as to the maximum rate of suppression during the initial phase, the subgroups were generally ranked {sup -}S-AA >> {sup +}R-MPD > {sup +}R-nonMPD. Relative to the overall strength of the recovery response, the subgroups were generally ranked {sup +}R-MPD > {sup +}R-nonMPD >>> {sup -}S-AA. In terms of overall maintenance levels of circulating blood cells during the recovery phase, however, the {sup +}R-nonMPD subgroup consistently exhibited stronger responses than the {sup +}R-MPD subgroup. These results support our contention that selected subgroups of dogs have strong propensities to specific hematopathologies (i.e. aplastic anemia and myeloid leukemia) under chronic irradiation and that these pathology-prone animals exhibit a series of marked differential hematopoietic responses during early preclinical phases, which serve effectively to prognosticate subsequent pathological progression. (author).

  13. {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.)

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

    International Nuclear Information System (INIS)

    Tsiamas, P; Moskvin, V; Shin, J; Axente, M; Pirlepesov, F; Krasin, M; Merchant, T; Farr, J

    2015-01-01

    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

  15. 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.

  16. 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 extended control of confounding factors and intervention studies may add to the understanding of a possible relationship between the diseases. In some cases, IE is caused by dental plaque bacteria. Several studies are suggestive of oral bacteria causing respiratory infection. The pathogenesis and course...... of a number of other diseases including DM and rheumatoid arthritis have been associated wish periodontitis, but more research is necessary to elucidate possible pathogenic interactions....

  17. 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.

  18. 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.

  19. 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.

  20. 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

  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. Behavioral and locomotor measurements using an open field activity monitoring system for skeletal muscle diseases.

    Science.gov (United States)

    Tatem, Kathleen S; Quinn, James L; Phadke, Aditi; Yu, Qing; Gordish-Dressman, Heather; Nagaraju, Kanneboyina

    2014-09-29

    The open field activity monitoring system comprehensively assesses locomotor and behavioral activity levels of mice. It is a useful tool for assessing locomotive impairment in animal models of neuromuscular disease and efficacy of therapeutic drugs that may improve locomotion and/or muscle function. The open field activity measurement provides a different measure than muscle strength, which is commonly assessed by grip strength measurements. It can also show how drugs may affect other body systems as well when used with additional outcome measures. In addition, measures such as total distance traveled mirror the 6 min walk test, a clinical trial outcome measure. However, open field activity monitoring is also associated with significant challenges: Open field activity measurements vary according to animal strain, age, sex, and circadian rhythm. In addition, room temperature, humidity, lighting, noise, and even odor can affect assessment outcomes. Overall, this manuscript provides a well-tested and standardized open field activity SOP for preclinical trials in animal models of neuromuscular diseases. We provide a discussion of important considerations, typical results, data analysis, and detail the strengths and weaknesses of open field testing. In addition, we provide recommendations for optimal study design when using open field activity in a preclinical trial.

  3. Estrogen in cardiovascular disease during systemic lupus erythematosus.

    Science.gov (United States)

    Gilbert, Emily L; Ryan, Michael J

    2014-12-01

    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. PubMed was used to search for articles with terms related to estradiol and SLE. The references of retrieved publications were also reviewed. 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 cardiovascular risk factors in

  4. 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

  5. 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

  6. Left ventricular remodeling in preclinical experimental mitral regurgitation of dogs.

    Science.gov (United States)

    Dillon, A Ray; Dell'Italia, Louis J; Tillson, Michael; Killingsworth, Cheryl; Denney, Thomas; Hathcock, John; Botzman, Logan

    2012-03-01

    Dogs with experimental mitral regurgitation (MR) provide insights into the left ventricular remodeling in preclinical MR. The early preclinical left ventricular (LV) changes after mitral regurgitation represent progressive dysfunctional remodeling, in that no compensatory response returns the functional stroke volume (SV) to normal even as total SV increases. The gradual disease progression leads to mitral annulus stretch and enlargement of the regurgitant orifice, further increasing the regurgitant volume. Remodeling with loss of collagen weave and extracellular matrix (ECM) is accompanied by stretching and hypertrophy of the cross-sectional area and length of the cardiomyocyte. Isolated ventricular cardiomyocytes demonstrate dysfunction based on decreased cell shortening and reduced intracellular calcium transients before chamber enlargement or decreases in contractility in the whole heart can be clinically appreciated. The genetic response to increased end-diastolic pressure is down-regulation of genes associated with support of the collagen and ECM and up-regulation of genes associated with matrix remodeling. Experiments have not demonstrated any beneficial effects on remodeling from treatments that decrease afterload via blocking the renin-angiotensin system (RAS). Beta-1 receptor blockade and chymase inhibition have altered the progression of the LV remodeling and have supported cardiomyocyte function. The geometry of the LV during the remodeling provides insight into the importance of regional differences in responses to wall stress. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Dupuytren's: a systems biology disease.

    NARCIS (Netherlands)

    Rehman, S.; Goodacre, R.; Day, P.J.; Bayat, A.; Westerhoff, H.V.

    2011-01-01

    Dupuytren's disease (DD) is an ill-defined fibroproliferative disorder of the palm of the hands leading to digital contracture. DD commonly occurs in individuals of northern European extraction. Cellular components and processes associated with DD pathogenesis include altered gene and protein

  8. Systems thinking in combating infectious diseases.

    Science.gov (United States)

    Xia, Shang; Zhou, Xiao-Nong; Liu, Jiming

    2017-09-11

    The transmission of infectious diseases is a dynamic process determined by multiple factors originating from disease pathogens and/or parasites, vector species, and human populations. These factors interact with each other and demonstrate the intrinsic mechanisms of the disease transmission temporally, spatially, and socially. In this article, we provide a comprehensive perspective, named as systems thinking, for investigating disease dynamics and associated impact factors, by means of emphasizing the entirety of a system's components and the complexity of their interrelated behaviors. We further develop the general steps for performing systems approach to tackling infectious diseases in the real-world settings, so as to expand our abilities to understand, predict, and mitigate infectious diseases.

  9. Sex Differences in Psychiatric Disease: A Focus on the Glutamate System

    Directory of Open Access Journals (Sweden)

    Megan M. Wickens

    2018-06-01

    Full Text Available Alterations in glutamate, the primary excitatory neurotransmitter in the brain, are implicated in several psychiatric diseases. Many of these psychiatric diseases display epidemiological sex differences, with either males or females exhibiting different symptoms or disease prevalence. However, little work has considered the interaction of disrupted glutamatergic transmission and sex on disease states. This review describes the clinical and preclinical evidence for these sex differences with a focus on two conditions that are more prevalent in women: Alzheimer's disease and major depressive disorder, and three conditions that are more prevalent in men: schizophrenia, autism spectrum disorder, and attention deficit hyperactivity disorder. These studies reveal sex differences at multiple levels in the glutamate system including metabolic markers, receptor levels, genetic interactions, and therapeutic responses to glutamatergic drugs. Our survey of the current literature revealed a considerable need for more evaluations of sex differences in future studies examining the role of the glutamate system in psychiatric disease. Gaining a more thorough understanding of how sex differences in the glutamate system contribute to psychiatric disease could provide novel avenues for the development of sex-specific pharmacotherapies.

  10. 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.

  11. Stepwise approach to myopathy in systemic disease.

    Science.gov (United States)

    Chawla, Jasvinder

    2011-01-01

    Muscle diseases can constitute a large variety of both acquired and hereditary disorders. Myopathies in systemic disease results from several different disease processes including endocrine, inflammatory, paraneoplastic, infectious, drug- and toxin-induced, critical illness myopathy, metabolic, and myopathies with other systemic disorders. Patients with systemic myopathies often present acutely or sub acutely. On the other hand, familial myopathies or dystrophies generally present in a chronic fashion with exceptions of metabolic myopathies where symptoms on occasion can be precipitated acutely. Most of the inflammatory myopathies can have a chance association with malignant lesions; the incidence appears to be specifically increased only in patients with dermatomyositis. In dealing with myopathies associated with systemic illnesses, the focus will be on the acquired causes. Management is beyond the scope of this chapter. Prognosis is based upon the underlying cause and, most of the time, carries a good prognosis. In order to approach a patient with suspected myopathy from systemic disease, a stepwise approach is utilized.

  12. 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

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

  14. 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.

  15. Fully Implantable Deep Brain Stimulation System with Wireless Power Transmission for Long-term Use in Rodent Models of Parkinson's Disease.

    Science.gov (United States)

    Heo, Man Seung; Moon, Hyun Seok; Kim, Hee Chan; Park, Hyung Woo; Lim, Young Hoon; Paek, Sun Ha

    2015-03-01

    The purpose of this study to develop new deep-brain stimulation system for long-term use in animals, in order to develop a variety of neural prostheses. Our system has two distinguished features, which are the fully implanted system having wearable wireless power transfer and ability to change the parameter of stimulus parameter. It is useful for obtaining a variety of data from a long-term experiment. To validate our system, we performed pre-clinical test in Parkinson's disease-rat models for 4 weeks. Through the in vivo test, we observed the possibility of not only long-term implantation and stability, but also free movement of animals. We confirmed that the electrical stimulation neither caused any side effect nor damaged the electrodes. We proved possibility of our system to conduct the long-term pre-clinical test in variety of parameter, which is available for development of neural prostheses.

  16. Urogenital system diseases's radiological evaluation

    Energy Technology Data Exchange (ETDEWEB)

    Bianchi, S; Mecozzi, B

    1985-01-01

    Radiological urogenital radiography reliability, can be compromised because of absence of a correct urodynamic diagnosis. It is then required that specialist radiologists know the problems concerning the urogenital system radiographies cannot be made in many cases, because of the scarcity in hospitals of idoneous urodynamic services.

  17. Accuracy of a clinical PET/CT vs. a preclinical μPET system for monitoring treatment effects in tumour xenografts

    Energy Technology Data Exchange (ETDEWEB)

    Palmowski, Karin [Department of Experimental Molecular Imaging, RWTH-Aachen University, Aachen (Germany); Department of Pneumology and Critical Care Medicine, Thoraxklinik Heidelberg, University of Heidelberg, Heidelberg (Germany); Winz, Oliver [Department of Nuclear Medicine, RWTH-Aachen University, Aachen (Germany); Rix, Anne; Bzyl, Jessica [Department of Experimental Molecular Imaging, RWTH-Aachen University, Aachen (Germany); Behrendt, Florian F.; Verburg, Frederic A.; Mottaghy, Felix M. [Department of Nuclear Medicine, RWTH-Aachen University, Aachen (Germany); Palmowski, Moritz, E-mail: mpalmowski@ukaachen.de [Department of Experimental Molecular Imaging, RWTH-Aachen University, Aachen (Germany); Department of Nuclear Medicine, RWTH-Aachen University, Aachen (Germany); Academic Radiology Baden Baden, Diagnostic and Interventional Radiology, University Medical Center Heidelberg, Heidelberg (Germany)

    2013-08-15

    Purpose: Small animal imaging is of growing importance for preclinical research and drug development. Tumour xenografts implanted in mice can be visualized with a clinical PET/CT (cPET); however, it is unclear whether early treatment effects can be monitored. Thus, we investigated the accuracy of a cPET versus a preclinical μPET using {sup 18}F-FDG for assessing early treatment effects. Materials and methods: The spatial resolution and the quantitative accuracy of a clinical and preclinical PET were evaluated in phantom experiments. To investigate the sensitivity for assessing treatment response, A431 tumour xenografts were implanted in nude mice. Glucose metabolism was measured in untreated controls and in two therapy groups (either one or four days of antiangiogenic treatment). Data was validated by γ-counting of explanted tissues. Results: In phantom experiments, cPET enabled reliable separation of boreholes ≥ 5 mm whereas μPET visualized boreholes ≥ 2 mm. In animal studies, μPET provided significantly higher tumour-to-muscle ratios for untreated control tumours than cPET (3.41 ± 0.87 vs. 1.60 ± .0.28, respectively; p < 0.01). During treatment, cPET detected significant therapy effects at day 4 (p < 0.05) whereas μPET revealed highly significant therapy effects even at day one (p < 0.01). Correspondingly, γ-counting of explanted tumours indicated significant therapy effects at day one and highly significant treatment response at day 4. Correlation with γ-counting was good for cPET (r = 0.74; p < 0.01) and excellent for μPET (r = 0.85; p < 0.01). Conclusion: Clinical PET is suited to investigate tumour xenografts ≥ 5 mm at an advanced time-point of treatment. For imaging smaller tumours or for the sensitive assessment of very early therapy effects, μPET should be preferred.

  18. 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.

  19. Preclinical electrogastrography in experimental pigs

    Science.gov (United States)

    Květina, Jaroslav; Varayil, Jithinraj Edakkanambeth; Ali, Shahzad Marghoob; Kuneš, Martin; Bureš, Jan; Tachecí, Ilja; Rejchrt, Stanislav; Kopáčová, Marcela

    2010-01-01

    Surface electrogastrography (EGG) is a non-invasive means of recording gastric myoelectric activity or slow waves from cutaneous leads placed over the stomach. This paper provides a comprehensive review of preclinical EGG. Our group recently set up and worked out the methods for EGG in experimental pigs. We gained our initial experience in the use of EGG in assessment of porcine gastric myoelectric activity after volume challenge and after intragastric administration of itopride and erythromycin. The mean dominant frequency in pigs is comparable with that found in humans. EGG in experimental pigs is feasible. Experimental EGG is an important basis for further preclinical projects in pharmacology and toxicology. PMID:21217873

  20. 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.......g. periodontal pocket depth or loss of attachment). All tools reviewed in this paper were developed based on the state of the science of the pathophysiology of periodontal disease at the time of their design and the need to provide valid and reliable measurements of the presence and severity of periodontal...... diseases. Therefore, some of these tools are no longer valid. Others, such as loss of periodontal attachment, are the current de-facto tools but demand many resources to undertake periodical assessment of the periodontal health of populations. Less complex tools such as the Community Periodontal Index...

  1. 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.

  2. 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.

  3. 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.

  4. Periodontal disease and systemic diseases in an older population.

    Science.gov (United States)

    Özçaka, Özgün; Becerik, Sema; Bıçakcı, Nurgün; Kiyak, Asuman H

    2014-01-01

    To evaluate the relationship between older adults' medical and oral conditions and their self-reports of periodontal conditions with clinically obtained data. Concerns about oral health of elders and its association with systemic diseases have been gaining more attention. A total of 201 older subjects were interviewed about their previous medical and dental histories and were asked to complete a health questionnaire. Each subject received full mouth exam, including counting number of natural teeth remaining, gingival (GI) and plaque index (PI), CPITN and denture status. Elders who completed health questionnaires had mean age of 62.5. Mean CPITN score was 1.62(± 1.12), PI was 1.57(± 1.48), and GI was 1.55(± 1.31). Women had higher prevalence of CVD and osteoporosis than men (p=0.008, p=0.0001, respectively). Subjects who reported bleeding upon brushing had higher PI and GI scores (p=0.03, p=0.05, respectively). Smokers were more likely to describe their periodontal tissues as unhealthy (72.3% vs. 27.7%, p=0.01), whereas self-reports of healthy vs. unhealthy gums did not differ between non-smokers. These findings suggest that a number of systemic conditions are associated with indicators of periodontal disease, and self-reports of oral conditions are independent of systemic diseases. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  5. 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.

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

    Science.gov (United States)

    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

    2018-01-01

    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. PMID:29349875

  7. Peripheral Nervous System Manifestations in Systemic Autoimmune Diseases

    OpenAIRE

    COJOCARU, Inimioara Mihaela; COJOCARU, Manole; SILOSI, Isabela; VRABIE, Camelia Doina

    2014-01-01

    The peripheral nervous system refers to parts of the nervous system outside the brain and spinal cord. Systemic autoimmune diseases can affect both the central and peripheral nervous systems in a myriad of ways and through a heterogeneous number of mechanisms leading to many different clinical manifestations. As a result, neurological complications of these disorders can result in significant morbidity and mortality. The most common complication of peripheral nervous system (PNS) involvement ...

  8. Health Systems Sustainability and Rare Diseases.

    Science.gov (United States)

    Ferrelli, Rita Maria; De Santis, Marta; Egle Gentile, Amalia; Taruscio, Domenica

    2017-01-01

    The paper is addressing aspects of health system sustainability for rare diseases in relation to the current economic crisis and equity concerns. It takes into account the results of the narrative review carried out in the framework of the Joint Action for Rare Diseases (Joint RD-Action) "Promoting Implementation of Recommendations on Policy, Information and Data for Rare Diseases", that identified networks as key factors for health systems sustainability for rare diseases. The legal framework of European Reference Networks and their added value is also presented. Networks play a relevant role for health systems sustainability, since they are based upon, pay special attention to and can intervene on health systems knowledge development, partnership, organizational structure, resources, leadership and governance. Moreover, sustainability of health systems can not be separated from the analysis of the context and the action on it, including fiscal equity. As a result of the financial crisis of 2008, cuts of public health-care budgets jeopardized health equity, since the least wealthy suffered from the greatest health effects. Moreover, austerity policies affected economic growth much more adversely than previously believed. Therefore, reducing public health expenditure not only is going to jeopardise citizens' health, but also to hamper fair and sustainable development.

  9. SU-E-J-03: Characterization of the Precision and Accuracy of a New, Preclinical, MRI-Guided Focused Ultrasound System for Image-Guided Interventions in Small-Bore, High-Field Magnets

    International Nuclear Information System (INIS)

    Ellens, N; Farahani, K

    2015-01-01

    Purpose: MRI-guided focused ultrasound (MRgFUS) has many potential and realized applications including controlled heating and localized drug delivery. The development of many of these applications requires extensive preclinical work, much of it in small animal models. The goal of this study is to characterize the spatial targeting accuracy and reproducibility of a preclinical high field MRgFUS system for thermal ablation and drug delivery applications. Methods: The RK300 (FUS Instruments, Toronto, Canada) is a motorized, 2-axis FUS positioning system suitable for small bore (72 mm), high-field MRI systems. The accuracy of the system was assessed in three ways. First, the precision of the system was assessed by sonicating regular grids of 5 mm squares on polystyrene plates and comparing the resulting focal dimples to the intended pattern, thereby assessing the reproducibility and precision of the motion control alone. Second, the targeting accuracy was assessed by imaging a polystyrene plate with randomly drilled holes and replicating the hole pattern by sonicating the observed hole locations on intact polystyrene plates and comparing the results. Third, the practicallyrealizable accuracy and precision were assessed by comparing the locations of transcranial, FUS-induced blood-brain-barrier disruption (BBBD) (observed through Gadolinium enhancement) to the intended targets in a retrospective analysis of animals sonicated for other experiments. Results: The evenly-spaced grids indicated that the precision was 0.11 +/− 0.05 mm. When image-guidance was included by targeting random locations, the accuracy was 0.5 +/− 0.2 mm. The effective accuracy in the four rodent brains assessed was 0.8 +/− 0.6 mm. In all cases, the error appeared normally distributed (p<0.05) in both orthogonal axes, though the left/right error was systematically greater than the superior/inferior error. Conclusions: The targeting accuracy of this device is sub-millimeter, suitable for many

  10. SU-E-J-03: Characterization of the Precision and Accuracy of a New, Preclinical, MRI-Guided Focused Ultrasound System for Image-Guided Interventions in Small-Bore, High-Field Magnets

    Energy Technology Data Exchange (ETDEWEB)

    Ellens, N [Johns Hopkins University, Baltimore, Maryland (United States); Farahani, K [National Cancer Institute, Bethesda, MD (United States)

    2015-06-15

    Purpose: MRI-guided focused ultrasound (MRgFUS) has many potential and realized applications including controlled heating and localized drug delivery. The development of many of these applications requires extensive preclinical work, much of it in small animal models. The goal of this study is to characterize the spatial targeting accuracy and reproducibility of a preclinical high field MRgFUS system for thermal ablation and drug delivery applications. Methods: The RK300 (FUS Instruments, Toronto, Canada) is a motorized, 2-axis FUS positioning system suitable for small bore (72 mm), high-field MRI systems. The accuracy of the system was assessed in three ways. First, the precision of the system was assessed by sonicating regular grids of 5 mm squares on polystyrene plates and comparing the resulting focal dimples to the intended pattern, thereby assessing the reproducibility and precision of the motion control alone. Second, the targeting accuracy was assessed by imaging a polystyrene plate with randomly drilled holes and replicating the hole pattern by sonicating the observed hole locations on intact polystyrene plates and comparing the results. Third, the practicallyrealizable accuracy and precision were assessed by comparing the locations of transcranial, FUS-induced blood-brain-barrier disruption (BBBD) (observed through Gadolinium enhancement) to the intended targets in a retrospective analysis of animals sonicated for other experiments. Results: The evenly-spaced grids indicated that the precision was 0.11 +/− 0.05 mm. When image-guidance was included by targeting random locations, the accuracy was 0.5 +/− 0.2 mm. The effective accuracy in the four rodent brains assessed was 0.8 +/− 0.6 mm. In all cases, the error appeared normally distributed (p<0.05) in both orthogonal axes, though the left/right error was systematically greater than the superior/inferior error. Conclusions: The targeting accuracy of this device is sub-millimeter, suitable for many

  11. 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

  12. The detection, diagnosis, therapy, and pre-clinical biology of breast cancer

    International Nuclear Information System (INIS)

    1978-01-01

    The Cancergram covers clinical aspects of cancers of the mammary glands, the fat pads and the supporting tissues. Abstracts included concern certain specific types of neoplasms which occur in the breast, and in ancillary tissues related to the breast (axillary lymph nodes, etc.). Also included are selected studies on receptors and the physiological aspects of lactation, pregnancy, and ontogeny related to cancer of the breast. The topic includes clinically relevant aspects of the prevention, detection, diagnosis, evaluation, and therapy of breast cancer. With certain exceptions, pre-clinical studies of tissue culture systems or animal model studies which are not directly related to primary human disease are excluded

  13. Systems-level thinking for nanoparticle-mediated therapeutic delivery to neurological diseases.

    Science.gov (United States)

    Curtis, Chad; Zhang, Mengying; Liao, Rick; Wood, Thomas; Nance, Elizabeth

    2017-03-01

    Neurological diseases account for 13% of the global burden of disease. As a result, treating these diseases costs $750 billion a year. Nanotechnology, which consists of small (~1-100 nm) but highly tailorable platforms, can provide significant opportunities for improving therapeutic delivery to the brain. Nanoparticles can increase drug solubility, overcome the blood-brain and brain penetration barriers, and provide timed release of a drug at a site of interest. Many researchers have successfully used nanotechnology to overcome individual barriers to therapeutic delivery to the brain, yet no platform has translated into a standard of care for any neurological disease. The challenge in translating nanotechnology platforms into clinical use for patients with neurological disease necessitates a new approach to: (1) collect information from the fields associated with understanding and treating brain diseases and (2) apply that information using scalable technologies in a clinically-relevant way. This approach requires systems-level thinking to integrate an understanding of biological barriers to therapeutic intervention in the brain with the engineering of nanoparticle material properties to overcome those barriers. To demonstrate how a systems perspective can tackle the challenge of treating neurological diseases using nanotechnology, this review will first present physiological barriers to drug delivery in the brain and common neurological disease hallmarks that influence these barriers. We will then analyze the design of nanotechnology platforms in preclinical in vivo efficacy studies for treatment of neurological disease, and map concepts for the interaction of nanoparticle physicochemical properties and pathophysiological hallmarks in the brain. WIREs Nanomed Nanobiotechnol 2017, 9:e1422. doi: 10.1002/wnan.1422 For further resources related to this article, please visit the WIREs website. © 2016 Wiley Periodicals, Inc.

  14. Capillaroscopy in diagnostic of systemic autoimmune diseases

    International Nuclear Information System (INIS)

    Garra, V.; Danese, N.; Rebella, M.

    2012-01-01

    The diagnosis of systemic autoimmune diseases is carried out by combining clinical, paraclinical, imaging and anatomopathological data. However, in many cases is necessary to access other guiding parameters. The capillaroscopy is a technique that consists in the observation of capillary microcirculation in the proximal nail fold hands. The methods used are the videocapillaroscopy (microscopy, stereoscopic)

  15. Interplay among gut microbiota, intestinal mucosal barrier and enteric neuro-immune system: a common path to neurodegenerative diseases?

    Science.gov (United States)

    Pellegrini, Carolina; Antonioli, Luca; Colucci, Rocchina; Blandizzi, Corrado; Fornai, Matteo

    2018-05-24

    Neurological diseases, such as Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS) and multiple sclerosis, are often associated with functional gastrointestinal disorders. These gastrointestinal disturbances may occur at all stages of the neurodegenerative diseases, to such an extent that they are now considered an integral part of their clinical picture. Several lines of evidence support the contention that, in central neurodegenerative diseases, changes in gut microbiota and enteric neuro-immune system alterations could contribute to gastrointesinal dysfunctions as well as initiation and upward spreading of the neurologic disorder. The present review has been intended to provide a comprehensive overview of the available knowledge on the role played by enteric microbiota, mucosal immune system and enteric nervous system, considered as an integrated network, in the pathophysiology of the main neurological diseases known to be associated with intestinal disturbances. In addition, based on current human and pre-clinical evidence, our intent was to critically discuss whether changes in the dynamic interplay between gut microbiota, intestinal epithelial barrier and enteric neuro-immune system are a consequence of the central neurodegeneration or might represent the starting point of the neurodegenerative process. Special attention has been paid also to discuss whether alterations of the enteric bacterial-neuro-immune network could represent a common path driving the onset of the main neurodegenerative diseases, even though each disease displays its own distinct clinical features.

