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Sample records for activity disease activity

  1. Disease Activity Measures in Paediatric Rheumatic Diseases

    PubMed Central

    Luca, Nadia J.; Feldman, Brian M.

    2013-01-01

    Disease activity refers to potentially reversible aspects of a disease. Measurement of disease activity in paediatric rheumatic diseases is a critical component of patient care and clinical research. Disease activity measures are developed systematically, often involving consensus methods. To be useful, a disease activity measure must be feasible, valid, and interpretable. There are several challenges in quantifying disease activity in paediatric rheumatology; namely, the conditions are multidimensional, the level of activity must be valuated in the context of treatment being received, there is no gold standard for disease activity, and it is often difficult to incorporate the patient's perspective of their disease activity. To date, core sets of response variables are defined for juvenile idiopathic arthritis, juvenile systemic lupus erythematosus, and juvenile dermatomyositis, as well as definitions for improvement in response to therapy. Several specific absolute disease activity measures also exist for each condition. Further work is required to determine the optimal disease activity measures in paediatric rheumatology. PMID:24089617

  2. Transglutaminase activation in neurodegenerative diseases

    PubMed Central

    Jeitner, Thomas M; Muma, Nancy A; Battaile, Kevin P; Cooper, Arthur JL

    2009-01-01

    The following review examines the role of calcium in promoting the in vitro and in vivo activation of transglutaminases in neurodegenerative disorders. Diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease exhibit increased transglutaminase activity and rises in intracellular calcium concentrations, which may be related. The aberrant activation of transglutaminase by calcium is thought to give rise to a variety of pathological moieties in these diseases, and the inhibition has been shown to have therapeutic benefit in animal and cellular models of neurodegeneration. Given the potential clinical relevance of transglutaminase inhibitors, we have also reviewed the recent development of such compounds. PMID:20161049

  3. Being active when you have heart disease

    MedlinePlus

    Heart disease - activity ... Getting regular exercise when you have heart disease is important. Exercise can make your heart muscle stronger. It may also help you be more active without chest pain or ...

  4. Cardiovascular Disease and Cancer: Student Awareness Activities.

    ERIC Educational Resources Information Center

    Meyer, James H., Comp.

    Awareness activities pertaining to cancer and cardiovascular disease are presented as a supplement for high school science classes. The exercises can be used to enrich units of study dealing with the circulatory system, the cell, or human diseases. Eight activities deal with the following topics: (1) cardiovascular disease risk factors; (2)…

  5. On Modelling Minimal Disease Activity

    PubMed Central

    Jackson, Christopher H.; Su, Li; Gladman, Dafna D.

    2016-01-01

    Objective To explore methods for statistical modelling of minimal disease activity (MDA) based on data from intermittent clinic visits. Methods The analysis was based on a 2‐state model. Comparisons were made between analyses based on “complete case” data from visits at which MDA status was known, and the use of hidden model methodology that incorporated information from visits at which only some MDA defining criteria could be established. Analyses were based on an observational psoriatic arthritis cohort. Results With data from 856 patients and 7,024 clinic visits, analysis was based on virtually all visits, although only 62.6% provided enough information to determine MDA status. Estimated mean times for an episode of MDA varied from 4.18 years to 3.10 years, with smaller estimates derived from the hidden 2‐state model analysis. Over a 10‐year period, the estimated expected times spent in MDA episodes of longer than 1 year was 3.90 to 4.22, and the probability of having such an MDA episode was estimated to be 0.85 to 0.91, with longer times and greater probabilities seen with the hidden 2‐state model analysis. Conclusion A 2‐state model provides a useful framework for the analysis of MDA. Use of data from visits at which MDA status can not be determined provide more precision, and notable differences are seen in estimated quantities related to MDA episodes based on complete case and hidden 2‐state model analyses. The possibility of bias, as well as loss of precision, should be recognized when complete case analyses are used. PMID:26315478

  6. Disease activity in osteomyelitis: role of radiography

    SciTech Connect

    Tumeh, S.S.; Aliabadi, P.; Weissman, B.N.; McNeil, B.J.

    1987-12-01

    To determine the impact of radiographic findings on the interpretation of bone and gallium scans of patients with active osteomyelitis, the authors reviewed the medical records and radiologic examinations of 104 patients. The only diagnostic finding of active disease on radiographs was the presence of a sequestrum (three patients). Other findings--such as erosion, soft-tissue swelling, and periosteal reaction--proved nonspecific and did not differentiate active from inactive disease. Furthermore, these findings did not significantly change the sensitivity or specificity of the bone and gallium scans, either in detecting or in excluding the presence of active disease.

  7. Physical Activity Fundamental to Preventing Disease.

    ERIC Educational Resources Information Center

    Office of the Assistant Secretary for Planning and Evaluation (DHHS), Washington, DC.

    Regular physical activity, fitness, and exercise are critically important for all people's health and wellbeing. It can reduce morbidity and mortality from many chronic diseases. Despite its well-known benefits, most U.S. adults, and many children, are not active enough to achieve these health benefits. Physical inactivity and related health…

  8. Biomarkers for Microglial Activation in Alzheimer's Disease

    PubMed Central

    Lautner, Ronald; Mattsson, Niklas; Schöll, Michael; Augutis, Kristin; Blennow, Kaj; Olsson, Bob; Zetterberg, Henrik

    2011-01-01

    Intensive research over the last decades has provided increasing evidence for neuroinflammation as an integral part in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Inflammatory responses in the central nervous system (CNS) are initiated by activated microglia, representing the first line of the innate immune defence of the brain. Therefore, biochemical markers of microglial activation may help us understand the underlying mechanisms of neuroinflammation in AD as well as the double-sided qualities of microglia, namely, neuroprotection and neurotoxicity. In this paper we summarize candidate biomarkers of microglial activation in AD along with a survey of recent neuroimaging techniques. PMID:22114747

  9. Activity.

    ERIC Educational Resources Information Center

    Clearing: Nature and Learning in the Pacific Northwest, 1984

    1984-01-01

    Presents three activities: (1) investigating succession in a schoolground; (2) investigating oak galls; and (3) making sun prints (photographs made without camera or darkroom). Each activity includes a list of materials needed and procedures used. (JN)

  10. Physical activity, nutrition, and chronic disease.

    PubMed

    Blair, S N; Horton, E; Leon, A S; Lee, I M; Drinkwater, B L; Dishman, R K; Mackey, M; Kienholz, M L

    1996-03-01

    Epidemiologic, animal, clinical, and metabolic studies demonstrate the independent roles of physical activity and nutrition in the prevention and treatment of several chronic diseases. Fewer data are available to describe the synergistic effects of exercise and diet, and questions remain as to whether and how these two lifestyle factors work together to promote health and prevent disease. This paper briefly reviews many of the known effects of physical activity and nutrition on the prevention and treatment of coronary heart disease, non-insulin-dependent diabetes mellitus, obesity, and osteoporosis as well as how exercise and diet may work together. A discussion of how to increase physical activity levels and how to improve dietary intake also is included. Finally, current exercise and dietary recommendations are summarized, as are directions for future research. PMID:8776222

  11. Release and activity of histone in diseases.

    PubMed

    Chen, R; Kang, R; Fan, X-G; Tang, D

    2014-01-01

    Histones and their post-translational modifications have key roles in chromatin remodeling and gene transcription. Besides intranuclear functions, histones act as damage-associated molecular pattern molecules when they are released into the extracellular space. Administration of exogenous histones to animals leads to systemic inflammatory and toxic responses through activating Toll-like receptors and inflammasome pathways. Anti-histone treatment (e.g., neutralizing antibodies, activated protein C, recombinant thrombomodulin, and heparin) protect mice against lethal endotoxemia, sepsis, ischemia/reperfusion injury, trauma, pancreatitis, peritonitis, stroke, coagulation, and thrombosis. In addition, elevated serum histone and nucleosome levels have been implicated in multiple pathophysiological processes and progression of diseases including autoimmune diseases, inflammatory diseases, and cancer. Therefore, extracellular histones could serve as biomarkers and novel therapeutic targets in human diseases. PMID:25118930

  12. Activities.

    ERIC Educational Resources Information Center

    Moody, Mally

    1992-01-01

    A series of four activities are presented to enhance students' abilities to appreciate and use trigonometry as a tool in problem solving. Activities cover problems applying the law of sines, the law of cosines, and matching equivalent trigonometric expressions. A teacher's guide, worksheets, and answers are provided. (MDH)

  13. Physical activity, brain plasticity, and Alzheimer's disease.

    PubMed

    Erickson, Kirk I; Weinstein, Andrea M; Lopez, Oscar L

    2012-11-01

    In this review we summarize the epidemiological, cross-sectional, and interventional studies examining the association between physical activity and brain volume, function, and risk for Alzheimer's disease. The epidemiological literature provides compelling evidence that greater amounts of physical activity are associated with a reduced risk of dementia in late life. In addition, randomized interventions using neuroimaging tools have reported that participation in physical activity increases the size of prefrontal and hippocampal brain areas, which may lead to a reduction in memory impairments. Consistent with these findings, longitudinal studies using neuroimaging tools also find that the volume of prefrontal and hippocampal brain areas are larger in individuals who engaged in more physical activity earlier in life. We conclude from this review that there is convincing evidence that physical activity has a consistent and robust association with brain regions implicated in age-related cognitive decline and Alzheimer's disease. In addition to summarizing this literature we provide recommendations for future research on physical activity and brain health. PMID:23085449

  14. [Plasma cholinesterase activity in hepatic diseases].

    PubMed

    Araoud, Manel; Mhenni, Hamida; Hellara, Ilhem; Hellara, Olfa; Neffati, Fadoua; Douki, Wahiba; Mili, Marwa; Saffar, Hammouda; Najjar, Mohamed Fadhel

    2013-01-01

    Plasma cholinesterase activity (ChE) may vary in some pathological circumstances. We studied the changes in activity of this enzyme according to the type of liver injury, to assess the interest of this parameter in the diagnosis of liver diseases. Our study was performed on 102 patients with different liver diseases and 53 healthy controls. The ChE activity was lower in patients compared to control group (p < 0.0001), and more pronounced in cirrhotic patients compared to those suffering from hepatitis. Elevated activities of AST, ALT, GGT and ALP and bilirubinemia, and decreased albuminemia were noted in patients compared to controls (p < 0.001). Hypoalbuminemia was significantly important in cirrhotic patients compared to those suffering from cholestasis or hepatitis. A correlation between ChE and bilirubin, albumin and serum protein was found in patients with cirrhosis or those with chronic hepatitis. A significantly lower activity of ChE was found in patients with hepatic insufficiency (HI). In case of suspicion of HI, the prescription of ChE activity could guide or confirm the diagnosis of the impairment. PMID:23747666

  15. Physical activity, obesity and cardiovascular diseases.

    PubMed

    Lakka, T A; Bouchard, C

    2005-01-01

    Sedentary lifestyle and overweight are major public health, clinical, and economical problems in modern societies. The worldwide epidemic of excess weight is due to imbalance between physical activity and dietary energy intake. Sedentary lifestyle, unhealthy diet, and consequent overweight and obesity markedly increase the risk of cardiovascular diseases. Regular physical activity 45-60 min per day prevents unhealthy weight gain and obesity, whereas sedentary behaviors such as watching television promote them. Regular exercise can markedly reduce body weight and fat mass without dietary caloric restriction in overweight individuals. An increase in total energy expenditure appears to be the most important determinant of successful exercise-induced weight loss. The best long-term results may be achieved when physical activity produces an energy expenditure of at least 2,500 kcal/week. Yet, the optimal approach in weight reduction programs appears to be a combination of regular physical activity and caloric restriction. A minimum of 60 min, but most likely 80-90 min of moderate-intensity physical activity per day may be needed to avoid or limit weight regain in formerly overweight or obese individuals. Regular moderate intensity physical activity, a healthy diet, and avoiding unhealthy weight gain are effective and safe ways to prevent and treat cardiovascular diseases and to reduce premature mortality in all population groups. Although the efforts to promote cardiovascular health concern the whole population, particular attention should be paid to individuals who are physically inactive, have unhealthy diets or are prone to weight gain. They have the highest risk for worsening of the cardiovascular risk factor profile and for cardiovascular disease. To combat the epidemic of overweight and to improve cardiovascular health at a population level, it is important to develop strategies to increase habitual physical activity and to prevent overweight and obesity in

  16. Active music therapy and Parkinson's disease: methods.

    PubMed

    Pacchetti, C; Aglieri, R; Mancini, F; Martignoni, E; Nappi, G

    1998-01-01

    Music therapy (MT) is an unconventional, multisensorial therapy poorly assessed in medical care but widely used to different ends in a variety of settings. MT has two branches: active and passive. In active MT the utilisation of instruments is structured to correspond to all sensory organs so as to obtain suitable motor and emotional responses. We conducted a prospective study to evaluate the effects of MT in the neurorehabilitation of patients with Parkinson's Disease (PD), a common degenerative disorder involving movement and emotional impairment. Sixteen PD patients took part in 13 weekly sessions of MT each lasting 2 hours. At the beginning and at the end of the session, every 2 weeks, the patients were evaluated by a neurologist, who assessed PD severity with UPDRS, emotional functions with Happiness Measures (HM) and quality of life using the Parkinson's Disease Quality of Life Questionnaire (PDQL). After every session a significant improvement in motor function, particularly in relation to hypokinesia, was observed both in the overall and in the pre-post session evaluations. HM, UPDRS-ADL and PDQL changes confirmed an improving effect of MT on emotional functions, activities of daily living and quality of life. In conclusion, active MT, operating at a multisensorial level, stimulates motor, affective and behavioural functions. Finally, we propose active MT as new method to include in PD rehabilitation programmes. This article describes the methods adopted during MT sessions with PD patients. PMID:9584875

  17. Macrophage activation syndrome in autoimmune disease.

    PubMed

    Deane, Sean; Selmi, Carlo; Teuber, Suzanne S; Gershwin, M Eric

    2010-01-01

    Macrophage activation syndrome (MAS) is a phenomenon characterized by cytopenia, organ dysfunction, and coagulopathy associated with an inappropriate activation of macrophages. Current diagnostic criteria are imprecise, but the syndrome is now recognized as a form of hemophagocytic lymphohistiocytosis that is characteristically associated with autoimmune diatheses. The diagnosis of incipient MAS in patients with autoimmune disease requires a high index of suspicion, as several characteristics of the disorder may be present in the underlying condition or infectious complications associated with the treatment thereof. Proposed treatment regimens include aggressive approaches that require validation in future controlled studies. This review discusses the major aspects of the pathophysiology, diagnosis, and management of MAS with a focus on the association with autoimmune disease. PMID:20407267

  18. Activities.

    ERIC Educational Resources Information Center

    Kincaid, Charlene; And Others

    1993-01-01

    Presents an activity in which students collect and organize data from a real-world simulation of the scientific concept of half life. Students collect data using a marble sifter, analyze the data using a graphing calculator, and determine an appropriate mathematical model. Includes reproducible worksheets. (MDH)

  19. Graves' disease: thyroid function and immunologic activity

    SciTech Connect

    Gossage, A.A.; Crawley, J.C.; Copping, S.; Hinge, D.; Himsworth, R.L.

    1982-11-01

    Patients with Graves' disease were studied for two years during and after a twelve-month course of treatment. Disease activity was determined by repeated measurements of thyroidal uptake of (/sup 99m/Tc)pertechnetate during tri-iodothyronine administration. These in-vivo measurements of thyroid stimulation were compared with the results of in-vitro assays of Graves, immunoglobulin (TSH binding inhibitory activity--TBIA). There was no correlation between the thyroid uptake and TBIA on diagnosis. Pertechnetate uptake and TBIA both declined during the twelve months of antithyroid therapy. TBIA was detectable in sera from 19 of the 27 patients at diagnosis; in 11 of these 19 patients there was a good correlation (p less than 0.05) throughout the course of their disease between the laboratory assay of the Graves, immunoglobulin and the thyroid uptake. Probability of recurrence can be assessed but sustained remission of Graves' disease after treatment cannot be predicted from either measurement alone or in combination.

  20. Graves' disease: thyroid function and immunologic activity

    SciTech Connect

    Gossage, A.A.R.; Crawley, J.C.W.; Copping, S.; Hinge, D.; Himsworth, R.L.

    1982-11-01

    Patients with Graves' disease were studied for two years during and after a twelve-month course of treatment. Disease activity was determined by repeated measurements of thyroidal uptake of (/sup 9/-9..mu..Tc)pertechnetate during tri-iodothyronine administration. These in-vivo measurements of thyroid stimulation were compared with the results of in-vitro assays of Graves, immunoglobulin (TSH binding inhibitory activity - TBIA). There was no correlation between the thyroid uptake and TBIA on diagnosis. Pertechnetate uptake and TBIA both declined during the twelve months of antithyroid therapy. TBIA was detectable in sera from 19 of the 27 patients at diagnosis; in 11 of these 19 patients there was a good correlation (p<0.05) throughout the course of their disease between the laboratory assay of the Graves, immunoglobulin and the thyroid uptake. Probability of recurrence can be assessed but sustained remission of Graves' disease after treatment cannot be predicted from either measurement alone or in combination.

  1. Helping People with Alzheimer's Disease Stay Physically Active

    MedlinePlus

    ... Free Stuff Be a Partner Helping People with Alzheimer's Disease Stay Physically Active Regular physical activity has many benefits for people with Alzheimer’s disease. Exercise helps keep muscles, joints, and the ...

  2. Inhibiting caspase-6 activation and catalytic activity for neurodegenerative diseases.

    PubMed

    Flygare, John A; Arkin, Michelle R

    2014-01-01

    Partnerships between industry and academia are becoming increasingly complex and relevant in the drive to discover innovative new medicines. We describe the structure of the collaboration between the University of California - San Francisco - Small Molecule Discovery Center (UCSF-SMDC) and Genentech to develop chemical matter that inhibits the activity of caspase-6. We focus on the scientific basis for the partnership and how the orientation- and transaction-related barriers were overcome. We describe the division of labor that allowed two groups to operate as a unified team to generate multiple chemical series with distinct mechanisms of action. The successful structure of the agreement serves as a model for future collaborations at both institutions. PMID:24283214

  3. Multiple plasma enzyme activities in liver disease

    PubMed Central

    Hargreaves, T.; Janota, I.; Smith, M. J. H.

    1961-01-01

    The measurement of the plasma activities of glutamic-oxaloacetic and glutamic-pyruvic transaminases, aldolase, cholinesterase, and isocitric, lactic, and phosphogluconic dehydrogenases in random samples of blood was found to be of no value in the differential diagnosis of hepatitis, obstructive jaundice, hepatic cirrhosis, and neoplastic conditions involving the liver. Serial determinations of the enzyme activities provided useful information about the course of certain hepatic disorders, particularly acute viral hepatitis. PMID:13711559

  4. Seasonal prevalence of MS disease activity(Podcast)

    PubMed Central

    Meier, D.S.; Balashov, K.E.; Healy, B.; Weiner, H.L.; Guttmann, C.R.G.

    2010-01-01

    Objective: This observational cohort study investigated the seasonal prevalence of multiple sclerosis (MS) disease activity (likelihood and intensity), as reflected by new lesions from serial T2-weighted MRI, a sensitive marker of subclinical disease activity. Methods: Disease activity was assessed from the appearance of new T2 lesions on 939 separate brain MRI examinations in 44 untreated patients with MS. Likelihood functions for MS disease activity were derived, accounting for the temporal uncertainty of new lesion occurrence, individual levels of disease activity, and uneven examination intervals. Both likelihood and intensity of disease activity were compared with the time of year (season) and regional climate data (temperature, solar radiation, precipitation) and among relapsing and progressive disease phenotypes. Contrast-enhancing lesions and attack counts were also compared for seasonal effects. Results: Unlike contrast enhancement or attacks, new T2 activity revealed a likelihood 2–3 times higher in March–August than during the rest of the year, and correlated strongly with regional climate data, in particular solar radiation. In addition to the likelihood or prevalence, disease intensity was also elevated during the summer season. The elevated risk season appears to lessen for progressive MS and occur about 2 months earlier. Conclusion: This study documents evidence of a strong seasonal pattern in subclinical MS activity based on noncontrast brain MRI. The observed seasonality in MS disease activity has implications for trial design and therapy assessment. The observed activity pattern is suggestive of a modulating role of seasonally changing environmental factors or season-dependent metabolic activity. GLOSSARY CEL = contrast-enhancing lesions; MS = multiple sclerosis. PMID:20805526

  5. Remote Physical Activity Monitoring in Neurological Disease: A Systematic Review

    PubMed Central

    Block, Valerie A. J.; Pitsch, Erica; Tahir, Peggy; Cree, Bruce A. C.; Allen, Diane D.; Gelfand, Jeffrey M.

    2016-01-01

    Objective To perform a systematic review of studies using remote physical activity monitoring in neurological diseases, highlighting advances and determining gaps. Methods Studies were systematically identified in PubMed/MEDLINE, CINAHL and SCOPUS from January 2004 to December 2014 that monitored physical activity for ≥24 hours in adults with neurological diseases. Studies that measured only involuntary motor activity (tremor, seizures), energy expenditure or sleep were excluded. Feasibility, findings, and protocols were examined. Results 137 studies met inclusion criteria in multiple sclerosis (MS) (61 studies); stroke (41); Parkinson's Disease (PD) (20); dementia (11); traumatic brain injury (2) and ataxia (1). Physical activity levels measured by remote monitoring are consistently low in people with MS, stroke and dementia, and patterns of physical activity are altered in PD. In MS, decreased ambulatory activity assessed via remote monitoring is associated with greater disability and lower quality of life. In stroke, remote measures of upper limb function and ambulation are associated with functional recovery following rehabilitation and goal-directed interventions. In PD, remote monitoring may help to predict falls. In dementia, remote physical activity measures correlate with disease severity and can detect wandering. Conclusions These studies show that remote physical activity monitoring is feasible in neurological diseases, including in people with moderate to severe neurological disability. Remote monitoring can be a psychometrically sound and responsive way to assess physical activity in neurological disease. Further research is needed to ensure these tools provide meaningful information in the context of specific neurological disorders and patterns of neurological disability. PMID:27124611

  6. Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis.

    PubMed

    Dweck, Marc R; Aikawa, Elena; Newby, David E; Tarkin, Jason M; Rudd, James H F; Narula, Jagat; Fayad, Zahi A

    2016-07-01

    Major focus has been placed on the identification of vulnerable plaques as a means of improving the prediction of myocardial infarction. However, this strategy has recently been questioned on the basis that the majority of these individual coronary lesions do not in fact go on to cause clinical events. Attention is, therefore, shifting to alternative imaging modalities that might provide a more complete pan-coronary assessment of the atherosclerotic disease process. These include markers of disease activity with the potential to discriminate between patients with stable burnt-out disease that is no longer metabolically active and those with active atheroma, faster disease progression, and increased risk of infarction. This review will examine how novel molecular imaging approaches can provide such assessments, focusing on inflammation and microcalcification activity, the importance of these processes to coronary atherosclerosis, and the advantages and challenges posed by these techniques. PMID:27390335

  7. Movement-related cortical activation in familial Parkinson disease.

    PubMed

    Delval, A; Defebvre, L; Labyt, E; Douay, X; Bourriez, J-L; Waucquiez, N; Derambure, P; Destée, A

    2006-09-26

    We sought to determine whether or not first-degree relatives of patients with familial Parkinson disease (FDRs) present impaired movement-related cortical activity. We studied 10 familial Parkinson disease subjects, 10 FDRs, and 10 controls and analyzed event-related mu desynchronization (ERD) and beta synchronization. Forty percent FDRs presented reduced premovement mu ERD latency, suggesting that premovement cortical activation is impaired in FDRs. PMID:17000986

  8. Downregulation of Sulfotransferase Expression and Activity in Diseased Human Livers

    PubMed Central

    Yalcin, Emine B.; More, Vijay; Neira, Karissa L.; Lu, Zhenqiang James; Cherrington, Nathan J.; Slitt, Angela L.

    2013-01-01

    Sulfotransferase (SULT) function has been well studied in healthy human subjects by quantifying mRNA and protein expression and determining enzyme activity with probe substrates. However, it is not well known if sulfotransferase activity changes in metabolic and liver disease, such as diabetes, steatosis, or cirrhosis. Sulfotransferases have significant roles in the regulation of hormones and excretion of xenobiotics. In the present study of normal subjects with nonfatty livers and patients with steatosis, diabetic cirrhosis, and alcoholic cirrhosis, we sought to determine SULT1A1, SULT2A1, SULT1E1, and SULT1A3 activity and mRNA and protein expression in human liver tissue. In general, sulfotransferase activity decreased significantly with severity of liver disease from steatosis to cirrhosis. Specifically, SULT1A1 and SULT1A3 activities were lower in disease states relative to nonfatty tissues. Alcoholic cirrhotic tissues further contained lower SULT1A1 and 1A3 activities than those affected by either of the two other disease states. SULT2A1, on the other hand, was only reduced in alcoholic cirrhotic tissues. SULT1E1 was reduced both in diabetic cirrhosis and in alcoholic cirrhosis tissues, relative to nonfatty liver tissues. In conclusion, the reduced levels of sulfotransferase expression and activity in diseased versus nondiseased liver tissue may alter the metabolism and disposition of xenobiotics and affect homeostasis of endobiotic sulfotransferase substrates. PMID:23775849

  9. Mast cells and their activation in lung disease.

    PubMed

    Virk, Harvinder; Arthur, Greer; Bradding, Peter

    2016-08-01

    Mast cells and their activation contribute to lung health via innate and adaptive immune responses to respiratory pathogens. They are also involved in the normal response to tissue injury. However, mast cells are involved in disease processes characterized by inflammation and remodeling of tissue structure. In these diseases mast cells are often inappropriately and chronically activated. There is evidence for activation of mast cells contributing to the pathophysiology of asthma, pulmonary fibrosis, and pulmonary hypertension. They may also play a role in chronic obstructive pulmonary disease, acute respiratory distress syndrome, and lung cancer. The diverse mechanisms through which mast cells sense and interact with the external and internal microenvironment account for their role in these diseases. Newly discovered mechanisms of redistribution and interaction between mast cells, airway structural cells, and other inflammatory cells may offer novel therapeutic targets in these disease processes. PMID:26845625

  10. Physical activity, functional ability, and disease activity in children and adolescents with juvenile idiopathic arthritis.

    PubMed

    Gueddari, S; Amine, B; Rostom, S; Badri, D; Mawani, N; Ezzahri, M; Moussa, F; Shyen, S; Abouqal, R; Chkirat, B; Hajjaj-Hassouni, N

    2014-09-01

    Juvenile idiopathic arthritis (JIA) is a chronic condition known to cause pain-related complications in youth and affect children's physical functioning. There is no data in Arabic children with JIA about the impact of illness upon their physical activity. The objective of this study was to explore physical activity (PA) in children and adolescents with JIA compared with a healthy population and to examine associations between PA, functional ability, and disease activity. Our study included patients with JIA and group control aged between 8 and 17 years. The diagnosis was used according to the International League of Association of Rheumatology (ILAR) criteria 2001. Sociodemographic data and clinical features were collected. Physical activity level and energy expenditure were assessed with a 1-day activity diary and the metabolic equivalent (MET), respectively. Functional ability was assessed with the Moroccan version of the Childhood Health Assessment Questionnaire (CHAQ). Disease activity was measured using the Juvenile Arthritis Disease Activity Score (JADAS). Fifty patients and 50 controls were included (mean ± SD age 11.5 ± 3.3 and 10.5 ± 3.8 years, respectively; p = 0.49) with masculine predominance n = 30 (59.6 %) and n = 29 (58 %), respectively (p = 0.26). The median disease duration was 4.3 years (2-5). The median analog scale (VAS) pain was 20 (10-40). Fourteen patients (28 %) had an active disease. Patient population consisted in majority of oligoarticular arthritis (28 %), 14 patients. The mean of energy expenditure and physical activity were significantly higher in the JIA group. The JIA group spent more time in bed and less time on moderate to vigorous PA than the control group. There is no significant relationship between PA, functional ability, and disease activity. Our study suggests that children and adolescents with JIA have low PA levels and are at risk of losing the benefits of PA. Low PA is not related to

  11. Immunologic findings, thrombocytopenia and disease activity in lupus nephritis.

    PubMed Central

    Clark, W. F.; Linton, A. L.; Cordy, P. E.; Keown, P. E.; Lohmann, R. C.; Lindsay, R. M.

    1978-01-01

    Twenty patients with nephritis due to systemic lupus erythematosus were followed up for a mean of 34 months after renal biopsy with serial determinations of total serum complement and C3 and C4 concentrations, binding of deoxyribonucleic acid (DNA), antinuclear antibody pattern and platelet count. There were 25 episodes of nonhematologic observed disease activity in 16 of the 20 patients; elevated DNA binding and thrombocytopenia correlated well with these episodes. The mean platelet count during episodes of observed disease activity was 96 +/- 42 X 10(9)/L, which was significantly different from the mean count of 248 +/- 90 X 10(9)/L during disease quiescence. The proportion of false-positive results with the immunologic tests varied from 25% to 67% and with platelet counts it was 11%. It is suggested that thrombocytopenia may be a simple and accurate index of disease activity in lupus nephritis. PMID:350367

  12. Exercise Decreases Risk of Future Active Disease in Inflammatory Bowel Disease Patients in Remission

    PubMed Central

    Jones, Patricia D.; Kappelman, Michael D.; Martin, Christopher F.; Chen, Wenli; Sandler, Robert S.; Long, Millie D.

    2015-01-01

    Background Although exercise impacts quality of life in patients with inflammatory bowel disease (IBD), little is known about its role in disease activity. Among IBD patients in remission, we aimed to evaluate the association between exercise and subsequent active disease. Methods We performed a prospective study using the Crohn's and Colitis Foundation of America (CCFA) Partners Internet-based cohort of individuals with self-reported IBD. We identified participants in remission, defined as short Crohn's disease activity index (sCDAI) <150 or simple clinical colitis activity index (SCCAI) ≤2. The primary exposure was exercise status, measured using the validated Godin leisure time activity index. The primary study outcome, assessed after six months, was active disease defined using the above disease activity index thresholds. We used bivariate and multivariate analyses to describe the independent association between exercise and risk of active disease. Results We identified 1308 patients with Crohn's Disease (CD) and 549 with ulcerative or indeterminate colitis (UC/IC) in remission, of whom 227(17.4%) with CD and 135 (24.6%) with UC/IC developed active disease after 6 months. Higher exercise level was associated with decreased risk of active disease for CD (adjusted RR 0.72, 95% CI 0.55-0.94) and UC/IC (adjusted RR 0.78, 95% CI 0.54-1.13). Conclusions In patients with CD in remission, those with higher exercise levels were significantly less likely to develop active disease at six months. In patients with UC/IC in remission, patients with higher exercise levels were less likely to develop active disease at six months, however this was not statistically significant. PMID:25723616

  13. NALP3 inflammasome activation in protein misfolding diseases.

    PubMed

    Shi, Fushan; Kouadir, Mohammed; Yang, Yang

    2015-08-15

    Protein-misfolding diseases, such as Alzheimer's disease, type 2 diabetes, Prion diseases, and Parkinson's disease, are characterized by inflammatory reactions. In all these diseases, IL-1β (Interlukine-1β) has been shown to be an important regulator, and the misfolded proteins are proved to be triggers of the release of IL-1β. Recently, several reports demonstrated that the inflammasome activation is involved in the progress of the misfolded protein diseases, and that the inflammasome can recognize pathogenic proteins leading to the release of IL-1β. In this review, we discuss the role of inflammasome in the pathogenesis of misfolded protein diseases and the potential of inflammasome-targeting therapeutic interventions in the management of these diseases. PMID:26037399

  14. A Bioassay for Lafora Disease and Laforin Glucan Phosphatase Activity

    PubMed Central

    Sherwood, Amanda R.; Johnson, Mary Beth; Delgado-Escueta, Antonio V.; Gentry, Matthew S.

    2013-01-01

    Objectives Lafora disease is a rare yet invariably fatal form of progressive neurodegenerative epilepsy resulting from mutations in the phosphatase laforin. Several therapeutic options for Lafora disease patients are currently being explored, and these therapies would benefit from a biochemical means of assessing functional laforin activity following treatment. To date, only clinical outcomes such as decreases in seizure frequency and severity have been used to indicate success of epilepsy treatment. However, these qualitative measures exhibit variability and must be assessed over long periods of time. In this work, we detail a simple and sensitive bioassay that can be used for the detection of functional endogenous laforin from human and mouse tissue. Design and methods We generated antibodies capable of detecting and immunoprecipitating endogenous laforin. Following laforin immunoprecipitation, laforin activity was assessed via phosphatase assays using para-nitrophenylphosphate (pNPP) and a malachite green-based assay specific for glucan phosphatase activity. Results We found that antibody binding to laforin does not impede laforin activity. Furthermore, the malachite green-based glucan phosphatase assay used in conjunction with a rabbit polyclonal laforin antibody was capable of detecting endogenous laforin activity from human and mouse tissue. Importantly, this assay discriminated between laforin activity and other phosphatases. Conclusions The bioassay that we have developed utilizing laforin antibodies and an assay specific for glucan phosphatase activity could prove valuable in the rapid detection of functional laforin in patients to which novel Lafora disease therapies have been administered. PMID:24012855

  15. Glucocerebrosidase enzyme activity in GBA mutation Parkinson's disease.

    PubMed

    Ortega, Roberto A; Torres, Paola A; Swan, Matthew; Nichols, William; Boschung, Sarah; Raymond, Deborah; Barrett, Matthew J; Johannes, Brooke A; Severt, Lawrence; Shanker, Vicki; Hunt, Ann L; Bressman, Susan; Pastores, Gregory M; Saunders-Pullman, Rachel

    2016-06-01

    Mutations in the glucocerebrosidase (GBA1) gene, the most common genetic contributor to Parkinson's disease (PD), are associated with an increased risk of PD in heterozygous and homozygous carriers. While glucocerebrosidase enzyme (GCase) activity is consistently low in Gaucher disease, there is a range of leukocyte GCase activity in healthy heterozygous GBA1 mutation carriers. To determine whether GCase activity may be a marker for PD with heterozygous GBA1 mutations (GBA1 mutation PD, GBA PD), GBA PD patients (n=15) were compared to PD patients without heterozygous GBA1 mutations (idiopathic PD; n=8), heterozygous GBA1 carriers without PD (asymptomatic carriers; n=4), and biallelic mutation carriers with PD (Gaucher disease with PD, GD1 PD; n=3) in a pilot study. GCase activity (nmol/mg protein/hour) in GD1 PD (median [interquartile range]; minimum-maximum: 6.4 [5.7]; 5.3-11) was lower than that of GBA PD (16.0 [7.0]; 11-40) (p=0.01), while GCase activity in GBA PD was lower than idiopathic PD (28.5 [15.0]; 16-56) (p=0.01) and asymptomatic carriers (25.5 [2.5]; 23-27) (p=0.04). Therefore, GCase activity appears to be a possible marker of heterozygous GBA1 mutation PD, and larger studies are warranted. Prospective studies are also necessary to determine whether lower GCase activity precedes development of PD. PMID:26857292

  16. EULAR Sjogren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren's syndrome

    PubMed Central

    Seror, Raphaèle; Ravaud, Philippe; Bowman, Simon; Baron, Gabriel; Tzioufas, Athanasios; Theander, Elke; Gottenberg, Jacques-Eric; Bootsma, Hendrika; Mariette, Xavier; Vitali, Claudio

    2010-01-01

    Objective To develop a disease activity index for patients with primary Sjögren’s syndrome (SS): the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI). Methods Thirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific “domains” contributing to disease activity. For each domain, features of disease activity were classified in 3 or 4 levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0–10 physician global assessment (PhGA) scale, each expert scored the disease activity of 5 patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain. Results All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p<0.0001). Compared to 57 (59.4%) of the real patient profiles, 468 (66.7%) of the realistic vignettes were considered likely or very likely to be true. Conclusion The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardized evaluation of primary SS should facilitate clinical research and should be helpful as an outcome measure in clinical trials. PMID:19561361

  17. Diet and Physical Activity for Cardiovascular Disease Prevention.

    PubMed

    Lanier, Jeffrey B; Bury, David C; Richardson, Sean W

    2016-06-01

    Cardiovascular disease (CVD) is the leading cause of death in the United States. One-third of these deaths may be preventable through healthy lifestyle choices including diet and physical activity. The Mediterranean diet is associated with reduced cardiovascular mortality, whereas the Dietary Approaches to Stop Hypertension (DASH) eating plan is associated with a reduced risk of coronary artery disease. Substituting dietary saturated fat with polyunsaturated fatty acids is associated with improved cardiovascular outcomes, although exogenous supplementation with omega-3 fatty acids does not improve cardiovascular outcomes. There is an association between increased sodium intake and cardiovascular risk, but reducing dietary sodium has not consistently shown a reduction in cardiovascular risk. Physical activity recommendations for adults are at least 150 minutes of moderate-intensity aerobic activity per week, 75 minutes of vigorous-intensity aerobic activity per week, or an equivalent combination. Increases in physical activity by any level are associated with reduced cardiovascular risk. Introducing muscle-strengthening activities at least twice per week in previously inactive adults is associated with improved cardiovascular outcomes. Inactive adults without known CVD can gradually increase activity to a moderate-intensity level without consulting a physician. The U.S. Preventive Services Task Force recommends behavioral counseling to promote healthy diet and physical activity in adults at high risk of CVD. Evidence of benefit for counseling patients at average risk is less established. PMID:27281836

  18. New advances on glial activation in health and disease

    PubMed Central

    Lee, Kim Mai; MacLean, Andrew G

    2015-01-01

    In addition to being the support cells of the central nervous system (CNS), astrocytes are now recognized as active players in the regulation of synaptic function, neural repair, and CNS immunity. Astrocytes are among the most structurally complex cells in the brain, and activation of these cells has been shown in a wide spectrum of CNS injuries and diseases. Over the past decade, research has begun to elucidate the role of astrocyte activation and changes in astrocyte morphology in the progression of neural pathologies, which has led to glial-specific interventions for drug development. Future therapies for CNS infection, injury, and neurodegenerative disease are now aimed at targeting astrocyte responses to such insults including astrocyte activation, astrogliosis and other morphological changes, and innate and adaptive immune responses. PMID:25964871

  19. Perivascular fat, AMP-activated protein kinase and vascular diseases

    PubMed Central

    Almabrouk, T A M; Ewart, M A; Salt, I P; Kennedy, S

    2014-01-01

    Perivascular adipose tissue (PVAT) is an active endocrine and paracrine organ that modulates vascular function, with implications for the pathophysiology of cardiovascular disease (CVD). Adipocytes and stromal cells contained within PVAT produce mediators (adipokines, cytokines, reactive oxygen species and gaseous compounds) with a range of paracrine effects modulating vascular smooth muscle cell contraction, proliferation and migration. However, the modulatory effect of PVAT on the vascular system in diseases, such as obesity, hypertension and atherosclerosis, remains poorly characterized. AMP-activated protein kinase (AMPK) regulates adipocyte metabolism, adipose biology and vascular function, and hence may be a potential therapeutic target for metabolic disorders such as type 2 diabetes mellitus (T2DM) and the vascular complications associated with obesity and T2DM. The role of AMPK in PVAT or the actions of PVAT have yet to be established, however. Activation of AMPK by pharmacological agents, such as metformin and thiazolidinediones, may modulate the activity of PVAT surrounding blood vessels and thereby contribute to their beneficial effect in cardiometabolic diseases. This review will provide a current perspective on how PVAT may influence vascular function via AMPK. We will also attempt to demonstrate how modulating AMPK activity using pharmacological agents could be exploited therapeutically to treat cardiometabolic diseases. PMID:24490856

  20. Activation of AMP-activated kinase as a strategy for managing autosomal dominant polycystic kidney disease.

    PubMed

    McCarty, Mark F; Barroso-Aranda, Jorge; Contreras, Francisco

    2009-12-01

    There is evidence that overactivity of both mammalian target of rapamycin (mTOR) and cystic fibrosis transmembrane conductance regulator (CFTR) contributes importantly to the progressive expansion of renal cysts in autosomal dominant polycystic kidney disease (ADPKD). Recent research has established that AMP-activated kinase (AMPK) can suppress the activity of each of these proteins. Clinical AMPK activators such as metformin and berberine may thus have potential in the clinical management of ADPKD. The traditional use of berberine in diarrhea associated with bacterial infections may reflect, in part, the inhibitory impact of AMPK on chloride extrusion by small intestinal enterocytes. PMID:19570618

  1. Platelet activity in the pathophysiology of inflammatory bowel diseases.

    PubMed

    Chen, Chunqiu; Li, Yongyu; Yu, Zhen; Liu, Zhanju; Shi, Yanhong; Lewandowska, Urszula; Sobczak, Marta; Fichna, Jakub; Kreis, Martin

    2015-01-01

    Platelets play a crucial role in immune responses. Impaired platelet activation may cause persistent mucosal inflammation through P-selectin, CD40-CD40L and other systems influencing granulocytes, macrophages or endothelial cells. Pharmacological regulation of platelet activation may reduce thromboembolism and limit the interaction of platelets with endothelial and inflammatory cells, in turn weakening the inflammatory responses. In this review we focus on pathophysiological activities of platelets in inflammatory bowel diseases and discuss the studies on currently available anti-platelet therapies in the treatment of gastrointestinal inflammation. Finally, we provide a prospective view to new anti-platelet agents currently under development. PMID:25585124

  2. Synchronizing activity of basal ganglia and pathophysiology of Parkinson's disease.

    PubMed

    Heimer, G; Rivlin, M; Israel, Z; Bergman, H

    2006-01-01

    Early physiological studies emphasized changes in the discharge rate of basal ganglia in the pathophysiology of Parkinson's disease (PD), whereas recent studies stressed the role of the abnormal oscillatory activity and neuronal synchronization of pallidal cells. However, human observations cast doubt on the synchronization hypothesis since increased synchronization may be an epi-phenomenon of the tremor or of independent oscillators with similar frequency. Here, we show that modern actor/ critic models of the basal ganglia predict the emergence of synchronized activity in PD and that significant non-oscillatory and oscillatory correlations are found in MPTP primates. We conclude that the normal fluctuation of basal ganglia dopamine levels combined with local cortico-striatal learning rules lead to noncorrelated activity in the pallidum. Dopamine depletion, as in PD, results in correlated pallidal activity, and reduced information capacity. We therefore suggest that future deep brain stimulation (DBS) algorithms may be improved by desynchronizing pallidal activity. PMID:17017503

  3. Linking estrogen receptor β expression with inflammatory bowel disease activity

    PubMed Central

    Pierdominici, Marina; Maselli, Angela; Varano, Barbara; Barbati, Cristiana; Cesaro, Paola; Spada, Cristiano; Zullo, Angelo; Lorenzetti, Roberto; Rosati, Marco; Rainaldi, Gabriella; Limiti, Maria Rosaria; Guidi, Luisa

    2015-01-01

    Crohn disease (CD) and ulcerative colitis (UC) are chronic forms of inflammatory bowel disease (IBD) whose pathogenesis is only poorly understood. Estrogens have a complex role in inflammation and growing evidence suggests that these hormones may impact IBD pathogenesis. Here, we demonstrated a significant reduction (p < 0.05) of estrogen receptor (ER)β expression in peripheral blood T lymphocytes from CD/UC patients with active disease (n = 27) as compared to those in remission (n = 21) and healthy controls (n = 29). Accordingly, in a subgroup of CD/UC patients undergoing to anti-TNF-α therapy and responsive to treatment, ERβ expression was higher (p < 0.01) than that observed in not responsive patients and comparable to that of control subjects. Notably, ERβ expression was markedly decreased in colonic mucosa of CD/UC patients with active disease, reflecting the alterations observed in peripheral blood T cells. ERβ expression inversely correlated with interleukin (IL)-6 serum levels and exogenous exposure of both T lymphocytes and intestinal epithelial cells to this cytokine resulted in ERβ downregulation. These results demonstrate that the ER profile is altered in active IBD patients at both mucosal and systemic levels, at least in part due to IL-6 dysregulation, and highlight the potential exploitation of T cell-associated ERβ as a biomarker of endoscopic disease activity. PMID:26497217

  4. [Macrophage activation syndrome associated with adult-onset Still's disease].

    PubMed

    Iwamoto, Masahiro

    2007-12-01

    Macrophage activation syndrome (MAS) is a rare and potentially lethal disease, resulting from uncontrolled activation and proliferation of T lymphocytes and macrophages. Adult-onset Still's disease (AOSD) is an inflammatory disease. AOSD resemble reactive MAS in its symptoms and laboratory data. Moreover, AOSD per se induces MAS. It is, therefore, quite difficult to differentiate these syndrome and disease. The immunodeficiency state induced by treatment in AOSD could reactivate latent viruses such as Epstein-Barr virus, which could potentially lead to MAS. The therapeutic agents for AOSD, such as sulfasalazine, also could provoke reactive MAS. Because multiple factors are involved in inducing MAS to a different degree, the main cause should be searched for and targeted for the therapy. PMID:18174671

  5. Natural Compounds Preventing Neurodegenerative Diseases Through Autophagic Activation.

    PubMed

    Huang, Zhe; Adachi, Hiroaki

    2016-06-01

    Neurodegenerative diseases (NDDs) are a group of intractable diseases that significantly affect human health. To date, the pathogenesis of NDDs is still poorly understood and effective disease-modifying therapies for NDDs have not been established. NDDs share the common morphological characteristic of the deposition of abnormal proteins in the nervous system, including neurons. Autophagy is one of the major processes by which damaged organelles and abnormal proteins are removed from cells. Impairment of autophagy has been found to be involved in the pathogenesis of NDDs, and the regulation of autophagy may become a therapeutic strategy for NDDs. In recent years, some active compounds from plants have been found to regulate autophagy and exert neuroprotection against NDDs, including Alzheimer's disease, Parkinson's disease, Huntington's disease, spinal and bulbar muscular atrophy, spinocerebellar ataxia 3, and amyotrophic lateral sclerosis, via activating autophagy. In this paper, we review recent advances in the use of active ingredients from plants for the regulation of autophagy and treatment of NDDs. PMID:27302727

  6. Elevation of Serum Acid Sphingomyelinase Activity in Acute Kawasaki Disease.

    PubMed

    Konno, Yuuki; Takahashi, Ikuko; Narita, Ayuko; Takeda, Osamu; Koizumi, Hiromi; Tamura, Masamichi; Kikuchi, Wataru; Komatsu, Akira; Tamura, Hiroaki; Tsuchida, Satoko; Noguchi, Atsuko; Takahashi, Tsutomu

    2015-01-01

    Kawasaki disease (KD) is an acute systemic vasculitis that affects both small and medium-sized vessels including the coronary arteries in infants and children. Acid sphingomyelinase (ASM) is a lysosomal glycoprotein that hydrolyzes sphingomyelin to ceramide, a lipid, that functions as a second messenger in the regulation of cell functions. ASM activation has been implicated in numerous cellular stress responses and is associated with cellular ASM secretion, either through alternative trafficking of the ASM precursor protein or by means of an unidentified mechanism. Elevation of serum ASM activity has been described in several human diseases, suggesting that patients with diseases involving vascular endothelial cells may exhibit a preferential elevation of serum ASM activity. As acute KD is characterized by systemic vasculitis that could affect vascular endothelial cells, the elevation of serum ASM activity should be considered in these patients. In the present study, serum ASM activity in the sera of 15 patients with acute KD was determined both before and after treatment with infusion of high-dose intravenous immunoglobulin (IVIG), a first-line treatment for acute KD. Serum ASM activity before IVIG was significantly elevated in KD patients when compared to the control group (3.85 ± 1.46 nmol/0.1 ml/6 h vs. 1.15 ± 0.10 nmol/0.1 ml/6 h, p < 0.001), suggesting that ASM activation may be involved in the pathophysiology of this condition. Serum ASM activity before IVIG was significantly correlated with levels of C-reactive protein (p < 0.05). These results suggest the involvement of sphingolipid metabolism in the pathophysiology of KD. PMID:26447086

  7. Cardiac parasympathetic activity in severe uncomplicated coronary artery disease.

    PubMed Central

    Nolan, J.; Flapan, A. D.; Reid, J.; Neilson, J. M.; Bloomfield, P.; Ewing, D. J.

    1994-01-01

    BACKGROUND--Previous studies have suggested that coronary artery disease is independently associated with reduced cardiac parasympathetic activity, and that this is important in its pathophysiology. These studies included many patients with complications that might be responsible for the reported autonomic abnormalities. OBJECTIVE--To measure cardiac parasympathetic activity in patients with uncomplicated coronary artery disease. PATIENTS AND METHODS--44 patients of mean (SD) age 56 (8) with severe uncomplicated coronary artery disease (symptoms uncontrolled on maximal medical treatment; > 70% coronary stenosis at angiography; normal ejection fraction; no evidence of previous infarction, diabetes, or hypertension). Heart rate variability was measured from 24 hour ambulatory electrocardiograms by counting the number of times successive RR intervals exceeded the preceding RR interval by > 50 ms, a previously validated sensitive and specific index of cardiac parasympathetic activity. RESULTS--Mean (range) of counts were: waking 112 (range 6-501)/h, sleeping 198 (0-812)/h, and total 3912 (151-14 454)/24 h. These mean results were unremarkable, and < 10% of patients fell below the lower 95% confidence interval for waking, sleeping, or total 24 hour counts in normal people. There was no relation between the severity of coronary artery disease or the use of concurrent antianginal drug treatment and cardiac parasympathetic activity. CONCLUSION--In contrast with previous reports no evidence of a specific independent association between coronary artery disease and reduced cardiac parasympathetic activity was found. The results of previous studies may reflect the inclusion of patients with complications and not the direct effect of coronary artery disease itself. PMID:7913823

  8. Antibacterial Activity of Hawaiian Corals: Possible Protection from Disease?

    NASA Astrophysics Data System (ADS)

    Gochfeld, D. J.; Aeby, G. S.; Miller, J. D.

    2006-12-01

    Reports of coral diseases in the Caribbean have appeared with increasing frequency over the past two decades; however, records of coral diseases in the Pacific have lagged far behind. Recent surveys of coral disease in the Hawaiian Islands indicate relatively low, but consistent, levels of disease throughout the inhabited Main and uninhabited Northwestern Hawaiian Islands, and demonstrate variation in levels of disease among the major genera of Hawaiian corals. Although little is known about immune defense to disease in corals, one potential mechanism of defense is the production of antimicrobial compounds that protect corals from pathogens. A preliminary survey of antibacterial chemical defenses among three dominant species of Hawaiian corals was undertaken. Crude aqueous extracts of Porites lobata, Pocillopora meandrina and Montipora capitata were tested against nine strains of bacteria in a growth inhibition assay. Inhibitory extracts were further tested to determine whether their effects were cytostatic or cytotoxic. The bacteria selected included known coral pathogens, potential marine pathogens found in human waste and strains previously identified from the surfaces of Hawaiian corals. Extracts from all three species of coral exhibited a high degree of antibacterial activity, but also a high degree of selectivity against different bacterial strains. In addition, some extracts were stimulatory to some bacteria. In addition to interspecific variability, extracts also exhibited intraspecific variability, both within and between sites. Hawaiian corals have significant antibacterial activity, which may explain the relatively low prevalence of disease in these corals; however, further characterization of pathogens specifically responsible for disease in Hawaiian corals is necessary before we can conclude that antibacterial activity protects Hawaiian corals from disease.

  9. Active immunotherapy options for Alzheimer’s disease

    PubMed Central

    2014-01-01

    Alzheimer’s disease (AD) is the most common cause of dementia and a major contributor to disability and dependency among older people. AD pathogenesis is associated with the accumulation of amyloid-beta protein (Aβ) and/or hyperphosphorylated tau protein in the brain. At present, current therapies provide temporary symptomatic benefit, but do not treat the underlying disease. Recent research has thus focused on investigating the molecular and cellular pathways and processes involved in AD pathogenesis to support the development of effective disease-modifying agents. In accordance with the existing Aβ-cascade hypothesis for AD pathogenesis, immunotherapy has been the most extensively studied approach in Aβ-targeted therapy. Both passive and active immunotherapies have been shown to effectively reduce Aβ accumulation and prevent downstream pathology in preclinical models. Following AN1792, second-generation active immunotherapies have shown promising results in terms of antibody response and safety. Comparatively, tau immunotherapy is not as advanced, but preclinical data support its development into clinical trials. Results from active amyloid-based immunotherapy studies in preclinical models indicate that intervention appears to be more effective in early stages of amyloid accumulation, highlighting the importance of diagnosing AD as early as possible and undertaking clinical trials at this stage. This strategy, combined with improving our understanding of the complex AD pathogenesis, is imperative to the successful development of these disease-modifying agents. This paper will review the active immunotherapies currently in development, including the benefits and challenges associated with this approach. PMID:24476230

  10. Glycosphingolipid synthesis inhibition limits osteoclast activation and myeloma bone disease

    PubMed Central

    Ersek, Adel; Xu, Ke; Antonopoulos, Aristotelis; Butters, Terry D.; Santo, Ana Espirito; Vattakuzhi, Youridies; Williams, Lynn M.; Goudevenou, Katerina; Danks, Lynett; Freidin, Andrew; Spanoudakis, Emmanouil; Parry, Simon; Papaioannou, Maria; Hatjiharissi, Evdoxia; Chaidos, Aristeidis; Alonzi, Dominic S.; Twigg, Gabriele; Hu, Ming; Dwek, Raymond A.; Haslam, Stuart M.; Roberts, Irene; Dell, Anne; Rahemtulla, Amin; Horwood, Nicole J.; Karadimitris, Anastasios

    2015-01-01

    Glycosphingolipids (GSLs) are essential constituents of cell membranes and lipid rafts and can modulate signal transduction events. The contribution of GSLs in osteoclast (OC) activation and osteolytic bone diseases in malignancies such as the plasma cell dyscrasia multiple myeloma (MM) is not known. Here, we tested the hypothesis that pathological activation of OCs in MM requires de novo GSL synthesis and is further enhanced by myeloma cell–derived GSLs. Glucosylceramide synthase (GCS) inhibitors, including the clinically approved agent N-butyl-deoxynojirimycin (NB-DNJ), prevented OC development and activation by disrupting RANKL-induced localization of TRAF6 and c-SRC into lipid rafts and preventing nuclear accumulation of transcriptional activator NFATc1. GM3 was the prevailing GSL produced by patient-derived myeloma cells and MM cell lines, and exogenous addition of GM3 synergistically enhanced the ability of the pro-osteoclastogenic factors RANKL and insulin-like growth factor 1 (IGF-1) to induce osteoclastogenesis in precursors. In WT mice, administration of GM3 increased OC numbers and activity, an effect that was reversed by treatment with NB-DNJ. In a murine MM model, treatment with NB-DNJ markedly improved osteolytic bone disease symptoms. Together, these data demonstrate that both tumor-derived and de novo synthesized GSLs influence osteoclastogenesis and suggest that NB-DNJ may reduce pathological OC activation and bone destruction associated with MM. PMID:25915583

  11. Chronic lymphocytic leukemia: a disease of activated monoclonal B cells

    PubMed Central

    Damle, Rajendra N.; Calissano, Carlo; Chiorazzi, Nicholas

    2010-01-01

    B-cell type chronic lymphocytic leukemia (CLL) has long been considered a disease of resting lymphocytes. However cell surface and intracellular phenotypes suggest that most CLL cells are activated cells, although only a small subset progresses beyond the G1 stage of the cell cycle. In addition, traditional teaching says that CLL cells divide rarely, and therefore the buildup of leukemic cells is due to an inherent defect in cell death. However, in vivo labeling of CLL cells indicates a much more active rate of cell birth than originally estimated, suggesting that CLL is a dynamic disease. Here we review the observations that have led to these altered views of the activation state and proliferative capacities of CLL cells and also provide our interpretation of these observations in light of their potential impact on patients. PMID:20620969

  12. Diversity and Activity of Lysobacter Species from Disease Suppressive Soils

    PubMed Central

    Gómez Expósito, Ruth; Postma, Joeke; Raaijmakers, Jos M.; De Bruijn, Irene

    2015-01-01

    The genus Lysobacter includes several species that produce a range of extracellular enzymes and other metabolites with activity against bacteria, fungi, oomycetes, and nematodes. Lysobacter species were found to be more abundant in soil suppressive against the fungal root pathogen Rhizoctonia solani, but their actual role in disease suppression is still unclear. Here, the antifungal and plant growth-promoting activities of 18 Lysobacter strains, including 11 strains from Rhizoctonia-suppressive soils, were studied both in vitro and in vivo. Based on 16S rRNA sequencing, the Lysobacter strains from the Rhizoctonia-suppressive soil belonged to the four species Lysobacter antibioticus, Lysobacter capsici, Lysobacter enzymogenes, and Lysobacter gummosus. Most strains showed strong in vitro activity against R. solani and several other pathogens, including Pythium ultimum, Aspergillus niger, Fusarium oxysporum, and Xanthomonas campestris. When the Lysobacter strains were introduced into soil, however, no significant and consistent suppression of R. solani damping-off disease of sugar beet and cauliflower was observed. Subsequent bioassays further revealed that none of the Lysobacter strains was able to promote growth of sugar beet, cauliflower, onion, and Arabidopsis thaliana, either directly or via volatile compounds. The lack of in vivo activity is most likely attributed to poor colonization of the rhizosphere by the introduced Lysobacter strains. In conclusion, our results demonstrated that Lysobacter species have strong antagonistic activities against a range of pathogens, making them an important source for putative new enzymes and antimicrobial compounds. However, their potential role in R. solani disease suppressive soil could not be confirmed. In-depth omics'–based analyses will be needed to shed more light on the potential contribution of Lysobacter species to the collective activities of microbial consortia in disease suppressive soils. PMID:26635735

  13. Diversity and Activity of Lysobacter Species from Disease Suppressive Soils.

    PubMed

    Gómez Expósito, Ruth; Postma, Joeke; Raaijmakers, Jos M; De Bruijn, Irene

    2015-01-01

    The genus Lysobacter includes several species that produce a range of extracellular enzymes and other metabolites with activity against bacteria, fungi, oomycetes, and nematodes. Lysobacter species were found to be more abundant in soil suppressive against the fungal root pathogen Rhizoctonia solani, but their actual role in disease suppression is still unclear. Here, the antifungal and plant growth-promoting activities of 18 Lysobacter strains, including 11 strains from Rhizoctonia-suppressive soils, were studied both in vitro and in vivo. Based on 16S rRNA sequencing, the Lysobacter strains from the Rhizoctonia-suppressive soil belonged to the four species Lysobacter antibioticus, Lysobacter capsici, Lysobacter enzymogenes, and Lysobacter gummosus. Most strains showed strong in vitro activity against R. solani and several other pathogens, including Pythium ultimum, Aspergillus niger, Fusarium oxysporum, and Xanthomonas campestris. When the Lysobacter strains were introduced into soil, however, no significant and consistent suppression of R. solani damping-off disease of sugar beet and cauliflower was observed. Subsequent bioassays further revealed that none of the Lysobacter strains was able to promote growth of sugar beet, cauliflower, onion, and Arabidopsis thaliana, either directly or via volatile compounds. The lack of in vivo activity is most likely attributed to poor colonization of the rhizosphere by the introduced Lysobacter strains. In conclusion, our results demonstrated that Lysobacter species have strong antagonistic activities against a range of pathogens, making them an important source for putative new enzymes and antimicrobial compounds. However, their potential role in R. solani disease suppressive soil could not be confirmed. In-depth omics'-based analyses will be needed to shed more light on the potential contribution of Lysobacter species to the collective activities of microbial consortia in disease suppressive soils. PMID:26635735

  14. Inflammation activation and resolution in human tendon disease

    PubMed Central

    Dakin, Stephanie G; Martinez, Fernando O; Yapp, Clarence; Wells, Graham; Oppermann, Udo; Dean, Benjamin JF; Smith, Richard DJ; Wheway, Kim; Watkins, Bridget; Roche, Lucy; Carr, Andrew J

    2016-01-01

    Improved understanding of the role of inflammation in tendon disease is required to facilitate therapeutic target discovery. We studied supraspinatus tendons from patients experiencing pain before and after surgical subacromial decompression treatment. Tendons were classified as having early, intermediate or advanced disease and inflammation was characterized through activation of pathways mediated by Interferon, NF-κB, glucocorticoid receptor and STAT-6. Inflammation signatures revealed expression of genes and proteins induced by Interferon and NF-κB in early stage disease and genes and proteins induced by STAT-6 and glucocorticoid receptor activation in advanced stage disease. The pro-resolving proteins FPR2/ALX and ChemR23 were increased in early stage disease compared to intermediate-advanced stage disease. Patients who were pain-free post-treatment had tendons with increased expression of CD206 and ALOX15 mRNA compared to tendons from patients who continued to experience pain post-treatment, suggesting that these genes and their pathways may moderate tendon pain. Stromal cells from diseased tendons cultured in vitro showed increased expression of NF-κB and Interferon target genes after treatment with lipopolysaccharide or IFNγ compared to stromal cells derived from healthy tendons. We identified 15-epi Lipoxin A4, a stable lipoxin metabolite derived from aspirin treatment, as potentially beneficial in the resolution of tendon inflammation. PMID:26511510

  15. Nutrition and Physical Activity in Nonalcoholic Fatty Liver Disease

    PubMed Central

    Oliveira, Claudia P.; de Lima Sanches, Priscila; de Abreu-Silva, Erlon Oliveira; Marcadenti, Aline

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and it is associated with other medical conditions such as diabetes mellitus, metabolic syndrome, and obesity. The mechanisms of the underlying disease development and progression are not completely established and there is no consensus concerning the pharmacological treatment. In the gold standard treatment for NAFLD weight loss, dietary therapy, and physical activity are included. However, little scientific evidence is available on diet and/or physical activity and NAFLD specifically. Many dietary approaches such as Mediterranean and DASH diet are used for treatment of other cardiometabolic risk factors such as insulin resistance and type-2 diabetes mellitus (T2DM), but on the basis of its components their role in NAFLD has been discussed. In this review, the implications of current dietary and exercise approaches, including Brazilian and other guidelines, are discussed, with a focus on determining the optimal nonpharmacological treatment to prescribe for NAFLD. PMID:26770987

  16. Nutrition and Physical Activity in Nonalcoholic Fatty Liver Disease.

    PubMed

    Oliveira, Claudia P; de Lima Sanches, Priscila; de Abreu-Silva, Erlon Oliveira; Marcadenti, Aline

    2016-01-01

    Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide and it is associated with other medical conditions such as diabetes mellitus, metabolic syndrome, and obesity. The mechanisms of the underlying disease development and progression are not completely established and there is no consensus concerning the pharmacological treatment. In the gold standard treatment for NAFLD weight loss, dietary therapy, and physical activity are included. However, little scientific evidence is available on diet and/or physical activity and NAFLD specifically. Many dietary approaches such as Mediterranean and DASH diet are used for treatment of other cardiometabolic risk factors such as insulin resistance and type-2 diabetes mellitus (T2DM), but on the basis of its components their role in NAFLD has been discussed. In this review, the implications of current dietary and exercise approaches, including Brazilian and other guidelines, are discussed, with a focus on determining the optimal nonpharmacological treatment to prescribe for NAFLD. PMID:26770987

  17. Inflammation, immune activation, and cardiovascular disease in HIV.

    PubMed

    Nou, Eric; Lo, Janet; Grinspoon, Steven K

    2016-06-19

    Cardiovascular disease is one of the leading causes of morbidity and mortality in people living with HIV. Several epidemiological studies have shown an increased risk of myocardial infarction and stroke compared to uninfected controls. Although traditional risk factors contribute to this increased risk of cardiovascular disease, HIV-specific mechanisms likely also play a role. Systemic inflammation has been linked to cardiovascular disease in several populations suffering from chronic inflammation, including people living with HIV. Although antiretroviral therapy reduces immune activation, levels of inflammatory markers remain elevated compared to uninfected controls. The causes of this sustained immune response are likely multifactorial and incompletely understood. In this review, we summarize the evidence describing the relationship between inflammation and cardiovascular disease and discuss potential anti-inflammatory treatment options for cardiometabolic disease in people living with HIV. PMID:27058351

  18. [Physical activity in basic and primary prevention of cardiovascular disease].