  16. [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.).

  17. 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.

  18. 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).

  19. The application of selective reaction monitoring confirms dysregulation of glycolysis in a preclinical model of schizophrenia

    NARCIS (Netherlands)

    D. Martins-de-Souza (Daniel); M. Alsaif (Murtada); A. Ernst (Agnes); L.W. Harris (Laura); N. Aerts (Nancy); I. Lenaerts (Ilse); P.J. Peeters (Pieter); K. Amess (Kevin); H. Rahmoune (Hassan); S. Bahn (Sabine); P.C. Guest (Paul)

    2012-01-01

    textabstractBackground: 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,

  20. Disease processes as hybrid dynamical systems

    Directory of Open Access Journals (Sweden)

    Pietro Liò

    2012-08-01

    Full Text Available We investigate the use of hybrid techniques in complex processes of infectious diseases. Since predictive disease models in biomedicine require a multiscale approach for understanding the molecule-cell-tissue-organ-body interactions, heterogeneous methodologies are often employed for describing the different biological scales. Hybrid models provide effective means for complex disease modelling where the action and dosage of a drug or a therapy could be meaningfully investigated: the infection dynamics can be classically described in a continuous fashion, while the scheduling of multiple treatment discretely. We define an algebraic language for specifying general disease processes and multiple treatments, from which a semantics in terms of hybrid dynamical system can be derived. Then, the application of control-theoretic tools is proposed in order to compute the optimal scheduling of multiple therapies. The potentialities of our approach are shown in the case study of the SIR epidemic model and we discuss its applicability on osteomyelitis, a bacterial infection affecting the bone remodelling system in a specific and multiscale manner. We report that formal languages are helpful in giving a general homogeneous formulation for the different scales involved in a multiscale disease process; and that the combination of hybrid modelling and control theory provides solid grounds for computational medicine.

  1. 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.

  2. 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.

  3. Information system for diagnosis of respiratory system diseases

    Science.gov (United States)

    Abramov, G. V.; Korobova, L. A.; Ivashin, A. L.; Matytsina, I. A.

    2018-05-01

    An information system is for the diagnosis of patients with lung diseases. The main problem solved by this system is the definition of the parameters of cough fragments in the monitoring recordings using a voice recorder. The authors give the recognition criteria of recorded cough moments, audio records analysis. The results of the research are systematized. The cough recognition system can be used by the medical specialists to diagnose the condition of the patients and to monitor the process of their treatment.

  4. Mesenchymal stem cells for the treatment of systemic lupus erythematosus: is the cure for connective tissue diseases within connective tissue?

    Science.gov (United States)

    Carrion, Flavio A; Figueroa, Fernando E

    2011-05-11

    Mesenchymal stem cells (MSCs) are now known to display not only adult stem cell multipotency but also robust anti-inflammatory and regenerative properties. After widespread in vitro and in vivo preclinical testing in several autoimmune disease models, allogenic MSCs have been successfully applied in patients with severe treatment-refractory systemic lupus erythematosus. The impressive results of these uncontrolled phase I and II trials - mostly in patients with non-responding renal disease - point to the need to perform controlled multicentric trials. In addition, they suggest that there is much to be learned from the basic and clinical science of MSCs in order to reap the full potential of these multifaceted progenitor cells in the treatment of autoimmune diseases.

  5. PERIODONTAL INFECTIONS AS A RISK FACTOR FOR VARIOUS SYSTEMIC DISEASES

    OpenAIRE

    Solanki, Gaurav; Solanki, Renu

    2012-01-01

    A healthy periodontium is needed for the general well being of an individual. However, periodontal diseases are common and periodontal infections are increasingly associated with systemic diseases. The literature is focused on the association between periodontal infections and systemic diseases. The individuals with periodontal disease may be at higher risk for adverse medical outcomes including cardiovascular diseases, respiratory infections, adverse pregnancy outcomes, rheumatoid arthritis ...

  6. 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.

  7. 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.

  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. 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

  10. Bone scintigraphy in systemic and metabolic diseases

    International Nuclear Information System (INIS)

    Engels, H.J.; Schmidt, H.A.E.

    1984-01-01

    Bone scintigraphy is a very sensitive method to identify pathological processes affecting the bone. Its specificity is, however, considerably lower than its sensitivity, particularly in systemic diseases. We therefore investigated the possibilities of differential diagnosis based on typical sites or patterns of distribution. The Paget syndrome with characteristic manifestation in the pelvic region, including crutch-shaped accumulation in the proximal femur, may be diagnosed by scintigraphy alone. If these typical sites are absent, however, differential diagnosis is difficult. Differential diagnosis for multiple myeloma, fibrous dysplasia, enchondromatosis, hyperparathyroidism, osteopathies, osteomalacia, inflammatory rheumatic diseases is also required and should be based on further examinations, taking into consideration the history, clinical signs and course. In this connexion scintigraphy is relevant both for early assessment and documentation of the spread of pathological processes and for the follow-up. (orig.) [de

  11. Drug-disease modeling in the pharmaceutical industry - where mechanistic systems pharmacology and statistical pharmacometrics meet.

    Science.gov (United States)

    Helmlinger, Gabriel; Al-Huniti, Nidal; Aksenov, Sergey; Peskov, Kirill; Hallow, Karen M; Chu, Lulu; Boulton, David; Eriksson, Ulf; Hamrén, Bengt; Lambert, Craig; Masson, Eric; Tomkinson, Helen; Stanski, Donald

    2017-11-15

    Modeling & simulation (M&S) methodologies are established quantitative tools, which have proven to be useful in supporting the research, development (R&D), regulatory approval, and marketing of novel therapeutics. Applications of M&S help design efficient studies and interpret their results in context of all available data and knowledge to enable effective decision-making during the R&D process. In this mini-review, we focus on two sets of modeling approaches: population-based models, which are well-established within the pharmaceutical industry today, and fall under the discipline of clinical pharmacometrics (PMX); and systems dynamics models, which encompass a range of models of (patho-)physiology amenable to pharmacological intervention, of signaling pathways in biology, and of substance distribution in the body (today known as physiologically-based pharmacokinetic models) - which today may be collectively referred to as quantitative systems pharmacology models (QSP). We next describe the convergence - or rather selected integration - of PMX and QSP approaches into 'middle-out' drug-disease models, which retain selected mechanistic aspects, while remaining parsimonious, fit-for-purpose, and able to address variability and the testing of covariates. We further propose development opportunities for drug-disease systems models, to increase their utility and applicability throughout the preclinical and clinical spectrum of pharmaceutical R&D. Copyright © 2017 Elsevier B.V. All rights reserved.

  12. 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.

  13. Common pitfalls in preclinical cancer target validation.

    Science.gov (United States)

    Kaelin, William G

    2017-07-01

    An alarming number of papers from laboratories nominating new cancer drug targets contain findings that cannot be reproduced by others or are simply not robust enough to justify drug discovery efforts. This problem probably has many causes, including an underappreciation of the danger of being misled by off-target effects when using pharmacological or genetic perturbants in complex biological assays. This danger is particularly acute when, as is often the case in cancer pharmacology, the biological phenotype being measured is a 'down' readout (such as decreased proliferation, decreased viability or decreased tumour growth) that could simply reflect a nonspecific loss of cellular fitness. These problems are compounded by multiple hypothesis testing, such as when candidate targets emerge from high-throughput screens that interrogate multiple targets in parallel, and by a publication and promotion system that preferentially rewards positive findings. In this Perspective, I outline some of the common pitfalls in preclinical cancer target identification and some potential approaches to mitigate them.

  14. Preclinical and clinical investigation of a CCR5 antagonist, AZD5672, in patients with rheumatoid arthritis receiving methotrexate

    NARCIS (Netherlands)

    Gerlag, Daniëlle M.; Hollis, Sally; Layton, Mark; Vencovský, Jiří; Szekanecz, Zoltán; Braddock, Martin; Tak, Paul P.; Oparanov, Boycho; Stoilov, Rumen; Yaneva, Tanya; Batalov, Anastas; Arteaga, Edgardo Tobias; Escalante, William Otero; Velez, Patricia; Restrepo, Jose Molina; Augustinova, Sevda; Blahova, Anna; Dvorak, Zdenek; Novosad, Libor; Rosa, Jan; Stehlikova, Helena; Vitek, Petr; Balazs, Tibor; Seregely, Katalin; Szombati, Istvan; Tarjan, Katalin; Csengei, Gabor; Galeazzi, Mauro; Saleniece, Sarmite; Saulite-Kandevica, Daina; Coleiro, Bernard; Badurski, Janusz; Brzosko, Marek; Chudzik, Dariusz; Gruszecka-Marczynska, Katarzyna; Hensel, Joanna; Pokrzywnicka-Gajek, Ines; Korpanty-Danda, Joanna; Sochocka-Bykowska, Malgorzata; Tlustochowicz, Witold; Stopinska-Polaszewska, Maria; Gluszko, Piotr; Nedelcovici, Corina; Radulescu, Florin; Gavrila, Mirea; Tanasescu, Coman; Korshunov, Nikolay; Matsievskaia, Galina; Damjanov, Nemanja; Dimic, Aleksandar

    2010-01-01

    To investigate both the preclinical effects of blocking the chemokine receptor CCR5 and the clinical effects of this approach on the signs and symptoms of rheumatoid arthritis (RA) in patients with active disease. Preclinical evaluations of AZD5672, a small-molecule antagonist of CCR5, were

  15. Effect of diseases on symbiotic systems.

    Science.gov (United States)

    Tiwari, Pankaj Kumar; Sasmal, Sourav Kumar; Sha, Amar; Venturino, Ezio; Chattopadhyay, Joydev

    2017-09-01

    There are many species living in symbiotic communities. In this study, we analyzed models in which populations are in the mutualism symbiotic relations subject to a disease spreading among one of the species. The main goal is the characterization of symbiotic relations of coexisting species through their mutual influences on their respective carrying capacities, taking into account that this influence can be quite strong. The functional dependence of the carrying capacities reflects the fact that the correlations between populations cannot be realized merely through direct interactions, as in the usual predator-prey Lotka-Volterra model, but also through the influence of each species on the carrying capacities of the other one. Equilibria are analyzed for feasibility and stability, substantiated via numerical simulations, and global sensitivity analysis identifies the important parameters having a significant impact on the model dynamics. The infective growth rate and the disease-related mortality rate may alter the stability behavior of the system. Our results show that introducing a symbiotic species is a plausible way to control the disease in the population. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Surveillance System for Infectious Diseases of Pets, Santiago, Chile

    Science.gov (United States)

    López, Javier; Abarca, Katia; Valenzuela, Berta; Lorca, Lilia; Olea, Andrea; Aguilera, Ximena

    2009-01-01

    Pet diseases may pose risks to human health but are rarely included in surveillance systems. A pilot surveillance system of pet infectious diseases in Santiago, Chile, found that 4 canine and 3 feline diseases accounted for 90.1% and 98.4% of notifications, respectively. Data also suggested association between poverty and pet diseases. PMID:19861073

  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. Accelerated atherosclerosis in patients with systemic autoimmune diseases

    NARCIS (Netherlands)

    De Leeuw, K.; Kallenberg, Cees; Bijl, Marc; Shoenfeld, Y.; Gershwin, M.E.; Shoenfeld, Y; Gershwin, ME

    2005-01-01

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

  19. Advanced and controlled drug delivery systems in clinical disease management

    NARCIS (Netherlands)

    Brouwers, JRBJ

    1996-01-01

    Advanced and controlled drug delivery systems are important for clinical disease management. In this review the most important new systems which have reached clinical application are highlighted. Microbiologically controlled drug delivery is important for gastrointestinal diseases like ulcerative

  20. In vivo 3-dimensional photoacoustic imaging of the renal vasculature in preclinical rodent models

    OpenAIRE

    Ogunlade, O.; Connell, J. J.; Huang, J. L.; Zhang, E.; Lythgoe, M. F.; Long, D. A.; Beard, P.

    2017-01-01

    Non-invasive imaging of the kidney vasculature in preclinical murine models is important for studying renal development, diseases and evaluating new therapies, but is challenging to achieve using existing imaging modalities. Photoacoustic imaging is a promising new technique that is particularly well suited to visualising the vasculature and could provide an alternative to existing preclinical imaging methods for studying renal vascular anatomy and function. To investigate this, an all-optica...

  1. 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

    2010-04-01

    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 dysfunction (EDF), disinhibition and apathy), associated in the literature with disruption of different underlying frontal-subcortical circuits, are a) more or less frequently reported than others and b) related to poor performance on tasks involving different cognitive processes. Seventy-eight participants (mean age 47 years, range 36-72) with DS and mild to moderate intellectual disability (based on ICD-10 criteria), without a diagnosis of dementia of Alzheimer's type (DAT) or other psychiatric disorders, were selected from a larger sample of older adults with DS (n = 122). Dementia diagnosis was based on the CAMDEX informant interview, conducted with each participant's main carer. Informant-reported changes in personality/behaviour and memory were recorded. Participants were scored based on symptoms falling into three behavioural domains and completed five executive function (EF) tasks, six memory tasks (two of which also had a strong executive component) and the BPVS (as a measure of general intellectual ability). Multiple regression analyses were conducted to determine the degree to which the behavioural variables of 'EDF', 'disinhibition' and 'apathy', along with informant-reported memory decline and antidepressant medication use, predicted performance on the cognitive tasks (whilst controlling for the effects of age and general intellectual ability). Strikingly, disinhibited behaviour was reported for 95.7% of participants with one or more behavioural change (n = 47) compared to 57.4% with reported apathy and 36.2% with reported EDF. 'Disinhibition' score significantly predicted performance on three EF tasks (designed to measure

  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. 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.)

  4. 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

    2016-01-01

    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. PMID:27042604

  5. Perspective: Recommendations for benchmarking pre-clinical studies of nanomedicines

    Science.gov (United States)

    Dawidczyk, Charlene M.; Russell, Luisa M.; Searson, Peter C.

    2015-01-01

    Nanoparticle-based delivery systems provide new opportunities to overcome the limitations associated with traditional small molecule drug therapy for cancer, and to achieve both therapeutic and diagnostic functions in the same platform. Pre-clinical trials are generally designed to assess therapeutic potential and not to optimize the design of the delivery platform. Consequently, progress in developing design rules for cancer nanomedicines has been slow, hindering progress in the field. Despite the large number of pre-clinical trials, several factors restrict comparison and benchmarking of different platforms, including variability in experimental design, reporting of results, and the lack of quantitative data. To solve this problem, we review the variables involved in the design of pre-clinical trials and propose a protocol for benchmarking that we recommend be included in in vivo pre-clinical studies of drug delivery platforms for cancer therapy. This strategy will contribute to building the scientific knowledge base that enables development of design rules and accelerates the translation of new technologies. PMID:26249177

  6. 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.

  7. 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.

  8. A study on periodontal disease and systemic disease relationship a hospital based study in Bangalore

    Directory of Open Access Journals (Sweden)

    Sukhvinder Singh Oberoi

    2013-01-01

    Full Text Available Background: Periodontal deterioration has been reported to be associated with various systemic conditions like Cardiovascular disease, Diabetes, Respiratory disease, Liver cirrhosis, Bacterial Pneumonia, Nutritional deficiencies and adverse pregnancy outcomes. Aim: To assess the periodontal disease among patients with systemic disease/conditions. Materials and Method: A total of 500 patients with systemic disease/conditions (Diabetes, Cardiovascular disease, Respiratory disease and Renal disease and 500-age and gender matched controls without systemic disease/conditions were selected from the Government Hospitals in Bangalore City. The medical conditions were recorded and the periodontal status of the study population was assessed using the CPITN index. Results: The prevalence of CPITN Code 4 was found to be more among the patients with systemic disease/conditions (46.2%. The mean number of sextants with CPITN code 3 and 4 were more among the patients with systemic disease/conditions. The prevalence of CPITN code was found to be more among the patients with Respiratory disease whereas the mean number of sextants was found to be more among the patients with Diabetes, Cardiovascular and Renal disease. Conclusion: It may be concluded that the systemic diseases/conditions are associated with higher severity of periodontal disease.

  9. The dopaminergic system in autoimmune diseases

    Directory of Open Access Journals (Sweden)

    Rodrigo ePacheco

    2014-03-01

    Full Text Available Bidirectional interactions between the immune and the nervous systems are of considerable interest both for deciphering their functioning and for designing novel therapeutic strategies. The past decade has brought a burst of insights into the molecular mechanisms involved in neuro-immune communications mediated by dopamine. Studies of dendritic cells (DCs revealed that they express the whole machinery to synthesize and store dopamine, which may act in an autocrine manner to stimulate dopamine receptors (DARs. Depending on specific DARs stimulated on DCs and T cells, dopamine may differentially favor CD4+ T cell differentiation into Th1 or Th17 inflammatory cells. Regulatory T cells can also release high amounts of dopamine that acts in an autocrine DAR-mediated manner to inhibit their suppressive activity. These dopaminergic regulations could represent a driving force during autoimmunity. Indeed, dopamine levels are altered in the brain of mouse models of multiple sclerosis (MS and lupus, and in inflamed tissues of patients with inflammatory bowel diseases or rheumatoid arthritis. The distorted expression of DARs in peripheral lymphocytes of lupus and MS patients also supports the importance of dopaminergic regulations in autoimmunity. Moreover, dopamine analogs had beneficial therapeutic effects in animal models, and in patients with lupus or rheumatoid arthritis. We propose models that may underlie key roles of dopamine and its receptors in autoimmune diseases.

  10. 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.

  11. Ethical Considerations of Preclinical Testing

    Directory of Open Access Journals (Sweden)

    Allen Goldenthal

    2015-12-01

    Full Text Available The numbers of animal tests being conducted are on a sharp incline.  Much of this increase is directly due to our ability to generate transgenic models and knock-outs, thereby increasing the validity of the animal model but not necessarily correlating directly with any translational medical benefits to the human counterpart.  In spite of our best efforts, there still exist species differences that prevent the application directly from animal to human, and in some examples having a completely different and adverse effect from that seen in the animal model. There are several ways in which we can improve the opportunity for a positive test outcome and at the same time reduce the animal usage which is associated with our current animal testing practices. The benefit of the 3R’s is that they encourage us not only to avoid wastage of life but that they require us to provide considerable foresight and extrapolated thought before directly engaging in the preclinical testing phase.

  12. 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

  13. 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.

  14. 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…

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

    OpenAIRE

    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 di...

  16. Endoscopic ultrasound-guided biliary drainage using a newly designed metal stent with a thin delivery system: a preclinical study in phantom and porcine models.

    Science.gov (United States)

    Minaga, Kosuke; Kitano, Masayuki; Itonaga, Masahiro; Imai, Hajime; Miyata, Takeshi; Yamao, Kentaro; Tamura, Takashi; Nuta, Junya; Warigaya, Kenji; Kudo, Masatoshi

    2017-12-08

    This study was designed to evaluate the feasibility and safety of a newly designed self-expandable metal stent for endoscopic ultrasound-guided biliary drainage (EUS-BD) when it was delivered via three different stent delivery systems: a 7.5Fr delivery catheter with a bullet-shaped tip (7.5Fr-bullet), a 7Fr catheter with a bullet-shaped tip (7Fr-bullet), or a 7Fr catheter with a tee-shaped tip (7Fr-tee). This experimental study utilized a porcine model of biliary dilatation involving ten pigs. In the animal study, technical feasibility and clinical outcomes of the stent when placed with each of the delivery systems were examined. In addition, a phantom model was used to measure the resistance of these delivery systems to advancement. Phantom experiments showed that, compared with 7Fr-bullet, 7Fr-tee had less resistance force to the advancement of the stent delivery system. EUS-BD was technically successful in all ten pigs. Fistulous tract dilation was necessary in 100% (2/2), 75% (3/4), and 0% (0/4) of the pigs that underwent EUS-BD using 7.5Fr-bullet, 7Fr-bullet, and 7Fr-tee, respectively. There were no procedure-related complications. Our newly designed metal stent may be feasible and safe for EUS-BD, particularly when delivered by 7Fr-tee, because it eliminates the need for fistulous tract dilation.

  17. 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

  18. Identification of new epilepsy treatments: 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, H Steve; O'Brien, Terence J; Simonato, Michele

    2012-03-01

    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: (1) new symptomatic antiseizure treatments for drug-resistant seizures with improved efficacy/tolerability profiles, (2) disease-modifying treatments that prevent or ameliorate the process of epileptogenesis, and (3) 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, that is, 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 antiepilepsy therapy development studies targeting drug-resistant seizures, epileptogenesis, and comorbidities. Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.

  19. Preclinical models of shock and sepsis: what can they tell us?

    NARCIS (Netherlands)

    Marshall, John C.; Deitch, Edwin; Moldawer, Lyle L.; Opal, Steven; Redl, Heinz; van der Poll, Tom

    2005-01-01

    The goal of translational research is to transform biologic knowledge into new treatments for human disease. Although preclinical models replicate some of the features of the disease process modeled, they invariably fail to reproduce the complexity of human illness, and by their very experimental

  20. 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.

  1. 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

  2. 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.

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

    Science.gov (United States)

    Jeong, Seri; Yang, Heeyoung; Hwang, Hyunyong

    2017-01-01

    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.

  4. Portable high-intensity focused ultrasound system with 3D electronic steering, real-time cavitation monitoring, and 3D image reconstruction algorithms: a preclinical study in pigs

    International Nuclear Information System (INIS)

    Choi, Jin Woo; Lee, Jae Young; Hwang, Eui Jin; Hwang, In Pyeong; Woo, Sung Min; Lee, Chang Joo; Park, Eun Joo; Choi, Byung Ihn

    2014-01-01

    The aim of this study was to evaluate the safety and accuracy of a new portable ultrasonography-guided high-intensity focused ultrasound (USg-HIFU) system with a 3-dimensional (3D) electronic steering transducer, a simultaneous ablation and imaging module, real-time cavitation monitoring, and 3D image reconstruction algorithms. To address the accuracy of the transducer, hydrophones in a water chamber were used to assess the generation of sonic fields. An animal study was also performed in five pigs by ablating in vivo thighs by single-point sonication (n=10) or volume sonication (n=10) and ex vivo kidneys by single-point sonication (n=10). Histological and statistical analyses were performed. In the hydrophone study, peak voltages were detected within 1.0 mm from the targets on the y- and z-axes and within 2.0-mm intervals along the x-axis (z-axis, direction of ultrasound propagation; y- and x-axes, perpendicular to the direction of ultrasound propagation). Twenty-nine of 30 HIFU sessions successfully created ablations at the target. The in vivo porcine thigh study showed only a small discrepancy (width, 0.5-1.1 mm; length, 3.0 mm) between the planning ultrasonograms and the pathological specimens. Inordinate thermal damage was not observed in the adjacent tissues or sonic pathways in the in vivo thigh and ex vivo kidney studies. Our study suggests that this new USg-HIFU system may be a safe and accurate technique for ablating soft tissues and encapsulated organs.

  5. Portable high-intensity focused ultrasound system with 3D electronic steering, real-time cavitation monitoring, and 3D image reconstruction algorithms: a preclinical study in pigs

    Energy Technology Data Exchange (ETDEWEB)

    Choi, Jin Woo; Lee, Jae Young; Hwang, Eui Jin; Hwang, In Pyeong; Woo, Sung Min; Lee, Chang Joo; Park, Eun Joo; Choi, Byung Ihn [Dept. of Radiology and Institute of Radiation Medicine, Seoul National University Hospital, Seoul (Korea, Republic of)

    2014-10-15

    The aim of this study was to evaluate the safety and accuracy of a new portable ultrasonography-guided high-intensity focused ultrasound (USg-HIFU) system with a 3-dimensional (3D) electronic steering transducer, a simultaneous ablation and imaging module, real-time cavitation monitoring, and 3D image reconstruction algorithms. To address the accuracy of the transducer, hydrophones in a water chamber were used to assess the generation of sonic fields. An animal study was also performed in five pigs by ablating in vivo thighs by single-point sonication (n=10) or volume sonication (n=10) and ex vivo kidneys by single-point sonication (n=10). Histological and statistical analyses were performed. In the hydrophone study, peak voltages were detected within 1.0 mm from the targets on the y- and z-axes and within 2.0-mm intervals along the x-axis (z-axis, direction of ultrasound propagation; y- and x-axes, perpendicular to the direction of ultrasound propagation). Twenty-nine of 30 HIFU sessions successfully created ablations at the target. The in vivo porcine thigh study showed only a small discrepancy (width, 0.5-1.1 mm; length, 3.0 mm) between the planning ultrasonograms and the pathological specimens. Inordinate thermal damage was not observed in the adjacent tissues or sonic pathways in the in vivo thigh and ex vivo kidney studies. Our study suggests that this new USg-HIFU system may be a safe and accurate technique for ablating soft tissues and encapsulated organs.