    PubMed

    Sobieszczańska, Małgorzata; Kałka, Dariusz; Pilecki, Witold; Adamus, Jerzy

    2009-06-01

    On account of the frequency of appearing and character of atherosclerosis cardiac vascular disease, one of the most crucial elements of effective fight against it is preparation of complex preventive programs including as vast number of population as possible. Consequently, Benjamin and Smitch suggested attaching the notion of basic prevention to the standard division into primary and secondary one. The basic prevention, carrying out in the general population, should concern genetic predisposition, psychosocial factors, keeping up proper body weight, healthy eating and physical activity. Especially high hopes are connected with high efficiency, simplicity and low money-consumption of preventive activities associated with physical activity modification, which has a crucial influence on reducing negative impact of atherosclerosis hazard. The results of numerous scientific research, carried out in many countries and on various, large groups, proved undoubtedly that at the healthy adult people of both sex the systematic physical activity of moderate intensification plays an essential part in preventing CVD and decreasing the death risk because of that reason as well. Moreover, systematic physical exercises show many other health-oriented actions, thanks to which they have an influence on decreasing premature and total death rate. The risk of incidence of civilization-related diseases such as diabetes type II, hypertension, obesity, osteoporosis, tumors (of large intestine, breast, prostatic gland) and depression has decreased significantly. Unequivocally positive influence has been proved at many observations dedicated to health recreational physical activity and physical activity connected with professional work based on aerobe effort. The positive effects have been also observed at children population and senior population which is more and more numerous and the most at risk. The beneficial action of physical activity is connected with direct effect on organism

  19. P21-activated kinase in inflammatory and cardiovascular disease

    PubMed Central

    Taglieri, Domenico M.; Ushio-Fukai, Masuko; Monasky, Michelle M.

    2014-01-01

    P-21 activated kinases, or PAKs, are serine–threonine kinases that serve a role in diverse biological functions and organ system diseases. Although PAK signaling has been the focus of many investigations, still our understanding of the role of PAK in inflammation is incomplete. This review consolidates what is known about PAK1 across several cell types, highlighting the role of PAK1 and PAK2 in inflammation in relation to NADPH oxidase activation. This review explores the physiological functions of PAK during inflammation, the role of PAK in several organ diseases with an emphasis on cardiovascular disease, and the PAK signaling pathway, including activators and targets of PAK. Also, we discuss PAK1 as a pharmacological anti-inflammatory target, explore the potentials and the limitations of the current pharmacological tools to regulate PAK1 activity during inflammation, and provide indications for future research. We conclude that a vast amount of evidence supports the idea that PAK is a central molecule in inflammatory signaling, thus making PAK1 itself a promising prospective pharmacological target. PMID:24794532

  20. Effect of 2 Psychotherapies on Depression and Disease Activity in Pediatric Crohn's Disease

    PubMed Central

    Youk, Ada O.; Gonzalez-Heydrich, Joseph; Bujoreanu, Simona I.; Weisz, John; Fairclough, Diane; Ducharme, Peter; Jones, Neil; Lotrich, Francis; Keljo, David; Srinath, Arvind; Bousvaros, Athos; Kupfer, David; DeMaso, David R.

    2015-01-01

    Background: Crohn's disease (CD) is associated with depression. It is unclear if psychosocial interventions offer benefit for depressive symptoms during active CD. In this secondary analysis of a larger study of treating depression in pediatric inflammatory bowel disease, we assessed whether cognitive behavioral therapy (CBT) would differentiate from supportive nondirective therapy in treating depression and disease activity in youth with CD. We also explored whether somatic depressive symptoms showed a different pattern of response in the overall sample and the subset with active inflammatory bowel disease. Methods: Youth with depression and CD (n = 161) were randomized to 3 months of CBT (teaching coping skills) or supportive nondirective therapy (supportive listening). Depressive severity was measured using the Children's Depression Rating Scale-Revised (CDRS-R) with the somatic depressive subtype consisting of those CDRS-R items, which significantly correlated with CD activity. Disease activity was measured by the Pediatric Crohn's disease Activity Index. Given the potential confound of higher dose steroids, subanalyses excluded subjects on >20 mg/d prednisone equivalent (n = 34). Results: Total CDRS-R scores in the overall sample significantly decreased over time after both treatments (P < 0.0001). Treatment with CBT was associated with a significantly greater improvement in the Pediatric Crohn's disease Activity Index (P = 0.05) and somatic depressive subtype (P = 0.03) in those with active inflammatory bowel disease (n = 95) compared with supportive nondirective therapy. After excluding those on steroids (n = 34), there was a significant improvement in total CDRS-R (P = 0.03) and in Pediatric Crohn's disease Activity Index (P = 0.03) after CBT. Conclusions: Psychotherapy may be a useful adjunct to treat depression in the context of CD-related inflammation in youth who are not concurrently on higher dose steroids. PMID:25822010

  1. Medicinal plant activity on Helicobacter pylori related diseases

    PubMed Central

    Wang, Yuan-Chuen

    2014-01-01

    More than 50% of the world population is infected with Helicobacter pylori (H. pylori). The bacterium highly links to peptic ulcer diseases and duodenal ulcer, which was classified as a group I carcinogen in 1994 by the WHO. The pathogenesis of H. pylori is contributed by its virulence factors including urease, flagella, vacuolating cytotoxin A (VacA), cytotoxin-associated gene antigen (Cag A), and others. Of those virulence factors, VacA and CagA play the key roles. Infection with H. pylori vacA-positive strains can lead to vacuolation and apoptosis, whereas infection with cagA-positive strains might result in severe gastric inflammation and gastric cancer. Numerous medicinal plants have been reported for their anti-H. pylori activity, and the relevant active compounds including polyphenols, flavonoids, quinones, coumarins, terpenoids, and alkaloids have been studied. The anti-H. pylori action mechanisms, including inhibition of enzymatic (urease, DNA gyrase, dihydrofolate reductase, N-acetyltransferase, and myeloperoxidase) and adhesive activities, high redox potential, and hydrophilic/hydrophobic natures of compounds, have also been discussed in detail. H. pylori-induced gastric inflammation may progress to superficial gastritis, atrophic gastritis, and finally gastric cancer. Many natural products have anti-H. pylori-induced inflammation activity and the relevant mechanisms include suppression of nuclear factor-κB and mitogen-activated protein kinase pathway activation and inhibition of oxidative stress. Anti-H. pylori induced gastric inflammatory effects of plant products, including quercetin, apigenin, carotenoids-rich algae, tea product, garlic extract, apple peel polyphenol, and finger-root extract, have been documented. In conclusion, many medicinal plant products possess anti-H. pylori activity as well as an anti-H. pylori-induced gastric inflammatory effect. Those plant products have showed great potential as pharmaceutical candidates for H. pylori

  2. Active immunization therapies for Parkinson's disease and multiple system atrophy.

    PubMed

    Schneeberger, Achim; Tierney, Lanay; Mandler, Markus

    2016-02-01

    Vaccination is increasingly being investigated as a potential treatment for synucleinopathies, a group of neurodegenerative diseases including Parkinson's disease, multiple system atrophy, and dementia with Lewy bodies associated with α-synuclein pathology. All lack a causal therapy. Development of novel, disease-altering treatment strategies is urgently needed. Vaccination has positioned itself as a prime strategy for addressing these diseases because it is broadly applicable, requires infrequent administration, and maintains low production costs for treating a large population or as a preventive measure. Current evidence points to a causal role of misfolded α-synuclein in the development and progression of synucleinopathies. In the past decade, significant progress in active immunization against α-synuclein has been shown both in preclinical animal models and in early clinical development. In this review, we describe the state-of-the-art in active immunization approaches to synucleinopathies, with a focus on advances in Parkinson's disease (PD) and multiple-system atrophy (MSA). We first review preclinical animal models, highlighting their progress in translation to the clinical setting. We then discuss current clinical applications, stressing different approaches taken to address α-synuclein pathology. Finally, we address challenges, trends, and future perspectives of current vaccination programs. PMID:26260853

  3. Calcium-Activated Potassium Channels: Potential Target for Cardiovascular Diseases.

    PubMed

    Dong, De-Li; Bai, Yun-Long; Cai, Ben-Zhi

    2016-01-01

    Ca(2+)-activated K(+) channels (KCa) are classified into three subtypes: big conductance (BKCa), intermediate conductance (IKCa), and small conductance (SKCa) KCa channels. The three types of KCa channels have distinct physiological or pathological functions in cardiovascular system. BKCa channels are mainly expressed in vascular smooth muscle cells (VSMCs) and inner mitochondrial membrane of cardiomyocytes, activation of BKCa channels in these locations results in vasodilation and cardioprotection against cardiac ischemia. IKCa channels are expressed in VSMCs, endothelial cells, and cardiac fibroblasts and involved in vascular smooth muscle proliferation, migration, vessel dilation, and cardiac fibrosis. SKCa channels are widely expressed in nervous and cardiovascular system, and activation of SKCa channels mainly contributes membrane hyperpolarization. In this chapter, we summarize the physiological and pathological roles of the three types of KCa channels in cardiovascular system and put forward the possibility of KCa channels as potential target for cardiovascular diseases. PMID:27038376

  4. Upper Airway Genioglossal Activity in Children with Sickle Cell Disease

    PubMed Central

    Huang, Jingtao; Pinto, Swaroop J.; Allen, Julian L.; Arens, Raanan; Bowdre, Cheryl Y.; Jawad, Abbas F.; Mason, Thornton B.A.; Ohene-Frempong, Kwaku; Smith-Whitley, Kim; Marcus, Carole L.

    2011-01-01

    Study Objectives: The prevalence of obstructive sleep apnea syndrome (OSAS) in sickle cell disease (SCD) has been reported to be higher than that in the general pediatric population. However, not all subjects with SCD develop OSAS. We hypothesized that SCD patients with OSAS have a blunted neuromuscular response to subatmospheric pressure loads during sleep, making them more likely to develop upper airway collapse. Design: Subjects with SCD with and without OSAS underwent pressure-flow measurements during sleep using intraoral surface electrodes to measure genioglossal EMG (EMGgg). Two techniques were applied to decrease the nasal pressure (PN) to subatmospheric levels, resulting in an activated and relatively hypotonic upper airway. The area under the curve of the inspiratory EMGgg moving time average was analyzed. EMGgg activity was expressed as a percentage of baseline. Changes in EMGgg in response to decrements in nasal pressure were expressed as the slope of the EMGgg vs. nasal pressure (slope of EMGgg-PN). Setting: Sleep laboratory. Participants: 4 children with SCD and OSAS and 18 children with SCD but without OSAS. Results: The major findings of this study were: (1) using the activated but not the hypotonic technique, the slope of EMGgg-PN was more negative in SCD controls than SCD OSAS; (2) the slope of EMGgg-PN was significantly lower using the activated technique compared to the hypotonic technique in SCD controls only; (3) similarly, the critical closing pressure, Pcrit, was more negative using the activated technique than the hypotonic technique in SCD controls but not in SCD OSAS. Conclusion: This preliminary study has shown that children with SCD but without OSAS have more prominent upper airway reflexes than children with SCD and OSAS. Citation: Huang J; Pinto SJ; Allen JL; Arens R; Bowdre CY; Jawad AF; Mason TBA; Ohene-Frempong K; Smith-Whitely K; Marcus CL. Upper airway genioglossal activity in children with sickle cell disease. SLEEP 2011

  5. Memory activation reveals abnormal EEG in preclinical Huntington's disease.

    PubMed

    van der Hiele, Karin; Jurgens, Caroline K; Vein, Alla A; Reijntjes, Robert H A M; Witjes-Ané, Marie-Noëlle W; Roos, Raymund A C; van Dijk, Gert; Middelkoop, Huub A M

    2007-04-15

    The EEG is potentially useful as a marker of early Huntington's disease (HD). In dementia, the EEG during a memory activation challenge showed abnormalities where the resting EEG did not. We investigated whether memory activation also reveals EEG abnormalities in preclinical HD. Sixteen mutation carriers for HD and 13 nonmutation carriers underwent neurological, neuropsychological, MRI and EEG investigations. The EEG was registered during a rest condition, i.e. eyes closed, and a working memory task. In each condition we determined absolute power in the theta (4-8 Hz) and alpha (8-13 Hz) bands and subsequently calculated relative alpha power. The EEG during eyes closed did not differ between groups. The EEG during memory activation showed less relative alpha power in mutation carriers as compared to nonmutation carriers, even though memory performance was similar [F (1,27) = 10.87; P = 0.003]. Absolute powers also showed less alpha power [F (1,27) = 7.02; P = 0.013] but similar theta power. No correlations were found between absolute and relative alpha power on the one hand and neuropsychological scores, motor scores or number of CAG repeats on the other. In conclusion, memory activation reveals functional brain changes in Huntington's disease before clinical signs become overt. PMID:17266047

  6. Neural activities during affective processing in people with Alzheimer's disease.

    PubMed

    Lee, Tatia M C; Sun, Delin; Leung, Mei-Kei; Chu, Leung-Wing; Keysers, Christian

    2013-03-01

    This study examined brain activities in people with Alzheimer's disease when viewing happy, sad, and fearful facial expressions of others. A functional magnetic resonance imaging and a voxel-based morphometry methodology together with a passive viewing of emotional faces paradigm were employed to compare the affective processing in 12 people with mild Alzheimer's disease and 12 matched controls. The main finding was that the clinical participants showed reduced activations in regions associated with the motor simulation system (the ventral premotor cortex) and in regions associated with emotional simulation-empathy (the anterior insula and adjacent frontal operculum). This regional decline in blood oxygen level-dependent signals appeared to be lateralized in the left hemisphere and was not related to any structural degeneration in the clinical participants. Furthermore, the regions that showed changes in neural activity differed for the 3 emotional facial expressions studied. Findings of our study indicate that neural changes in regions associated with the motor and emotional simulation systems might play an important role in the development of Alzheimer's disease. PMID:22840336

  7. Metabolic correlates of pallidal neuronal activity in Parkinson's disease.

    PubMed

    Eidelberg, D; Moeller, J R; Kazumata, K; Antonini, A; Sterio, D; Dhawan, V; Spetsieris, P; Alterman, R; Kelly, P J; Dogali, M; Fazzini, E; Beric, A

    1997-08-01

    We have used [18F]fluorodeoxyglucose and PET to identify specific metabolic covariance patterns associated with Parkinson's disease and related disorders previously. Nonetheless, the physiological correlates of these abnormal patterns are unknown. In this study we used PET to measure resting state glucose metabolism in 42 awake unmedicated Parkinson's disease patients prior to unilateral stereotaxic pallidotomy for relief of symptoms. Spontaneous single unit activity of the internal segment of the globus pallidus (GPi) was recorded intraoperatively in the same patients under identical conditions. The first 24 patients (Group A) were scanned on an intermediate resolution tomograph (full width at half maximum, 8 mm); the subsequent 18 patients (Group B) were scanned on a higher resolution tomograph (full width half maximum, 4.2 mm). We found significant positive correlations between GPi firing rates and thalamic glucose metabolism in both patient groups (Group A: r = 0.41, P < 0.05; Group B: r = 0.69, P < 0.005). In Group B, pixel-based analysis disclosed a significant focus of physiological-metabolic correlation involving the ventral thalamus and the GPi (statistical parametric map: P < 0.05, corrected). Regional covariance analysis demonstrated that internal pallidal neuronal activity correlated significantly (r = 0.65, P < 0.005) with the expression of a unique network characterized by covarying pallidothalamic and brainstem metabolic activity. Our findings suggest that the variability in pallidal neuronal firing rates in Parkinson's disease patients is associated with individual differences in the metabolic activity of efferent projection systems. PMID:9278625

  8. Parkinson's disease and CYP1A2 activity

    PubMed Central

    Forsyth, J T; Grünewald, R A; Rostami-Hodjegan, A; Lennard, M S; Sagar, H J; Tucker, G T

    2000-01-01

    Aims MPTP, a neurotoxin which induces parkinsonism is partially metabolized by the enzyme CYP1A2. Smoking appears to protect against Parkinson's disease (PD) and cigarette smoke induces CYP1A2 activity. Thus, we investigated the hypothesis that idiopathic PD is associated with lower CYP1A2 activity using caffeine as a probe compound. Methods CYP1A2 activity was assessed using saliva paraxanthine (PX) to caffeine (CA) ratios. Caffeine half-life was also estimated from salivary concentrations of caffeine at 2 and 5 h post dose. 117 treated and 40 untreated patients with PD and 105 healthy control subjects were studied. Results PX/CA ratios were 0.57, 0.93 and 0.77 in treated patients, untreated patients and healthy control subjects, respectively, with no significant differences between study groups (95% CI: treated patients vs controls −0.24, 0.57; untreated patients vs controls −0.75, 0.35). However, patients with PD (treated or untreated) had caffeine half-lives shorter than that in controls (treated patients: 262 min, untreated patients: 244 min, controls: 345 min; 95% CI: controls vs treated patients 23, 143 (P = 0.003); controls vs untreated patients 19, 184 (P = 0.011)). Amongst the patients with PD, caffeine half-life was also inversely related to the age of onset of disease (P = 0.012); gender and concomitant drugs did not influence this significantly. Conclusions Based on PX/CA ratio, there was no evidence of decreased CYP1A2 activity in patients compared with control subjects. The observed decrease in the elimination half-life of caffeine in PD may be caused by increased CYP2E1 activity, an enzyme that also contributes to the metabolism of caffeine. The latter warrants further investigation. PMID:11012552

  9. Reductions in disease activity in the AMPLE trial: clinical response by baseline disease duration

    PubMed Central

    Schiff, Michael; Weinblatt, Michael E; Valente, Robert; Citera, Gustavo; Maldonado, Michael; Massarotti, Elena; Yazici, Yusuf; Fleischmann, Roy

    2016-01-01

    Objectives To evaluate clinical response by baseline disease duration using 2-year data from the AMPLE trial. Methods Patients were randomised to subcutaneous abatacept 125 mg weekly or adalimumab 40 mg bi-weekly, with background methotrexate. As part of a post hoc analysis, the achievement of validated definitions of remission (Clinical Disease Activity Index (CDAI) ≤2.8, Simplified Disease Activity Index (SDAI) ≤3.3, Routine Assessment of Patient Index Data 3 (RAPID3) ≤3.0, Boolean score ≤1), low disease activity (CDAI <10, SDAI <11, RAPID3 ≤6.0), Health Assessment Questionnaire-Disability Index response and American College of Rheumatology responses were evaluated by baseline disease duration (≤6 vs >6 months). Disease Activity Score 28 (C-reactive protein) <2.6 or ≤3.2 and radiographic non-progression in patients achieving remission were also evaluated. Results A total of 646 patients were randomised and treated (abatacept, n=318; adalimumab, n=328). In both treatment groups, comparable responses were achieved in patients with early rheumatoid arthritis (≤6 months) and in those with later disease (>6 months) across multiple clinical measures. Conclusions Abatacept or adalimumab with background methotrexate were associated with similar onset and sustainability of response over 2 years. Patients treated early or later in the disease course achieved comparable clinical responses. Trial registration number NCT00929864, Post-results. PMID:27110385

  10. Sulforaphane Protects against Cardiovascular Disease via Nrf2 Activation

    PubMed Central

    Bai, Yang; Wang, Xiaolu; Zhao, Song; Ma, Chunye; Cui, Jiuwei; Zheng, Yang

    2015-01-01

    Cardiovascular disease (CVD) causes an unparalleled proportion of the global burden of disease and will remain the main cause of mortality for the near future. Oxidative stress plays a major role in the pathophysiology of cardiac disorders. Several studies have highlighted the cardinal role played by the overproduction of reactive oxygen or nitrogen species in the pathogenesis of ischemic myocardial damage and consequent cardiac dysfunction. Isothiocyanates (ITC) are sulfur-containing compounds that are broadly distributed among cruciferous vegetables. Sulforaphane (SFN) is an ITC shown to possess anticancer activities by both in vivo and epidemiological studies. Recent data have indicated that the beneficial effects of SFN in CVD are due to its antioxidant and anti-inflammatory properties. SFN activates NF-E2-related factor 2 (Nrf2), a basic leucine zipper transcription factor that serves as a defense mechanism against oxidative stress and electrophilic toxicants by inducing more than a hundred cytoprotective proteins, including antioxidants and phase II detoxifying enzymes. This review will summarize the evidence from clinical studies and animal experiments relating to the potential mechanisms by which SFN modulates Nrf2 activation and protects against CVD. PMID:26583056

  11. Functional activity of human hepatocytes under traumatic disease.

    PubMed

    Kudryavtseva, M V; Stein, G I; Shashkov, B V; Kudryavtsev, B N

    1998-03-01

    Absorption and fluorescent cytophotometry techniques were applied to studies of RNA as well as of total glycogen and its fractions as the parameters of functional activity of the hepatocytes in patients with severe mechanical trauma, both with and without autointoxication (AI). Slides were stained with gallocyanine-chromalums to determine the RNA content and were processed by the fluorescent PAS-reaction for the glycogen content. To trace the dynamics of RNA and glycogen contents in the liver punction biopsies were done in the same patients. A quick increase in the RNA content took place in both groups of patients at the first period (within the first 3 days) of traumatic disease. At the second period of disease the hepatocyte RNA content in patients without AI was found to decrease up to the initial level whereas that in patients with AI increased on the average by 36% of the initial values. The total glycogen content in hepatocytes of all the patients changed insignificantly in the course of disease but its labile fraction in patients with AI decreased to 70% of the total. The increase of hepatocyte synthetic activity and the maintenance of the high glycogen level are indicative of the large compensatory potential of the liver that enables it to carry an intensive functional load under AI conditions. PMID:9570502

  12. Subcortical evoked activity and motor enhancement in Parkinson's disease

    PubMed Central

    Anzak, Anam; Tan, Huiling; Pogosyan, Alek; Khan, Sadaquate; Javed, Shazia; Gill, Steven S.; Ashkan, Keyoumars; Akram, Harith; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Green, Alexander L.; Aziz, Tipu; Brown, Peter

    2016-01-01

    Enhancements in motor performance have been demonstrated in response to intense stimuli both in healthy subjects and in the form of ‘paradoxical kinesis’ in patients with Parkinson's disease. Here we identify a mid-latency evoked potential in local field potential recordings from the region of the subthalamic nucleus, which scales in amplitude with both the intensity of the stimulus delivered and corresponding enhancements in biomechanical measures of maximal handgrips, independent of the dopaminergic state of our subjects with Parkinson's disease. Recordings of a similar evoked potential in the related pedunculopontine nucleus – a key component of the reticular activating system – provide support for this neural signature in the subthalmic nucleus being a novel correlate of ascending arousal, propagated from the reticular activating system to exert an ‘energizing’ influence on motor circuitry. Future manipulation of this system linking arousal and motor performance may provide a novel approach for the non-dopaminergic enhancement of motor performance in patients with hypokinetic disorders such as Parkinson's disease. PMID:26687971

  13. Pharmacological treatment options for mast cell activation disease.

    PubMed

    Molderings, Gerhard J; Haenisch, Britta; Brettner, Stefan; Homann, Jürgen; Menzen, Markus; Dumoulin, Franz Ludwig; Panse, Jens; Butterfield, Joseph; Afrin, Lawrence B

    2016-07-01

    Mast cell activation disease (MCAD) is a term referring to a heterogeneous group of disorders characterized by aberrant release of variable subsets of mast cell (MC) mediators together with accumulation of either morphologically altered and immunohistochemically identifiable mutated MCs due to MC proliferation (systemic mastocytosis [SM] and MC leukemia [MCL]) or morphologically ordinary MCs due to decreased apoptosis (MC activation syndrome [MCAS] and well-differentiated SM). Clinical signs and symptoms in MCAD vary depending on disease subtype and result from excessive mediator release by MCs and, in aggressive forms, from organ failure related to MC infiltration. In most cases, treatment of MCAD is directed primarily at controlling the symptoms associated with MC mediator release. In advanced forms, such as aggressive SM and MCL, agents targeting MC proliferation such as kinase inhibitors may be provided. Targeted therapies aimed at blocking mutant protein variants and/or downstream signaling pathways are currently being developed. Other targets, such as specific surface antigens expressed on neoplastic MCs, might be considered for the development of future therapies. Since clinicians are often underprepared to evaluate, diagnose, and effectively treat this clinically heterogeneous disease, we seek to familiarize clinicians with MCAD and review current and future treatment approaches. PMID:27132234

  14. Subcortical evoked activity and motor enhancement in Parkinson's disease.

    PubMed

    Anzak, Anam; Tan, Huiling; Pogosyan, Alek; Khan, Sadaquate; Javed, Shazia; Gill, Steven S; Ashkan, Keyoumars; Akram, Harith; Foltynie, Thomas; Limousin, Patricia; Zrinzo, Ludvic; Green, Alexander L; Aziz, Tipu; Brown, Peter

    2016-03-01

    Enhancements in motor performance have been demonstrated in response to intense stimuli both in healthy subjects and in the form of 'paradoxical kinesis' in patients with Parkinson's disease. Here we identify a mid-latency evoked potential in local field potential recordings from the region of the subthalamic nucleus, which scales in amplitude with both the intensity of the stimulus delivered and corresponding enhancements in biomechanical measures of maximal handgrips, independent of the dopaminergic state of our subjects with Parkinson's disease. Recordings of a similar evoked potential in the related pedunculopontine nucleus - a key component of the reticular activating system - provide support for this neural signature in the subthalmic nucleus being a novel correlate of ascending arousal, propagated from the reticular activating system to exert an 'energizing' influence on motor circuitry. Future manipulation of this system linking arousal and motor performance may provide a novel approach for the non-dopaminergic enhancement of motor performance in patients with hypokinetic disorders such as Parkinson's disease. PMID:26687971

  15. Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease

    PubMed Central

    Naranjo, José R.; Zhang, Hongyu; Villar, Diego; González, Paz; Dopazo, Xose M.; Morón-Oset, Javier; Higueras, Elena; Oliveros, Juan C.; Arrabal, María D.; Prieto, Angela; Cercós, Pilar; González, Teresa; De la Cruz, Alicia; Casado-Vela, Juan; Rábano, Alberto; Valenzuela, Carmen; Gutierrez-Rodriguez, Marta; Li, Jia-Yi; Mellström, Britt

    2016-01-01

    Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD. PMID:26752648

  16. Study on cholesteryl ester transfer activity in coronary heart disease.

    PubMed

    Fujinuma, Y; Tanaka, A; Maezawa, H

    1991-09-01

    The net cholesterol transfer activity from high density lipoprotein (HDL) to low density lipoprotein (LDL) was determined in the patients with coronary heart disease (CHD) to examine its effect on the pathogenesis of arteriosclerosis. Furthermore, in the CHD patients with high HDL cholesterolemia (more than 60 mg/dl), the HDL particle size was measured by high performance liquid chromatography. A significant cholesteryl ester transfer activity (P less than 0.02) was noted in the CHD patients with low HDL cholesterolemia (less than 60 mg/dl). The rate of cholesteryl ester transfer activity (cholesteryl ester transfer activity/hour) inversely correlated with the serum HDL cholesterol value (r = -0.483, P = 0.096) in the patients with CHD. These results suggest that an increase of CETA caused a low HDL cholesterol value in the CHD patients with low HDL cholesterolemia and it may have the risk of causing CHD. However, an increase of the CETA was not found in the CHD patients with high HDL cholesterolemia compared to the normal subjects, the HDL particle size being significantly greater than that in the normal subjects. In the CHD patients with high HDL cholesterolemia, the large size of HDL may have the risk of causing CHD. PMID:1934199

  17. Activating transcription factor 6 derepression mediates neuroprotection in Huntington disease.

    PubMed

    Naranjo, José R; Zhang, Hongyu; Villar, Diego; González, Paz; Dopazo, Xose M; Morón-Oset, Javier; Higueras, Elena; Oliveros, Juan C; Arrabal, María D; Prieto, Angela; Cercós, Pilar; González, Teresa; De la Cruz, Alicia; Casado-Vela, Juan; Rábano, Alberto; Valenzuela, Carmen; Gutierrez-Rodriguez, Marta; Li, Jia-Yi; Mellström, Britt

    2016-02-01

    Deregulated protein and Ca2+ homeostasis underlie synaptic dysfunction and neurodegeneration in Huntington disease (HD); however, the factors that disrupt homeostasis are not fully understood. Here, we determined that expression of downstream regulatory element antagonist modulator (DREAM), a multifunctional Ca2+-binding protein, is reduced in murine in vivo and in vitro HD models and in HD patients. DREAM downregulation was observed early after birth and was associated with endogenous neuroprotection. In the R6/2 mouse HD model, induced DREAM haplodeficiency or blockade of DREAM activity by chronic administration of the drug repaglinide delayed onset of motor dysfunction, reduced striatal atrophy, and prolonged life span. DREAM-related neuroprotection was linked to an interaction between DREAM and the unfolded protein response (UPR) sensor activating transcription factor 6 (ATF6). Repaglinide blocked this interaction and enhanced ATF6 processing and nuclear accumulation of transcriptionally active ATF6, improving prosurvival UPR function in striatal neurons. Together, our results identify a role for DREAM silencing in the activation of ATF6 signaling, which promotes early neuroprotection in HD. PMID:26752648

  18. [The biological activity of macrophages in health and disease].

    PubMed

    Nazimek, Katarzyna; Bryniarski, Krzysztof

    2012-01-01

    Macrophages are involved in immune response as phagocytes, antigen presenting cells and as effector cells of delayed-type hypersensitivity. Moreover, the activity of macrophages is associated with modulation of many biological processes during the whole life and depends on the actual macrophage phenotype induced under the influence of various microenvironmental stimuli. In pregnancy, placental macrophages induce the development of maternal tolerance to fetal antigens, while fetal macrophages are responsible for proper formation of tissues and organs. Residual macrophages play a very important role in tissue homeostasis, apoptotic cell clearance to prevent autoimmunization and first defense in infections. The inflammatory response of macrophages may be modulated by pathogens. Their suppressive activity is observed in immunologically privileged organs such as testes. In pathologies, macrophages are responsible for tissue damage in a case of nonspecific activation followed by overproduction of proinflammatory factors. Suppression of a specific immune response against tumors is mainly the effect of tumor associated macrophage (TAM) action. On the other hand, presentation of allergens or self-antigens by macrophages and their nonspecific activation by necrotic adipocytes leads to the induction of a chronic inflammatory response and impairment of immunity. Therefore, modulation of macrophage functions may be the key for improvement of therapy of cancer and allergic, autoimmune, metabolic, cardiovascular and Alzheimer's diseases. PMID:22922151

  19. Activity enhances dopaminergic long-duration response in Parkinson disease

    PubMed Central

    Auinger, Peggy; Fahn, Stanley; Oakes, David; Shoulson, Ira; Kieburtz, Karl; Rudolph, Alice; Marek, Kenneth; Seibyl, John; Lang, Anthony; Olanow, C. Warren; Tanner, Caroline; Schifitto, Giovanni; Zhao, Hongwei; Reyes, Lydia; Shinaman, Aileen; Comella, Cynthia L.; Goetz, Christopher; Blasucci, Lucia M.; Samanta, Johan; Stacy, Mark; Williamson, Kelli; Harrigan, Mary; Greene, Paul; Ford, Blair; Moskowitz, Carol; Truong, Daniel D.; Pathak, Mayank; Jankovic, Joseph; Ondo, William; Atassi, Farah; Hunter, Christine; Jacques, Carol; Friedman, Joseph H.; Lannon, Margaret; Russell, David S.; Jennings, Danna; Fussell, Barbara; Standaert, David; Schwarzschild, Michael A.; Growdon, John H.; Tennis, Marsha; Gauthier, Serge; Panisset, Michel; Hall, Jean; Gancher, Stephen; Hammerstad, John P.; Stone, Claudia; Alexander-Brown, Barbara; Factor, Stewart A.; Molho, Eric; Brown, Diane; Evans, Sharon; Clark, Jeffrey; Manyam, Bala; Simpson, Patricia; Wulbrecht, Brian; Whetteckey, Jacqueline; Martin, Wayne; Roberts, Ted; King, Pamela; Hauser, Robert; Zesiewicz, Theresa; Gauger, Lisa; Trugman, Joel; Wooten, G. Frederick; Rost-Ruffner, Elke; Perlmutter, Joel; Racette, Brad A.; Suchowersky, Oksana; Ranawaya, Ranjit; Wood, Susan; Pantella, Carol; Kurlan, Roger; Richard, Irene; Pearson, Nancy; Caviness, John N.; Adler, Charles; Lind, Marlene; Simuni, Tanya; Siderowf, Andrew; Colcher, Amy; Lloyd, Mary; Weiner, William; Shulman, Lisa; Koller, William; Lyons, Kelly; Feldman, Robert G.; Saint-Hilaire, Marie H.; Ellias, Samuel; Thomas, Cathi-Ann; Juncos, Jorge; Watts, Ray; Partlow, Anna; Tetrud, James; Togasaki, Daniel M.; Stewart, Tracy; Mark, Margery H.; Sage, Jacob I.; Caputo, Debbie; Gould, Harry; Rao, Jayaraman; McKendrick, Ann; Brin, Mitchell; Danisi, Fabio; Benabou, Reina; Hubble, Jean; Paulson, George W.; Reider, Carson; Birnbaum, Alex; Miyasaki, Janis; Johnston, Lisa; So, Julie; Pahwa, Rajesh; Dubinsky, Richard M.; Wszolek, Zbigniew; Uitti, Ryan; Turk, Margaret; Tuite, Paul; Rottenberg, David; Hansen, Joy; Ramos, Serrano; Waters, Cheryl; Lew, Mark; Welsh, Mickie; Kawai, Connie; O'Brien, Christopher; Kumar, Rajeev; Seeberger, Lauren; Judd, Deborah; Barclay, C. Lynn; Grimes, David A.; Sutherland, Laura; Dawson, Ted; Reich, Stephen; Dunlop, Rebecca; Albin, Roger; Frey, Kirk; Wernette, Kristine; Fahn, Stanley; Oakes, David; Shoulson, Ira; Kieburtz, Karl; Rudolph, Alice; Marek, Kenneth; Seibyl, John; Lang, Anthony; Olanow, C. Warren; Tanner, Caroline; Schifitto, Giovanni; Zhao, Hongwei; Reyes, Lydia; Shinaman, Aileen; Comella, Cynthia L.; Goetz, Christopher; Blasucci, Lucia M.; Samanta, Johan; Stacy, Mark; Williamson, Kelli; Harrigan, Mary; Greene, Paul; Ford, Blair; Moskowitz, Carol; Truong, Daniel D.; Pathak, Mayank; Jankovic, Joseph; Ondo, William; Atassi, Farah; Hunter, Christine; Jacques, Carol; Friedman, Joseph H.; Lannon, Margaret; Russell, David S.; Jennings, Danna; Fussell, Barbara; Standaert, David; Schwarzschild, Michael A.; Growdon, John H.; Tennis, Marsha; Gauthier, Serge; Panisset, Michel; Hall, Jean; Gancher, Stephen; Hammerstad, John P.; Stone, Claudia; Alexander-Brown, Barbara; Factor, Stewart A.; Molho, Eric; Brown, Diane; Evans, Sharon; Clark, Jeffrey; Manyam, Bala; Simpson, Patricia; Wulbrecht, Brian; Whetteckey, Jacqueline; Martin, Wayne; Roberts, Ted; King, Pamela; Hauser, Robert; Zesiewicz, Theresa; Gauger, Lisa; Trugman, Joel; Wooten, G. Frederick; Rost-Ruffner, Elke; Perlmutter, Joel; Racette, Brad A.; Suchowersky, Oksana; Ranawaya, Ranjit; Wood, Susan; Pantella, Carol; Kurlan, Roger; Richard, Irene; Pearson, Nancy; Caviness, John N.; Adler, Charles; Lind, Marlene; Simuni, Tanya; Siderowf, Andrew; Colcher, Amy; Lloyd, Mary; Weiner, William; Shulman, Lisa; Koller, William; Lyons, Kelly; Feldman, Robert G.; Saint-Hilaire, Marie H.; Ellias, Samuel; Thomas, Cathi-Ann; Juncos, Jorge; Watts, Ray; Partlow, Anna; Tetrud, James; Togasaki, Daniel M.; Stewart, Tracy; Mark, Margery H.; Sage, Jacob I.; Caputo, Debbie; Gould, Harry; Rao, Jayaraman; McKendrick, Ann; Brin, Mitchell; Danisi, Fabio; Benabou, Reina; Hubble, Jean; Paulson, George W.; Reider, Carson; Birnbaum, Alex; Miyasaki, Janis; Johnston, Lisa; So, Julie; Pahwa, Rajesh; Dubinsky, Richard M.; Wszolek, Zbigniew; Uitti, Ryan; Turk, Margaret; Tuite, Paul; Rottenberg, David; Hansen, Joy; Ramos, Serrano; Waters, Cheryl; Lew, Mark; Welsh, Mickie; Kawai, Connie; O'Brien, Christopher; Kumar, Rajeev; Seeberger, Lauren; Judd, Deborah; Barclay, C. Lynn; Grimes, David A.; Sutherland, Laura; Dawson, Ted; Reich, Stephen; Dunlop, Rebecca; Albin, Roger; Frey, Kirk; Wernette, Kristine; Mendis, Tilak

    2012-01-01

    Objective: We tested the hypothesis that dopamine-dependent motor learning mechanism underlies the long-duration response to levodopa in Parkinson disease (PD) based on our studies in a mouse model. By data-mining the motor task performance in dominant and nondominant hands of the subjects in a double-blind randomized trial of levodopa therapy, the effects of activity and dopamine therapy were examined. Methods: We data-mined the Earlier versus Later Levodopa Therapy in Parkinson's Disease (ELLDOPA) study published in 2005 and performed statistical analysis comparing the effects of levodopa and dominance of handedness over 42 weeks. Results: The mean change in finger-tapping counts from baseline before the initiation of therapy to predose at 9 weeks and 40 weeks increased more in the dominant compared to nondominant hand in levodopa-treated subjects in a dose-dependent fashion. There was no significant difference in dominant vs nondominant hands in the placebo group. The short-duration response assessed by the difference of postdose performance compared to predose performance at the same visit did not show any significant difference between dominant vs nondominant hands. Conclusions: Active use of the dominant hand and dopamine replacement therapy produces synergistic effect on long-lasting motor task performance during “off” medication state. Such effect was confined to dopamine-responsive symptoms and not seen in dopamine-resistant symptoms such as gait and balance. We propose that long-lasting motor learning facilitated by activity and dopamine is a form of disease modification that is often seen in trials of medications that have symptomatic effects. PMID:22459675

  20. Metabolic correlates of subthalamic nucleus activity in Parkinson's disease.

    PubMed

    Lin, Tanya P; Carbon, Maren; Tang, Chengke; Mogilner, Alon Y; Sterio, Djordje; Beric, Aleksandar; Dhawan, Vijay; Eidelberg, David

    2008-05-01

    Overactivity of subthalamic nucleus (STN) neurons is a consistent feature of Parkinson's disease (PD) and is a target of therapy for this disorder. However, the relationship of STN firing rate to regional brain function is not known. We scanned 17 PD patients with (18)F-fluorodeoxyglucose (FDG) PET to measure resting glucose metabolism before the implantation of STN deep brain stimulation electrodes. Spontaneous STN firing rates were recorded during surgery and correlated with preoperative regional glucose metabolism on a voxel-by-voxel basis. We also examined the relationship between firing rate and the activity of metabolic brain networks associated with the motor and cognitive manifestations of the disease. Mean firing rates were 47.2 +/- 6.1 and 48.7 +/- 8.5 Hz for the left and right hemispheres, respectively. These measures correlated (P < 0.007) with glucose metabolism in the putamen and globus pallidus, which receive projections from this structure. Significant correlations (P < 0.0005) were also evident in the primary motor (BA4) and dorsolateral prefrontal (BA46/10) cortical areas. The activity of both the motor (P < 0.0001) and the cognitive (P < 0.006) PD-related metabolic networks was elevated in these patients. STN firing rates correlated with the activity of the former (P < 0.007) but not the latter network (P = 0.39). The findings suggest that the functional pathways associated with motor disability in PD are linked to the STN firing rate. These pathways are likely to mediate the clinical benefit that is seen following targeted STN interventions for this disease. PMID:18400841

  1. Active learning based segmentation of Crohns disease from abdominal MRI.

    PubMed

    Mahapatra, Dwarikanath; Vos, Franciscus M; Buhmann, Joachim M

    2016-05-01

    This paper proposes a novel active learning (AL) framework, and combines it with semi supervised learning (SSL) for segmenting Crohns disease (CD) tissues from abdominal magnetic resonance (MR) images. Robust fully supervised learning (FSL) based classifiers require lots of labeled data of different disease severities. Obtaining such data is time consuming and requires considerable expertise. SSL methods use a few labeled samples, and leverage the information from many unlabeled samples to train an accurate classifier. AL queries labels of most informative samples and maximizes gain from the labeling effort. Our primary contribution is in designing a query strategy that combines novel context information with classification uncertainty and feature similarity. Combining SSL and AL gives a robust segmentation method that: (1) optimally uses few labeled samples and many unlabeled samples; and (2) requires lower training time. Experimental results show our method achieves higher segmentation accuracy than FSL methods with fewer samples and reduced training effort. PMID:27040833

  2. Physical Activity and Hemodynamic Reactivity in Chronic Kidney Disease

    PubMed Central

    Agarwal, Rajiv; Light, Robert P.

    2008-01-01

    Background and objectives: Patients with chronic kidney disease (CKD) have an elevated cardiovascular risk. This study was designed to understand better the presence and strength of the relationship between physical activity and BP and to explore determinants of hemodynamic reactivity. Design, setting, participants, & measurements: Twenty-four patients with CKD (mean age 69.5 yr; 3.1 antihypertensive drugs; estimated GFR 47 ml/min per 1.73 m2, albumin/creatinine ratio 403 mg/g) were studied on three occasions during a 6-wk period with 24-h ambulatory BP monitoring and simultaneous activity monitoring with wrist actigraphy. Results: Nondippers were found have a greater level of sleep activity compared with dippers, although the awake activity level was similar (7.06 versus 6.73) between groups (P = 0.042 for interaction). In 3587 BP activity pairs, hemodynamic reactivity was variable between individuals (systolic BP reactivity 1.06 [SD 10.50]; diastolic BP reactivity 0.89 [SD 7.80] heart rate reactivity 1.18 [SD 11.00]); those who were more sedentary had a greater increment in systolic BP compared with those who were less sedentary. Antihypertensive drugs blunted hemodynamic reactivity. Hemodynamic reactivity was greatest between 12 a.m. and 8 a.m., making this a vulnerable period for cardiovascular events. Conclusions: Greater hemodynamic reactivity in sedentary people with CKD offers a possible and thus far unrecognized mechanism of cardiovascular damage. Besides reducing BP, antihypertensive drugs reduce hemodynamic reactivity, which offers another plausible mechanism of cardiovascular protection with their use. PMID:18922983

  3. Peroxisome proliferator-activated receptor-delta agonist ameliorated inflammasome activation in nonalcoholic fatty liver disease

    PubMed Central

    Lee, Hyun Jung; Yeon, Jong Eun; Ko, Eun Jung; Yoon, Eileen L; Suh, Sang Jun; Kang, Keunhee; Kim, Hae Rim; Kang, Seoung Hee; Yoo, Yang Jae; Je, Jihye; Lee, Beom Jae; Kim, Ji Hoon; Seo, Yeon Seok; Yim, Hyung Joon; Byun, Kwan Soo

    2015-01-01

    AIM: To evaluate the inflammasome activation and the effect of peroxisome proliferator-activated receptors (PPAR)-δ agonist treatment in nonalcoholic fatty liver disease (NAFLD) models. METHODS: Male C57BL/6J mice were classified according to control or high fat diet (HFD) with or without PPAR-δ agonist (GW) over period of 12 wk [control, HFD, HFD + lipopolysaccharide (LPS), HFD + LPS + GW group]. HepG2 cells were exposed to palmitic acid (PA) and/or LPS in the absence or presence of GW. RESULTS: HFD caused glucose intolerance and hepatic steatosis. In mice fed an HFD with LPS, caspase-1 and interleukin (IL)-1β in the liver were significantly increased. Treatment with GW ameliorated the steatosis and inhibited overexpression of pro-inflammatory cytokines. In HepG2 cells, PA and LPS treatment markedly increased mRNA of several nucleotide-binding and oligomerization domain-like receptor family members (NLRP3, NLRP6, and NLRP10), caspase-1 and IL-1β. PA and LPS also exaggerated reactive oxygen species production. All of the above effects of PA and LPS were reduced by GW. GW also enhanced the phosphorylation of AMPK-α. CONCLUSION: PPAR-δ agonist reduces fatty acid-induced inflammation and steatosis by suppressing inflammasome activation. Targeting the inflammasome by the PPAR-δ agonist may have therapeutic implication for NAFLD. PMID:26668503

  4. Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease

    PubMed Central

    Azhar, Salman

    2011-01-01

    Metabolic syndrome (MetS) is a constellation of risk factors including insulin resistance, central obesity, dyslipidemia and hypertension that markedly increase the risk of Type 2 diabetes (T2DM) and cardiovascular disease (CVD). The peroxisome proliferators-activated receptor (PPAR) isotypes, PPARα, PPARδ/β and PPARγ are ligand-activated nuclear transcription factors, which modulate the expression of an array of genes that play a central role in regulating glucose, lipid and cholesterol metabolism, where imbalance can lead to obesity, T2DM and CVD. They are also drug targets, and currently, PPARα (fibrates) and PPARγ (thiazolodinediones) agonists are in clinical use for treating dyslipidemia and T2DM, respectively. These metabolic characteristics of the PPARs, coupled with their involvement in metabolic diseases, mean extensive efforts are underway worldwide to develop new and efficacious PPAR-based therapies for the treatment of additional maladies associated with the MetS. This article presents an overview of the functional characteristics of three PPAR isotypes, discusses recent advances in our understanding of the diverse biological actions of PPARs, particularly in the vascular system, and summarizes the developmental status of new single, dual, pan (multiple) and partial PPAR agonists for the clinical management of key components of MetS, T2DM and CVD. It also summarizes the clinical outcomes from various clinical trials aimed at evaluating the atheroprotective actions of currently used fibrates and thiazolodinediones. PMID:20932114

  5. Peroxisome proliferator-activated receptors, metabolic syndrome and cardiovascular disease.

    PubMed

    Azhar, Salman

    2010-09-01

    Metabolic syndrome (MetS) is a constellation of risk factors including insulin resistance, central obesity, dyslipidemia and hypertension that markedly increase the risk of Type 2 diabetes (T2DM) and cardiovascular disease (CVD). The peroxisome proliferators-activated receptor (PPAR) isotypes, PPARα, PPARδ/ß and PPARγ are ligand-activated nuclear transcription factors, which modulate the expression of an array of genes that play a central role in regulating glucose, lipid and cholesterol metabolism, where imbalance can lead to obesity, T2DM and CVD. They are also drug targets, and currently, PPARα (fibrates) and PPARγ (thiazolodinediones) agonists are in clinical use for treating dyslipidemia and T2DM, respectively. These metabolic characteristics of the PPARs, coupled with their involvement in metabolic diseases, mean extensive efforts are underway worldwide to develop new and efficacious PPAR-based therapies for the treatment of additional maladies associated with the MetS. This article presents an overview of the functional characteristics of three PPAR isotypes, discusses recent advances in our understanding of the diverse biological actions of PPARs, particularly in the vascular system, and summarizes the developmental status of new single, dual, pan (multiple) and partial PPAR agonists for the clinical management of key components of MetS, T2DM and CVD. It also summarizes the clinical outcomes from various clinical trials aimed at evaluating the atheroprotective actions of currently used fibrates and thiazolodinediones. PMID:20932114

  6. Brain Na(+), K(+)-ATPase Activity In Aging and Disease.

    PubMed

    de Lores Arnaiz, Georgina Rodríguez; Ordieres, María Graciela López

    2014-06-01

    Na(+)/K(+) pump or sodium- and potassium-activated adenosine 5'-triphosphatase (Na(+), K(+)-ATPase), its enzymatic version, is a crucial protein responsible for the electrochemical gradient across the cell membranes. It is an ion transporter, which in addition to exchange cations, is the ligand for cardenolides. This enzyme regulates the entry of K(+) with the exit of Na(+) from cells, being the responsible for Na(+)/K(+) equilibrium maintenance through neuronal membranes. This transport system couples the hydrolysis of one molecule of ATP to exchange three sodium ions for two potassium ions, thus maintaining the normal gradient of these cations in animal cells. Oxidative metabolism is very active in brain, where large amounts of chemical energy as ATP molecules are consumed, mostly required for the maintenance of the ionic gradients that underlie resting and action potentials which are involved in nerve impulse propagation, neurotransmitter release and cation homeostasis. Protein phosphorylation is a key process in biological regulation. At nervous system level, protein phosphorylation is the major molecular mechanism through which the function of neural proteins is modulted in response to extracellular signals, including the response to neurotransmitter stimuli. It is the major mechanism of neural plasticity, including memory processing. The phosphorylation of Na(+), K(+)-ATPase catalytic subunit inhibits enzyme activity whereas the inhibition of protein kinase C restores the enzyme activity. The dephosphorylation of neuronal Na(+), K(+)-ATPase is mediated by calcineurin, a serine / threonine phosphatase. The latter enzyme is involved in a wide range of cellular responses to Ca(2+) mobilizing signals, in the regulation of neuronal excitability by controlling the activity of ion channels, in the release of neurotransmitters and hormones, as well as in synaptic plasticity and gene transcription. In the present article evidence showing Na(+), K(+)-ATPase involvement

  7. Brain Na+, K+-ATPase Activity In Aging and Disease

    PubMed Central

    de Lores Arnaiz, Georgina Rodríguez; Ordieres, María Graciela López

    2014-01-01

    Na+/K+ pump or sodium- and potassium-activated adenosine 5’-triphosphatase (Na+, K+-ATPase), its enzymatic version, is a crucial protein responsible for the electrochemical gradient across the cell membranes. It is an ion transporter, which in addition to exchange cations, is the ligand for cardenolides. This enzyme regulates the entry of K+ with the exit of Na+ from cells, being the responsible for Na+/K+ equilibrium maintenance through neuronal membranes. This transport system couples the hydrolysis of one molecule of ATP to exchange three sodium ions for two potassium ions, thus maintaining the normal gradient of these cations in animal cells. Oxidative metabolism is very active in brain, where large amounts of chemical energy as ATP molecules are consumed, mostly required for the maintenance of the ionic gradients that underlie resting and action potentials which are involved in nerve impulse propagation, neurotransmitter release and cation homeostasis. Protein phosphorylation is a key process in biological regulation. At nervous system level, protein phosphorylation is the major molecular mechanism through which the function of neural proteins is modulted in response to extracellular signals, including the response to neurotransmitter stimuli. It is the major mechanism of neural plasticity, including memory processing. The phosphorylation of Na+, K+-ATPase catalytic subunit inhibits enzyme activity whereas the inhibition of protein kinase C restores the enzyme activity. The dephosphorylation of neuronal Na+, K+-ATPase is mediated by calcineurin, a serine / threonine phosphatase. The latter enzyme is involved in a wide range of cellular responses to Ca2+ mobilizing signals, in the regulation of neuronal excitability by controlling the activity of ion channels, in the release of neurotransmitters and hormones, as well as in synaptic plasticity and gene transcription. In the present article evidence showing Na+, K+-ATPase involvement in signaling pathways

  8. Human ZMPSTE24 disease mutations: residual proteolytic activity correlates with disease severity

    PubMed Central

    Barrowman, Jemima; Wiley, Patricia A.; Hudon-Miller, Sarah E.; Hrycyna, Christine A.; Michaelis, Susan

    2012-01-01

    The zinc metalloprotease ZMPSTE24 plays a critical role in nuclear lamin biology by cleaving the prenylated and carboxylmethylated 15-amino acid tail from the C-terminus of prelamin A to yield mature lamin A. A defect in this proteolytic event, caused by a mutation in the lamin A gene (LMNA) that eliminates the ZMPSTE24 cleavage site, underlies the premature aging disease Hutchinson-Gilford Progeria Syndrome (HGPS). Likewise, mutations in the ZMPSTE24 gene that result in decreased enzyme function cause a spectrum of diseases that share certain features of premature aging. Twenty human ZMPSTE24 alleles have been identified that are associated with three disease categories of increasing severity: mandibuloacral dysplasia type B (MAD-B), severe progeria (atypical ‘HGPS’) and restrictive dermopathy (RD). To determine whether a correlation exists between decreasing ZMPSTE24 protease activity and increasing disease severity, we expressed mutant alleles of ZMPSTE24 in yeast and optimized in vivo yeast mating assays to directly compare the activity of alleles associated with each disease category. We also measured the activity of yeast crude membranes containing the ZMPSTE24 mutant proteins in vitro. We determined that, in general, the residual activity of ZMPSTE24 patient alleles correlates with disease severity. Complete loss-of-function alleles are associated with RD, whereas retention of partial, measureable activity results in MAD-B or severe progeria. Importantly, our assays can discriminate small differences in activity among the mutants, confirming that the methods presented here will be useful for characterizing any new ZMPSTE24 mutations that are discovered. PMID:22718200

  9. Phospholipase A2 activating protein and idiopathic inflammatory bowel disease.

    PubMed Central

    Peterson, J W; Dickey, W D; Saini, S S; Gourley, W; Klimpel, G R; Chopra, A K

    1996-01-01

    BACKGROUND: Crohn's disease and ulcerative colitis are idiopathic inflammatory bowel diseases (IBD) involving synthesis of eicosanoids from arachidonic acid (AA), which is released from membrane phospholipids by phospholipase A2 (PLA2). A potentially important regulator of the production of these mediators is a protein activator of PLA2, referred to as PLA2 activating protein (PLAP). AIMS: The purpose of this investigation was to discover if PLAP values might be increased in the inflamed intestinal tissue of patients with IBD and in intestinal tissue of mice with colitis. PATIENTS: Biopsy specimens were taken from patients with ulcerative colitis and Crohn's disease undergoing diagnostic colonoscopy, and normal colonic mucosa was obtained from patients without IBD after surgical resection. METHODS: Immunocytochemistry with affinity purified antibodies to PLAP synthetic peptides was used to locate PLAP antigen in sections of intestinal biopsy specimens from IBD patients compared with that of normal intestinal tissue. Northern blot analysis with a murine [32P] labelled plap cDNA probe was performed on RNA extracted from the colons of mice fed dextran sulphate sodium (DSS) and cultured HT-29 cells exposed to lipopolysaccharide (LPS). RESULTS: PLAP antigen was localised predominantly within monocytes and granulocytes in intestinal tissue sections from IBD patients, and additional deposition of extracellular PLAP antigen was associated with blood vessels and oedema fluid in the inflamed tissues. In contrast, tissue sections from normal human intestine were devoid of PLAP reactive antigen, except for some weak cytoplasmic reaction of luminal intestinal epithelial cells. Similarly, colonic tissue from DSS treated mice contained an increased amount of PLAP antigen compared with controls. The stroma of the lamina propria of the colonic mucosa from the DSS treated mice reacted intensely with antibodies to PLAP synthetic peptides, while no reaction was observed with control

  10. Imaging Microglial Activation with TSPO PET: Lighting Up Neurologic Diseases?

    PubMed

    Vivash, Lucy; O'Brien, Terence J

    2016-02-01

    Neuroinflammation is implicated in the pathogenesis of a wide range of neurologic and neuropsychiatric diseases. For over 20 years, (11)C-PK11195 PET, which aims to image expression of the translocator protein (TSPO) on activated microglia in the brain, has been used in preclinical and clinical research to investigate neuroinflammation in vivo in patients with brain diseases. However, (11)C-PK11195 suffers from two major limitations: its low brain permeability and high nonspecific and plasma binding results in a low signal-to-noise ratio, and the use of (11)C restricts its use to PET research centers and hospitals with an on-site cyclotron. In recent years, there has been a great deal of work into the development of new TSPO-specific PET radiotracers. This work has focused on fluorinated radiotracers, which would enable wider use and improved signal-to-noise ratios. These radiotracers have been utilized in preclinical and clinical studies of several neurologic diseases with varying degrees of success. Unfortunately, the application of these second-generation TSPO radiotracers has revealed additional problems, including a polymorphism that affects TSPO binding. In this review, the developments in TSPO imaging are discussed, and current limitations and suggestions for future directions are explored. PMID:26697963

  11. Constitutive Activation of G Protein-Coupled Receptors and Diseases: Insights into Mechanisms of Activation and Therapeutics

    PubMed Central

    Tao, Ya-Xiong

    2008-01-01

    The existence of constitutive activity for G protein-coupled receptors (GPCRs) was first described in 1980s. In 1991, the first naturally occurring constitutively active mutations in GPCRs that cause diseases were reported in rhodopsin. Since then, numerous constitutively active mutations that cause human diseases were reported in several additional receptors. More recently, loss of constitutive activity was postulated to also cause diseases. Animal models expressing some of these mutants confirmed the roles of these mutations in the pathogenesis of the diseases. Detailed functional studies of these naturally occurring mutations, combined with homology modeling using rhodopsin crystal structure as the template, lead to important insights into the mechanism of activation in the absence of crystal structure of GPCRs in active state. Search for inverse agonists on these receptors will be critical for correcting the diseases cause by activating mutations in GPCRs. Theoretically, these inverse agonists are better therapeutics than neutral antagonists in treating genetic diseases caused by constitutively activating mutations in GPCRs. PMID:18768149

  12. Measurement of Fractional Exhaled Nitric Oxide as a Marker of Disease Activity in Inflammatory Bowel Disease

    PubMed Central

    Ikonomi, Erkanda; Rothstein, Robin D.; Ehrlich, Adam C.; Friedenberg, Frank K.

    2016-01-01

    Background and Aims Definitive diagnosis of IBD requires endoscopic and pathologic confirmation. These tools are also used to classify disease activity. Our aim was to determine if the fractional exhaled nitric oxide (FeNO) could be utilized to screen for IBD and assess for disease activity. Methods We matched weighted IBD cases and controls from the 2009–2010 NHANES dataset. All subjects underwent measurement of FeNO using standardized techniques. We assessed for potential confounders for FeNO measurement including age, height, and asthma. For IBD subjects, we used the presence of diarrhea, fatigue, and weight loss as a proxy for IBD activity. Laboratory parameters examined to estimate disease activity included anemia (≤ 10 g/dl), iron deficiency (ferritin ≤ 20 ng/ml), hypoalbuminemia (≤ 3.2 g/dl), and CRP (≥ 1.1 mg/dl). Results The weighted sample represented 199,414,901 subjects. The weighted prevalence of IBD was 2,084,895 (1.0%). IBD subjects had nearly the same FeNO level as those without IBD (17.0 ± 16.2 vs. 16.7 ± 14.5 ppb). The odds of a FeNO > 25 ppb was half (OR=0.501; 95% CI 0.497–0.504) for subjects with IBD compared to those without IBD after controlling for confounders. The AUROC curve for FeNO was 0.47 (0.35–0.59). FeNO levels were not higher in patients with laboratory values suggestive of active disease. FeNO levels were higher in IBD patients with diarrhea, rectal urgency, and fatigue but were lower in those with unintentional weight loss. Conclusion Measurement of FeNO does not appear to be useful to screen for IBD or assess disease activity. PMID:27398403

  13. Usefulness of Endoscopic Indices in Determination of Disease Activity in Patients with Crohn's Disease

    PubMed Central

    Kucharski, Marcin; Karczewski, Jacek; Mańkowska-Wierzbicka, Dorota; Karmelita-Katulska, Katarzyna; Kaczmarek, Elżbieta; Iwanik, Katarzyna; Rzymski, Piotr; Grzymisławski, Marian; Linke, Krzysztof; Dobrowolska, Agnieszka

    2016-01-01

    Background. Assessment of endoscopic activity of Crohn's disease (CD) is of growing importance both in clinical practice and in clinical trials. The study aimed to assess which of the endoscopic indices used for evaluation of mucosal changes correlates with the currently used clinical indices for determination of disease activity and with the results of histopathological examination. Study. A group of 71 patients with CD and 52 individuals without a diagnosis of GI tract disease as a control group were investigated, considering clinical and histological severity of the disease and the severity of inflammatory changes in the bowel. Evaluation was conducted with the use of clinical, endoscopic, and histopathological indices. Endoscopic indices were then correlated with different clinical and histopathological indices with the aim of finding the strongest correlations. Results and Conclusions. Correlation between the clinical disease activity and the severity of endoscopic lesions in CD was shown in this study to be poor. The results also indicate that the optimal endoscopic index used in the diagnostic stage and in the assessment of treatment effects in CD is Simple Endoscopic Score for Crohn's Disease (SES-CD). PMID:26997952

  14. Distinct features of circulating microparticles and their relationship with disease activity in inflammatory bowel disease

    PubMed Central

    Voudoukis, Evangelos; Vetsika, Eleni-Kyriaki; Giannakopoulou, Konstantina; Karmiris, Konstantinos; Theodoropoulou, Angeliki; Sfiridaki, Aekaterini; Georgoulias, Vassilis; Paspatis, Gregorios A.; Koutroubakis, Ioannis E.

    2016-01-01

    Background There is evidence that circulating microparticles (MPs) and annexin (+) platelet-derived MPs (PDMPs) are increased in inflammatory bowel disease (IBD). The aim of our study was to characterize the abundance, origin, and annexin V binding of MPs in patients with IBD and correlate them with the disease characteristics. Methods Case-control study of 46 IBD patients (23 Crohn’s disease, 23 ulcerative colitis) and 40 matched healthy controls (HC). MPs were divided according to annexin V binding, their origin was estimated based on specific cell membrane markers in plasma samples and their number was calculated via flow cytometry. Clinical and laboratory activity indices were also analyzed. Results Annexin (-) PDMPs (P=0.0004), total (P=0.04) and annexin (+) monocyte-derived MPs (P=0.02) were increased and annexin (-) total MPs (P=0.0007) were decreased in IBD patients compared to HC. The annexin (+)/(-) ratio of all MP types were significantly elevated in IBD patients compared to HC (P<0.003). IBD patients with active disease displayed elevated total and annexin (+) total MPs, total, annexin (+) and (-) PDMPs compared with those in remission (P<0.05). Annexin (-) PDMPs were considerably increased in IBD patients with active compared to those with inactive disease (P=0.0013). Total and annexin (-) PDMPs were significantly correlated with most of the disease activity indices (P<0.05). Conclusion The majority of circulating MPs, their counterparts and particularly annexin (-) PDMPs are increased in active IBD patients. Annexin (+)/(-) ratio proved to be the most reliable distinctive MP index between HC and IBD patients. PMID:27065731

  15. CENPA a Genomic Marker for Centromere Activity and Human Diseases

    PubMed Central

    M. Valdivia, Manuel; Hamdouch, Khaoula; Ortiz, Manuela; Astola, Antonio

    2009-01-01

    Inheritance of genetic material requires that chromosomes segregate faithfully during cell division. Failure in this process can drive to aneuploidy phenomenon. Kinetochores are unique centromere macromolecular protein structures that attach chromosomes to the spindle for a proper movement and segregation. A unique type of nucleosomes of centromeric chromatin provides the base for kinetochore formation. A specific histone H3 variant, CENPA, replaces conventional histone H3 and together with centromere-specific-DNA-binding factors directs the assembly of active kinetochores. Recent studies on CENPA nucleosomal structure, epigenetic inheritance of centromeric chromatin and transcription of pericentric heterochromatin provide new clues to our understanding of centromere structure and function. This review highlights the role and dynamics of CENPA assembly into centromeres and the potential contribution of this kinetochore protein to autoimmune and cancer diseases in humans. PMID:20119530

  16. Dopaminergic correlates of metabolic network activity in Parkinson's disease.

    PubMed

    Holtbernd, Florian; Ma, Yilong; Peng, Shichun; Schwartz, Frank; Timmermann, Lars; Kracht, Lutz; Fink, Gereon R; Tang, Chris C; Eidelberg, David; Eggers, Carsten

    2015-09-01

    Parkinson's disease (PD) is associated with distinct metabolic covariance patterns that relate to the motor and cognitive manifestations of the disorder. It is not known, however, how the expression of these patterns relates to measurements of nigrostriatal dopaminergic activity from the same individuals. To explore these associations, we studied 106 PD subjects who underwent cerebral PET with both (18) F-fluorodeoxyglucose (FDG) and (18) F-fluoro-L-dopa (FDOPA). Expression values for the PD motor- and cognition-related metabolic patterns (PDRP and PDCP, respectively) were computed for each subject; these measures were correlated with FDOPA uptake on a voxel-by-voxel basis. To explore the relationship between dopaminergic function and local metabolic activity, caudate and putamen FDOPA PET signal was correlated voxel-wise with FDG uptake over the entire brain. PDRP expression correlated with FDOPA uptake in caudate and putamen (P < 0.001), while PDCP expression correlated with uptake in the anterior striatum (P < 0.001). While statistically significant, the correlations were only of modest size, accounting for less than 20% of the overall variation in these measures. After controlling for PDCP expression, PDRP correlations were significant only in the posterior putamen. Of note, voxel-wise correlations between caudate/putamen FDOPA uptake and whole-brain FDG uptake were significant almost exclusively in PDRP regions. Overall, the data indicate that PDRP and PDCP expression correlates significantly with PET indices of presynaptic dopaminergic functioning obtained in the same individuals. Even so, the modest size of these correlations suggests that in PD patients, individual differences in network activity cannot be explained solely by nigrostriatal dopamine loss. PMID:26037537

  17. Fecal Calprotectin and Clinical Disease Activity in Pediatric Ulcerative Colitis

    PubMed Central

    Kolho, Kaija-Leena; Turner, Dan

    2013-01-01

    Objective. To explore fecal calprotectin levels in pediatric ulcerative colitis (UC) in relation with the validated clinical activity index PUCAI. Methods. This study included all 37 children (median age 14 years) with UC who had calprotectin measured (PhiCal ELISA Test) by the time of PUCAI assessment at the Children's Hospital of Helsinki in a total of 62 visits. Calprotectin values <100 μg/g of stool were considered as normal. The best cut-off value of each measure to predict 3-month clinical outcome was derived by maximizing sensitivity and specificity. Results. In clinically active disease (PUCAI ≥ 10), calprotectin was elevated in 29/32 patients (91% sensitivity). When in clinical remission, 26% (8/30) of the children had normal calprotectin but 7 (23%) had an exceedingly high level (>1000 μg/g). The best cut-off value for calprotectin for predicting poor outcome was 800 μg/g (sensitivity 73%, specificity 72%; area under the ROC curve being 0.71 (95%CI 0.57–0.85)) and for the PUCAI best cut-off values >10 (sensitivity 62%, specificity 64%; area under the ROC curve 0.714 (95%CI 0.58–0.85)). Conclusion. The clinical relevance of somewhat elevated calprotectin during clinical remission in pediatric UC is not known and, until further evidence accumulates, does not indicate therapy escalation. PMID:23533791

  18. Steroid receptor RNA activator: Biologic function and role in disease.

    PubMed

    Liu, Chan; Wu, Hong-Tao; Zhu, Neng; Shi, Ya-Ning; Liu, Zheng; Ao, Bao-Xue; Liao, Duan-Fang; Zheng, Xi-Long; Qin, Li

    2016-08-01

    Steroid receptor RNA activator (SRA) is a type of long noncoding RNA (lncRNA) which coordinates the functions of various transcription factors, enhances steroid receptor-dependent gene expression, and also serves as a distinct scaffold. The novel, profound and expanded roles of SRA are emerging in critical aspects of coactivation of nuclear receptors (NRs). As a nuclear receptor coactivator, SRA can coactivate androgen receptor (AR), estrogen receptor α (ERα), ERβ, progesterone receptor (PR), glucocorticoid receptor (GR), thyroid hormone receptor and retinoic acid receptor (RAR). Although SRA is one of the least well-understood molecules, increasing studies have revealed that SRA plays a key role in both biological processes, such as myogenesis and steroidogenesis, and pathological changes, including obesity, cardiomyopathy, and tumorigenesis. Furthermore, the SRA-related signaling pathways, such as the mitogen-activated protein kinase (p38 MAPK), Notch and tumor necrosis factor α (TNFα) pathways, play critical roles in the pathogenesis of estrogen-dependent breast cancers. In addition, the most recent data demonstrates that SRA expression may serve as a new prognostic marker in patients with ER-positive breast cancer. Thus, elucidating the molecular mechanisms underlying SRA-mediated functions is important to develop proper novel strategies to target SRA in the diagnosis and treatment of human diseases. PMID:27282881

  19. Diaphragm activation during exercise in chronic obstructive pulmonary disease.

    PubMed

    Sinderby, C; Spahija, J; Beck, J; Kaminski, D; Yan, S; Comtois, N; Sliwinski, P

    2001-06-01

    Although it has been postulated that central inhibition of respiratory drive may prevent development of diaphragm fatigue in patients with chronic obstructive pulmonary disease (COPD) during exercise, this premise has not been validated. We evaluated diaphragm electrical activation (EAdi) relative to maximum in 10 patients with moderately severe COPD at rest and during incremental exhaustive bicycle exercise. Flow was measured with a pneumotachograph and volume by integration of flow. EAdi and transdiaphragmatic pressures (Pdi) were measured using an esophageal catheter. End-expiratory lung volume (EELV) was assessed by inspiratory capacity (IC) maneuvers, and maximal voluntary EAdi was obtained during these maneuvers. Minute ventilation (V E) was 12.2 +/- 1.9 L/min (mean +/- SD) at rest, and increased progressively (p < 0.001) to 31.0 +/- 7.8 L/min at end-exercise. EELV increased during exercise (p < 0.001) causing end-inspiratory lung volume to attain 97 +/- 3% of TLC at end-exercise. Pdi at rest was 9.4 +/- 3.2 cm H(2)O and increased during the first two thirds of exercise (p < 0.001) to plateau at about 13 cm H(2)O. EAdi was 24 +/- 6% of voluntary maximal at rest and increased progressively during exercise (p < 0.001) to reach 81 +/- 7% at end-exercise. In conclusion, dynamic hyperinflation during exhaustive exercise in patients with COPD reduces diaphragm pressure-generating capacity, promoting high levels of diaphragm activation. PMID:11401887

  20. Ubiquitin, Proteasomes and Proteolytic Mechanisms Activated by Kidney Disease

    PubMed Central

    Rajan, Vik; Mitch, William E.

    2008-01-01

    Summary The ubiquitin-proteasome system (UPS) includes 3 enzymes that conjugate ubiquitin to intracellular proteins that are then recognized and degraded in the proteasome. The process participates in the regulation of cell metabolism. In the kidney, the UPS regulates the turnover of transporters and signaling proteins and its activity is down regulated in acidosis-induced proximal tubular cell hypertrophy. In chronic kidney disease (CKD), muscle wasting occurs because complications of CKD including acidosis, insulin resistance, inflammation, and increased angiotensin II levels stimulate the UPS to degrade muscle proteins. This response also includes caspase-3 and calpains which act to cleave muscle proteins to provide substrates for the UPS. For example, caspase-3 degrades actomyosin, leaving a 14kD fragment of actin in muscle. The 14 kD actin fragment is increased in muscle of patient with kidney disease, burn injury and surgery. In addition, acidosis, insulin resistance, inflammation and angiotensin II stimulate glucocorticoid production. Glucocorticoids are also required for the muscle wasting that occurs in CKD. Thus, the UPS is involved in regulating kidney function and participates in highly organized responses that degrade muscle protein in response to loss of kidney function. PMID:18723090

  1. Markers of endothelial cell activation and immune activation are increased in patients with severe leptospirosis and associated with disease severity

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Objectives: Previous studies concluded that haemorrhage is one of the most accurate prognostic factors of mortality in leptospirosis. Therefore, endothelial cell activation was investigated in relation to disease severity in severe leptospirosis. Methods: Prospective cohort study of severe leptospi...

  2. Urinary glucaric acid excretion in rheumatoid arthritis: influence of disease activity and disease modifying drugs.

    PubMed Central

    Addyman, R; Beyeler, C; Astbury, C; Bird, H A

    1996-01-01

    OBJECTIVE: To examine if a correlation exists between cytochrome P-450 enzyme induction and disease activity in patients with rheumatoid arthritis (RA), measuring urinary excretion of D-glucaric acid (GA) as an index of phase II drug metabolism. METHODS: Patients with RA were treated with sulphasalazine, sodium aurothiomalate, or D-penicillamine in standard dose regimens, for 24 weeks. Patients with ankylosing spondylitis (AS) or non-inflammatory arthritis (NIA) acted as controls. The urinary GA:creatinine ratio was measured at 0, 12, and 24 weeks of treatment. RESULTS: Patients with RA had a slightly greater urinary GA:creatinine ratio than patients with AS or NIA at baseline; this increased during treatment with disease modifying antirheumatic drugs (DMARDs). Sulphasalazine treatment had a greater effect on GA excretion than sodium aurothiomalate or D-penicillamine; this difference was statistically significant between weeks 0 and 12 (p = 0.01). Gamma glutamyltranspeptidase concentration showed a weak correlation with GA excretion between weeks 0 and 12 (p = 0.03), but all other measurements of changes in disease activity (plasma viscosity, C reactive protein, platelets, and articular index) were found not to correlate with GA excretion between weeks 0-12 or 0-24. CONCLUSION: The increased excretion of GA in patients with RA receiving DMARD treatment is probably the result of an indirect effect on hepatic metabolism bearing no relationship to disease activity. PMID:8774168

  3. Biomarkers of basic activities of daily living in Alzheimer's disease.

    PubMed

    Hall, James R; Johnson, Leigh A; Barber, Robert C; Vo, Hoa T; Winter, A Scott; O'Bryant, Sid E

    2012-01-01

    Functional impairment is common in Alzheimer's disease (AD) and related to increased caregiver burden and institutionalization. There is a dearth of research investigating the relationship between specific biomarkers and basic activities of daily living (BADLs) such as toileting, feeding, dressing, grooming, bathing, and ambulating. The present study examined the relationship between serum based biomarkers and specific ADLs in a sample of AD patients. Data were collected from 196 participants enrolled in the Texas Alzheimer's Research and Care Consortium Project and diagnosed with AD. BADLs were measured using the Lawton-Brody Physical Self-Maintenance Scale. A panel of 22 biomarkers previously found to be related to AD pathology was used for the analysis. Stepwise regression modeling was used to assess the link between the biomarkers and BADLs. Results were also examined by gender. Nine of the 22 biomarkers were significantly related to BADLs. When stratified by gender, the biomarkers accounted for 32% of the variance in the males and 27% in females. The pattern of significant biomarkers differed by gender with IL 7 and Tenascin C significantly related to BADLs for females and IL 15 significantly related to BADLs for males. The results of this study indicated that a small number of serum based biomarkers are related to BADLs, and these biomarkers differed by gender. PMID:22571981

  4. Active ingredients of ginger as potential candidates in the prevention and treatment of diseases via modulation of biological activities

    PubMed Central

    Rahmani, Arshad H; shabrmi, Fahad M Al; Aly, Salah M

    2014-01-01

    The current mode of treatment based on synthetic drugs is expensive and also causes genetic and metabolic alterations. However, safe and sound mode of treatment is needed to control the diseases development and progression. In this regards, medicinal plant and its constituents play an important role in diseases management via modulation of biological activities. Ginger, the rhizome of the Zingiber officinale, has shown therapeutic role in the health management since ancient time and considered as potential chemopreventive agent. Numerous studies based on clinical trials and animal model has shown that ginger and its constituents shows significant role in the prevention of diseases via modulation of genetic and metabolic activities. In this review, we focused on the therapeutics effects of ginger and its constituents in the diseases management, and its impact on genetic and metabolic activities. PMID:25057339

  5. Invasive pneumococcal disease leads to activation and hyperreactivity of platelets.

    PubMed

    Tunjungputri, Rahajeng N; de Jonge, Marien I; de Greeff, Astrid; van Selm, Saskia; Buys, Herma; Harders-Westerveen, Jose F; Stockhofe-Zurwieden, Norbert; Urbanus, Rolf T; de Groot, Phillip G; Smith, Hilde E; van der Ven, Andre J; de Mast, Quirijn

    2016-08-01

    Using a novel porcine model of intravenous Streptococcus pneumoniae infection, we showed that invasive pneumococcal infections induce marked platelet activation and hyperreactivity. This may contribute to the vascular complications seen in pneumococcal infection. PMID:27322088

  6. Evaluation of telomerase activity in non-genital Bowen's disease.

    PubMed

    Mitsuishi, T; Nakatake, M; Kaneko, T; Ohara, K; Kato, T; Iida, K; Iwabu, Y; Tokunaga, K; Sata, T; Kawana, S; Yamada, O

    2009-06-01

    We investigated the level of telomerase activity (TA) in 17 specimens of non-genital Bowen's disease (BD) and in 14 specimens of skin without sun exposure (non-exposed skin) using a non-isotopic PCR-based telomeric repeat amplification protocol (TRAP) assay. Expression of human telomerase reverse transcriptase (hTERT; the catalytic subunit of telomerase) was also evaluated by immunochemistry in the non-genital BD tissues. Moderate to high levels of TA were detected in 41.2% of 17 non-genital BD specimens (P = 0.001). In contrast, TA was not evident in non-exposed skin. Recently, nucleolin was reported to be associated with hTERT, so we used this antibody instead of hTERT antibody. Immunohistochemistry showed that nucleolin expression was associated with high TA levels in non-genital BD. Our results also revealed differences of TA levels among non-genital BD specimens. High levels of TA in those specimens were not age related. Five out of 7 specimens (71.4%) with moderate to high TA levels were from sun-exposed sites, while the remaining 10 specimens with low levels of TA were from non-exposed sites. These results suggested that cellular DNA damage caused by ultraviolet irradiation might be associated with an increase of TA in non-genital BD. Among non-genital BD specimens, 4 out of 17 (23.5%) showed high levels of TA (median relative TA value: 79.8%; P = 0.003), which might be associated with immortalization or transformation to invasive squamous cell carcinoma. PMID:19250332

  7. Liposomes for Targeted Delivery of Active Agents against Neurodegenerative Diseases (Alzheimer's Disease and Parkinson's Disease)

    PubMed Central

    Spuch, Carlos; Navarro, Carmen

    2011-01-01

    Neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease represent a huge unmet medical need. The prevalence of both diseases is increasing, but the efficacy of treatment is still very limited due to various factors including the blood brain barrier (BBB). Drug delivery to the brain remains the major challenge for the treatment of all neurodegenerative diseases because of the numerous protective barriers surrounding the central nervous system. New therapeutic drugs that cross the BBB are critically needed for treatment of many brain diseases. One of the significant factors on neurotherapeutics is the constraint of the blood brain barrier and the drug release kinetics that cause peripheral serious side effects. Contrary to common belief, neurodegenerative and neurological diseases may be multisystemic in nature, and this presents numerous difficulties for their potential treatment. Overall, the aim of this paper is to summarize the last findings and news related to liposome technology in the treatment of neurodegenerative diseases and demonstrate the potential of this technology for the development of novel therapeutics and the possible applications of liposomes in the two most widespread neurodegenerative diseases, Alzheimer's disease and Parkinson's disease. PMID:22203906

  8. Difference Between Latent TB Infection and Active TB Disease

    MedlinePlus

    ... ray, or positive sputum smear or culture • • Has active TB bacteria in his/her body • • Usually feels sick and may have symptoms such as coughing, fever, and weight loss • • May spread TB bacteria to others • • Needs treatment to treat ...

  9. Serum ST2 in inflammatory bowel disease: a potential biomarker for disease activity.

    PubMed

    Boga, Salih; Alkim, Huseyin; Koksal, Ali Riza; Ozagari, Ayse Aysim; Bayram, Mehmet; Tekin Neijmann, Sebnem; Sen, Ilker; Alkim, Canan

    2016-06-01

    ST2, a specific ligand of interleukin 33, was described as a biomarker protein of inflammatory processes and overexpression of ST2 in ulcerative colitis (UC) was shown previously. We aimed to investigate the potential relationship of serum ST2 levels with the clinical, endoscopic and histopathological activity scores in UC and Crohn's disease (CD). Serum ST2 levels were determined in 143 patients with inflammatory bowel disease (IBD) (83 UC and 60 CD), in 50 healthy controls (HC), and in 32 patients with irritable bowel syndrome (IBS). Serum ST2 levels were elevated in IBD (56.8 (41.9-87.2) pg/mL) compared to HC and IBS (30.7 (20.2-54.3), p<0.001 and 39.9 (25.9-68.7) pg/mL, p=0.002, respectively). No significant difference was found between UC (54.2 (41.3-93.0) pg/mL) and CD (63.8 (42.7-88.4) pg/mL) and between IBS and HC. Serum ST2 levels were significantly increased in active UC compared to inactive UC (72.5 (44.1-99.5) vs 40.0 (34.7-51.6) pg/mL, p<0.001) and in active CD in comparison with inactive CD (63.8 (42.7-88.4) vs 48.4 (29.6-56.9) pg/mL, p=0.036). Patients with CD showing fistulizing behavior had significantly higher ST2 levels compared to patients with inflammatory and stricturing CD (p<0.001). Clinical activity scores of patients with UC and CD were correlated with serum ST2 levels (r=0.692, p<0.001 and r=0.242, p=0.043, respectively). Serum ST2 levels showed stepwise increases with the increasing histopathological scores of patients with UC and CD (p<0.001 for both). The present study highlights significant associations between ST2 and IBD presence and activity and demonstrates elevated serum ST2 levels in patients with active CD as a novel finding. PMID:27001944

  10. Leisure Time Physical Activity and Mortality in Chronic Kidney Disease: Preliminary findings from the MDRD study

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease and all-cause mortality. In the general population, physical activity is associated with reduced mortality. We examined physical activity status in CKD patients and its relation to all-cause mortality. The Modified...

  11. Ghrelin and adipokines as circulating markers of disease activity in patients with Takayasu arteritis

    PubMed Central

    2012-01-01

    Introduction The current markers of disease activity in Takayasu arteritis (TA) are insufficient for proper assessment. We investigated circulating levels of unacylated and acylated ghrelin, leptin and adiponectin and their relationships with disease activity in patients with TA. Methods This study included 31 patients with TA and 32 sex-, age- and body mass index-matched healthy controls. Disease activity was assessed in TA patients using various tools, including Kerr's criteria, disease extent index-Takayasu, physician's global assessment, radiological parameters, and laboratory markers. Plasma unacylated and acylated ghrelin, and serum leptin and adiponectin levels were measured using an enzyme-linked immunosorbent assay. Results Unacylated and acylated ghrelin levels were found to be significantly lower in TA patients than that in healthy controls. Patients with active disease had lower unacylated ghrelin levels than those with inactive disease and had lower acylated ghrelin levels than healthy controls. Ghrelin levels were negatively correlated with various parameters of disease activity. The leptin/ghrelin ratio was significantly higher in TA patients than controls. It was positively correlated with disease activity. There was a positive correlation between unacylated and acylated ghrelin and a negative correlation between leptin and ghrelin. There was no statistical difference in adiponectin levels between TA patients and controls. The radiological activity markers were positively correlated with other parameters of disease activity. Conclusions This study suggests that plasma unacylated and acylated ghrelin levels may be useful in monitoring disease activity and planning treatment strategies for patients with TA. The serum leptin level and leptin/ghrelin ratio may also be used to help assess the disease activity. PMID:23259466

  12. Metabolic activity of sodium, measured by neutron activation, in the hands of patients suffering from bone diseases: concise communication

    SciTech Connect

    Spinks, T.J.; Bewley, D.K.; Paolillo, M.; Vlotides, J.; Joplin, G.F.; Ranicar, A.S.O.

    1980-01-01

    Turnover of sodium in the human hand was studied by neutron activation. Patients suffering from various metabolic abnormalities affecting the skeleton, who were undergoing routine neutron activation for the measurement of calcium, were investigated along with a group of healthy volunteers. Neutron activation labels the sodium atoms simultaneously and with equal probability regardless of the turnover time of individual body compartments. The loss of sodium can be described either by a sum of two exponentials or by a single power function. Distinctions between patients and normal subjects were not apparent from the exponential model but were brought out by the power function. The exponent of time in the latter is a measure of clearance rate. The mean values of this parameter in (a) a group of patients suffering from acromegaly; (b) a group including Paget's disease, osteoporosis, Cushing's disease, and hyperparathyroidism; and (c) a group of healthy subjects, were found to be significantly different from each other.

  13. Odorant receptor-mediated sperm activation in disease vector mosquitoes

    PubMed Central

    Pitts, R. Jason; Liu, Chao; Zhou, Xiaofan; Malpartida, Juan C.; Zwiebel, Laurence J.

    2014-01-01

    Insects, such as the malaria vector mosquito, Anopheles gambiae, depend upon chemoreceptors to respond to volatiles emitted from a range of environmental sources, most notably blood meal hosts and oviposition sites. A subset of peripheral signaling pathways involved in these insect chemosensory-dependent behaviors requires the activity of heteromeric odorant receptor (OR) ion channel complexes and ligands for numerous A. gambiae ORs (AgOrs) have been identified. Although AgOrs are expressed in nonhead appendages, studies characterizing potential AgOr function in nonolfactory tissues have not been conducted. In the present study, we explore the possibility that AgOrs mediate responses of spermatozoa to endogenous signaling molecules in A. gambiae. In addition to finding AgOr transcript expression in testes, we show that the OR coreceptor, AgOrco, is localized to the flagella of A. gambiae spermatozoa where Orco-specific agonists, antagonists, and other odorant ligands robustly activate flagella beating in an Orco-dependent process. We also demonstrate Orco expression and Orco-mediated activation of spermatozoa in the yellow fever mosquito, Aedes aegypti. Moreover, we find Orco localization in testes across distinct insect taxa and posit that OR-mediated responses in spermatozoa may represent a general characteristic of insect reproduction and an example of convergent evolution. PMID:24550284

  14. [Measurement of physical activity in patients with chronic obstructive pulmonary disease].

    PubMed

    Magnussen, Helgo; Waschki, Benjamin; Watz, Henrik

    2009-04-15

    Physical activity is an important parameter related to morbidity and mortality in cardiovascular disease, metabolic syndrome/diabetes, mental disorders, cancer, and chronic obstructive pulmonary disease (COPD). In COPD, lower levels of physical activity as reported by the patients are associated with a faster annual lung function decline, increased number of hospitalizations, and higher risk of mortality. Self-reported physical activity, however, correlates only poorly with objectively quantified physical activity in patients with COPD. Recent data show that physical activity can reliably be measured in a substantial number of patients with COPD. Extrapulmonary effects of COPD are associated with reduced physical activity. Clinical characteristics commonly used to assess disease severity like the forced expiratory volume in 1 s or the 6-min walk distance only incompletely reflect the physical activity of patients with COPD. PMID:19399389

  15. The Peroxisome Proliferator Activated Receptor‐γ Pioglitazone Improves Vascular Function and Decreases Disease Activity in Patients With Rheumatoid Arthritis

    PubMed Central

    Marder, Wendy; Khalatbari, Shokoufeh; Myles, James D.; Hench, Rita; Lustig, Susan; Yalavarthi, Srilakshmi; Parameswaran, Aishwarya; Brook, Robert D.; Kaplan, Mariana J.

    2013-01-01

    Background Rheumatoid arthritis (RA) is associated with heightened mortality due to atherosclerotic cardiovascular disease (CVD). Inflammatory pathways in RA negatively affect vascular physiology and promote metabolic disturbances that contribute to CVD. We hypothesized that the peroxisome proliferator activated receptor‐γ (PPAR‐γ) pioglitazone could promote potent vasculoprotective and anti‐inflammatory effects in RA. Methods and Results One hundred forty‐three non‐diabetic adult RA patients (76.2% female, age 55.2±12.1 [mean±SD]) on stable RA standard of care treatment were enrolled in a randomized, double‐blind placebo controlled crossover trial of 45 mg daily pioglitazone versus placebo, with a 3‐month duration/arm and a 2‐month washout period. Pulse wave velocity of the aorta (PWV), brachial artery flow mediated dilatation (FMD), nitroglycerin mediated dilatation (NMD), microvascular endothelial function (reactive hyperemia index [RHI]), and circulating biomarkers of inflammation, insulin resistance, and atherosclerosis risk all were quantified. RA disease activity was assessed with the 28‐Joint Count Disease Activity Score (DAS‐28) C‐reactive protein (CRP) and the Short Form (36) Health Survey quality of life questionnaire. When added to standard of care RA treatment, pioglitazone significantly decreased pulse wave velocity (ie, aortic stiffness) (P=0.01), while FMD and RHI remained unchanged when compared to treatment with placebo. Further, pioglitazone significantly reduced RA disease activity (P=0.02) and CRP levels (P=0.001), while improving lipid profiles. The drug was well tolerated. Conclusions Addition of pioglitazone to RA standard of care significantly improves aortic elasticity and decreases inflammation and disease activity with minimal safety issues. The clinical implications of these findings remain to be established. Clinical Trial Registration URL: ClinicalTrials.gov Unique Identifier: NCT00554853. PMID:24252844

  16. Development and assessment of a modified Pediatric Crohn Disease Activity Index.

    PubMed

    Leach, Steven T; Nahidi, Lily; Tilakaratne, Samantha; Day, Andrew S; Lemberg, Daniel A

    2010-08-01

    The Pediatric Crohn Disease Activity Index (PCDAI) is an established and validated measure of disease activity in children with Crohn disease. However, its use in the research setting can be limited because of ambiguity of the subjective and anthropometric components of the index. Here we propose and evaluate a modified PCDAI (Mod PCDAI) consisting of the laboratory measures of the PCDAI plus C-reactive protein. This Mod PCDAI can provide an indication of disease activity because it correlates with the PCDAI, physicians' global assessment, and fecal calprotectin, and therefore may provide a suitable alternative to the PCDAI when required. PMID:20479686

  17. Pivotal Role of Mitogen-Activated Protein Kinase-Activated Protein Kinase 2 in Inflammatory Pulmonary Diseases

    PubMed Central

    Qian, Feng; Deng, Jing; Wang, Gang; Ye, Richard D.; Christman, John W.

    2016-01-01

    Mitogen-activated protein kinase (MAPK)-activated protein kinase (MK2) is exclusively regulated by p38 MAPK in vivo. Upon activation of p38 MAPK, MK2 binds with p38 MAPK, leading to phosphorylation of TTP, Hsp27, Akt and Cdc25 that are involved in regulation of various essential cellular functions. In this review, we discuss current knowledge about molecular mechanisms of MK2 in regulation of TNF-α production, NADPH oxidase activation, neutrophil migration, and DNA-damage-induced cell cycle arrest which are involved in the molecular pathogenesis of acute lung injury, pulmonary fibrosis, and non-small-cell lung cancer. Collectively current and emerging new information indicate that developing MK2 inhibitors and blocking MK2-mediated signal pathways is a potential therapeutic strategy for treatment of inflammatory and fibrotic lung diseases and lung cancer. PMID:26119506

  18. The Correlation of Serum IL-12B Expression With Disease Activity in Patients With Inflammatory Bowel Disease

    PubMed Central

    Lee, Hye Won; Chung, Sook Hee; Moon, Chang Mo; Che, Xiumei; Kim, Seung Won; Park, Soo Jung; Hong, Sung Pil; Kim, Tae Il; Kim, Won Ho; Cheon, Jae Hee

    2016-01-01

    Abstract Genetic variants in IL12B, encoding the p40 subunit common in interleukin-12 (IL-12) and interleukin-23, were identified as the susceptibility loci for inflammatory bowel disease (IBD). This study aimed to identify the correlation of serum IL-12B expression with disease activity in patients with IBD and evaluate the possibility of IL-12B as a biomarker for assessing inflammatory status in IBD. A total of 102 patients with IBD, including 38, 32, and 32 patients with Crohn's disease (CD), ulcerative colitis (UC), and intestinal Behçet's disease (intestinal BD), respectively, were included. The clinical and laboratory data from the patients were collected at the time of serum IL-12B measurement. Serum IL-12B levels were measured using an enzyme-linked immunosorbent assay. The median IL-12B levels in patients with CD, UC, and intestinal BD were significantly higher than those in controls (1.87, 2.74, and 2.73 pg/mL, respectively, vs. 1.42 pg/mL, all P <0.05). IL-12B concentrations were associated with disease activity in patients with UC and intestinal BD but not in those with CD. IL-12B levels were increased with increasing disease activity in patients with UC (P <0.001). Likewise, patients with active intestinal BD had higher IL-12B levels than those without active disease (P = 0.008). IL-12B levels were correlated with the endoscopic disease activity of UC (P = 0.002) and intestinal BD (P = 0.001) but not that of CD. Serum IL-12B levels were significantly correlated with clinical and endoscopic disease activity in patients with UC and intestinal BD, suggesting its potential use as a biomarker for assessing disease activity in these patients. PMID:27281077

  19. High IL-23 level is a marker of disease activity in rheumatoid arthritis.

    PubMed

    Abu Al Fadl, Esam M; Fattouh, Mona; Allam, Ahmed A

    2013-01-01

    Rheumatoid arthritis (RA) is a chronic autoimmune systemic disorder characterized by inflammatory responses mainly affecting the synovial joints. Interleukin-23 (IL-23) is a heterodimeric pro-inflammatory cytokine secreted by activated dendritic cells and activated macrophages. IL-23 is the key cytokine controlling inflammation in peripheral tissues leading to the development of autoimmune diseases. The objective of our study was to determine the relationship between the IL-23 level and disease activity in RA patients. Sixty RA patients were included in the study with mean age of 40 years; they included 44 (73.3 %) females and 16 males (26.7 %). The clinical parameters of disease activity were determined, including the 28-joint disease activity score (DAS28), serum levels of C-reactive protein (CRP), Anti-citrullinated peptide antibody (ACPA), rheumatoid factor (RF), and TNF-alpha and the degree of bony erosions based on X-rays. Patients were subdivided into active disease group (n = 30) with DAS28 score higher than 5.1 (Group I); and remission group (n = 30) with DAS28 score less than 2.6 (Group II). Thirty healthy individuals in the same age group of RA patients including 22 (73.3%) females and 8 males (26.7%) were randomly selected as the control group (Group III). The levels of IL-23 were determined by enzyme-linked immunosorbent assay (ELISA) and the correlations between the serum levels of IL-23 and disease activity parameters of patients with RA were determined. Serum levels of IL-23 were significantly higher in RA patients during active stage of the disease in comparison to the patients in remission and the control group. There was a significant positive correlation between serum IL-23 levels in RA patients and individual disease activity parameters. It is concluded that elevated serum IL-23 level may be a useful marker to detect active RA and disease progression in patients with RA. PMID:24617049

  20. Drug−disease interaction: Crohn's disease elevates verapamil plasma concentrations but reduces response to the drug proportional to disease activity

    PubMed Central

    Sanaee, Forough; Clements, John D; Waugh, Alistair W G; Fedorak, Richard N; Lewanczuk, Richard; Jamali, Fakhreddin

    2011-01-01

    AIM Inflammation is involved in the pathogenesis of cardiovascular diseases that includes reduced response to pharmacotherapy due to altered pharmacokinetics and pharmacodynamics. It is not known if these effects exist in general in all inflammatory conditions. It also remains unknown whether in a given population the effect is a function of disease severity. We investigated whether pharmacokinetics and pharmacodynamics of a typical calcium channel inhibitor are influenced by Crohn's disease (CD), a disease for which the disease severity can be readily ranked. METHODS We administered 80 mg verapamil orally to (i) healthy control subjects (n = 9), (ii) patients with clinically quiescent CD (n = 22) and (iii) patients with clinically active CD (n = 14). Serial analysis of verapamil enantiomers (total and plasma unbound), blood pressure and electrocardiograms were recorded over 8 h post dose. The severity of CD was measured using the Harvey-Bradshaw Index. RESULTS CD substantially and significantly increased plasma verapamil concentration and in a stereoselective fashion (S, 9-fold; R, 2-fold). The elevated verapamil concentration, however, failed to result in an increased verapamil pharmacodynamic effect so that the patients with elevated verapamil concentration demonstrated no significant increase in response measured as PR interval and blood pressure. Instead, the greater the disease severity, the lower was the drug potency to prolong PR interval (r = 0.86, P < 0.0006), CONCLUSIONS CD patients with severe disease may not respond to cardiovascular therapy with calcium channel blockers. Reducing the severity increases response despite reduced drug concentration. This observation may have therapeutic implication beyond the disease and the drug studies herein. PMID:21592185

  1. Influence of liver disease and environmental factors on hepatic monooxygenase activity in vitro.

    PubMed

    Brodie, M J; Boobis, A R; Bulpitt, C J; Davies, D S

    1981-01-01

    The effects of liver disease and environmental factors on hepatic microsomal cytochrome P-450 content, NADPH-cytochrome c reductase (reductase) activity and aryl hydrocarbon hydroxylase (AHH) activity have been simultaneously investigated in 70 patients undergoing diagnostic liver biopsy. The activity of reductase was not significantly affected by the presence of liver disease or any of the environmental factors studied. Cytochrome P-450 content decreased with increasing severity of liver disease whereas AHH activity was only significantly reduced in biopsies showing hepatocellular destruction. None of the parameters of monooxygenase activity varied significantly with the age or sex of the patients. Alcohol excess was associated with decreased cytochrome P-450 content and AHH activity and this effect was independent of the histological status of the biopsy. Both high caffeine intake and cigarette smoking increased AHH activity in the absence of any change in cytochrome P-450 content. There was a positive correlation between the number of meat meals eaten per week and cytochrome P-450 content. Chronic treatment with enzyme-inducing anticonvulsants appeared to increase both cytochrome P-450 content and AHH activity. Despite differential effects of liver disease and environmental influences on cytochrome P-450 content and AHH activity there was a highly significant correlation between the two parameters. The results of the present study correlate well with the known effects of disease and environment on drug metabolism in vivo. PMID:7308271

  2. Can red cell distribution width be a marker of disease activity in ulcerative colitis?

    PubMed Central

    Ipek, Serkan; Cekic, Cem; Alper, Emrah; Coban, Eyup; Eliacik, Eylem; Arabul, Mahmut; Aslan, Fatih; Vatansever, Sezgin; Yalcin, Hulya; Unsal, Belkis

    2015-01-01

    Aim: The current study aimed to investigate the association between disease activity and red cell distribution width (RDW) levels in ulcerative colitis and to determine whether RDW can be used as a marker of disease activity in non-anemic ulcerative colitis. Methods: The RDW levels of 310 ulcerative colitis patients who underwent colonoscopy were analyzed retrospectively. The patients were divided into two groups (active disease and remission) according to the endoscopic activity index. In addition, the accuracy of RDW in determining disease activity in non-anemic patients was assessed. The efficacy of RDW in determining disease activity was compared to that of white blood cell count, platelet count, C-reactive protein, and erythrocyte sedimentation rate. Results: Two hundred and six (66.5%) patients had active disease, and 104 (33.5%) were in remission. The mean RDW levels in patients with active ulcerative colitis and in those in remission were 16.8±2.9 and 15.5±1.4, respectively (P<0.001). Ninety-six (46.6%) patients in the active disease group and 89 (85.6%) in the remission group were non-anemic, and their respective RDW levels were 15.4±1.2 and 15.3±1.1 (P=0.267). The sensitivity and specificity of RDW in determining inflammation were 41% and 91%, respectively (AUC 0.65, P<0.001). Conclusions: This study demonstrated that RDW can be used as a marker for disease activity in ulcerative colitis, but it did not have the same efficacy in the non-anemic group. PMID:26550336

  3. The role of microglial activation in disease progression.

    PubMed

    Correale, Jorge

    2014-09-01

    Microglia, a unique type of myeloid cell, play a key role in the inflammation-mediated neurodegeneration occurring during both acute and chronic stages of multiple sclerosis (MS). These highly specialized cells trigger neurotoxic pathways, producing pro-inflammatory cytokines, reactive oxygen and nitrogen species and proteolytic enzymes, causing progressive neurodegeneration. Microglia have also been associated with development of cortical lesions in progressive MS, as well as with alterations of synaptic transmission in experimental autoimmune encephalomyelitis (EAE). However, they also play an important role in the promotion of neuroprotection, downregulation of inflammation, and stimulation of tissue repair. Notably, microglia undergo changes in morphology and function with normal aging, resulting in a decline of their ability to repair central nervous system damage, making axons and neurons more vulnerable with age. Modulation of microglial activation for therapeutic purposes must consider suppressing deleterious effects of these cells, while simultaneously preserving their protective functions. PMID:24812046

  4. Temporal Effect of Depressive Symptoms on the Longitudinal Evolution of Rheumatoid Arthritis Disease Activity

    PubMed Central

    Rathbun, Alan M.; Harrold, Leslie R.; Reed, George W.

    2016-01-01

    Objective Depression is common in the rheumatoid arthritis (RA) population, yet little is known of its effect on the course of disease activity. The aim of our study was to determine if prevalent and incident depressive symptoms influenced longitudinal changes in RA disease activity. Methods RA patients with and without depressive symptoms were identified using single-item questions from an existing registry sample. Mixed-effects models were used to examine changes in disease activity over 2 years in those with and without prevalent and incident depressive symptoms. Outcome variables included composite disease activity, joint counts, global assessments, pain, function, and acute-phase reactants. Model-based outcome estimations at the index dates and corresponding 1- and 2-year changes were calculated. Results Rates of disease activity change were significantly different in patients with a lifetime prevalence of symptomology, but not incident depressive symptoms, when compared to controls. Prior symptoms were associated with slower rates of disease activity decline, evidenced by the estimated 1-year Clinical Disease Activity Index changes: −3.0 (−3.3, −2.6) and −4.0 (−4.3, −3.6) in patients with and without lifetime prevalence, respectively. Analogous results were obtained for most of the other disease activity outcomes; although, there was no temporal effect of prevalent symptoms of depression on swollen joints and acute-phase reactants. Conclusion Depressive symptoms temporally influence the evolution of RA disease activity, and the magnitude is dependent on the time of symptomatic onset. However, the effect is limited to patient-reported pain, global assessment, and function, as well as physician-reported global assessment and tender joints. PMID:25384985

  5. Development and Retrospective Validation of the Juvenile Spondyloarthritis Disease Activity (JSpADA) Index

    PubMed Central

    Weiss, Pamela F.; Colbert, Robert A.; Xiao, Rui; Feudtner, Chris; Beukelman, Timothy; DeWitt, Esi Morgan; Pagnini, Ilaria; Wright, Tracey B.; Wallace, Carol A.

    2014-01-01

    Objectives To develop and validate a Juvenile Spondyloarthritis (JSpA) Disease Activity (JSpADA) index for use in clinical practice and research. Methods Using modified Delphi consensus techniques, ten items were selected by participants in the international pediatric rheumatology list-serve, the Childhood Arthritis and Rheumatology Research Alliance, and the list-serve for the Pediatric Section of the American College of Rheumatology. Validation was performed in a retrospective multicenter cohort of 243 children. Results 106 physicians representing 14 countries completed the initial questionnaire. Completion rates for the subsequent questionnaires were 84%, 75%, and 77% of the original respondents. Ten items reached 80% consensus: arthritis, enthesitis, patient pain assessment, inflammatory markers, morning stiffness, clinical sacroiliitis, uveitis, back mobility, and patient and physician assessments of disease activity. Two items were eliminated after item analysis (patient and physician assessments of disease activity). Factor analysis identified 3 primary domains that explain 58% of variance: peripheral disease, axial disease, and uveitis. Cronbach α coefficient was 0.66. The JSpADA had high or moderate correlations with the Juvenile Arthritis disease activity score (r=0.80), patient and physician assessments of disease activity (r=0.70 and 0.66), and the Childhood Health Assessment Questionnaire (r=0.56). The JSpADA discriminated well between subjects with active versus inactive disease (p<0.001) and was responsive to improvement or worsening in disease activity over time (p<0.001). Conclusion Using international input and consensus formation techniques, we developed and validated the first disease activity assessment for JSpA. Future studies should validate the JSpADA index in a prospective multi-center cohort. PMID:25047959

  6. Signal transducer and activator of transcription 5 is implicated in disease activity in adult and juvenile onset systemic lupus erythematosus.

    PubMed

    Meshaal, Safa; El Refai, Rasha; El Saie, Ahmed; El Hawary, Rabab

    2016-06-01

    The Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway is one of a handful of pleiotropic cascades used to transduce a multitude of signals for development and homeostasis in humans. It is the principal signaling mechanism for a wide array of cytokines and growth factors. Dysregulated cytokine action on immune cells plays an important role in the initiation and progress of systemic lupus erythematosus (SLE). In this study, we tried to assess the role of STAT5 in systemic lupus erythematosus and correlate its phosphorylation level with the disease activity. The activation of the STAT5 was assessed by measuring the level of expression of phosphorylated STAT5 (pSTAT5) using flow cytometry on the peripheral blood T and B cells in 58 SLE patients (40 adult and 18 juvenile onset) and on 23 healthy age- and sex-matched controls for both groups. Serum prolactin level was also assessed in the patients and control by ELISA. The study revealed that the level of pSTAT5 was higher in adult SLE patients than in healthy control (p = 0.001) and in juvenile-onset SLE patients versus age-matched control (p = 0.031). A positive correlation existed between the pSTAT5 levels and Systemic Lupus Activity Measure (SLAM) score and also with multiple clinical manifestations indicating a potential role of STAT5 signaling in pathogenesis SLE. The pSTAT5 signaling is implicated in the disease activity of SLE and may be a useful target of therapy by correcting the dysregulation of cytokines involved in the disease pathogenesis. PMID:27041383

  7. Influence of medical treatment, smoking and disease activity on pregnancy outcomes in Crohn's disease.

    PubMed

    Julsgaard, Mette; Nørgaard, Mette; Hvas, Christian Lodberg; Grosen, Anne; Hasseriis, Sara; Christensen, Lisbet Ambrosius

    2014-03-01

    OBJECTIVE. Little is known about predictors for adverse pregnancy outcomes among women with Crohn's disease (CD). In this population-based study, we examined pregnancy outcomes in CD stratified by medical treatment and smoking status while accounting for disease activity. METHODS. In two Danish regions with a population of 1.6 million, we identified 154 CD women who had given birth within a 6-year period. We combined questionnaire data, prescription data, data from medical records and population-based medical databases. We used logistic regression to estimate prevalence odds ratios (POR) for adverse pregnancy outcomes by different predictors. RESULTS. Among 105 (80%) respondents, 55 (52%) reported taking medication during pregnancy. The majority (95%) were in disease remission. The children's mean birth weight did not differ by maternal medical treatment. As expected, smoking was a predictor of low birth weight. Mean birth weight in children of smokers in medical treatment was significantly reduced by 274 g compared with children of non-smokers who received medical treatment. In children of women without medical treatment, this difference was 126 g between smokers and non-smokers. Women in medical treatment did not have an increased risk of preterm delivery (POR 0.71; 95% confidence interval (CI) 0.18-2.79), congenital malformations (POR 0.60; 0.10-3.76) or cesarean section (POR 1.40; 0.63-3.08). CONCLUSIon. In CD, smoking was negatively associated with child birth weight. This association was most pronounced among women who received medical treatment. Maternal medical treatment for CD did not seem to be a risk factor for adverse pregnancy outcomes. PMID:24417179

  8. Rheumatoid arthritis and pregnancy: evolution of disease activity and pathophysiological considerations for drug use

    PubMed Central

    Hazes, Johanna M.W.; Coulie, Pierre G.; Geenen, Vincent; Vermeire, Séverine; Carbonnel, Franck; Louis, Edouard; Masson, Pierre

    2011-01-01

    It has long been known that pregnancy and childbirth have a profound effect on the disease activity of rheumatic diseases. For clinicians, the management of patients with RA wishing to become pregnant involves the challenge of keeping disease activity under control and adequately adapting drug therapy during pregnancy and post-partum. This article aims to summarize the current evidence on the evolution of RA disease activity during and after pregnancy and the use of anti-rheumatic drugs around this period. Of recent interest is the potential use of anti-TNF compounds in the preconception period and during pregnancy. Accumulating experience with anti-TNF therapy in other immune-mediated inflammatory diseases, such as Crohn’s disease, provides useful insights for the use of TNF blockade in pregnant women with RA, or RA patients wishing to become pregnant. PMID:21890617

  9. The MicroActive project: automatic detection of disease-related molecular cell activity

    NASA Astrophysics Data System (ADS)

    Furuberg, Liv; Mielnik, Michal; Johansen, Ib-Rune; Voitel, Jörg; Gulliksen, Anja; Solli, Lars; Karlsen, Frank; Bayer, Tobias; Schönfeld, Friedhelm; Drese, Klaus; Keegan, Helen; Martin, Cara; O'Leary, John; Riegger, Lutz; Koltay, Peter

    2007-05-01

    The aim of the MicroActive project is to develop an instrument for molecular diagnostics. The instrument will first be tested for patient screening for a group of viruses causing cervical cancer. Two disposable polymer chips with reagents stored on-chip will be inserted into the instrument for each patient sample. The first chip performs sample preparation of the epithelial cervical cells while mRNA amplification and fluorescent detection takes place in the second chip. More than 10 different virus markers will be analysed in one chip. We report results on sub-functions of the amplification chip. The sample is split into smaller droplets, and the droplets move in parallel channels containing different dried reagents for the different analyses. We report experimental results on parallel droplet movement control using one external pump only, combined with hydrophobic valves. Valve burst pressures are controlled by geometry. We show droplet control using valves with burst pressures between 800 and 4500 Pa. We also monitored the re-hydration times for two necessary dried reagents. After sample insertion, uniform concentration of the reagents in the droplet was reached after respectively 60 s and 10 min. These times are acceptable for successful amplification. Finally we have shown positive amplification of HPV type 16 using dried enzymes stored in micro chambers.

  10. Flare, Persistently Active Disease, and Serologically Active Clinically Quiescent Disease in Systemic Lupus Erythematosus: A 2-Year Follow-Up Study

    PubMed Central

    Conti, Fabrizio; Ceccarelli, Fulvia; Perricone, Carlo; Miranda, Francesca; Truglia, Simona; Massaro, Laura; Pacucci, Viviana Antonella; Conti, Virginia; Bartosiewicz, Izabella; Spinelli, Francesca Romana; Alessandri, Cristiano; Valesini, Guido

    2012-01-01

    Objective Several indices have been proposed to assess disease activity in patients with Systemic Lupus Erythematosus (SLE). Recent studies have showed a prevalence of flare between 28–35.3%, persistently active disease (PAD) between 46%–52% and serologically active clinically quiescent (SACQ) disease ranging from 6 to 15%. Our goal was to evaluate the flare, PAD and SACQ rate incidence in a cohort of SLE patients over a 2-year follow-up. Methods We evaluated 394 SLE patients. Flare was defined as an increase in SLEDAI-2K score of ≥4 from the previous visit; PAD was defined as a SLEDAI-2K score of ≥4, on >2 consecutive visits; SACQ was defined as at least a 2-year period without clinical activity and with persistent serologic activity. Results Among the 95 patients eligible for the analysis in 2009, 7 (7.3%) had ≥1 flare episode, whereas 9 (9.4%) had PAD. Similarly, among the 118 patients selected for the analysis in 2010, 6 (5%) had ≥1 flare episode, whereas 16 (13.5%) had PAD. Only 1/45 patient (2.2%) showed SACQ during the follow-up. Conclusion We showed a low incidence of flare, PAD and SACQ in Italian SLE patients compared with previous studies which could be partly explained by ethnic differences. PMID:23029327

  11. Adjuvant oestrogen therapy does not improve disease activity in postmenopausal patients with rheumatoid arthritis.

    PubMed Central

    van den Brink, H R; van Everdingen, A A; van Wijk, M J; Jacobs, J W; Bijlsma, J W

    1993-01-01

    OBJECTIVE--To investigate whether oestrogens can be used as treatment to diminish disease activity in women with rheumatoid arthritis. METHODS--Forty postmenopausal female patients with active rheumatoid arthritis participated in a placebo-controlled, double-blind study on the possible beneficial effect of adjuvant treatment of oestradiol on disease activity. RESULTS--Thirty three patients completed 52 weeks of treatment with 2 mg oestradiol-valerate or placebo. No statistically significant difference was found in and between both treatment groups with regard to articular indices, pain score by visual analogue scale, erythrocyte sedimentation rate and health questionnaire on daily activities before, during and at the end of the study. CONCLUSION--This first randomised prospective placebo-controlled study shows no beneficial effect of oestrogens on disease activity in postmenopausal female patients with rheumatoid arthritis. PMID:8311536

  12. Why and how should we measure disease activity and damage in lupus?

    PubMed

    Feld, Joy; Isenberg, David

    2014-06-01

    The assessment of disease activity and flare and differentiating them from permanent damage in patients with SLE is challenging. The SLEDAI, SLEDAI-2K and SELENA-SLEDAI measure global disease activity. The BILAG measures organ-specific activity. The BILAG better captures the change in the different organs at the expense of complexity. The SRI is a composite index incorporating both BILAG and SLEDAI indices and a physician's global assessment. It has been used in the most recent clinical trials. Damage correlates with prognosis; it is assessed by the SLICC/SDI index. This index scores damage whatever the cause, disease or treatment related, or the consequence of concomitant disease. The disease activity and damage indices do not correlate well with the patient's health related quality of life (HRQoL), the degree of disability or the impact of disease. The impact of the patients' joint disease on their HRQoL is assessed via the HAQ questionnaire and the global health status via the SF-36 index, or one of the more recently described lupus specific quality of life indices [Lupus QoL]. The global assessment instruments and the BILAG index can also be used in children and adolescents with SLE. However, a modified paediatric version of the SLICC/SDI damage index is advised. Many advances have been achieved in disease activity and damage measurement in the past 20 years but the problem of how best to capture flare accurately remains. PMID:24791651

  13. Daily energy expenditure, physical activity, and weight loss in Parkinson's disease patients

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Patients with Parkinson's disease (PD) commonly exhibit weight loss (WL) which investigators attribute to various factors, including elevated energy expenditure. We tested the hypothesis that daily energy expenditure (DEE) and its components, resting energy expenditure (REE) and physical activity (P...

  14. Can directed activity improve mobility in Huntington's disease?

    PubMed

    Busse, M E; Rosser, A E

    2007-04-30

    Huntington's disease is an inherited disorder of the CNS that results in progressive deterioration of mobility and cognition and also affects behaviour. There are no disease-modifying interventions available to date, although there has been considerable progress in research directed at understanding the pathological basis of the disease with a view to identifying potential treatments. It is however important not to overlook currently available treatment strategies, including rehabilitation approaches. There has been little work to date to explore the potential of such approaches and here we highlight the need for more systematic studies in this area as well as the need for good objective assessment tools and the potential role that rehabilitation and training may have in the application of novel treatment options. PMID:17352942

  15. Serum Amyloid A Circulating Levels and Disease Activity in Patients with Juvenile Idiopathic Arthritis

    PubMed Central

    Giani, Teresa; Fioravanti, Antonella; Iacoponi, Francesca; Simonini, Gabriele; Pagnini, Ilaria; Spreafico, Adriano; Chellini, Federico; Galeazzi, Mauro; Cimaz, Rolando

    2012-01-01

    The aim of our study was to evaluate the association between circulating levels of serum amyloid A protein (SAA) and disease activity in patients with juvenile idiopathic arthritis (JIA). Our study group included 41 JIA patients (9 male, 32 female), classified according to the International League of Associations for Rheumatology (ILAR) criteria (5); 16 had polyarticular onset disease and 25 had oligoarticular onset disease. Among 25 patients with oligoarticular disease, three had extended oligoarthritis. Serum amyloid A (SAA), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were measured in both patients and 26 healthy controls. SAA levels were higher in JIA patients versus healthy controls (p<0.001). Significant positive correlations were found between SAA and the presence of active joints (rho=0.363, p<0.05), the number of active joints (rho=0.418, p<0.05), ESR (R=0.702, p<0.05) and CRP (R=0.827, p<0.05). No significant correlations between ESR and the presence of active joints (rho=0.221, p=0.225) or between ESR and the number of active joints (rho=0.118, p=0.520) were demonstrated in JIA patients. No significant correlations were obtained between CRP and the presence of active joints (rho=0.034, p=0.855) or between CRP and the number of active joints (rho=0.033, p=0.859). We discovered a significant increase in SAA levels in JIA patients, compared to controls, and a strong positive correlation between SAA level and JIA disease activity. We also discerned SAA to be a more sensitive laboratory marker than ESR and CRP for evaluating the presence and number of active joints. We suggest that SAA can be used as an additional indicator of disease activity in JIA. PMID:22869491

  16. Performance characteristics of the simplified version of ankylosing spondylitis disease activity score (SASDAS).

    PubMed

    Solmaz, Dilek; Yildirim, Tulay; Avci, Okan; Tomas, Nazmiye; Akar, Servet

    2016-07-01

    Various types of disease activity measures are available for axial spondyloarthritis (axSpA), and there is no gold standard for all individual patients. The ankylosing spondylitis disease activity score (ASDAS) is highly discriminatory, sensitive to change, and associated with structural progression. A simplified version of the ASDAS (SASDAS) was proposed and found to be a simple and practical tool to assess disease activity. Our aim was to test the performance characteristics of the SASDAS and compare it with validated tools. In total, 97 consecutive ankylosing spondylitis (AS) patients were included in the study. Disease activity was assessed by the ASDAS-erythrocyte sedimentation rate (ESR), ASDAS-C-reactive protein (CRP), bath ankylosing spondylitis disease activity index (BASDAI), and SASDAS. The relationship among these activity indices and the level of agreement of various activity categories were tested. There was a strong correlation between the SASDAS and other activity indices, including the BASDAI (r = 0.916, p < 0.001), ASDAS-CRP (r = 0.847, p < 0.001), and ASDAS-ESR (r = 0.942, p < 0.001). Although the agreement between the ASDAS-ESR and SASDAS was good (weighted kappa of 0.744 and total agreement of 77 %), there was moderate agreement between the ASDAS-CRP and SASDAS (weighted kappa of 0.579 and total agreement of 66 %). The disagreement was particularly striking in "moderate" and "high disease activity" states. Approximately 40 % of patients classified as moderate activity according to the ASDAS-ESR and 45 % according to the ASDAS-CRP were differentially categorized by the SASDAS. The results of the present analysis suggest that the simplified version of the ASDAS-ESR should be further validated in various settings and populations due to a questionable level of agreement between the ASDAS-CRP and SASDAS. PMID:26670454

  17. Persons with moderate Alzheimer's disease use simple technology aids to manage daily activities and leisure occupation.