  6. Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions

    International Nuclear Information System (INIS)

    Sieber, Martin A.; Frenzel, Thomas; Golfier, Sven; Weinmann, Hanns-Joachim; Pietsch, Hubertus; Lengsfeld, Philipp; Schmitt-Willich, Heribert; Siegmund, Fred; Walter, Jakob

    2008-01-01

    Recent reports suggest that nephrogenic systemic fibrosis (NSF) is associated with the administration of gadolinium (Gd)-based contrast agents (GBCAs) and in particular with the stability of the Gd-complex. The aim of this investigation was to compare GBCAs and their potential to trigger NSF. Forty-two healthy male rats received repeated intravenous injections of six different GBCAs at high doses to simulate the exposure seen in patients with severe renal dysfunction. Histopathological and immunohistochemical analysis of the skin was performed, and the concentrations of Gd, zinc and copper were measured in several tissues by inductive coupled plasma atomic emission spectroscopy. Macroscopic and histological skin changes similar to those seen in NSF patients were only observed in rats receiving Omniscan. In addition, very high concentrations of Gd were observed in the animals treated with Omniscan, and, to a lesser extent, in animals treated with OptiMARK. Significantly lower levels of Gd were found after the treatment with ionic linear agents and even less after the treatment with macrocyclic agents. The data in this investigation strongly suggest that the stability of the Gd-complex is a key factor for the development of NSF-like symptoms in this experimental setting. (orig.)

  7. Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions

    Energy Technology Data Exchange (ETDEWEB)

    Sieber, Martin A.; Frenzel, Thomas; Golfier, Sven; Weinmann, Hanns-Joachim; Pietsch, Hubertus [Bayer Schering Pharma AG, TRG Diagnostic Imaging, Berlin (Germany); Lengsfeld, Philipp [Bayer Schering Pharma AG, GMA DG Diagnostic Imaging, Berlin (Germany); Schmitt-Willich, Heribert [Bayer Schering Pharma AG, GDD Diagnostic Imaging, Berlin (Germany); Siegmund, Fred; Walter, Jakob [Bayer Schering Pharma AG, Nonclinical Drug Safety, Berlin (Germany)

    2008-10-15

    Recent reports suggest that nephrogenic systemic fibrosis (NSF) is associated with the administration of gadolinium (Gd)-based contrast agents (GBCAs) and in particular with the stability of the Gd-complex. The aim of this investigation was to compare GBCAs and their potential to trigger NSF. Forty-two healthy male rats received repeated intravenous injections of six different GBCAs at high doses to simulate the exposure seen in patients with severe renal dysfunction. Histopathological and immunohistochemical analysis of the skin was performed, and the concentrations of Gd, zinc and copper were measured in several tissues by inductive coupled plasma atomic emission spectroscopy. Macroscopic and histological skin changes similar to those seen in NSF patients were only observed in rats receiving Omniscan. In addition, very high concentrations of Gd were observed in the animals treated with Omniscan, and, to a lesser extent, in animals treated with OptiMARK. Significantly lower levels of Gd were found after the treatment with ionic linear agents and even less after the treatment with macrocyclic agents. The data in this investigation strongly suggest that the stability of the Gd-complex is a key factor for the development of NSF-like symptoms in this experimental setting. (orig.)

  8. 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

  9. Pre-clinical testing of a phased array ultrasound system for MRI-guided noninvasive surgery of the brain--a primate study.

    Science.gov (United States)

    Hynynen, Kullervo; McDannold, Nathan; Clement, Greg; Jolesz, Ferenc A; Zadicario, Eyal; Killiany, Ron; Moore, Tara; Rosen, Douglas

    2006-08-01

    MRI-guided and monitored focused ultrasound thermal surgery of brain through intact skull was tested in three rhesus monkeys. The aim of this study was to determine the amount of skull heating in an animal model with a head shape similar to that of a human. The ultrasound beam was generated by a 512 channel phased array system (Exablate 3000, InSightec, Haifa, Israel) that was integrated within a 1.5-T MR-scanner. The skin was pre-cooled by degassed temperature controlled water circulating between the array surface and the skin. Skull surface temperature was measured with invasive thermocouple probes. The results showed that by applying surface cooling the skin and skull surface can be protected, and that the brain surface temperature becomes the limiting factor. The MRI thermometry was shown to be useful in detecting the tissue temperature distribution next to the bone, and it should be used to monitor the brain surface temperature. The acoustic intensity values during the 20 s sonications were adequate for thermal ablation in the human brain provided that surface cooling is used.

  10. 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

  11. Pre-clinical test of the virtual wedge option of a PRIMUS linear accelerator and verification of the calculation algorithm in the treatment planning system HEAX-TMS

    International Nuclear Information System (INIS)

    Gesheva-Atanassova, N.; Balabanova, A.

    2006-01-01

    Full text: The purpose of the study is to check the long-time stability of the wedge angle and the wedge factor (WF) of Virtual Wedges for 6 and 18 MV photon beams, and the accuracy of the TPS HELAX-TMS, in order to accept the virtual wedge technique for patient treatment. All measurements - dose profiles, central axis dose distributions and applied dose for pre-calculated monitor units, have been performed in water, applying a calibrated 0.3 cm 3 ion chamber, 47 ion chamber array LA48 and the beam analyzing system MP3. The measured data has been compared with the corresponding planned data. During a four years time period the long time stability checking revealed no changes in the central axis distributions and variations of the wedge angles are within ± 2 deg. The values of WFs and the differences between calculated and measured dose values are in the acceptable limits, except for the 6 MV beam with wedge angle 60 deg and field size 20x20 cm 2 , where the deviation reaches 6.5%. The dose profile for depth up to 10 cm showed a good coincidence. Non acceptable deviations have been found for beam profiles at depth 20 cm and field size 20x20 cm 2 for both 6 and 18 MV. The Virtual Wedge Option of PRIMUS in combination with HELAX-TMS can be applied with confidence for radiotherapy with wedged beams except for the combination of field 20x20 cm 2 and angle 60 deg

  12. Distribution of Glutathione-Stabilized Gold Nanoparticles in Feline Fibrosarcomas and Their Role as a Drug Delivery System for Doxorubicin—Preclinical Studies in a Murine Model

    Directory of Open Access Journals (Sweden)

    Katarzyna Zabielska-Koczywąs

    2018-03-01

    Full Text Available Feline injection site sarcomas (FISS are malignant skin tumors with high recurrence rates despite the primary treatment of radical surgical resections. Adjunctive radiotherapy or chemotherapy with doxorubicin is mostly ineffective. Cellular and molecular causes of multidrug resistance, specific physio-chemical properties of solid tumors impairing drug transport, and the tumor microenvironment have been indicated for causing standard chemotherapy failure. Gold nanoparticles are promising imaging tools, nanotherapeutics, and drug delivery systems (DDS for chemotherapeutics, improving drug transport within solid tumors. This study was conducted to assess the distribution of 4-nm glutathione-stabilized gold nanoparticles in FISS and their influence on kidney and liver parameters in nude mice. The role of gold nanoparticles as a doxorubicin DDS in FISS was examined to determine the potential reasons for failure to translate results from in vitro to in vivo studies. Grade III tumors characterized by a large area of necrosis at their core displayed positive immuneexpression of tumor-associated macrophages (TAM at both the periphery and within the tumor core near the area of necrosis. Gold nanoparticles did not cause necrosis at the injection site and had no negative effect on liver and kidney parameters in nude mice. Gold nanoparticles accumulated in the tumor core and at the periphery and co-internalized with TAM—an important observation and potential therapeutic target warranting further investigation. The large area of necrosis and high immunoexpression of TAM, indicating “pro-tumor macrophages”, may be responsible for FISS tumor progression and therapeutic failure. However, further studies are required to test this hypothesis.

  13. Genetic modification of risk assessment based on staging of preclinical type 1 diabetes in siblings of affected children.

    Science.gov (United States)

    Mrena, S; Savola, K; Kulmala, P; Reijonen, H; Ilonen, J; Akerblom, H K; Knip, M

    2003-06-01

    We set out to study the association between human leukocyte antigen-defined genetic disease susceptibility and the stage of preclinical type 1 diabetes and whether genetic predisposition affects the natural course of preclinical diabetes in initially nondiabetic siblings of affected children. A total of 701 initially unaffected siblings were graded into four stages of preclinical type 1 diabetes based on the initial number of disease-associated autoantibodies detectable close to the time of diagnosis of the index case: no prediabetes (no antibodies), early (one antibody specificity), advanced (two antibodies), and late prediabetes (three or more antibodies). Another classification system covering 659 siblings was based on a combination of the initial number of antibodies and the first-phase insulin response (FPIR) to iv glucose: no prediabetes (no antibodies), early (one antibody specificity, normal FPIR), advanced (two or more antibodies, normal FPIR), and late prediabetes (at least one antibody, reduced FPIR). Genetic susceptibility to type 1 diabetes was defined by human leukocyte antigen identity and DR and DQ genotypes. There was a higher proportion of siblings with late prediabetes initially among those with strong genetic disease susceptibility than among those with decreased genetic predisposition (16.7% vs. 0.5%; P siblings with no signs of prediabetes among those with genotypes conferring decreased risk (91.2% vs. 70.4% among those with high-risk DQB1 genotypes; P siblings than when combined with genetic susceptibility. Genetic susceptibility played a role in whether the initial prediabetic stage progressed (progression in 29.6% of the high-risk siblings compared with 6.6% of the siblings with DQB1 genotypes conferring decreased risk; P siblings of affected children.

  14. 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.

  15. Peripheral Vestibular System Disease in Vestibular Schwannomas

    DEFF Research Database (Denmark)

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

    2015-01-01

    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...

  16. 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.

  17. 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.

  18. 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.

  19. 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.

  20. 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.

  1. 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...... to four different systemic diseases with world-wide distribution........ Inclusion body disease affected all layers of the spectacle with intracytoplasmic eosinophilic inclusions. Two cases of neoplasia, lymphoma and myeloproliferative disease, affected the ocular adnexa and the spectacular transition zone. These cases provide novel insight into how the spectacle may respond...

  2. Central nervous system involvement in Whipple's disease

    International Nuclear Information System (INIS)

    Ludwig, B.; Bohl, J.; Heferkamp, G.

    1981-01-01

    A case of Whipple's disease is presented manifesting itself predominantly with neurological and mental symptoms but without gastrointestinal complaints. Although the first cranial CT in the fourth year of the disease was normal, the second, 1.5 years later, revealed intensive hypodensity of the white matter and cortical enhancement. CT findings are compared with autopsy results and a review of the pertinent literature is given. (orig.)

  3. A Systems Model of Parkinson's Disease Using Biochemical Systems Theory.

    Science.gov (United States)

    Sasidharakurup, Hemalatha; Melethadathil, Nidheesh; Nair, Bipin; Diwakar, Shyam

    2017-08-01

    Parkinson's disease (PD), a neurodegenerative disorder, affects millions of people and has gained attention because of its clinical roles affecting behaviors related to motor and nonmotor symptoms. Although studies on PD from various aspects are becoming popular, few rely on predictive systems modeling approaches. Using Biochemical Systems Theory (BST), this article attempts to model and characterize dopaminergic cell death and understand pathophysiology of progression of PD. PD pathways were modeled using stochastic differential equations incorporating law of mass action, and initial concentrations for the modeled proteins were obtained from literature. Simulations suggest that dopamine levels were reduced significantly due to an increase in dopaminergic quinones and 3,4-dihydroxyphenylacetaldehyde (DOPAL) relating to imbalances compared to control during PD progression. Associating to clinically observed PD-related cell death, simulations show abnormal parkin and reactive oxygen species levels with an increase in neurofibrillary tangles. While relating molecular mechanistic roles, the BST modeling helps predicting dopaminergic cell death processes involved in the progression of PD and provides a predictive understanding of neuronal dysfunction for translational neuroscience.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

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

    African Journals Online (AJOL)

    It is thus useful for the physician to be familiar with the ocular manifestations of common systemic diseases at primary care level. ... It is important for the primary care physician to be familiar with the spectrum of ocular involvement in systemic diseases since appropriate intervention and referral can be sight saving for the ...

  9. [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.

  10. 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

  11. Pre-clinical MR elastography: Principles, techniques, and applications

    Science.gov (United States)

    Bayly, P. V.; Garbow, J. R.

    2018-06-01

    Magnetic resonance elastography (MRE) is a method for measuring the mechanical properties of soft tissue in vivo, non-invasively, by imaging propagating shear waves in the tissue. The speed and attenuation of waves depends on the elastic and dissipative properties of the underlying material. Tissue mechanical properties are essential for biomechanical models and simulations, and may serve as markers of disease, injury, development, or recovery. MRE is already established as a clinical technique for detecting and characterizing liver disease. The potential of MRE for diagnosing or characterizing disease in other organs, including brain, breast, and heart is an active research area. Studies involving MRE in the pre-clinical setting, in phantoms and artificial biomaterials, in the mouse, and in other mammals, are critical to the development of MRE as a robust, reliable, and useful modality.

  12. 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.

  13. 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.

  14. Nervous system disease associated with dominant cellular radiosensitivity

    International Nuclear Information System (INIS)

    Kidson, C.; Chen, P.; Imray, F.P.; Gipps, E.

    1983-01-01

    Ionizing radiation sensitivity has been demonstrated in the following neurological diseases: sporadic and familial Alzheimer's disease, familial non-specific dementia, amyotrophic lateral sclerosis and Parkinsonism dementia of Guam, Huntington's disease, multiple sclerosis. Family studies in many cases give data consistent with dominant genetics, as does cell fusion analysis in the one disease so studied. In no case was there an absolute association between radiosensitivity and a given neurological disease. It is proposed that the underlying mutations are in genes controlling facets of nervous or immune system differentiation and development. 15 references, 2 tables

  15. 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

  16. 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.

  17. Thyroid disease and the nervous system.

    Science.gov (United States)

    Wood-Allum, Clare A; Shaw, Pamela J

    2014-01-01

    Thyroid disorders are common in the general population and in hospitalized patients. Thyroid disease may present first with neurological complications or else may occur concurrently in patients suffering other neurological disorders, particularly those with an autoimmune etiology. For this reason neurologists will commonly encounter patients with thyroid disease. This chapter provides an overview of the neurological complications and associations of disorders of the thyroid gland. Particular emphasis is placed on conditions such as thyrotoxic periodic paralysis and myxedema coma in which the underlying thyroid disorder may be occult leading to a first, often emergency, presentation to a neurologist. Information about clinical features, diagnosis, pathogenesis, therapy, and prognosis is provided. Emphasis is placed on those aspects most likely to be relevant to the practicing neurologist and the interested reader is directed to references to good, recent review articles for further information. © 2014 Elsevier B.V. All rights reserved.

  18. 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.

  19. 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

  20. Multi-disease data management system platform for vector-borne diseases.

    Directory of Open Access Journals (Sweden)

    Lars Eisen

    2011-03-01

    Full Text Available Emerging information technologies present new opportunities to reduce the burden of malaria, dengue and other infectious diseases. For example, use of a data management system software package can help disease control programs to better manage and analyze their data, and thus enhances their ability to carry out continuous surveillance, monitor interventions and evaluate control program performance.We describe a novel multi-disease data management system platform (hereinafter referred to as the system with current capacity for dengue and malaria that supports data entry, storage and query. It also allows for production of maps and both standardized and customized reports. The system is comprised exclusively of software components that can be distributed without the user incurring licensing costs. It was designed to maximize the ability of the user to adapt the system to local conditions without involvement of software developers. Key points of system adaptability include 1 customizable functionality content by disease, 2 configurable roles and permissions, 3 customizable user interfaces and display labels and 4 configurable information trees including a geographical entity tree and a term tree. The system includes significant portions of functionality that is entirely or in large part re-used across diseases, which provides an economy of scope as new diseases downstream are added to the system at decreased cost.We have developed a system with great potential for aiding disease control programs in their task to reduce the burden of dengue and malaria, including the implementation of integrated vector management programs. Next steps include evaluations of operational implementations of the current system with capacity for dengue and malaria, and the inclusion in the system platform of other important vector-borne diseases.

  1. Imaging findings in systemic childhood diseases presenting with dermatologic manifestations.

    Science.gov (United States)

    Fink, Adam Z; Gittler, Julia K; Nakrani, Radhika N; Alis, Jonathan; Blumfield, Einat; Levin, Terry L

    Many childhood diseases often present with skin abnormalities with which radiologists are largely unfamiliar. Knowledge of associated dermatologic manifestations may aid the radiologist in confirming the diagnosis and recommending targeted imaging of affected organs. We review the imaging findings in childhood diseases associated with dermatologic manifestations. Diseases include dermatologic findings which herald underlying malignancy (Neuroblastoma, leukemia/lymphoma, Langerhans cell histiocytosis),are associated with risk of malignancy (Epidermolysis Bullosa, basal cell nevus syndrome, Cowden's syndrome, Tuberous Sclerosis),or indicate a systemic inflammatory/immune disorder (Kawasaki's disease, Henoch Schonlein Purpura, systemic lupus erythematosus, scleroderma, sarcoidosis, dermatomyositis and immune thrombocytopenic purpura). Familiarity with pertinent findings in childhood diseases presenting with dermatologic manifestations in childhood diseases aids the radiologist in confirming the diagnosis and guiding imaging workup. Copyright © 2017 Elsevier Inc. All rights reserved.

  2. Standards and Methodological Rigor in Pulmonary Arterial Hypertension Preclinical and Translational Research.

    Science.gov (United States)

    Provencher, Steeve; Archer, Stephen L; Ramirez, F Daniel; Hibbert, Benjamin; Paulin, Roxane; Boucherat, Olivier; Lacasse, Yves; Bonnet, Sébastien

    2018-03-30

    Despite advances in our understanding of the pathophysiology and the management of pulmonary arterial hypertension (PAH), significant therapeutic gaps remain for this devastating disease. Yet, few innovative therapies beyond the traditional pathways of endothelial dysfunction have reached clinical trial phases in PAH. Although there are inherent limitations of the currently available models of PAH, the leaky pipeline of innovative therapies relates, in part, to flawed preclinical research methodology, including lack of rigour in trial design, incomplete invasive hemodynamic assessment, and lack of careful translational studies that replicate randomized controlled trials in humans with attention to adverse effects and benefits. Rigorous methodology should include the use of prespecified eligibility criteria, sample sizes that permit valid statistical analysis, randomization, blinded assessment of standardized outcomes, and transparent reporting of results. Better design and implementation of preclinical studies can minimize inherent flaws in the models of PAH, reduce the risk of bias, and enhance external validity and our ability to distinguish truly promising therapies form many false-positive or overstated leads. Ideally, preclinical studies should use advanced imaging, study several preclinical pulmonary hypertension models, or correlate rodent and human findings and consider the fate of the right ventricle, which is the major determinant of prognosis in human PAH. Although these principles are widely endorsed, empirical evidence suggests that such rigor is often lacking in pulmonary hypertension preclinical research. The present article discusses the pitfalls in the design of preclinical pulmonary hypertension trials and discusses opportunities to create preclinical trials with improved predictive value in guiding early-phase drug development in patients with PAH, which will need support not only from researchers, peer reviewers, and editors but also from

  3. 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

  4. [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.

  5. Neurodegenerative diseases of the central motor system in MRI

    International Nuclear Information System (INIS)

    Alfke, K.

    2005-01-01

    Neurodegenerative diseases of the central motor system often lead to discrete but functionally important parenchymal abnormalities in various parts of the brain. MRI is the most sensitive imaging method to detect these abnormalities. Various neurodegenerative diseases are presented with their clinical symptoms and MRI findings. Criteria for differential diagnosis are provided as well. (orig.)

  6. 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…

  7. 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

  8. COPD is a systemic disease – the ex trapulmonary manifestations

    African Journals Online (AJOL)

    Peripheral skeletal muscle dysfunction is an established systemic feature of COPD.12 .... vitamin A status in chronic obstructive pulmonary disease patients and ... Kempainen RR, Savik K, Whelan TP, Dunitz JM, Herrington CS, Billings. JL.

  9. Nutritional and metabolic diseases involving the nervous system.

    Science.gov (United States)

    Kopcha, M

    1987-03-01

    This article will discuss eight diseases that alter normal nervous system function: hypovitaminosis A, water deprivation/salt toxicity, ammonia toxicosis, hypomagnesemia, hypocalcemia, nervous ketosis, hepatoencephalopathy, and rumen metabolic acidosis.

  10. End-Stage Renal Disease Prospective Payment System

    Data.gov (United States)

    U.S. Department of Health & Human Services — This final rule implements a case-mix adjusted bundled prospective payment system (PPS) for Medicare outpatient end-stage renal disease (ESRD) dialysis facilities...

  11. Predictive modeling of coral disease distribution within a reef system.

    Directory of Open Access Journals (Sweden)

    Gareth J Williams

    2010-02-01

    Full Text Available Diseases often display complex and distinct associations with their environment due to differences in etiology, modes of transmission between hosts, and the shifting balance between pathogen virulence and host resistance. Statistical modeling has been underutilized in coral disease research to explore the spatial patterns that result from this triad of interactions. We tested the hypotheses that: 1 coral diseases show distinct associations with multiple environmental factors, 2 incorporating interactions (synergistic collinearities among environmental variables is important when predicting coral disease spatial patterns, and 3 modeling overall coral disease prevalence (the prevalence of multiple diseases as a single proportion value will increase predictive error relative to modeling the same diseases independently. Four coral diseases: Porites growth anomalies (PorGA, Porites tissue loss (PorTL, Porites trematodiasis (PorTrem, and Montipora white syndrome (MWS, and their interactions with 17 predictor variables were modeled using boosted regression trees (BRT within a reef system in Hawaii. Each disease showed distinct associations with the predictors. Environmental predictors showing the strongest overall associations with the coral diseases were both biotic and abiotic. PorGA was optimally predicted by a negative association with turbidity, PorTL and MWS by declines in butterflyfish and juvenile parrotfish abundance respectively, and PorTrem by a modal relationship with Porites host cover. Incorporating interactions among predictor variables contributed to the predictive power of our models, particularly for PorTrem. Combining diseases (using overall disease prevalence as the model response, led to an average six-fold increase in cross-validation predictive deviance over modeling the diseases individually. We therefore recommend coral diseases to be modeled separately, unless known to have etiologies that respond in a similar manner to

  12. 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.

  13. Research of Uncertainty Reasoning in Pineapple Disease Identification System

    Science.gov (United States)

    Liu, Liqun; Fan, Haifeng

    In order to deal with the uncertainty of evidences mostly existing in pineapple disease identification system, a reasoning model based on evidence credibility factor was established. The uncertainty reasoning method is discussed,including: uncertain representation of knowledge, uncertain representation of rules, uncertain representation of multi-evidences and update of reasoning rules. The reasoning can fully reflect the uncertainty in disease identification and reduce the influence of subjective factors on the accuracy of the system.

  14. Systems Biology of Glucocorticoids in Muscle Disease

    Science.gov (United States)

    2010-10-01

    Introduction Duchenne muscular dystrophy (DMD) is the most common and incurable muscular dystrophy of childhood. Muscle regeneration fails with...SUBJECT TERMS Duchenne Muscular dystrophy , Glucocorticoids, Systems biology, Drug mechanism 16. SECURITY CLASSIFICATION OF: U 17. LIMITATION...better targeted and more effective therapies for Duchenne muscular dystrophy dynamically. This MDA grant proposal is led by Dr. Eric Hoffman, and it

  15. 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.

  16. Modeling human gastrointestinal inflammatory diseases using microphysiological culture systems.

    Science.gov (United States)

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

    2014-09-01

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

  17. Lung Infections in Systemic Rheumatic Disease: Focus on Opportunistic Infections.

    Science.gov (United States)

    Di Franco, Manuela; Lucchino, Bruno; Spaziante, Martina; Iannuccelli, Cristina; Valesini, Guido; Iaiani, Giancarlo

    2017-01-29

    Systemic rheumatic diseases have significant morbidity and mortality, due in large part to concurrent infections. The lung has been reported among the most frequent sites of infection in patients with rheumatic disease, who are susceptible to developing pneumonia sustained both by common pathogens and by opportunistic microorganisms. Patients with rheumatic disease show a peculiar vulnerability to infectious complications. This is due in part to intrinsic disease-related immune dysregulation and in part to the immunosuppressive treatments. Several therapeutic agents have been associated to a wide spectrum of infections, complicating the management of rheumatic diseases. This review discusses the most frequent pulmonary infections encountered in rheumatic diseases, focusing on opportunistic agents, consequent diagnostic challenges and appropriate therapeutic strategies.

  18. [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.

  19. [Hepatobiliary System Diseases as the Predictors of Psoriasis Progression].

    Science.gov (United States)

    Smirnova, S V; Barilo, A A; Smolnikova, M V

    2016-01-01

    To assess the state of the hepatobiliary system in psoriasis andpsoriatic arthritis in order to establish a causal relationship and to identify clinical and functional predictors of psoriatic disease progression. The study includedpatients with extensive psoriasis vulgaris (n = 175) aged 18 to 66 years old and healthy donors (n = 30), matched by sex and age: Group 1--patients with psoriasis (PS, n = 77), group 2--patients with psoriatic arthritis (PsA, n = 98), group 3--control. The evaluation of functional state of the hepatobiliary system was performed by the analysis of the clinical and anamnestic data and by the laboratory-instrumental methods. We identified predictors of psoriasis: triggers (stress and nutritionalfactor), increased total bilirubin, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, eosinophilia, giardiasis, carriers of hepatitis C virus, ductal changes andfocal leisons in the liver, thickening of the walls of the gallbladder detected by ultrasound. Predictors ofpsoriatic arthritis: age over 50 years, dyspeptic complaints, the presence of hepatobiliary system diseases, the positive right hypochondrium syndrome, the clinical symptoms of chronic cholecystitis, excess body weight, high levels of bilirubin, cholesterol and low density lipoprotein, hepatomegaly, non-alcoholic fatty liver disease. High activity of hepatocytes cytolysis, cholestasis, inflammation, metabolic disorders let us considerpsoriatic arthritis as a severe clinical stage psoriatic disease when the hepatobiliary system, in turn, is one of the main target organs in systemic psoriatic process. Non-alcoholic fatty liver disease and chronic cholecystitis are predictors of psoriatic disease progression.

  20. 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.

  1. A digital-signal-processor-based optical tomographic system for dynamic imaging of joint diseases

    Science.gov (United States)

    Lasker, Joseph M.

    Over the last decade, optical tomography (OT) has emerged as viable biomedical imaging modality. Various imaging systems have been developed that are employed in preclinical as well as clinical studies, mostly targeting breast imaging, brain imaging, and cancer related studies. Of particular interest are so-called dynamic imaging studies where one attempts to image changes in optical properties and/or physiological parameters as they occur during a system perturbation. To successfully perform dynamic imaging studies, great effort is put towards system development that offers increasingly enhanced signal-to-noise performance at ever shorter data acquisition times, thus capturing high fidelity tomographic data within narrower time periods. Towards this goal, I have developed in this thesis a dynamic optical tomography system that is, unlike currently available analog instrumentation, based on digital data acquisition and filtering techniques. At the core of this instrument is a digital signal processor (DSP) that collects, collates, and processes the digitized data set. Complementary protocols between the DSP and a complex programmable logic device synchronizes the sampling process and organizes data flow. Instrument control is implemented through a comprehensive graphical user interface which integrates automated calibration, data acquisition, and signal post-processing. Real-time data is generated at frame rates as high as 140 Hz. An extensive dynamic range (˜190 dB) accommodates a wide scope of measurement geometries and tissue types. Performance analysis demonstrates very low system noise (˜1 pW rms noise equivalent power), excellent signal precision (˜0.04%--0.2%) and long term system stability (˜1% over 40 min). Experiments on tissue phantoms validate spatial and temporal accuracy of the system. As a potential new application of dynamic optical imaging I present the first application of this method to use vascular hemodynamics as a means of characterizing

  2. Insights From Pre-Clinical and Clinical Studies on the Role of Innate Inflammation in Atherosclerosis Regression

    Directory of Open Access Journals (Sweden)

    Karishma Rahman

    2018-05-01

    Full Text Available Atherosclerosis, the underlying cause of coronary artery (CAD and other cardiovascular diseases, is initiated by macrophage-mediated immune responses to lipoprotein and cholesterol accumulation in artery walls, which result in the formation of plaques. Unlike at other sites of inflammation, the immune response becomes maladaptive and inflammation fails to resolve. The most common treatment for reducing the risk from atherosclerosis is low density lipoprotein cholesterol (LDL-C lowering. Studies have shown, however, that while significant lowering of LDL-C reduces the risk of heart attacks to some degree, there is still residual risk for the majority of the population. We and others have observed “residual inflammatory risk” of atherosclerosis after plasma cholesterol lowering in pre-clinical studies, and that this phenomenon is clinically relevant has been dramatically reinforced by the recent Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS trial. This review will summarize the role of the innate immune system, specifically macrophages, in atherosclerosis progression and regression, as well as the pre-clinical and clinical models that have provided significant insights into molecular pathways involved in the resolution of plaque inflammation and plaque regression. Partnered with clinical studies that can be envisioned in the post-CANTOS period, including progress in developing targeted plaque therapies, we expect that pre-clinical studies advancing on the path summarized in this review, already revealing key mechanisms, will continue to be essential contributors to achieve the goals of dampening plaque inflammation and inducing its resolution in order to maximize the therapeutic benefits of conventional risk factor modifications, such as LDL-C lowering.

  3. Quantitation of autoantibodies in systemic autoimmune diseases : clinically useful?

    NARCIS (Netherlands)

    Kallenberg, C. G. M.; Stegeman, C. A.; Bootsma, H.; Biji, M.; Limburg, P. C.

    2006-01-01

    Serial assessment of levels of autoantibodies has been proposed as being clinically useful in certain systemic autoimmune diseases. In particular, attention has been given to anti-dsDNA antibodies in systemic lupus erythematosus (SLE) and ANCA in the ANCA-associated vasculitides (AAV). Much

  4. Diseases of the nervous system associated with calcium channelopathies

    NARCIS (Netherlands)

    Todorov, Boyan Bogdanov

    2010-01-01

    The aim of the studies described in this thesis was to investigate how abnormal CaV2.1 channel function can cause disease, in particular motor coordination dysfunction. The chapters illustrate how various neuronal cell types in the periphery (peripheral nervous system) and the central nervous system

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

    DEFF Research Database (Denmark)

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

    2000-01-01

    Annexin XI, a calcyclin-associated protein, has been shown to be identical to a 56,000 Da antigen recognized by antibodies found in sera from patients suffering from systemic autoimmune diseases. In this work hexahistidine-tagged recombinant annexin XI (His6- rAnn XI) was used as antigen in ELISA...... experiments for determination of autoantibodies to annexin XI in sera of patients with systemic rheumatic autoimmune diseases. Immunoblotting with HeLa cell extract and with His6-rAnn XI as antigen was used for confirmation of positive ELISA results. We found eleven anti-annexin XI positive sera (3.9%) out...... 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...

  6. Present Status and Future Challenges of New Therapeutic Targets in Preclinical Models of Stroke in Aged Animals with/without Comorbidities

    Directory of Open Access Journals (Sweden)

    Aurel Popa-Wagner

    2018-01-01

    Full Text Available The aging process, comorbidities, and age-associated diseases are closely dependent on each other. Cerebral ischemia impacts a wide range of systems in an age-dependent manner. However, the aging process has many facets which are influenced by the genetic background and epigenetic or environmental factors, which can explain why some people age differently than others. Therefore, there is an urgent need to identify age-related changes in body functions or structures that increase the risk for stroke and which are associated with a poor outcome. Multimodal imaging, electrophysiology, cell biology, proteomics, and transcriptomics, offer a useful approach to link structural and functional changes in the aging brain, with or without comorbidities, to post-stroke rehabilitation. This can help us to improve our knowledge about senescence firstly, and in this context, aids in elucidating the pathophysiology of age-related diseases that allows us to develop therapeutic strategies or prevent diseases. These processes, including potential therapeutical interventions, need to be studied first in relevant preclinical models using aged animals, with and without comorbidities. Therefore, preclinical research on ischemic stroke should consider age as the most important risk factor for cerebral ischemia. Furthermore, the identification of effective therapeutic strategies, corroborated with successful translational studies, will have a dramatic impact on the lives of millions of people with cerebrovascular diseases.

  7. Drug Delivery Systems for Imaging and Therapy of Parkinson's Disease.

    Science.gov (United States)

    Gunay, Mine Silindir; Ozer, A Yekta; Chalon, Sylvie

    2016-01-01

    Although a variety of therapeutic approaches are available for the treatment of Parkinson's disease, challenges limit effective therapy. Among these challenges are delivery of drugs through the blood brain barier to the target brain tissue and the side effects observed during long term administration of antiparkinsonian drugs. The use of drug delivery systems such as liposomes, niosomes, micelles, nanoparticles, nanocapsules, gold nanoparticles, microspheres, microcapsules, nanobubbles, microbubbles and dendrimers is being investigated for diagnosis and therapy. This review focuses on formulation, development and advantages of nanosized drug delivery systems which can penetrate the central nervous system for the therapy and/or diagnosis of PD, and highlights future nanotechnological approaches. It is esential to deliver a sufficient amount of either therapeutic or radiocontrast agents to the brain in order to provide the best possible efficacy or imaging without undesired degradation of the agent. Current treatments focus on motor symptoms, but these treatments generally do not deal with modifying the course of Parkinson's disease. Beyond pharmacological therapy, the identification of abnormal proteins such as α -synuclein, parkin or leucine-rich repeat serine/threonine protein kinase 2 could represent promising alternative targets for molecular imaging and therapy of Parkinson's disease. Nanotechnology and nanosized drug delivery systems are being investigated intensely and could have potential effect for Parkinson's disease. The improvement of drug delivery systems could dramatically enhance the effectiveness of Parkinson's Disease therapy and reduce its side effects.

  8. 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.

  9. 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

  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. The oral-systemic disease connection: a retrospective study.

    Science.gov (United States)

    Joseph, Bobby K; Kullman, Leif; Sharma, Prem N

    2016-11-01

    The study aimed at determining the association between oral disease and systemic health based on panoramic radiographs and general health of patients treated at Kuwait University Dental Center. The objective was to determine whether individuals exhibiting good oral health have lower propensity to systemic diseases. A total of 1000 adult patients treated at Kuwait University Dental Center were randomly selected from the patient's records. The general health of patients was assessed from the medical history of each patient recorded during their visit to the clinic. The number of reported diseases and serious symptoms were used to develop a medical index. The oral health of these patients was assessed from panoramic radiographs to create an oral index by evaluating such parameters as caries, periodontitis, periapical lesions, pericoronitis, and tooth loss. In a total of 887 patients, 43.8 % had an oral index between 3 and 8, of which significantly higher (62.1 %) patients were with medical conditions compared to those without (33.2 %; p relationship when the diagnosis of oral disease was based primarily on radiographic findings. Future research needs to include prospective clinical and interventional studies. The significance of the oral-systemic disease connection highlights the importance of preventing and treating oral disease which have profound medical implications on general health.

  12. [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.

  13. Oxidative Stress in Oral Diseases: Understanding Its Relation with Other Systemic Diseases

    Directory of Open Access Journals (Sweden)

    Jaya Kumar

    2017-09-01

    Full Text Available Oxidative stress occurs in diabetes, various cancers, liver diseases, stroke, rheumatoid arthritis, chronic inflammation, and other degenerative diseases related to the nervous system. The free radicals have deleterious effect on various organs of the body. This is due to lipid peroxidation and irreversible protein modification that leads to cellular apoptosis or programmed cell death. During recent years, there is a rise in the oral diseases related to oxidative stress. Oxidative stress in oral disease is related to other systemic diseases in the body such as periodontitis, cardiovascular, pancreatic, gastric, and liver diseases. In the present review, we discuss the various pathways that mediate oxidative cellular damage. Numerous pathways mediate oxidative cellular damage and these include caspase pathway, PERK/NRF2 pathway, NADPH oxidase 4 pathways and JNK/mitogen-activated protein (MAP kinase pathway. We also discuss the role of inflammatory markers, lipid peroxidation, and role of oxygen species linked to oxidative stress. Knowledge of different pathways, role of inflammatory markers, and importance of low-density lipoprotein, fibrinogen, creatinine, nitric oxide, nitrates, and highly sensitive C-reactive proteins may be helpful in understanding the pathogenesis and plan better treatment for oral diseases which involve oxidative stress.

  14. 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.

  15. 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.

  16. 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.

  17. 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.

  18. 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.

  19. Disease scoring systems for oral lichen planus; a critical appraisal

    Science.gov (United States)

    Wang, Jing

    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 of both the objective and subjective parameters used in these systems and the lack of acceptance of one of these systems for uniform use, there is a need for an international, authorized consensus meeting on this subject. Because of the natural course of OLP characterized by remissions and exacerbations and also due to the varying distribution pattern and the varying clinical types, e.g. reticular and erosive, the relevance of a DSS based on morphologic parameters is somewhat questionable. Instead, one may consider to only look for a quality of life scoring system adapted for use in OLP patients. Key words:Oral lichen planus, disease scoring system, classification. PMID:25681372

  20. Systemic disease manifestations associated with epilepsy in tuberous sclerosis complex.

    Science.gov (United States)

    Jeong, Anna; Wong, Michael

    2016-09-01

    Epilepsy is one of the most disabling symptoms of tuberous sclerosis complex (TSC) and is a leading cause of morbidity and mortality in affected individuals. The relationship between systemic disease manifestations and the presence of epilepsy has not been thoroughly investigated. This study utilizes a multicenter TSC Natural History Database including 1,816 individuals to test the hypothesis that systemic disease manifestations of TSC are associated with epilepsy. Univariate analysis was used to identify patient characteristics (e.g., age, gender, race, and TSC mutation status) associated with the presence of epilepsy. Individual logistic regression models were built to examine the association between epilepsy and each candidate systemic or neurologic disease variable, controlling for the patient characteristics found to be significant on univariate analysis. Finally, a multivariable logistic regression model was constructed, using the variables found to be significant on the individual analyses as well as the patient characteristics that were significant on univariate analysis. Nearly 88% of our cohort had a history of epilepsy. After adjusting for age, gender, and TSC mutation status, multiple systemic disease manifestations including cardiac rhabdomyomas (odds ratio [OR] 2.3, 95% confidence interval [CI] 1.3-3.9, p = 0.002), retinal hamartomas (OR 2.1, CI 1.0-4.3, p = 0.04), renal cysts (OR 2.1, CI 1.3-3.4, p = 0.002), renal angiomyolipomas (OR 3.0, CI 1.8-5.1, p epilepsy. In the multivariable logistic regression model, cardiac rhabdomyomas (OR 1.9, CI 1.0-3.5, p = 0.04) remained significantly associated with the presence of epilepsy. The identification of systemic disease manifestations such as cardiac rhabdomyomas that confer a higher risk of epilepsy development in TSC could contribute to disease prognostication and assist in the identification of individuals who may receive maximal benefit from potentially novel, targeted, preventative therapies. Wiley

  1. 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)

  2. An intelligent medical system for diagnosis of bone diseases

    Energy Technology Data Exchange (ETDEWEB)

    Hatzilygeroudis, I [University of Patras, School of Engineering, Department of Computer Engineering and Informatics, 26500 Patras, Greece (Greece); Vassilakos, P J [Regional University Hospital of Patras, Department of Nuclear Medicine, Patras Greece (Greece); Tsakalidis, A [Computer Technology Institute, P.O. Box 1122, 26110 Patras, Greece (Greece)

    1994-12-31

    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). 10 refs., 2 figs.

  3. 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.

  4. 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.

  5. Imaging Manifestations in Systemic Cat Scratch Disease: Case report

    International Nuclear Information System (INIS)

    Forero M, Julian F; Perez A, Maria C; Cerquera C, Fredy M

    2011-01-01

    Cat scratch disease is a zoonosis caused by Bartonella henselae, which is transmitted by scratches, bites or exposition to cats saliva (1). The disease typically manifests with local lymphadenitis after bacterial inoculation in the skin, however, there is an atypical systemic presentation in 5 to 10% of patients, which causes unspecific symptoms. There are several imaging findings that lead the radiologist to consider this diagnosis, in order to prevent an invasive procedure, especially if we consider that the majority of cases occur in the pediatric population (2,3). Although in the majority of cases the symptoms and imaging findings resolve spontaneously, there are specific indications like the systemic form of the disease,which requires antibiotic treatment. In the present article we are exposing a case report from Fundacion Cardioinfantil; we will review some epidemiologic aspects, clinical manifestations, diagnostic methods as well as imaging findings in Ultrasonography, Computed Tomography, Magnetic Resonance and Nuclear Medicine.

  6. Imaging Manifestations in Systemic Cat Scratch Disease: Case report

    International Nuclear Information System (INIS)

    Forero Melo, Julian Francisco; Perez Alvarado, Maria Carolina; Cerquera Cabrera, Fredy Martin

    2011-01-01

    Cat scratch disease is a zoonosis caused by Bartonella henselae, which is transmitted by scratches, bites or exposition to cats saliva (1). The disease typically manifests with local lymphadenitis after bacterial inoculation in the skin, however, there is an atypical systemic presentation in 5 to 10% of patients, which causes unspecific symptoms. There are several imaging findings that lead the radiologist to consider this diagnosis, in order to prevent an invasive procedure, especially if we consider that the majority of cases occur in the pediatric population (2,3). Although in the majority of cases the symptoms and imaging findings resolve spontaneously, there are specific indications like the systemic form of the disease, which requires antibiotic treatment. In the present article we are exposing a case report from Fundacion Cardio infantil; we will review some epidemiologic aspects, clinical manifestations, diagnostic methods as well as imaging findings in Ultrasonography, Computed Tomography, Magnetic Resonance and Nuclear Medicine.

  7. 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.

  8. 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.

  9. 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. 

  10. 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. 

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

    NARCIS (Netherlands)

    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

    2017-01-01

    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

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

    NARCIS (Netherlands)

    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

    2017-01-01

    BACKGROUND: 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

  13. CINRG: Systems Biology of Glucocorticoids in Muscle Disease

    Science.gov (United States)

    2013-10-01

    Contract W81XWH-09-1-0726 SYSTEMS BIOLOGY OF GLUCOCORTICOIDS IN MUSCLE DISEASE Introduction Duchenne muscular dystrophy (DMD) is the most... muscle and enable the development of better targeted and more effective therapies for Duchenne muscular dystrophy dynamically. This MDA grant...common and incurable muscular dystrophy of childhood. Muscle regeneration fails with advancing age, leading to considerable fibrosis. Corticosteroid

  14. 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 ...

  15. 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 ...

  16. 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

  17. 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

  18. The influence of systemic diseases on the diagnosis of oral diseases: a problem-based approach

    NARCIS (Netherlands)

    Lockhart, P.B.; Hong, C.H.L.; van Diermen, D.E.

    2011-01-01

    lthough all dentists are taught about the importance of oral health to general health and that systemic disease can manifest in the oral cavity, the 4-year dental school curriculum does not allow time to gain competency in these relationships. Nevertheless, all dentists must have skills in taking a

  19. 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.

  20. Epstein-Barr virus in systemic autoimmune diseases.

    Science.gov (United States)

    Draborg, Anette Holck; Duus, Karen; Houen, Gunnar

    2013-01-01

    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.

  1. 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.

  2. Longitudinal trends and subgroup analysis in publication patterns for preclinical data of newly approved drugs.

    Science.gov (United States)

    Köster, Ursula; Nolte, Ingo; Michel, Martin C

    2016-02-01

    Having observed a large variation in the number and type of original preclinical publications for newly registered drugs, we have explored whether longitudinal trends and/or factors specific for certain drugs or their manufacturers may explain such variation. Our analysis is based on 1954 articles related to 170 newly approved drugs. The number of preclinical publications per compound declined from a median of 10.5 in 1991 to 3 in 2011. A similar trend was observed for the number of in vivo studies in general, but not in the subset of in vivo studies in animal models of disease. The percentage of compounds with studies using isolated human cells or cell lines almost doubled over time from 37 to 72%. Number of publications did not exhibit major differences between compounds intended for human versus veterinary use, therapeutic areas, small molecules versus biologicals, or innovator versus follow-up compounds; however, some companies may publish fewer studies per compound than others. However, there were qualitative differences in the types of models being used depending on the therapeutic area; specifically, compounds for use in oncology very often used isolated cells and cell lines, often from human origin. We conclude that the large variation in number and type of reported preclinical data is not easily explained. We propose that pharmaceutical companies should consistently provide a comprehensive documentation of the preclinical data they generate as part of their development programs in the public domain to enable a better understanding of the drugs they intend to market.

  3. 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

  4. Interstitial lung disease in systemic autoimmune rheumatic diseases: a comprehensive review.

    Science.gov (United States)

    Atzeni, Fabiola; Gerardi, Maria Chiara; Barilaro, Giuseppe; Masala, Ignazio Francesco; Benucci, Maurizio; Sarzi-Puttini, Piercarlo

    2018-01-01

    Interstitial lung diseases (ILDs) are among the most serious complications associated with systemic rheumatic diseases, and lead to significant morbidity and mortality; they may also be the first manifestation of connective tissue diseases (CTDs). The aim of this narrative review is to summarise the data concerning the pathogenesis of CTD/ILD and its distinguishing features in different rheumatic diseseas. Areas covered: The pathogenesis, clinical aspects and treatment of ILD associated with rheumatic systemic diseases and CTDs were reviewed by searching the PubMed, Medline, and Cochrane Library databases for papers published between 1995 and February 2017 using combinations of words or terms. Articles not written in English were excluded. Expert commentary: The management of CTD-ILD is challenging because of the lack of robust data regarding the treatments used, the heterogeneity of the diseases themselves, and the scarcity of well-defined outcome measures. Treatment decisions are often made clinically on the basis of functional, radiographic progression, and exacerbating factors such as age and the burden of comorbidities. Given the complexities of diagnosis and the paucity of treatment trials, the management of CTD patients with ILD requires multidisciplinary collaboration between rheumatologists and pulmonologists in CTD-ILD clinics.

  5. 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

  6. Chagas disease: 100 years after its discovery. A systemic review.

    Science.gov (United States)

    Coura, José Rodrigues; Borges-Pereira, José

    2010-01-01

    Although Chagas disease was only discovered in 1909, it began millions of years ago as an enzootic disease among wild animals. Its transmission to man began accidentally as an anthropozoonosis when mankind invaded wild ecotopes. Endemic Chagas disease became established as a zoonosis over the last 200-300 years through deforestation for agriculture and livestock rearing and adaptation of triatomines to dwellings and to humans and domestic animals as food sources. When T. cruzi is transmitted to man, it invades the bloodstream and lymphatic system and lodges in muscle and heart tissue, the digestive system and phagocytic cells. Through this, it causes inflammatory lesions and an immune response, particularly mediated by CD4(+), CD8(+), IL2 and IL4, with cell and neuron destruction and fibrosis. These processes lead to blockage of the heart's conductive system, arrhythmias, heart failure, aperistalsis and dilatation of hollow viscera, especially the esophagus and colons. Chagas disease is characterized by an acute phase with or without symptoms, with (or more often without) T. cruzi penetration signs (inoculation chagoma or Romaña's sign), fever, adenomegaly, hepatosplenomegaly and patent parasitemia; and a chronic phase: indeterminate (asymptomatic, with normal electrocardiogram and heart, esophagus and colon X-rays) or cardiac, digestive or cardiac/digestive forms. There is great regional variation in the morbidity caused by Chagas disease: severe cardiac or digestive forms may occur in 10-50%, and indeterminate forms in the remaining, asymptomatic cases. The epidemiological and control characteristics of Chagas disease vary according to each country's ecological conditions and health policies. 2010. Published by Elsevier B.V.

  7. 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.

  8. Thrombomodulin Expression in Tissues From Dogs With Systemic Inflammatory Disease.

    Science.gov (United States)

    Kim, S D; Baker, P; DeLay, J; Wood, R D

    2016-07-01

    Thrombomodulin (TM) is a membrane glycoprotein expressed on endothelial cells, which plays a major role in the protein C anticoagulation pathway. In people with inflammation, TM expression can be down-regulated on endothelial cells and a soluble form released into circulation, resulting in increased risk of thrombosis and disseminated intravascular coagulation. TM is present in dogs; however, there has been minimal investigation of its expression in canine tissues, and the effects of inflammation on TM expression in canine tissues have not been investigated. The objective of this study was to evaluate endothelial TM expression in tissues from dogs with systemic inflammatory diseases. A retrospective evaluation of tissue samples of lung, spleen, and liver from dogs with and without systemic inflammatory diseases was performed using immunohistochemistry (IHC) and a modified manual IHC scoring system. TM expression was significantly reduced in all examined tissues in dogs diagnosed with septic peritonitis or acute pancreatitis. © The Author(s) 2016.

  9. 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.