    PubMed

    Lancioni, Giulio E; Singh, Nirbhay N; O'Reilly, Mark F; Sigafoos, Jeff; Renna, Caterina; Pinto, Katia; De Vanna, Floriana; Caffò, Alessandro O; Stasolla, Fabrizio

    2014-09-01

    Two studies assessed technology-aided programs to support performance of daily activities and selection/activation of music items with patients with moderate Alzheimer's disease. In Study I, four patients were presented with activity-related pictorial instructions via a computer fitted with inexpensive, commercial software. In Study II, four patients were (a) presented with different music options and (b) allowed to select and activate the preferred option via a microswitch response. Study I showed that each patient learned to perform the two activities available with percentages of correct responses exceeding 85 by the end of the intervention. Study II showed that all patients learned to choose and activate music options. Psychology students, employed in a social validation check, scored the patients' behavior within the program better than their behavior in a control situation. The relevance and usability of simplified pictorial-instruction programs and music choice programs for patients with moderate Alzheimer's disease were discussed. PMID:24881006

  18. Cytomegalovirus Infection in Inflammatory Bowel Disease Is Not Associated with Worsening of Intestinal Inflammatory Activity

    PubMed Central

    do Carmo, Alexandre Medeiros; Santos, Fabiana Maria; Ortiz-Agostinho, Carmen Lucia; Nishitokukado, Iêda; Frota, Cintia S.; Gomes, Flavia Ubeda; de Arruda Leite, André Zonetti; Pannuti, Claudio Sérgio; Boas, Lucy Santos Vilas; Teixeira, Magaly Gemio; Sipahi, Aytan Miranda

    2014-01-01

    Background Cytomegalovirus is highly prevalent virus and usually occurs in immunocompromised patients. The pathophysiology and treatment of inflammatory bowel disease often induce a state of immunosuppression. Because this, there are still doubts and controversies about the relationship between inflammatory bowel disease and cytomegalovirus. Aim Evaluate the frequency of cytomegalovirus in patients with inflammatory bowel disease and identify correlations. Methods Patients with inflammatory bowel disease underwent an interview, review of records and collection of blood and fecal samples. The search for cytomegalovirus was performed by IgG and IgM blood serology, by real-time PCR in the blood and by qualitative PCR in feces. Results were correlated with red blood cell levels, C-reactive protein levels, erythrocyte sedimentation rates and fecal calprotectin levels for each patient. Results Among the 400 eligible patients, 249 had Crohn's disease, and 151 had ulcerative colitis. In the group of Crohn's disease, 67 of the patients had moderate or severe disease, but 126 patients presented with active disease, based on the evaluation of the fecal calprotectin. In patients with ulcerative colitis, only 21 patients had moderate disease, but 76 patients presented with active disease, based on the evaluation of the fecal calprotectin. A large majority of patients had positive CMV IgG. Overall, 10 patients had positive CMV IgM, and 9 patients had a positive qualitative detection of CMV DNA by PCR in the feces. All 400 patients returned negative results after the quantitative detection of CMV DNA in blood by real-time PCR. Analyzing the 19 patients with active infections, we only found that such an association occurred with the use of combined therapy (anti-TNF-alpha + azathioprine) Conclusion The findings show that latent cytomegalovirus infections are frequent and active cytomegalovirus infection is rare. We did not find any association between an active infection of CMV

  19. Rapid fecal calprotectin testing to assess for endoscopic disease activity in inflammatory bowel disease: A diagnostic cohort study

    PubMed Central

    Kwapisz, Lukasz; Mosli, Mahmoud; Chande, Nilesh; Yan, Brian; Beaton, Melanie; Micsko, Jessica; Mennill, Pauline W.; Barnett, William; Bax, Kevin; Ponich, Terry; Howard, John; Tirolese, Anthony; Lannigan, Robert; Gregor, James

    2015-01-01

    Background and Aim: With increasing numbers of patients diagnosed with inflammatory bowel disease (IBD), it is important to identify noninvasive methods of detecting disease activity. The aim of this study is to examine the diagnostic accuracy of fecal rapid calprotectin (FC) testing in the detection of endoscopically active IBD. Patients and Methods: All consecutive patients presenting to outpatient clinics with lower gastrointestinal symptoms were prospectively recruited. Patients provided FC samples. Sensitivity (Sn), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) for FC were calculated. Receiver–operator characteristics (ROC) curve was used to identify the ideal FC cutoff that predicts endoscopic disease activity. Correlation between FC and endoscopic disease activity, disease location, and C-reactive protein (CRP) levels were measured. Results: One hundred and twenty-six patients, of whom 52% were females, were included in the final analysis with a mean age of 44.4 ± 16.7 years. Comparing FC to endoscopic findings, the following results were calculated: A cutoff point of 100 μg/g showed Sn = 83%, Sp = 67%, PPV = 65%, and NPV = 85%; and 200 μg/g showed Sn = 66%, Sp = 82%, PPV = 73%, and NPV = 77%. Based on ROC curve, the best FC cutoff point to predict endoscopic disease activity was 140 μg/g. Using this reference, FC levels strongly correlated with colorectal, ileocolonic, and ileal disease and predicted endoscopic activity. Conclusions: FC is an accurate test when used as an initial screening tool for patients suspected of having active IBD. Given its noninvasive nature, it may prove to reduce the need for colonoscopy and be an added tool in the management of IBD. PMID:26655130

  20. Withanolides: Biologically Active Constituents in the Treatment of Alzheimer's Disease.

    PubMed

    Khan, Shahid A; Khan, Sher B; Shah, Zarbad; Asiri, Abdullah M

    2016-01-01

    The use of natural products in drug discovery and development have an important history. Several therapeutic agents have been investigated during the biological screenings of natural compounds. It is well documented that plants are possibly the core of novel substances that led to the discovery of new, novel, and effective therapeutic agents. Therefore, in the last few decades, scientists were thoroughly attempting for the search of benevolent drugs to protect mankind from various diseases and discomforts. The diverse chemical structures of natural products are the key element of their success in modern drug discovery. Cholinesterase enzyme inhibitors (ChEI) are chemicals which inhibit the splitting of cholinesterase enzymes (acetylcholinesterase and butyrylcholinesterase). Acetyl cholinesterase (AChE) and butyrylcholinesterase (BChE) are two types of cholinesterase enzymes that have been identified in vertebrates that are responsible for Alzheimer's disease and related dementia. Withanolides are affective plant secondary metabolites which inhibit acetylcholinesterase and butyrylcholinesterase enzyme and thus possibly will be the future drug for Alzheimer's disease. By viewing the importance of natural products in drug discovery and development, we present here, the importance of withanolides in the treatment of Alzheimer's disease. In this article, we also describe the classification and structural characterization of withanolides. This review comprises of 114 compounds. PMID:26527154

  1. Validity of a Questionnaire to Assess the Physical Activity Level in Coronary Artery Disease Patients

    ERIC Educational Resources Information Center

    Guiraud, Thibaut; Granger, Richard; Bousquet, Marc; Gremeaux, Vincent

    2012-01-01

    The aim of the study is to compare, in coronary artery disease patients, physical activity (PA) assessed with the Dijon Physical Activity Questionnaire (DPAQ) and the true PA objectively measured using an accelerometer. Seventy patients wore an accelerometer (MyWellness Key actimeter) throughout 1 week after a cardiac rehabilitation program that…

  2. Implementation of the Simple Endoscopic Activity Score in Crohn's Disease

    PubMed Central

    Koutroumpakis, Efstratios; Katsanos, Konstantinos H.

    2016-01-01

    Simple Endoscopic Score for Crohn's Disease (SES-CD) was developed as an attempt to simplify Crohn's Disease Endoscopic Index of Severity (CDEIS). Since it was constructed from CDEIS, SES-CD performs comparably but also carries similar limitations. Several studies have utilized SES-CD scoring to describe disease severity or response to therapy. Some of them used SES-CD score as a continuous variable while others utilized certain cutoff values to define severity grades. All SES-CD cutoff values reported in published clinical trials were empirically selected by experts. Although in most of the studies that used SEC-CD scoring to define disease severity, a score <3 reflected inactive disease, no study is using score 0 to predefine inactivity. Studies applying SES-CD to define response to treatment used score 0. There is no optimal SES-CD cut-off for endoscopic remission. The quantification of mucosal healing using SES-CD scoring has not been standardized yet. As the definition of mucosal healing by SES-CD is unset, the concept of deep remission is also still evolving. Serum and fecal biomarkers as well as new radiologic imaging techniques are complementary to SES-CD. Current practice as well as important changes in endoscopy should be taken into consideration when defining SES-CD cutoffs. The optimal timing of SES-CD scoring to assess mucosal healing is not defined yet. To conclude, SES-CD represents a valuable tool. However, a consensus agreement on its optimal use is required. PMID:27184635

  3. Women, men, and rheumatoid arthritis: analyses of disease activity, disease characteristics, and treatments in the QUEST-RA Study

    PubMed Central

    Sokka, Tuulikki; Toloza, Sergio; Cutolo, Maurizio; Kautiainen, Hannu; Makinen, Heidi; Gogus, Feride; Skakic, Vlado; Badsha, Humeira; Peets, Tõnu; Baranauskaite, Asta; Géher, Pál; Újfalussy, Ilona; Skopouli, Fotini N; Mavrommati, Maria; Alten, Rieke; Pohl, Christof; Sibilia, Jean; Stancati, Andrea; Salaffi, Fausto; Romanowski, Wojciech; Zarowny-Wierzbinska, Danuta; Henrohn, Dan; Bresnihan, Barry; Minnock, Patricia; Knudsen, Lene Surland; Jacobs, Johannes WG; Calvo-Alen, Jaime; Lazovskis, Juris; Pinheiro, Geraldo da Rocha Castelar; Karateev, Dmitry; Andersone, Daina; Rexhepi, Sylejman; Yazici, Yusuf; Pincus, Theodore

    2009-01-01

    Introduction Gender as a predictor of outcomes of rheumatoid arthritis (RA) has evoked considerable interest over the decades. Historically, there is no consensus whether RA is worse in females or males. Recent reports suggest that females are less likely than males to achieve remission. Therefore, we aimed to study possible associations of gender and disease activity, disease characteristics, and treatments of RA in a large multinational cross-sectional cohort of patients with RA called Quantitative Standard Monitoring of Patients with RA (QUEST-RA). Methods The cohort includes clinical and questionnaire data from patients who were seen in usual care, including 6,004 patients at 70 sites in 25 countries as of April 2008. Gender differences were analyzed for American College of Rheumatology Core Data Set measures of disease activity, DAS28 (disease activity score using 28 joint counts), fatigue, the presence of rheumatoid factor, nodules and erosions, and the current use of prednisone, methotrexate, and biologic agents. Results Women had poorer scores than men in all Core Data Set measures. The mean values for females and males were swollen joint count-28 (SJC28) of 4.5 versus 3.8, tender joint count-28 of 6.9 versus 5.4, erythrocyte sedimentation rate of 30 versus 26, Health Assessment Questionnaire of 1.1 versus 0.8, visual analog scales for physician global estimate of 3.0 versus 2.5, pain of 4.3 versus 3.6, patient global status of 4.2 versus 3.7, DAS28 of 4.3 versus 3.8, and fatigue of 4.6 versus 3.7 (P < 0.001). However, effect sizes were small-medium and smallest (0.13) for SJC28. Among patients who had no or minimal disease activity (0 to 1) on SJC28, women had statistically significantly higher mean values compared with men in all other disease activity measures (P < 0.001) and met DAS28 remission less often than men. Rheumatoid factor was equally prevalent among genders. Men had nodules more often than women. Women had erosions more often than men, but

  4. The relationship between infliximab concentrations, antibodies to infliximab and disease activity in Crohn's disease

    PubMed Central

    Vande Casteele, Niels; Khanna, Reena; Levesque, Barrett G; Stitt, Larry; Zou, G Y; Singh, Sharat; Lockton, Steve; Hauenstein, Scott; Ohrmund, Linda; Greenberg, Gordon R; Rutgeerts, Paul J; Gils, Ann; Sandborn, William J; Vermeire, Séverine; Feagan, Brian G

    2015-01-01

    Objective Although low infliximab trough concentrations and antibodies to infliximab (ATI) are associated with poor outcomes in patients with Crohn's disease (CD), the clinical relevance of ATI in patients with adequate infliximab concentrations is uncertain. We evaluated this question using an assay sensitive for identification of ATI in the presence of infliximab. Design In an observational study, 1487 trough serum samples from 483 patients with CD who participated in four clinical studies of maintenance infliximab therapy were analysed using a fluid phase mobility shift assay. Infliximab and ATI concentrations most discriminant for remission, defined as a C-reactive protein concentration of ≤5 mg/L, were determined by receiver operating characteristic curves. A multivariable regression model evaluated these factors as independent predictors of remission. Results Based upon analysis of 1487 samples, 77.1% of patients had detectable and 22.9% had undetectable infliximab concentrations, of which 9.5% and 71.8%, respectively, were positive for ATI. An infliximab concentration of >2.79 μg/mL (area under the curve (AUC)=0.681; 95% CI 0.632 to 0.731) and ATI concentration of <3.15 U/mL (AUC=0.632; 95% CI 0.589 to 0.676) were associated with remission. Multivariable analysis showed that concentrations of both infliximab trough (OR 1.8; 95% CI 1.3 to 2.5; p<0.001) and ATI (OR 0.57; 95% CI 0.39 to 0.81; p=0.002) were independent predictors of remission. Conclusions The development of ATI increases the probability of active disease even at low concentrations and in the presence of a therapeutic concentration of drug during infliximab maintenance therapy. Evaluation of strategies to prevent ATI formation, including therapeutic drug monitoring with selective infliximab dose intensification, is needed. PMID:25336114

  5. Carotid body chemoreceptors, sympathetic neural activation, and cardiometabolic disease.

    PubMed

    Iturriaga, Rodrigo; Del Rio, Rodrigo; Idiaquez, Juan; Somers, Virend K

    2016-01-01

    The carotid body (CB) is the main peripheral chemoreceptor that senses the arterial PO2, PCO2 and pH. In response to hypoxemia, hypercapnia and acidosis, carotid chemosensory discharge elicits reflex respiratory, autonomic and cardiovascular adjustments. The classical construct considers the CB as the main peripheral oxygen sensor, triggering reflex physiological responses to acute hypoxemia and facilitating the ventilatory acclimation to chronic hypoxemia at high altitude. However, a growing body of experimental evidence supports the novel concept that an abnormally enhanced CB chemosensory input to the brainstem contributes to overactivation of the sympathetic nervous system, and consequent pathology. Indeed, the CB has been implicated in several diseases associated with increases in central sympathetic outflow. These include hypertension, heart failure, sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome. Indeed, ablation of the CB has been proposed for the treatment of severe and resistant hypertension in humans. In this review, we will analyze and discuss new evidence supporting an important role for the CB chemoreceptor in the progression of autonomic and cardiorespiratory alterations induced by heart failure, obstructive sleep apnea, chronic obstructive pulmonary disease and metabolic syndrome. PMID:26920146

  6. Gut microbiome composition and function in experimental colitis during active disease and treatment-induced remission

    PubMed Central

    Rooks, Michelle G; Veiga, Patrick; Wardwell-Scott, Leslie H; Tickle, Timothy; Segata, Nicola; Michaud, Monia; Gallini, Carey Ann; Beal, Chloé; van Hylckama-Vlieg, Johan ET; Ballal, Sonia A; Morgan, Xochitl C; Glickman, Jonathan N; Gevers, Dirk; Huttenhower, Curtis; Garrett, Wendy S

    2014-01-01

    Dysregulated immune responses to gut microbes are central to inflammatory bowel disease (IBD), and gut microbial activity can fuel chronic inflammation. Examining how IBD-directed therapies influence gut microbiomes may identify microbial community features integral to mitigating disease and maintaining health. However, IBD patients often receive multiple treatments during disease flares, confounding such analyses. Preclinical models of IBD with well-defined disease courses and opportunities for controlled treatment exposures provide a valuable solution. Here, we surveyed the gut microbiome of the T-bet−/− Rag2−/− mouse model of colitis during active disease and treatment-induced remission. Microbial features modified among these conditions included altered potential for carbohydrate and energy metabolism and bacterial pathogenesis, specifically cell motility and signal transduction pathways. We also observed an increased capacity for xenobiotics metabolism, including benzoate degradation, a pathway linking host adrenergic stress with enhanced bacterial virulence, and found decreased levels of fecal dopamine in active colitis. When transferred to gnotobiotic mice, gut microbiomes from mice with active disease versus treatment-induced remission elicited varying degrees of colitis. Thus, our study provides insight into specific microbial clades and pathways associated with health, active disease and treatment interventions in a mouse model of colitis. PMID:24500617

  7. Effect of dietary restrictions on disease activity in rheumatoid arthritis.

    PubMed Central

    Beri, D; Malaviya, A N; Shandilya, R; Singh, R R

    1988-01-01

    Additions in five steps were made, as a possible therapeutic measure, to the diet of 27 patients with rheumatoid arthritis (RA) after a period of two weeks of a basal isocaloric diet free from pulses, cereals, milk, and non-vegetarian protein foods. Fourteen patients finally took part in the trial, 10 (71%) of whom showed significant clinical improvement. Only three patients (11%) adhered to the diet for a period of 10 months. The others discontinued the diet and were then treated with conventional disease modifying drugs. The study indicates that dietary factors may influence inflammatory response in RA. PMID:3278696

  8. Relationship of lipoprotein(a) levels to physical activity and family history of coronary heart disease.

    PubMed Central

    Martín, S; Elosua, R; Covas, M I; Pavesi, M; Vila, J; Marrugat, J

    1999-01-01

    OBJECTIVES: This study evaluated the association of physical activity with serum lipoprotein(a) [La(a)] levels in individuals according to whether they had a family history of coronary heart disease (CHD). METHODS: Lp(a) levels in 332 healthy Spanish men aged 20 to 60 years were measured. Physical activity and family history of CHD were assessed. RESULTS: For men with a family history of CHD, the odds ratio for Lp(a) levels above the median value was 0.13 (95% confidence interval = 0.03, 0.50) in very active men (energy expended in physical activity > 300 kcal/day) compared with active men (energy expended in physical activity < 300 kcal/day). CONCLUSIONS: Regular daily physical activity in individuals with a family history of CHD could be useful for controlling Lp(a) levels. PMID:10076490

  9. Health-related quality of life in adolescents with inflammatory bowel disease depends on disease activity and psychiatric comorbidity.

    PubMed

    Engelmann, G; Erhard, D; Petersen, M; Parzer, P; Schlarb, A A; Resch, F; Brunner, R; Hoffmann, G F; Lenhartz, H; Richterich, A

    2015-04-01

    Adolescent patients with inflammatory bowel disease (IBD) show an increased risk for behavioral and emotional dysfunction. Health-related quality of life (HRQoL) is influenced by medical illnesses, as well as by psychiatric disorders, but for adolescents with IBD, the extent to which HRQoL is influenced by these two factors is unclear. For 47 adolescent IBD patients, we analyzed disease activity, HRQoL and whether or not a psychiatric disorder was present. Disease activity was estimated using pediatric Ulcerative Colitis Activity Index and pediatric Crohn's Disease Activity Index. The IMPACT-III and the EQ-5D were used to measure HRQoL and QoL, respectively. In addition, patient and parent diagnostic interviews were performed. 55.3 % patients fulfilled DSM-IV criteria for one or more psychiatric disorders. In all patients, psychiatric comorbidity together with disease activity contributed to a reduction in quality of life. Adolescents with IBD are at a high risk for clinically relevant emotional or behavioral problems resulting in significantly lower HRQoL. We conclude that accessible, optimally structured psychotherapeutic and/or psychiatric help is needed in adolescent patients with IBD. PMID:24838299

  10. Predictors of Alzheimer's Disease Caregiver Depression and Burden: What Noncaregiving Adults Can Learn from Active Caregivers

    ERIC Educational Resources Information Center

    Hayslip, Bert, Jr.; Han, GiBaeg; Anderson, Cristina L.

    2008-01-01

    This study examined similarities and differences between active caregivers (adult children and spouses whose family member had Alzheimer's disease) and not-as-yet caregiving adults (adult children and spouses whose family members are older, but do not as yet suffer from Alzheimer's disease). The objective was to determine what factors predict…

  11. Altered Activation of the Tibialis Anterior in Individuals with Pompe Disease: Implications for Motor Unit Dysfunction

    PubMed Central

    Corti, Manuela; Smith, Barbara K; Falk, Darin J; Lawson, Lee Ann; Fuller, David D; Subramony, S.H.; Byrne, Barry J; Christou, Evangelos A

    2014-01-01

    Introduction Pompe disease is a progressive disease that affects skeletal muscles and leads to loss of ambulation. We investigated the activation of the tibialis anterior (TA) in late onset Pompe disease (LOPD) individuals during maximal voluntary contraction (MVC) and evoked involuntary responses. Methods Four LOPD patients and matched control subjects performed MVC of the TA using dorsiflexion and TA evoked responses. Activation of the TA was recorded with surface EMG. Results The Pompe patients exhibited greater power at frequencies below 60 Hz and reduced power above 100 Hz. They exhibited reduced increase in M-wave and prolonged M-wave latency and duration in response to stimulation. Discussion These results provide evidence that LOPD individuals have an altered activation pattern of the TA during maximal contractions. The observed activation pattern may reflect impairments in voluntary command, neuromuscular junction pathology, or compensatory drive due to a reduced number of functional motoneurons. PMID:25186912

  12. Rho guanine nucleotide exchange factors: regulators of Rho GTPase activity in development and disease

    PubMed Central

    Cook, Danielle R.; Rossman, Kent L.; Der, Channing J.

    2016-01-01

    The aberrant activity of Ras homologous (Rho) family small GTPases (20 human members) has been implicated in cancer and other human diseases. However, in contrast to the direct mutational activation of Ras found in cancer and developmental disorders, Rho GTPases are activated most commonly by indirect mechanisms in disease. One prevalent mechanism involves aberrant Rho activation via the deregulated expression and/or activity of Rho family guanine nucleotide exchange factors (RhoGEFs). RhoGEFs promote formation of the active GTP-bound state of Rho GTPases. The largest family of RhoGEFs is comprised of the Dbl family RhoGEFs with 70 human members. The multitude of RhoGEFs that activate a single Rho GTPase reflect the very specific role of each RhoGEF in controlling distinct signaling mechanisms involved in Rho activation. In this review, we summarize the role of Dbl RhoGEFs in development and disease, with a focus on Ect2, Tiam1, Vav and P-Rex1/2. PMID:24037532

  13. Physical Activity and Exercise for Secondary Prevention among Patients with Cardiovascular Disease.

    PubMed

    Darden, Douglas; Richardson, Caroline; Jackson, Elizabeth A

    2013-12-01

    Most adults do not achieve the recommended levels of physical activity, including patients with cardiovascular disease (CVD). Furthermore, healthcare providers often do not understand the benefits of physical activity in CVD patients, rather over emphasizing the potential risks related to activity. Recent studies suggest reductions in cardiovascular events including mortality with concomitant improvements in quality of life for many vascular conditions. However gaps in our current knowledge base remain. Recent research on physical activity including use of novel internet based interventions are developing areas of interest have moved to reduce such knowledge gaps. PMID:24396552

  14. New Insights into Glomerular Parietal Epithelial Cell Activation and Its Signaling Pathways in Glomerular Diseases

    PubMed Central

    Su, Hua; Chen, Shan; He, Fang-Fang; Wang, Yu-Mei; Bondzie, Philip; Zhang, Chun

    2015-01-01

    The glomerular parietal epithelial cells (PECs) have aroused an increasing attention recently. The proliferation of PECs is the main feature of crescentic glomerulonephritis; besides that, in the past decade, PEC activation has been identified in several types of noninflammatory glomerulonephropathies, such as focal segmental glomerulosclerosis, diabetic glomerulopathy, and membranous nephropathy. The pathogenesis of PEC activation is poorly understood; however, a few studies delicately elucidate the potential mechanisms and signaling pathways implicated in these processes. In this review we will focus on the latest observations and concepts about PEC activation in glomerular diseases and the newest identified signaling pathways in PEC activation. PMID:25866774

  15. Low Serum Lysosomal Acid Lipase Activity Correlates with Advanced Liver Disease

    PubMed Central

    Shteyer, Eyal; Villenchik, Rivka; Mahamid, Mahmud; Nator, Nidaa; Safadi, Rifaat

    2016-01-01

    Fatty liver has become the most common liver disorder and is recognized as a major health burden in the Western world. The causes for disease progression are not fully elucidated but lysosomal impairment is suggested. Here we evaluate a possible role for lysosomal acid lipase (LAL) activity in liver disease. To study LAL levels in patients with microvesicular, idiopathic cirrhosis and nonalcoholic fatty liver disease (NAFLD). Medical records of patients with microvesicular steatosis, cryptogenic cirrhosis and NAFLD, diagnosed on the basis of liver biopsies, were included in the study. Measured serum LAL activity was correlated to clinical, laboratory, imaging and pathological data. No patient exhibited LAL activity compatible with genetic LAL deficiency. However, serum LAL activity inversely predicted liver disease severity. A LAL level of 0.5 was the most sensitive for detecting both histologic and noninvasive markers for disease severity, including lower white blood cell count and calcium, and elevated γ-glutamyltransferase, creatinine, glucose, glycated hemoglobin, uric acid and coagulation function. Serum LAL activity <0.5 indicates severe liver injury in patients with fatty liver and cirrhosis. Further studies should define the direct role of LAL in liver disease severity and consider the possibility of replacement therapy. PMID:26927097

  16. Low Serum Lysosomal Acid Lipase Activity Correlates with Advanced Liver Disease.

    PubMed

    Shteyer, Eyal; Villenchik, Rivka; Mahamid, Mahmud; Nator, Nidaa; Safadi, Rifaat

    2016-01-01

    Fatty liver has become the most common liver disorder and is recognized as a major health burden in the Western world. The causes for disease progression are not fully elucidated but lysosomal impairment is suggested. Here we evaluate a possible role for lysosomal acid lipase (LAL) activity in liver disease. To study LAL levels in patients with microvesicular, idiopathic cirrhosis and nonalcoholic fatty liver disease (NAFLD). Medical records of patients with microvesicular steatosis, cryptogenic cirrhosis and NAFLD, diagnosed on the basis of liver biopsies, were included in the study. Measured serum LAL activity was correlated to clinical, laboratory, imaging and pathological data. No patient exhibited LAL activity compatible with genetic LAL deficiency. However, serum LAL activity inversely predicted liver disease severity. A LAL level of 0.5 was the most sensitive for detecting both histologic and noninvasive markers for disease severity, including lower white blood cell count and calcium, and elevated γ-glutamyltransferase, creatinine, glucose, glycated hemoglobin, uric acid and coagulation function. Serum LAL activity <0.5 indicates severe liver injury in patients with fatty liver and cirrhosis. Further studies should define the direct role of LAL in liver disease severity and consider the possibility of replacement therapy. PMID:26927097

  17. EULAR Sjögren's syndrome disease activity index (ESSDAI): a user guide

    PubMed Central

    Seror, Raphaèle; Bowman, Simon J; Brito-Zeron, Pilar; Theander, Elke; Bootsma, Hendrika; Tzioufas, Athanasios; Gottenberg, Jacques-Eric; Ramos-Casals, Manel; Dörner, Thomas; Ravaud, Philippe; Vitali, Claudio; Mariette, Xavier

    2015-01-01

    The EULAR Sjögren's syndrome (SS) disease activity index (ESSDAI) is a systemic disease activity index that was designed to measure disease activity in patients with primary SS. With the growing use of the ESSDAI, some domains appear to be more challenging to rate than others. The ESSDAI is now in use as a gold standard to measure disease activity in clinical studies, and as an outcome measure, even a primary outcome measure, in current randomised clinical trials. Therefore, ensuring an accurate and reproducible rating of each domain, by providing a more detailed definition of each domain, has emerged as an urgent need. The purpose of the present article is to provide a user guide for the ESSDAI. This guide provides definitions and precisions on the rating of each domain. It also includes some minor improvement of the score to integrate advance in knowledge of disease manifestations. This user guide may help clinicians to use the ESSDAI, and increase the reliability of rating and consequently of the ability to detect true changes over time. This better appraisal of ESSDAI items, along with the recent definition of disease activity levels and minimal clinically important change, will improve the assessment of patients with primary SS and facilitate the demonstration of effectiveness of treatment for patients with primary SS. PMID:26509054

  18. Chronic osteomyelitis: bone and gallium scan patterns associated with active disease

    SciTech Connect

    Tumeh, S.S.; Aliabadi, P.; Weissman, B.N.; McNeil, B.J.

    1986-03-01

    Bone and gallium scans are used to assess osteomyelitis patients with prior bone disease. To refine the criteria for interpreting these scans, the data from 136 consecutive patients with clinically suspected osteomyelitis were reviewed. Active osteomyelitis was diagnosed with surgery or biopsy and culture in 49 patients, excluded with the same criteria in 16, and excluded by clinical follow-up for at least 6 months in 71. Five different scintigraphic patterns were found. The true-positive and false-positive ratios, the likelihood ratios, and posterior probabilities for active osteomyelitis in each pattern were calculated. Only one pattern (gallium uptake exceeding bone-seeking radiopharmaceutical uptake) was indicative of active disease. Other patterns slightly raised or decreased the probability of disease. The extent of these changes varies directly with the prior probability of disease, determined from patient-specific factors (e.g., clinical data, laboratory data, findings on plain films) known best by the referring clinician.

  19. Decreased ADAMTS 13 Activity is Associated With Disease Severity and Outcome in Pediatric Severe Sepsis

    PubMed Central

    Lin, Jainn-Jim; Chan, Oi-Wa; Hsiao, Hsiang-Ju; Wang, Yu; Hsia, Shao-Hsuan; Chiu, Cheng-Hsun

    2016-01-01

    Abstract Decreased ADAMTS 13 activity has been reported in severe sepsis and in sepsis-induced disseminated intravascular coagulation. This study aimed to investigate the role of ADAMTS 13 in different pediatric sepsis syndromes and evaluate its relationship with disease severity and outcome. We prospectively collected cases of sepsis treated in a pediatric intensive care unit, between July 2012 and June 2014 in Chang Gung Children's Hospital in Taoyuan, Taiwan. Clinical characteristics and ADAMTS-13 activity were analyzed. All sepsis syndromes had decreased ADAMTS 13 activity on days 1 and 3 of admission compared to healthy controls. Patients with septic shock had significantly decreased ADAMTS 13 activity on days 1 and 3 compared to those with sepsis and severe sepsis. There was a significant negative correlation between ADAMTS 13 activity on day 1 and day 1 PRISM-II, PELOD, P-MOD, and DIC scores. Patients with mortality had significantly decreased ADAMTS 13 activity on day 1 than survivors, but not on day 3. Different pediatric sepsis syndromes have varying degrees of decreased ADAMTS 13 activity. ADAMTS 13 activity is strongly negatively correlated with disease severity of pediatric sepsis syndrome, whereas decreased ADAMTS 13 activity on day 1 is associated with increased risk of mortality. PMID:27100422

  20. Cumulative disease activity predicts incidental hearing impairment in patients with rheumatoid arthritis (RA).

    PubMed

    Pascual-Ramos, Virginia; Contreras-Yáñez, Irazú; Rivera-Hoyos, Paula; Enríquez, Lorena; Ramírez-Anguiano, Jaqueline

    2014-03-01

    We previously reported that 24% of 113 rheumatoid arthritis (RA) patients had hearing impairment (HI). We investigated if disease activity was a predictor of incidental HI. One hundred and four patients completed three consecutive 6 months-apart rheumatic evaluations and concomitant audiometric evaluations which included at least an interview, an otoscopic evaluation, and a pure tone audiometry. HI was defined if the average thresholds for at least one of low-, mid-, or high-frequency ranges were ≥25 decibels (dB) hearing level in one or both ears. Appropriated statistics was used. Internal review board approval was obtained. Patients were most frequently middle-aged (43.4 ± 13.3 years), female (89.4%), and had median disease duration of 5 years and low disease activity. All were receiving RA treatment. At inclusion, 24 patients had HI which was sensorineural in 91.7% of them. Among the 80 patients without HI at baseline, 10 (12.5%) developed incidental HI, and they had more disease activity either at baseline ([median, range] disease activity score-28 joints evaluated-C-reactive protein [DAS28-CRP], 3.9 [1.6-7.3] vs. 2.1 [1-8.7], p = 0.006) or cumulative previous incidental HI (3.4 [1.8-4.8] vs. 2 [1-6.2], p = 0.007) and were more frequently on combined methotrexate and sulfasalazine (20 vs. 1.4%, p = 0.05) than their counterparts. In the adjusted Cox proportional model, cumulative DAS28-CRP was the only variable to predict incidental HI (odds ratio, 1.8; 95% confidence interval, 1.1-2.7; p = 0.01). Almost 13% of RA patients with short disease duration and low disease activity developed incidental HI during 1 year. Cumulative disease activity predicted incidental HI. PMID:24435352

  1. Correlation Between Low Bone Density and Disease Activity in Patients with Ulcerative Colitis

    PubMed Central

    Amiriani, Taghi; Besharat, Sima; Pourramezan, Zahra; Mirkarimi, Honey Sadat; Aghaei, Mehrdad; Joshaghani, Hamidreza; Roshandel, Gholamreza; Faghani, Maryam; Besharat, Mahsa

    2015-01-01

    BACKGROUND Different clinical and epidemiological studies using dual-energy X-ray absorptiometry have shown an increased prevalence of low bone mineral density in patients with inflammatory bowel diseases. The aim of this study was to assess the correlation between bone density and the disease activity in patients with ulcerative colitis. METHODS In this cross-sectional study, 52 patients with ulcerative colitis (duration of the disease less than 5 years) were invited to our research center, Golestan province, northeast of Iran, during February 2012 up to August 2012. A demographic checklist and Simple Clinical Colitis Activity Index was completed for each patients and 5 cc of blood sample was taken after obtaining the informed consent. We used colorimetry method for measuring serum calcium, UV method for serum phosphorus and ELISA for serum vitamin D. Dual-energy X-ray absorptiometry was done to evaluate the bone density. Data analysis was done using SPSS software version 16. Normality of data was assessed using Kolmogorov– Smirnov test. T and ANOVA tests were used if data had normal distribution. Mann-Whitney U or Kruskal-Wallis tests were used for the remaining data. Correlation between qualitative variables was evaluated by Chi-square test. RESULTS The mean (±SD) age and disease activity of the patients were 37.72 (±12.18) years and 4.78 (±1.98), respectively. There were no correlation between disease activity and mean age. Low bone density was seen in 30.8%, 11.5%, and 15.4% in spine, femur neck, and hip, respectively. There was no relationship between Z-score of total hip, spine, and femur neck with disease activity, age, and duration of disease (p>0.05). CONCLUSION Our results showed an acceptable rate of low bone density in patients with ulcerative colitis without any correlation with the disease activity index. PMID:25628850

  2. Correlation between low bone density and disease activity in patients with ulcerative colitis.

    PubMed

    Amiriani, Taghi; Besharat, Sima; Pourramezan, Zahra; Mirkarimi, Honey Sadat; Aghaei, Mehrdad; Joshaghani, Hamidreza; Roshandel, Gholamreza; Faghani, Maryam; Besharat, Mahsa

    2015-01-01

    BACKGROUND Different clinical and epidemiological studies using dual-energy X-ray absorptiometry have shown an increased prevalence of low bone mineral density in patients with inflammatory bowel diseases. The aim of this study was to assess the correlation between bone density and the disease activity in patients with ulcerative colitis. METHODS In this cross-sectional study, 52 patients with ulcerative colitis (duration of the disease less than 5 years) were invited to our research center, Golestan province, northeast of Iran, during February 2012 up to August 2012. A demographic checklist and Simple Clinical Colitis Activity Index was completed for each patients and 5 cc of blood sample was taken after obtaining the informed consent. We used colorimetry method for measuring serum calcium, UV method for serum phosphorus and ELISA for serum vitamin D. Dual-energy X-ray absorptiometry was done to evaluate the bone density. Data analysis was done using SPSS software version 16. Normality of data was assessed using Kolmogorov- Smirnov test. T and ANOVA tests were used if data had normal distribution. Mann-Whitney U or Kruskal-Wallis tests were used for the remaining data. Correlation between qualitative variables was evaluated by Chi-square test. RESULTS The mean (±SD) age and disease activity of the patients were 37.72 (±12.18) years and 4.78 (±1.98), respectively. There were no correlation between disease activity and mean age. Low bone density was seen in 30.8%, 11.5%, and 15.4% in spine, femur neck, and hip, respectively. There was no relationship between Z-score of total hip, spine, and femur neck with disease activity, age, and duration of disease (p>0.05). CONCLUSION Our results showed an acceptable rate of low bone density in patients with ulcerative colitis without any correlation with the disease activity index. PMID:25628850

  3. Vitamin D Status Is Associated with Disease Activity among Rheumatology Outpatients

    PubMed Central

    Sabbagh, Zohreh; Markland, Janet; Vatanparast, Hassanali

    2013-01-01

    The co-existence of high prevalence of vitamin D inadequacy among Canadians and high prevalence of systematic autoimmune rheumatic diseases (SARDs) raise the question on relationship between the two situations. Objective: To determine vitamin D status in known cases of common SARDs and compare to those with non-autoimmune diseases; further, to evaluate the impact of vitamin D on disease activity in rheumatoid arthritis (RA) cases. Methods: In a retrospective case-control study design, we evaluated 116 patients in a community clinic classified in two groups, Control group: patients with non-rheumatic disease (n = 56), and Case group: those with rheumatic diseases (n = 60). We compared plasma vitamin D status (25(OH)D), indicators of disease activity and other potential confounders. Further, we determined factors associated with disease activity in RA cases. Results: The plasma 25(OH)D was significantly lower in Case group (64.8 ± 29.8) compared to Control group (86.8 ± 37.7). High number of SARDs outpatients 56%) had considerably low plasma 25(OH)D concentration. RA cases with low plasma 25(OH)D had over five times higher risk of disease activity (OR = 5.15 95% CI 1.16, 22.9; p = 0.031). Conclusion: Inadequate vitamin D status in SARDs cases, along with considerably strong association with disease activity in RA cases, indicate the need for proper evaluation of vitamin D status in this clinical population. Moreover, appropriate training should be given to the patients to ensure the intake of the recommended amount of vitamin D per day through diet or supplement. PMID:23803739

  4. Measuring Physical Activity in Older Adults with and without Early Stage Alzheimer’s Disease

    PubMed Central

    Watts, Amber S.; Vidoni, Eric D.; Loskutova, Natalia; Johnson, David K.; Burns, Jeffrey M.

    2013-01-01

    We compared subjective reports of physical activity with objective measures of physical fitness including cardiorespiratory capacity, body composition, and physical performance in 146 older adults with and without early stage Alzheimer’s disease (ESAD). Respondents reported primarily unstructured and low-intensity activities, including walking and housework. Individuals with ESAD participated in fewer and lower intensity physical activities than those without ESAD. In those without ESAD, housework was related to lower body mass index, leisure walking was related to faster speed on a timed walking test, and participation in sports was related to higher peak oxygen intake. In individuals with ESAD, reported physical activities did not predict any of the physical fitness, body composition, or physical performance measures. We conclude that measures of physical activity require expansion of unstructured and low intensity activities to improve sensitivity in sedentary populations, especially in older adults with ESAD. PMID:24062599

  5. Wearable Systems for Monitoring Mobility-Related Activities in Chronic Disease: A Systematic Review

    PubMed Central

    Allet, Lara; Knols, Ruud H.; Shirato, Kei; de Bruin, Eling D.

    2010-01-01

    The use of wearable motion sensing technology offers important advantages over conventional methods for obtaining measures of physical activity and/or physical functioning in individuals with chronic diseases. This review aims to identify the actual state of applying wearable systems for monitoring mobility-related activity in individuals with chronic disease conditions. In this review we focus on technologies and applications, feasibility and adherence aspects, and clinical relevance of wearable motion sensing technology. PubMed (Medline since 1990), PEdro, and reference lists of all relevant articles were searched. Two authors independently reviewed randomised trials systematically. The quality of selected articles was scored and study results were summarised and discussed. 163 abstracts were considered. After application of inclusion criteria and full text reading, 25 articles were taken into account in a full text review. Twelve of these papers evaluated walking with pedometers, seven used uniaxial accelerometers to assess physical activity, six used multiaxial accelerometers, and two papers used a combination approach of a pedometer and a multiaxial accelerometer for obtaining overall activity and energy expenditure measures. Seven studies mentioned feasibility and/or adherence aspects. The number of studies that use movement sensors for monitoring of activity patterns in chronic disease (postural transitions, time spent in certain positions or activities) is nonexistent on the RCT level of study design. Although feasible methods for monitoring human mobility are available, evidence-based clinical applications of these methods in individuals with chronic diseases are in need of further development. PMID:22163393

  6. Identification of miRNAs that modulate glucocerebrosidase activity in Gaucher disease cells.

    PubMed

    Siebert, Marina; Westbroek, Wendy; Chen, Yu-Chi; Moaven, Nima; Li, Yan; Velayati, Arash; Saraiva-Pereira, Maria Luiza; Martin, Scott E; Sidransky, Ellen

    2014-01-01

    Gaucher disease is an autosomal recessive disorder caused by deficiency of the enzyme glucocerebrosidase. Although it is a monogenic disease, there is vast phenotypic heterogeneity, even among patients with the same genotype. MicroRNAs (miRNAs) are small non-coding RNAs involved in many biological processes and diseases. To determine whether miRNAs can affect glucocerebrosidase activity, we performed a screen of 875 different miRNA mimics. The screen was performed using Gaucher fibroblasts, and glucocerebrosidase activity was used as the initial outcome parameter. We found several miRNAs that either up- or down-regulated glucocerebrosidase activity. In follow-up assays, we confirmed that one specific miRNA (miR-127-5p) down-regulated both glucocerebrosidase activity and protein levels by down-regulation of LIMP-2, the receptor involved in proper trafficking of glucocerebrosidase from the endoplasmic reticulum to the lysosome. A conditioned media assay demonstrated that cells treated with this miRNA secreted glucocerebrosidase into the extracellular environment, supporting impaired LIMP-2 function. Two other miRNAs, miR-16-5p and miR-195-5p, were found to up-regulate glucocerebrosidase activity by greater than 40% and to enhance expression and protein levels of the enzyme. In conclusion, we show that miRNAs can alter glucocerebrosidase activity in patient cells, indicating that miRNAs can potentially act as modifiers in Gaucher disease. PMID:25584808

  7. Identification of miRNAs that modulate glucocerebrosidase activity in Gaucher disease cells

    PubMed Central

    Siebert, Marina; Westbroek, Wendy; Chen, Yu-Chi; Moaven, Nima; Li, Yan; Velayati, Arash; Saraiva-Pereira, Maria Luiza; Martin, Scott E; Sidransky, Ellen

    2014-01-01

    Gaucher disease is an autosomal recessive disorder caused by deficiency of the enzyme glucocerebrosidase. Although it is a monogenic disease, there is vast phenotypic heterogeneity, even among patients with the same genotype. MicroRNAs (miRNAs) are small non-coding RNAs involved in many biological processes and diseases. To determine whether miRNAs can affect glucocerebrosidase activity, we performed a screen of 875 different miRNA mimics. The screen was performed using Gaucher fibroblasts, and glucocerebrosidase activity was used as the initial outcome parameter. We found several miRNAs that either up- or down-regulated glucocerebrosidase activity. In follow-up assays, we confirmed that one specific miRNA (miR-127–5p) down-regulated both glucocerebrosidase activity and protein levels by down-regulation of LIMP-2, the receptor involved in proper trafficking of glucocerebrosidase from the endoplasmic reticulum to the lysosome. A conditioned media assay demonstrated that cells treated with this miRNA secreted glucocerebrosidase into the extracellular environment, supporting impaired LIMP-2 function. Two other miRNAs, miR-16–5p and miR-195–5p, were found to up-regulate glucocerebrosidase activity by greater than 40% and to enhance expression and protein levels of the enzyme. In conclusion, we show that miRNAs can alter glucocerebrosidase activity in patient cells, indicating that miRNAs can potentially act as modifiers in Gaucher disease. PMID:25584808

  8. The Case for Increased Physical Activity in Chronic Inflammatory Bowel Disease: A Brief Review.

    PubMed

    Shephard, R J

    2016-06-01

    Regular physical activity reduces the risk of colon cancer, but there is little information on the merits of such activity in the prevention and management of chronic inflammatory bowel disease (CIBD). The present systematic review thus documents current levels of habitual physical activity and aerobic and muscular function in CIBD, and examines the safety, practicality and efficacy of exercise programmes in countering the disease process, correcting functional deficits and enhancing quality of life. A systematic search of the Ovid/Medline database from January 1996 to May 2015 linked the terms physical activity/motor activity/physical fitness/physical training/physical education/training/exercise/exercise therapy with Crohn's disease/colitis/ulcerative colitis/inflammatory bowel disease, supplementing this information by a scanning of reference lists and personal files.12 of 16 published studies show a low level of habitual physical activity in CIBD, with sub-normal values for aerobic power, lean tissue mass and muscular strength. 3 of 4 studies suggest physical activity may reduce the risk of developing IBD, and 11 interventions all note that exercise programmes are well tolerated with some decreases of disease activity, and functional gains leading to an increased health-related quality of life. Moreover, programme compliance rates compare favourably with those seen in the treatment of other chronic conditions. More information on mechanisms is needed, but regular moderate aerobic and/or resistance exercise improves the health status of patients with CIBD both by modulating immune function and by improving physical function. A regular exercise programme should thus become an important component in the management of CIBD. PMID:27116344

  9. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    SciTech Connect

    Wu, Weibin; Zhu, Bo; Peng, Xiaomin; Zhou, Meiling; Jia, Dongwei; Gu, Jianxin

    2014-01-03

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.

  10. Physical activity and sedentary behaviour: applying lessons to chronic obstructive pulmonary disease.

    PubMed

    Hill, K; Gardiner, P A; Cavalheri, V; Jenkins, S C; Healy, G N

    2015-05-01

    In health and disease, the benefits of regular participation in moderate to vigorous intensity physical activity are well documented. However, individuals with chronic conditions, such as those with chronic obstructive pulmonary disease (COPD), typically do very little activity at a moderate or vigorous intensity. Much of their day is instead spent in sedentary behaviour, such as sitting or reclining, which requires very little energy expenditure. This high level of time spent in sedentary behaviour can have serious health consequences, including increased risk of diabetes, cardiovascular disease and premature mortality. There is emerging evidence to suggest that participation in light intensity physical activities (e.g. standing or slow walking) may have benefits for cardio-metabolic health. Given the low aerobic capacity of individuals with moderate to severe COPD, increasing light intensity activity (through reducing sedentary time) may be a feasible additional strategy to improve health in this population, alongside traditional recommendations to increase the time spent in moderate to vigorous intensity physical activity. This review provides an overview of physical activity and sedentary behaviour, with a particular emphasis on these behaviours for people with COPD. It provides suggestions for the measurement of these behaviours within the clinical setting, as well as for interventions that may be effective at increasing physical activity and reducing sedentary behaviour in this population. PMID:25164319

  11. Heat Shock Protein-70 Expression in Vitiligo and its Relation to the Disease Activity

    PubMed Central

    Doss, Reham William; El-Rifaie, Abdel-Aziz A; Abdel-Wahab, Amr M; Gohary, Yasser M; Rashed, Laila A

    2016-01-01

    Background: Vitiligo is a progressive depigmenting disorder characterized by the loss of functional melanocytes from the epidermis. The etiopathogenesis of vitiligo is still unclear. Heat shock proteins (HSPs) are prime candidates to connect stress to the skin. HSPs were found to be implicated in autoimmune diseases such as rheumatoid arthritis and other skin disorders as psoriasis. Aim and Objectives: The aim of this study was to map the level of HSP-70 in vitiligo lesions to declare its role in the pathogenesis and activity of vitiligo. Materials and Methods: The study included thirty patients with vitiligo and 30 age- and sex-matched healthy controls. Vitiligo patients were divided as regards to the disease activity into highly active, moderately active, and inactive vitiligo groups. Skin biopsies were taken from the lesional and nonlesional skin of patients and from the normal skin of the controls. HSP-70 messenger RNA (mRNA) expression was estimated using quantitative real-time polymerase chain reaction. Results: Our analysis revealed a significantly higher expression of HSP-70 mRNA in lesional skin biopsies from vitiligo patients compared to nonlesional skin biopsies from vitiligo patients (P < 0.001) and compared to skin biopsies from healthy controls (P < 0.001). The level of HSP-70 was not found to be correlated with age, sex, or disease duration. The expression of HSP-70 was correlated with the disease activity and patients with active vitiligo showed higher mean HSP-70 level compared to those with inactive disease. Conclusions: HSP-70 plays a role in the pathogenesis of vitiligo and may enhance the immune response in active disease. PMID:27512186

  12. Vitamin D concentrations and disease activity in Moroccan children with juvenile idiopathic arthritis

    PubMed Central

    2014-01-01

    Background In addition to its important metabolic activities, vitamin D also contributes to the regulation of the immune system. The aim of this study was to assess the relationship between hypovitaminosis D and disease activity in Moroccan children with juvenile idiopathic arthritis (JIA). Methods In this cross-sectional study, forty children with JIA were included, all having been diagnosed according to the classification criteria of International League of Associations for Rheumatology (ILAR). The children underwent anthropometric assessment and clinical evaluation. Disease activity was measured using the Disease Activity Score in 28 joints (DAS28) for polyarticular and oligoarticular JIA and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) for enthesitis-related arthritis. Serum 25-hydroxyvitamin [25(OH)D] D2 and D3 were measured using radioimmunoassay (RIA). Hypovitaminosis D was defined as serum 25(OH)D <30 ng/ml. Results The average age of participants was 11 years ± 4.23. Hypovitaminosis D was observed in 75% of patients. In univariate analyses, 25(OH)D levels were negatively associated with DAS28 for polyarticular and oligoarticular JIA. No significant relationship was found between 25(OH)D levels and BASDAI for juvenile spondylarthropathy. In multivariate linear regression analysis, no association persisted between 25(OH)D levels and DAS28. Conclusions Our study suggested that serum levels of vitamin D were low in Moroccan children with JIA disease. Future studies with a larger population are needed to confirm our results. PMID:24690195

  13. Toward Development of a Fibromyalgia Responder Index and Disease Activity Score: OMERACT Module Update

    PubMed Central

    Mease, PJ; Clauw, DJ; Christensen, R; Crofford, L; Gendreau, M; Martin, SA; Simon, L; Strand, V; Williams, DA; Arnold, LM

    2012-01-01

    Following development of the core domain set for fibromyalgia (FM) in OMERACT 7–9, the FM working group has progressed toward the development of an FM responder index and a disease activity score based on these domains, utilizing outcome indices of these domains from archived randomized clinical trials (RCTs) in FM. Possible clinical domains that could be included in a responder index and disease activity score include: pain, fatigue, sleep disturbance, cognitive dysfunction, mood disturbance, tenderness, stiffness, and functional impairment. Outcome measures for these domains demonstrate good to adequate psychometric properties, although measures of cognitive dysfunction need to be further developed. The approach used in the development of responder indices and disease activity scores for rheumatoid arthritis and ankylosing spondylitis represent heuristic models for our work, but FM is challenging in that there is no clear algorithm of treatment that defines disease activity based on treatment decisions, nor are there objective markers that define thresholds of severity or response to treatment. The process of developing candidate dichotomous responder definitions and continuous quantitative disease activity measures is described, as is participant discussion that transpired at OMERACT 10. Final results of this work will be published in a separate manuscript pending completion of analyses. PMID:21724721

  14. Complement activity is associated with disease severity in multifocal motor neuropathy

    PubMed Central

    Vlam, Lotte; Cats, Elisabeth A.; Harschnitz, Oliver; Jansen, Marc D.; Piepers, Sanne; Veldink, Jan Herman; Franssen, Hessel; Stork, Abraham C.J.; Heezius, Erik; Rooijakkers, Suzan H.M.; Herpers, Bjorn L.; van Strijp, Jos A.; van den Berg, Leonard H.

    2015-01-01

    Objective: To investigate whether high innate activity of the classical and lectin pathways of complement is associated with multifocal motor neuropathy (MMN) and whether levels of innate complement activity or the potential of anti-GM1 antibodies to activate the complement system correlate with disease severity. Methods: We performed a case-control study including 79 patients with MMN and 79 matched healthy controls. Muscle weakness was documented with Medical Research Council scale sum score and axonal loss with nerve conduction studies. Activity of the classical and lectin pathways of complement was assessed by ELISA. We also determined serum mannose-binding lectin (MBL) concentrations and polymorphisms in the MBL gene (MBL2) and quantified complement-activating properties of anti-GM1 IgM antibodies by ELISA. Results: Activity of the classical and lectin pathways, MBL2 genotypes, and serum MBL concentrations did not differ between patients and controls. Complement activation by anti-GM1 IgM antibodies was exclusively mediated through the classical pathway and correlated with antibody titers (p < 0.001). Logistic regression analysis showed that both high innate activity of the classical pathway of complement and high complement-activating capacity of anti-GM1 IgM antibodies were significantly associated with more severe muscle weakness and axonal loss. Conclusion: High innate activity of the classical pathway of complement and efficient complement-activating properties of anti-GM1 IgM antibodies are determinants of disease severity in patients with MMN. These findings underline the importance of anti-GM1 antibody–mediated complement activation in the pathogenesis and clinical course of MMN. PMID:26161430

  15. Health-related quality of life in youth with Crohn's disease: The role of disease activity and parenting stress

    PubMed Central

    Gray, Wendy N.; Boyle, Shana L.; Graef, Danielle M.; Janicke, David M.; Jolley, Christopher D.; Denson, Lee A.; Baldassano, Robert N.; Hommel, Kevin A.

    2015-01-01

    Objectives Health-related quality of life (HRQOL) is an important, but understudied construct in pediatric IBD. Family-level predictors of HRQOL have been understudied as are the mechanisms through which disease activity impacts HRQOL. The current study examines the relationship between a family-level factor (parenting stress) and HRQOL in youth with Crohn's disease. Parenting stress is examined as a mechanism through with disease activity impacts HRQOL. Methods 99 adolescents with Crohn's disease and their parents were recruited across three sites. Adolescents completed the IMPACT-III (IBD-specific HRQOL). Parents completed the Pediatric Inventory for Parents, a measure of medically-related parenting stress that assesses: 1) stress due to the occurrence of medical stressors and 2) stress due to the perceived difficulty of stressors. Disease activity was obtained from medical records. Results Parenting stress due to the occurrence of medical stressors partially mediated the disease severity-HRQOL relationship, reducing the relationship between these variables from 49.67% to 31.58% (B = -.56, p <.0001). Boot strapping analysis confirmed that the indirect effect of disease severity on HQROL via parenting stress significantly differed from zero. Parenting stress due to the perceived difficulty of medical stressors partially mediated the disease severity-HRQOL relationship, reducing the relationship from 49.67% to 30.29% (B = -.55, p < .0001). The indirect effect was confirmed via bootstrapping procedures. Conclusions As disease severity increased, parenting stress also increased, and adolescent HRQOL decreased. Parenting stress should be considered and assessed for along with medical factors as part of a comprehensive approach to improving HRQOL in adolescents with Crohn's disease. PMID:25564807

  16. Immunoresponsiveness in Ulcerative Colitis and Crohn's Disease—Effect of Colectomy and Suppression of Disease Activity

    PubMed Central

    Lyanga, John; Davis, Paul; Thomson, Alan B. R.

    1988-01-01

    We evaluated the effect of medically induced symptomatic disease improvement on in vitro tests of cell-mediated immune responses in 33 patients with Crohn's disease. When results obtained in 17 patients with ulcerative colitis were compared with those of 10 patients with ulcerative colitis who had undergone a colectomy, no significant correlation was detected between individual clinical and laboratory variables or the Crohn's disease activity index and in vitro tests of cell-mediated immunity. A different pattern emerged from the longitudinal tests of cell-mediated immunity: when these test results were initially abnormal in patients with Crohn's disease, clinical improvement as assessed by the Crohn's disease activity index was associated with normalizing cell-mediated immunity. In contrast, when the test results were initially normal, clinical improvement was not associated with any change in the immune response. Following colectomy in patients with ulcerative colitis, some abnormalities of suppressed immune responses remained, although patients were cured of their disease. Factors other than clinical disease activity may be responsible for the suppressed immunoresponsiveness in some patients with inflammatory bowel disease, and variable changes in cell-mediated immunity occur after both surgical and medical treatment. PMID:3388844

  17. Activity performance problems of patients with cardiac diseases and their impact on quality of life

    PubMed Central

    Duruturk, Neslihan; Tonga, Eda; Karatas, Metin; Doganozu, Ersin

    2015-01-01

    [Purpose] To describe the functional consequences of patients with cardiac diseases and analyze associations between activity limitations and quality of life. [Subjects and Methods] Seventy subjects (mean age: 60.1±12.0 years) were being treated by Physical Medicine and Rehabilitation and Cardiology Departments were included in the study. Activity limitations and participation restrictions as perceived by the individual were measured by the Canadian Occupational Performance Measure (COPM). The Nottingham Extended Activities of Daily Living (NEADL) Scale was used to describe limitations in daily living activities. To detect the impact of activity limitations on quality of life the Nottingham Health Profile (NHP) was used. [Results] The subjects described 46 different types of problematic activities. The five most identified problems were walking (45.7%), climbing up the stairs (41.4%), bathing (30%), dressing (28.6%) and outings (27.1%). The associations between COPM performance score with all subgroups of NEADL and NHP; total, energy, physical abilities subgroups, were statistically significant. [Conclusion] Our results showed that patients with cardiac diseases reported problems with a wide range of activities, and that also quality of life may be affected by activities of daily living. COPM can be provided as a patient-focused outcome measure, and it may be a useful tool for identifying those problems. PMID:26311919

  18. Activity performance problems of patients with cardiac diseases and their impact on quality of life.

    PubMed

    Duruturk, Neslihan; Tonga, Eda; Karatas, Metin; Doganozu, Ersin

    2015-07-01

    [Purpose] To describe the functional consequences of patients with cardiac diseases and analyze associations between activity limitations and quality of life. [Subjects and Methods] Seventy subjects (mean age: 60.1±12.0 years) were being treated by Physical Medicine and Rehabilitation and Cardiology Departments were included in the study. Activity limitations and participation restrictions as perceived by the individual were measured by the Canadian Occupational Performance Measure (COPM). The Nottingham Extended Activities of Daily Living (NEADL) Scale was used to describe limitations in daily living activities. To detect the impact of activity limitations on quality of life the Nottingham Health Profile (NHP) was used. [Results] The subjects described 46 different types of problematic activities. The five most identified problems were walking (45.7%), climbing up the stairs (41.4%), bathing (30%), dressing (28.6%) and outings (27.1%). The associations between COPM performance score with all subgroups of NEADL and NHP; total, energy, physical abilities subgroups, were statistically significant. [Conclusion] Our results showed that patients with cardiac diseases reported problems with a wide range of activities, and that also quality of life may be affected by activities of daily living. COPM can be provided as a patient-focused outcome measure, and it may be a useful tool for identifying those problems. PMID:26311919

  19. Remission in rheumatoid arthritis: benefit over low disease activity in patient-reported outcomes and costs

    PubMed Central

    2014-01-01

    Introduction Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes a considerable burden for the patient and society. It is not clear yet whether aiming for remission (REM) is worthwhile, especially when compared with low disease activity (LDA). Methods In 356 consecutive RA patients, we obtained data on physical function (health assessment questionnaire (HAQ)), health-related quality of life (HRQoL: Short Form 36 (SF36), Short Form 6 dimensions (SF-6D), Euro QoL 5D (EQ-5D)), work productivity (work productivity and activity impairment questionnaire (WPAI)), as well as estimation of direct and indirect costs. Cross-sectionally, data were compared in patients within different levels of disease activity according to the simplified disease activity index (SDAI; remission (REM ≤3.3); n = 87; low disease activity (LDA: 3.3 < SDAI ≤11); n = 103; moderate to high disease activity (MDA/HDA) >11 n = 119) by using analyses of variance (ANOVA). Longitudinal investigations assessed patients who changed from LDA to REM and vice versa. Results We found differences in patients achieving REM compared with LDA for HAQ (0.39 ± 0.58 versus 0.72 ± 68), WPAI (percentage impairment while working 11.8% ± 18.7% versus 26.8% ± 23.9%; percentage of overall activity impairment, 10.8% ± 14.1% versus 29.0% ± 23.6%)), EQ-5D (0.89 ± 0.12 versus 0.78 ± 0.6) and SF-36 (physical component score (PCS): 46.0 ± 8.6 versus 38.3 ± 10.5; mental component score (MCS): 49.9 ± 11.1 versus 47.9 ± 12.3) (P < 0.01 for all, except for SF36 MCS). Regarding costs, we found significant differences of direct and indirect costs (P < 0.05) within different levels of disease activity, with higher costs in patients with higher states of disease activity. Longitudinal evaluations confirmed the main analyses. Conclusion Patients with REM show better function, HRQoL, and productivity, even when compared with another

  20. Is the serum cholesterol-coronary heart disease relationship modified by activity level in older persons?

    PubMed

    Harris, T B; Makuc, D M; Kleinman, J C; Gillum, R F; Curb, J D; Schatzkin, A; Feldman, J J

    1991-08-01

    Although coronary heart disease remains a leading cause of death and disability in old age, the relationship of serum cholesterol level to risk of coronary heart disease in old age is controversial. Data for 2,388 white persons aged 65-74 who participated in the National Health and Nutrition Examination Survey (NHANES) I Epidemiologic Follow-up Study (NHEFS) were examined to determine the relationship of serum cholesterol level to coronary heart disease incidence and whether activity level would modify this relationship. While there was no overall relationship between serum cholesterol level and coronary heart disease risk in either men or women, the relationship between serum cholesterol level and coronary heart disease differed within activity groups. For persons who were more active, serum cholesterol level was associated with a graded increase in risk of coronary heart disease, from 1.3 (95% CI 0.7, 2.3) in those with serum cholesterol level of 4.7-5.1 to 1.7 in those with serum cholesterol level of 6.2 mmol/L or more (95% CI 1.0, 2.7), when compared with those with serum cholesterol level below 4.7. For the least active persons, all levels of cholesterol were associated with a significant inverse relative risk, including cholesterol of 6.2 mmol/L or more (Relative risk = 0.4 (95% CI 0.2, 0.7]. These data suggest that factors such as activity level may modify the serum cholesterol-coronary heart disease association in old age. The serum cholesterol-coronary heart disease association in more active older persons resembles that seen in younger populations, whereas the association in less active persons is that of serum cholesterol level and risk of cancer or death. The modification of the serum cholesterol-coronary heart disease association by activity level may have implications for appropriate clinical management as well as appropriate design of research studies of this association. PMID:2071804

  1. Persons with mild or moderate Alzheimer's disease managing daily activities via verbal instruction technology.

    PubMed

    Lancioni, Giulio E; La Martire, Maria L; Singh, Nirbhay N; O'Reilly, Mark F; Sigafoos, Jeff; Pinto, Katia; Minervini, Mauro G

    Four studies assessed the effectiveness of verbal instructions presented via technology in helping persons with mild or moderate Alzheimer's disease perform daily activities. The first 2 studies were replication efforts concerning morning bathroom routine and table setting and included 4 and 2 participants, respectively. The third study targeted coffee preparation with 3 participants. The fourth study assessed maintenance and generalization of morning bathroom routine and dressing with 1 participant. Nonconcurrent multiple baseline designs served for the first 3 studies and a 5-month postintervention data collection for the fourth study. Verbal instructions for the activity steps presented via technology were effective in helping the participants of the first 3 studies reacquire basic daily activities and the participant of the fourth study retain the reacquired activities across time and settings. These results suggest that the approach reported may be a useful strategy for helping persons with Alzheimer's disease. PMID:19106276

  2. Matriptase initiates epidermal prokallikrein activation and disease onset in a mouse model of Netherton syndrome

    PubMed Central

    Sales, Katiuchia Uzzun; Masedunskas, Andrius; Bey, Alexandra L.; Rasmussen, Amber; Weigert, Roberto; List, Karin; Szabo, Roman; Overbeek, Paul A.; Bugge, Thomas H.

    2010-01-01

    Deficiency in the serine protease inhibitor LEKTI is the etiological origin of Netherton syndrome. The principal morbidities of the disease are stratum corneum detachment and chronic inflammation. We show that the membrane protease, matriptase, initiates Netherton syndrome in a LEKTI-deficient mouse model by premature activation of a pro-kallikrein-related cascade. Auto-activation of pro-inflammatory and stratum corneum detachment-associated pro-kallikrein-related peptidases was either low or undetectable, but they were efficiently activated by matriptase. Ablation of matriptase from LEKTI-deficient mice dampened inflammation, eliminated aberrant protease activity, prevented stratum corneum detachment, and improved epidermal barrier function. The study uncovers a pathogenic matriptase-pro-kallikrein pathway that could be operative in several human skin and inflammatory diseases. PMID:20657595

  3. Vitamin D Receptor Activators and Clinical Outcomes in Chronic Kidney Disease

    PubMed Central

    Gravellone, Luciana; Rizzo, Maria Antonietta; Martina, Valentina; Mezzina, Nicoletta; Regalia, Anna; Gallieni, Maurizio

    2011-01-01

    Vitamin D deficiency appears to be an underestimated risk factor for cardiovascular disease in patients with chronic kidney disease. Evidence from both basic science and clinical studies supports the possible protective role of vitamin D beyond its effect on mineral metabolism. Toxicity of pharmacologic doses of active vitamin D metabolites, in particular calcitriol, is mainly due to the possibility of positive calcium and phosphorus balance. Therefore, vitamin D analogs have been developed, which suppress PTH secretion and synthesis with reduced calcemic and phosphatemic effects. Observational studies suggest that in hemodialysis patients the use of a vitamin D receptor (VDR) activator, such as calcitriol, doxercalciferol, paricalcitol, or alfacalcidol, is associated with a reduced mortality when compared with nonusers of any VDR activator. In this article the existing literature on the topic is reviewed, although a more robust answer to the question of whether or not VDR activators have beneficial effects in hemodialysis patients will hopefully come from a randomized controlled trial. PMID:21647319

  4. Tau-based therapeutics for Alzheimer's disease: active and passive immunotherapy.

    PubMed

    Panza, Francesco; Solfrizzi, Vincenzo; Seripa, Davide; Imbimbo, Bruno P; Lozupone, Madia; Santamato, Andrea; Tortelli, Rosanna; Galizia, Ilaria; Prete, Camilla; Daniele, Antonio; Pilotto, Alberto; Greco, Antonio; Logroscino, Giancarlo

    2016-09-01

    Pharmacological manipulation of tau protein in Alzheimer's disease included microtubule-stabilizing agents, tau protein kinase inhibitors, tau aggregation inhibitors, active and passive immunotherapies and, more recently, inhibitors of tau acetylation. Animal studies have shown that both active and passive approaches can remove tau pathology and, in some cases, improve cognitive function. Two active vaccines targeting either nonphosphorylated (AAD-vac1) and phosphorylated tau (ACI-35) have entered Phase I testing. Notwithstanding, the recent discontinuation of the monoclonal antibody RG7345 for Alzheimer's disease, two other antitau antibodies, BMS-986168 and C2N-8E12, are also currently in Phase I testing for progressive supranuclear palsy. After the recent impressive results in animal studies obtained by salsalate, the dimer of salicylic acid, inhibitors of tau acetylation are being actively pursued. PMID:27485083

  5. Sarcoid-like lymphocytosis of the lower respiratory tract in patients with active Crohn's disease.

    PubMed

    Smiéjan, J M; Cosnes, J; Chollet-Martin, S; Soler, P; Basset, F M; Le Quintrec, Y; Hance, A J

    1986-01-01

    To re-evaluate the relationship between Crohn's disease and sarcoidosis, we compared the numbers and types of cells recovered by bronchoalveolar lavage from normal volunteers and patients with Crohn's disease, with other forms of inflammatory bowel disease, and with sarcoidosis. Patients with Crohn's disease, but not patients with other inflammatory bowel disorders, had an increase in the number of T lymphocytes on the surface of the lower respiratory tract similar to that seen in patients with sarcoidosis. As in sarcoidosis, this lymphocytosis results from an expansion of the T4+ T-lymphocyte subset, is characteristic of patients with active disease only, and is not associated with similar abnormalities in the peripheral blood. Thus, patients with apparently localized Crohn's disease have sarcoid-like lymphocytosis of the lower respiratory tract, a finding that emphasizes the systemic nature of Crohn's disease and the disorder's close relationship to sarcoidosis. PMID:3940500

  6. Active-R filter

    DOEpatents

    Soderstrand, Michael A.

    1976-01-01

    An operational amplifier-type active filter in which the only capacitor in the circuit is the compensating capacitance of the operational amplifiers, the various feedback and coupling elements being essentially solely resistive.

  7. UPS Activation in the Battle Against Aging and Aggregation-Related Diseases: An Extended Review.

    PubMed

    Papaevgeniou, Nikoletta; Chondrogianni, Niki

    2016-01-01

    Aging is a biological process accompanied by gradual increase of damage in all cellular macromolecules, i.e., nucleic acids, lipids, and proteins. When the proteostasis network (chaperones and proteolytic systems) cannot reverse the damage load due to its excess as compared to cellular repair/regeneration capacity, failure of homeostasis is established. This failure is a major hallmark of aging and/or aggregation-related diseases. Dysfunction of the major cellular proteolytic machineries, namely the proteasome and the lysosome, has been reported during the progression of aging and aggregation-prone diseases. Therefore, activation of these pathways is considered as a possible preventive or therapeutic approach against the progression of these processes. This chapter focuses on UPS activation studies in cellular and organismal models and the effects of such activation on aging, longevity and disease prevention or reversal. PMID:27613027

  8. Controlled trial of polymeric versus elemental diet in treatment of active Crohn's disease.

    PubMed

    Giaffer, M H; North, G; Holdsworth, C D

    1990-04-01

    30 patients with active Crohn's disease, mean Crohn's Disease Activity Index 301 (SE 32), who would otherwise have been treated with steroids, were randomised to receive for 4 weeks either an elemental diet ('Vivonex') (n = 16) or a polymeric diet ('Fortison') (n = 14). Assessment on days 10 and 28 showed that clinical remission occurred in 5 (36%) of the 14 patients on fortison compared with 12 (75%) of the 16 patients assigned to vivonex. The difference in remission rate was significant (p less than 0.03). Dietary treatment resulted in little change in the nutritional state and various laboratory indices of activity over a 4 week period despite clinical improvement. Polymeric diets do not seem to offer an effective therapeutic alternative to elemental diets in patients with acute exacerbations of Crohn's disease. PMID:1969560

  9. Understanding the impact of deep brain stimulation on ambulatory activity in advanced Parkinson's disease.

    PubMed

    Rochester, Lynn; Chastin, Sebastien Francois Martin; Lord, Sue; Baker, Katherine; Burn, David John

    2012-06-01

    Whilst deep brain stimulation of the subthalamic nucleus (DBS-STN) improves the motor symptoms of Parkinson's disease (PD), its effect on daily activity is unknown. We aimed to quantify changes in ambulatory activity following DBS-STN in advanced PD using novel accelerometry based measures that describe changes to the volume and pattern of walking. Seventeen participants with advanced PD were measured over a 7-day period using an activPAL (™) activity monitor. Data were collected 6 weeks before and 6 months after surgery and included measures that describe the volume and pattern of ambulatory activity (number of steps per day, accumulation, diversity and variability of walking time), alongside standard measures for disease severity, freezing of gait, gait speed, and extended activities of daily living. Activity outcomes were compared pre- and 6 months post-surgery using linear mixed models and correlated with standard outcomes. The results of this study are despite significant improvements in motor symptoms after surgery, the volume of ambulatory activity (total number of steps per day) did not change (P = 0.468). However, significant increases in length and variability of walking bouts emerged, suggesting improvements in diversity and flexibility of walking patterns. Motor severity and extended activities of daily living scores were significantly correlated with walking bout variability but not with volume of walking. Thus, the conclusions are reduction in motor symptom severity after DBS-STN translated into selective improvements in daily activity. Novel measures derived from accelerometry provide a discrete measure of performance and allow closer interpretation of the impact of DBS-STN on real-world activity. PMID:22086738

  10. Depressive Symptoms in Crohn's Disease: Relationship with Immune Activation and Tryptophan Availability

    PubMed Central

    Guloksuz, Sinan; Wichers, Marieke; Kenis, Gunter; Russel, Maurice G. V. M.; Wauters, Annick; Verkerk, Robert; Arts, Baer; van Os, Jim

    2013-01-01

    Crohn's disease (CD) is associated with immune activation and depressive symptoms. This study determines the impact of anti-tumor necrosis factor (TNF)-α treatment in CD patients on depressive symptoms and the degree to which tryptophan (TRP) availability and immune markers mediate this effect. Fifteen patients with CD, eligible for anti-TNF-α treatment were recruited. Disease activity (Harvey-Bradshaw Index (HBI), Crohn's Disease Activity Index (CDAI)), fatigue (Multidimensional Fatigue Inventory (MFI)), quality of life (Inflammatory Bowel Disease Questionnaire (IBDQ)), symptoms of depression and anxiety (Symptom Checklist (SCL-90), Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS)), immune activation (acute phase proteins (APP)), zinc and TRP availability were assessed before treatment and after 2, 4 and 8 weeks. Anti-TNF-α increased IBDQ scores and reduced all depression scores; however only SCL-90 depression scores remained decreased after correction for HBI. Positive APPs decreased, while negative APPs increased after treatment. After correction for HBI, both level and percentage of γ fraction were associated with SCL-90 depression scores over time. After correction for HBI, patients with current/past depressive disorder displayed higher levels of positive APPs and lower levels of negative APPs and zinc. TRP availability remained invariant over time and there was no association between SCL-90 depression scores and TRP availability. Inflammatory reactions in CD are more evident in patients with comorbid depression, regardless of disease activity. Anti-TNF-α treatment in CD reduces depressive symptoms, in part independently of disease activity; there was no evidence that this effect was mediated by immune-induced changes in TRP availability. PMID:23544139

  11. Fecal calprotectin is associated with disease activity in patients with ankylosing spondylitis.

    PubMed

    Duran, Arzu; Kobak, Senol; Sen, Nazime; Aktakka, Seniha; Atabay, Tennur; Orman, Mehmet

    2016-01-01

    Calprotectin is one of the major antimicrobial S100 leucocyte proteins. Serum calprotectin levels are associated with certain inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease. The aim of this study was to investigate serum and fecal calprotectin levels in patients with ankylosing spondylitis (AS) and show their potential relations to the clinical findings of the disease. Fifty-one patients fulfilling the New York criteria of AS and 43 healthy age- and gender-matched volunteers were included in the study. Physical and locomotor system examinations were performed and history data were obtained for all patients. Disease activity parameters were assessed together with anthropometric parameters. Routine laboratory examinations and genetic testing (HLA-B27) were performed. Serum calprotectin levels and fecal calprotectin levels were measured by an enzyme-linked immunosorbent assay. The mean age of the patients was 41.5 years, the mean duration of the disease was 8.6 years, and the delay in diagnosis was 4.2 years. Serum calprotectin levels were similar in both AS patients and in the control group (p=0.233). Serum calprotectin level was correlated with Bath AS disease activity index (BASDAI) and Bath AS functional index (BASFI) (p=0.001, p=0.002, respectively). A higher level of fecal calprotectin was detected in AS patients when compared with the control group. A statistically significant correlation between fecal calprotectin level and BASDAI, BASFI, C-reactive protein and Erythrocyte sedimentation rate were detected (p=0.002, p=0.005, p=0.001, p=0.002, respectively). The results indicated that fecal calprotectin levels were associated with AS disease findings and activity parameters. Calprotectin is a vital disease activity biomarker for AS and may have an important role in the pathogenesis of the disease. Multi-centered prospective studies are needed in order to provide further insight. PMID:26773186

  12. Fecal calprotectin is associated with disease activity in patients with ankylosing spondylitis

    PubMed Central

    Duran, Arzu; Kobak, Senol; Sen, Nazime; Aktakka, Seniha; Atabay, Tennur; Orman, Mehmet

    2016-01-01

    Calprotectin is one of the major antimicrobial S100 leucocyte proteins. Serum calprotectin levels are associated with certain inflammatory diseases such as rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease. The aim of this study was to investigate serum and fecal calprotectin levels in patients with ankylosing spondylitis (AS) and show their potential relations to the clinical findings of the disease. Fifty-one patients fulfilling the New York criteria of AS and 43 healthy age- and gender-matched volunteers were included in the study. Physical and locomotor system examinations were performed and history data were obtained for all patients. Disease activity parameters were assessed together with anthropometric parameters. Routine laboratory examinations and genetic testing (HLA-B27) were performed. Serum calprotectin levels and fecal calprotectin levels were measured by an enzyme-linked immunosorbent assay. The mean age of the patients was 41.5 years, the mean duration of the disease was 8.6 years, and the delay in diagnosis was 4.2 years. Serum calprotectin levels were similar in both AS patients and in the control group (p=0.233). Serum calprotectin level was correlated with Bath AS disease activity index (BASDAI) and Bath AS functional index (BASFI) (p=0.001, p=0.002, respectively). A higher level of fecal calprotectin was detected in AS patients when compared with the control group. A statistically significant correlation between fecal calprotectin level and BASDAI, BASFI, C-reactive protein and Erythrocyte sedimentation rate were detected (p=0.002, p=0.005, p=0.001, p=0.002, respectively). The results indicated that fecal calprotectin levels were associated with AS disease findings and activity parameters. Calprotectin is a vital disease activity biomarker for AS and may have an important role in the pathogenesis of the disease. Multi-centered prospective studies are needed in order to provide further insight. PMID:26773186

  13. Impact of Network Activity on the Spread of Infectious Diseases through the German Pig Trade Network

    PubMed Central

    Lebl, Karin; Lentz, Hartmut H. K.; Pinior, Beate; Selhorst, Thomas

    2016-01-01

    The trade of livestock is an important and growing economic sector, but it is also a major factor in the spread of diseases. The spreading of diseases in a trade network is likely to be influenced by how often existing trade connections are active. The activity α is defined as the mean frequency of occurrences of existing trade links, thus 0 < α ≤ 1. The observed German pig trade network had an activity of α = 0.11, thus each existing trade connection between two farms was, on average, active at about 10% of the time during the observation period 2008–2009. The aim of this study is to analyze how changes in the activity level of the German pig trade network influence the probability of disease outbreaks, size, and duration of epidemics for different disease transmission probabilities. Thus, we want to investigate the question, whether it makes a difference for a hypothetical spread of an animal disease to transport many animals at the same time or few animals at many times. A SIR model was used to simulate the spread of a disease within the German pig trade network. Our results show that for transmission probabilities <1, the outbreak probability increases in the case of a decreased frequency of animal transports, peaking range of α from 0.05 to 0.1. However, for the final outbreak size, we find that a threshold exists such that finite outbreaks occur only above a critical value of α, which is ~0.1, and therefore in proximity of the observed activity level. Thus, although the outbreak probability increased when decreasing α, these outbreaks affect only a small number of farms. The duration of the epidemic peaks at an activity level in the range of α = 0.2–0.3. Additionally, the results of our simulations show that even small changes in the activity level of the German pig trade network would have dramatic effects on outbreak probability, outbreak size, and epidemic duration. Thus, we can conclude and recommend that the network activity

  14. Can fecal calprotectin better stratify Crohn’s disease activity index?

    PubMed Central

    Scaioli, Eleonora; Cardamone, Carla; Scagliarini, Michele; Zagari, Rocco Maurizio; Bazzoli, Franco; Belluzzi, Andrea

    2015-01-01

    Background Crohn’s disease (CD) activity index (CDAI) is still widely used for monitoring clinical activity in CD patients, but is of little value as indicator of persistent inflammation in symptomless patients. Fecal calprotectin levels ≥150 µg/g are strongly indicative of endoscopically and/or histologically active disease. Our aim was to study, in a large cohort of CD patients, the relationship between CDAI and fecal calprotectin levels. Methods CDAI and fecal calprotectin levels were evaluated in consecutive patients from a CD outpatient clinic. Results We enrolled 193 CD patients, of whom 38% with CDAI <150 had a calprotectin value ≥150 µg/g, suggestive of active disease. A logistic regression model showed that for CDAI levels between 100 and 150, the estimated logistic probability of calprotectin ≥150 µg/g increased progressively to 76%, reaching 94% where disease activity was localized in the colon. With a CDAI cut-off >120, we found a high diagnostic accuracy of 72%, with 88% specificity and 50% sensitivity (positive predictive value: 76%, negative predictive value: 71%) to identify a calprotectin value ≥150 µg/g. Conclusion CDAI scores between 100 and 150 display an acceptable ability to quantify the risk of persistent inflammation as expressed by the high calprotectin level. PMID:25831217

  15. Synapses, NMDA receptor activity and neuronal Aβ production in Alzheimer's disease.

    PubMed

    Bordji, Karim; Becerril-Ortega, Javier; Buisson, Alain

    2011-01-01

    A direct relationship has been established between synaptic activity and amyloid-β secretion. Dysregulation of neuronal calcium homeostasis was shown to increase production of amyloid-β, contributing to the initiation of Alzheimer's disease. Among the different routes of Ca(2+) entry, N-methyl-d-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptors, are especially involved in this process because of their ability to gate high levels of Ca(2+) influx. These receptors have been extensively studied for their crucial roles in synaptic plasticity that underlies learning and memory but also in neurotoxicity occurring during acute brain injuries and neurodegenerative diseases. For one decade, several studies provided evidence that NMDA receptor activation could have distinct consequences on neuronal fate, depending on their location. Synaptic NMDA receptor activation is neuroprotective, whereas extrasynaptic NMDA receptors trigger neuronal death and/or neurodegenerative processes. Recent data suggest that chronic activation of extrasynaptic NMDA receptors leads to a sustained neuronal amyloid-β release and could be involved in the pathogenesis of Alzheimer's disease. Thus, as for other neurological diseases, therapeutic targeting of extrasynaptic NMDA receptors could be a promising strategy. Following this concept, memantine, unlike other NMDA receptor antagonists was shown, to preferentially target the extrasynaptic NMDA receptor signaling pathways, while relatively sparing normal synaptic activity. This molecular mechanism could therefore explain why memantine is, to date, the only clinically approved NMDA receptor antagonist for the treatment of dementia. PMID:21568789

  16. Pulmonary Rehabilitation and Physical Activity in Patients with Chronic Obstructive Pulmonary Disease.

    PubMed

    Spruit, Martijn A; Pitta, Fabio; McAuley, Edward; ZuWallack, Richard L; Nici, Linda

    2015-10-15

    Physical inactivity is common in patients with chronic obstructive pulmonary disease (COPD) compared with age-matched healthy individuals or patients with other chronic diseases. Physical inactivity independently predicts poor outcomes across several aspects of this disease, but it is (at least in principle) treatable in patients with COPD. Pulmonary rehabilitation has arguably the greatest positive effect of any current therapy on exercise capacity in COPD; as such, gains in this area should facilitate increases in physical activity. Furthermore, because pulmonary rehabilitation also emphasizes behavior change through collaborative self-management, it may aid in the translation of increased exercise capacity to greater participation in activities involving physical activity. Both increased exercise capacity and adaptive behavior change are necessary to achieve significant and lasting increases in physical activity in patients with COPD. Unfortunately, it is readily assumed that this translation occurs naturally. This concise clinical review will focus on the effects of a comprehensive pulmonary rehabilitation program on physical activity in patients with COPD. Changing physical activity behavior in patients with COPD needs an interdisciplinary approach, bringing together respiratory medicine, rehabilitation sciences, social sciences, and behavioral sciences. PMID:26161676

  17. Increasing Patient Activation Could Improve Outcomes for Patients with Inflammatory Bowel Disease.

    PubMed

    Shah, Shawn L; Siegel, Corey A

    2015-12-01

    Inflammatory bowel disease (IBD) is a complex disease process that often requires the integration of skills from various health care providers to adequately meet the needs of patients with IBD. The medical and surgical treatment options for IBD have become more complicated and are frequently a source of angst for both the patient and provider. However, it has become more important than ever to engage patients in navigating the treatment algorithm. Although novel in the IBD world, the concept of patients' becoming more active and effective managers of their care has been well studied in other disease processes such as diabetes mellitus and mental illness. This idea of patient activation refers to a patient understanding his or her role in the care process and having the skill sets and self-reliance necessary to manage his or her own health care. Over the past decade, evidence supporting the role of patient activation in chronic illness has grown, revealing improved health outcomes, enhanced patient experiences, and lower overall costs. Patient activation can be measured, and interventions have been shown to improve levels of activation over time and influence outcomes. A focus on patient activation is very appropriate for patients with IBD because this may potentially serve as a tool for IBD providers to not only improve patient outcomes and experience but also reduce health care costs. PMID:26422517

  18. Histone deacetylase inhibitors increase glucocerebrosidase activity in Gaucher disease by modulation of molecular chaperones

    PubMed Central

    Yang, Chunzhang; Rahimpour, Shervin; Lu, Jie; Pacak, Karel; Ikejiri, Barbara; Brady, Roscoe O.; Zhuang, Zhengping

    2013-01-01

    Gaucher disease is caused by mutations of the GBA gene that encodes the lysosomal enzyme glucocerebrosidase (GCase). GBA mutations often result in protein misfolding and premature degradation, but usually exert less effect on catalytic activity. In this study, we identified the molecular mechanism by which histone deacetylase inhibitors increase the quantity and activity of GCase. Specifically, these inhibitors limit the deacetylation of heat shock protein 90, resulting in less recognition of the mutant peptide and GCase degradation. These findings provide insight into a possible therapeutic strategy for Gaucher disease and other genetic disorders by modifying molecular chaperone and protein degradation pathways. PMID:23277556

  19. Thermal Inactivation of Newcastle Disease Virus I. Coupled Inactivation Rates of Hemagglutinating and Neuraminidase Activities

    PubMed Central

    Pierce, John S.; Haywood, A. M.

    1973-01-01

    The thermal stability of Newcastle disease virus has been characterized in terms of the rate constants for inactivation of hemagglutinating activity (HA), neuraminidase activity (NA), and infectivity. Inactivation of HA results in the concomitant loss of NA. Infectivity, however, is much more thermolabile. Disintegration of the virus particle is not responsible for the identical rate constants for inactivation of HA and NA, nor is their parallel inactivation uncoupled in envelope fragments produced by pretreating the virus with phospholipase-C. The data indicate that a common envelope factor(s) can influence the thermal stability of both activities. PMID:4734647

  20. Evaluation of antiviral activity of plant extracts against foot and mouth disease virus in vitro.

    PubMed

    Younus, Ishrat; Siddiq, Afshan; Ishaq, Humera; Anwer, Laila; Badar, Sehrish; Ashraf, Muhammad

    2016-07-01

    The aim of this study was to evaluate antiviral activity of chloroformic leaves extracts of three plants: Azadirachta indica, Moringa oleifera and Morus alba against Foot and Mouth disease virus using MTT assay (3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide). Antiviral and cytotoxic activity of each extract was evaluated as cell survival percentage and results were expressed as Means ± S.D. The concentrations which resulted in cell survival percentages of greater than 50% are considered to be effective antiviral concentrations. From the tested plant extracts, Moringa oleifera showed potent antiviral activity (p<0.05) while Azadirachta indica showed significant antiviral activity in the range of 1-50μ/ml & 12-100μ/ml respectively. In contrast no antiviral activity was observed by Morus alba as all the tested concentration resulted in significant reduction (p<0.05) in cell survival percentage. PMID:27393440

  1. Identification of a protein kinase activity in purified foot- and-mouth disease virus.

    PubMed Central

    Grubman, M J; Baxt, B; La Torre, J L; Bachrach, H L

    1981-01-01

    Purified preparations of foot-and-mouth disease virus types A, O, and C contain a protein kinase activity which can transfer the gamma phosphate of [32P]ATP to virion structural proteins VP2 and VP3 and exogenous acceptor proteins. Utilizing protamine sulfate as an acceptor, the kinase activity can be demonstrated in disrupted virus but not in intact virus. The enzyme is heat labile with optimal activity at pH 7 or greater. Serine residues of protamine sulfate were identified as the amino acid phosphorylated by the protein kinase. Treatment of purified virus with trypsin, which cleaves VP3, did not affect the protein kinase activity. The results indicate that the protein kinase activity found in FMDV is present in an internally located protein of viral or host origin. Images PMID:6268834

  2. Development of the chronic obstructive pulmonary disease activity rating scale: reliability, validity and factorial structure.

    PubMed

    Morimoto, Michiko; Takai, Kenichi; Nakajima, Kazuo; Kagawa, Koujiro

    2003-03-01

    The purpose of the present study was to develop the Chronic Obstructive Pulmonary Disease (COPD) Activity Rating Scale (CARS) to measure life-related activity in patients with COPD, and to confirm its reliability and constructive validity in a factorial structure model. The subjects consisted of 114 patients with COPD. An 88-item life-related activity list, generated previously from a literature review, was administered. The secondary structural model consisted of four factors with 12 items. The results of the confirmatory factor analysis by structural equation modeling showed the fit criteria to be statistically significant. The internal consistency of the 12 items was highly reliable (Cronbach's alpha = 0.924). The CARS score was correlated with pulmonary function tests, breathlessness, and the health-related quality of life (QOL) scales in Pearson correlation coefficient. The results suggest that the COPD Activity Rating Scale is a valid scale for the assessment of life-related activity in patients with COPD. PMID:12603718

  3. Platelet Mitochondrial Activity and Pesticide Exposure in Early Parkinson’s Disease

    PubMed Central

    Bronstein, Jeff M.; Paul, Kimberly; Yang, Laurice; Haas, Richard H.; Shults, Clifford W.; Le, Thuy; Ritz, Beate

    2015-01-01

    Background Mitochondrial dysfunction has been implicated in the pathogenesis of Parkinson’s disease (PD) but the cause of this dysfunction is unclear. Methods Platelet mitochondrial complex I and I/III (NADH cytochrome c reductase, NCCR) activities were measured in early PD patients and matched controls enrolled in a population based case-control study. Ambient agricultural pesticide exposures were assessed with a geographic information system and California Pesticide Use Registry. Results In contrast to some previous reports, we found no differences in complex I and I/III activities in subjects with PD and controls. We did find that NCCR activity correlated with subjects’ exposure to pesticides known to inhibit mitochondrial activity regardless of their diagnosis. Conclusions ETC activity is not altered in PD in this well-characterized cohort when compared to community-matched controls but appears to be affected by environmental toxins, such as mitochondria-inhibiting pesticides. PMID:25757798

  4. Electromyographic Activity in the EEG in Alzheimer's Disease: Noise or Signal?

    PubMed Central

    van der Hiele, Karin; Reijntjes, Robert H. A. M.; Vein, Alla A.; Westendorp, Rudi G. J.; van Buchem, Mark A.; Bollen, Eduard L. E. M.; Middelkoop, Huub A. M.; van Dijk, J. Gert

    2011-01-01

    Many efforts have been directed at negating the influence of electromyographic (EMG) activity on the EEG, especially in elderly demented patients. We wondered whether these “artifacts” might reflect cognitive and behavioural aspects of dementia. In this pilot study, 11 patients with probable Alzheimer's disease (AD), 13 with amnestic mild cognitive impairment (MCI) and 13 controls underwent EEG registration. As EMG measures, we used frontal and temporal 50–70 Hz activity. We found that the EEGs of AD patients displayed more theta activity, less alpha reactivity, and more frontal EMG than controls. Interestingly, increased EMG activity indicated more cognitive impairment and more depressive complaints. EEG variables on the whole distinguished better between groups than EMG variables, but an EMG variable was best for the distinction between MCI and controls. Our results suggest that EMG activity in the EEG could be more than noise; it differs systematically between groups and may reflect different cerebral functions than the EEG. PMID:21559240

  5. Electromyographic activity in the EEG in Alzheimer's disease: noise or signal?

    PubMed

    van der Hiele, Karin; Reijntjes, Robert H A M; Vein, Alla A; Westendorp, Rudi G J; van Buchem, Mark A; Bollen, Eduard L E M; Middelkoop, Huub A M; van Dijk, J Gert

    2011-01-01

    Many efforts have been directed at negating the influence of electromyographic (EMG) activity on the EEG, especially in elderly demented patients. We wondered whether these "artifacts" might reflect cognitive and behavioural aspects of dementia. In this pilot study, 11 patients with probable Alzheimer's disease (AD), 13 with amnestic mild cognitive impairment (MCI) and 13 controls underwent EEG registration. As EMG measures, we used frontal and temporal 50-70 Hz activity. We found that the EEGs of AD patients displayed more theta activity, less alpha reactivity, and more frontal EMG than controls. Interestingly, increased EMG activity indicated more cognitive impairment and more depressive complaints. EEG variables on the whole distinguished better between groups than EMG variables, but an EMG variable was best for the distinction between MCI and controls. Our results suggest that EMG activity in the EEG could be more than noise; it differs systematically between groups and may reflect different cerebral functions than the EEG. PMID:21559240

  6. Activated eosinophils and interleukin 5 expression in early recurrence of Crohn's disease.

    PubMed Central

    Dubucquoi, S; Janin, A; Klein, O; Desreumaux, P; Quandalle, P; Cortot, A; Capron, M; Colombel, J F

    1995-01-01

    Endoscopic recurrences after radical surgery for Crohn's disease are useful for studying the pathogenesis of initial lesions of Crohn's disease. Factors predisposing to recurrence are poorly understood, but it has been shown that eosinophilic infiltration of the neoileum may occur within a few weeks of resection. The aim of this study was to compare, in nine patients having an ileocolectomy, the infiltration of eosinophils and their activation state in normal and diseased areas of the neoileum, three months after surgery. Tissue eosinophils were studied by histochemical methods and electron microscopy. Mucosal expression of interleukin 5 (IL 5), an important eosinophil activating factor was studied using in situ hybridisation. Sixty per cent of patients had endoscopic recurrence at three months. Eosinophil infiltration was more pronounced in diseased than in endoscopically normal areas and was associated with a high expression of IL 5 mRNA. Ultrastructural analysis showed features of eosinophil activation, but no cytotoxic lesions of surrounding inflammatory or epithelial cells. This study suggests that local synthesis of IL 5 associated with eosinophil activation in the tissues could participate in early mucosal damage in Crohn's disease. Images Figure 1 Figure 2 Figure 3 PMID:7557575

  7. Salivary Acetylcholinesterase Activity Is Increased in Parkinson's Disease: A Potential Marker of Parasympathetic Dysfunction

    PubMed Central

    Fedorova, Tatyana; Knudsen, Cindy Soendersoe; Mouridsen, Kim; Nexo, Ebba; Borghammer, Per

    2015-01-01

    Introduction. Decreased salivary flow and xerostomia are frequent findings in Parkinson's disease (PD), possibly caused by alterations in the parasympathetic tonus. Here we explore salivary acetylcholinesterase (AChE) activity as a potential biomarker in PD. Methods. We measured salivary flow, AChE activity, and total protein concentration in 30 PD patients and 49 healthy controls. We also performed exploratory correlation analyses with disease duration, motor symptom severity, autonomic complaints, and other nonmotor symptoms. Results. PD patients displayed significantly decreased salivary flow rate, significantly increased salivary AChE activity, and total protein concentration. Importantly, the AChE activity/total protein ratio was significantly increased in PD patients, suggesting that increased AChE activity cannot be explained solely by upconcentration of saliva. The Unified PD Rating Scale (UPDRS) score displayed significant correlation with total salivary protein (P = 0.002) and near-significant correlation with salivary flow (P = 0.07). Color vision test scores were also significantly correlated with AChE activity (P = 0.04) and total protein levels (P = 0.002). Conclusion. Salivary AChE activity is increased in PD patients compared to healthy controls. Future studies are needed to elucidate whether this parameter reflects the extent of neuronal damage and parasympathetic denervation in the salivary glands of PD patients. PMID:25767737

  8. Behavioral and Locomotor Measurements Using an Open Field Activity Monitoring System for Skeletal Muscle Diseases

    PubMed Central

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

    2014-01-01

    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. PMID:25286313

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

    PubMed

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

    2014-01-01

    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. PMID:25286313

  10. Pharmacogenetics of paraoxonase activity: elucidating the role of high-density lipoprotein in disease

    PubMed Central

    Kim, Daniel Seung; Marsillach, Judit; Furlong, Clement E; Jarvik, Gail P

    2014-01-01

    PON1 is a key component of high-density lipoproteins (HDLs) and is at least partially responsible for HDL's antioxidant/atheroprotective properties. PON1 is also associated with numerous human diseases, including cardiovascular disease, Parkinson's disease and cancer. In addition, PON1 metabolizes a broad variety of substrates, including toxic organophosphorous compounds, statin adducts, glucocorticoids, the likely atherogenic l-homocysteine thiolactone and the quorum-sensing factor of Pseudomonas aeruginosa. Numerous cardiovascular and antidiabetic pharmacologic agents, dietary macronutrients, lifestyle factors and antioxidant supplements affect PON1 expression and enzyme activity levels. Owing to the importance of PON1 to HDL function and its individual association with diverse human diseases, pharmacogenomic interactions between PON1 and the various factors that alter its expression and activity may represent an important therapeutic target for future investigation. PMID:24024900

  11. Deficient Rab11 activity underlies glucose hypometabolism in primary neurons of Huntington's disease mice

    SciTech Connect

    Li, Xueyi; Valencia, Antonio; McClory, Hollis; Sapp, Ellen; Kegel, Kimberly B.; DiFiglia, Marian

    2012-05-18

    Highlights: Black-Right-Pointing-Pointer Primary Huntington's disease neurons are impaired in taking up glucose. Black-Right-Pointing-Pointer Rab11 modulates glucose uptake in neurons. Black-Right-Pointing-Pointer Increasing Rab11 activity attenuates the glucose uptake defect in disease neurons. Black-Right-Pointing-Pointer We provide a novel mechanism for glucose hypometabolism in Huntington's disease. -- Abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene. Positron emission tomography studies have revealed a decline in glucose metabolism in the brain of patients with HD by a mechanism that has not been established. We examined glucose utilization in embryonic primary cortical neurons of wild-type (WT) and HD knock-in mice, which have 140 CAG repeats inserted in the endogenous mouse huntingtin gene (HD{sup 140Q/140Q}). Primary HD{sup 140Q/140Q} cortical neurons took up significantly less glucose than did WT neurons. Expression of permanently inactive and permanently active forms of Rab11 correspondingly altered glucose uptake in WT neurons, suggesting that normal activity of Rab11 is needed for neuronal uptake of glucose. It is known that Rab11 activity is diminished in HD{sup 140Q/140Q} neurons. Expression of dominant active Rab11 to enhance the activity of Rab11 normalized glucose uptake in HD{sup 140Q/140Q} neurons. These results suggest that deficient activity of Rab11 is a novel mechanism for glucose hypometabolism in HD.

  12. Assessment of inflammatory bowel disease activity by technetium 99m phagocyte scanning

    SciTech Connect

    Pullman, W.E.; Sullivan, P.J.; Barratt, P.J.; Lising, J.; Booth, J.A.; Doe, W.F.

    1988-10-01

    Autologous technetium 99m-labeled phagocyte scanning has been used to assess disease activity in inflammatory bowel disease in 51 consecutive patients. Strong correlations were found between the 24-h fecal excretion of isotope and the histologic score of mucosal biopsy specimens (rS = 0.84, p less than 0.001, where rS is Spearman's rank correlation coefficient), and between the 24-h fecal excretion of isotope and a clinical inflammatory bowel disease activity index based on the Crohn's disease activity index (rS = 0.87, p less than 0.001). To develop a clinically useful and objective measure of inflammatory bowel disease activity that did not require a 24-h stool collection, the intensity of bowel uptake on scanning was graded visually from 0 to 4, a ratio of count rates for the region of interest to the iliac crest reference region was calculated, and the rapidity of labeled phagocyte uptake into inflamed bowel was measured as the peak uptake time. Visual grading of disease activity on the scans was validated by comparing it with the ratio of count rates from inflamed bowel regions of interest and those from the iliac crest reference region. The ratio of count rates showed a significant correlation with the clinical disease activity index (r = 0.75, p less than 0.001). The visual scan grade also correlated well with the clinical activity index (r = 0.87, p less than 0.001). Count rates from hourly scans were also used to calculate the time of peak uptake of counts for a given region of interest. There was a strong negative correlation between this peak uptake time and the fecal excretion of isotope (rS = -0.81, p less than 0.001), a clinical activity index (r = -0.60, p less than 0.001), and the histologic score of the mucosal biopsy specimens (r = -0.84, p less than 0.001).

  13. Glycoprotein YKL-40: a novel biomarker of chronic graft-vs-host disease activity and severity?

    PubMed Central

    Duraković, Nadira; Krečak, Ivan; Perić, Zinaida; Milošević, Milan; Desnica, Lana; Pulanić, Dražen; Pusic, Iskra; Kušec, Vesna; Vrhovac, Radovan; Pavletic, Steven Z.; Nemet, Damir

    2016-01-01

    Aim To investigate whether increased YKL-40 levels positively correlate with graft-vs-host disease (cGVHD) activity and severity and if YKL-40 could serve as a disease biomarker. Methods This case-control study was conducted at the University Hospital Centre Zagreb from July 2013 to October 2015. 56 patients treated with hematopoietic stem cell transplantation (HSCT) were included: 35 patients with cGVHD and 21 without cGVHD. There was no difference between groups in age, sex, median time from transplant to study enrollment, intensity of conditioning, type of donor, or source of stem cells. Blood samples were collected at study enrollment and YKL-40 levels were measured with ELISA. Disease activity was estimated using Clinician’s Impression of Activity and Intensity of Immunosuppression scales and disease severity using Global National Institutes of Health (NIH) score. Results YKL-40 levels were significantly higher in cGVHD patients than in controls (P = 0.003). The difference remained significant when patients with myelofibrosis were excluded from the analysis (P = 0.017). YKL-40 level significantly positively correlated with disease severity (P < 0.001; correlation coefficient 0.455), and activity estimated using Clinician’s Impression of Activity (P = 0.016; correlation coefficient 0.412) but not using Intensity of Immunosuppression (P = 0.085; correlation coefficient 0.296). Conclusion YKL-40 could be considered a biomarker of cGVHD severity and activity. However, validation in a larger group of patients is warranted, as well as longitudinal testing of YKL-40 levels in patients at risk of developing cGVHD. PMID:27374825

  14. Role of Inflammasome Activation in the Pathophysiology of Vascular Diseases of the Neurovascular Unit

    PubMed Central

    Mohamed, Islam N.; Ishrat, Tauheed; Fagan, Susan C.

    2015-01-01

    Abstract Significance: Inflammation is the standard double-edged defense mechanism that aims at protecting the human physiological homeostasis from devastating threats. Both acute and chronic inflammation have been implicated in the occurrence and progression of vascular diseases. Interference with components of the immune system to improve patient outcome after ischemic injury has been uniformly unsuccessful. There is a need for a deeper understanding of the innate immune response to injury in order to modulate, rather than to block inflammation and improve the outcome for vascular diseases. Recent Advances: Nucleotide-binding oligomerization domain-like receptors or NOD-like receptor proteins (NLRPs) can be activated by sterile and microbial inflammation. NLR family plays a major role in activating the inflammasome. Critical Issues: The aim of this work is to review recent findings that provided insights into key inflammatory mechanisms and define the place of the inflammasome, a multi-protein complex involved in instigating inflammation in neurovascular diseases, including retinopathy, neurodegenerative diseases, and stroke. Future Directions: The significant contribution of NLRP-inflammasome activation to vascular disease of the neurovascular unit in the brain and retina suggests that therapeutic strategies focused on specific targeting of inflammasome components could significantly improve the outcomes of these diseases. Antioxid. Redox Signal. 22, 1188–1206. PMID:25275222

  15. Survival effects of physical activity on mortality among persons with liver disease.

    PubMed

    Loprinzi, Paul D; VanWagner, Lisa B

    2016-06-01

    Physical activity is protective of premature mortality and those with liver disease are at an increased risk of early mortality. It is thus plausible to suggest that physical activity may have survival benefits among those with liver disease, but this has yet to be investigated. In a national sample, we examine the prospective association of objectively-measured physical activity on all-cause mortality among those with liver disease. Data from the 2003-2006 National Health and Nutrition Examination Survey (with follow-up through 2011) were evaluated (analyzed in 2015). Physical activity was assessed via accelerometry over 7 days. Liver disease was assessed via self-report of physician diagnosis. Covariates included age, gender, race-ethnicity, serum cotinine, income-to-poverty ratio, C-reactive protein, cholesterol medication use, blood pressure medication use, alcohol behavior, self-reported liver disease status, serum alanine aminotransferase (ALT), serum gamma-glutamyltransferase (GGT) and comorbid illness. The sample included 162 adults who self-reported a physician-diagnosis of liver disease. The unweighted median follow-up period was 80.0 months (IQR = 68-91; SD = 18.0). In the sample, 12,815 person-months occurred with a mortality incidence rate of 1.09 deaths per 1000 person-months. After adjustments, for every 10 min/day increase in moderate-to-vigorous physical activity (MVPA), participants had an 89% reduced risk of all-cause mortality (HRadjusted = 0.11; 95% CI: 0.02-0.47; P = 0.004). There was no evidence of moderation by alcohol behavior, ALT, GGT or Hepatitis C virus status. These findings demonstrate that modest increases in MVPA may have survival benefits among those with a self-reported liver condition. PMID:26844199

  16. Faecal alpha-1-antitrypsin and excretion of 111indium granulocytes in assessment of disease activity in chronic inflammatory bowel diseases.

    PubMed Central

    Fischbach, W; Becker, W; Mössner, J; Koch, W; Reiners, C

    1987-01-01

    Intestinal protein loss in chronic inflammatory bowel diseases may be easily determined by measurement of alpha-1-antitrypsin (alpha 1-AT) stool concentration and alpha 1-AT clearance. Both parameters were significantly raised in 36 and 34 patients respectively with chronic inflammatory bowel diseases, compared with eight patients with non-inflammatory bowel diseases, or 19 healthy volunteers. There was wide range of overlap between active and inactive inflammatory disease. Contrary to serum alpha 1-AT, faecal excretion and clearance of alpha 1-AT did not correlate with ESR, serum-albumin, orosomucoid, and two indices of disease activity. A comparison of alpha 1-AT faecal excretion and clearance with the faecal excretion of 111In labelled granulocytes in 27 patients with chronic inflammatory bowel diseases, showed no correlation between the intestinal protein loss and this highly specific marker of intestinal inflammation. Enteric protein loss expressed by faecal excretion and clearance of alpha 1-AT does not depend on mucosal inflammation only, but may be influenced by other factors. PMID:3495470

  17. Epicatechin and Catechin Modulate Endothelial Activation Induced by Platelets of Patients with Peripheral Artery Disease

    PubMed Central

    Carnevale, R.; Loffredo, L.; Nocella, C.; Bartimoccia, S.; Bucci, T.; De Falco, E.; Peruzzi, M.; Chimenti, I.; Biondi-Zoccai, G.; Pignatelli, P.; Violi, F.; Frati, G.

    2014-01-01

    Platelet activation contributes to the alteration of endothelial function, a critical initial step in atherogenesis through the production and release of prooxidant mediators. There is uncertainty about the precise role of polyphenols in interaction between platelets and endothelial cells (ECs). We aimed to investigate whether polyphenols are able to reduce endothelial activation induced by activated platelets. First, we compared platelet activation and flow-mediated dilation (FMD) in 10 healthy subjects (HS) and 10 patients with peripheral artery disease (PAD). Then, we evaluated the effect of epicatechin plus catechin on platelet-HUVEC interaction by measuring soluble cell adhesion molecules (CAMs), NOx production, and eNOS phosphorylation (p-eNOS) in HUVEC. Compared to HS, PAD patients had enhanced platelet activation. Conversely, PAD patients had lower FMD than HS. Supernatant of activated platelets from PAD patients induced an increase of sCAMs release and a decrease of p-eNOS and nitric oxide (NO) bioavailability compared to unstimulated HUVEC. Coincubation of HUVEC, with supernatant of PAD platelets patients, pretreated with a scalar dose of the polyphenols, resulted in a decrease of sCAMs release and in an increase of p-eNOS and NO bioavailability. This study demonstrates that epicatechin plus catechin reduces endothelial activation induced by activated platelets. PMID:25180068

  18. Epicatechin and catechin modulate endothelial activation induced by platelets of patients with peripheral artery disease.

    PubMed

    Carnevale, R; Loffredo, L; Nocella, C; Bartimoccia, S; Bucci, T; De Falco, E; Peruzzi, M; Chimenti, I; Biondi-Zoccai, G; Pignatelli, P; Violi, F; Frati, G

    2014-01-01

    Platelet activation contributes to the alteration of endothelial function, a critical initial step in atherogenesis through the production and release of prooxidant mediators. There is uncertainty about the precise role of polyphenols in interaction between platelets and endothelial cells (ECs). We aimed to investigate whether polyphenols are able to reduce endothelial activation induced by activated platelets. First, we compared platelet activation and flow-mediated dilation (FMD) in 10 healthy subjects (HS) and 10 patients with peripheral artery disease (PAD). Then, we evaluated the effect of epicatechin plus catechin on platelet-HUVEC interaction by measuring soluble cell adhesion molecules (CAMs), NOx production, and eNOS phosphorylation (p-eNOS) in HUVEC. Compared to HS, PAD patients had enhanced platelet activation. Conversely, PAD patients had lower FMD than HS. Supernatant of activated platelets from PAD patients induced an increase of sCAMs release and a decrease of p-eNOS and nitric oxide (NO) bioavailability compared to unstimulated HUVEC. Coincubation of HUVEC, with supernatant of PAD platelets patients, pretreated with a scalar dose of the polyphenols, resulted in a decrease of sCAMs release and in an increase of p-eNOS and NO bioavailability. This study demonstrates that epicatechin plus catechin reduces endothelial activation induced by activated platelets. PMID:25180068

  19. Multifunctional activity of polyphenolic compounds associated with a potential for Alzheimer's disease therapy from Ecklonia cava.

    PubMed

    Choi, Byoung Wook; Lee, Hye Sook; Shin, Hyeon-Cheol; Lee, Bong Ho

    2015-04-01

    Five polyphenols were isolated and purified from a brown alga Ecklonia cava. These compounds showed diverse biological activities such as antioxidative, antiinflammatory, and enzyme inhibitory activities. This led us to investigate the potential of these compounds as Alzheimer's disease drugs. All of the compounds showed moderate acetylcholinesterase inhibitory activity in a micromolar range (IC50 from 16.0 to 96.3 μM). For butyrylcholinesterase, a new target for the treatment of Alzheimer's disease, phlorofucofuroeckol-A (PFF-A), showed a particularly potent inhibitory activity (IC50 0.95 μM), which is over 100-fold greater than for acetylcholinesterase. These compounds inhibited glycogen synthase kinase 3 beta, which is related to the formation of hyperphosphorylated tau and generation Aβ. Bieckol and PFF-A inhibited amyloid precursor protein biosynthesis. PFF-A also showed very strong β-secretase inhibitory activity with IC50 of submicromole. These results render these compounds as interesting potential drug candidates for Alzheimer's disease. PMID:25640212

  20. Assessment of Activity of Crohn Disease by Diffusion-Weighted Magnetic Resonance Imaging.

    PubMed

    Li, Xue-Hua; Sun, Can-Hui; Mao, Ren; Zhang, Zhong-Wei; Jiang, Xiao-Song; Pui, Margaret H; Chen, Min-Hu; Li, Zi-Ping

    2015-10-01

    To assess the diagnostic efficacy of diffusion-weighted MR imaging (DWI) for evaluating inflammatory activity in patients with Crohn's disease (CD). A total of 47 CD patients underwent MR enterography (MRE) and DWI using 3 b values of 50, 400, and 800 s/mm. Apparent diffusion coefficients (ADCs) of inflamed and normal bowel wall were calculated. The conventional MRE findings and DWI signal intensities were qualitatively scored from 0 to 3. The correlation between Crohn disease activity index (CDAI) and both ADCs and magnetic resonance imaging scores was analyzed. Receiver-operating characteristic curve analysis was used to determine the diagnostic accuracy of CD activity. Of the 47 patients, 25 were active CD (CDAI≥150) and 22 were inactive (CDAI<150). Diffusion-weighted MR imaging and MRE + DWI scores of active CD were significantly higher than that of inactive CD (both P < 0.001). Apparent diffusion coefficients in inflamed segments of active CD were lower than that of inactive CD (P < 0.001). The DWI scores (r = 0.74, P < 0.001), ADCs (r = -0.71, P < 0.001), MRE scores (r = 0.54, P < 0.001), and MRE + DWI scores (r = 0.66, P < 0.001) were all correlated with CDAI. The areas under the receiver-operating characteristics curves for ADCs, DWI scores, MRE scores, and MRE + DWI scores ranged from 0.83 to 0.98. The threshold ADC value of 1.17 × 10 mm/s allowed differentiation of active from inactive CD with 100% sensitivity and 88% specificity. Diffusion-weighted MR imaging and ADC correlated with CD activity, and had excellent diagnostic accuracy for differentiating active from inactive CD. PMID:26512584

  1. Gender, body mass index and rheumatoid arthritis disease activity: results from the QUEST-RA study

    PubMed Central

    Jawaheer, Damini; Olsen, Jørn; Lahiff, Maureen; Forsberg, Sinikka; Lähteenmäki, Jukka; Silveira, Ines Guimaraes da; Rocha, Francisco Airton; Laurindo, Ieda Maria Magalhães; Mota, Licia Maria Henrique da; Drosos, Alexandros A.; Murphy, Eithne; Sheehy, Claire; Quirke, Edel; Cutolo, Maurizio; Rexhepi, Sylejman; Dadoniene, Jolanta; Verstappen, Suzan M.M.; Sokka, Tuulikki

    2010-01-01

    Objective To investigate whether body mass index (BMI), as a proxy for body fat, influences rheumatoid arthritis (RA) disease activity in a gender-specific manner. Methods Consecutive patients with RA were enrolled from 25 countries into the QUEST-RA program between 2005 and 2008. Clinical and demographic data were collected by treating rheumatologists and by patient self-report. Distributions of Disease Activity Scores (DAS28), BMI, age, and disease duration were assessed for each country and for the entire dataset; mean values between genders were compared using Student’s t-tests. An association between BMI and DAS28 was investigated using linear regression, adjusting for age, disease duration and country. Results A total of 5,161 RA patients (4,082 women and 1,079 men) were included in the analyses. Overall, women were younger, had longer disease duration, and higher DAS28 scores than men, but BMI was similar between genders. The mean DAS28 scores increased with increasing BMI from normal to overweight and obese, among women, whereas the opposite trend was observed among men. Regression results showed BMI (continuous or categorical) to be associated with DAS28. Compared to the normal BMI range, being obese was associated with a larger difference in mean DAS28 (0.23, 95% CI: 0.11, 0.34) than being overweight (0.12, 95% CI: 0.03, 0.21); being underweight was not associated with disease activity. These associations were more pronounced among women, and were not explained by any single component of the DAS28. Conclusion BMI appears to be associated with RA disease activity in women, but not in men. PMID:20810033

  2. Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease

    PubMed Central

    Flynn, Ryan; Allen, Jessica L.; Luznik, Leo; MacDonald, Kelli P.; Paz, Katelyn; Alexander, Kylie A.; Vulic, Ante; Du, Jing; Panoskaltsis-Mortari, Angela; Taylor, Patricia A.; Poe, Jonathan C.; Serody, Jonathan S.; Murphy, William J.; Hill, Geoffrey R.; Maillard, Ivan; Koreth, John; Cutler, Corey S.; Soiffer, Robert J.; Antin, Joseph H.; Ritz, Jerome; Chao, Nelson J.; Clynes, Raphael A.; Sarantopoulos, Stefanie

    2015-01-01

    Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B-cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multiorgan system, nonsclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells, but not T cells, for disease progression. Bone marrow–specific Syk deletion in vivo was effective in treating established cGVHD, as was a small-molecule inhibitor of Syk, fostamatinib, which normalized GC formation and decreased activated CD80/86+ dendritic cells. In multiple distinct models of sclerodermatous cGVHD, clinical and pathological disease manifestations were not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these scleroderma models. We further demonstrated that Syk inhibition was effective at inducing apoptosis of human cGVHD B cells. Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD. PMID:25852057

  3. Disease Activity, Proteinuria, and Vitamin D Status in Children with Systemic Lupus Erythematosus and Juvenile Dermatomyositis

    PubMed Central

    Robinson, Angela Byun; Thierry-Palmer, Myrtle; Gibson, Keisha L.; Rabinovich, C. Egla

    2011-01-01

    Objective To evaluate relationships between vitamin D, proteinuria, and disease activity in pediatric systemic lupus erythematosus (SLE) and juvenile dermatomyositis (JDM). Study design Multiple linear regression was used to associate subject-reported race, sunscreen use, and vitamin D intake with physician-assessed disease activity and serum 25-hydroxyvitamin D [25(OH)D] in subjects with pediatric SLE (n = 37) or JDM (n = 21). Serum 25(OH)D was correlated with urinary vitamin D binding protein/creatinine ratio (DBP/C) and other indicators of proteinuria. Results Serum 25(OH)D levels in subjects with SLE were inversely associated with the natural log of urinary DBP/C (r = −0.63, p < 0.001) and urine protein to creatinine ratio (r = −0.60, p<0.001), with an adjusted mean 10.9 (95% CI 5.1, 16.8) ng/mL decrease in 25(OH)D for those with proteinuria. Excluding subjects with proteinuria, serum 25(OH)D levels were inversely associated with disease activity in JDM, but not in SLE. Overall, 66% of all subjects were taking concurrent corticosteroids, but this was not associated with 25(OH)D levels. Conclusions Low serum 25(OH)D in patients with SLE is associated with proteinuria and urinary DBP. Vitamin D deficiency is associated with disease activity in patients with JDM and SLE; this relationship in SLE may be confounded by proteinuria. PMID:21924736

  4. Physical Activity and Sport Participation in Youth with Congenital Heart Disease: Perceptions of Children and Parents

    ERIC Educational Resources Information Center

    Moola, Fiona; Faulkner, Guy E. J.; Kirsh, Joel A.; Kilburn, Jennifer

    2008-01-01

    This study explored perceptions toward physical activity and sport in the lives of youth with congenital heart disease. Thirteen cardiac participants were interviewed in the presence of their parents, and a process of inductive analysis was conducted. Sport was not considered a valued pursuit despite the belief that it is essential for the…

  5. 25-hydroxyvitamin D levels and juvenile idiopathic arthritis: is there an association with disease activity?

    Technology Transfer Automated Retrieval System (TEKTRAN)

    To examine the association between serum levels of 25-hydroxyvitamin D [25(OH)D] and disease activity in juvenile idiopathic arthritis (JIA), to determine the prevalence of vitamin D (VD) deficiency [25(OH)D=19 ng/ml] and insufficiency [25(OH)D 20-29 ng/ml], and to determine factors associated with ...

  6. Search for Antiprotozoal Activity in Herbal Medicinal Preparations; New Natural Leads against Neglected Tropical Diseases.

    PubMed

    Llurba Montesino, Núria; Kaiser, Marcel; Brun, Reto; Schmidt, Thomas J

    2015-01-01

    Sleeping sickness, Chagas disease, Leishmaniasis, and Malaria are infectious diseases caused by unicellular eukaryotic parasites ("protozoans"). The three first mentioned are classified as Neglected Tropical Diseases (NTDs) by the World Health Organization and together threaten more than one billion lives worldwide. Due to the lack of research interest and the high increase of resistance against the existing treatments, the search for effective and safe new therapies is urgently required. In view of the large tradition of natural products as sources against infectious diseases [1,2], the aim of the present study is to investigate the potential of legally approved and marketed herbal medicinal products (HMPs) as antiprotozoal agents. Fifty-eight extracts from 53 HMPs on the German market were tested by a Multiple-Target-Screening (MTS) against parasites of the genera Leishmania, Trypanosoma, and Plasmodium. Sixteen HMPs showed in vitro activity against at least one of the pathogens (IC50 < 10 µg/mL). Six extracts from preparations of Salvia, Valeriana, Hypericum, Silybum, Arnica, and Curcuma exhibited high activity (IC50 < 2.5 µg/mL). They were analytically characterized by UHPLC/ESI-QqTOF-MSMS and the activity-guided fractionation of the extracts with the aim to isolate and identify the active compounds is in progress. PMID:26248069

  7. Often seen, rarely recognized: mast cell activation disease--a guide to diagnosis and therapeutic options.

    PubMed

    Afrin, Lawrence B; Butterfield, Joseph H; Raithel, Martin; Molderings, Gerhard J

    2016-01-01

    Mast cell (MC) disease has long been thought to be just the rare disease of mastocytosis (in various forms, principally cutaneous and systemic), with aberrant MC mediator release at symptomatic levels due to neoplastic MC proliferation. Recent discoveries now show a new view is in order, with mastocytosis capping a metaphorical iceberg now called "MC activation disease" (MCAD, i.e. disease principally manifesting inappropriate MC activation), with the bulk of the iceberg being the recently recognized "MC activation syndrome" (MCAS), featuring inappropriate MC activation to symptomatic levels with little to no inappropriate MC proliferation. Given increasing appreciation of a great menagerie of mutations in MC regulatory elements in mastocytosis and MCAS, the great heterogeneity of MCAD's clinical presentation is unsurprising. Most MCAD patients present with decades of chronic multisystem polymorbidity generally of an inflammatory ± allergic theme. Preliminary epidemiologic investigation suggests MCAD, while often misrecognized, may be substantially prevalent, making it increasingly important that practitioners of all stripes learn how to recognize its more common forms such as MCAS. We review the diagnostically challenging presentation of MCAD (with an emphasis on MCAS) and current thoughts regarding its biology, epidemiology, natural history, diagnostic evaluation, and treatment. PMID:27012973

  8. Controlled trial of oligopeptide versus amino acid diet in treatment of active Crohn's disease.

    PubMed Central

    Mansfield, J C; Giaffer, M H; Holdsworth, C D

    1995-01-01

    Elemental diets are effective in inducing remission in active Crohn's disease, but how they exert this therapeutic effect is unclear. In a previous study a whole protein containing diet proved less effective than one in which food antigens were excluded, suggesting that exclusion of food antigens from the gut was a possible mechanism. This study was designed to test whether an oligopeptide diet of hydrolysed proteins was as effective as an amino acid based diet. These diets were equally antigen free but with different nitrogen sources. Forty four patients with active Crohn's disease were randomised in a controlled trial of amino acid versus oligopeptide diet. The feeds were given by nasogastric tube in equicaloric quantities and were the sole form of nutrition. Treatment was continued for four weeks although failure to improve by day 10 resulted in withdrawal. Quantitative leucocyte scintigraphy was used to investigate the effect of diet treatment on gut inflammation. Clinical and nutritional responses to treatment were also measured. Sixteen patients entered remission (including withdrawal of corticosteroids), six patients could not tolerate the nasogastric tube, and 22 patients failed to respond. The two diets were equally effective. Patients who responded had a rapid drop in clinical index of disease activity and a major reduction in the bowel uptake of leucocytes on scintigraphy. The oligopeptide and amino acid based enteral feeds were equally effective at inducing remission in active Crohn's disease. With both diets clinical improvement was accompanied by a reduction in intestinal inflammation. Images Figure 3 PMID:7890238

  9. Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease.

    PubMed

    Flynn, Ryan; Allen, Jessica L; Luznik, Leo; MacDonald, Kelli P; Paz, Katelyn; Alexander, Kylie A; Vulic, Ante; Du, Jing; Panoskaltsis-Mortari, Angela; Taylor, Patricia A; Poe, Jonathan C; Serody, Jonathan S; Murphy, William J; Hill, Geoffrey R; Maillard, Ivan; Koreth, John; Cutler, Corey S; Soiffer, Robert J; Antin, Joseph H; Ritz, Jerome; Chao, Nelson J; Clynes, Raphael A; Sarantopoulos, Stefanie; Blazar, Bruce R

    2015-06-25

    Novel therapies for chronic graft-versus-host disease (cGVHD) are needed. Aberrant B-cell activation has been demonstrated in mice and humans with cGVHD. Having previously found that human cGVHD B cells are activated and primed for survival, we sought to further evaluate the role of the spleen tyrosine kinase (Syk) in cGVHD in multiple murine models and human peripheral blood cells. In a murine model of multiorgan system, nonsclerodermatous disease with bronchiolitis obliterans where cGVHD is dependent on antibody and germinal center (GC) B cells, we found that activation of Syk was necessary in donor B cells, but not T cells, for disease progression. Bone marrow-specific Syk deletion in vivo was effective in treating established cGVHD, as was a small-molecule inhibitor of Syk, fostamatinib, which normalized GC formation and decreased activated CD80/86(+) dendritic cells. In multiple distinct models of sclerodermatous cGVHD, clinical and pathological disease manifestations were not eliminated when mice were therapeutically treated with fostamatinib, though both clinical and immunologic effects could be observed in one of these scleroderma models. We further demonstrated that Syk inhibition was effective at inducing apoptosis of human cGVHD B cells. Together, these data demonstrate a therapeutic potential of targeting B-cell Syk signaling in cGVHD. PMID:25852057

  10. Daytime Physical Activity and Sleep in Hospitalized Older Adults: Association with Demographic Characteristics and Disease Severity

    PubMed Central

    Beveridge, Claire; Knutson, Kristen; Spampinato, Lisa; Flores, Andrea; Meltzer, David O.; Van Cauter, Eve; Arora, Vineet M.

    2016-01-01

    OBJECTIVES To assess objectively measured daytime physical activity and sleep duration and efficiency in hospitalized older adults and explore associations with demographic characteristics and disease severity. DESIGN Prospective cohort study. SETTING University of Chicago Medical Center general medicine wards. PARTICIPANTS Community-dwelling inpatients aged 50 and older (N = 120) MEASUREMENTS Physical activity and sleep were measured using wrist accelerometers. Information on Charlson Comorbidity Index and length of stay was collected from charts. Random-effects linear regression analysis was used to examine the association between in-hospital sleep and physical activity. RESULTS From March 2010 to May 2013, 120 participants wore wrist actigraphy monitors for at least 2 nights and 1 intervening day. Median activity level over the waking period was 77 counts/min (interquartile range 51–121 counts/min), an activity level that approximately corresponds to sitting while watching television (65 counts/min). Mean sleep duration the night before the activity interval was 289 ± 157 minutes, and mean sleep efficiency the night before the activity interval was 65.2 ± 26.9%. Mean activity counts/min were lowest for the oldest participants (oldest quartile 62, 95% confidence interval (CI) = 50–75; youngest quartile 121, 95% CI = 98–145, trend test P < .001) and those with highest Charlson Comorbidity Index (highest tertile 71, 95% CI = 60–83; lowest tertile 125, 95% CI = 104–147, trend test P = .01). Controlling for severity of illness and demographic characteristics, activity declined by 3 counts/min (95% CI = −5.65 to −0.43, P = .02) for each additional hour of inpatient sleep. CONCLUSION Older, sicker adults are less physically active during hospitalization. In contrast to studies in the community, inpatients who slept more were not more active. This may highlight that need for sleep is greater in the hospital than in the community. PMID:26131982

  11. [Myeloperoxidase activity in blood plasma as a criterion of therapy for patients with cardiovascular disease].