  10. Empirical validation of the Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire for suspected Lyme disease.

    Science.gov (United States)

    Citera, Maryalice; Freeman, Phyllis R; Horowitz, Richard I

    2017-01-01

    Lyme disease is spreading worldwide, with multiple Borrelia species causing a broad range of clinical symptoms that mimic other illnesses. A validated Lyme disease screening questionnaire would be clinically useful for both providers and patients. Three studies evaluated such a screening tool, namely the Horowitz Multiple Systemic Infectious Disease Syndrome (MSIDS) Questionnaire. The purpose was to see if the questionnaire could accurately distinguish between Lyme patients and healthy individuals. Study 1 examined the construct validity of the scale examining its factor structure and reliability of the questionnaire among 537 individuals being treated for Lyme disease. Study 2 involved an online sample of 999 participants, who self-identified as either healthy (N=217) or suffering from Lyme now (N=782) who completed the Horowitz MSIDS Questionnaire (HMQ) along with an outdoor activity survey. We examined convergent validity among components of the scale and evaluated discriminant validity with the Big Five personality characteristics. The third study compared a sample of 236 patients with confirmed Lyme disease with an online sample of 568 healthy individuals. Factor analysis results identified six underlying latent dimensions; four of these overlapped with critical symptoms identified by Horowitz - neuropathy, cognitive dysfunction, musculoskeletal pain, and fatigue. The HMQ showed acceptable levels of internal reliability using Cronbach's coefficient alpha and exhibited evidence of convergent and divergent validity. Components of the HMQ correlated more highly with each other than with unrelated traits. The results consistently demonstrated that the HMQ accurately differentiated those with Lyme disease from healthy individuals. Three migratory pain survey items (persistent muscular pain, arthritic pain, and nerve pain/paresthesias) robustly identified individuals with verified Lyme disease. The results support the use of the HMQ as a valid, efficient, and low

  11. Orchid Classification Disease Identification And Healthiness Prediction System

    Directory of Open Access Journals (Sweden)

    K. W. V Sanjaya

    2015-03-01

    Full Text Available Abstract Floriculture has become one of Sri Lankas major foreign exchange ventures and it has grown substantially during the last few years. Currently we can find three major types of growers in floriculture. They are Large Commercial Ventures Middle Level growers and Village Level growers. Both Middle Level and Village level growers usually go for low cost cultivation with minimum advanced techniques sticking to conventional methods. Orchid cultivation is more pleasurable and profitable than any other floriculture ventures. As the orchid cultivation is so pleasurable we can introduce another group of growers who cultivate orchid in their home gardens for making their home gardens beautiful. But the problem is that most of these growers may not have the knowledge to identify the specie of the plants as there are a number of similar looking plants which are in different species. And also they may not have the knowledge about the orchid diseases. Because of that they may not be able to get the maximum outcome from their cultivations. So the aim of our project is to address the above mentioned issues by introducing a system which can identify orchid species amp diseases and predict the healthiness of the orchid plants. The only input to this system is an image of an orchid leaf and the system will provide the orchid specie name diseases if there any healthiness of the orchid plant and suggestions to overcome the issues associated with the orchid plant as the output. We identify the orchid species and diseases by extracting the features of orchid plant leaf in the input image using image processing technics and with the use of data mining technics we predict the healthiness of the orchid plant. So this system will be a great help for the people who love to grow orchids but dont have knowledge about the orchid species and diseases. And also they will be able to find the healthiness of their orchid plants.

  12. A novel pre-clinical in vivo mouse model for malignant brain tumor growth and invasion.

    Science.gov (United States)

    Shelton, Laura M; Mukherjee, Purna; Huysentruyt, Leanne C; Urits, Ivan; Rosenberg, Joshua A; Seyfried, Thomas N

    2010-09-01

    Glioblastoma multiforme (GBM) is a rapidly progressive disease of morbidity and mortality and is the most common form of primary brain cancer in adults. Lack of appropriate in vivo models has been a major roadblock to developing effective therapies for GBM. A new highly invasive in vivo GBM model is described that was derived from a spontaneous brain tumor (VM-M3) in the VM mouse strain. Highly invasive tumor cells could be identified histologically on the hemisphere contralateral to the hemisphere implanted with tumor cells or tissue. Tumor cells were highly expressive for the chemokine receptor CXCR4 and the proliferation marker Ki-67 and could be identified invading through the pia mater, the vascular system, the ventricular system, around neurons, and over white matter tracts including the corpus callosum. In addition, the brain tumor cells were labeled with the firefly luciferase gene, allowing for non-invasive detection and quantitation through bioluminescent imaging. The VM-M3 tumor has a short incubation time with mortality occurring in 100% of the animals within approximately 15 days. The VM-M3 brain tumor model therefore can be used in a pre-clinical setting for the rapid evaluation of novel anti-invasive therapies.

  13. 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.

  14. Modeling Acute Traumatic Hemorrhagic Shock Injury: Challenges and Guidelines for Preclinical Studies.

    Science.gov (United States)

    Tremoleda, Jordi L; Watts, Sarah A; Reynolds, Penny S; Thiemermann, Christoph; Brohi, Karim

    2017-12-01

    Trauma is responsible for a large proportion of the world's burden of disease, and is by far the biggest killer of young adults. Hemorrhage is the leading cause of preventable death and its effects are directly correlated with the incidence multi-organ failure in survivors. Trauma research is challenging due to patient heterogeneity, limited randomized controlled trials, and in vitro studies that fail to mimic the systemic injury response. Preclinical research remains essential for mechanistic and therapeutic discovery. Yet modeling the multifaceted nature of traumatic injury poses important experimental and welfare challenges associated with the onset of injury and prehospital and intra-operative care, the limited inter-species validation of coagulation profiles, the use of anesthesia/analgesia, and its impact on the systemic response to trauma; and the challenge of sustaining intensive care in recovery models. Proper model selection depends on the purpose of a given model and the criteria by which the experimental readouts will be clinically relevant. Such complexity warrants further refinement of experimental methodology and outcome measures to improve its clinical efficacy, while ensuring animal well-being. We review the experimental methodologies currently used for modeling traumatic hemorrhagic shock and addressing their impact on clinical translation. The aim of the review is to improve transparency and form a consensus when reporting methodology in trauma modeling.

  15. Myelin injury in the central nervous system and Alzheimer's diseases.

    Science.gov (United States)

    Wang, Sha-Sha; Zhang, Zhao; Zhu, Tian-Bi; Chu, Shi-Feng; He, Wen-Bin; Chen, Nai-Hong

    2018-05-03

    Myelin is a membrane wrapped around the axon of the nerve cell, which is composed of the mature oligodendrocytes. The role of myelin is to insulate and prevent the nerve electrical impulses from the axon of the neurons to the axons of the other neurons, which is essential for the proper functioning of the nervous system. Minor changes in myelin thickness could lead to substantial changes in conduction speed and may thus alter neural circuit function. Demyelination is the myelin damage, which characterized by the loss of nerve sheath and the relative fatigue of the neuronal sheath and axon. Studies have shown that myelin injury may be closely related to neurodegenerative diseases and may be an early diagnostic criteria and therapeutic target. Thus this review summarizes the recent result of pathologic effect and signal pathways of myelin injury in neurodegenerative diseases, especially the Alzheimer's disease to provide new and effective therapeutic targets. Copyright © 2018. Published by Elsevier Inc.

  16. Simple model systems: a challenge for Alzheimer's disease

    Directory of Open Access Journals (Sweden)

    Di Carlo Marta

    2012-04-01

    Full Text Available Abstract The success of biomedical researches has led to improvement in human health and increased life expectancy. An unexpected consequence has been an increase of age-related diseases and, in particular, neurodegenerative diseases. These disorders are generally late onset and exhibit complex pathologies including memory loss, cognitive defects, movement disorders and death. Here, it is described as the use of simple animal models such as worms, fishes, flies, Ascidians and sea urchins, have facilitated the understanding of several biochemical mechanisms underlying Alzheimer's disease (AD, one of the most diffuse neurodegenerative pathologies. The discovery of specific genes and proteins associated with AD, and the development of new technologies for the production of transgenic animals, has helped researchers to overcome the lack of natural models. Moreover, simple model systems of AD have been utilized to obtain key information for evaluating potential therapeutic interventions and for testing efficacy of putative neuroprotective compounds.

  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. Preclinical Murine Models for Lung Cancer: Clinical Trial Applications

    Directory of Open Access Journals (Sweden)

    Amelia Kellar

    2015-01-01

    Full Text Available Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer.

  19. 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...

  20. 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.

  1. 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.

  2. Association between Systemic Diseases and Endodontic Outcome: A Systematic Review.

    Science.gov (United States)

    Aminoshariae, Anita; Kulild, James C; Mickel, Andre; Fouad, Ashraf F

    2017-04-01

    To date, the relationships between systemic diseases and endodontic treatment outcomes remain poorly studied. Thus, the purpose of this systematic review was to evaluate the relationship between host-modifying factors and their association with endodontic outcomes. Two reviewers independently conducted a comprehensive literature search. The MEDLINE, Embase, Cochrane, and PubMed databases were searched. In addition, the bibliographies and gray literature of all relevant articles and textbooks were manually searched. There was no disagreement between the 2 reviewers. Sixteen articles met the inclusion criteria with moderate to high risk of bias. There was no article with low risk of bias. Available scientific evidence remains inconclusive as to whether diabetes and/or cardiovascular disease(s) may be associated with endodontic outcomes. Human immunodeficiency virus and oral bisphosphonate did not appear to be associated with endodontic outcomes. Although additional well-designed longitudinal clinical studies are needed, the results of this systematic review suggest that some systemic diseases may be correlated with endodontic outcomes. Copyright © 2016 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  3. A review of occupational disease surveillance systems in Modernet countries.

    Science.gov (United States)

    Carder, M; Bensefa-Colas, L; Mattioli, S; Noone, P; Stikova, E; Valenty, M; Telle-Lamberton, M

    2015-11-01

    To improve occupational health public policies and to facilitate coordinated research within the European Union to reduce the incidence of occupational diseases (ODs), it is important to know what OD surveillance systems exist and how they compare. Monitoring trends in occupational diseases and tracing new and emerging risks in a network (Modernet) participants are well placed to provide this information as most either contribute data to and/or are involved in the management of OD systems. To identify and describe OD surveillance systems in Modernet countries with the longer-term objective of identifying a core template to be used on a large scale. A questionnaire sent to Modernet participants, seeking structured information about the OD surveillance system(s) in their country. Overall 14 countries (70%) provided information for 33 OD systems, among them 11 compensation-based (CB) systems. Six countries provided information for non-CB systems reporting for any type of OD. The other systems reported either only ODs from a prescribed list, or specific diagnoses or diagnostic groups, with reports to most schemes being physician-based. Data collected varied but all systems collected diagnosis, age, gender, date reported and occupation (and/or industry) and most collected information on exposure. This review provides information beneficial to both policy makers and researchers by identifying data sources useable to measure OD trends in European countries and opening the way to future work, both on trend comparisons within Europe and on the definition of a core template to extend OD surveillance on a larger scale. © The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  4. Decision Support System for Hepatitis Disease Diagnosis using Bayesian Network

    Directory of Open Access Journals (Sweden)

    Shamshad Lakho

    2017-12-01

    Full Text Available Medical judgments are tough and challenging as the decisions are often based on the deficient and ambiguous information. Moreover, the result of decision process has direct effects on human lives. The act of human decision declines in emergency situations due to the complication, time limit, and high risks. Therefore, provision of medical diagnosis plays a dynamic role, specifically in the preliminary stage when a physician has limited diagnosis experience and identifies the directions to be taken for the treatment process. Computerized Decision Support Systems have brought a revolution in the medical diagnosis. These automatic systems support the diagnosticians in the course of diagnosis. The major role of Decision Support Systems is to support the medical personnel in decision-making procedures regarding disease diagnosis and treatment recommendation. The proposed system provides easy support in Hepatitis disease recognition. The system is developed using the Bayesian network model. The physician provides the input to the system in the form of symptoms stated by the patient. These signs and symptoms match with the casual relationships present in the knowledge model. The Bayesian network infers conclusion from the knowledge model and calculates the probability of occurrence of Hepatitis B, C and D disorders.

  5. 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

  6. Role of sulfiredoxin in systemic diseases influenced by oxidative stress

    Directory of Open Access Journals (Sweden)

    Asha Ramesh

    2014-01-01

    Full Text Available Sulfiredoxin is a recently discovered member of the oxidoreductases family which plays a crucial role in thiol homoeostasis when under oxidative stress. A myriad of systemic disorders have oxidative stress and reactive oxygen species as the key components in their etiopathogenesis. Recent studies have evaluated the role of this enzyme in oxidative stress mediated diseases such as atherosclerosis, chronic obstructive pulmonary disease and a wide array of carcinomas. Its action is responsible for the normal functioning of cells under oxidative stress and the promotion of cell survival in cancerous cells. This review will highlight the cumulative effects of sulfiredoxin in various systemic disorders with a strong emphasis on its target activity and the factors influencing its expression in such conditions.

  7. 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.

  8. 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

  9. 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

  10. Preliminary study for small animal preclinical hadrontherapy facility

    Science.gov (United States)

    Russo, G.; Pisciotta, P.; Cirrone, G. A. P.; Romano, F.; Cammarata, F.; Marchese, V.; Forte, G. I.; Lamia, D.; Minafra, L.; Bravatá, V.; Acquaviva, R.; Gilardi, M. C.; Cuttone, G.

    2017-02-01

    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

  11. Preliminary study for small animal preclinical hadrontherapy facility

    International Nuclear Information System (INIS)

    Russo, G.; Pisciotta, P.; Cirrone, G.A.P.; Romano, F.; Cammarata, F.; Marchese, V.; Forte, G.I.; Lamia, D.; Minafra, L.; Bravatá, V.; Acquaviva, R.; Gilardi, M.C.; Cuttone, G.

    2017-01-01

    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

  12. 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

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. 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

  18. 'Muscle-sparing' statins: preclinical profiles and future clinical use.

    Science.gov (United States)

    Pfefferkorn, Jeffrey A

    2009-03-01

    Coronary heart disease (CHD) is a leading cause of death in the US, and hypercholesterolemia is a key risk factor for this disease. The current standard of care for treating hypercholesterolemia is the use of HMG-CoA reductase inhibitors, also known as statins, which block the rate-limiting step of cholesterol biosynthesis. In widespread clinical use, statins have proven safe and effective for both primary prevention of CHD and secondary prevention of coronary events. Results from several recent clinical trials have demonstrated that increasingly aggressive cholesterol-lowering therapy might offer additional protection against CHD compared with less aggressive treatment standards. While higher doses of current statin therapies are capable of achieving these more aggressive treatment goals, in certain cases statin-induced myalgia, the muscle pain or weakness that sometimes accompanies high-dose statin therapy, limits patient compliance with a treatment regimen. To address this limitation, efforts have been undertaken to develop highly hepatoselective statins that are capable of delivering best-in-class efficacy with minimized risk of dose-limiting myalgia. In this review, the preclinical and early clinical data for these next generation statins are discussed.

  19. Familial occurrence of systemic mast cell activation disease.

    Directory of Open Access Journals (Sweden)

    Gerhard J Molderings

    Full Text Available Systemic mast cell activation disease (MCAD comprises disorders characterized by an enhanced release of mast cell mediators accompanied by accumulation of dysfunctional mast cells. Demonstration of familial clustering would be an important step towards defining the genetic contribution to the risk of systemic MCAD. The present study aimed to quantify familial aggregation for MCAD and to investigate the variability of clinical and molecular findings (e.g. somatic mutations in KIT among affected family members in three selected pedigrees. Our data suggest that systemic MCAD pedigrees include more systemic MCAD cases than would be expected by chance, i.e., compared with the prevalence of MCAD in the general population. The prevalence of MCAD suspected by symptom self-report in first-degree relatives of patients with MCAD amounted to approximately 46%, compared to prevalence in the general German population of about 17% (p<0.0001. In three families with a high familial loading of MCAD, the subtype of MCAD and the severity of mediator-related symptoms varied between family members. In addition, genetic alterations detected in KIT were variable, and included mutations at position 816 of the amino acid sequence. In conclusion, our data provide evidence for common familial occurrence of MCAD. Our findings observed in the three pedigrees together with recent reports in the literature suggest that, in familial cases (i.e., in the majority of MCAD, mutated disease-related operator and/or regulator genes could be responsible for the development of somatic mutations in KIT and other proteins important for the regulation of mast cell activity. Accordingly, the immunohistochemically different subtypes of MCAD (i.e. mast cell activation syndrome and systemic mastocytosis should be more accurately regarded as varying presentations of a common generic root process of mast cell dysfunction, than as distinct diseases.

  20. Combined preclinical magnetic particle imaging and magnetic resonance imaging. Initial results in mice

    International Nuclear Information System (INIS)

    Kaul, M.G.; Mummert, T.; Jung, C.; Raabe, N.; Ittrich, H.; Adam, G.; Heinen, U.; Reitmeier, A.

    2015-01-01

    Magnetic particle imaging (MPI) is a new radiologic imaging modality. For the first time, a commercial preclinical scanner is installed. The goal of this study was to establish a workflow between MPI and magnetic resonance imaging (MRI) scanners for a complete in vivo examination of a mouse and to generate the first co-registered in vivo MR-MP images. The in vivo examination of five mice were performed on a preclinical MPI scanner and a 7 Tesla preclinical MRI system. MRI measurements were used for anatomical referencing and validation of the injection of superparamagnetic iron oxide (SPIO) particles during a dynamic MPI scan. We extracted MPI data of the injection phase and co-registered it with MRI data. A workflow process for a combined in vivo MRI and MPI examination was established. A successful injection of ferucarbotran was proven in MPI and MRI. MR-MPI co-registration allocated the SPIOs in the inferior vena cava and the heart during and shortly after the injection. The acquisition of preclinical MPI and MRI data is feasible and allows the combined analysis of MR-MPI information.

  1. Combined preclinical magnetic particle imaging and magnetic resonance imaging. Initial results in mice

    Energy Technology Data Exchange (ETDEWEB)

    Kaul, M.G.; Mummert, T.; Jung, C.; Raabe, N.; Ittrich, H.; Adam, G. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Diagnostic and Interventional Radiology; Weber, O. [Philips Medical Systems DMC GmbH, Hamburg (Germany); Heinen, U. [Bruker BioSpin MRI GmbH, Ettlingen (Germany); Reitmeier, A. [Medical Center Hamburg-Eppendorf, Hamburg (Germany). Animal Facility; Knopp, T. [University Medical Center Hamburg-Eppendorf, Hamburg (Germany). Dept. of Diagnostic and Interventional Radiology; Hamburg University of Technology, Hamburg (Germany)

    2015-05-15

    Magnetic particle imaging (MPI) is a new radiologic imaging modality. For the first time, a commercial preclinical scanner is installed. The goal of this study was to establish a workflow between MPI and magnetic resonance imaging (MRI) scanners for a complete in vivo examination of a mouse and to generate the first co-registered in vivo MR-MP images. The in vivo examination of five mice were performed on a preclinical MPI scanner and a 7 Tesla preclinical MRI system. MRI measurements were used for anatomical referencing and validation of the injection of superparamagnetic iron oxide (SPIO) particles during a dynamic MPI scan. We extracted MPI data of the injection phase and co-registered it with MRI data. A workflow process for a combined in vivo MRI and MPI examination was established. A successful injection of ferucarbotran was proven in MPI and MRI. MR-MPI co-registration allocated the SPIOs in the inferior vena cava and the heart during and shortly after the injection. The acquisition of preclinical MPI and MRI data is feasible and allows the combined analysis of MR-MPI information.

  2. Natural evolution, disease, and localization in the immune system

    Science.gov (United States)

    Deem, Michael

    2004-03-01

    Adaptive vertebrate immune system is a wonder of modern evolution. Under most circumstances, the dynamics of the immune system is well-matched to the dynamics of pathogen growth during a typical infection. Some pathogens, however, have evolved escape mechanisms that interact in subtle ways with the immune system dynamics. In addition, negative interactions the immune system, which has evolved over 400 000 000 years, and vaccination,which has been practiced for only 200 years, are possible. For example,vaccination against the flu can actually increase susceptibility to the flu in the next year. As another example, vaccination against one of the four strains of dengue fever typically increases susceptibility against the other three strains. Immunodominance also arises in the immune system control of nascent tumors--the immune system recognizes only a small subset of the tumor specific antigens, and the rest are free to grow and cause tumor growth. In this talk, I present a physical theory of original antigenic sin and immunodominance. How localization in the immune system leads to the observed phenomena is discussed. 1) M. W. Deem and H. Y. Lee, ``Sequence Space Localization in the Immune System Response to Vaccination and Disease,'' Phys. Rev. Lett. 91 (2003) 068101

  3. 77 FR 29678 - National Institute of Allergy and Infectious Diseases; Notice of Closed Meeting

    Science.gov (United States)

    2012-05-18

    ... Infectious Diseases Special Emphasis Panel; ``Integrated Preclinical/Clinical Program for HIV Topical..., Microbiology and Infectious Diseases Research, National Institutes of Health, HHS) Dated: May 11, 2012...

  4. 78 FR 40756 - National Institute of Allergy and Infectious Diseases; Notice of Closed Meeting

    Science.gov (United States)

    2013-07-08

    ... Infectious Diseases Special Emphasis Panel; Integrated Preclinical/Clinical AIDS Vaccine Development Program..., and Transplantation Research; 93.856, Microbiology and Infectious Diseases Research, National...

  5. 77 FR 13133 - National Institute of Allergy and Infectious Diseases; Notice of Closed Meeting

    Science.gov (United States)

    2012-03-05

    ... Infectious Diseases Special Emphasis Panel Integrated Preclinical/Clinical Program for HIV Topical..., and Transplantation Research; 93.856, Microbiology and Infectious Diseases Research, National...

  6. 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

  7. New preclinical antimalarial drugs potently inhibit hepatitis C virus genotype 1b RNA replication.

    Directory of Open Access Journals (Sweden)

    Youki Ueda

    Full Text Available BACKGROUND: Persistent hepatitis C virus (HCV infection causes chronic liver diseases and is a global health problem. Although new triple therapy (pegylated-interferon, ribavirin, and telaprevir/boceprevir has recently been started and is expected to achieve a sustained virologic response of more than 70% in HCV genotype 1 patients, there are several problems to be resolved, including skin rash/ageusia and advanced anemia. Thus a new type of anti-HCV drug is still needed. METHODOLOGY/PRINCIPAL FINDINGS: Recently developed HCV drug assay systems using HCV-RNA-replicating cells (e.g., HuH-7-derived OR6 and Li23-derived ORL8 were used to evaluate the anti-HCV activity of drug candidates. During the course of the evaluation of anti-HCV candidates, we unexpectedly found that two preclinical antimalarial drugs (N-89 and its derivative N-251 showed potent anti-HCV activities at tens of nanomolar concentrations irrespective of the cell lines and HCV strains of genotype 1b. We confirmed that replication of authentic HCV-RNA was inhibited by these drugs. Interestingly, however, this anti-HCV activity did not work for JFH-1 strain of genotype 2a. We demonstrated that HCV-RNA-replicating cells were cured by treatment with only N-89. A comparative time course assay using N-89 and interferon-α demonstrated that N-89-treated ORL8 cells had more rapid anti-HCV kinetics than did interferon-α-treated cells. This anti-HCV activity was largely canceled by vitamin E. In combination with interferon-α and/or ribavirin, N-89 or N-251 exhibited a synergistic inhibitory effect. CONCLUSIONS/SIGNIFICANCE: We found that the preclinical antimalarial drugs N-89 and N-251 exhibited very fast and potent anti-HCV activities using cell-based HCV-RNA-replication assay systems. N-89 and N-251 may be useful as a new type of anti-HCV reagents when used singly or in combination with interferon and/or ribavirin.

  8. Periodontal disease in Chinese patients with systemic lupus erythematosus.

    Science.gov (United States)

    Zhang, Qiuxiang; Zhang, Xiaoli; Feng, Guijaun; Fu, Ting; Yin, Rulan; Zhang, Lijuan; Feng, Xingmei; Li, Liren; Gu, Zhifeng

    2017-08-01

    Disease of systemic lupus erythematosus (SLE) and periodontal disease (PD) shares the common multiple characteristics. The aims of the present study were to evaluate the prevalence and severity of periodontal disease in Chinese SLE patients and to determine the association between SLE features and periodontal parameters. A cross-sectional study of 108 SLE patients together with 108 age- and sex-matched healthy controls was made. Periodontal status was conducted by two dentists independently. Sociodemographic characteristics, lifestyle factors, medication use, and clinical parameters were also assessed. The periodontal status was significantly worse in SLE patients compared to controls. In univariate logistic regression, SLE had a significant 2.78-fold [95% confidence interval (CI) 1.60-4.82] increase in odds of periodontitis compared to healthy controls. Adjusted for potential risk factors, patients with SLE had 13.98-fold (95% CI 5.10-38.33) increased odds against controls. In multiple linear regression model, the independent variable negatively and significantly associated with gingival index was education (P = 0.005); conversely, disease activity (P periodontitis of SLE in multivariate logistic regression (OR 1.348; 95% CI: 1.183-1.536, P < 0.001). Chinese SLE patients were likely to suffer from higher odds of PD. These findings confirmed the importance of early interventions in combination with medical therapy. It is necessary for a close collaboration between dentists and clinicians when treating those patients.

  9. PTPN22 gene polymorphisms in autoimmune diseases with special reference to systemic lupus erythematosus disease susceptibility

    Directory of Open Access Journals (Sweden)

    Pradhan V

    2010-01-01

    Full Text Available Systemic lupus erythematosus (SLE is a prototype autoimmune disease. SLE is a result of one or more immune mechanisms, like autoantibody production, complement activation, multiple inflammation and immune complex deposition leading to organ tissue damage. SLE affected patients are susceptible to common and opportunistic infections. There are several reports suggesting that Mycobacterium tuberculosis infection precipitates SLE in patients from endemic areas. Genetic factors and environmental factors also play an important role in the overall susceptibility to SLE pathophysiology. Recently, protein tyrosine phosphatase, non-receptor type 22 (PTPN22 gene, has been found to be associated with several autoimmune diseases like SLE, Grave′s disease and Hashimoto thyroiditis. The missense R620W polymorphism, rs 2476601, in PTPN22 gene at the nucleotide 1858 in codon 620 (620Arg > Trp has been associated with autoimmune diseases. The PTPN22 locus is also found to be responsible for development of pulmonary tuberculosis in certain populations. The PTPN22 1858C/T gene locus will be ideal to look for SLE susceptibility to tuberculosis in the Indian population. In this review, we focus on human PTPN22 gene structure and function as well as the association of PTPN22 gene polymorphisms with SLE susceptibility

  10. Clearance systems in the brain—implications for Alzheimer disease

    Science.gov (United States)

    Tarasoff-Conway, Jenna M.; Carare, Roxana O.; Osorio, Ricardo S.; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V.; Frangione, Blas; Blennow, Kaj; Ménard, Joël; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J.