    PubMed

    Grigorieva, D V; Gorudko, I V; Kostevich, V A; Sokolov, A V; Buko, I V; Vasilyev, V B; Polonetsky, L Z; Panasenko, O M; Cherenkevich, S N

    2016-03-01

    A significant increase in the myeloperoxidase (MPO) activity has been found in plasma of patients with stable angina and with acute coronary syndrome (ACS) in comparison with the control group. MPO concentration was significantly increased in plasma of ACS patients. Reduced MPO activity in the treated ACS patients correlated with a favorable outcome of the disease. Generally, changes in plasma MPO concentration coincided with changes in lactoferrin concentration thus confirming the role of neutrophil degranulation in the increase of plasma concentrations of these proteins. The increase in MPO activity was obviously determined by modification of the MPO protein caused by reactive oxygen species and halogen in the molar ratio of 1 : 25 and 1 : 50. The decrease in plasma MPO activity may be associated with increased plasma concentrations of the physiological inhibitor of its activity, ceruloplasmin, and also with modification of the MPO protein with reactive oxygen species and halogen at their molar ratio of 1 : 100 and higher. Thus, MPO activity may be used for evaluation of effectiveness of the treatment of cardiovascular diseases. PMID:27420626

  12. Circulating ADAM17 Level Reflects Disease Activity in Proteinase-3 ANCA-Associated Vasculitis.

    PubMed

    Bertram, Anna; Lovric, Svjetlana; Engel, Alissa; Beese, Michaela; Wyss, Kristin; Hertel, Barbara; Park, Joon-Keun; Becker, Jan U; Kegel, Johanna; Haller, Hermann; Haubitz, Marion; Kirsch, Torsten

    2015-11-01

    ANCA-associated vasculitides are characterized by inflammatory destruction of small vessels accompanied by enhanced cleavage of membrane-bound proteins. One of the main proteases responsible for ectodomain shedding is disintegrin and metalloproteinase domain-containing protein 17 (ADAM17). Given its potential role in aggravating vascular dysfunction, we examined the role of ADAM17 in active proteinase-3 (PR3)-positive ANCA-associated vasculitis (AAV). ADAM17 concentration was significantly increased in plasma samples from patients with active PR3-AAV compared with samples from patients in remission or from other controls with renal nonvascular diseases. Comparably, plasma levels of the ADAM17 substrate syndecan-1 were significantly enhanced in active AAV. We also observed that plasma-derived ADAM17 retained its specific proteolytic activity and was partly located on extracellular microparticles. Transcript levels of ADAM17 were increased in blood samples of patients with active AAV, but those of ADAM10 or tissue inhibitor of metalloproteinases 3, which inhibits ADAMs, were not. We also performed a microRNA (miR) screen and identified miR-634 as significantly upregulated in blood samples from patients with active AAV. In vitro, miR-634 mimics induced a proinflammatory phenotype in monocyte-derived macrophages, with enhanced expression and release of ADAM17 and IL-6. These data suggest that ADAM17 has a prominent role in AAV and might account for the vascular complications associated with this disease. PMID:25788529

  13. Disease Mutations in Rab7 Result in Unregulated Nucleotide Exchange and Inappropriate Activation

    SciTech Connect

    B McCray; E Skordalakes; J Taylor

    2011-12-31

    Rab GTPases are molecular switches that orchestrate vesicular trafficking, maturation and fusion by cycling between an active, GTP-bound form, and an inactive, GDP-bound form. The activity cycle is coupled to GTP hydrolysis and is tightly controlled by regulatory proteins. Missense mutations of the GTPase Rab7 cause a dominantly inherited axonal degeneration known as Charcot-Marie-Tooth type 2B through an unknown mechanism. We present the 2.8 A crystal structure of GTP-bound L129F mutant Rab7 which reveals normal conformations of the effector binding regions and catalytic site, but an alteration to the nucleotide binding pocket that is predicted to alter GTP binding. Through extensive biochemical analysis, we demonstrate that disease-associated mutations in Rab7 do not lead to an intrinsic GTPase defect, but permit unregulated nucleotide exchange leading to both excessive activation and hydrolysis-independent inactivation. Consistent with augmented activity, mutant Rab7 shows significantly enhanced interaction with a subset of effector proteins. In addition, dynamic imaging demonstrates that mutant Rab7 is abnormally retained on target membranes. However, we show that the increased activation of mutant Rab7 is counterbalanced by unregulated, GTP hydrolysis-independent membrane cycling. Notably, disease mutations are able to rescue the membrane cycling of a GTPase-deficient mutant. Thus, we demonstrate that disease mutations uncouple Rab7 from the spatial and temporal control normally imposed by regulatory proteins and cause disease not by a gain of novel toxic function, but by misregulation of native Rab7 activity.

  14. Clinical value of fecal calprotectin in determining disease activity of ulcerative colitis

    PubMed Central

    Xiang, Jun-Ying; Ouyang, Qin; Li, Guo-Dong; Xiao, Nan-Ping

    2008-01-01

    AIM: To investigate possibility and clinical application of fecal calprotectin in determining disease activity of ulcerative colitis (UC). METHODS: The enzyme-linked immunosorbent assay (ELISA) was used to measure the concentrations of calprotectin in feces obtained from 66 patients with UC and 20 controls. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), acid glycoprotein (AGP) were also measured and were compared with calprotectin in determining disease activity of UC. The disease activity of UC was also determined by the Sutherland criteria. RESULTS: The fecal calprotectin concentration in the patients with active UC was significantly higher than that in the inactive UC and in the controls (402.16 ± 48.0 μg/g vs 35.93 ± 3.39 μg/g, 11.5 ± 3.42 μg/g, P < 0.01). The fecal calprotectin concentration in the inactive UC group was significantly higher than that in the control group (P < 0.05). A significant difference was also found in the patients with active UC of mild, moderate and severe degrees. The area under the curve of the receiver operating characteristics (AUCROC) was 0.975, 0.740, 0.692 and 0.737 for fecal calprotectin, CRP, ESR and AGP, respectively. There was a strong correlation between the fecal calprotectin concentration and the endoscopic gradings for UC (r = 0.866, P < 0.001). CONCLUSION: Calprotectin in the patient’s feces can reflect the disease activity of UC and can be used as a rational fecal marker for intestinal inflammation in clinical practice. This kind of marker is relatively precise, simple and noninvasive when compared with other commonly-used markers such as CRP, ESR and AGP. PMID:18176961

  15. Interdicting Gq Activation in Airway Disease by Receptor-Dependent and Receptor-Independent Mechanisms.

    PubMed

    Carr, Richard; Koziol-White, Cynthia; Zhang, Jie; Lam, Hong; An, Steven S; Tall, Gregory G; Panettieri, Reynold A; Benovic, Jeffrey L

    2016-01-01

    Gαqβγ heterotrimer (Gq), an important mediator in the pathology of airway disease, plays a central role in bronchoconstriction and airway remodeling, including airway smooth muscle growth and inflammation. Current therapeutic strategies to treat airway disease include the use of muscarinic and leukotriene receptor antagonists; however, these pharmaceuticals demonstrate a limited clinical efficacy as multiple Gq-coupled receptor subtypes contribute to these pathologies. Thus, broadly inhibiting the activation of Gq may be an advantageous therapeutic approach. Here, we investigated the effects of broadly inhibiting Gq activation in vitro and ex vivo using receptor-dependent and receptor-independent strategies. P4pal-10 is a protease activated receptor 4-derived pepducin that exhibits efficacy toward multiple Gq-coupled receptors. Mechanistic studies demonstrated that P4pal-10 selectively inhibits all G protein coupling to several Gq-coupled receptors, including protease activated receptor 1, muscarinic acetylcholine M3, and histamine H1 receptors, while demonstrating no direct effect on Gq. We also evaluated the ability of FR900359, also known as UBO-QIC, to directly inhibit Gq activation. FR900359 inhibited spontaneous Gαq nucleotide exchange, while having little effect on Gαsβγ, Gαiβγ, or Gα12/13βγ heterotrimer activity. Both P4pal-10 and FR900359 inhibited Gq-mediated intracellular signaling and primary human airway smooth muscle growth, whereas only FR900359 effectively interdicted agonist-promoted airway contraction in human precision cut lung slices. These studies serve as a proof of concept that the broad-based inhibition of Gq activation may be a useful therapeutic approach to treat multiple common pathologies of airway disease. PMID:26464325

  16. Identification of novel urinary biomarkers for assessing disease activity and prognosis of rheumatoid arthritis

    PubMed Central

    Park, Yune-Jung; Yoo, Seung-Ah; Hwang, Daehee; Cho, Chul-Soo; Kim, Wan-Uk

    2016-01-01

    To optimize treatment for rheumatoid arthritis (RA), it is ideal to monitor the disease activity on a daily basis because RA activity fluctuates over time. Urine can be collected routinely at home by patients. Recently, we identified four urinary biomarker candidates—gelsolin (GSN), orosomucoid (ORM)1, ORM2 and soluble CD14 (sCD14)—in RA patients through transcriptomic and proteomic studies. Here, we investigated the clinical significance of the aforementioned urinary biomarker candidates in a prospective manner. For the first time, we found that urinary ORM1, ORM2 and sCD14 levels, but not GSN, were elevated in RA patients and had a positive correlation with the status of the disease activity. In particular, urine tests for ORM 1, ORM 2 and sCD14 efficiently represented the presence of high RA activity without the need for measuring blood markers. In a parallel study, a more rapid radiographic progression over 3 years was observed in patients with higher ORM2 levels. Combined measurements of urinary ORM2 and serum C-reactive protein synergistically increased the predictability of the radiographic progression of RA (odds ratio: 46.5). Collectively, our data provide evidence that blood-free, urinary biomarkers are promising surrogates for assessing disease activity and prognosis of RA. We anticipate that our urinary biomarkers will provide novel candidates for patient-driven measurements of RA activity at home and can shift the paradigm from blood to urine testing in the assessment of RA activity and prognosis in hospitals. PMID:26915672

  17. Identification of novel urinary biomarkers for assessing disease activity and prognosis of rheumatoid arthritis.

    PubMed

    Park, Yune-Jung; Yoo, Seung-Ah; Hwang, Daehee; Cho, Chul-Soo; Kim, Wan-Uk

    2016-01-01

    To optimize treatment for rheumatoid arthritis (RA), it is ideal to monitor the disease activity on a daily basis because RA activity fluctuates over time. Urine can be collected routinely at home by patients. Recently, we identified four urinary biomarker candidates-gelsolin (GSN), orosomucoid (ORM)1, ORM2 and soluble CD14 (sCD14)-in RA patients through transcriptomic and proteomic studies. Here, we investigated the clinical significance of the aforementioned urinary biomarker candidates in a prospective manner. For the first time, we found that urinary ORM1, ORM2 and sCD14 levels, but not GSN, were elevated in RA patients and had a positive correlation with the status of the disease activity. In particular, urine tests for ORM 1, ORM 2 and sCD14 efficiently represented the presence of high RA activity without the need for measuring blood markers. In a parallel study, a more rapid radiographic progression over 3 years was observed in patients with higher ORM2 levels. Combined measurements of urinary ORM2 and serum C-reactive protein synergistically increased the predictability of the radiographic progression of RA (odds ratio: 46.5). Collectively, our data provide evidence that blood-free, urinary biomarkers are promising surrogates for assessing disease activity and prognosis of RA. We anticipate that our urinary biomarkers will provide novel candidates for patient-driven measurements of RA activity at home and can shift the paradigm from blood to urine testing in the assessment of RA activity and prognosis in hospitals. PMID:26915672

  18. Hedgehog Pathway Activation Parallels Histologic Severity of Injury and Fibrosis in Human Nonalcoholic Fatty Liver Disease

    PubMed Central

    Guy, Cynthia D.; Suzuki, Ayako; Zdanowicz, Marzena; Abdelmalek, Manal F.; Burchette, James; Unalp, Aynur; Diehl, Anna Mae

    2012-01-01

    The Hedgehog (Hh) signaling pathway mediates several processes that are deregulated in patients with the metabolic syndrome (e.g., fat mass regulation, vascular/endothelial remodeling, liver injury and repair, and carcinogenesis). The severity of nonalcoholic fatty liver disease (NAFLD) and the metabolic syndrome generally correlate. Therefore, we hypothesized that the level of Hh pathway activation would increase in parallel with the severity of liver damage in NAFLD. To assess potential correlations between known histologic and clinical predictors of advanced liver disease and Hh pathway activation, immunohistochemistry was performed on liver biopsies from a large well-characterized cohort of NAFLD patients (n=90) enrolled in the Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) Database 1 study. Increased Hh activity (evidenced by accumulation of Hh-ligand producing cells and Hh-responsive target cells) strongly correlated with portal inflammation, ballooning, and fibrosis stage (each p<0.0001), supporting a relationship between Hh pathway activation and liver damage. Pathway activity also correlated significantly with markers of liver repair, including numbers of hepatic progenitors and myofibroblastic cells (both p<0.03). In addition, various clinical parameters that have been linked to histologically-advanced NAFLD, including increased patient age (p<0.005), BMI (p<0.002), waist circumference (p<0.0007), homeostatic model assessment of insulin resistance (HOMA-IR) (p<0.0001) and hypertension (p<0.02), correlated with hepatic Hh activity. Conclusion: In NAFLD patients, the level of hepatic Hh pathway activity is highly correlated with the severity of liver damage and with metabolic syndrome parameters that are known to be predictive of advanced liver disease. Hence, deregulation of the Hh signaling network may contribute to the pathogenesis and sequelae of liver damage that develops with the metabolic syndrome. PMID:22213086

  19. Engineering neprilysin activity and specificity to create a novel therapeutic for Alzheimer's disease.

    PubMed

    Webster, Carl I; Burrell, Matthew; Olsson, Lise-Lotte; Fowler, Susan B; Digby, Sarah; Sandercock, Alan; Snijder, Arjan; Tebbe, Jan; Haupts, Ulrich; Grudzinska, Joanna; Jermutus, Lutz; Andersson, Christin

    2014-01-01

    Neprilysin is a transmembrane zinc metallopeptidase that degrades a wide range of peptide substrates. It has received attention as a potential therapy for Alzheimer's disease due to its ability to degrade the peptide amyloid beta. However, its broad range of peptide substrates has the potential to limit its therapeutic use due to degradation of additional peptides substrates that tightly regulate many physiological processes. We sought to generate a soluble version of the ectodomain of neprilysin with improved activity and specificity towards amyloid beta as a potential therapeutic for Alzheimer's disease. Extensive amino acid substitutions were performed at positions surrounding the active site and inner surface of the enzyme and variants screened for activity on amyloid beta 1-40, 1-42 and a variety of other physiologically relevant peptides. We identified several mutations that modulated and improved both enzyme selectivity and intrinsic activity. Neprilysin variant G399V/G714K displayed an approximately 20-fold improved activity on amyloid beta 1-40 and up to a 3,200-fold reduction in activity on other peptides. Along with the altered peptide substrate specificity, the mutant enzyme produced a markedly altered series of amyloid beta cleavage products compared to the wild-type enzyme. Crystallisation of the mutant enzyme revealed that the amino acid substitutions result in alteration of the shape and size of the pocket containing the active site compared to the wild-type enzyme. The mutant enzyme offers the potential for the more efficient degradation of amyloid beta in vivo as a therapeutic for the treatment of Alzheimer's disease. PMID:25089527

  20. Interleukin 35 Synovial Fluid Levels Are Associated with Disease Activity of Rheumatoid Arthritis

    PubMed Central

    Šenolt, Ladislav; Šumová, Barbora; Jandová, Romana; Hulejová, Hana; Mann, Heřman; Pavelka, Karel; Vencovský, Jiří; Filková, Mária

    2015-01-01

    Objectives To study the association of systemic and local interleukin-35 (IL-35) levels in rheumatoid arthritis. Methods 37 patients with treatment naïve early RA, 49 with established RA and 29 control patients with osteoarthritis (OA) were studied. Serum and paired synovial fluid samples were analysed for IL-35. Disease activity of RA patients was assessed according to the 28-Joint Count Disease Activity Score (DAS28). Results The levels of serum IL-35 were significantly higher in patients with treatment naïve early RA compared to those with established disease and control OA subjects. In addition, serum levels of IL-35 significantly decreased 12 weeks after initiation of glucocorticoids and conventional synthetic disease modifying antirheumatic drugs in patients with treatment naïve early RA. Synovial fluid IL-35 levels were significantly higher in RA compared to OA patients, were significantly elevated compared to serum counterparts and correlated with synovial fluid leukocyte count (r=0.412; p<0.01), serum CRP levels (r=0.362; p<0.05) and DAS28 (r=0.430, p<0.01). Conclusion This is the first study showing elevated circulating levels of IL-35 in treatment naïve early RA, its significant decrease after treatment initiation and positive association between increased synovial fluid IL-35 and disease activity in patients with long-lasting RA. PMID:26204444

  1. Aortic ascorbic acid, trace elements, and superoxide dismutase activity in human aneurysmal and occlusive disease

    SciTech Connect

    Dubick, M.A.; Hunter, G.C.; Casey, S.M.; Keen, C.L.

    1987-02-01

    Altered trace elements and ascorbic acid metabolism have been implicated in the pathogenesis of atherosclerotic cardiovascular disease. However, their role in the disease process, or the effect of atherosclerosis on their tissue levels within plaque, is poorly understood. The presence study analyzes the concentrations of Fe, Cu, Zn, and Mn, and ascorbic acid and superoxide dismutase (SOD) activity in tissue samples from 29 patients with abdominal aortic aneurysms (AAA) and 14 patients with atherosclerotic occlusive disease (AOD). It was observed that the Fe and Mn concentrations in AAA and AOD tissue were higher than the levels in nondiseased control aorta, whereas Cu and Zn levels in AAA and AOD tissue were similar to the levels in controls. The Zn:Cu ratio was significantly lower in the AAA tissue in comparison to both AOD and control tissue. In addition, AAA and AOD tissue had low ascorbic acid levels and low Cu, Zn-SOD activity with Cu,Zn-SOD:Mn-SOD ratios of 0.27 and 0.19, respectively, compared to a ratio of 3.20 in control aorta. These data indicate that aorta affected by aneurysms and occlusive disease have altered trace element and ascorbic acid concentrations, as well as low Cu,Zn-SOD activity. Although these observations do not directly support the hypothesis that AAA is associated with aortic Cu deficiency they do suggest a role for oxygen radicals or increased lipid peroxidation in occlusive and aneurysmal disease of the aorta.

  2. Circulating activated T cell subsets in autoimmune thyroid diseases: differences between untreated and treated patients.

    PubMed

    Ohashi, H; Okugawa, T; Itoh, M

    1991-11-01

    To investigate the relationships between lymphocyte subsets and thyroid function, peripheral blood lymphocytes were analysed with cell surface antigens of activated (HLA-DR+) T, helper T (CD4+ 2H4-, CD4+ 4B4+) and suppressor-inducer T (CD4+ 2H4+, CD4+ 4B4-) cells subsets in 56 patients with Graves' disease, 16 patients with Hashimoto's thyroiditis, 7 patients with typical subacute thyroiditis and 2 patients with the thyrotoxic phase of autoimmune thyroiditis. Both patients with Graves' disease and Hashimoto's thyroiditis had increased percentages of HLA-DR+ T (Ia+ CD3+) cells as well as HLA-DR+ helper-inducer T (Ia+ CD4+) cells, which seemed to be independent of treatments. The percentage of HLA-DR+ suppressor-cytotoxic T (Ia+ CD8+) cells was increased in euthyroid or hypothyroid patients with Graves' disease following treatment, but was normal in hyperthyroid patients. The percentages of Ia+ CD4+ cells and Ia+ CD8+ were also increased in patients with thyroiditis, whereas these abnormal values normalized in the remission phase. These findings suggest that an increase in Ia+ CD4+ cells characteristically occurs during immune system activation in patients with hyperthyroid Graves' disease, Hashimoto's thyroiditis and the thyrotoxic phase of subacute thyroiditis, whereas the activated CD8+ cells in Graves' disease are induced by antithyroidal therapy. PMID:1684685

  3. Correlation between clinical and MRI disease activity scores in axial spondyloarthritis.

    PubMed

    MacKay, James W; Aboelmagd, Sharief; Gaffney, J Karl

    2015-09-01

    Magnetic resonance (MR) imaging-based disease activity scores (DAS) in axial spondyloarthritis (axSpA) are rarely employed in the normal clinical setting, whereas clinical DAS are used routinely to monitor disease activity and set thresholds for biologic treatment. The objectives of this study were to evaluate the correlation between MR and clinical DAS in a general axSpA outpatient population and to assess the difference in MR DAS in individuals with high and low clinical DAS. This was a prospective, cross-sectional observational study. Forty participants with axSpA who presented for MR of the whole spine and sacroiliac joints as part of ongoing management were included. Completion of Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score (ASDAS) was performed at the time of MR examination. MR images were scored by two independent observers using the Spondyloarthritis Research Consortium of Canada (SPARCC) MR DAS. There were weak, non-significant correlations between total SPARCC score and BASDAI (r = 0.18, p = 0.26), ASDAS using erythrocyte sedimentation rate (ASDAS-ESR) (r = 0.31, p = 0.07) and ASDAS using C-reactive protein level (ASDAS-CRP) (r = 0.31, p = 0.05). There was no significant difference in the SPARCC score of participants with high and low clinical DAS. MR DAS may provide information about disease activity not provided by the current standard of clinical DAS and may be considered as a useful adjunct in clinical practice. PMID:25894437

  4. The impact of microglial activation on blood-brain barrier in brain diseases

    PubMed Central

    da Fonseca, Anna Carolina Carvalho; Matias, Diana; Garcia, Celina; Amaral, Rackele; Geraldo, Luiz Henrique; Freitas, Catarina; Lima, Flavia Regina Souza

    2014-01-01

    The blood-brain barrier (BBB), constituted by an extensive network of endothelial cells (ECs) together with neurons and glial cells, including microglia, forms the neurovascular unit (NVU). The crosstalk between these cells guarantees a proper environment for brain function. In this context, changes in the endothelium-microglia interactions are associated with a variety of inflammation-related diseases in brain, where BBB permeability is compromised. Increasing evidences indicate that activated microglia modulate expression of tight junctions, which are essential for BBB integrity and function. On the other hand, the endothelium can regulate the state of microglial activation. Here, we review recent advances that provide insights into interactions between the microglia and the vascular system in brain diseases such as infectious/inflammatory diseases, epilepsy, ischemic stroke and neurodegenerative disorders. PMID:25404894

  5. Role of Peroxisome Proliferator-Activated Receptor γ in Ocular Diseases

    PubMed Central

    Zhang, Su; Gu, Hongwei; Hu, Nan

    2015-01-01

    Peroxisome proliferator-activated receptor γ (PPAR γ), a member of the nuclear receptor superfamily, is a ligand-activated transcription factor that plays an important role in the control of a variety of physiological processes. The last decade has witnessed an increasing interest for the role played by the agonists of PPAR γ in antiangiogenesis, antifibrosis, anti-inflammation effects and in controlling oxidative stress response in various organs. As the pathologic mechanisms of major blinding diseases, such as age-related macular degeneration (AMD), diabetic retinopathy (DR), keratitis, and optic neuropathy, often involve neoangiogenesis and inflammation- and oxidative stress-mediated cell death, evidences are accumulating on the potential benefits of PPAR γ to improve or prevent these vision threatening eye diseases. In this paper we describe what is known about the role of PPAR γ in the ocular pathophysiological processes and PPAR γ agonists as novel adjuvants in the treatment of eye diseases. PMID:26146566

  6. Longitudinal influence of microglial activation and amyloid on neuronal function in Alzheimer's disease.

    PubMed

    Fan, Zhen; Okello, Aren A; Brooks, David J; Edison, Paul

    2015-12-01

    Amyloid deposition, tangle formation, neuroinflammation and neuronal dysfunction are pathological processes involved in Alzheimer's disease. However, the relative role of these processes in driving disease progression is still unclear. The aim of this positron emission tomography study was to: (i) investigate longitudinal changes of microglial activation, amyloid and glucose metabolism; and (ii) assess the temporospatial relationship between these three processes in Alzheimer's disease. A group of eight patients with a diagnosis of Alzheimer's disease (66 ± 4.8 years) and 14 healthy controls (65 ± 5.5 years) underwent T1 and T2 magnetic resonance imaging, along with (11)C-(R)-PK11195, (11)C-Pittsburgh compound B and (18)F-fluorodeoxyglucose positron emission tomography scans for microglial activation, amyloid deposition and glucose metabolism. All patients were followed-up with repeated magnetic resonance imaging and three positron emission tomography scans after 16 months. Parametric maps were interrogated using region of interest analysis, Statistical Parametric Mapping, and between-group correlation analysis at voxel-level using Biological Parametric Mapping. At baseline, patients with Alzheimer's disease showed significantly increased microglial activation compared to the control subjects. During follow-up, for the first time, we found that while there is a progressive reduction of glucose metabolism, there was a longitudinal increase of microglial activation in the majority of the patients with Alzheimer's disease. Voxel-wise correlation analysis revealed that microglial activation in patients with Alzheimer's disease was positively correlated with amyloid deposition and inversely correlated with regional cerebral metabolic rate at voxel level over time. Even though one of the limitations of this study is the lack of longitudinal follow-up of healthy control subjects, this study demonstrates that there is persistent neuroinflammation throughout the Alzheimer

  7. Adults Eligible for Cardiovascular Disease Prevention Counseling and Participation in Aerobic Physical Activity - United States, 2013.

    PubMed

    Omura, John D; Carlson, Susan A; Paul, Prabasaj; Watson, Kathleen B; Loustalot, Fleetwood; Foltz, Jennifer L; Fulton, Janet E

    2015-09-25

    Cardiovascular disease (CVD) is the leading cause of death in the United States, and physical inactivity is a major risk factor (1). Health care professionals have a role in counseling patients about physical activity for CVD prevention. In August 2014, the U.S. Preventive Services Task Force (USPSTF) recommended that adults who are overweight or obese and have additional CVD risk factors be offered or referred to intensive behavioral counseling interventions to promote a healthful diet and physical activity for CVD prevention. Although the USPSTF recommendation does not specify an amount of physical activity, the 2008 Physical Activity Guidelines for Americans state that for substantial health benefits adults should achieve ≥150 minutes per week of moderate-intensity aerobic physical activity or ≥75 minutes per week of vigorous-intensity aerobic activity, or an equivalent combination of moderate- and vigorous-intensity aerobic physical activity. To assess the proportion of adults eligible for intensive behavioral counseling and not meeting the aerobic physical activity guideline, CDC analyzed data from the 2013 Behavioral Risk Factor Surveillance System (BRFSS). This analysis indicated that 36.8% of adults were eligible for intensive behavioral counseling for CVD prevention. Among U.S. states and the District of Columbia (DC), the prevalence of eligible adults ranged from 29.0% to 44.6%. Nationwide, 19.9% of all adults were eligible and did not meet the aerobic physical activity guideline. These data can inform the planning and implementation of health care interventions for CVD prevention that are based on physical activity. PMID:26401758

  8. Human Tissue Kallikrein Activity in Angiographically Documented Chronic Stable Coronary Artery Disease

    PubMed Central

    Figueiredo, Estêvão Lanna; Magalhães, Carolina Antunes; Belli, Karlyse Claudino; Mandil, Ari; Garcia, José Carlos Faria; Araújo, Rosanã Aparecida; Figueiredo, Amintas Fabiano de Souza; Pellanda, Lucia Campos

    2015-01-01

    Background Human tissue kallikrein (hK1) is a key enzyme in the kallikrein–kinin system (KKS). hK1-specific amidase activity is reduced in urine samples from hypertensive and heart failure (HF) patients. The pathophysiologic role of hK1 in coronary artery disease (CAD) remains unclear. Objective To evaluate hK1-specific amidase activity in the urine of CAD patients Methods Sixty-five individuals (18–75 years) who underwent cardiac catheterism (CATH) were included. Random midstream urine samples were collected immediately before CATH. Patients were classified in two groups according to the presence of coronary lesions: CAD (43 patients) and non-CAD (22 patients). hK1 amidase activity was estimated using the chromogenic substrate D-Val-Leu-Arg-Nan. Creatinine was determined using Jaffé’s method. Urinary hK1-specific amidase activity was expressed as µM/(min · mg creatinine) to correct for differences in urine flow rates. Results Urinary hK1-specific amidase activity levels were similar between CAD [0.146 µM/(min ·mg creatinine)] and non-CAD [0.189 µM/(min . mg creatinine)] patients (p = 0.803) and remained similar to values previously reported for hypertensive patients [0.210 µM/(min . mg creatinine)] and HF patients [0.104 µM/(min . mg creatinine)]. CAD severity and hypertension were not observed to significantly affect urinary hK1-specific amidase activity. Conclusion CAD patients had low levels of urinary hK1-specific amidase activity, suggesting that renal KKS activity may be reduced in patients with this disease. PMID:26351984

  9. Beyond endoscopic assessment in inflammatory bowel disease: real-time histology of disease activity by non-linear multimodal imaging.

    PubMed

    Chernavskaia, Olga; Heuke, Sandro; Vieth, Michael; Friedrich, Oliver; Schürmann, Sebastian; Atreya, Raja; Stallmach, Andreas; Neurath, Markus F; Waldner, Maximilian; Petersen, Iver; Schmitt, Michael; Bocklitz, Thomas; Popp, Jürgen

    2016-01-01

    Assessing disease activity is a prerequisite for an adequate treatment of inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. In addition to endoscopic mucosal healing, histologic remission poses a promising end-point of IBD therapy. However, evaluating histological remission harbors the risk for complications due to the acquisition of biopsies and results in a delay of diagnosis because of tissue processing procedures. In this regard, non-linear multimodal imaging techniques might serve as an unparalleled technique that allows the real-time evaluation of microscopic IBD activity in the endoscopy unit. In this study, tissue sections were investigated using the non-linear multimodal microscopy combination of coherent anti-Stokes Raman scattering (CARS), two-photon excited auto fluorescence (TPEF) and second-harmonic generation (SHG). After the measurement a gold-standard assessment of histological indexes was carried out based on a conventional H&E stain. Subsequently, various geometry and intensity related features were extracted from the multimodal images. An optimized feature set was utilized to predict histological index levels based on a linear classifier. Based on the automated prediction, the diagnosis time interval is decreased. Therefore, non-linear multimodal imaging may provide a real-time diagnosis of IBD activity suited to assist clinical decision making within the endoscopy unit. PMID:27406831

  10. Beyond endoscopic assessment in inflammatory bowel disease: real-time histology of disease activity by non-linear multimodal imaging

    NASA Astrophysics Data System (ADS)

    Chernavskaia, Olga; Heuke, Sandro; Vieth, Michael; Friedrich, Oliver; Schürmann, Sebastian; Atreya, Raja; Stallmach, Andreas; Neurath, Markus F.; Waldner, Maximilian; Petersen, Iver; Schmitt, Michael; Bocklitz, Thomas; Popp, Jürgen

    2016-07-01

    Assessing disease activity is a prerequisite for an adequate treatment of inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis. In addition to endoscopic mucosal healing, histologic remission poses a promising end-point of IBD therapy. However, evaluating histological remission harbors the risk for complications due to the acquisition of biopsies and results in a delay of diagnosis because of tissue processing procedures. In this regard, non-linear multimodal imaging techniques might serve as an unparalleled technique that allows the real-time evaluation of microscopic IBD activity in the endoscopy unit. In this study, tissue sections were investigated using the non-linear multimodal microscopy combination of coherent anti-Stokes Raman scattering (CARS), two-photon excited auto fluorescence (TPEF) and second-harmonic generation (SHG). After the measurement a gold-standard assessment of histological indexes was carried out based on a conventional H&E stain. Subsequently, various geometry and intensity related features were extracted from the multimodal images. An optimized feature set was utilized to predict histological index levels based on a linear classifier. Based on the automated prediction, the diagnosis time interval is decreased. Therefore, non-linear multimodal imaging may provide a real-time diagnosis of IBD activity suited to assist clinical decision making within the endoscopy unit.

  11. Beyond endoscopic assessment in inflammatory bowel disease: real-time histology of disease activity by non-linear multimodal imaging

    PubMed Central

    Chernavskaia, Olga; Heuke, Sandro; Vieth, Michael; Friedrich, Oliver; Schürmann, Sebastian; Atreya, Raja; Stallmach, Andreas; Neurath, Markus F.; Waldner, Maximilian; Petersen, Iver; Schmitt, Michael; Bocklitz, Thomas; Popp, Jürgen

    2016-01-01

    Assessing disease activity is a prerequisite for an adequate treatment of inflammatory bowel diseases (IBD) such as Crohn’s disease and ulcerative colitis. In addition to endoscopic mucosal healing, histologic remission poses a promising end-point of IBD therapy. However, evaluating histological remission harbors the risk for complications due to the acquisition of biopsies and results in a delay of diagnosis because of tissue processing procedures. In this regard, non-linear multimodal imaging techniques might serve as an unparalleled technique that allows the real-time evaluation of microscopic IBD activity in the endoscopy unit. In this study, tissue sections were investigated using the non-linear multimodal microscopy combination of coherent anti-Stokes Raman scattering (CARS), two-photon excited auto fluorescence (TPEF) and second-harmonic generation (SHG). After the measurement a gold-standard assessment of histological indexes was carried out based on a conventional H&E stain. Subsequently, various geometry and intensity related features were extracted from the multimodal images. An optimized feature set was utilized to predict histological index levels based on a linear classifier. Based on the automated prediction, the diagnosis time interval is decreased. Therefore, non-linear multimodal imaging may provide a real-time diagnosis of IBD activity suited to assist clinical decision making within the endoscopy unit. PMID:27406831

  12. Diamine oxidase plasma activities after treatment with heparin and jejunal morphometry in untreated coeliac disease.

    PubMed Central

    Corazza, G R; Ginaldi, L; Falasca, A; Strocchi, A; Rossi, C A; Quaglino, D; Gasbarrini, G

    1989-01-01

    Diamine oxidase plasma concentrations after treatment with heparin were measured and compared with the surface to volume ratio of jejunal biopsy samples assessed by a morphometric technique in patients with untreated and treated coeliac disease and in biopsied controls. As expected, enzyme activity was significantly lower in patients with untreated coeliac disease than in patients on a gluten-free diet and in biopsied controls. No difference was found between treated patients and biopsied controls. There was a significant overall correlation between plasma enzyme activity and surface to volume ratio of jejunal mucosa, although two untreated patients without an overt malabsorption syndrome but with a very low surface to volume ratio had normal enzyme activity. This study shows that in coeliac disease plasma diamine oxidase activity after treatment with heparin does not always mirror the extent of the jejunal lesions, particularly in those patients with minimal or unrelated symptoms who would benefit most from a valid screening test to identify their condition. PMID:2511229

  13. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease.

    PubMed

    Wu, Weibin; Zhu, Bo; Peng, Xiaomin; Zhou, Meiling; Jia, Dongwei; Gu, Jianxin

    2014-01-01

    Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients. PMID:24269813

  14. Inhibition of histone deacetylase 6 activity reduces cyst growth in polycystic kidney disease.

    PubMed

    Cebotaru, Liudmila; Liu, Qiangni; Yanda, Murali K; Boinot, Clement; Outeda, Patricia; Huso, David L; Watnick, Terry; Guggino, William B; Cebotaru, Valeriu

    2016-07-01

    Abnormal proliferation of cyst-lining epithelium and increased intracystic fluid secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) are thought to contribute to cyst growth in autosomal dominant polycystic kidney disease (ADPKD). Histone deacetylase 6 (HDAC6) expression and activity are increased in certain cancers, neurodegenerative diseases, and in Pkd1-mutant renal epithelial cells. Inhibition of HDAC6 activity with specific inhibitors slows cancer growth. Here we studied the effect of tubacin, a specific HDAC6 inhibitor, on cyst growth in polycystic kidney disease. Treatment with tubacin prevented cyst formation in MDCK cells, an in vitro model of cystogenesis. Cyclic AMP stimulates cell proliferation and activates intracystic CFTR-mediated chloride secretion in ADPKD. Treatment with tubacin downregulated cyclic AMP levels, inhibited cell proliferation, and inhibited cyclic AMP-activated CFTR chloride currents in MDCK cells. We also found that tubacin reduced cyst growth by inhibiting proliferation of cyst-lining epithelial cells, downregulated cyclic AMP levels, and improved renal function in a Pkd1-conditional mouse model of ADPKD. Thus, HDAC6 could play a role in cyst formation and could serve as a potential therapeutic target in ADPKD. PMID:27165822

  15. Evaluation of disease activity in rheumatic patients by leucocyte adhesiveness/aggregation.

    PubMed Central

    Berliner, S; Fried, M; Caspi, D; Weinberger, A; Yaron, M; Pinkhas, J; Aronson, M

    1988-01-01

    Previous work has shown that leucocyte adhesiveness/aggregation (LAA), as measured by the leukergy test, correlates well with disease severity in rheumatic patients. As LAA is probably a manifestation of the acute phase reaction various components of the acute phase reaction were measured in order to identify the best marker of disease activity. In addition to LAA, the following variables were measured in 79 patients with various rheumatic diseases and in 10 controls: white blood cell and platelet counts, erythrocyte sedimentation rate, haptoglobin, fibrinogen, C reactive protein, albumin, globulin, caeruloplasmin, alpha 1, alpha 2, beta, and gamma globulin, and haemoglobin concentrations. Patients were graded according to the state of their disease as mild, moderate, or severe. The extent of leucocyte adhesiveness/aggregation in peripheral blood proved to be the best laboratory variable for the grading of disease activity. Correct grading was obtained in 63% of the patients by means of the LAA, compared with 48% with C reactive protein, 41% with caeruloplasmin, 40% with haptoglobin, and 32% with haemoglobin. It is suggested that LAA of the peripheral blood during inflammation may be used as a reliable marker of disease severity. PMID:3260093

  16. REACTIN: Regulatory activity inference of transcription factors underlying human diseases with application to breast cancer

    PubMed Central

    2013-01-01

    Background Genetic alterations of transcription factors (TFs) have been implicated in the tumorigenesis of cancers. In many cancers, alteration of TFs results in aberrant activity of them without changing their gene expression level. Gene expression data from microarray or RNA-seq experiments can capture the expression change of genes, however, it is still challenge to reveal the activity change of TFs. Results Here we propose a method, called REACTIN (REgulatory ACTivity INference), which integrates TF binding data with gene expression data to identify TFs with significantly differential activity between disease and normal samples. REACTIN successfully detect differential activity of estrogen receptor (ER) between ER+ and ER- samples in 10 breast cancer datasets. When applied to compare tumor and normal breast samples, it reveals TFs that are critical for carcinogenesis of breast cancer. Moreover, Reaction can be utilized to identify transcriptional programs that are predictive to patient survival time of breast cancer patients. Conclusions REACTIN provides a useful tool to investigate regulatory programs underlying a biological process providing the related case and control gene expression data. Considering the enormous amount of cancer gene expression data and the increasingly accumulating ChIP-seq data, we expect wide application of REACTIN for revealing the regulatory mechanisms of various diseases. PMID:23885756

  17. No association of tobacco use and disease activity in multiple sclerosis

    PubMed Central

    Myhr, Kjell-Morten; Holmøy, Trygve; Benth, Jūratė Šaltytė; Løken-Amsrud, Kristin I.; Wergeland, Stig; Beiske, Antonie G.; Bjerve, Kristian S.; Hovdal, Harald; Lilleås, Finn; Midgard, Rune; Pedersen, Tom; Bakke, Søren J.; Torkildsen, Øivind

    2016-01-01

    Objective: To study whether tobacco use is associated with MRI and clinical disease activity in patients with multiple sclerosis (MS). Methods: Prospective cohort study of 87 patients with relapsing-remitting MS originally included in a randomized placebo-controlled trial of omega-3 fatty acids in MS (the OFAMS Study). Serum levels of cotinine (biomarker of tobacco use) were analyzed at baseline and every 6 months for 2 years. MRI activity was assessed at baseline and monthly for 9 months and after 12 and 24 months. Results: Fifty-three patients (61%) had serum cotinine levels ≥85 nmol/L on ≥60% of the measurements and were considered tobacco users and 34 (39%) had cotinine levels <85 nmol/L, consistent with non–tobacco use. There was no association between tobacco use and the occurrence of new gadolinium-enhancing T1 lesions, new or enlarging T2 lesions, or their aggregate (combined unique activity). Furthermore, there was no association between cotinine levels and MRI activity for the tobacco users, and tobacco users did not have more relapses or Expanded Disability Status Scale progression. Conclusion: Our results indicate that tobacco use does not directly influence MRI activity or relapse rate in MS. This may implicate that the reported association between smoking and MS disease progression could be mediated through other mechanisms. PMID:27458599

  18. S100A9 is a Biliary Protein Marker of Disease Activity in Primary Sclerosing Cholangitis

    PubMed Central

    Ruppert, Thomas; Giese, Thomas; Flechtenmacher, Christa; Weiss, Karl Heinz; Kloeters-Plachky, Petra; Stremmel, Wolfgang; Schirmacher, Peter; Sauer, Peter; Gotthardt, Daniel Nils

    2012-01-01

    Background and Aims Bile analysis has the potential to serve as a surrogate marker for inflammatory and neoplastic disorders of the biliary epithelium and may provide insight into biliary pathophysiology and possible diagnostic markers. We aimed to identify biliary protein markers of patients with primary sclerosing cholangitis (PSC) by a proteomic approach. Methods Bile duct-derived bile samples were collected from PSC patients (n = 45) or patients with choledocholithiasis (n = 24, the control group). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was performed to analyse the proteins, 2-D-gel patterns were compared by densitometry, and brush cytology specimens were analysed by RT-PCR. Results A reference bile-duct bile proteome was established in the control group without signs of inflammation or maligancy comprising a total of 379 non-redundant biliary proteins; 21% were of unknown function and 24% had been previously described in serum. In PSC patients, the biliary S100A9 expression was elevated 95-fold (p<0.005), serum protein expression was decreased, and pancreatic enzyme expression was unchanged compared to controls. The S100A9 expression was 2-fold higher in PSC patients with high disease activity than in those with low activity (p<0.05). The brush cytology specimens from the PSC patients with high disease activity showed marked inflammatory activity and leukocyte infiltration compared to the patients with low activity, which correlated with S100A9 mRNA expression (p<0.05). Conclusions The bile-duct bile proteome is complex and its analysis might enhance the understanding of cholestatic liver disease. Biliary S100A9 levels may be a useful marker for PSC activity, and its implication in inflammation and carcinogenesis warrants further investigation. PMID:22253789

  19. Coagulation Activation in Children with Sickle Cell Disease Is Associated with Cerebral Small Vessel Vasculopathy

    PubMed Central

    Colombatti, Raffaella; De Bon, Emiliano; Bertomoro, Antonella; Casonato, Alessandra; Pontara, Elena; Omenetto, Elisabetta; Saggiorato, Graziella; Steffan, Agostino; Damian, Tamara; Cella, Giuseppe; Teso, Simone; Manara, Renzo; Rampazzo, Patrizia; Meneghetti, Giorgio; Basso, Giuseppe; Sartori, Maria Teresa; Sainati, Laura

    2013-01-01

    Background Thrombotic complications in Sickle Cell Disease (SCD) arise since infancy, but the role of the coagulation system in children has been poorly explored. To determine its role in the development of clinical complications in childhood we measured coagulation and endothelial parameters in children with SCD at steady state. Methods Markers of thrombin generation, fibrin dissolution and endothelial activation were evaluated in 38 children with SS-Sβ°, 6 with SC disease and 50 age and blood group matched controls. Coagulation variables were correlated with markers of hemolysis and inflammation, with the presence of cerebral and lung vasculopathy and with the frequency of clinical complications. Results SS-Sβ° patients presented higher levels of factor VIII, von Willebrand factor antigen (VWF:Ag) and collagen binding activity, tissue plasminogen activator antigen (t-PA:Ag), D-dimer, p-selectin, prothrombin fragment1+2 (F1+2) and lower ADAMTS-13:activity/VWF:Ag (p<0.05) compared to controls and SC patients. In SS-Sβ° patients coagulation variables correlated positively with markers of inflammation, hemolysis, and negatively with HbF (p<0.05). Patients with cerebral silent infarcts showed significant decrease in t-PA:Ag and ADAMTS-13 Antigen and a tendency toward higher D-dimer, F1+2, TAT compared to patients without them. D-dimer was associated with a six fold increased risk of cerebral silent infarcts. No correlation was found between coagulation activation and large vessel vasculopathy or other clinical events except for decreased t-PA:Ag in patients with tricuspid Rigurgitant Velocity >2.5m/sec. Conclusions SS-Sβ° disease is associated with extensive activation of the coagulation system at steady state since young age. ADAMTS-13 and t-PA:Ag are involved in the development of cerebral silent infarcts. PMID:24205317

  20. Sec63 and Xbp1 regulate IRE1α activity and polycystic disease severity

    PubMed Central

    Fedeles, Sorin V.; So, Jae-Seon; Shrikhande, Amol; Lee, Seung Hun; Gallagher, Anna-Rachel; Barkauskas, Christina E.; Somlo, Stefan; Lee, Ann-Hwee

    2015-01-01

    The HSP40 cochaperone SEC63 is associated with the SEC61 translocon complex in the ER. Mutations in the gene encoding SEC63 cause polycystic liver disease in humans; however, it is not clear how altered SEC63 influences disease manifestations. In mice, loss of SEC63 induces cyst formation both in liver and kidney as the result of reduced polycystin-1 (PC1). Here we report that inactivation of SEC63 induces an unfolded protein response (UPR) pathway that is protective against cyst formation. Specifically, using murine genetic models, we determined that SEC63 deficiency selectively activates the IRE1α-XBP1 branch of UPR and that SEC63 exists in a complex with PC1. Concomitant inactivation of both SEC63 and XBP1 exacerbated the polycystic kidney phenotype in mice by markedly suppressing cleavage at the G protein–coupled receptor proteolysis site (GPS) in PC1. Enforced expression of spliced XBP1 (XBP1s) enhanced GPS cleavage of PC1 in SEC63-deficient cells, and XBP1 overexpression in vivo ameliorated cystic disease in a murine model with reduced PC1 function that is unrelated to SEC63 inactivation. Collectively, the findings show that SEC63 function regulates IRE1α/XBP1 activation, SEC63 and XBP1 are required for GPS cleavage and maturation of PC1, and activation of XBP1 can protect against polycystic disease in the setting of impaired biogenesis of PC1. PMID:25844898

  1. Activity and school attendance monitoring system for adolescents with sickle cell disease.

    PubMed

    Venugopalan, Janani; Brown, Clark; Cheng, Chihwen; Stokes, Todd H; Wang, May D

    2012-01-01

    Sickle cell disease, the most common hemoglobin disorder, affects major organ systems with symptoms of pain, anemia and a multitude of chronic conditions. For adolescents, the disease adversely affects school attendance, academic progress and social activity. To effectively study the relationship among school attendance and other factors like demographics and academic performance, studies have relied on self-reporting and school records, all of which have some bias. In this study we design and prototype a system, called SickleSAM (Sickle cell School attendance and Activity Monitoring system), for automatically monitoring school attendance and daily activity of adolescents with sickle cell disease. SickleSAM intends to remove human bias and inaccuracies. The system uses built-in GPS to collect data which will be recorded into a cloud database using Short Messaging Service technology. SickleSAM is developed by Georgia Institute of Technology in conjunction with Children's Healthcare of Atlanta (CHOA). System effectiveness is being evaluated using a trial of 10 adolescents with the disease. PMID:23366422

  2. Unraveling the actions of AMP-activated protein kinase in metabolic diseases: Systemic to molecular insights.

    PubMed

    Weikel, Karen A; Ruderman, Neil B; Cacicedo, José M

    2016-05-01

    AMP-activated protein kinase (AMPK) plays a critical role both in sensing and regulating cellular energy state. In experimental animals, its activation has been shown to reduce the risk of obesity and diabetes-related co-morbidities such as insulin resistance, the metabolic syndrome and atherosclerotic cardiovascular disease. However, in humans, AMPK activation alone often does not completely resolve these conditions. Thus, an improved understanding of AMPK action and regulation in metabolic and other diseases is needed. Herein, we provide a brief description of the enzymatic regulation of AMPK and review its role in maintaining energy homeostasis. We then discuss tissue-specific actions of AMPK that become distorted during such conditions as obesity, type 2 diabetes and certain cancers. Finally, we explore recent findings regarding the interactions of AMPK with mammalian target of rapamycin complex 1 and the lysosome and discuss how changes in these relationships during overnutrition may lead to AMPK dysfunction. A more thorough understanding of AMPK's molecular interactions during diseases of overnutrition may provide key insights for the development of AMPK-based combinatorial treatments for metabolic disease. PMID:27085772

  3. Mitotic activation: a convergent mechanism for a cohort of neurodegenerative diseases.

    PubMed

    Husseman, J W; Nochlin, D; Vincent, I

    2000-01-01

    Previous evidence from our lab and others has implicated the mitotic cdc2/cyclin B1 kinase in the neurofibrillary degeneration of Alzheimer's disease. To examine the specificity of this relationship, and define conditions leading to atypical activation of mitotic kinase in postmitotic neurons, we have applied antibodies specific for the cdc2 kinase, its activator, cyclin B1, and three cdc2 produced phosphoepitopes: the TG-3 phosphoepitope in tau and nucleolin, the MPM-2 phosphoepitope in a variety of substrates, and the H5 phosphoepitope in RNA polymerase II, to affected brain regions from a spectrum of neurodegenerative disorders. Our results demonstrate that neurons containing characteristic lesions in a subset of diseases including Down Syndrome (DS), Frontotemporal Dementia linked to chromosome 17 (FTD-17), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Parkinson-Amyotrophic Lateral Sclerosis of Guam (GP-ALS), Niemann Pick disease type C (NPDC), and Pick's disease, display mitotic indices, implicating diverse etiologies in mitotic activation. The convergence of various degenerative schemes into a unified mitotic kinase-driven pathway provides a common target for therapeutic treatment of these different disorders. PMID:11124425

  4. Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington's disease.

    PubMed

    Ramsingh, Arlene I; Manley, Kevin; Rong, Yinghui; Reilly, Andrew; Messer, Anne

    2015-11-01

    Immunotherapy, both active and passive, is increasingly recognized as a powerful approach to a wide range of diseases, including Alzheimer's and Parkinson's. Huntington's disease (HD), an autosomal dominant disorder triggered by misfolding of huntingtin (HTT) protein with an expanded polyglutamine tract, could also benefit from this approach. Individuals can be identified genetically at the earliest stages of disease, and there may be particular benefits to a therapy that can target peripheral tissues in addition to brain. In this active vaccination study, we first examined safety and immunogenicity for a broad series of peptide, protein and DNA plasmid immunization protocols, using fragment (R6/1), and knock-in (zQ175) models. No safety issues were found. The strongest and most uniform immune response was to a combination of three non-overlapping HTT Exon1 coded peptides, conjugated to KLH, delivered with alum adjuvant. An N586-82Q plasmid, delivered via gene gun, also showed ELISA responses, mainly in the zQ175 strain, but with more variability, and less robust responses in HD compared with wild-type controls. Transcriptome profiling of spleens from the triple peptide-immunized cohort showed substantial HD-specific differences including differential activation of genes associated with innate immune responses, absence of negative feedback control of gene expression by regulators, a temporal dysregulation of innate immune responses and transcriptional repression of genes associated with memory T cell responses. These studies highlight critical issues for immunotherapy and HD disease management in general. PMID:26307082

  5. Raised serum level of APRIL in patients with systemic lupus erythematosus: correlations with disease activity indices.

    PubMed

    Hegazy, M; Darwish, H; Darweesh, H; El-Shehaby, A; Emad, Y

    2010-04-01

    The aim of the present study is to assess serum APRIL levels in SLE patients versus rheumatoid arthritis (RA) patients and normal control and to correlate serum APRIL levels in SLE patients with disease activity indices. Serum APRIL levels was measured in 40 SLE patients, 20 patients with RA and 20 healthy volunteers who served as control group. Disease activity in SLE patients was assessed by the British Isles Lupus Assessment Group (BILAG) index and SLE disease activity index (SLEDAI), and results were correlated with serum APRIL levels. Significantly higher serum APRIL levels was observed in SLE patients compared to RA patients and normal controls (p=0.003 and p < or = 0.001, respectively). Positive correlations were found between serum APRIL levels and total BILAG index (r=0.486 and p=0.001), BILAG musculoskeletal score (r=0.848 and p < or = 0.001) and BILAG cardiorespiratory score (r=0.326 and 0.04). Serum APRIL was higher in SLE patients compared to RA patients and normal control subjects and positively correlates with BILAG index and higher levels may be associated with musculoskeletal manifestations of the disease. APRIL antagonism could be a potential therapeutic target in SLE. PMID:20116334

  6. Activity and School Attendance Monitoring System for Adolescents with Sickle Cell Disease

    PubMed Central

    Venugopalan, Janani; Brown, Clark; Cheng, Chihwen; Stokes, Todd H.; Wang, May D.

    2016-01-01

    Sickle cell disease, the most common hemoglobin disorder, affects major organ systems with symptoms of pain, anemia and a multitude of chronic conditions. For adolescents, the disease adversely affects school attendance, academic progress and social activity. To effectively study the relationship among school attendance and other factors like demographics and academic performance, studies have relied on self-reporting and school records, all of which have some bias. In this study we design and prototype a system, called SickleSAM (Sickle cell School attendance and Activity Monitoring system), for automatically monitoring school attendance and daily activity of adolescents with sickle cell disease. SickleSAM intends to remove human bias and inaccuracies. The system uses built-in GPS to collect data which will be recorded into a cloud database using Short Messaging Service technology. SickleSAM is developed by Georgia Institute of Technology in conjunction with Children's Healthcare of Atlanta (CHOA). System effectiveness is being evaluated using a trial of 10 adolescents with the disease. PMID:23366422

  7. Niemann-Pick disease: prenatal diagnoses and studies of sphingomyelinase activities.

    PubMed

    Wenger, D A; Wharton, C; Sattler, M; Clark, C

    1978-01-01

    Five pregnancies were monitored for couples at-risk for having a child with some form of Niemann-Pick disease (NPD). Three of these were for the classic Type A form in which affected children usually have less than 1% of normal sphingomyelinase activity. Two of these pregnancies were terminated after the cultured amniotic-fluid cells were determined to have less than 1% of normal sphingomyelinase activity (0.4 and 0.6 nmole/mg protein/hr versus the control mean of 61.7). In the other pregnancy at risk for Type A NPD near normal activity was measured and it was continued to term. The two other pregnancies were monitored for couples in which severely affected children were found to have partially deficient sphingomyelinase activity (about 20% of normal) in cultured skin fibroblasts. Cultural amniotic-fluid cells from one of these pregnancies also had about 20% of control sphingomyelinase activity, but the woman underwent a spontaneous abortion soon after the cells were received and no studies on the fetus were done. The other sample was taken at the time of abortion for social reasons. In this case the cultured amniotic-fluid cells and cultured fetal skin fibroblasts gave normal sphingomyelinase activity. Enzymatic studies on tissues from the two fetuses predicted to be affected with Type A NPD confirmed the prenatal diagnosis. Studies of sphingomyelinase activity in the brains from these fetuses and from a child who died with Type A NPD indicated significant levels of activity when measured at pH 7.4 in the presence of magnesium. The higher level of the pH 7.4 sphingomyelinase activity in developing brain may indicate some important role in normal brain development. PMID:233699

  8. Mitochondrial superoxide flashes: metabolic biomarkers of skeletal muscle activity and disease

    PubMed Central

    Wei, Lan; Salahura, Gheorghe; Boncompagni, Simona; Kasischke, Karl A.; Protasi, Feliciano; Sheu, Shey-Shing; Dirksen, Robert T.

    2011-01-01

    Mitochondrial superoxide flashes (mSOFs) are stochastic events of quantal mitochondrial superoxide generation. Here, we used flexor digitorum brevis muscle fibers from transgenic mice with muscle-specific expression of a novel mitochondrial-targeted superoxide biosensor (mt-cpYFP) to characterize mSOF activity in skeletal muscle at rest, following intense activity, and under pathological conditions. Results demonstrate that mSOF activity in muscle depended on electron transport chain and adenine nucleotide translocase functionality, but it was independent of cyclophilin-D-mediated mitochondrial permeability transition pore activity. The diverse spatial dimensions of individual mSOF events were found to reflect a complex underlying morphology of the mitochondrial network, as examined by electron microscopy. Muscle activity regulated mSOF activity in a biphasic manner. Specifically, mSOF frequency was significantly increased following brief tetanic stimulation (18.1±1.6 to 22.3±2.0 flashes/1000 μm2·100 s before and after 5 tetani) and markedly decreased (to 7.7±1.6 flashes/1000 μm2·100 s) following prolonged tetanic stimulation (40 tetani). A significant temperature-dependent increase in mSOF frequency (11.9±0.8 and 19.8±2.6 flashes/1000 μm2·100 s at 23°C and 37°C) was observed in fibers from RYR1Y522S/WT mice, a mouse model of malignant hyperthermia and heat-induced hypermetabolism. Together, these results demonstrate that mSOF activity is a highly sensitive biomarker of mitochondrial respiration and the cellular metabolic state of muscle during physiological activity and pathological oxidative stress.—Wei, L., Salahura, G., Boncompagni, S., Kasischke, K. A., Protasi, F., Sheu, S.-S., Dirksen, R. T. Mitochondrial superoxide flashes: metabolic biomarkers of skeletal muscle activity and disease. PMID:21646399

  9. Adjunctive use of systematic retinal thickness map analysis to monitor disease activity in punctate inner choroidopathy.

    PubMed

    Madhusudhan, Savitha; Keane, Pearse A; Denniston, Alastair K

    2016-12-01

    A challenge in the management of 'white dot syndromes' is the lack of sensitive objective measures of disease activity. Retinal thickness maps from spectral domain optical coherence tomography (SD-OCT) inform treatment decisions in other retinal conditions such as age-related macular degeneration and diabetic maculopathy. In this report, we demonstrate their value in providing quantitative monitoring of a patient with punctate inner choroidopathy (PIC). Retinal thickness maps referenced against a baseline scan reliably detected focal areas of increased macular volume in active PIC lesions during symptomatic episodes, highlighting these as 'hot spots' that could be quantified, providing an objective basis for treatment decisions. PMID:26965893

  10. Activation of benign autoimmunity as both tumor and autoimmune disease immunotherapy: a comprehensive review.

    PubMed

    Cohen, Irun R

    2014-11-01

    Here, I consider how benign autoimmunity, the immunological homunculus, can be used to reinstate the healthy regulation of inflammation in both autoimmune diseases and in tumor immunotherapy. Different autoimmune diseases manifest clinically distinct phenotypes, but, in general, they all result from the transition of benign, healthy recognition of key body molecules into a damaging effector reaction. Tumors, in contrast to autoimmune diseases, grow by subverting the immune system into supporting and protecting the growing tumor from immune surveillance. Therefore our therapeutic aim in autoimmune disease is to induce the immune system to down-regulate the specific autoimmune effector reaction that causes the disease; in tumor immunotherapy, on the contrary, we aim to deprive the growing tumor of its illicit activation of immune suppression and to unleash an autoimmune disease targeted to the tumor. The recent success of anti-PD1 and anti-CTLR4 treatments exemplify the reinstatement of tumor autoimmunity subsequent to inhibition of immune suppression. With regard to the therapy of autoimmune diseases, I cite examples of immune system down-regulation of autoimmune diseases by T cell vaccination or HSP60 peptide treatment. Inducing the immune system to regulate itself is safer than global immune suppression and may be more effective in the long run. PMID:24924121

  11. Chronic active destructive herpes simplex encephalitis with recovery of viral DNA 12 years after disease onset.

    PubMed

    Asenbauer, B; McEntagart, M; King, M D; Gallagher, P; Burke, M; Farrell, M A

    1998-06-01

    Acute herpes simplex encephalitis (HSE) carries significant morbidity and mortality even after early treatment with antiviral agents (7). As well as causing acute neurological disease, Herpes viruses are associated with relapsing--remitting (Varicella--Zoster, Epstein-Barr) and chronic (Rasmussen encephalitis) disease processes (1). A two-year-old girl developed acute HSE which was followed by a 10-year neurologic illness characterised by asymmetric spastic tetraparesis, pseudobulbar palsy, the opercular syndrome of Foix-Chavany-Marie (4) and seizures. The neurological signs remained static until the child died suddenly 12 years after disease onset. Neuropathologic examination demonstrated active chronic encephalitis. Herpes simplex virus (HSV) DNA was recovered from formalin-fixed paraffin-embedded brain tissue. This case provides additional evidence for the development of chronic neurological disease attributable to persistence of herpes simplex virus type 1. PMID:9706620

  12. Rosai-Dorfman Disease Harboring an Activating KRAS K117N Missense Mutation.

    PubMed

    Shanmugam, Vignesh; Margolskee, Elizabeth; Kluk, Michael; Giorgadze, Tamara; Orazi, Attilio

    2016-09-01

    Rosai-Dorfman disease (RDD) or sinus histiocytosis with massive lymphadenopathy is a rare histiocytic proliferation that is generally considered to be reactive with a benign clinical course. The etiology of RDD is very poorly understood. Recent studies have shown frequent BRAF, NRAS, KRAS, and PIK3CA activating mutations in several histiocytic neoplasms highlighting the emerging importance of the RAF/MEK/ERK pathway in the pathogenesis of these diseases. Here we report a case of Rosai-Dorfman disease involving the submandibular salivary gland with a KRAS K117N missense mutation discovered by next-generation sequencing. These results suggest that at least a subset of RDD cases may be clonal processes. Further mutational studies on this rare histiocytic disease should be undertaken to better characterize its pathogenesis as well as open up potential avenues for therapy. PMID:26922062

  13. Acetylcholinesterase activity in CSF in schizophrenia, depression, Alzheimer's disease and normals.

    PubMed

    Deutsch, S I; Mohs, R C; Levy, M I; Rothpearl, A B; Stockton, D; Horvath, T; Coco, A; Davis, K L

    1983-12-01

    Acetylcholinesterase (AChE) activity and protein were measured in the CSF of patients with Alzheimer's disease, depression, schizophrenia with and without tardive dyskinesia, and control subjects. AChE activity was assayed by a radioenzymatic method involving the direct extraction of hydrolyzed 3H-acetate into a toluene-based scintillation fluid followed by liquid scintillation spectrometry. AChE activity was proportional to the amount of CSF protein. Greater than 90% of AChE activity in CSF could be inhibited by 10(-3) M eserine. In addition, activity remained stable despite repeated freeze-thawing in an acetone-dry ice bath. Age was found to be positively correlated with CSF protein and AChE activity expressed per volume CSF, but not with AChE measured per milligram protein. No differences between diagnostic groups were found on either measure of AChE when the extraneous factors of age and CSF protein concentrations were controlled, nor were any differences found between groups for CSF protein when age was controlled. PMID:6661467

  14. Surveillance for Neisseria meningitidis Disease Activity and Transmission Using Information Technology

    PubMed Central

    Ahmed, S. Sohail; Oviedo-Orta, Ernesto; Mekaru, Sumiko R.; Freifeld, Clark C.; Tougas, Gervais; Brownstein, John S.

    2015-01-01

    Background While formal reporting, surveillance, and response structures remain essential to protecting public health, a new generation of freely accessible, online, and real-time informatics tools for disease tracking are expanding the ability to raise earlier public awareness of emerging disease threats. The rationale for this study is to test the hypothesis that the HealthMap informatics tools can complement epidemiological data captured by traditional surveillance monitoring systems for meningitis due to Neisseria meningitides (N. meningitides) by highlighting severe transmissible disease activity and outbreaks in the United States. Methods Annual analyses of N. meningitides disease alerts captured by HealthMap were compared to epidemiological data captured by the Centers for Disease Control’s Active Bacterial Core surveillance (ABCs) for N. meningitides. Morbidity and mortality case reports were measured annually from 2010 to 2013 (HealthMap) and 2005 to 2012 (ABCs). Findings HealthMap N. meningitides monitoring captured 80-90% of alerts as diagnosed N. meningitides, 5-20% of alerts as suspected cases, and 5-10% of alerts as related news articles. HealthMap disease alert activity for emerging disease threats related to N. meningitides were in agreement with patterns identified historically using traditional surveillance systems. HealthMap’s strength lies in its ability to provide a cumulative “snapshot” of weak signals that allows for rapid dissemination of knowledge and earlier public awareness of potential outbreak status while formal testing and confirmation for specific serotypes is ongoing by public health authorities. Conclusions The underreporting of disease cases in internet-based data streaming makes inadequate any comparison to epidemiological trends illustrated by the more comprehensive ABCs network published by the Centers for Disease Control. However, the expected delays in compiling confirmatory reports by traditional surveillance systems

  15. Serotonin content of platelets in inflammatory rheumatic diseases. Correlation with clinical activity.

    PubMed

    Zeller, J; Weissbarth, E; Baruth, B; Mielke, H; Deicher, H

    1983-04-01

    Significantly decreased platelet serotonin contents were measured in rheumatoid arthritis, systemic lupus erythematosus (SLE), progressive systemic sclerosis, and mixed connective tissue disease. An inverse relationship between platelet serotonin levels and clinical disease activity was observed in both rheumatoid arthritis and systemic lupus erythematosus. SLE patients with multiple organ involvement showed the lowest platelet serotonin values. No correlation was observed between platelet serotonin contents and nonsteroidal antiinflammatory drug treatment, presence of circulating platelet reactive IgG, or the amount of circulating immune complexes. The results are interpreted as indicating platelet release occurring in vivo during inflammatory episodes of the rheumatic disorders investigated. PMID:6838676

  16. Repurposing psychiatric medicines to target activated microglia in anxious mild cognitive impairment and early Parkinson's disease.

    PubMed

    Lauterbach, Edward C

    2016-01-01

    Anxiety is common in the Mild Cognitive Impairment (MCI) stage of Alzheimer's disease (AD) and the pre-motor stages of Parkinson's disease (PD). A concomitant and possible cause of this anxiety is microglial activation, also considered a key promoter of neurodegeneration in MCI and early PD via inflammatory mechanisms and the generation of degenerative proinflammatory cytokines. Psychiatric disorders, prevalent in AD and PD, are often treated with psychiatric drugs (psychotropics), raising the question of whether psychotropics might therapeutically affect microglial activation, MCI, and PD. The literature of common psychotropics used in treating psychiatric disorders was reviewed for preclinical and clinical findings regarding microglial activation. Findings potentially compatible with reduced microglial activation or reduced microglial inflammogen release were evident for: antipsychotics including neuroleptics (chlorpromazine, thioridazine, loxapine) and atypicals (aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone); mood stabilizers (carbamazepine, valproate, lithium); antidepressants including tricyclics (amitriptyline, clomipramine, imipramine, nortriptyline), SSRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline), venlafaxine, and bupropion; benzodiazepine anxiolytics (clonazepam, diazepam); cognitive enhancers (donepezil, galantamine, memantine); and other drugs (dextromethorphan, quinidine, amantadine). In contrast, pramipexole and methylphenidate might promote microglial activation. The most promising replicated findings of reduced microglial activation are for quetiapine, valproate, lithium, fluoxetine, donepezil, and memantine but further study is needed and translation of their microglial effects to human disease still requires investigation. In AD-relevant models, risperidone, valproate, lithium, fluoxetine, bupropion, donepezil, and memantine have therapeutic microglial effects in need of replication. Limited

  17. Long-term assessment of No Evidence of Disease Activity with natalizumab in relapsing multiple sclerosis.

    PubMed

    Prosperini, Luca; Fanelli, Fulvia; Pozzilli, Carlo

    2016-05-15

    In this study we assessed the proportion of patients with relapsing multiple sclerosis (R-MS) who had No Evidence of Disease Activity (NEDA-3), defined as absence of relapses, absence of confirmed disability worsening, and absence of radiological activity (detected by magnetic resonance imaging of the brain and spinal cord) up to 7years after starting natalizumab. Out of 152 patients considered, 58 were still on treatment and 94 discontinued treatment after a median time of 3years. According to an intention-to-treat approach, 52 (34%) patients maintained the NEDA status at the end of follow-up. The proportion of patients with NEDA increases to 41% after excluding from the analysis 64 patients who discontinued natalizumab due to concerns about progressive multifocal leukoencephalopathy. Our findings suggest that natalizumab may ensure higher proportion of patients achieving sustained long-term disease remission than that previously reported with self-injectable treatments (<10%). PMID:27084235

  18. MicroRNAs Control Macrophage Formation and Activation: The Inflammatory Link between Obesity and Cardiovascular Diseases

    PubMed Central

    Chang, Richard Cheng-An; Ying, Wei; Bazer, Fuller W.; Zhou, Beiyan

    2014-01-01

    Activation and recruitment of resident macrophages in tissues in response to physiological stress are crucial regulatory processes in promoting the development of obesity-associated metabolic disorders and cardiovascular diseases. Recent studies have provided compelling evidence that microRNAs play important roles in modulating monocyte formation, macrophage maturation, infiltration into tissues and activation. Macrophage-dependent systemic physiological and tissue-specific responses also involve cell-cell interactions between macrophages and host tissue niche cell components, including other tissue-resident immune cell lineages, adipocytes, vascular smooth muscle and others. In this review, we highlight the roles of microRNAs in regulating the development and function of macrophages in the context of obesity, which could provide insights into the pathogenesis of obesity-related metabolic syndrome and cardiovascular diseases. PMID:25014161

  19. Two Analogues of Fenarimol Show Curative Activity in an Experimental Model of Chagas Disease

    PubMed Central

    2013-01-01

    Chagas disease, caused by the protozoan parasite Trypanosoma cruzi (T. cruzi), is an increasing threat to global health. Available medicines were introduced over 40 years ago, have undesirable side effects, and give equivocal results of cure in the chronic stage of the disease. We report the development of two compounds, 6 and (S)-7, with PCR-confirmed curative activity in a mouse model of established T. cruzi infection after once daily oral dosing for 20 days at 20 mg/kg 6 and 10 mg/kg (S)-7. Compounds 6 and (S)-7 have potent in vitro activity, are noncytotoxic, show no adverse effects in vivo following repeat dosing, are prepared by a short synthetic route, and have druglike properties suitable for preclinical development. PMID:24304150

  20. Elevated serum interleukin-23 levels in ankylosing spondylitis patients and the relationship with disease activity

    PubMed Central

    Ugur, Mahir; Baygutalp, Nurcan Kilic; Melikoglu, Meltem Alkan; Baygutalp, Fatih; Altas, Elif Umay; Seferoglu, Buminhan

    2015-01-01

    ABSTRACT This study was aimed to evaluate the relationship between serum interleukin-23 (IL-23) levels and ankylosing spondylitis (AS).Twenty male patients diagnosed with ankylosing spondylitis according to the 1984 modified New York criteria for AS and twenty male healthy controls were included in this study.The demographic characteristics, clinical and laboratory findings of the patients were recorded. Serum IL-23 levels, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were measured in both the AS and control groups. The Bath ankylosing spondylitis disease activity ındex (BASDAI), the Bath ankylosing spondylitis functional index (BASFI), and the Bath ankylosing spondylitis metrology index (BASMI) were evaluated as disease activity parameters. The AS patients were divided into two subgroups as active and inactive in respect of CRP, ESR levels and BASDAI scores. The mean serum IL-23 levels of the AS and control groups were 334.45±176.54 pg/ml and 166.49±177.50 pg/ml respectively, and there was a significant difference between the groups. Correlation analysis of serum IL-23 levels with clinical and laboratory parameters showed that there were positive correlations between serum IL-23 levels and the BASDAI, BASFI scores in total, active and inactive patients and the BASMI scores in total and inactive patients and negative correlations between serum IL-23 levels and ESR in inactive patients. It was shown that altered serum IL-23 levels were related to AS disease activity. Further studies in large patient series are necessary to investigate the role of IL-23 protein in etiopathogenesis of AS. PMID:26663940

  1. FOXP3+Helios+ Regulatory T Cells, Immune Activation, and Advancing Disease in HIV-Infected Children.

    PubMed

    Khaitan, Alka; Kravietz, Adam; Mwamzuka, Mussa; Marshed, Fatma; Ilmet, Tiina; Said, Swalehe; Ahmed, Aabid; Borkowsky, William; Unutmaz, Derya

    2016-08-15

    Regulatory T cells (Tregs) are functionally suppressive CD4 T cells, critical for establishing peripheral tolerance and controlling inflammatory responses. Previous reports of Tregs during chronic HIV disease have conflicting results with higher or lower levels compared with controls. Identifying true Tregs with suppressive activity proves challenging during HIV infection, as traditional Treg markers, CD25 and FOXP3, may transiently upregulate expression as a result of immune activation (IA). Helios is an Ikaros family transcription factor that marks natural Tregs with suppressive activity and does not upregulate expression after activation. Coexpression of FOXP3 and Helios has been suggested as a highly specific marker of "bona fide" Tregs. We evaluated Treg subsets by FOXP3 coexpressed with either CD25 or Helios and their association with HIV disease progression in perinatally infected HIV-positive children. Identifying Tregs by FOXP3 coexpression with Helios rather than CD25 revealed markedly higher Treg frequencies, particularly in HIV+ children. Regardless of antiretroviral therapy, HIV-infected children had a selective expansion of memory FOXP3+Helios+ Tregs. The rise in memory Tregs correlated with declining HIV clinical status, indicated by falling CD4 percentages and CD4:CD8 ratios and increasing HIV plasma viremia and IA. In addition, untreated HIV+ children exhibited an imbalance between the levels of Tregs and activated T cells. Finally, memory Tregs expressed IA markers CD38 and Ki67 and exhaustion marker, PD-1, that tightly correlated with a similar phenotype in memory CD4 T cells. Overall, HIV-infected children had significant disruptions of memory Tregs that associated with advancing HIV disease. PMID:27003495

  2. Decreased glycogen synthase kinase-3 levels and activity contribute to Huntington's disease.

    PubMed

    Fernández-Nogales, Marta; Hernández, Félix; Miguez, Andrés; Alberch, Jordi; Ginés, Silvia; Pérez-Navarro, Esther; Lucas, José J

    2015-09-01

    Huntington's disease (HD) is a hereditary neurodegenerative disorder characterized by brain atrophy particularly in striatum leading to personality changes, chorea and dementia. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase in the crossroad of many signaling pathways that is highly pleiotropic as it phosphorylates more than hundred substrates including structural, metabolic, and signaling proteins. Increased GSK-3 activity is believed to contribute to the pathogenesis of neurodegenerative diseases like Alzheimer's disease and GSK-3 inhibitors have been postulated as therapeutic agents for neurodegeneration. Regarding HD, GSK-3 inhibitors have shown beneficial effects in cell and invertebrate animal models but no evident efficacy in mouse models. Intriguingly, those studies were performed without interrogating GSK-3 level and activity in HD brain. Here we aim to explore the level and also the enzymatic activity of GSK-3 in the striatum and other less affected brain regions of HD patients and of the R6/1 mouse model to then elucidate the possible contribution of its alteration to HD pathogenesis by genetic manipulation in mice. We report a dramatic decrease in GSK-3 levels and activity in striatum and cortex of HD patients with similar results in the mouse model. Correction of the GSK-3 deficit in HD mice, by combining with transgenic mice with conditional GSK-3 expression, resulted in amelioration of their brain atrophy and behavioral motor and learning deficits. Thus, our results demonstrate that decreased brain GSK-3 contributes to HD neurological phenotype and open new therapeutic opportunities based on increasing GSK-3 activity or attenuating the harmful consequences of its decrease. PMID:26082469

  3. Rapid inflammasome activation in microglia contributes to brain disease in HIV/AIDS

    PubMed Central

    2014-01-01

    Background Human immunodeficiency virus type 1(HIV-1) infects and activates innate immune cells in the brain resulting in inflammation and neuronal death with accompanying neurological deficits. Induction of inflammasomes causes cleavage and release of IL-1β and IL-18, representing pathogenic processes that underlie inflammatory diseases although their contribution HIV-associated brain disease is unknown. Results Investigation of inflammasome-associated genes revealed that IL-1β, IL-18 and caspase-1 were induced in brains of HIV-infected persons and detected in brain microglial cells. HIV-1 infection induced pro-IL-1β in human microglia at 4 hr post-infection with peak IL-1β release at 24 hr, which was accompanied by intracellular ASC translocation and caspase-1 activation. HIV-dependent release of IL-1β from a human macrophage cell line, THP-1, was inhibited by NLRP3 deficiency and high extracellular [K+]. Exposure of microglia to HIV-1 gp120 caused IL-1β production and similarly, HIV-1 envelope pseudotyped viral particles induced IL-1β release, unlike VSV-G pseudotyped particles. Infection of cultured feline macrophages by the related lentivirus, feline immunodeficiency virus (FIV), also resulted in the prompt induction of IL-1β. In vivo FIV infection activated multiple inflammasome-associated genes in microglia, which was accompanied by neuronal loss in cerebral cortex and neurological deficits. Multivariate analyses of data from FIV-infected and uninfected animals disclosed that IL-1β, NLRP3 and caspase-1 expression in cerebral cortex represented key molecular determinants of neurological deficits. Conclusions NLRP3 inflammasome activation was an early and integral aspect of lentivirus infection of microglia, which was associated with lentivirus-induced brain disease. Inflammasome activation in the brain might represent a potential target for therapeutic interventions in HIV/AIDS. PMID:24886384

  4. Altered Theta Oscillations and Aberrant Cortical Excitatory Activity in the 5XFAD Model of Alzheimer's Disease

    PubMed Central

    Siwek, Magdalena Elisabeth; Müller, Ralf; Henseler, Christina; Trog, Astrid; Lundt, Andreas; Wormuth, Carola; Broich, Karl; Weiergräber, Marco; Papazoglou, Anna

    2015-01-01

    Alzheimer's disease (AD) is an age-related neurodegenerative disorder characterized by impairment of memory function. The 5XFAD mouse model was analyzed and compared with wild-type (WT) controls for aberrant cortical excitability and hippocampal theta oscillations by using simultaneous video-electroencephalogram (EEG) monitoring. Seizure staging revealed that 5XFAD mice exhibited cortical hyperexcitability whereas controls did not. In addition, 5XFAD mice displayed a significant increase in hippocampal theta activity from the light to dark phase during nonmotor activity. We also observed a reduction in mean theta frequency in 5XFAD mice compared to controls that was again most prominent during nonmotor activity. Transcriptome analysis of hippocampal probes and subsequent qPCR validation revealed an upregulation of Plcd4 that might be indicative of enhanced muscarinic signalling. Our results suggest that 5XFAD mice exhibit altered cortical excitability, hippocampal dysrhythmicity, and potential changes in muscarinic signaling. PMID:25922768

  5. Utility of Consumer Physical Activity Trackers as an Intervention Tool in Cardiovascular Disease Prevention and Treatment.

    PubMed

    Hickey, Amanda M; Freedson, Patty S

    2016-01-01

    Consumer activity trackers have grown in popularity over the last few years. These devices are typically worn on the hip or wrist and provide the user with information about physical activity measures such as steps taken, energy expenditure, and time spent in moderate to vigorous physical activity. The consumer may also use the computer interface (e.g. device websites, smartphone applications) to monitor and track achievement of PA goals and compete with other users. This review will describe some of the most popular consumer devices and discuss the user feedback tools. We will also present the limited evidence available about the accuracy of these devices and highlight how they have been used in cardiovascular disease management. We conclude with some recommendations for future research, focusing on how consumer devices might be used to assess effectiveness of various cardiovascular treatments. PMID:26943981

  6. [Activity and function of neurons in the globus pallidus in Parkinson's disease].

    PubMed

    Marković, L; Sterio, D; Berić, A

    1996-01-01

    We investigated the activity and functional distribution of globus pallidus neurons in Parkinson's disease patients and recorded single cell activity of globus pallidus medialis and changes related to the movements of different joints in 31 patients during stereotactic ventral pallidotomy procedure. We showed that discharge rates of 19% of medial globus pallidus neurons were modulated by passive contralateral movements; 77.2% of these pallidal units showed changes related solely to single joint movement and 22.8% showed different patterns of activity in relation to two and more joints. We also identified somatotopically arranged cell clusters that alter the discharge rate with related movements; oro-facial movement-related cells in caudo-ventral region and, leg-related cells in dorso-rostral part and arm-related cells between these two parts of medial globus pallidus. These findings suggest a partial somatotopic organization of human globus pallidus medialis. PMID:8643063

  7. Validity of activity monitors in health and chronic disease: a systematic review

    PubMed Central

    2012-01-01

    The assessment of physical activity in healthy populations and in those with chronic diseases is challenging. The aim of this systematic review was to identify whether available activity monitors (AM) have been appropriately validated for use in assessing physical activity in these groups. Following a systematic literature search we found 134 papers meeting the inclusion criteria; 40 conducted in a field setting (validation against doubly labelled water), 86 in a laboratory setting (validation against a metabolic cart, metabolic chamber) and 8 in a field and laboratory setting. Correlation coefficients between AM outcomes and energy expenditure (EE) by the criterion method (doubly labelled water and metabolic cart/chamber) and percentage mean differences between EE estimation from the monitor and EE measurement by the criterion method were extracted. Random-effects meta-analyses were performed to pool the results across studies where possible. Types of devices were compared using meta-regression analyses. Most validation studies had been performed in healthy adults (n = 118), with few carried out in patients with chronic diseases (n = 16). For total EE, correlation coefficients were statistically significantly lower in uniaxial compared to multisensor devices. For active EE, correlations were slightly but not significantly lower in uniaxial compared to triaxial and multisensor devices. Uniaxial devices tended to underestimate TEE (−12.07 (95%CI; -18.28 to −5.85) %) compared to triaxial (−6.85 (95%CI; -18.20 to 4.49) %, p = 0.37) and were statistically significantly less accurate than multisensor devices (−3.64 (95%CI; -8.97 to 1.70) %, p<0.001). TEE was underestimated during slow walking speeds in 69% of the lab validation studies compared to 37%, 30% and 37% of the studies during intermediate, fast walking speed and running, respectively. The high level of heterogeneity in the validation studies is only partly explained by the type of activity

  8. Krabbe disease: psychosine-mediated activation of phospholipase A2 in oligodendrocyte cell death.

    PubMed

    Giri, S; Khan, M; Rattan, R; Singh, I; Singh, A K

    2006-07-01

    Globoid cell leukodystrophy (Krabbe disease) is an inherited neurological disorder caused by the pathogenomic accumulation of psychosine (galactosylsphingosine), a substrate for the deficient enzyme galactocerebroside beta-galactosidase. This study underscores the mechanism of action of psychosine in the regulation of oligodendrocyte cell death via the generation of lysophosphatidylcholine (LPC) and arachidonic acid (AA) by the activation of secretory phospholipase A2 (sPLA2). There was a significant increase in the level of LPC, indicating a phospholipase A2 (PLA2)-dependent pathobiology, in the brains of Krabbe disease patients and those of twitcher mice, an animal model of Krabbe disease. In vitro studies of the treatment of primary oligodendrocytes and the oligodendrocyte MO3.13 cell line with psychosine also showed the generation of LPC and the release of AA in a dose- and time-dependent manner, indicating psychosine-induced activation of PLA2. Studies with various pharmacological inhibitors of cytosolic phospholipase A2 and sPLA2 and psychosine-mediated induction of sPLA2 enzymatic activity in media supernatant suggest that psychosine-induced release of AA and generation of LPC is mainly contributed by sPLA2. An inhibitor of sPLA2, 7,7-dimethyl eicosadienoic acid, completely attenuated the psychosine-mediated accumulation of LPC levels, release of AA, and generation of reactive oxygen species, and blocked oligodendroyte cell death, as evident from cell survival, DNA fragmentation, and caspase 3 activity assays. This study documents for the first time that psychosine-induced cell death is mediated via the sPLA2 signaling pathway and that inhibitors of sPLA2 may hold a therapeutic potential for protection against oligodendrocyte cell death and resulting demyelination in Krabbe disease. PMID:16645197

  9. Neutrophil proteolytic activation cascades: a possible mechanistic link between chronic periodontitis and coronary heart disease.

    PubMed

    Alfakry, Hatem; Malle, Ernst; Koyani, Chintan N; Pussinen, Pirkko J; Sorsa, Timo

    2016-01-01

    Cardiovascular diseases are chronic inflammatory diseases that affect a large segment of society. Coronary heart disease (CHD), the most common cardiovascular disease, progresses over several years and affects millions of people worldwide. Chronic infections may contribute to the systemic inflammation and enhance the risk for CHD. Periodontitis is one of the most common chronic infections that affects up to 50% of the adult population. Under inflammatory conditions the activation of endogenous degradation pathways mediated by immune responses leads to the release of destructive cellular molecules from both resident and immigrant cells. Matrix metalloproteinases (MMPs) and their regulators can activate each other and play an important role in immune response via degrading extracellular matrix components and modulating cytokines and chemokines. The action of MMPs is required for immigrant cell recruitment at the site of inflammation. Stimulated neutrophils represent the major pathogen-fighting immune cells that upregulate expression of several proteinases and oxidative enzymes, which can degrade extracellular matrix components (e.g. MMP-8, MMP-9 and neutrophil elastase). The activity of MMPs is regulated by endogenous inhibitors and/or candidate MMPs (e.g. MMP-7). The balance between MMPs and their inhibitors is thought to mirror the proteolytic burden. Thus, neutrophil-derived biomarkers, including myeloperoxidase, may activate proteolytic destructive cascades that are involved in subsequent immune-pathological events associated with both periodontitis and CHD. Here, we review the existing studies on the contribution of MMPs and their regulators to the infection-related pathology. Also, we discuss the possible proteolytic involvement and role of neutrophil-derived enzymes as an etiological link between chronic periodontitis and CHD. PMID:26608308

  10. Absence of CD14 Delays Progression of Prion Diseases Accompanied by Increased Microglial Activation

    PubMed Central

    Sakai, Keiko; Hasebe, Rie; Takahashi, Yusuke; Song, Chang-Hyun; Suzuki, Akio; Yamasaki, Takeshi

    2013-01-01

    Prion diseases are fatal neurodegenerative disorders characterized by accumulation of PrPSc, vacuolation of neurons and neuropil, astrocytosis, and microglial activation. Upregulation of gene expressions of innate immunity-related factors, including complement factors and CD14, is observed in the brains of mice infected with prions even in the early stage of infections. When CD14 knockout (CD14−/−) mice were infected intracerebrally with the Chandler and Obihiro prion strains, the mice survived longer than wild-type (WT) mice, suggesting that CD14 influences the progression of the prion disease. Immunofluorescence staining that can distinguish normal prion protein from the disease-specific form of prion protein (PrPSc) revealed that deposition of PrPSc was delayed in CD14−/− mice compared with WT mice by the middle stage of the infection. Immunohistochemical staining with Iba1, a marker for activated microglia, showed an increased microglial activation in prion-infected CD14−/− mice compared to WT mice. Interestingly, accompanied by the increased microglial activation, anti-inflammatory cytokines interleukin-10 (IL-10) and transforming growth factor β (TGF-β) appeared to be expressed earlier in prion-infected CD14−/− mice. In contrast, IL-1β expression appeared to be reduced in the CD14−/− mice in the early stage of infection. Double immunofluorescence staining demonstrated that CD11b- and Iba1-positive microglia mainly produced the anti-inflammatory cytokines, suggesting anti-inflammatory status of microglia in the CD14−/− mice in the early stage of infection. These results imply that CD14 plays a role in the disease progression by suppressing anti-inflammatory responses in the brain in the early stage of infection. PMID:24089559

  11. Notoginsenoside R1 attenuates experimental inflammatory bowel disease via pregnane X receptor activation.

    PubMed

    Zhang, Jingjing; Ding, Lili; Wang, Baocan; Ren, Gaiyan; Sun, Aning; Deng, Chao; Wei, Xiaohui; Mani, Sridhar; Wang, Zhengtao; Dou, Wei

    2015-02-01

    Notoginsenoside R1 (R1) is the main bioactive component in Panax notoginseng, an old herb medicine widely used in Asian countries in the treatment of microcirculatory diseases. However, little is known about the effect of R1 on inflammatory bowel disease (IBD). The present study demonstrated that R1 alleviated the severity of dextran sulfate sodium-induced colitis in mice by decreasing the activity of myeloperoxidase, the production of cytokines, the expression of proinflammatory genes, and the phosphorylation of IκB kinase, IκBα, and p65 in the colon. Further studies indicated that R1 dose-dependently activated human/mouse pregnane X receptor (PXR), a known target for decreasing inflammation in IBD, and upregulated the expression of genes involved in xenobiotic metabolism in colorectal cells and the colon. Ligand pocket-filling mutant (S247W/C284W or S247W/C284W/S208W) of the human PXR abrogated the effect of R1 on PXR activation. Time-resolved fluorescence resonance energy transfer PXR competitive binding assay confirmed R1 (ligand) binding affinity. In addition, PXR overexpression inhibited nuclear factor-κB (NF-κB)-luciferase activity, which was potentiated by R1 treatment. PXR knockdown by small interfering RNA demonstrated the necessity of PXR in R1-induced upregulation of the expression of xenobiotic-metabolizing enzymes and downregulation of NF-κB activity. Finally, the anti-inflammatory effect of R1 was confirmed in trinitrobenzene sulfonic acid-induced colitis in mice. These findings suggest that R1 attenuates experimental IBD possibly via the activation of intestinal PXR signaling. PMID:25472953

  12. Notoginsenoside R1 Attenuates Experimental Inflammatory Bowel Disease via Pregnane X Receptor Activation

    PubMed Central

    Zhang, Jingjing; Ding, Lili; Wang, Baocan; Ren, Gaiyan; Sun, Aning; Deng, Chao; Wei, Xiaohui; Mani, Sridhar

    2015-01-01

    Notoginsenoside R1 (R1) is the main bioactive component in Panax notoginseng, an old herb medicine widely used in Asian countries in the treatment of microcirculatory diseases. However, little is known about the effect of R1 on inflammatory bowel disease (IBD). The present study demonstrated that R1 alleviated the severity of dextran sulfate sodium–induced colitis in mice by decreasing the activity of myeloperoxidase, the production of cytokines, the expression of proinflammatory genes, and the phosphorylation of IκB kinase, IκBα, and p65 in the colon. Further studies indicated that R1 dose-dependently activated human/mouse pregnane X receptor (PXR), a known target for decreasing inflammation in IBD, and upregulated the expression of genes involved in xenobiotic metabolism in colorectal cells and the colon. Ligand pocket–filling mutant (S247W/C284W or S247W/C284W/S208W) of the human PXR abrogated the effect of R1 on PXR activation. Time-resolved fluorescence resonance energy transfer PXR competitive binding assay confirmed R1 (ligand) binding affinity. In addition, PXR overexpression inhibited nuclear factor-κB (NF-κB)–luciferase activity, which was potentiated by R1 treatment. PXR knockdown by small interfering RNA demonstrated the necessity of PXR in R1-induced upregulation of the expression of xenobiotic-metabolizing enzymes and downregulation of NF-κB activity. Finally, the anti-inflammatory effect of R1 was confirmed in trinitrobenzene sulfonic acid–induced colitis in mice. These findings suggest that R1 attenuates experimental IBD possibly via the activation of intestinal PXR signaling. PMID:25472953

  13. The spectrum of nasal involvement in systemic lupus erythematosus and its association with the disease activity.

    PubMed

    Kusyairi, K A; Gendeh, B S; Sakthiswary, R; Shaharir, S S; Haizlene, A H; Yusof, K H

    2016-04-01

    The purpose of this study was to determine the spectrum of nasal involvement in systemic lupus erythematosus (SLE) and its association with the disease activity of SLE based on the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). This was a cross-sectional and observational study involving 73 stable SLE patients. All subjects were evaluated for the SLEDAI scores and had nasal endoscopic examination. The most commonly reported symptom was nasal congestion (31.5%) followed by nasal itchiness (26.0%), runny nose (20.5%) and nasal dryness (19.2%). Almost half (42.9%) of the subjects had nasal mucosal abnormalities, which included mucositis, crusting, ulceration, bifid middle turbinate, septal spur, Jacobson's organ, deviated nasal septum, bilateral inferior turbinate hypertrophy, everted uncinate process, nasopharynx cleft and torus palatinus. The median SLEDAI score for subjects with nasal symptoms was significantly higher than subjects without nasal symptoms (p < 0.05). Similarly, subjects with moderate to high activity (SLEDAI scores of 6-19) had a significantly higher frequency of both nasal symptoms and nasal mucosal abnormalities (p < 0.05) compared to subjects with no to mild activity (SLEDAI scores of 0-5). PMID:26657735

  14. [Adapted Physical Activity for patients with chronic diseases in a therapeutic community].

    PubMed

    Bouricha, Rémy; Thöni, Gilles; Raffard, Laurence; Cochet, Laurence; Saucourt, Vincent; Tirode, Véronique

    2015-01-01

    The French therapeutic communities ("Appartements de Coordination Therapeutique (ACT)") are mostly members of the "National Federation of Accommodation for HIV+ and other chronic diseases. They provide accommodation for people living with chronic conditions (HIV hepatitis, cancers...) and in a situation of high psychosocial frailty. As a result of their coordinated multidisciplinary intervention, these structures provide the required support to access health care and facilitate social inclusion. They are designed to provide an appropriate response to people with cumulative medical and social conditions (chronic diseases, precariousness, addictions and other comorbidities). Our innovative local experiment integrates Adapted Physical Activities (APA) into the global medical and social follow-up, in line with the patient's individual health care project. The characteristics of each APA project (nature of the activities proposed, intensity, duration, frequency, individual vs. team activity and accompanying methods) are defined on an individual basis, according to the user's motivations and inputs from the support team (medical, psychological and social coordination). The follow-up ensured by our APA professionals allows the residents to participate in a regular and attractive physical activity and could contribute to their social inclusion. The multidisciplinary approach proposed by ACTs determines the beneficial effects observed in such vulnerable patients. PMID:26168635

  15. A molecular link between the active component of marijuana and Alzheimer's disease pathology.

    PubMed

    Eubanks, Lisa M; Rogers, Claude J; Beuscher, Albert E; Koob, George F; Olson, Arthur J; Dickerson, Tobin J; Janda, Kim D

    2006-01-01

    Alzheimer's disease is the leading cause of dementia among the elderly, and with the ever-increasing size of this population, cases of Alzheimer's disease are expected to triple over the next 50 years. Consequently, the development of treatments that slow or halt the disease progression have become imperative to both improve the quality of life for patients and reduce the health care costs attributable to Alzheimer's disease. Here, we demonstrate that the active component of marijuana, Delta9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid beta-peptide (Abeta) aggregation, the key pathological marker of Alzheimer's disease. Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer's disease, THC is a considerably superior inhibitor of Abeta aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease. PMID:17140265

  16. Peroxisome proliferator-activated receptors: potential therapeutic targets in lung disease?

    PubMed

    Denning, Gerene M; Stoll, Lynn L

    2006-01-01

    The peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that play central roles in lipid and glucose homeostasis, cellular differentiation, and the immune/inflammatory response. Growing evidence indicates that changes in expression and activation of PPARs likely modulate conditions as diverse as diabetes, atherosclerosis, cancer, asthma, Parkinson's disease, and Alzheimer's disease. Activation of these receptors by natural or pharmacologic ligands leads to both gene-dependent and gene-independent effects that alter the expression of a wide array of proteins. In the lung, PPARs are expressed by alveolar macrophages, as well as by epithelial, endothelial, and smooth muscle cells. Studies both in vitro and in vivo suggest that PPAR ligands may have anti-inflammatory effects in asthma, pulmonary sarcoidosis, and pulmonary alveolar proteinosis, as well as antiproliferative and antiangiogenic effects in epithelial lung cancers. Further studies to understand the contribution of these receptors to health and disease will be important for determining whether they represent a promising target for therapeutic intervention. PMID:16267824

  17. Modulation of inflammasome activity by Porphyromonas gingivalis in periodontitis and associated systemic diseases.

    PubMed

    Olsen, Ingar; Yilmaz, Özlem

    2016-01-01

    Inflammasomes are large multiprotein complexes localized in the cytoplasm of the cell. They are responsible for the maturation of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as for the activation of inflammatory cell death, the so-called pyroptosis. Inflammasomes assemble in response to cellular infection, cellular stress, or tissue damage; promote inflammatory responses and are of great importance in regulating the innate immune system in chronic inflammatory diseases such as periodontitis and several chronic systemic diseases. In addition to sensing cellular integrity, inflammasomes are involved in the homeostatic mutualism between the indigenous microbiota and the host. There are several types of inflammasomes of which NLRP3 is best characterized in microbial pathogenesis. Many opportunistic bacteria try to evade the innate immune system in order to survive in the host cells. One of these is the periodontopathogen Porphyromonas gingivalis which has been shown to have several mechanisms of modulating innate immunity by limiting the activation of the NLRP3 inflammasome. Among them, ATP-/P2X7- signaling is recently associated not only with periodontitis but also with development of several systemic diseases. The present paper reviews multiple mechanisms through which P. gingivalis can modify innate immunity by affecting inflammasome activity. PMID:26850450

  18. The Role of Power Doppler Ultrasonography as Disease Activity Marker in Rheumatoid Arthritis

    PubMed Central

    Bhasin, Shaloo; Cheung, Peter P.

    2015-01-01

    Structural damage in rheumatoid arthritis (RA) occurs early if inflammation is not treated promptly. Treatment targeted to reduce inflammation, in particular, that of synovial inflammation in the joints (synovitis), has been recommended as standard treat-to-target recommendations by rheumatologists. The goal is to achieve disease remission (i.e., no disease activity). Several accepted remission criteria have not always equated to the complete absence of true inflammation. Over the last decade, musculoskeletal ultrasonography has been demonstrated to detect subclinical synovitis not appreciated by routine clinical or laboratory assessments, with the Power Doppler modality allowing clinicians to more readily appreciate true inflammation. Thus, targeting therapy to Power Doppler activity may provide superior outcomes compared with treating to clinical targets alone, making it an attractive marker of disease activity in RA. However, more validation on its true benefits such as its benefits to patients in regard to patient related outcomes and issues with standardized training in acquisition and interpretation of power Doppler findings are required. PMID:26063952

  19. Serum proteome changes in acromegalic patients following transsphenoidal surgery: novel biomarkers of disease activity

    PubMed Central

    Cruz-Topete, Diana; Christensen, Britt; Sackmann-Sala, Lucila; Okada, Shigeru; Jorgensen, Jens Otto L; Kopchick, John J

    2014-01-01

    Context Transsphenoidal adenomectomy is the primary treatment for acromegaly. However, assessment of the therapeutical outcome remains problematic since the existing biomarkers of disease activity frequently show discordant results. Objective To discover novel serum biomarkers of disease activity in acromegalic patients before and after surgery. Design Serum samples of eight newly diagnosed acromegaly patients before and after transsphenoidal surgery were analyzed for proteomic changes by two-dimensional gel electrophoresis. Protein spots displaying statistically significant changes, pre- versus post-surgery, were identified by mass spectrometry (MS), tandem MS (MS/MS), and western blot analysis. Results Six protein spots displaying decreased intensities after surgery were identified as transthyretin (two isoforms), haptoglobin a2, b-hemoglobin, and apolipoprotein A-1 (two isoforms). One protein spot, identified as complement C4B precursor, was increased after the surgery. Conclusions Seven serum protein spots were differentially expressed following surgery in acromegalic patients. The identified proteins represent potential novel biomarkers to assess the effectiveness of surgical treatment in acromegalic individuals. Future studies will validate the use of the identified proteins as biomarkers of disease activity after medical treatment of acromegaly. PMID:21059862

  20. Asymptomatic Atherosclerosis in Egyptian Rheumatoid Arthritis Patients and Its Relation to Disease Activity

    PubMed Central

    Elshereef, Rawhya R.; Darwish, Aymen; Ali, Amal; Abdel-kadar, Mohammed; Hamdy, Lamiaa

    2015-01-01

    Aim. To detect the frequency of subclinical atherosclerosis in rheumatoid arthritis patients without clinically evident atherosclerosis and to correlate its presence with the disease activity. Patients and Methods. Our study includes 112 RA patients (group 1) and 40 healthy controls (group 11). All patients and controls were subjected to full history taking, clinical examination, and laboratory investigations. Carotid intima media wall thickness (IMT) and carotid plaques were measured in both groups by B-mode ultrasonography; also color duplex Doppler ultrasound of the brachial artery was done to detect endothelial function. Results. There is atherosclerosis in 31.3% of asymptomatic RA patients compared with only 5% in controls (P = 0.003**). A significant difference was detected in patients with and without atherosclerosis regarding duration of the disease (P = 0.0001***) and patient's age (P = 0.01*). There is highly statistical significant correlation between atherosclerosis and disease activity index. Conclusion. The frequency of subclinical atherosclerosis was high in long-term active RA patients. PMID:25737726

  1. Modulation of inflammasome activity by Porphyromonas gingivalis in periodontitis and associated systemic diseases

    PubMed Central

    Olsen, Ingar; Yilmaz, Özlem

    2016-01-01

    Inflammasomes are large multiprotein complexes localized in the cytoplasm of the cell. They are responsible for the maturation of pro-inflammatory cytokines such as interleukin-1β (IL-1β) and IL-18 as well as for the activation of inflammatory cell death, the so-called pyroptosis. Inflammasomes assemble in response to cellular infection, cellular stress, or tissue damage; promote inflammatory responses and are of great importance in regulating the innate immune system in chronic inflammatory diseases such as periodontitis and several chronic systemic diseases. In addition to sensing cellular integrity, inflammasomes are involved in the homeostatic mutualism between the indigenous microbiota and the host. There are several types of inflammasomes of which NLRP3 is best characterized in microbial pathogenesis. Many opportunistic bacteria try to evade the innate immune system in order to survive in the host cells. One of these is the periodontopathogen Porphyromonas gingivalis which has been shown to have several mechanisms of modulating innate immunity by limiting the activation of the NLRP3 inflammasome. Among them, ATP-/P2X7- signaling is recently associated not only with periodontitis but also with development of several systemic diseases. The present paper reviews multiple mechanisms through which P. gingivalis can modify innate immunity by affecting inflammasome activity. PMID:26850450

  2. Neurovascular dysfunction, inflammation and endothelial activation: Implications for the pathogenesis of Alzheimer's disease

    PubMed Central

    2011-01-01

    Alzheimer's disease (AD) is an age-related disorder characterized by progressive cognitive decline and dementia. Alzheimer's disease is an increasingly prevalent disease with 5.3 million people in the United States currently affected. This number is a 10 percent increase from previous estimates and is projected to sharply increase to 8 million by 2030; it is the sixth-leading cause of death. In the United States the direct and indirect costs of Alzheimer's and other dementias to Medicare, Medicaid and businesses amount to more than $172 billion each year. Despite intense research efforts, effective disease-modifying therapies for this devastating disease remain elusive. At present, the few agents that are FDA-approved for the treatment of AD have demonstrated only modest effects in modifying clinical symptoms for relatively short periods and none has shown a clear effect on disease progression. New therapeutic approaches are desperately needed. Although the idea that vascular defects are present in AD and may be important in disease pathogenesis was suggested over 25 years ago, little work has focused on an active role for cerebrovascular mechanisms in the pathogenesis of AD. Nevertheless, increasing literature supports a vascular-neuronal axis in AD as shared risk factors for both AD and atherosclerotic cardiovascular disease implicate vascular mechanisms in the development and/or progression of AD. Also, chronic inflammation is closely associated with cardiovascular disease, as well as a broad spectrum of neurodegenerative diseases of aging including AD. In this review we summarize data regarding, cardiovascular risk factors and vascular abnormalities, neuro- and vascular-inflammation, and brain endothelial dysfunction in AD. We conclude that the endothelial interface, a highly synthetic bioreactor that produces a large number of soluble factors, is functionally altered in AD and contributes to a noxious CNS milieu by releasing inflammatory and neurotoxic species

  3. Clinicians’ guide to the use of fecal calprotectin to identify and monitor disease activity in inflammatory bowel disease

    PubMed Central

    Bressler, Brian; Panaccione, Remo; Fedorak, Richard N; Seidman, Ernest G

    2015-01-01

    BACKGROUND: Objective monitoring of the severity of inflammation in patients with inflammatory bowel disease (IBD) is an essential part of disease management. However, repeat endoscopy to define extent and severity of inflammation is not practical. Fecal calprotectin (FC) is a biomarker that can be used as a surrogate test to distinguish inflammatory from noninflammatory gastrointestinal disease. METHODS: A targeted search of the literature regarding FC, focusing primarily on the past three years, was conducted to develop practical clinical guidance on the current utility of FC in the routine management of IBD patients. RESULTS: It is recommended that samples for FC testing be obtained from the first bowel excretion of the day. FC testing should be used as standard of care to accurately confirm inflammation and ‘real-time’ disease activity when a clinician suspects an IBD flare. Although FC is a reliable marker of inflammation, its role in routine monitoring in improving long-term outcomes has not yet been fully assessed. Based on available evidence, the authors suggest the following cut-off values and management strategies: when FC levels are <50 μg/g to 100 μg/g, quiescent disease is likely and therapy should be continued; when FC levels are >100 μg/g to 250 μg/g, inflammation is possible and further testing (eg, colonoscopy) is required to confirm inflammation; and when FC levels are >250 μg/g, active inflammation is likely and strategies to control inflammation should be initiated (eg, optimizing current therapies or switching to an alternative therapy). DISCUSSION: FC is a useful biomarker to accurately assess the degree of inflammation and should be incorporated into the management of patients with IBD. PMID:26125109

  4. Immunometabolic biomarkers of inflammation in Behçet's disease: relationship with epidemiological profile, disease activity and therapeutic regimens.

    PubMed

    Cantarini, L; Pucino, V; Vitale, A; Talarico, R; M Lucherini, O; Magnotti, F; De Rosa, V; Galgani, M; Alviggi, C; Marone, G; Galeazzi, M; Matarese, G

    2016-05-01

    Behcet's disease (BD) is a systemic inflammatory disease with a still unclear pathogenesis. Although several inflammatory molecules have been studied, current biomarkers are largely insensitive in BD and unable to predict disease progression and response to treatment. Our primary aim was to explore serum levels of soluble CD40 L (sCD40L), soluble intracellular adhesion molecule (sICAM-1), monocyte chemoattractant protein-1 (MCP-1), myeloperoxidase (MPO), leptin, resistin, osteoprotegerin (OPG), soluble type 1 tumour necrosis factor receptor (sTNFR), interleukin (IL)-6 and serum amyloid A (SAA) serum concentration in a cohort of 27 BD patients. The secondary aim was to evaluate potential correlations between the putative circulating biomarkers, demographic profile of patients, the status of disease activity, the specific organ involvement at the time of sample collection and different therapeutic regimens. Serum concentrations of sTNFR (P = 0·008), leptin (P = 0·0011), sCD40L (P < 0·0001) and IL-6 (P = 0·0154) were significantly higher in BD patients than in HC, while no difference was found in MCP-1, MPO and resistin serum levels. Moreover, we observed significantly higher sTNFR serum concentrations in BD patients presenting inactive disease than HC (P = 0·0108). A correlation between sTNFR and age was also found, with higher levels in patients over 40 years than HC (P = 0·0329). Although further research is warranted to elucidate the role of circulating biomarkers, some of that may contribute to the understanding of the physiopathology processes underlying BD activity and damage as well as to provide useful tools for prognostic purposes and a personalized treatment approach. PMID:26756979

  5. Physical activity

    MedlinePlus

    ... this page: //medlineplus.gov/ency/article/001941.htm Physical activity To use the sharing features on this page, please enable JavaScript. Physical activity -- which includes an active lifestyle and routine exercise -- ...

  6. Infectious Diseases (ID) Learning Unit: How Rapidly to Evaluate for Active Tuberculosis Disease in Low-Prevalence Settings.

    PubMed

    Chida, Natasha; Shah, Maunank

    2016-03-01

    With declining tuberculosis (TB) incidence in low-prevalence settings, many clinicians are likely unaware that the approach to diagnosing active TB is evolving with newer technologies. Rapid molecular assays are commercially available, and more are likely to enter the market in the coming years. These tests, such as the Xpert MTB/RIF, which can detect TB and drug-resistance in 2 hours, are increasingly used in settings with higher TB prevalence; however, uptake has been slower in low-prevalence settings. Newer algorithms incorporating rapid TB diagnostics have the ability to alter current clinical and infection control practice patterns. In this learning unit, we review current and newly available tests for the detection of active TB disease and their usage in low-prevalence settings. PMID:27186583

  7. Infectious Diseases (ID) Learning Unit: How Rapidly to Evaluate for Active Tuberculosis Disease in Low-Prevalence Settings

    PubMed Central

    Chida, Natasha; Shah, Maunank

    2016-01-01

    With declining tuberculosis (TB) incidence in low-prevalence settings, many clinicians are likely unaware that the approach to diagnosing active TB is evolving with newer technologies. Rapid molecular assays are commercially available, and more are likely to enter the market in the coming years. These tests, such as the Xpert MTB/RIF, which can detect TB and drug-resistance in 2 hours, are increasingly used in settings with higher TB prevalence; however, uptake has been slower in low-prevalence settings. Newer algorithms incorporating rapid TB diagnostics have the ability to alter current clinical and infection control practice patterns. In this learning unit, we review current and newly available tests for the detection of active TB disease and their usage in low-prevalence settings. PMID:27186583

  8. Hypoxia and GABA shunt activation in the pathogenesis of Alzheimer's disease.

    PubMed

    Salminen, Antero; Jouhten, Paula; Sarajärvi, Timo; Haapasalo, Annakaisa; Hiltunen, Mikko

    2016-01-01

    We have previously observed that the conversion of mild cognitive impairment to definitive Alzheimer's disease (AD) is associated with a significant increase in the serum level of 2,4-dihydroxybutyrate (2,4-DHBA). The metabolic generation of 2,4-DHBA is linked to the activation of the γ-aminobutyric acid (GABA) shunt, an alternative energy production pathway activated during cellular stress, when the function of Krebs cycle is compromised. The GABA shunt can be triggered by local hypoperfusion and subsequent hypoxia in AD brains caused by cerebral amyloid angiopathy. Succinic semialdehyde dehydrogenase (SSADH) is a key enzyme in the GABA shunt, converting succinic semialdehyde (SSA) into succinate, a Krebs cycle intermediate. A deficiency of SSADH activity stimulates the conversion of SSA into γ-hydroxybutyrate (GHB), an alternative route from the GABA shunt. GHB can exert not only acute neuroprotective activities but unfortunately also chronic detrimental effects which may lead to cognitive impairment. Subsequently, GHB can be metabolized to 2,4-DHBA and secreted from the brain. Thus, the activation of the GABA shunt and the generation of GHB and 2,4-DHBA can have an important role in the early phase of AD pathogenesis. PMID:26617286

  9. Mitogen-activated Tasmanian devil blood mononuclear cells kill devil facial tumour disease cells.

    PubMed

    Brown, Gabriella K; Tovar, Cesar; Cooray, Anne A; Kreiss, Alexandre; Darby, Jocelyn; Murphy, James M; Corcoran, Lynn M; Bettiol, Silvana S; Lyons, A Bruce; Woods, Gregory M

    2016-08-01

    Devil facial tumour disease (DFTD) is a transmissible cancer that has brought the host species, the Tasmanian devil, to the brink of extinction. The cancer cells avoid allogeneic immune recognition by downregulating cell surface major histocompatibility complex (MHC) I expression. This should prevent CD8(+) T cell, but not natural killer (NK) cell, cytotoxicity. The reason why NK cells, normally reactive to MHC-negative cells, are not activated to kill DFTD cells has not been determined. The immune response of wild devils to DFTD, if it occurs, is uncharacterised. To investigate this, we tested 12 wild devils with DFTD, and found suggestive evidence of low levels of antibodies against DFTD cells in one devil. Eight of these devils were also analysed for cytotoxicity, however, none showed evidence for cytotoxicity against cultured DFTD cells. To establish whether mimicking activation of antitumour responses could induce cytotoxic activity against DFTD, Tasmanian devil peripheral blood mononuclear cells (PBMCs) were treated with either the mitogen Concanavalin A, the Toll-like receptor agonist polyinosinic:polycytidylic acid or recombinant Tasmanian devil IL-2. All induced the PBMC cells to kill cultured DFTD cells, suggesting that activation does not occur after encounter with DFTD cells in vivo, but can be induced. The identification of agents that activate cytotoxicity against DFTD target cells is critical for developing strategies to protect against DFTD. Such agents could function as adjuvants to induce functional immune responses capable of targeting DFTD cells and tumours in vivo. PMID:27089941

  10. Active Aging for Individuals with Parkinson's Disease: Definitions, Literature Review, and Models

    PubMed Central

    Lökk, Johan

    2014-01-01

    Active aging has been emerged to optimize different aspects of health opportunities during the aging process in order to enhance quality of life. Yet, most of the efforts are on normal aging and less attention has been paid for the elderly suffering from a chronic illness such as Parkinson's disease (PD). The aim of this review was to investigate how the concept of “active aging” fit for the elderly with PD and to propose a new model for them using the recent improvements in caring models and management approaches. For this purpose, biomedical databases have been assessed using relevant keywords to find out appropriate articles. Movement problems of PD affect physical activity, psychiatric symptoms lessen social communication, and cognitive impairment could worsen mental well-being in elderly with PD, all of which could lead to earlier retirement and poorer quality of life compared with healthy elderly. Based on the multisystematic nature of PD, a new “Active Aging Model for Parkinson's Disease” is proposed consisting of self-care, multidisciplinary and interdisciplinary care, palliative care, patient-centered care, and personalized care. These strategies could potentially help the individuals with PD to have a better management approach for their condition towards the concept of active aging. PMID:25225618

  11. [In vitro activity of doripenem against strains from pediatric diseases and strains causing purulent meningitis].

    PubMed

    Ohta, Merime; Toba, Shinsuke; Ito, Akinobu; Nakamura, Rio; Tsuji, Masakatsu

    2012-12-01

    This study evaluated the in vitro activity of doripenem (DRPM) against 200 Streptococcus pneumoniae and 197 Haemophilus influenzae from children and adults in 2007, 50 H. influenzae type b in 2006, 20 Listeria monocytogenes in 1990-2005, 23 Neisseria meningitidis in 2007-2009 and 83 Bordetella pertussis in 1989-2003. All strains were isolated from Japanese clinical facilities. We also investigated in vitro activity of other carbapenems (meropenem, imipenem, panipenem, biapenem), cephems (ceftriaxone, cefotaxime), ampicillin and clarithromycin. The all MICs were determined by a broth micro dilution method or an agar dilution method according to CLSI. The MIC90(s) of DRPM against S. pneumoniae and H. influenzae from children were 0.25 microg/mL, 1 microg/mL, respectively, which were similar to strains from adults. These results suggested that antibacterial activity of DRPM is not variable by patient's age. DRPM also showed excellent activities against H. influenzae type b, L. monocytogenes and N. meningitidis, which cause purulent meningitis, and B. pertussis causing whooping cough more than the other carbapenems. DRPM showed superior activities against serious strains of pediatric infection diseases. PMID:23593734

  12. Lateralization of brain activity pattern during unilateral movement in Parkinson's disease.

    PubMed

    Wu, Tao; Hou, Yanan; Hallett, Mark; Zhang, Jiarong; Chan, Piu

    2015-05-01

    We investigated the lateralization of brain activity pattern during performance of unilateral movement in drug-naïve Parkinson's disease (PD) patients with only right hemiparkinsonian symptoms. Functional MRI was obtained when the subjects performed strictly unilateral right hand movement. A laterality index was calculated to examine the lateralization. Patients had decreased activity in the left putamen and left supplementary motor area, but had increased activity in the right primary motor cortex, right premotor cortex, left postcentral gyrus, and bilateral cerebellum. The laterality index was significantly decreased in PD patients compared with controls (0.41 ± 0.14 vs. 0.84 ± 0.09). The connectivity from the left putamen to cortical motor regions and cerebellum was decreased, while the interactions between the cortical motor regions, cerebellum, and right putamen were increased. Our study demonstrates that in early PD, the lateralization of brain activity during unilateral movement is significantly reduced. The dysfunction of the striatum-cortical circuit, decreased transcallosal inhibition, and compensatory efforts from cortical motor regions, cerebellum, and the less affected striatum are likely reasons contributing to the reduced motor lateralization. The disruption of the lateralized brain activity pattern might be a reason underlying some motor deficits in PD, like mirror movements or impaired bilateral motor coordination. PMID:25644527

  13. Hepatocellular expression of a novel glycoprotein with sialylated difucosyl Lex activity in the active inflammatory lesions of chronic liver disease.

    PubMed Central

    Okada, Y.; Shimoe, T.; Muguruma, M.; Usumoto, R.; Tsuji, T.; Jinno, K.; Moriwaki, S.; Shin, S.; Hakomori, S.

    1988-01-01

    Hepatic expression of sialylated difucosyl Lex antigen (SDLex, NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-) was studied with monoclonal antibody FH6, which defines this structure. Hepatocytes in the severe form of chronic active hepatitis and liver cirrhosis strongly expressed SDLex. The antigen was only weakly and focally detected in chronic persistent hepatitis. The mild form of chronic active hepatitis showed intermediate expression. SDLex expressed along the liver cell membranes displayed a honeycomb pattern when extensively expressed in the severe form of chronic active hepatitis or in liver cirrhosis. Cytoplasmic expression was faint and focal. Preferential tissue distribution was at the periphery of the hepatic lobules where the distruction of the limiting plate was present. The antigen was also expressed in sinusoidal lining cells and polymorphonuclear cells but not in the biliary epithelia. Hepatocytes expressing SDLex did not express related carbohydrate antigens, ie, Type 2 chain N-acetyllactosamine, Lex, and sialylated Lea. On subcellular fractionation, the microsome fraction contained the majority of the antigen activity. SDS-PAGE and Western blot analysis revealed one major SDLex-active glycoprotein with an apparent molecular weight of 110 kilodaltons. This glycoprotein was different from SDLex-active glycoproteins found in the sera of cancer patients. No ganglioside showed FH6 reactivity. These results indicate that liver cells in active inflammatory lesion expressed a novel glycoprotein carrying SDLex antigen in honeycomblike membrane-associated pattern. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:3341453

  14. Novel Risk Factors of Cardiovascular Disease and Their Associations Between Obesity, Physical Activity And Physical Fitness

    PubMed Central

    Buchan, Duncan S.; Thomas, Non E.; Baker, Julien S.