    2015-01-01

    Accumulation of toxic protein aggregates—amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles—is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood–brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ. PMID:26195256

  11. Clearance systems in the brain-implications for Alzheimer disease.

    Science.gov (United States)

    Tarasoff-Conway, Jenna M; Carare, Roxana O; Osorio, Ricardo S; Glodzik, Lidia; Butler, Tracy; Fieremans, Els; Axel, Leon; Rusinek, Henry; Nicholson, Charles; Zlokovic, Berislav V; Frangione, Blas; Blennow, Kaj; Ménard, Joël; Zetterberg, Henrik; Wisniewski, Thomas; de Leon, Mony J

    2015-08-01

    Accumulation of toxic protein aggregates-amyloid-β (Aβ) plaques and hyperphosphorylated tau tangles-is the pathological hallmark of Alzheimer disease (AD). Aβ accumulation has been hypothesized to result from an imbalance between Aβ production and clearance; indeed, Aβ clearance seems to be impaired in both early and late forms of AD. To develop efficient strategies to slow down or halt AD, it is critical to understand how Aβ is cleared from the brain. Extracellular Aβ deposits can be removed from the brain by various clearance systems, most importantly, transport across the blood-brain barrier. Findings from the past few years suggest that astroglial-mediated interstitial fluid (ISF) bulk flow, known as the glymphatic system, might contribute to a larger portion of extracellular Aβ (eAβ) clearance than previously thought. The meningeal lymphatic vessels, discovered in 2015, might provide another clearance route. Because these clearance systems act together to drive eAβ from the brain, any alteration to their function could contribute to AD. An understanding of Aβ clearance might provide strategies to reduce excess Aβ deposits and delay, or even prevent, disease onset. In this Review, we describe the clearance systems of the brain as they relate to proteins implicated in AD pathology, with the main focus on Aβ.

  12. Insulin-Like Growth Factor (IGF System in Liver Diseases

    Directory of Open Access Journals (Sweden)

    Agnieszka Adamek

    2018-04-01

    Full Text Available Hepatocyte differentiation, proliferation, and apoptosis are affected by growth factors produced in liver. Insulin-like growth factor 1 and 2 (IGF1 and IGF2 act in response to growth hormone (GH. Other IGF family components include at least six binding proteins (IGFBP1 to 6, manifested by both IGFs develop due to interaction through the type 1 receptor (IGF1R. The data based on animal models and/or in vitro studies suggest the role of IGF system components in cellular aspects of hepatocarcinogenesis (cell cycle progression, uncontrolled proliferation, cell survival, migration, inhibition of apoptosis, protein synthesis and cell growth, and show that systemic IGF1 administration can reduce fibrosis and ameliorate general liver function. In epidemiologic and clinicopathological studies on chronic liver disease (CLD, lowered serum levels, decreased tissue expression of IGF1, elevated production of IGF1R and variable IGF2 expression has been noted, from the start of preneoplastic alterations up to the developed hepatocellular carcinoma (HCC stage. These changes result in well-known clinical symptoms of IGF1 deficiency. This review summarized the current data of the complex role of IGF system components in the most common CLD (nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma. Better recognition and understanding of this system can contribute to discovery of new and improved versions of current preventive and therapeutic actions in CLD.

  13. The development of neural stimulators: a review of preclinical safety and efficacy studies.

    Science.gov (United States)

    Shepherd, Robert K; Villalobos, Joel; Burns, Owen; Nayagam, David

    2018-05-14

    Given the rapid expansion of the field of neural stimulation and the rigorous regulatory approval requirements required before these devices can be applied clinically, it is important that there is clarity around conducting preclinical safety and efficacy studies required for the development of this technology. The present review examines basic design principles associated with the development of a safe neural stimulator and describes the suite of preclinical safety studies that need to be considered when taking a device to clinical trial. Neural stimulators are active implantable devices that provide therapeutic intervention, sensory feedback or improved motor control via electrical stimulation of neural or neuro-muscular tissue in response to trauma or disease. Because of their complexity, regulatory bodies classify these devices in the highest risk category (Class III), and they are therefore required to go through a rigorous regulatory approval process before progressing to market. The successful development of these devices is achieved through close collaboration across disciplines including engineers, scientists and a surgical/clinical team, and the adherence to clear design principles. Preclinical studies form one of several key components in the development pathway from concept to product release of neural stimulators. Importantly, these studies provide iterative feedback in order to optimise the final design of the device. Key components of any preclinical evaluation include: in vitro studies that are focussed on device reliability and include accelerated testing under highly controlled environments; in vivo studies using animal models of the disease or injury in order to assess safety and, given an appropriate animal model, the efficacy of the technology under both passive and electrically active conditions; and human cadaver and ex vivo studies designed to ensure the device's form factor conforms to human anatomy, to optimise the surgical approach and to

  14. Endodontic medicine: connections between apical periodontitis and systemic diseases.

    Science.gov (United States)

    Segura-Egea, J J; Martín-González, J; Castellanos-Cosano, L

    2015-10-01

    The prevalence of apical periodontitis (AP) in Europe has been reported to affect 61% of individuals and 14% of teeth, and increase with age. Likewise, the prevalence of root canal treatment (RCT) in Europe is estimated to be around 30-50% of individuals and 2-9% of teeth with radiographic evidence of chronic persistent AP in 30-65% of root filled teeth (RFT). AP is not only a local phenomenon and for some time the medical and dental scientific community have analysed the possible connection between apical periodontits and systemic health. Endodontic medicine has developed, with increasing numbers of reports describing the association between periapical inflammation and systemic diseases. The results of studies carried out both in animal models and humans are not conclusive, but suggest an association between endodontic variables, that is AP and RCT, and diabetes mellitus (DM), tobacco smoking, coronary heart disease and other systemic diseases. Several studies have reported a higher prevalence of periapical lesions, delayed periapical repair, greater size of osteolityc lesions, greater likelihood of asymptomatic infections and poorer prognosis for RFT in diabetic patients. On the other hand, recent studies have found that a poorer periapical status correlates with higher HbA1c levels and poor glycaemic control in type 2 diabetic patients. However, there is no scientific evidence supporting a causal effect of periapical inflammation on diabetes metabolic control. The possible association between smoking habits and endodontic infection has also been investigated, with controversial results. The aim of this paper was to review the literature on the association between endodontic variables and systemic health (especially DM and smoking habits). © 2015 International Endodontic Journal. Published by John Wiley & Sons Ltd.

  15. Novel systems biology insights using antifibrotic approaches for diabetic kidney disease

    KAUST Repository

    RamachandraRao, Satish Posettihalli; Talwar, Priti; Ravasi, Timothy; Sharma, Kumar

    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.

  16. 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

  17. New classification system-based visual outcome in Eales′ disease

    Directory of Open Access Journals (Sweden)

    Saxena Sandeep

    2007-01-01

    Full Text Available Purpose: A retrospective tertiary care center-based study was undertaken to evaluate the visual outcome in Eales′ disease, based on a new classification system, for the first time. Materials and Methods: One hundred and fifty-nine consecutive cases of Eales′ disease were included. All the eyes were staged according to the new classification: Stage 1: periphlebitis of small (1a and large (1b caliber vessels with superficial retinal hemorrhages; Stage 2a: capillary non-perfusion, 2b: neovascularization elsewhere/of the disc; Stage 3a: fibrovascular proliferation, 3b: vitreous hemorrhage; Stage 4a: traction/combined rhegmatogenous retinal detachment and 4b: rubeosis iridis, neovascular glaucoma, complicated cataract and optic atrophy. Visual acuity was graded as: Grade I 20/20 or better; Grade II 20/30 to 20/40; Grade III 20/60 to 20/120 and Grade IV 20/200 or worse. All the cases were managed by medical therapy, photocoagulation and/or vitreoretinal surgery. Visual acuity was converted into decimal scale, denoting 20/20=1 and 20/800=0.01. Paired t-test / Wilcoxon signed-rank tests were used for statistical analysis. Results: Vitreous hemorrhage was the commonest presenting feature (49.32%. Cases with Stages 1 to 3 and 4a and 4b achieved final visual acuity ranging from 20/15 to 20/40; 20/80 to 20/400 and 20/200 to 20/400, respectively. Statistically significant improvement in visual acuities was observed in all the stages of the disease except Stages 1a and 4b. Conclusion: Significant improvement in visual acuities was observed in the majority of stages of Eales′ disease following treatment. This study adds further to the little available evidences of treatment effects in literature and may have effect on patient care and health policy in Eales′ disease.

  18. The utility of information collected by occupational disease surveillance systems.

    Science.gov (United States)

    Money, A; Carder, M; Hussey, L; Agius, R M

    2015-11-01

    The Health and Occupation Research (THOR) network in the UK and the Republic of Ireland (ROI) is an integrated system of surveillance schemes collecting work-related ill-health (WRIH) data since 1989. In addition to providing information about disease incidence, trends in incidence and the identification of new hazards, THOR also operates an ad hoc data enquiry service enabling interested parties to request information about cases of WRIH reported to THOR. To examine requests for information made to a network of surveillance schemes for WRIH in the UK. Analysis via SPSS of data requests received by THOR between 2002 and 2014. A total of 631 requests were received by THOR between 2002 and 2014. Requests were predominantly submitted by participating THOR physicians (34%) and the main THOR funder-the UK Health & Safety Executive (HSE) (31%). The majority (67%) of requests were for information about work-related respiratory or skin disease with relatively few requests for other diagnoses, such as musculoskeletal or mental ill-health. Requests frequently related to a specific industry and/or occupation (42%) and/or a specific causal agent (58%). Data collected by occupational disease surveillance systems such as THOR are an extremely useful source of information, the use of which extends beyond informing government on disease incidence and trends in incidence. The data collected provide a framework that can assist a wide range of enquirers with clinical diagnoses, identification of suspected causative agents/exposures and to highlight growing risks in particular industrial and occupational sectors. © The Author 2015. Published by Oxford University Press on behalf of the Society of Occupational Medicine. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  19. 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.

  20. Activity of the hypoxia-activated prodrug, TH-302, in preclinical human acute myeloid leukemia models.

    Science.gov (United States)

    Portwood, Scott; Lal, Deepika; Hsu, Yung-Chun; Vargas, Rodrigo; Johnson, Megan K; Wetzler, Meir; Hart, Charles P; Wang, Eunice S

    2013-12-01

    Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm. Recent evidence has shown the bone marrow microenvironment in patients with AML to be intrinsically hypoxic. Adaptive cellular responses by leukemia cells to survive under low oxygenation also confer chemoresistance. We therefore asked whether therapeutic exploitation of marrow hypoxia via the hypoxia-activated nitrogen mustard prodrug, TH-302, could effectively inhibit AML growth. We assessed the effects of hypoxia and TH-302 on human AML cells, primary samples, and systemic xenograft models. We observed that human AML cells and primary AML colonies cultured under chronic hypoxia (1% O2, 72 hours) exhibited reduced sensitivity to cytarabine-induced apoptosis as compared with normoxic controls. TH-302 treatment resulted in dose- and hypoxia-dependent apoptosis and cell death in diverse AML cells. TH-302 preferentially decreased proliferation, reduced HIF-1α expression, induced cell-cycle arrest, and enhanced double-stranded DNA breaks in hypoxic AML cells. Hypoxia-induced reactive oxygen species by AML cells were also diminished. In systemic human AML xenografts (HEL, HL60), TH-302 [50 mg/kg intraperitoneally (i.p.) 5 times per week] inhibited disease progression and prolonged overall survival. TH-302 treatment reduced the number of hypoxic cells within leukemic bone marrows and was not associated with hematologic toxicities in nonleukemic or leukemic mice. Later initiation of TH-302 treatment in advanced AML disease was as effective as earlier TH-302 treatment in xenograft models. Our results establish the preclinical activity of TH-302 in AML and provide the rationale for further clinical studies of this and other hypoxia-activated agents for leukemia therapy. ©2013 AACR.

  1. A HUMANIZED CLINICALLY CALIBRATED QUANTITATIVE SYSTEMS PHARMACOLOGY MODEL FOR HYPOKINETIC MOTOR SYMPTOMS IN PARKINSON’S DISEASE

    Directory of Open Access Journals (Sweden)

    Hugo eGeerts

    2016-02-01

    Full Text Available The current treatment of Parkinson’s disease with dopamine-centric approaches such as L-DOPA and dopamine agonists, although very succesfull, is in need of alternative treatment strategies, both in terms of disease modification and symptom management. Various non-dopaminergic treatment approaches did not result in a clear clinical benefit, despite showing a clear effect in preclinical animal models. In addition, polypharmacy is common, sometimes leading to unintended effects on non-motor symptoms such as in cognitive and psychiatric domains. To explore novel targets for symptomatic treatment and possible synergistic pharmacodynamic effects between different drugs, we developed a Quantitative Systems Pharmacology (QSP platform of the closed cortico-striatal-thalamic-cortical basal ganglia loop of the dorsal motor circuit. This mechanism-based simulation platform is based on the known neuro-anatomy and neurophysiology of the basal ganglia and explicitly incorporates domain expertise in a formalized way. The calculated beta/gamma power ratio of the local field potential in the subthalamic nucleus correlates well (R2=0.71 with clinically observed extra-pyramidal symptoms triggered by antipsychotics during schizophrenia treatment (43 drug-dose combinations. When incorporating Parkinsonian (PD pathology and reported compensatory changes, the computer model suggests a major increase in b/g ratio (corresponding to bradykinesia and rigidity from a dopamine depletion of 70% onwards. The correlation between the outcome of the QSP model and the reported changes in UPDRS III Motor Part for 22 placebo-normalized drug-dose combinations is R2=0.84. The model also correctly recapitulates the lack of clinical benefit for perampanel, MK-0567 and flupirtine and offers a hypothesis for the translational disconnect. Finally, using human PET imaging studies with placebo response, the computer model predicts well the placebo response for chronic treatment, but not

  2. Systems Biology of Meridians, Acupoints, and Chinese Herbs in Disease

    Directory of Open Access Journals (Sweden)

    Li-Ling Lin

    2012-01-01

    Full Text Available Meridians, acupoints, and Chinese herbs are important components of traditional Chinese medicine (TCM. They have been used for disease treatment and prevention and as alternative and complementary therapies. Systems biology integrates omics data, such as transcriptional, proteomic, and metabolomics data, in order to obtain a more global and complete picture of biological activity. To further understand the existence and functions of the three components above, we reviewed relevant research in the systems biology literature and found many recent studies that indicate the value of acupuncture and Chinese herbs. Acupuncture is useful in pain moderation and relieves various symptoms arising from acute spinal cord injury and acute ischemic stroke. Moreover, Chinese herbal extracts have been linked to wound repair, the alleviation of postmenopausal osteoporosis severity, and anti-tumor effects, among others. Different acupoints, variations in treatment duration, and herbal extracts can be used to alleviate various symptoms and conditions and to regulate biological pathways by altering gene and protein expression. Our paper demonstrates how systems biology has helped to establish a platform for investigating the efficacy of TCM in treating different diseases and improving treatment strategies.

  3. Canine visceral leishmaniasis as a systemic fibrotic disease

    Science.gov (United States)

    Silva, Lucelia C; Castro, Rodrigo S; Figueiredo, Maria M; Michalick, Marilene S M; Tafuri, Washington L; Tafuri, Wagner L

    2013-01-01

    We propose that canine visceral leishmaniasis (CVL) is a systemic fibrotic disease, as evidenced by the wide distribution of fibrosis that we have found in the dogs suffering from chronic condition. The inflammatory cells apparently direct fibrosis formation. Twenty-four cases (symptomatic dogs) were identified from a total of one hundred and five cases that had been naturally infected with Leishmania chagasi and had been documented during an epidemiological survey of CVL carried out by the metropolitan area of the municipality of Belo Horizonte, MG, Brazil. The histological criterion was intralobular liver fibrosis, as has been described previously in dogs with visceral leishmaniasis. In addition to the findings in the liver, here we describe and quantify conspicuous and systemic deposition of collagen in other organs, including spleen, cervical lymph nodes, lung and kidney of all the infected symptomatic dogs. Thus we report that there is a systematic fibrotic picture in these animals, where inflammatory cells appear to direct fibrosis in all organs that have been studied. Therefore we propose that CVL is a systemic fibrotic disease. PMID:23419132

  4. [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.

  5. 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

  6. Management system of occupational diseases in Korea: statistics, report and monitoring system.

    Science.gov (United States)

    Rhee, Kyung Yong; Choe, Seong Weon

    2010-12-01

    The management system of occupational diseases in Korea can be assessed from the perspective of a surveillance system. Workers' compensation insurance reports are used to produce official statistics on occupational diseases in Korea. National working conditions surveys are used to monitor the magnitude of work-related symptoms and signs in the labor force. A health examination program was introduced to detect occupational diseases through both selective and mass screening programs. The Working Environment Measurement Institution assesses workers' exposure to hazards in the workplace. Government regulates that the employer should do health examinations and working conditions measurement through contracted private agencies and following the Occupational Safety and Health Act. It is hoped that these institutions may be able to effectively detect and monitor occupational diseases and hazards in the workplace. In view of this, the occupational management system in Korea is well designed, except for the national survey system. In the future, national surveys for detection of hazards and ill-health outcomes in workers should be developed. The existing surveillance system for occupational disease can be improved by providing more refined information through statistical analysis of surveillance data.

  7. 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.

  8. 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.

  9. 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.

  10. Quantitative Systems Pharmacology: A Case for Disease Models.

    Science.gov (United States)

    Musante, C J; Ramanujan, S; Schmidt, B J; Ghobrial, O G; Lu, J; Heatherington, A C

    2017-01-01

    Quantitative systems pharmacology (QSP) has emerged as an innovative approach in model-informed drug discovery and development, supporting program decisions from exploratory research through late-stage clinical trials. In this commentary, we discuss the unique value of disease-scale "platform" QSP models that are amenable to reuse and repurposing to support diverse clinical decisions in ways distinct from other pharmacometrics strategies. © 2016 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of The American Society for Clinical Pharmacology and Therapeutics.

  11. 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.

  12. 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

  13. 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)

  14. Tomography patterns of lung disease in systemic sclerosis

    International Nuclear Information System (INIS)

    Bastos, Andrea de Lima; Correa, Ricardo de Amorim; Ferreira, Gilda Aparecida

    2016-01-01

    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)

  15. 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.

  16. 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.

  17. [Preclinical horizon of depression in adults].

    Science.gov (United States)

    Jiménez-Báez, María Valeria; Márquez-González, Horacio; Monsreal-Góngora, Juan Leonardo; Góngora-González, Gonzalo; Sandoval-Jurado, Luis; Boquer-Hernández, Rubén

    2016-01-01

    Identify factors related to preclinical depression in healthy adults, their risk factors and concordance with family doctor diagnostic. Case-control study in adult from family medicine consulting room. Beck inventory for depression was applied. The correlation between depression and the diagnosis by the family physician was evaluated. Odds ratio (OR) was determined. Involved 138 patients randomly from four family medicine units (FMU) in the Northern Region of Quintana Roo, Mexico. The mean age 34.9 ± 11.4 years, 55.8% women, prevalence for depression was 26.1%. Being male OR: 3.76; 95% CI: 1.69-8.36, under 30 years OR: 2.76; 95% CI: 1.27-5.99, low socioeconomic status (SES) OR: 2.11; 95% CI: 0.97-4.59 and be married OR: 3.22; 95% CI: 1.41.-7.36 had depression risk. Diagnosis by the family physician and inventory Beck. Kappa Index 0.2, 95% CI: -0057-0176; p = 0.05. Almost a third of young adults have some depression degree in family medicine consulting room, it is necessary a depression screening for male patients, low SES, married, and under 30 years old, attending medical consultation familiar, for a early diagnosis and improve prognosis.

  18. Time management for preclinical safety professionals.

    Science.gov (United States)

    Wells, Monique Y

    2010-08-01

    A survey about time management in the workplace was distributed to obtain a sense of the level of job satisfaction among preclinical safety professionals in the current economic climate, and to encourage reflection upon how we manage time in our work environment. Roughly equal numbers of respondents (approximately 32%) identified themselves as management or staff, and approximately 27% indicated that they are consultants. Though 45.2% of respondents indicated that time management is very challenging for the profession in general, only 36.7% find it very challenging for themselves. Ten percent of respondents view time management to be exceedingly challenging for themselves. Approximately 34% of respondents indicated that prioritization of tasks was the most challenging aspect of time management for them. Focusing on an individual task was the second most challenging aspect (26%), followed equally by procrastination and delegation of tasks (12.4%). Almost equal numbers of respondents said that they would (35.2%) or might (33.3%) undertake training to improve their time management skills. Almost equal numbers of participants responded "perhaps" (44.6%) or "yes" (44.2%) to the question of whether management personnel should be trained in time management.

  19. Preclinical animal anxiety research - flaws and prejudices.

    Science.gov (United States)

    Ennaceur, Abdelkader; Chazot, Paul L

    2016-04-01

    The current tests of anxiety in mice and rats used in preclinical research include the elevated plus-maze (EPM) or zero-maze (EZM), the light/dark box (LDB), and the open-field (OF). They are currently very popular, and despite their poor achievements, they continue to exert considerable constraints on the development of novel approaches. Hence, a novel anxiety test needs to be compared with these traditional tests, and assessed against various factors that were identified as a source of their inconsistent and contradictory results. These constraints are very costly, and they are in most cases useless as they originate from flawed methodologies. In the present report, we argue that the EPM or EZM, LDB, and OF do not provide unequivocal measures of anxiety; that there is no evidence of motivation conflict involved in these tests. They can be considered at best, tests of natural preference for unlit and/or enclosed spaces. We also argued that pharmacological validation of a behavioral test is an inappropriate approach; it stems from the confusion of animal models of human behavior with animal models of pathophysiology. A behavioral test is developed to detect not to produce symptoms, and a drug is used to validate an identified physiological target. In order to overcome the major methodological flaws in animal anxiety studies, we proposed an open space anxiety test, a 3D maze, which is described here with highlights of its various advantages over to the traditional tests.

  20. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

    Science.gov (United States)

    Voorhees, Jaymie R.; Rohlman, Diane S.; Lein, Pamela J.; Pieper, Andrew A.

    2017-01-01

    Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally. PMID:28149268

  1. Soil microbiome characteristics and soilborne disease development associated with long-term potato cropping system practices

    Science.gov (United States)

    Potato cropping system practices substantially affect soil microbial communities and the development of soilborne diseases. Cropping systems incorporating soil health management practices, such as longer rotations, disease-suppressive crops, reduced tillage, and/or organic amendments can potentially...

  2. Surveillance of systemic autoimmune rheumatic diseases using administrative data.

    Science.gov (United States)

    Bernatsky, S; Lix, L; Hanly, J G; Hudson, M; Badley, E; Peschken, C; Pineau, C A; Clarke, A E; Fortin, P R; Smith, M; Bélisle, P; Lagace, C; Bergeron, L; Joseph, L

    2011-04-01

    There is growing interest in developing tools and methods for the surveillance of chronic rheumatic diseases, using existing resources such as administrative health databases. To illustrate how this might work, we used population-based administrative data to estimate and compare the prevalence of systemic autoimmune rheumatic diseases (SARDs) across three Canadian provinces, assessing for regional differences and the effects of demographic factors. Cases of SARDs (systemic lupus erythematosus, scleroderma, primary Sjogren's, polymyositis/dermatomyositis) were ascertained from provincial physician billing and hospitalization data. We combined information from three case definitions, using hierarchical Bayesian latent class regression models that account for the imperfect nature of each case definition. Using methods that account for the imperfect nature of both billing and hospitalization databases, we estimated the over-all prevalence of SARDs to be approximately 2-3 cases per 1,000 residents. Stratified prevalence estimates suggested similar demographic trends across provinces (i.e. greater prevalence in females-versus-males, and in persons of older age). The prevalence in older females approached or exceeded 1 in 100, which may reflect the high burden of primary Sjogren's syndrome in this group. Adjusting for demographics, there was a greater prevalence in urban-versus-rural settings. In our work, prevalence estimates had good face validity and provided useful information about potential regional and demographic variations. Our results suggest that surveillance of some rheumatic diseases using administrative data may indeed be feasible. Our work highlights the usefulness of using multiple data sources, adjusting for the error in each.

  3. 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.

  4. 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.

  5. 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.

  6. Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments.

    Directory of Open Access Journals (Sweden)

    Valerie C Henderson

    Full Text Available The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external or programmatic research activity they primarily address.We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria--most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation.By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary.

  7. Threats to validity in the design and conduct of preclinical efficacy studies: a systematic review of guidelines for in vivo animal experiments.

    Science.gov (United States)

    Henderson, Valerie C; Kimmelman, Jonathan; Fergusson, Dean; Grimshaw, Jeremy M; Hackam, Dan G

    2013-01-01

    The vast majority of medical interventions introduced into clinical development prove unsafe or ineffective. One prominent explanation for the dismal success rate is flawed preclinical research. We conducted a systematic review of preclinical research guidelines and organized recommendations according to the type of validity threat (internal, construct, or external) or programmatic research activity they primarily address. We searched MEDLINE, Google Scholar, Google, and the EQUATOR Network website for all preclinical guideline documents published up to April 9, 2013 that addressed the design and conduct of in vivo animal experiments aimed at supporting clinical translation. To be eligible, documents had to provide guidance on the design or execution of preclinical animal experiments and represent the aggregated consensus of four or more investigators. Data from included guidelines were independently extracted by two individuals for discrete recommendations on the design and implementation of preclinical efficacy studies. These recommendations were then organized according to the type of validity threat they addressed. A total of 2,029 citations were identified through our search strategy. From these, we identified 26 guidelines that met our eligibility criteria--most of which were directed at neurological or cerebrovascular drug development. Together, these guidelines offered 55 different recommendations. Some of the most common recommendations included performance of a power calculation to determine sample size, randomized treatment allocation, and characterization of disease phenotype in the animal model prior to experimentation. By identifying the most recurrent recommendations among preclinical guidelines, we provide a starting point for developing preclinical guidelines in other disease domains. We also provide a basis for the study and evaluation of preclinical research practice. Please see later in the article for the Editors' Summary.

  8. S1P prophylaxis mitigates acute hypobaric hypoxia-induced molecular, biochemical, and metabolic disturbances: A preclinical report.

    Science.gov (United States)

    Chawla, Sonam; Rahar, Babita; Saxena, Shweta

    2016-05-01

    Sphingosine-1-phosphate (S1P) is emerging to have hypoxic preconditioning potential in various preclinical studies. The study aims to evaluate the preclinical preconditioning efficacy of exogenously administered S1P against acute hypobaric hypoxia (HH)-induced pathological disturbances. Male Sprague Dawley rats (200 ± 20 g) were preconditioned with 1, 10, and 100 μg/kg body weight (b.w.) S1P (i.v.) for three consecutive days. On the third day, S1P preconditioned animals, along with hypoxia control animals, were exposed to HH equivalent to 7,620 m (280 mm Hg) for 6 h. Postexposure status of cardiac energy production, circulatory vasoactive mediators, pulmonary and cerebral oxidative damage, and inflammation were assessed. HH exposure led to cardiac energy deficit indicated by low ATP levels and pronounced AMPK activation levels, raised circulatory levels of brain natriuretic peptide and endothelin-1 with respect to total nitrate (NOx), redox imbalance, inflammation, and alterations in NOx levels in the pulmonary and cerebral tissues. These pathological precursors have been routinely reported to be coincident with high-altitude diseases. Preconditioning with S1P, especially 1 µg/kg b.w. dose, was seen to reverse the manifestation of these pathological disturbances. The protective efficacy could be attributed, at least in part, to enhanced activity of cardioprotective protein kinase C and activation of small GTPase Rac1, which led to further induction of hypoxia-adaptive molecular mediators: hypoxia-inducible factor (HIF)-1α and Hsp70. This is a first such report, to the best of our knowledge, elucidating the mechanism of exogenous S1P-mediated HIF-1α/Hsp70 induction. Conclusively, systemic preconditioning with 1 μg/kg b.w. S1P in rats protects against acute HH-induced pathological disturbances. © 2016 IUBMB Life 68(5):365-375, 2016. © 2016 International Union of Biochemistry and Molecular Biology.

  9. 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.

  10. 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.

  11. Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study.

    Directory of Open Access Journals (Sweden)

    Maha M Eissa

    Full Text Available Miltefosine (MFS is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD. This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%, good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs

  12. AVN-492, A Novel Highly Selective 5-HT6R Antagonist: Preclinical Evaluation.

    Science.gov (United States)

    Ivachtchenko, Alexandre V; Okun, Ilya; Aladinskiy, Vladimir; Ivanenkov, Yan; Koryakova, Angela; Karapetyan, Ruben; Mitkin, Oleg; Salimov, Ramiz; Ivashchenko, Andrey

    2017-01-01

    Discovery of 5-HT6 receptor subtype and its exclusive localization within the central nervous system led to extensive investigations of its role in Alzheimer's disease, schizophrenia, and obesity. In the present study, we present preclinical evaluation of a novel highly-potent and highly-selective 5-HT6R antagonist, AVN-492. The affinity of AVN-492 to bind to 5-HT6R (Ki = 91 pM) was more than three orders of magnitude higher than that to bind to the only other target, 5-HT2BR, (Ki = 170 nM). Thus, the compound displayed great 5-HT6R selectivity against all other serotonin receptor subtypes, and is extremely specific against any other receptors such as adrenergic, GABAergic, dopaminergic, histaminergic, etc. AVN-492 demonstrates good in vitro and in vivo ADME profile with high oral bioavailability and good brain permeability in rodents. In behavioral tests, AVN-492 shows anxiolytic effect in elevated plus-maze model, prevents an apomorphine-induced disruption of startle pre-pulse inhibition (the PPI model) and reverses a scopolamine- and MK-801-induced memory deficit in passive avoidance model. No anti-obesity effect of AVN-492 was found in a murine model. The data presented here strongly indicate that due to its high oral bioavailability, extremely high selectivity, and potency to block the 5-HT6 receptor, AVN-492 is a very promising tool for evaluating the role the 5-HT6 receptor might play in cognitive and neurodegenerative impairments. AVN-492 is an excellent drug candidate to be tested for treatment of such diseases, and is currently being tested in Phase I trials.

  13. Preclinical efficacy and safety of herbal formulation for management ...

    African Journals Online (AJOL)

    Preclinical efficacy and safety of herbal formulation for management of wounds. ... The effects of the treatments on rate of wound closure, epithelialisation time ... inflammation and better tissue remodeling for rats treated with herbal product.

  14. 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.)

  15. Nitric oxide nanoparticles: Pre-clinical utility as a therapeutic for intramuscular abscesses

    OpenAIRE

    Schairer, David O.; Martinez, Luis R.; Blecher, Karin; Chouake, Jason S.; Nacharaju, Parimala; Gialanella, Philip; Friedman, Joel M.; Nosanchuk, Joshua D.; Friedman, Adam J.

    2012-01-01

    Nitric oxide (NO) is a critical component of host defense against invading pathogens; however, its therapeutic utility is limited due to a lack of practical delivery systems. Recently, a NO-releasing nanoparticulate platform (NO-np) was shown to have in vitro broad-spectrum antimicrobial activity and in vivo pre-clinical efficacy in a dermal abscess model. To extend these findings, both topical (TP) and intralesional (IL) NO-np administration was evaluated in a MRSA intramuscular murine absce...

  16. At the Crossroads of Clinical and Preclinical Research for Muscular Dystrophy-Are We Closer to Effective Treatment for Patients?

    Science.gov (United States)

    Gawlik, Kinga I

    2018-05-16

    Among diseases affecting skeletal muscle, muscular dystrophy is one of the most devastating and complex disorders. The term 'muscular dystrophy' refers to a heterogeneous group of genetic diseases associated with a primary muscle defect that leads to progressive muscle wasting and consequent loss of muscle function. Muscular dystrophies are accompanied by numerous clinical complications and abnormalities in other tissues that cause extreme discomfort in everyday life. The fact that muscular dystrophy often takes its toll on babies and small children, and that many patients die at a young age, adds to the cruel character of the disease. Clinicians all over the world are facing the same problem: they have no therapy to offer except for symptom-relieving interventions. Patients, their families, but also clinicians, are in urgent need of an effective cure. Despite advances in genetics, increased understanding of molecular mechanisms underlying muscle disease, despite a sweeping range of successful preclinical strategies and relative progress of their implementation in the clinic, therapy for patients is currently out of reach. Only a greater comprehension of disease mechanisms, new preclinical studies, development of novel technologies, and tight collaboration between scientists and physicians can help improve clinical treatment. Fortunately, inventiveness in research is rapidly extending the limits and setting new standards for treatment design. This review provides a synopsis of muscular dystrophy and considers the steps of preclinical and clinical research that are taking the muscular dystrophy community towards the fundamental goal of combating the traumatic disease.

  17. 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.

  18. Rigor or mortis: best practices for preclinical research in neuroscience.

    Science.gov (United States)

    Steward, Oswald; Balice-Gordon, Rita

    2014-11-05

    Numerous recent reports document a lack of reproducibility of preclinical studies, raising concerns about potential lack of rigor. Examples of lack of rigor have been extensively documented and proposals for practices to improve rigor are appearing. Here, we discuss some of the details and implications of previously proposed best practices and consider some new ones, focusing on preclinical studies relevant to human neurological and psychiatric disorders. Copyright © 2014 Elsevier Inc. All rights reserved.

  19. Systemic inflammation is higher in peripheral artery disease than in stable coronary artery disease.

    Science.gov (United States)

    Rein, Philipp; Saely, Christoph H; Silbernagel, Günther; Vonbank, Alexander; Mathies, Rainer; Drexel, Heinz; Baumgartner, Iris

    2015-04-01

    The knowledge on the level of systemic inflammation in peripheral artery disease (PAD) is less well established than that in coronary artery disease (CAD). Systemic inflammation frequently coincides with atherosclerosis, but also with various traits of the metabolic syndrome (MetS). The individual contribution of CAD, PAD, and the MetS to inflammation is not known. We enrolled a total of 1396 patients, 460 patients with PAD Fontaine stages IIa-IV verified by duplex ultrasound (PAD group) and 936 patients free of limb claudication undergoing coronary angiography, of whom 507 had significant CAD with coronary stenoses ≥50% (CAD group), and 429 did not have significant CAD at angiography (control group). C-reactive protein (CRP) was significantly higher in the PAD than in the CAD or in the control group (0.86 ± 1.85 mg/dl versus 0.44 ± 0.87 mg/dl and 0.39 ± 0.52 mg/dl, respectively, p < 0.001 for both comparisons). These significant differences were confirmed when patients with and subjects without the MetS were analyzed separately. In particular, within the PAD group, CRP was significantly higher in patients with the MetS than in subjects without the MetS (1.04 ± 2.01 vs. 0.67 ± 1.64 mg/dl; p = 0.001) and both, the presence of PAD and the MetS proved to be independently associated with CRP in analysis of covariance (F = 31.84; p < 0.001 and F = 10.52; p = 0.001, respectively). Inflammatory activity in PAD patients is higher than in CAD patients and is particularly high in PAD patients affected by the MetS. Low grade systemic inflammation is independently associated with both the MetS and PAD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  20. High prevalence of systemic autoimmune diseases in patients with Menière's disease.

    Directory of Open Access Journals (Sweden)

    Irene Gazquez

    Full Text Available BACKGROUND: Autoimmunity appears to be associated with the pathophysiology of Meniere's disease (MD, an inner ear disorder characterized by episodes of vertigo associated with hearing loss and tinnitus. However, the prevalence of autoimmune diseases (AD in patients with MD has not been studied in individuals with uni or bilateral sensorineural hearing loss (SNHL. METHODS AND FINDINGS: We estimated the prevalence of AD in 690 outpatients with MD with uni or bilateral SNHL from otoneurology clinics at six tertiary referral hospitals by using clinica criteria and an immune panel (lymphocyte populations, antinuclear antibodies, C3, C4 and proinflammatory cytokines TNFα, INFγ. The observed prevalence of rheumatoid arthritis (RA, systemic lupus erythematosus (SLE and ankylosing spondylitis (AS was higher than expected for the general population (1.39 for RA, 0.87 for SLE and 0.70 for AS, respectively. Systemic AD were more frequently observed in patients with MD and diagnostic criteria for migraine than cases with MD and tension-type headache (p = 0.007. There were clinical differences between patients with uni or bilateral SNHL, but no differences were found in the immune profile. Multiple linear regression showed that changes in lymphocytes subpopulations were associated with hearing loss and persistence of vertigo, suggesting a role for the immune response in MD. CONCLUSIONS: Despite some limitations, MD displays an elevated prevalence of systemic AD such as RA, SLE and AS. This finding, which suggests an autoimmune background in a subset of patients with MD, has important implications for the treatment of MD.

  1. Preclinical Polymodal Hallucinations for 13 Years before Dementia with Lewy Bodies

    Directory of Open Access Journals (Sweden)

    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.

  2. 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

  3. The preclinical discovery and development of quetiapine for the treatment of mania and depression.

    Science.gov (United States)

    Miranda, Aline Silva de; Moreira, Fabrício A; Teixeira, Antônio Lúcio

    2017-05-01

    Bipolar disorder is a chronic disabling condition characterized by alternating manic and depressive episodes. Bipolar disorder has been associated with functional impairment, poor quality of life, morbidity and mortality. Despite its significant clinical, social and economic burden, treatment options for bipolar disorder are still limited. Several clinical trials have shown efficacy of the atypical antipsychotic quetiapine (QTP) in the treatment of this condition. However, the mechanisms underlying the antidepressant and anti-manic effects of QTP remain poorly understood. Areas covered: The article provides the emerging evidence from pre-clinical studies regarding the antidepressant and anti-manic mechanisms of action of QTP. In combination with its primary active metabolite norquetiapine, QTP modulates several neurotransmitter systems, including serotonin, dopamine, noradrenaline and histamine. QTP also seems to influence mediators of the immune system. Expert opinion: Pre-clinical studies have provided valuable information on the potential antidepressant mechanisms of action of QTP, but pre-clinical studies on QTP's anti-manic effects are still scarce. A major problem refers to the lack of valid experimental models for bipolar disorder. Additionally, immune and genetic based studies are largely descriptive. The role of the QTP metabolite norquetiapine in modulating non-neurotransmitter systems also needs to be further addressed.

  4. 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.

  5. 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.

  6. Use of Preclinical Drug vs. Food Choice Procedures to Evaluate Candidate Medications for Cocaine Addiction.

    Science.gov (United States)

    Banks, Matthew L; Hutsell, Blake A; Schwienteck, Kathryn L; Negus, S Stevens

    2015-06-01

    Drug addiction is a disease that manifests as an inappropriate allocation of behavior towards the procurement and use of the abused substance and away from other behaviors that produce more adaptive reinforcers (e.g. exercise, work, family and social relationships). The goal of treating drug addiction is not only to decrease drug-maintained behaviors, but also to promote a reallocation of behavior towards alternative, nondrug reinforcers. Experimental procedures that offer concurrent access to both a drug reinforcer and an alternative, nondrug reinforcer provide a research tool for assessment of medication effects on drug choice and behavioral allocation. Choice procedures are currently the standard in human laboratory research on medications development. Preclinical choice procedures have been utilized in biomedical research since the early 1940's, and during the last 10-15 years, their use for evaluation of medications to treat drug addiction has increased. We propose here that parallel use of choice procedures in preclinical and clinical studies will facilitate translational research on development of medications to treat cocaine addiction. In support of this proposition, a review of the literature suggests strong concordance between preclinical effectiveness of candidate medications to modify cocaine choice in nonhuman primates and rodents and clinical effectiveness of these medications to modify either cocaine choice in human laboratory studies or metrics of cocaine abuse in patients with cocaine use disorder. The strongest evidence for medication effectiveness in preclinical choice studies has been obtained with maintenance on the monoamine releaser d -amphetamine, a candidate agonist medication for cocaine use analogous to use of methadone to treat heroin abuse or nicotine formulations to treat tobacco dependence.

  7. Modeling Parkinson's disease falls associated with brainstem cholinergic systems decline.

    Science.gov (United States)

    Kucinski, Aaron; Sarter, Martin

    2015-04-01

    In addition to the primary disease-defining symptoms, approximately half of patients with Parkinson's disease (PD) suffer from postural instability, impairments in gait control and a propensity for falls. Consistent with evidence from patients, we previously demonstrated that combined striatal dopamine (DA) and basal forebrain (BF) cholinergic cell loss causes falls in rats traversing dynamic surfaces. Because evidence suggests that degeneration of brainstem cholinergic neurons arising from the pedunculopontine nucleus (PPN) also contributes to impaired gait and falls, here we assessed the effects of selective cholinergic PPN lesions in combination with striatal DA loss or BF cholinergic cells loss as well as losses in all 3 regions. Results indicate that all combination losses that included the BF cholinergic system slowed traversal and increased slips and falls. However, the performance of rats with losses in all 3 regions (PPN, BF, and DA) was not more severely impaired than following combined BF cholinergic and striatal DA lesions. These results confirm the hypothesis that BF cholinergic-striatal disruption of attentional-motor interactions is a primary source of falls. Additional losses of PPN cholinergic neurons may worsen posture and gait control in situations not captured by the current testing conditions. (PsycINFO Database Record (c) 2015 APA, all rights reserved).

  8. Radionuclide imaging of bone marrow in hematologic systemic disease

    Energy Technology Data Exchange (ETDEWEB)

    Kessel, F.; Hahn, K.; Gamm, H.

    1987-02-01

    Radionuclide imaging studies of the bone marrow were carried out in 164 patients suffering from hematologic systemic disease. One third of 90 patients with Hodgkin lymphoma (HL) or Non Hodgkin lymphoma (NHL) displayed a pathological distribution pattern representing bone marrow expansion. In HL there were 17% accumulation defects caused by metastases in contrast to only 7% in NHL. Among 30 patients with chronic myelocytic leukemia bone marrow expansion was found in 60%, bone marrow displacement and aplasia 10%. Focal bone marrow defects were found in 3 patients. All patients with primary polycythemia rubra vera displayed a pathologic bone marrow distribution pattern as well as splenomegaly. All patients with acute myelocytic leukemia (AML) and one patient with an acute lymphatic leukemia (ALL) had a pathological distribution pattern with bone marrow expansion and displacement. Focal bone marrow defects were not seen. Multiple myeloma with bone marrow expansion was found in 6 of 12 patients and focal accumulation defects were found in 40%, the latter lesions being not visible or equivocal on skeletal imaging studies. Pathological changes in liver and spleen were found in a high percentage of the total collective. The results document the important clinical value of bone marrow scintigraphy among the hematologic diseases studied.

  9. Periodontal disease, periodontal treatment and systemic nitric oxide in dogs.

    Science.gov (United States)

    Nemec, A; Verstraete, F J M; Jerin, A; Šentjurc, M; Kass, P H; Petelin, M; Pavlica, Z

    2013-06-01

    Thirty-two client-owned dogs treated for periodontal disease were divided in group 1 if no periodontitis, group 2 if ≤25%, and group 3 if >25% of the teeth present were affected with periodontitis. Blood was tested before and 2 weeks after periodontal therapy for nitrosyl hemoglobin (HbNO), plasma nitrite/nitrate (NOx) and 3-nitrotyrosine (NT) levels. No HbNO was detected in any of the animals tested. There was no significant difference in the NOx plasma levels within each group or across the groups before and after the treatment, but a noticeable increase in NOx plasma levels was observed in group 3 after the treatment. Plasma NT was detected in only one third of the animals. NO levels varied greatly across individual dogs. The data are suggestive of an overall increase in systemic NO response 2 weeks after periodontal treatment in dogs with advanced periodontal disease, but the response is greatly individually-dependent. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Poverty, Disease, and the Ecology of Complex Systems

    Science.gov (United States)

    Pluciński, Mateusz M.; Murray, Megan B.; Farmer, Paul E.; Barrett, Christopher B.; Keenan, Donald C.

    2014-01-01

    Understanding why some human populations remain persistently poor remains a significant challenge for both the social and natural sciences. The extremely poor are generally reliant on their immediate natural resource base for subsistence and suffer high rates of mortality due to parasitic and infectious diseases. Economists have developed a range of models to explain persistent poverty, often characterized as poverty traps, but these rarely account for complex biophysical processes. In this Essay, we argue that by coupling insights from ecology and economics, we can begin to model and understand the complex dynamics that underlie the generation and maintenance of poverty traps, which can then be used to inform analyses and possible intervention policies. To illustrate the utility of this approach, we present a simple coupled model of infectious diseases and economic growth, where poverty traps emerge from nonlinear relationships determined by the number of pathogens in the system. These nonlinearities are comparable to those often incorporated into poverty trap models in the economics literature, but, importantly, here the mechanism is anchored in core ecological principles. Coupled models of this sort could be usefully developed in many economically important biophysical systems—such as agriculture, fisheries, nutrition, and land use change—to serve as foundations for deeper explorations of how fundamental ecological processes influence structural poverty and economic development. PMID:24690902

  11. Targeting Renin–Angiotensin System Against Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Abadi Kahsu Gebre

    2018-04-01

    Full Text Available Renin Angiotensin System (RAS is a hormonal system that regulates blood pressure and fluid balance through a coordinated action of renal, cardiovascular, and central nervous systems. In addition to its hemodynamic regulatory role, RAS involves in many brain activities, including memory acquisition and consolidation. This review has summarized the involvement of RAS in the pathology of Alzheimer’s disease (AD, and the outcomes of treatment with RAS inhibitors. We have discussed the effect of brain RAS in the amyloid plaque (Aβ deposition, oxidative stress, neuroinflammation, and vascular pathology which are directly and indirectly associated with AD. Angiotensin II (AngII via AT1 receptor is reported to increase brain Aβ level via different mechanisms including increasing amyloid precursor protein (APP mRNA, β-secretase activity, and presenilin expression. Similarly, it was associated with tau phosphorylation, and reactive oxygen species generation. However, these effects are counterbalanced by Ang II mediated AT2 signaling. The protective effect observed with angiotensin receptor blockers (ARBs and angiotensin converting enzyme inhibitors (ACEIs could be as the result of inhibition of Ang II signaling. ARBs also offer additional benefit by shifting the effect of Ang II toward AT2 receptor. To conclude, targeting RAS in the brain may benefit patients with AD though it still requires further in depth understanding.

  12. Association of periodontal disease with systemic health indices in dogs and the systemic response to treatment of periodontal disease.

    Science.gov (United States)

    Rawlinson, Jennifer E; Goldstein, Richard E; Reiter, Alexander M; Attwater, Daniel Z; Harvey, Colin E

    2011-03-01

    To determine whether severity of periodontal disease (PD) was associated with systemic health indices in dogs and whether treatment of PD altered systemic health indices. Prospective cohort study. 38 dogs. Healthy dogs with clinical signs of PD were included in the study. Physical examination, serum biochemical analysis, a CBC, urine evaluation, measurement of serum C-reactive protein (CRP) concentration, and a microalbuminuria test were performed prior to treatment of PD. All tooth roots were scored for gingivitis and attachment loss, and appropriate treatment of PD was performed. Laboratory data were obtained 4 weeks after treatment. The Spearman rank correlation and Wilcoxon signed rank test were used for statistical analysis. Analyses of the correlation of several variables with attachment loss or gingivitis or of differences before and after treatment revealed significant results for several variables. After applying Bonferroni corrections for family-wise error rate, significant rank correlations were found between attachment loss and platelet number (r = 0.54), creatinine concentration (r = -0.49), and the within-dog difference in CRP concentrations before and after treatment (r = 0.40). The BUN concentration was significantly higher after treatment than before treatment. Increasing severity of attachment loss was associated with changes in systemic inflammatory variables and renal indices. A decrease in CRP concentration after treatment was correlated with the severity of PD. The BUN concentration increased significantly after treatment of PD. There is a need for continued research into the systemic impact of PD.

  13. Parkinson disease: the enteric nervous system spills its guts.

    Science.gov (United States)

    Derkinderen, P; Rouaud, T; Lebouvier, T; Bruley des Varannes, S; Neunlist, M; De Giorgio, R

    2011-11-08

    Lewy pathology in Parkinson disease (PD) extends well beyond the CNS, also affecting peripheral autonomic neuronal circuits, especially the enteric nervous system (ENS). The ENS is an integrative neuronal network also referred to as "the brain in the gut" because of its similarities to the CNS. We have recently shown that the ENS can be readily analyzed using routine colonic biopsies. This led us to propose that the ENS could represent a unique window to assess the neuropathology in living patients with PD. In this perspective, we discuss current evidence which indicates that the presence of ENS pathology may by exploited to improve our understanding and management of PD and likely other neurodegenerative disorders.

  14. A System Dynamics Model for Planning Cardiovascular Disease Interventions

    Science.gov (United States)

    Homer, Jack; Evans, Elizabeth; Zielinski, Ann

    2010-01-01

    Planning programs for the prevention and treatment of cardiovascular disease (CVD) is a challenge to every community that wants to make the best use of its limited resources. Selecting programs that provide the greatest impact is difficult because of the complex set of causal pathways and delays that link risk factors to CVD. We describe a system dynamics simulation model developed for a county health department that incorporates and tracks the effects of those risk factors over time on both first-time and recurrent events. We also describe how the model was used to evaluate the potential impacts of various intervention strategies for reducing the county's CVD burden and present the results of those policy tests. PMID:20167899

  15. [The role of selenium in endocrine system diseases].

    Science.gov (United States)

    Balázs, Csaba; Rácz, Károly

    2013-10-13

    Oxygen derived free radicals, generated by a number of cellular reactions, include superoxide anion, hydrogen peroxide and hydroxyl radicals. They exert their cytotoxic effects mainly via peroxidation of the cell membrane resulting in the loss of membrane integrity. The essential trace element, selenium exerts complex effects on the endocrine systems, partly due to its antioxidant capacity. Well-characterized selenoproteins include iodothyronine deiodinases, glutathione peroxidases and thioredoxin reductases involved in thyroid hormone metabolism and protection from oxidative damage. The value of selenium supplementation in autoimmune thyroid disorders has been investigated and most studies confirmed the beneficial effect of selenium supplementation in Hashimoto's and Graves's diseases. Recently, selenium proved to be effective in mild inflammatory orbitopathy. There are a number of reports about the effect of selenium in diabetes mellitus, but the data are controversial as both insulin-like and diabetes-inducing effects of selenium have been described. Selenium was successfully used in both female and male infertility of autoimmune origin.

  16. Regenerative Therapies for Central Nervous System Diseases: a Biomaterials Approach

    Science.gov (United States)

    Tam, Roger Y; Fuehrmann, Tobias; Mitrousis, Nikolaos; Shoichet, Molly S

    2014-01-01

    The central nervous system (CNS) has a limited capacity to spontaneously regenerate following traumatic injury or disease, requiring innovative strategies to promote tissue and functional repair. Tissue regeneration strategies, such as cell and/or drug delivery, have demonstrated promising results in experimental animal models, but have been difficult to translate clinically. The efficacy of cell therapy, which involves stem cell transplantation into the CNS to replace damaged tissue, has been limited due to low cell survival and integration upon transplantation, while delivery of therapeutic molecules to the CNS using conventional methods, such as oral and intravenous administration, have been limited by diffusion across the blood–brain/spinal cord-barrier. The use of biomaterials to promote graft survival and integration as well as localized and sustained delivery of biologics to CNS injury sites is actively being pursued. This review will highlight recent advances using biomaterials as cell- and drug-delivery vehicles for CNS repair. PMID:24002187

  17. 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.

  18. Preclinical incorporation dosimetry of (+)-[18F) flubatine in piglets

    International Nuclear Information System (INIS)

    Sattler, B.; Patt, M.; Sabri, O.; Kranz, M.; Donat, C.K.; Deuther-Conrad, W.; Fischer, S.; Brust, P.; Sattler, T.; Smits, R.; Hoepping, A.; Steinbach, J.

    2015-01-01

    Full text of publication follows. Aim: (+)-[ 18 F] flubatine is the mirror image isomer of (-)-[ 18 F] flubatine, which is successfully used for neuroimaging of alpha4beta2 nAChRs with PET. To assess the radiation risk by this new radiotracer, biodistribution, organ doses (OD) and the effective dose (ED) were investigated in a preclinical trials using piglets. Method: whole body dosimetry of (+)-[ 18 F] flubatine was performed in 3 female piglets (age: 43 ± 1.2 days, weight: 14 ± 1.0 kg). The animals were narcotized using 20 mg/kg Ketamine, 2 mg/kg Azaperone; 1.5% Isoflurane in 70% N 2 O/30% O 2 and sequentially PET-imaged up to 5 hours post i.v. injection of 183.5 ± 9.0 MBq on a SIEMENS Biograph16 PET/CT-system on 7 bed positions (BP) per frame, 1.5 to 6 min/BP, CT-attenuation correction (AC) and iterative reconstruction. All relevant organs were defined by volumes of interest. Exponential curves were fitted to the time-activity-data (%ID/g, and %ID/organ). Time- and mass-scales were adapted to the human order of magnitude. The ODs were calculated using the adult male model with OLINDA. The ED was calculated using tissue weighting factors as published in the ICRP103. Results: The highest OD was received by the urinary bladder (71.7 ± 26.3 μSv/MBq), the kidneys (45.1 ± 6.5 μSv/MBq) and the brain (32.3 ± 3.24 μSv/MBq). The highest contribution to the ED was by the urinary bladder (2.9 ± 1.1 μSv/MBq), the lungs (1.7 ± 0.02 μSv/MBq) and the red marrow (1.4 ± 0.1μSv/MBq). According to this data, the ED to humans is 14.3 ± 0.3 μSv/MBq. Conclusion: considering 40% underestimation of the ED to humans by preclinical dosimetry [1] the expected ED to humans after 300 MBq i.v. is 7.2 mSv, which is about the ED by (-)-[ 18 F]flubatine (6.8 mSv/300 MBq) and well within the range of what other 18 F-labeled compounds cause to humans. This risk assessment encourages to transfer (+)-[F 18 ] flubatine from preclinical to clinical study phases and to further develop

  19. Bioluminescence Tomography–Guided Radiation Therapy for Preclinical Research

    Energy Technology Data Exchange (ETDEWEB)

    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 research, it is challenging to localize soft tissue targets based on cone beam computed tomography (CBCT) guidance. As a more effective method to localize soft tissue targets, we developed an online bioluminescence tomography (BLT) system for small-animal radiation research platform (SARRP). We demonstrated BLT-guided radiation therapy and validated targeting accuracy based on a newly developed reconstruction algorithm. Methods and Materials: The BLT system was designed to dock with the SARRP for image acquisition and to be detached before radiation delivery. A 3-mirror system was devised to reflect the bioluminescence emitted from the subject to a stationary charge-coupled device (CCD) camera. Multispectral BLT and the incomplete variables truncated conjugate gradient method with a permissible region shrinking strategy were used as the optimization scheme to reconstruct bioluminescent source distributions. To validate BLT targeting accuracy, a small cylindrical light source with high CBCT contrast was placed in a phantom and also in the abdomen of a mouse carcass. The center of mass (CoM) of the source was recovered from BLT and used to guide radiation delivery. The accuracy of the BLT-guided targeting was validated with films and compared with the CBCT-guided delivery. In vivo experiments were conducted to demonstrate BLT localization capability for various source geometries. Results: Online BLT was able to recover the CoM of the embedded light source with an average accuracy of 1 mm compared to that with CBCT localization. Differences between BLT- and CBCT-guided irradiation shown on the films were consistent with the source localization revealed in the BLT and CBCT images. In vivo results demonstrated that our BLT system could potentially be applied for multiple targets and tumors. Conclusions: The online BLT/CBCT/SARRP system provides an effective solution for soft tissue targeting, particularly for small, nonpalpable, or

  20. Bioluminescence Tomography–Guided Radiation Therapy for Preclinical Research

    International Nuclear Information System (INIS)

    Zhang, Bin; Wang, Ken Kang-Hsin; Yu, Jingjing; Eslami, Sohrab; Iordachita, Iulian; Reyes, Juvenal; Malek, Reem; Tran, Phuoc T.; Patterson, Michael S.; Wong, John W.

    2016-01-01

    Purpose: In preclinical radiation research, it is challenging to localize soft tissue targets based on cone beam computed tomography (CBCT) guidance. As a more effective method to localize soft tissue targets, we developed an online bioluminescence tomography (BLT) system for small-animal radiation research platform (SARRP). We demonstrated BLT-guided radiation therapy and validated targeting accuracy based on a newly developed reconstruction algorithm. Methods and Materials: The BLT system was designed to dock with the SARRP for image acquisition and to be detached before radiation delivery. A 3-mirror system was devised to reflect the bioluminescence emitted from the subject to a stationary charge-coupled device (CCD) camera. Multispectral BLT and the incomplete variables truncated conjugate gradient method with a permissible region shrinking strategy were used as the optimization scheme to reconstruct bioluminescent source distributions. To validate BLT targeting accuracy, a small cylindrical light source with high CBCT contrast was placed in a phantom and also in the abdomen of a mouse carcass. The center of mass (CoM) of the source was recovered from BLT and used to guide radiation delivery. The accuracy of the BLT-guided targeting was validated with films and compared with the CBCT-guided delivery. In vivo experiments were conducted to demonstrate BLT localization capability for various source geometries. Results: Online BLT was able to recover the CoM of the embedded light source with an average accuracy of 1 mm compared to that with CBCT localization. Differences between BLT- and CBCT-guided irradiation shown on the films were consistent with the source localization revealed in the BLT and CBCT images. In vivo results demonstrated that our BLT system could potentially be applied for multiple targets and tumors. Conclusions: The online BLT/CBCT/SARRP system provides an effective solution for soft tissue targeting, particularly for small, nonpalpable, or

  1. A mobile, high-throughput semi-automated system for testing cognition in large non-primate animal models of Huntington disease.

    Science.gov (United States)

    McBride, Sebastian D; Perentos, Nicholas; Morton, A Jennifer

    2016-05-30

    For reasons of cost and ethical concerns, models of neurodegenerative disorders such as Huntington disease (HD) are currently being developed in farm animals, as an alternative to non-human primates. Developing reliable methods of testing cognitive function is essential to determining the usefulness of such models. Nevertheless, cognitive testing of farm animal species presents a unique set of challenges. The primary aims of this study were to develop and validate a mobile operant system suitable for high throughput cognitive testing of sheep. We designed a semi-automated testing system with the capability of presenting stimuli (visual, auditory) and reward at six spatial locations. Fourteen normal sheep were used to validate the system using a two-choice visual discrimination task. Four stages of training devised to acclimatise animals to the system are also presented. All sheep progressed rapidly through the training stages, over eight sessions. All sheep learned the 2CVDT and performed at least one reversal stage. The mean number of trials the sheep took to reach criterion in the first acquisition learning was 13.9±1.5 and for the reversal learning was 19.1±1.8. This is the first mobile semi-automated operant system developed for testing cognitive function in sheep. We have designed and validated an automated operant behavioural testing system suitable for high throughput cognitive testing in sheep and other medium-sized quadrupeds, such as pigs and dogs. Sheep performance in the two-choice visual discrimination task was very similar to that reported for non-human primates and strongly supports the use of farm animals as pre-clinical models for the study of neurodegenerative diseases. Copyright © 2015 Elsevier B.V. All rights reserved.

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

    Science.gov (United States)

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

    2013-07-01

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

  3. The Innate Immune System in Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    Allal Boutajangout

    2013-01-01

    Full Text Available Alzheimer’s disease (AD is the leading cause for dementia in the world. It is characterized by two biochemically distinct types of protein aggregates: amyloid β (Aβ peptide in the forms of parenchymal amyloid plaques and congophilic amyloid angiopathy (CAA and aggregated tau protein in the form of intraneuronal neurofibrillary tangles (NFT. Several risk factors have been discovered that are associated with AD. The most well-known genetic risk factor for late-onset AD is apolipoprotein E4 (ApoE4 (Potter and Wisniewski (2012, and Verghese et al. (2011. Recently, it has been reported by two groups independently that a rare functional variant (R47H of TREM2 is associated with the late-onset risk of AD. TREM2 is expressed on myeloid cells including microglia, macrophages, and dendritic cells, as well as osteoclasts. Microglia are a major part of the innate immune system in the CNS and are also involved in stimulating adaptive immunity. Microglia express several Toll-like receptors (TLRs and are the resident macrophages of the central nervous system (CNS. In this review, we will focus on the recent advances regarding the role of TREM2, as well as the effects of TLRs 4 and 9 on AD.

  4. Fast infectious diseases diagnostics based on microfluidic biochip system

    Directory of Open Access Journals (Sweden)

    Qin Huang

    2017-03-01

    Full Text Available Molecular diagnostics is one of the most important tools currently in use for clinical pathogen detection due to its high sensitivity, specificity, and low consume of sample and reagent is keyword to low cost molecular diagnostics. In this paper, a sensitive DNA isothermal amplification method for fast clinical infectious diseases diagnostics at aM concentrations of DNA was developed using a polycarbonate (PC microfluidic chip. A portable confocal optical fluorescence detector was specifically developed for the microfluidic chip that was capable of highly sensitive real-time detection of amplified products for sequence-specific molecular identification near the optical diffraction limit with low background. The molecular diagnostics of Listeria monocytogenes with nucleic acid extracted from stool samples was performed at a minimum DNA template concentration of 3.65aM, and a detection limit of less than five copies of genomic DNA. Contrast to the general polymerase chain reaction (PCR at eppendorf (EP tube, the detection time in our developed method was reduced from 1.5h to 45min for multi-target parallel detection, the consume of sample and reagent was dropped from 25μL to 1.45μL. This novel microfluidic chip system and method can be used to develop a micro total analysis system as a clinically relevant pathogen molecular diagnostics method via the amplification of targets, with potential applications in biotechnology, medicine, and clinical molecular diagnostics.

  5. Pre-Clinical Models of Diffuse Intrinsic Pontine Glioma

    Directory of Open Access Journals (Sweden)

    Oren J Becher

    2015-07-01

    Full Text Available Diffuse Intrinsic Pontine Glioma (DIPG is a rare and incurable brain tumor that arises in the brainstem of children predominantly between the ages of six and eight. Its intricate morphology and involvement of normal pons tissue precludes surgical resection, and the standard of care today remains fractionated radiation alone. In the past 30 years, there have been no significant advances made in the treatment of DIPG. This is largely because we lack good models of DIPG and therefore have little biological basis for treatment. In recent years however, due to increased biopsy and acquisition of autopsy specimens, research is beginning to unravel the genetic and epigenetic drivers of DIPG. Insight gleaned from these studies has led to improvements in approaches to both model these tumors in the lab, as well as to potentially treat them in the clinic. This review will detail the initial strides towards modeling DIPG in animals, which included allograft and xenograft rodent models using non-DIPG glioma cells. Important advances in the field came with the development of in vitro cell and in vivo xenograft models derived directly from autopsy material of DIPG patients or from human embryonic stem cells. Lastly, we will summarize the progress made in the development of genetically engineered mouse models of DIPG. Cooperation of studies incorporating all of these modeling systems to both investigate the unique mechanisms of gliomagenesis in the brainstem and to test potential novel therapeutic agents in a preclinical setting will result in improvement in treatments for DIPG patients.

  6. Improving treatment of neurodevelopmental disorders: recommendations based on preclinical studies.

    Science.gov (United States)

    Homberg, Judith R; Kyzar, Evan J; Stewart, Adam Michael; Nguyen, Michael; Poudel, Manoj K; Echevarria, David J; Collier, Adam D; Gaikwad, Siddharth; Klimenko, Viktor M; Norton, William; Pittman, Julian; Nakamura, Shun; Koshiba, Mamiko; Yamanouchi, Hideo; Apryatin, Sergey A; Scattoni, Maria Luisa; Diamond, David M; Ullmann, Jeremy F P; Parker, Matthew O; Brown, Richard E; Song, Cai; Kalueff, Allan V

    2016-01-01

    Neurodevelopmental disorders (NDDs) are common and severely debilitating. Their chronic nature and reliance on both genetic and environmental factors makes studying NDDs and their treatment a challenging task. Herein, the authors discuss the neurobiological mechanisms of NDDs, and present recommendations on their translational research and therapy, outlined by the International Stress and Behavior Society. Various drugs currently prescribed to treat NDDs also represent a highly diverse group. Acting on various neurotransmitter and physiological systems, these drugs often lack specificity of action, and are commonly used to treat multiple other psychiatric conditions. There has also been relatively little progress in the development of novel medications to treat NDDs. Based on clinical, preclinical and translational models of NDDs, our recommendations cover a wide range of methodological approaches and conceptual strategies. To improve pharmacotherapy and drug discovery for NDDs, we need a stronger emphasis on targeting multiple endophenotypes, a better dissection of genetic/epigenetic factors or "hidden heritability," and a careful consideration of potential developmental/trophic roles of brain neurotransmitters. The validity of animal NDD models can be improved through discovery of novel (behavioral, physiological and neuroimaging) biomarkers, applying proper environmental enrichment, widening the spectrum of model organisms, targeting developmental trajectories of NDD-related behaviors and comorbid conditions beyond traditional NDDs. While these recommendations cannot be addressed all in once, our increased understanding of NDD pathobiology may trigger innovative cross-disciplinary research expanding beyond traditional methods and concepts.

  7. Activation of Liver AMPK with PF-06409577 Corrects NAFLD and Lowers Cholesterol in Rodent and Primate Preclinical Models.

    Science.gov (United States)

    Esquejo, Ryan M; Salatto, Christopher T; Delmore, Jake; Albuquerque, Bina; Reyes, Allan; Shi, Yuji; Moccia, Rob; Cokorinos, Emily; Peloquin, Matthew; Monetti, Mara; Barricklow, Jason; Bollinger, Eliza; Smith, Brennan K; Day, Emily A; Nguyen, Chuong; Geoghegan, Kieran F; Kreeger, John M; Opsahl, Alan; Ward, Jessica; Kalgutkar, Amit S; Tess, David; Butler, Lynne; Shirai, Norimitsu; Osborne, Timothy F; Steinberg, Gregory R; Birnbaum, Morris J; Cameron, Kimberly O; Miller, Russell A

    2018-04-08

    Dysregulation of hepatic lipid and cholesterol metabolism is a significant contributor to cardiometabolic health, resulting in excessive liver lipid accumulation and ultimately non-alcoholic steatohepatitis (NASH). Therapeutic activators of the AMP-Activated Protein Kinase (AMPK) have been proposed as a treatment for metabolic diseases; we show that the AMPK β1-biased activator PF-06409577 is capable of lowering hepatic and systemic lipid and cholesterol levels in both rodent and monkey preclinical models. PF-06409577 is able to inhibit de novo lipid and cholesterol synthesis pathways, and causes a reduction in hepatic lipids and mRNA expression of markers of hepatic fibrosis. These effects require AMPK activity in the hepatocytes. Treatment of hyperlipidemic rats or cynomolgus monkeys with PF-06409577 for 6weeks resulted in a reduction in circulating cholesterol. Together these data suggest that activation of AMPK β1 complexes with PF-06409577 is capable of impacting multiple facets of liver disease and represents a promising strategy for the treatment of NAFLD and NASH in humans. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

  8. [Treatable diseases of the nervous system with cataract formation].

    Science.gov (United States)

    Baumgartner, R W; Waespe, W

    1993-02-01

    The detection of a cataract in combination with a neurological deficit may provide the physician with important diagnostic help. But a minority of underlying diseases (angiokeratoma corporis diffusum, cerebrotendinous xanthomatosis, diabetes mellitus, galactosemia, hypocalcemia, Refsum's disease, Wilson's disease; Charles Bonnet syndrome; relapsing Perichondritis; adverse effects of medication and intoxications) can be treated causally. Therefore they are summed up and discussed in this paper.

  9. Surveillance and early warning systems of infectious disease in China: From 2012 to 2014.

    Science.gov (United States)

    Zhang, Honglong; Wang, Liping; Lai, Shengjie; Li, Zhongjie; Sun, Qiao; Zhang, Peng

    2017-07-01

    Appropriate surveillance and early warning of infectious diseases have very useful roles in disease control and prevention. In 2004, China established the National Notifiable Infectious Disease Surveillance System and the Public Health Emergency Event Surveillance System to report disease surveillance and events on the basis of data sources from the National Notifiable Infectious Disease Surveillance System, China Infectious Disease Automated-alert and Response System in this country. This study provided a descriptive summary and a data analysis, from 2012 to 2014, of these 3 key surveillance and early warning systems of infectious disease in China with the intent to provide suggestions for system improvement and perfection. Copyright © 2017 John Wiley & Sons, Ltd.

  10. Idiopathic inflammatory-demyelinating diseases of the central nervous system

    Energy Technology Data Exchange (ETDEWEB)

    Rovira Canellas, A. [Vall d' Hebron University Hospital, Magnetic Resonance Unit (I.D.I.), Department of Radiology, Barcelona (Spain); Rovira Gols, A. [Parc Tauli University Institute - UAB, UDIAT, Diagnostic Centre, Sabadell (Spain); Rio Izquierdo, J.; Tintore Subirana, M.; Montalban Gairin, X. [Vall d' Hebron University Hospital, Neuroimmunology Unit, Department of Neurology, Barcelona (Spain)

    2007-05-15

    Idiopathic inflammatory-demyelinating diseases (IIDDs) include a broad spectrum of central nervous system disorders that can usually be differentiated on the basis of clinical, imaging, laboratory and pathological findings. However, there can be a considerable overlap between at least some of these disorders, leading to misdiagnoses or diagnostic uncertainty. The relapsing-remitting and secondary progressive forms of multiple sclerosis (MS) are the most common IIDDs. Other MS phenotypes include those with a progressive course from onset (primary progressive and progressive relapsing) or with a benign course continuing for years after onset (benign MS). Uncommon forms of IIDDs can be classified clinically into: (1) fulminant or acute IIDDs, such as the Marburg variant of MS, Balo's concentric sclerosis, Schilder's disease, and acute disseminated encephalomyelitis; (2) monosymptomatic IIDDs, such as those involving the spinal cord (transverse myelitis), optic nerve (optic neuritis) or brainstem and cerebellum; and (3) IIDDs with a restricted topographical distribution, including Devic's neuromyelitis optica, recurrent optic neuritis and relapsing transverse myelitis. Other forms of IIDD, which are classified clinically and radiologically as pseudotumoral, can have different forms of presentation and clinical courses. Although some of these uncommon IIDDs are variants of MS, others probably correspond to different entities. MR imaging of the brain and spine is the imaging technique of choice for diagnosing these disorders, and together with the clinical and laboratory findings can accurately classify them. Precise classification of these disorders may have relevant prognostic and treatment implications, and might be helpful in distinguishing them from tumoral or infectious lesions, avoiding unnecessary aggressive diagnostic or therapeutic procedures. (orig.)

  11. Idiopathic inflammatory-demyelinating diseases of the central nervous system

    International Nuclear Information System (INIS)

    Rovira Canellas, A.; Rovira Gols, A.; Rio Izquierdo, J.; Tintore Subirana, M.; Montalban Gairin, X.

    2007-01-01

    Idiopathic inflammatory-demyelinating diseases (IIDDs) include a broad spectrum of central nervous system disorders that can usually be differentiated on the basis of clinical, imaging, laboratory and pathological findings. However, there can be a considerable overlap between at least some of these disorders, leading to misdiagnoses or diagnostic uncertainty. The relapsing-remitting and secondary progressive forms of multiple sclerosis (MS) are the most common IIDDs. Other MS phenotypes include those with a progressive course from onset (primary progressive and progressive relapsing) or with a benign course continuing for years after onset (benign MS). Uncommon forms of IIDDs can be classified clinically into: (1) fulminant or acute IIDDs, such as the Marburg variant of MS, Balo's concentric sclerosis, Schilder's disease, and acute disseminated encephalomyelitis; (2) monosymptomatic IIDDs, such as those involving the spinal cord (transverse myelitis), optic nerve (optic neuritis) or brainstem and cerebellum; and (3) IIDDs with a restricted topographical distribution, including Devic's neuromyelitis optica, recurrent optic neuritis and relapsing transverse myelitis. Other forms of IIDD, which are classified clinically and radiologically as pseudotumoral, can have different forms of presentation and clinical courses. Although some of these uncommon IIDDs are variants of MS, others probably correspond to different entities. MR imaging of the brain and spine is the imaging technique of choice for diagnosing these disorders, and together with the clinical and laboratory findings can accurately classify them. Precise classification of these disorders may have relevant prognostic and treatment implications, and might be helpful in distinguishing them from tumoral or infectious lesions, avoiding unnecessary aggressive diagnostic or therapeutic procedures. (orig.)

  12. Parkinson disease: systemic and orofacial manifestations, medical and dental management.

    Science.gov (United States)

    Friedlander, Arthur H; Mahler, Michael; Norman, Keith M; Ettinger, Ronald L

    2009-06-01

    More than 1.5 million Americans have Parkinson disease (PD), and this figure is expected to rise as the population ages. However, the dental literature offers little information about the illness. The authors conducted a MEDLINE search using the key terms "Parkinson's disease," "medical management" and "dentistry." They selected contemporaneous articles published in peer-reviewed journals and gave preference to articles reporting randomized controlled trials. PD is a progressive neurodegenerative disorder caused by loss of dopaminergic and nondopaminergic neurons in the brain. These deficits result in tremor, slowness of movement, rigidity, postural instability and autonomic and behavioral dysfunction. Treatment consists of administering medications that replace dopamine, stimulate dopamine receptors and modulate other neurotransmitter systems. Oral health may decline because of tremors, muscle rigidity and cognitive deficits. The dentist should consult with the patient's physician to establish the patient's competence to provide informed consent and to determine the presence of comorbid illnesses. Scheduling short morning appointments that begin 90 minutes after administration of PD medication enhances the patient's ability to cooperate with care. Inclination of the dental chair at 45 degrees, placement of a bite prop, use of a rubber dam and high-volume oral evacuation enhance airway protection. To avoid adverse drug interactions with levodopa and entacapone, the dentist should limit administration of local anesthetic agents to three cartridges of 2 percent lidocaine with 1:100,000 epinephrine per half hour, and patients receiving selegiline should not be given agents containing epinephrine or levonordefrin. The dentist should instruct the patient and the caregiver in good oral hygiene techniques.

  13. Interaction of lifestyle, behaviour or systemic diseases with dental caries and periodontal diseases

    DEFF Research Database (Denmark)

    Chapple, Iain L C; Bouchard, Philippe; Cagetti, Maria Grazia

    2017-01-01

    Periodontal diseases and dental caries are the most common diseases of humans and the main cause of tooth loss. Both diseases can lead to nutritional compromise and negative impacts upon self-esteem and quality of life. As complex chronic diseases, they share common risk factors, such as a requir......Periodontal diseases and dental caries are the most common