    2012-01-01

    The prevalence of cardiovascular disease (CVD) is increasing around the globe and is the leading cause of death around the world. Though once thought of as an adult problem, it is now recognised that the early manifestations of disease may occur during childhood. Numerous risk factors have been linked to CVD with much of the research focusing on understanding the prevalence and relationship of traditional risk factors such as dyslipidemia, smoking, diabetes mellitus, hypertension, obesity, psychosocial stress, poor diet, physical inactivity and alcohol consumption to the early etiology of disease. While this line of investigation has greatly enhanced our understanding of the relationship between these risk factors and disease, they do not fully explain all cardiovascular events. To enhance our understanding and help with the management of CVD, investigations that involve the measurement of traditional as well as novel risk factors may be necessary. Public health strategies that aim to reduce the prevalence of obesity and overweight encourage youth to increase their physical activity levels as a means of protecting against poor cardiometabolic profiles. Interventions that increase physical activity levels and improve cardiorespiratory fitness cause a reduction in certain CVD risk factors but the lack of agreement between findings makes it impossible to give precise recommendations that will ensure CVD risk reduction. Yet it is important that research continues in order to establish the most appropriate means of improving the health and well-being of those at most risk of future CVD. PMID:25170447

  15. Post-traumatic stress in Crohn's disease and its association with disease activity

    PubMed Central

    Cámara, Rafael J A; Gander, Marie-Louise; Begré, Stefan; von Känel, Roland

    2011-01-01

    Objective Violence, accidents and natural disasters are known to cause post-traumatic stress, which is typically accompanied by fear, suffering and impaired quality of life. Similar to chronic diseases, such events preoccupy the patient over longer periods. We hypothesised that post-traumatic stress could also be caused by Crohn's disease (CD), and that CD specific post-traumatic stress could be associated with an increased risk of disease exacerbation. Methods A cohort of CD patients was observed over 18 months in various types of locations providing gastroenterological treatment in Switzerland. The cohort included 597 consecutively recruited adults. At inclusion, CD specific post-traumatic stress was assessed using the Post-traumatic Diagnostic Scale (range 0–51 points). During follow-up, clinical aggravation was assessed by combining important outcome measures. Patients with post-traumatic stress levels suggestive of a post-traumatic stress disorder (≥ 15 points) were compared with patients with lower post-traumatic stress levels as well as with patients without post-traumatic stress. Also, the continuous relation between post-traumatic stress severity and risk of disease exacerbation was assessed. Results The 88 (19.1%) patients scoring ≥15 points had 4.3 times higher odds of exacerbation (95% CI 2.6 to 7.2) than the 372 (80.9%) patients scoring <15 points, and 13.0 times higher odds (95% CI 3.6 to 46.2) than the 45 (9.8%) patients scoring 0 points. The odds of exacerbation increased by 2.2 (95% CI 1.6 to 2.8) per standard deviation of post-traumatic stress. Conclusions CD specific post-traumatic stress is frequent and seems to be associated with exacerbation of CD. Thus gastroenterologists may want to ask about symptoms of post-traumatic stress and, where relevant, offer appropriate management according to current knowledge. PMID:24349679

  16. Physical activity in patients with stable coronary heart disease: an international perspective

    PubMed Central

    Stewart, Ralph; Held, Claes; Brown, Rebekkah; Vedin, Ola; Hagstrom, Emil; Lonn, Eva; Armstrong, Paul; Granger, Christopher B.; Hochman, Judith; Davies, Richard; Soffer, Joseph; Wallentin, Lars; White, Harvey

    2013-01-01

    Aims Despite the known benefits of regular exercise, the reasons why many coronary heart disease (CHD) patients engage in little physical activity are not well understood. This study identifies factors associated with low activity levels in individuals with chronic CHD participating in the STABILITY study, a global clinical outcomes trial evaluating the lipoprotein phospholipaseA2 inhibitor darapladib. Methods and results Prior to randomization, 15 486 (97.8%) participants from 39 countries completed a lifestyle questionnaire. Total physical activity was estimated from individual subject self-reports of hours spend each week on mild, moderate, and vigorous exercise, corresponding approximately to 2, 4, and 8 METS, respectively. Multivariate logistic regression evaluated clinical and demographic variables for the lowest compared with higher overall exercise levels, and for individuals who decreased rather than maintained or increased activity since diagnosis of CHD. The least active 5280 subjects (34%) reported exercise of ≤24MET.h/week. A total of 7191 subjects (46%) reported less exercise compared with before diagnosis of CHD. The majority of participants were either ‘not limited’ or ‘limited a little’ walking 100 m (84%), climbing one flight of stairs (82%), or walking 1 km/½ mile (68%), and <10% were limited ‘a lot’ by dyspnoea or angina. Variables independently associated with both low physical activity and decreasing exercise after diagnosis of CHD included more co-morbid conditions, poorer general health, fewer years of education, race, and country (P < 0.001 for all). Conclusion In this international study, low physical activity was only partly explained by cardiovascular symptoms. Potentially modifiable societal and health system factors are important determinants of physical inactivity in patients with chronic CHD. PMID:24014220

  17. Influence of peripheral arterial disease on daily living activities in elderly women.

    PubMed

    Cucato, Gabriel Grizzo; Ritti-Dias, Raphael Mendes; Franco, Fábio Gazelato de Mello; de Mattos, Luciana Diniz Nagem Janot; Cendoroglo, Maysa Seabra; Wolosker, Nelson; Nasri, Fábio; Costa, Maria Luiza Monteiro; de Carvalho, José Antônio Maluf

    2016-06-01

    Aging has been associated with decreases in physical and cognitive functions. Peripheral artery disease (PAD) has been associated with further impairments in these functions, especially in women. However, no detailed information is available indicating whether PAD leads to further impairment in these functions in elderly women. Thus, the aims of this study were 1) to compare the capacity to perform daily living activities between elderly women with and without PAD and 2) to identify the factors related with the performance in daily activities. Twenty-seven elderly women with PAD and 22 elderly non-PAD women were surveyed in a geriatric hospital. Women aged ≥65 years and with no signal of dementia were included. PAD was identified by the ankle-brachial index ≤0.90, whereas elderly non-PAD women presented ankle-brachial index >1.0. Patients were interviewed to obtain information regarding basic (Katz questionnaire) and instrumental daily living activities (Lawton-Brody scale) and performed the mini-mental state examination, handgrip strength test, and timed up and go tests. PAD and non-PAD women had similar age, clinical characteristics, handgrip strength test, and cognitive function (P > 0.05). The capacity to perform basic and instrumental daily living activities was similar between PAD and non-PAD women (P > 0.05). In PAD and non-PAD, the instrumental daily living activities were significantly correlated with cognitive function (r = 0.44, P < 0.05 and r = 0.74 and P < 0.05, respectively). PAD elderly women present similar capacity to perform basic and instrumental daily activities than non-PAD women. In addition, in both groups, the capacity to perform instrumental daily activities was related with cognitive function. PMID:27210449

  18. Elevated NADPH oxidase activity contributes to oxidative stress and cell death in Huntington's disease

    PubMed Central

    Valencia, Antonio; Sapp, Ellen; Kimm, Jeffrey S.; McClory, Hollis; Reeves, Patrick B.; Alexander, Jonathan; Ansong, Kwadwo A.; Masso, Nicholas; Frosch, Matthew P.; Kegel, Kimberly B.; Li, Xueyi; DiFiglia, Marian

    2013-01-01

    A mutation in the huntingtin (Htt) gene produces mutant Htt and Huntington's disease (HD), a neurodegenerative disorder. HD patients have oxidative damage in the brain, but the causes are unclear. Compared with controls, we found brain levels of NADPH oxidase (NOX) activity, which produces reactive oxygen species (ROS), elevated in human HD postmortem cortex and striatum and highest in striatum of presymptomatic individuals. Synaptosome fractions from cortex and striatum of HD140Q/140Q mice had elevated NOX activity at 3 months of age and a further rise at 6 and 12 months compared with synaptosomes of age-matched wild-type (WT) mice. High NOX activity in primary cortical and striatal neurons of HD140Q/140Q mice correlated with more ROS and neurite swellings. These features and neuronal cell death were markedly reduced by treatment with NOX inhibitors such as diphenyleneiodonium (DPI), apocynin (APO) and VAS2870. The rise in ROS levels in mitochondria of HD140Q/140Q neurons followed the rise in NOX activity and inhibiting only mitochondrial ROS was not neuroprotective. Mutant Htt colocalized at plasma membrane lipid rafts with gp91-phox, a catalytic subunit for the NOX2 isoform. Assembly of NOX2 components at lipid rafts requires activation of Rac1 which was also elevated in HD140Q/140Q neurons. HD140Q/140Q mice bred to gp91-phox knock-out mice had lower NOX activity in the brain and in primary neurons, and neurons had normal ROS levels and significantly improved survival. These findings suggest that increased NOX2 activity at lipid rafts is an early and major source of oxidative stress and cell death in HD140Q/140Q neurons. PMID:23223017

  19. Alveolar hydatid disease. Review of the surgical experience in 42 cases of active disease among Alaskan Eskimos.

    PubMed Central

    Wilson, J F; Rausch, R L; Wilson, F R

    1995-01-01

    OBJECTIVE: The authors reviewed the pathophysiology and clinical management of endemic alveolar hydatid disease in Alaskan Eskimos, incorporating recent developments in diagnosis and treatment. SUMMARY BACKGROUND DATA: Alveolar hydatid disease is a highly lethal zoonotic infection caused by the larval stage of Echinococcus multilocularis. This cestode is restricted geographically to northern climates, where foxes and small rodents represent the natural hosts. Domestic dogs also may serve as definitive hosts, and thus, transmit the parasite to humans. Human infection is characterized by the development of a cancer-like hepatic mass, which may extend to adjacent structures or metastasize to distant sites. If the infection goes untreated, mortality reaches 80%. METHODS: The medical records of all patients with alveolar hydatid disease diagnosed or treated at the Alaska Native Medical Center between 1951 and 1993 were reviewed. Forty-two cases of active disease are presented. RESULTS: Nine patients underwent resection of hepatic lesions with intent to cure, and each had a favorable result. Average post-diagnosis survival of those patients was 22 years; six still are living and free of disease. Partial resections or drainage procedures were performed in ten patients. Chemotherapy was used to augment the surgical treatment of eight patients, and four received chemotherapy alone, resulting in improved outcomes compared with historic controls. Late complications included hepatic abscess, biliary obstruction, and portal venous hypertension. CONCLUSIONS: Whereas alveolar hydatid disease rarely is encountered in other areas of North America, the biologic potential for spread of the disease may be increasing because of illegal importation of infected foxes to the Eastern seaboard. Therefore, the surgical community should maintain an awareness of the diagnosis and management of this potentially devastating parasitic infection. Images Figure 2. Figure 3. PMID:7717785

  20. [Diseases of the kidneys and urinary tract and possibilities of their active detection in miners].

    PubMed

    Kozyr', V I; Plotkin, V Ia

    1992-01-01

    The examination of 630 miners aged 18-64 working in the mines of the Lugansk region revealed urinary and renal diseases in 15.7% of them. They were affected with chronic prostatitis (34.3%), urolithiasis (27.2%), chronic pyelonephritis (14.2%), 162 miners (33%) out of 490 had urinary shifts (hematuria in 91, proteinuria in 52, both hematuria and proteinuria in 19 examinees) when examined upon ascending from the mine. 61 miners had urinary syndrome only after working shifts. It was unrelated to relevant diseases. The authors point out the necessity of active screening of renal and urinary diseases during routine medical check-ups in miners. PMID:1387182

  1. Transgenerational transmission of systemic mast cell activation disease-genetic and epigenetic features.

    PubMed

    Molderings, Gerhard J

    2016-08-01

    Systemic mast cell activation disease (MCAD) comprises disorders characterized by an enhanced release of mast cell mediators accompanied by a varying accumulation of dysfunctional mast cells. Within the last years, evidence has been presented that MCAD is a multifactorial polygenic determined disease with the KIT(D816V) mutation and its induced functional consequences considered as special case. The respective genes encode proteins for various signaling pathways, epigenetic regulators, the RNA splicing machinery, and transcription factors. Transgenerational transmission of MCAD appears to be quite common. The basics of the molecular mechanisms underlying predisposition of the disease, that is, somatic and germline mutations and the contribution of epigenetic processes have become identifiable. The aim of the present review is to present and discuss available genetic, epigenetic and epidemiological findings, and to present a model of MCAD pathogenesis. PMID:26880691

  2. A new recombinant hybrid polypeptide and its immunologic adjuvant activity for inactivated infectious bursal disease vaccine.

    PubMed

    Cai, Mei-hong; Zhu, Feng; Wu, Hao-chen; Shen, Ping-ping

    2014-07-01

    Both bursin (Lys-His-Gly-NH2) and Gagnon's peptides (Lys-Asn-Pro-Tyr) can induce B-cell differentiation. However, it is unclear whether a recombinant hybrid polypeptide consisting of a tandem array of 14 copies of bursin and two copies of Gagnon's peptide can induce the proliferative activity of lymphocytes. Here, this recombinant hybrid polypeptide was expressed in Escherichia coli and purified by SDS-PAGE. Various assays showed that it not only promoted B-lymphocyte proliferation in vitro but also increased the titers of antibodies directed against infectious bursal disease virus fourfold in the sera of chickens vaccinated with the inactivated infectious bursal disease virus vaccine. The recombinant hybrid polypeptide also reduced the pathological lesions in the bursa of Fabricius caused by infectious bursal disease virus BC6/85. Our results show that this recombinant hybrid polypeptide may be a promising immune adjuvant. PMID:24652544

  3. Studies of generalized elemental imbalances in neurological disease patients using INAA (instrumental neutron activation analysis)

    SciTech Connect

    Ehmann, W.D.; Vance, D.E.; Khare, S.S.; Kasarskis, E.J.; Markesbery, W.R.

    1988-01-01

    Evidence has been presented in the literature to implicate trace elements in the etiology of several age-related neurological diseases. Most of these studies are based on brain analyses. Using instrumental neutron activation analysis (INAA), we have observed trace element imbalances in brains of patients with Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Picks's disease. The most prevalent elemental imbalances found in the brain were for bromine, mercury, and the alkali metals. In this study the authors report INAA studies of trace elements in nonneural tissues from Alzheimer's disease and ALS patients. Samples from household relatives were collected for use as controls wherever possible. Hair samples were washed according to the International Atomic Energy Agency recommended procedure. Fingernail samples were scraped with a quartz knife prior to washing by the same procedure. For ALS patients, blood samples were also collected. These data indicate that elemental imbalances in Alzheimer's disease and ALS are not restricted to the brain. Many elements perturbed in the brain are also altered in the several nonneural tissues examined to date. The imbalances in different tissues, however, are not always in the same direction. The changes observed may represent causes, effects, or simply epiphenomena. Longitudinal studies of nonneural tissues and blood, as well as tissue microprobe analyses at the cellular and subcellular level, will be required in order to better assess the role of trace elements in the etiology of these diseases.

  4. Disease activity, quality of life and indirect costs of psoriatic arthritis in Poland.

    PubMed

    Kawalec, Paweł; Malinowski, Krzysztof Piotr; Pilc, Andrzej

    2016-09-01

    The aim of the study was to assess the indirect costs, health-related quality of life and clinical characteristics of patients with psoriatic arthritis (PsA), measured using a PsA disease activity index in Poland. Additionally, we aimed to investigate the association between the activity, utility of PsA-affected patients and productivity loss in a Polish setting. A questionnaire survey was conducted to assess disease activity, as well as productivity loss, and a paper version of the EuroQoly-5D-3L questionnaire was used to assess productivity loss and the quality of life. Indirect costs were assessed with the human capital approach employing the gross domestic product (GDP) per capita, gross value added (GVA) and gross income (GI) per worker in 2014 in Poland and were expressed in Polish zlotys (PLN) as well as in euros. The correlation was presented using the Spearman correlation coefficient. Our analysis was performed on the basis of 50 full questionnaires collected. We observed a mean utility value of 0.6567. The mean number of days off work was 2.88 days per month, and mean on-the-job productivity loss was 24.1 %. Average monthly indirect costs per patient were €206.7 (864.01 PLN) calculated using the GDP; €484.56 (2025.46 PLN) calculated using the GVA; and €209.70 (876.56 PLN) calculated using the GI. PsA reduces the patients' quality of life as well as their productivity loss associated with both absenteeism and presenteeism. Total indirect costs were negatively correlated with utility. The greater the disease activity, the lower the utility and the greater the indirect costs. PMID:27339273

  5. Pilot surveillance for childhood encephalitis in Australia using the Paediatric Active Enhanced Disease Surveillance (PAEDS) network.

    PubMed

    Britton, P N; Dale, R C; Elliott, E; Festa, M; Macartney, K; Booy, R; Jones, C A

    2016-07-01

    We aimed to assess the performance of active surveillance for hospitalized childhood encephalitis in New South Wales (NSW) using the Paediatric Active Enhanced Disease Surveillance (PAEDS) network to inform methodology for the nationwide Australian childhood encephalitis (ACE) study. We piloted active surveillance for suspected encephalitis from May to December 2013 at the Children's Hospital at Westmead, Sydney, NSW. Cases were ascertained using four screening methods: weekday nurse screening of admission records (PAEDS), cerebrospinal fluid (CSF) microscopy records, magnetic resonance imaging (MRI) reports, and pharmacy dispensing records. Comprehensive clinical data were prospectively collected on consented participants and subsequently reviewed by an expert panel. Cases were categorized as confirmed encephalitis or 'not encephalitis'; encephalitis cases were sub-categorized as infectious, immune-mediated or unknown. We performed an ICD-10 diagnostic code audit of hospitalizations for the pilot period. We compared case ascertainment in the four screening methods and with the ICD code audit. Forty-eight cases of suspected encephalitis were identified by one or more methods. PAEDS was the most efficient mechanism (yield 34%), followed by MRI, CSF, and pharmacy audits (yield 14%, 12%, and 7% respectively). Twenty-five cases met the criteria for confirmed encephalitis. PAEDS was the most sensitive of the mechanisms for confirmed encephalitis (92%) with a positive predictive value (PPV) of 72%. The ICD audit was moderately sensitive (64%) but poorly specific (Sp 9%, PPV 14%). Of the 25 confirmed encephalitis cases, 19 (76%) were sub-categorized as infectious, three (12%) were immune-mediated, and three (12%) were 'unknown'. We identified encephalitis cases associated with two infectious disease outbreaks (enterovirus 71, parechovirus 3). PAEDS is an efficient, sensitive and accurate surveillance mechanism for detecting cases of childhood encephalitis including those

  6. Comparison of Fixed versus Calculated Activity of Radioiodine for the Treatment of Graves Disease in Adults

    PubMed Central

    Dominguez, Paulette N.; Jimeno, Cecilia A.; Obaldo, Jerry M.; Ogbac, Ruben V.

    2016-01-01

    Background Radioactive iodine as a treatment modality has been shown in several studies to be a safe and effective therapy for Graves disease. However, there is still no uniformity regarding optimal dosing method. The aim of this study is to compare the efficacy of calculated and fixed dosing of radioiodine for the treatment of Graves disease. Methods A hundred twenty-two patients diagnosed with Graves disease were randomized to receive either fixed or calculated dose of radioiodine. Those randomized to fixed activity received either low fixed activity at 9.9 mCi for thyroid gland size <40 g or high fixed activity at 14.9 mCi for thyroid gland size 40 to 80 g, and those grouped to calculated activity received 160 µCi/g of thyroid tissue adjusted for 24 hours radioiodine uptake. Thyroid function tests (free thyroxine [T4] and thyroid stimulating hormone [TSH]) were monitored at 10, 16, and 24 weeks after radioactive iodine therapy. The primary outcome, treatment failure was defined as persistently elevated free T4 and low TSH. Results Of the 122 patients randomized, 56 in the fixed dose group and 56 in the calculated dose group completed the follow-up. At the end of 6 months, the percentage of treatment failure was 37.50% in the calculated dose group versus 19.64% in the fixed dose group with a relative risk of 0.53 (95% confidence interval, 0.28 to 0.98) favoring the fixed dose group. Conclusion Fixed dose radioiodine has a significantly lower incidence of persistent hyperthyroidism at 6 months post-radioactive therapy. PMID:26996425

  7. Chagas’ disease parasite-derived neurotrophic factor activates cholinergic gene expression in neuronal PC12 cells

    PubMed Central

    Akpan, Nsikan; Caradonna, Kacey; Chuenkova, Marina V.; PereiraPerrin, Mercio

    2008-01-01

    A parasite-derived neurotrophic factor (PDNF) produced by the Chagas’ disease parasite Trypanosoma cruzi binds nerve growth factor (NGF) receptor TrkA, increasing receptor autophosphorylation, activating phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK/Erk) pathways, and transcription factor CREB. The end-result is enhanced survival and neuritogenesis of various types of neurons. PDNF also enhances the expression and activity of tyrosine hydroxylase, a rate limiting enzyme in the synthesis of dopamine and other catecholamine neurotransmitters. It remains unknown, however, if PDNF alters expression and metabolism of acetylcholine (ACh), a neurotransmitter thought to play a role in Chagas’ disease progression. Here we demonstrate that PDNF stimulates mRNA and protein expression of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT), which are critical for synthesis and storage of ACh. Stimulation requires functional TrkA because it did not occur in cell mutants that lack the receptor and in TrkA-expressing wild-type cells treated with K252a, an inhibitor of TrkA kinase activity. It also requires TrkA-dependent PI3K and MAPK/Erk signaling pathways because PDNF stimulation of cholinergic transcripts is abolished by specific pharmacological inhibitors. Furthermore, the cholinergic actions of PDNF were reproduced by PDNF-expressing extracellular T. cruzi trypomastigotes at the start of host cell invasion. In contrast, host cells bearing intracellular T. cruzi showed decreased, rather than increased, cholinergic gene expression. These results suggest that T. cruzi invasion of the nervous system alters cholinergic gene expression and that could play a role in neuropathology, and/or lack thereof, in Chagas’ disease patients. PMID:18502403

  8. Chagas' disease parasite-derived neurotrophic factor activates cholinergic gene expression in neuronal PC12 cells.

    PubMed

    Akpan, Nsikan; Caradonna, Kacey; Chuenkova, Marina V; PereiraPerrin, Mercio

    2008-06-27

    A parasite-derived neurotrophic factor (PDNF) produced by the Chagas' disease parasite Trypanosoma cruzi binds nerve growth factor (NGF) receptor TrkA, increasing receptor autophosphorylation, and activating phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK/Erk) pathways, and transcription factor CREB. The end-result is enhanced survival and neuritogenesis of various types of neurons. PDNF also enhances the expression and activity of tyrosine hydroxylase, a rate limiting enzyme in the synthesis of dopamine and other catecholamine neurotransmitters. It remains unknown, however, if PDNF alters expression and metabolism of acetylcholine (ACh), a neurotransmitter thought to play a role in Chagas' disease progression. Here we demonstrate that PDNF stimulates mRNA and protein expression of choline acetyltransferase (ChAT) and vesicular acetylcholine transporter (VAChT), which are critical for synthesis and storage of ACh. Stimulation requires functional TrkA because it did not occur in cell mutants that lack the receptor and in TrkA-expressing wild-type cells treated with K252a, an inhibitor of TrkA kinase activity. It also requires TrkA-dependent PI3K and MAPK/Erk signaling pathways because PDNF stimulation of cholinergic transcripts is abolished by specific pharmacological inhibitors. Furthermore, the cholinergic actions of PDNF were reproduced by PDNF-expressing extracellular T. cruzi trypomastigotes at the start of host cell invasion. In contrast, host cells bearing intracellular T. cruzi showed decreased, rather than increased, cholinergic gene expression. These results suggest that T. cruzi invasion of the nervous system alters cholinergic gene expression and that could play a role in neuropathology, and/or lack thereof, in Chagas' disease patients. PMID:18502403

  9. Protein Kinase Activity Decreases with Higher Braak Stages of Alzheimer’s Disease Pathology

    PubMed Central

    Rosenberger, Andrea F.N.; Hilhorst, Riet; Coart, Elisabeth; García Barrado, Leandro; Naji, Faris; Rozemuller, Annemieke J.M.; van der Flier, Wiesje M.; Scheltens, Philip; Hoozemans, Jeroen J.M.; van der Vies, Saskia M.

    2015-01-01

    Alzheimer’s disease (AD) is characterized by a long pre-clinical phase (20–30 years), during which significant brain pathology manifests itself. Disease mechanisms associated with pathological hallmarks remain elusive. Most processes associated with AD pathogenesis, such as inflammation, synaptic dysfunction, and hyper-phosphorylation of tau are dependent on protein kinase activity. The objective of this study was to determine the involvement of protein kinases in AD pathogenesis. Protein kinase activity was determined in postmortem hippocampal brain tissue of 60 patients at various stages of AD and 40 non-demented controls (Braak stages 0-VI) using a peptide-based microarray platform. We observed an overall decrease of protein kinase activity that correlated with disease progression. The phosphorylation of 96.7% of the serine/threonine peptides and 37.5% of the tyrosine peptides on the microarray decreased significantly with increased Braak stage (p-value <0.01). Decreased activity was evident at pre-clinical stages of AD pathology (Braak I-II). Increased phosphorylation was not observed for any peptide. STRING analysis in combination with pathway analysis and identification of kinases responsible for peptide phosphorylation showed the interactions between well-known proteins in AD pathology, including the Ephrin-receptor A1 (EphA1), a risk gene for AD, and sarcoma tyrosine kinase (Src), which is involved in memory formation. Additionally, kinases that have not previously been associated with AD were identified, e.g., protein tyrosine kinase 6 (PTK6/BRK), feline sarcoma oncogene kinase (FES), and fyn-associated tyrosine kinase (FRK). The identified protein kinases are new biomarkers and potential drug targets for early (pre-clinical) intervention. PMID:26519433

  10. Hypersensitivity pneumonitis in nonhuman primates: studies on the relationship of immunoregulation and disease activity

    SciTech Connect

    Keller, R.H.; Calvanico, N.J.; Stevens, J.O.

    1982-01-01

    We investigated the relationship of immunoregulation to disease activity in a nonhuman primate model of pigeon breeder's disease. Two Macaca arctoides monkeys developed classical symptoms of hypersensitivity pneumonitis after sensitization and prolonged bronchial challenge, whereas 2 other monkeys remained asymptomatic after in vivo challenge. There were no differences in the percentages of T cells, B cells, monocytes, or FC..gamma..-bearing T cells between symptomatic and asymptomatic animals. Nonetheless, we found a population of concanavalin A-induced, pigeon serum- (PS) induced, and spontaneous T cells that functioned as suppressor cells in autologous in vitro co-cultures in asymptomatic animals that were missing or nonfunctional in symptomatic animals. Monocyte suppressors functioned in both groups. We used low-dose total body irradiation (TBI) to inactivate T suppressor cells. Fifteen radiation units of TBI caused no change in the physical activity, routine chemistries, or blood counts of the 4 animals. After TBI, however, the previously asymptomatic animals developed fever, tachypnea, and signs of pulmonary congestion after in vivo challenge with PS. There was no change in the response to challenge in the symptomatic group. This altered response to in vivo challenge in the previously asymptomatic group persisted for 2 wk after TBI. During this period the difference in in vitro immunoregulatory activity between Con A-induced, PS-induced, and spontaneous T cells in symptomatic and asymptomatic animals disappeared. Monocyte suppressors, however, continued to function in both groups after TBI. these data suggest that the monkey is an appropriate model for studies of human HP and that T cell immunoregulation may be an important element in the pathogenesis and disease activity of HP.

  11. Antiviral activity of Paulownia tomentosa against enterovirus 71 of hand, foot, and mouth disease.

    PubMed

    Ji, Ping; Chen, Changmai; Hu, Yanan; Zhan, Zixuan; Pan, Wei; Li, Rongrong; Li, Erguang; Ge, Hui-Ming; Yang, Guang

    2015-01-01

    The bark, leaves, and flowers of Paulownia trees have been used in traditional Chinese medicine to treat infectious and inflammatory diseases. We investigated the antiviral effects of Paulownia tomentosa flowers, an herbal medicine used in some provinces of P. R. China for the treatment of skin rashes and blisters. Dried flowers of P. tomentosa were extracted with methanol and tested for antiviral activity against enterovirus 71 (EV71) and coxsackievirus A16 (CAV16), the predominant etiologic agents of hand, foot, and mouth disease in P. R. China. The extract inhibited EV71 infection, although no effect was detected against CAV16 infection. Bioactivity-guided fractionation was performed to identify apigenin as an active component of the flowers. The EC50 value for apigenin to block EV71 infection was 11.0 µM, with a selectivity index of approximately 9.3. Although it is a common dietary flavonoid, only apigenin, and not similar compounds like naringenin and quercetin, were active against EV71 infection. As an RNA virus, the genome of EV71 has an internal ribosome entry site that interacts with heterogeneous nuclear ribonucleoproteins (hnRNPs) and regulates viral translation. Cross-linking followed by immunoprecipitation and reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that EV71 RNA was associated with hnRNPs A1 and A2. Apigenin treatment disrupted this association, indicating that apigenin suppressed EV71 replication through a novel mechanism by targeting the trans-acting factors. This study therefore validates the effects of Paulownia against EV71 infection. It also yielded mechanistic insights on apigenin as an active compound for the antiviral activity of P. tomentosa against EV71 infection. PMID:25744451

  12. Correlation of Paraoxonase Status with Disease Activity Score and Systemic Inflammation in Rheumatoid Arthritic Patients

    PubMed Central

    Bindal, Usha Dudeja; Siddiqui, Merajul Haque; Sharma, Dilutpal

    2016-01-01

    Introduction Despite, various preventive efforts on conventional cardiovascular disease (CVD) risk factors, the incidence of CVD in rheumatoid arthritis (RA) patients increases continuously. To solve this conundrum one needs more investigations. Aim The present study was conducted to evaluate the plasma paraoxonase (PON) activity along with the markers of systemic inflammation, oxidative stress and disease activity score-28 (DAS28) in RA patients and clarify their role in determining the probability of RA patients to develop future CVD risk. Materials and Methods Plasma PON, total antioxidant activity (TAA), C-reactive protein (CRP), synovial interleukin-6 (IL-6) and erythrocyte malondialdehyde (MDA) levels were estimated in 40 RA patients aged 40-55 years aged and 40 age-matched healthy controls. The data obtained were compared statistically by using Student’s t-test and Pearson correlation test. Results Besides dyslipidaemia, marked reduction in plasma PON and TAA (p< 0.05) were observed in RA patients as compared with that of healthy controls. Erythrocyte MDA, plasma CRP and synovial IL-6 levels were increased significantly (p<0.05) in RA patients. PON was negatively correlated with MDA (r = - 0.672; p < 0.001), CRP (r = -0.458; p<0.05), IL-6 (r = -0.426; p<0.05) and DAS28 (r = -0.598; p < 0.001), and positively correlated with HDL cholesterol (r = 0.648; p<0.001) and TAA (r = 0.608; p< 0.001) levels in RA patients. Conclusion Alteration in PON activity might contribute to the progression of future CVD risk in RA patients, which may result from interplay of several confounding factors, such as inflammation, oxidative stress and dyslipidaemia. Furthermore, plasma PON activity, CRP and TAA levels could be considered as non-traditional factors to predict CVD risk. Thus, it is suggested that future drugs could be developed to target the non-traditional risk factors in RA patients. PMID:27134854

  13. The Impact of Physical Activity on Non-Motor Symptoms in Parkinson's Disease: A Systematic Review.

    PubMed

    Cusso, Melanie E; Donald, Kenneth J; Khoo, Tien K

    2016-01-01

    Parkinson's disease (PD) is a neurological disorder that is associated with both motor and non-motor symptoms (NMS). The management of PD is primarily via pharmaceutical treatment; however, non-pharmaceutical interventions have become increasingly recognized in the management of motor and NMS. In this review, the efficacy of physical activity, including physiotherapy and occupational therapy, as an intervention in NMS will be assessed. The papers were extracted between the 20th and 22nd of June 2016 from PubMed, Web of Science, Medline, Ovid, SportsDiscuss, and Scopus using the MeSH search terms "Parkinson's," "Parkinson," and "Parkinsonism" in conjunction with "exercise," "physical activity," "physiotherapy," "occupational therapy," "physical therapy," "rehabilitation," "dance," and "martial arts." Twenty studies matched inclusion criteria of having 10 or more participants with diagnosed idiopathic PD participating in the intervention as well as having to evaluate the effects of physical activity on NMS in PD as controlled, randomized intervention studies. The outcomes of interest were NMS, including depression, cognition, fatigue, apathy, anxiety, and sleep. Risk of bias in the studies was evaluated using the Cochrane Collaboration's tool for assessing risk of bias. Comparability of the various intervention methods, however, was challenging due to demographic variability and methodological differences. Nevertheless, physical activity can positively impact the global NMS burden including depression, apathy, fatigue, day time sleepiness, sleep, and cognition, thus supporting its therapeutic potential in neurodegenerative conditions such as PD. It is recommended that further adequately powered studies are conducted to assess the therapeutic role of physical activity on both motor and non-motor aspects of PD. These studies should be optimally designed to assess non-motor elements of disease using instruments validated in PD. PMID:27583249

  14. Selective targeting of TGF-β activation to treat fibroinflammatory airway disease.

    PubMed

    Minagawa, Shunsuke; Lou, Jianlong; Seed, Robert I; Cormier, Anthony; Wu, Shenping; Cheng, Yifan; Murray, Lynne; Tsui, Ping; Connor, Jane; Herbst, Ronald; Govaerts, Cedric; Barker, Tyren; Cambier, Stephanie; Yanagisawa, Haruhiko; Goodsell, Amanda; Hashimoto, Mitsuo; Brand, Oliver J; Cheng, Ran; Ma, Royce; McKnelly, Kate J; Wen, Weihua; Hill, Arthur; Jablons, David; Wolters, Paul; Kitamura, Hideya; Araya, Jun; Barczak, Andrea J; Erle, David J; Reichardt, Louis F; Marks, James D; Baron, Jody L; Nishimura, Stephen L

    2014-06-18

    Airway remodeling, caused by inflammation and fibrosis, is a major component of chronic obstructive pulmonary disease (COPD) and currently has no effective treatment. Transforming growth factor-β (TGF-β) has been widely implicated in the pathogenesis of airway remodeling in COPD. TGF-β is expressed in a latent form that requires activation. The integrin αvβ8 (encoded by the itgb8 gene) is a receptor for latent TGF-β and is essential for its activation. Expression of integrin αvβ8 is increased in airway fibroblasts in COPD and thus is an attractive therapeutic target for the treatment of airway remodeling in COPD. We demonstrate that an engineered optimized antibody to human αvβ8 (B5) inhibited TGF-β activation in transgenic mice expressing only human and not mouse ITGB8. The B5 engineered antibody blocked fibroinflammatory responses induced by tobacco smoke, cytokines, and allergens by inhibiting TGF-β activation. To clarify the mechanism of action of B5, we used hydrodynamic, mutational, and electron microscopic methods to demonstrate that αvβ8 predominantly adopts a constitutively active, extended-closed headpiece conformation. Epitope mapping and functional characterization of B5 revealed an allosteric mechanism of action due to locking-in of a low-affinity αvβ8 conformation. Collectively, these data demonstrate a new model for integrin function and present a strategy to selectively target the TGF-β pathway to treat fibroinflammatory airway diseases. PMID:24944194

  15. Selective Targeting of TGF-β Activation to Treat Fibroinflammatory Airway Disease

    PubMed Central

    Minagawa, Shunsuke; Lou, Jianlong; Seed, Robert I.; Cormier, Anthony; Wu, Shenping; Cheng, Yifan; Murray, Lynne; Tsui, Ping; Connor, Jane; Herbst, Ronald; Govaerts, Cedric; Barker, Tyren; Cambier, Stephanie; Yanagisawa, Haruhiko; Goodsell, Amanda; Hashimoto, Mitsuo; Brand, Oliver J.; Cheng, Ran; Ma, Royce; McKnelly, Kate J.; Wen, Weihua; Hill, Arthur; Jablons, David; Wolters, Paul; Kitamura, Hideya; Araya, Jun; Barczak, Andrea J.; Erle, David J.; Reichardt, Louis F.; Marks, James D.; Baron, Jody L.; Nishimura, Stephen L.

    2015-01-01

    Airway remodeling, caused by inflammation and fibrosis, is a major component of chronic obstructive pulmonary disease (COPD) and currently has no effective treatment. Transforming growth factor–β (TGF-β) has been widely implicated in the pathogenesis of airway remodeling in COPD. TGF-β is expressed in a latent form that requires activation. The integrin αvβ8 (encoded by the itgb8 gene) is a receptor for latent TGF-β and is essential for its activation. Expression of integrin αvβ8 is increased in airway fibroblasts in COPD and thus is an attractive therapeutic target for the treatment of airway remodeling in COPD. We demonstrate that an engineered optimized antibody to human αvβ8 (B5) inhibited TGF-β activation in transgenic mice expressing only human and not mouse ITGB8. The B5 engineered antibody blocked fibroinflammatory responses induced by tobacco smoke, cytokines, and allergens by inhibiting TGF-β activation. To clarify the mechanism of action of B5, we used hydrodynamic, mutational, and electron microscopic methods to demonstrate that αvβ8 predominantly adopts a constitutively active, extended-closed headpiece conformation. Epitope mapping and functional characterization of B5 revealed an allosteric mechanism of action due to locking-in of a low-affinity αvβ8 conformation. Collectively, these data demonstrate a new model for integrin function and present a strategy to selectively target the TGF-β pathway to treat fibroinflammatory airway diseases. PMID:24944194

  16. Activation of Asparaginyl Endopeptidase Leads to Tau Hyperphosphorylation in Alzheimer Disease*

    PubMed Central

    Basurto-Islas, Gustavo; Grundke-Iqbal, Inge; Tung, Yunn Chyn; Liu, Fei; Iqbal, Khalid

    2013-01-01

    Neurofibrillary pathology of abnormally hyperphosphorylated Tau is a key lesion of Alzheimer disease and other tauopathies, and its density in the brain directly correlates with dementia. The phosphorylation of Tau is regulated by protein phosphatase 2A, which in turn is regulated by inhibitor 2, I2PP2A. In acidic conditions such as generated by brain ischemia and hypoxia, especially in association with hyperglycemia as in diabetes, I2PP2A is cleaved by asparaginyl endopeptidase at Asn-175 into the N-terminal fragment (I2NTF) and the C-terminal fragment (I2CTF). Both I2NTF and I2CTF are known to bind to the catalytic subunit of protein phosphatase 2A and inhibit its activity. Here we show that the level of activated asparaginyl endopeptidase is significantly increased, and this enzyme and I2PP2A translocate, respectively, from neuronal lysosomes and nucleus to the cytoplasm where they interact and are associated with hyperphosphorylated Tau in Alzheimer disease brain. Asparaginyl endopeptidase from Alzheimer disease brain could cleave GST-I2PP2A, except when I2PP2A was mutated at the cleavage site Asn-175 to Gln. Finally, an induction of acidosis by treatment with kainic acid or pH 6.0 medium activated asparaginyl endopeptidase and consequently produced the cleavage of I2PP2A, inhibition of protein phosphatase 2A, and hyperphosphorylation of Tau, and the knockdown of asparaginyl endopeptidase with siRNA abolished this pathway in SH-SY5Y cells. These findings suggest the involvement of brain acidosis in the etiopathogenesis of Alzheimer disease, and asparaginyl endopeptidase-I2PP2A-protein phosphatase 2A-Tau hyperphosphorylation pathway as a therapeutic target. PMID:23640887

  17. Increased oxidative stress in pemphigus vulgaris is related to disease activity and HLA-association.

    PubMed

    Shah, Amit Aakash; Dey-Rao, Rama; Seiffert-Sinha, Kristina; Sinha, Animesh A

    2016-06-01

    Pemphigus vulgaris (PV) is a rare blistering skin disorder characterized by the disadhesion of keratinocytes due to autoantibody attack against epidermal targets including desmoglein (Dsg) 3, Dsg 1 and possibly other adhesion and non-adhesion molecules. The mechanisms leading to immune-mediated pathology in PV are multifactorial and not fully understood. Recently, oxidative stress (antioxidant/oxidant disequilibrium) has been proposed as a contributory mechanism of autoimmune skin diseases, including PV. In this study, we directly assessed oxidative stress via measurement of total antioxidant capacity (TAC) using ELISA in 47 PV patients, 25 healthy controls and 18 bullous pemphigoid (BP) patients. We also performed microarray gene expression analysis on a separate set of 21 PV patients and 10 healthy controls to evaluate transcriptional dysregulation in oxidative stress-related pathways. Our data indicate that there is a significant reduction in TAC levels in PV patients compared with healthy controls, as well as BP patients. Furthermore, PV patients with active disease have significantly lower TAC levels than PV patients in remission. We also find that HLA allele status has a significant influence on oxidative stress. These findings are corroborated by microarray analysis showing differentially expressed genes involved in oxidative stress between the aforementioned groups. Collectively, our findings provide support for a role of oxidative stress in PV. Whether increased oxidative stress leads to disease manifestation and/or activity, or if disease activity leads to increased oxidative stress remains unknown. Future longitudinal studies may help to further elucidate the relationship between PV and oxidative stress. PMID:26911801

  18. Serum Vitamin D Level and Rheumatoid Arthritis Disease Activity: Review and Meta-Analysis

    PubMed Central

    Lin, Jin; Liu, Jian; Davies, Michael L.; Chen, Weiqian

    2016-01-01

    Background The evidence from epidemiological studies concerning the relationship between serum vitamin D concentrations and rheumatoid arthritis (RA) is inconsistent. This meta-analysis is aimed at determining the magnitude of the correlation between this common autoimmune disease and vitamin D, an important nutrient known to dampen adaptive immune responses. Methods Through multiple search strategies, relevant literature was identified and evaluated for quality before May 16 2015. Data extracted from eligible studies was synthesized to calculate pooled correlation coefficient (r), mean difference (MD) and odds ratio (OR). The Venice criteria were applied to assess the credibility of the evidence for each statistically significant association. Results A total of 24 reports involving 3489 patients were selected for analysis. RA patients had lower vitamin D levels than healthy controls (MD:-16.52 nmol/L, 95% confidence intervals [CI]:-18.85 to -14.19 nmol/L). There existed a negative relationship between serum 25-hydroxyvitamin D (25OHD) level and disease activity index, e.g. 25OHD vs. Disease Activity Score in 28 joints (DAS28): r = -0.13, 95% CI -0.16 to -0.09; 25OHD vs. C-reactive protein: r = -0.12, 95% CI -0.23 to -0.00. Additionally, latitude-stratified subgroup analysis yielded a relatively stronger negative correlation between 25OHD and DAS28 in low-latitude areas. This inverse relationship also appeared more significant in developing countries than in developed countries. No publication bias was detected. Conclusion RA patients had lower vitamin D values than healthy controls. There was a negative association between serum vitamin D and RA disease activity. However, more strictly controlled studies are needed to validate these findings. PMID:26751969

  19. Sleep and its relationship to pain, dysfunction, and disease activity in juvenile idiopathic arthritis.

    PubMed

    Shyen, S; Amine, B; Rostom, S; E L Badri, D; Ezzahri, M; Mawani, N; Moussa, F; Gueddari, S; Wabi, M; Abouqal, R; Chkirate, B; Hajjaj-Hassouni, N

    2014-01-01

    The objective of this study was to determine the sleep abnormalities that may exist in Moroccan children with juvenile idiopathic arthritis (JIA) and their relationship to pain, dysfunction, and disease activity. Case control study including 47 patients diagnosed with JIA, according to the criteria of the International League of Associations for Rheumatology (ILAR), and 47 healthy children, age and sex matched. Sleep was assessed by Children's Sleep Habits Questionnaire (CSHQ). All parents have filled the 45 items of the CSHQ and grouped into eight subscales: bedtime resistance, sleep onset delay, sleep duration, sleep anxiety, sleep-disordered breathing, night awakenings, parasomnias, and morning awakening/daytime sleepiness. The disease activity was assessed by the number of painful joints, swelling joints, erythrocyte sedimentation rate, c-protein reactive, and Juvenile Arthritis Disease Activity Score (JADAS). Functional assessment was based on the value of Childhood Health Assessment Questionnaire. Pain was assessed by visual analog scale pain. Forty-seven patients were included, with 28 males (59.6 %). Children with JIA had a total score of CSHQ significantly higher than the control cases (p < 0.0001); significant differences were also found in the subscale sleep onset delay, sleep anxiety, sleep-disordered breathing, night awakenings, and parasomnias with a p value of <0.0001, 0.034, <0.0001, 0.001, and 0.00, respectively. Significant association was found between the CSHQ total score and visual analog scale (VAS) physician activity (p = 0.016) and JADAS (p = 0.05). There was a correlation between the sleep-disordered breathing and JADAS (p = 0.04). Sleep onset delay was associated with VAS patient pain (p = 0.05), as nocturnal awakenings and VAS patient pain (p = 0.016). Finally, parasomnias and physician's VAS activity (p = 0.015) and VAS patient pain (p = 0.03) were also correlated. This study suggests that sleep

  20. Foodborne Diseases Active Surveillance Network-2 Decades of Achievements, 1996-2015.

    PubMed

    Henao, Olga L; Jones, Timothy F; Vugia, Duc J; Griffin, Patricia M

    2015-09-01

    The Foodborne Diseases Active Surveillance Network (FoodNet) provides a foundation for food safety policy and illness prevention in the United States. FoodNet conducts active, population-based surveillance at 10 US sites for laboratory-confirmed infections of 9 bacterial and parasitic pathogens transmitted commonly through food and for hemolytic uremic syndrome. Through FoodNet, state and federal scientists collaborate to monitor trends in enteric illnesses, identify their sources, and implement special studies. FoodNet's major contributions include establishment of reliable, active population-based surveillance of enteric diseases; development and implementation of epidemiologic studies to determine risk and protective factors for sporadic enteric infections; population and laboratory surveys that describe the features of gastrointestinal illnesses, medical care-seeking behavior, frequency of eating various foods, and laboratory practices; and development of a surveillance and research platform that can be adapted to address emerging issues. The importance of FoodNet's ongoing contributions probably will grow as clinical, laboratory, and informatics technologies continue changing rapidly. PMID:26292181

  1. Mitochondrial ATP synthase activity is impaired by suppressed O-GlcNAcylation in Alzheimer's disease.

    PubMed

    Cha, Moon-Yong; Cho, Hyun Jin; Kim, Chaeyoung; Jung, Yang Ouk; Kang, Min Jueng; Murray, Melissa E; Hong, Hyun Seok; Choi, Young-Joo; Choi, Heesun; Kim, Dong Kyu; Choi, Hyunjung; Kim, Jisoo; Dickson, Dennis W; Song, Hyun Kyu; Cho, Jin Won; Yi, Eugene C; Kim, Jungsu; Jin, Seok Min; Mook-Jung, Inhee

    2015-11-15

    Glycosylation with O-linked β-N-acetylglucosamine (O-GlcNAc) is one of the protein glycosylations affecting various intracellular events. However, the role of O-GlcNAcylation in neurodegenerative diseases such as Alzheimer's disease (AD) is poorly understood. Mitochondrial adenosine 5'-triphosphate (ATP) synthase is a multiprotein complex that synthesizes ATP from ADP and Pi. Here, we found that ATP synthase subunit α (ATP5A) was O-GlcNAcylated at Thr432 and ATP5A O-GlcNAcylation was decreased in the brains of AD patients and transgenic mouse model, as well as Aβ-treated cells. Indeed, Aβ bound to ATP synthase directly and reduced the O-GlcNAcylation of ATP5A by inhibition of direct interaction between ATP5A and mitochondrial O-GlcNAc transferase, resulting in decreased ATP production and ATPase activity. Furthermore, treatment of O-GlcNAcase inhibitor rescued the Aβ-induced impairment in ATP production and ATPase activity. These results indicate that Aβ-mediated reduction of ATP synthase activity in AD pathology results from direct binding between Aβ and ATP synthase and inhibition of O-GlcNAcylation of Thr432 residue on ATP5A. PMID:26358770

  2. The Activity of Menkes Disease Protein ATP7A Is Essential for Redox Balance in Mitochondria*

    PubMed Central

    Bhattacharjee, Ashima; Yang, Haojun; Duffy, Megan; Robinson, Emily; Conrad-Antoville, Arianrhod; Lu, Ya-Wen; Capps, Tony; Braiterman, Lelita; Wolfgang, Michael; Murphy, Michael P.; Yi, Ling; Kaler, Stephen G.; Lutsenko, Svetlana; Ralle, Martina

    2016-01-01

    Copper-transporting ATPase ATP7A is essential for mammalian copper homeostasis. Loss of ATP7A activity is associated with fatal Menkes disease and various other pathologies. In cells, ATP7A inactivation disrupts copper transport from the cytosol into the secretory pathway. Using fibroblasts from Menkes disease patients and mouse 3T3-L1 cells with a CRISPR/Cas9-inactivated ATP7A, we demonstrate that ATP7A dysfunction is also damaging to mitochondrial redox balance. In these cells, copper accumulates in nuclei, cytosol, and mitochondria, causing distinct changes in their redox environment. Quantitative imaging of live cells using GRX1-roGFP2 and HyPer sensors reveals highest glutathione oxidation and elevation of H2O2 in mitochondria, whereas the redox environment of nuclei and the cytosol is much less affected. Decreasing the H2O2 levels in mitochondria with MitoQ does not prevent glutathione oxidation; i.e. elevated copper and not H2O2 is a primary cause of glutathione oxidation. Redox misbalance does not significantly affect mitochondrion morphology or the activity of respiratory complex IV but markedly increases cell sensitivity to even mild glutathione depletion, resulting in loss of cell viability. Thus, ATP7A activity protects mitochondria from excessive copper entry, which is deleterious to redox buffers. Mitochondrial redox misbalance could significantly contribute to pathologies associated with ATP7A inactivation in tissues with paradoxical accumulation of copper (i.e. renal epithelia). PMID:27226607

  3. The Activity of Menkes Disease Protein ATP7A Is Essential for Redox Balance in Mitochondria.

    PubMed

    Bhattacharjee, Ashima; Yang, Haojun; Duffy, Megan; Robinson, Emily; Conrad-Antoville, Arianrhod; Lu, Ya-Wen; Capps, Tony; Braiterman, Lelita; Wolfgang, Michael; Murphy, Michael P; Yi, Ling; Kaler, Stephen G; Lutsenko, Svetlana; Ralle, Martina

    2016-08-01

    Copper-transporting ATPase ATP7A is essential for mammalian copper homeostasis. Loss of ATP7A activity is associated with fatal Menkes disease and various other pathologies. In cells, ATP7A inactivation disrupts copper transport from the cytosol into the secretory pathway. Using fibroblasts from Menkes disease patients and mouse 3T3-L1 cells with a CRISPR/Cas9-inactivated ATP7A, we demonstrate that ATP7A dysfunction is also damaging to mitochondrial redox balance. In these cells, copper accumulates in nuclei, cytosol, and mitochondria, causing distinct changes in their redox environment. Quantitative imaging of live cells using GRX1-roGFP2 and HyPer sensors reveals highest glutathione oxidation and elevation of H2O2 in mitochondria, whereas the redox environment of nuclei and the cytosol is much less affected. Decreasing the H2O2 levels in mitochondria with MitoQ does not prevent glutathione oxidation; i.e. elevated copper and not H2O2 is a primary cause of glutathione oxidation. Redox misbalance does not significantly affect mitochondrion morphology or the activity of respiratory complex IV but markedly increases cell sensitivity to even mild glutathione depletion, resulting in loss of cell viability. Thus, ATP7A activity protects mitochondria from excessive copper entry, which is deleterious to redox buffers. Mitochondrial redox misbalance could significantly contribute to pathologies associated with ATP7A inactivation in tissues with paradoxical accumulation of copper (i.e. renal epithelia). PMID:27226607

  4. A Survey on the Willingness to Use Physical Activity Smartphone Applications (Apps) in Patients with Chronic Diseases.

    PubMed

    Sun, Liu; Jiao, Chen; Wang, Yanling; Xiao, Qian; Zhang, Yiling; Wu, Ying

    2016-01-01

    This study aimed to explore the willingness of using physical activity smartphone apps among patients with chronic diseases. 218 outpatients from a tertiary hospital in Beijing were involved using a questionnaire. Over half of the patients (53.7%) were willing to use smartphone apps to promote physical activities. The individuals more likely to use physical activity apps tended to be younger (≤44 years), be more educated, perceiving their disease need exercise instruction or professional support, current smartphone user, having previous experience of using physical activity apps, and accepting paid apps (P<0.05). The results could help health educator suggest chronic disease patients to use apps to do more exercises. Further research could be focus on evaluate the effects of using physical activity apps in chronic disease patients. PMID:27332468

  5. Reduced Denitration Activity in Peripheral Lung of Chronic Obstructive Pulmonary Disease

    PubMed Central

    Osoata, Grace O.; Ito, Misako; Elliot, Mark; Hogg, James; Barnes, Peter J.

    2012-01-01

    Background Accumulation of nitrated protein is seen in peripheral lung and cells from patients with chronic obstructive pulmonary disease (COPD). Nitrated protein causes abnormal protein function, but the nitration was believed to be an irreversible process. However, there are accumulating evidences that this process is reversible by an active denitration pathway. The aim of this study is to detect denitration activity in protein extracts from peripheral lung tissue of COPD and to compare with those in healthy subjects. Materials and Methods Peripheral lung tissue from 4 healthy, 4 smokers without COPD, 4 GOLD stage 1 and 4 GOLD stage 2 were used for denitration assay. Denitration activity was determined as reduction of nitro-tyrosine level of nitrated histone protein after incubation with protein extracts from peripheral lung, which was determined by western blotting. In addition, RNA is extracted from peripheral lung of 8 healthy, 7 smoking control, 8 stage 1 and 2 COPD and 10 stage 3 and 4 COPD and nitrate reductase mRNA expression was determined by real time RT-PCR. Results Peripheral lung protein extracts from healthy subjects reduced nitro-tyrosine level of nitrated histone. Thus, we were able to show denitration activity in peripheral lungs. The denitration activity was slightly reduced in smoking controls, and significantly reduced in COPD patients. We also showed that the expression of the human homologue of nitrate reductase (chytochrome β2 reductase), a potential candidate of denitrase, was significanty reduced in COPD lung. Conclusion This study suggests that accumulation of nitrated protein in lung tissue of COPD may, at least in part, be induced by a reduction in denitration activity or nitrate reductase. PMID:25191434

  6. Sexual activity and concerns in people with coronary heart disease from a population-based study

    PubMed Central

    Steptoe, Andrew; Jackson, Sarah E; Wardle, Jane

    2016-01-01

    Objective Sexual activity is a central component of intimate relationships, but sexual function may be impaired by coronary heart disease (CHD). There have been few representative population-based comparisons of sexual behaviour and concerns in people with and without CHD. We therefore investigated these issues in a large nationally representative sample of older people. Methods We analysed cross-sectional data from 2979 men and 3711 women aged 50 and older from the English Longitudinal Study of Ageing. Sexual behaviour and concerns were assessed by validated self-completion questionnaire and analyses were weighted for non-response. Covariates included age, partnerships status and comorbidities. Results There were 376 men and 279 women with CHD. Men with CHD were less likely to be sexually active (68.7% vs 80.0%, adjusted OR 0.62, 95% CI 0.47 to 0.81), thought less about sex (74.7% vs 81.9%, OR 0.72, CI 0.54 to 0.95), and reported more erectile difficulties (47.4% vs 38.1%, OR 1.46, CI 1.10 to 1.93) than men without CHD. Effects were more pronounced among those diagnosed within the past 4 years. Women diagnosed <4 years ago were also less likely to be sexually active (35.4% vs 55.6%, OR 0.44, CI 0.23 to 0.84). There were few differences in concerns about sexual activity. Cardiovascular medication showed weak associations with erectile dysfunction. Conclusions There is an association between CHD and sexual activity, particularly among men, but the impact of CHD is limited. More effective advice after diagnosis might reverse the reduction in sexual activity, leading to improved quality of life. PMID:27126394

  7. The increased risk of active tuberculosis disease in patients with dermatomyositis – a nationwide retrospective cohort study

    PubMed Central

    Wu, Ping-Hsun; Lin, Yi-Ting; Yang, Yi-Hsin; Lin, Yu-Chih; Lin, Yi-Ching

    2015-01-01

    The risk of active tuberculosis (TB) in patients with dermatomyositis (DM) is poorly understood. The cohort study aimed to investigate the association between DM and the risk of active TB disease. We conducted a population based study on 4,958 patients with newly diagnosed DM and 19,832 matched controls according to age, sex, and index date between 1998 and 2008. The hazard ratios (HRs) and cumulative incidences of active TB disease between DM patients and controls were analyzed. During the study period, a total of 85 (1.7%) DM patients developed active TB disease, which was significantly higher than that of non-DM patients (0.64%). The incidence rate of active TB disease was higher among DM patients than controls (incidence rate ratio 2.95; 95% confidence interval [CI], 2.24 to 3.88). The Cox regression model demonstrated significantly higher active TB disease rate among DM patients compared with controls (adjusted HR, 2.64; 95% CI, 1.97 to 3.54; p < 0.001) after adjusting for age, sex, and underlying medical disorders. The most significant risk factors for developing active TB included male sex, diabetes mellitus comorbidity, and use of corticosteroids and azathioprine in DM patients. In conclusion, DM patients are at a greater risk for active TB disease. PMID:26573418

  8. Activation detector

    DOEpatents

    Bell, Zane William [Oak Ridge, TN; Boatner, Lynn Allen [Oak Ridge, TN

    2009-12-08

    A method of detecting an activator, the method including impinging with an activator a receptor material lacking a photoluminescent material and generating a by-product of a radioactive decay due to the activator impinging the reeptor material. The method further including, generating light from the by-product via the Cherenkov effect and identifying a characteristic of the activator based on the light.

  9. Role of proteolytic activation of protein kinase Cδ in the pathogenesis of prion disease

    PubMed Central

    Harischandra, Dilshan S; Kondru, Naveen; Martin, Dustin P; Kanthasamy, Arthi; Jin, Huajun; Anantharam, Vellareddy; Kanthasamy, Anumantha G

    2014-01-01

    Prion diseases are infectious and inevitably fatal neurodegenerative diseases characterized by prion replication, widespread protein aggregation and spongiform degeneration of major brain regions controlling motor function. Oxidative stress has been implicated in prion-related neuronal degeneration, but the molecular mechanisms underlying prion-induced oxidative damage are not well understood. In this study, we evaluated the role of oxidative stress-sensitive, pro-apoptotic protein kinase Cδ (PKCδ) in prion-induced neuronal cell death using cerebellar organotypic slice cultures (COSC) and mouse models of prion diseases. We found a significant upregulation of PKCδ in RML scrapie-infected COSC, as evidenced by increased levels of both PKCδ protein and its mRNA. We also found an enhanced regulatory phosphorylation of PKCδ at its two regulatory sites, Thr505 in the activation loop and Tyr311 at the caspase-3 cleavage site. The prion infection also induced proteolytic activation of PKCδ in our COSC model. Immunohistochemical analysis of scrapie-infected COSC revealed loss of PKCδ positive Purkinje cells and enhanced astrocyte proliferation. Further examination of PKCδ signaling in the RML scrapie adopted in vivo mouse model showed increased proteolytic cleavage and Tyr 311 phosphorylation of the kinase. Notably, we observed a delayed onset of scrapie-induced motor symptoms in PKCδ knockout (PKCδ−/−) mice as compared with wild-type (PKCδ+/+) mice, further substantiating the role of PKCδ in prion disease. Collectively, these data suggest that PKCδ signaling likely plays a role in the neurodegenerative processes associated with prion diseases. PMID:24576946

  10. Preventing severe respiratory syncytial virus disease: passive, active immunisation and new antivirals.

    PubMed

    Murray, Joanna; Saxena, Sonia; Sharland, Mike

    2014-05-01

    In most high-income countries palivizumab prophylaxis is considered safe, efficacious and cost-effective for preventing respiratory syncytial virus (RSV) hospital admissions among specific subgroups of infants born preterm, with chronic lung disease or with congenital heart disease. Virtually all babies acquire RSV during infancy and previously healthy babies are not eligible to receive palivizumab. Emerging evidence suggests some benefit of palivizumab use in reducing recurrent wheeze among infants born preterm. Better longitudinal studies are needed to examine its clinical and cost-effectiveness on recurrent and chronic respiratory illness and associated healthcare burden on resources in the community and hospitals. Since 99% of child deaths attributed to RSV occur in resource poor countries where expensive prophylaxis is not available or affordable, palivizumab has limited potential to impact on the current global burden of RSV lower respiratory tract infection (LRTI). A range of candidate vaccines for active immunisation against RSV are now in clinical trials. Two promising new antivirals are also currently in phase I/II trials to test their effectiveness in preventing severe RSV LRTI. These agents may be effective in preventing severe disease and phase III studies are in development. In the absence of effective active immunisation against RSV infection, population level approaches to prevent severe RSV LRTI should continue to focus on reducing prenatal and environmental risk factors including prematurity, smoking and improving hygiene practices. PMID:24464977

  11. Lipoproteins, inflammatory biomarkers, and cardiovascular imaging in the assessment of atherosclerotic disease activity.

    PubMed

    Vanhecke, Thomas E; Franklin, Barry A; Maciejko, James; Chinnaiyan, Kavitha; McCullough, Peter A

    2009-01-01

    Atherosclerosis is present in about 50% of asymptomatic adults at middle age and in nearly all elderly individuals. The traditional diagnostic and treatment paradigm has addressed risk detection and reduction of binary events, including myocardial infarction (MI), stroke, and cardiovascular death. About 50% of all acute coronary syndromes occur in previously asymptomatic subjects, 90% of whom have modifiable risk factors; yet our current screening approaches fail to prevent the 1.2 million acute cardiovascular events that occur annually in the United States. In a patient with active disease, multiple treatment targets can be approached with a variety of lifestyle changes and medical therapy to render the disease quiescent in theory. A future approach may be interception of atherosclerosis before the identification of theoretical or actual risk of episodic events. This case review highlights use of advanced biomarkers and imaging to assess atherosclerotic disease activity in a 49-year-old asymptomatic woman who presents for evaluation after the death of her father from MI. PMID:19367236

  12. The Role of MR Enterography in Assessing Crohn's Disease Activity and Treatment Response.

    PubMed

    Moy, Matthew P; Sauk, Jenny; Gee, Michael S

    2016-01-01

    MR enterography (MRE) has become the primary imaging modality in the assessment of Crohn's disease (CD) in both children and adults at many institutions in the United States and worldwide, primarily due to its noninvasiveness, superior soft tissue contrast, and lack of ionizing radiation. MRE technique includes distention of the small bowel with oral contrast media with the acquisition of T2-weighted, balanced steady-state free precession, and multiphase T1-weighted fat suppressed gadolinium contrast-enhanced sequences. With the introduction of molecule-targeted biologic agents into the clinical setting for CD and their potential to reverse the inflammatory process, MRE is increasingly utilized to evaluate disease activity and response to therapy as an imaging complement to clinical indices or optical endoscopy. New and emerging MRE techniques, such as diffusion-weighted imaging (DWI), magnetization transfer, ultrasmall superparamagnetic iron oxide- (USPIO-) enhanced MRI, and PET-MR, offer the potential for an expanded role of MRI in detecting occult disease activity, evaluating early treatment response/resistance, and differentiating inflammatory from fibrotic strictures. Familiarity with MR enterography is essential for radiologists and gastroenterologists as the technique evolves and is further incorporated into the clinical management of CD. PMID:26819611

  13. The Role of MR Enterography in Assessing Crohn's Disease Activity and Treatment Response

    PubMed Central

    Moy, Matthew P.; Sauk, Jenny; Gee, Michael S.

    2016-01-01

    MR enterography (MRE) has become the primary imaging modality in the assessment of Crohn's disease (CD) in both children and adults at many institutions in the United States and worldwide, primarily due to its noninvasiveness, superior soft tissue contrast, and lack of ionizing radiation. MRE technique includes distention of the small bowel with oral contrast media with the acquisition of T2-weighted, balanced steady-state free precession, and multiphase T1-weighted fat suppressed gadolinium contrast-enhanced sequences. With the introduction of molecule-targeted biologic agents into the clinical setting for CD and their potential to reverse the inflammatory process, MRE is increasingly utilized to evaluate disease activity and response to therapy as an imaging complement to clinical indices or optical endoscopy. New and emerging MRE techniques, such as diffusion-weighted imaging (DWI), magnetization transfer, ultrasmall superparamagnetic iron oxide- (USPIO-) enhanced MRI, and PET-MR, offer the potential for an expanded role of MRI in detecting occult disease activity, evaluating early treatment response/resistance, and differentiating inflammatory from fibrotic strictures. Familiarity with MR enterography is essential for radiologists and gastroenterologists as the technique evolves and is further incorporated into the clinical management of CD. PMID:26819611

  14. Aryl Hydrocarbon Receptor Activation by TCDD Reduces Inflammation Associated with Crohn's Disease

    PubMed Central

    Benson, Jenna M.; Shepherd, David M.

    2011-01-01

    Crohn's disease results from a combination of genetic and environmental factors that trigger an inappropriate immune response to commensal gut bacteria. The aryl hydrocarbon receptor (AhR) is well known for its involvement in the toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental contaminant that affects people primarily through the diet. Recently, TCDD was shown to suppress immune responses by generating regulatory T cells (Tregs). We hypothesized that AhR activation dampens inflammation associated with Crohn's disease. To test this hypothesis, we utilized the 2,4,6-trinitrobenzenesulfonic acid (TNBS) murine model of colitis. Mice were gavaged with TCDD prior to colitis induction with TNBS. Several parameters were examined including colonic inflammation via histological and flow cytometric analyses. TCDD-treated mice recovered body weight faster and experienced significantly less colonic damage. Reduced levels of interleukin (IL) 6, IL-12, interferon-gamma, and tumor necrosis factor-α demonstrated suppression of inflammation in the gut following TCDD exposure. Forkhead box P3 (Foxp3)egfp mice revealed that TCDD increased the Foxp3+ Treg population in gut immune tissue following TNBS exposure. Collectively, these results suggest that activation of the AhR by TCDD decreases colonic inflammation in a murine model of colitis in part by generating regulatory immune cells. Ultimately, this work may lead to the development of more effective therapeutics for the treatment of Crohn's disease. PMID:21131560

  15. The Relationship between Coenzyme Q10, Oxidative Stress, and Antioxidant Enzymes Activities and Coronary Artery Disease

    PubMed Central

    Lee, Bor-Jen; Lin, Yi-Chin; Huang, Yi-Chia; Ko, Ya-Wen; Hsia, Simon; Lin, Ping-Ting

    2012-01-01

    A higher oxidative stress may contribute to the pathogenesis of coronary artery disease (CAD). The purpose of this study was to investigate the relationship between coenzyme Q10 concentration and lipid peroxidation, antioxidant enzymes activities and the risk of CAD. Patients who were identified by cardiac catheterization as having at least 50% stenosis of one major coronary artery were assigned to the case group (n = 51). The control group (n = 102) comprised healthy individuals with normal blood biochemical values. The plasma coenzyme Q10, malondialdehyde (MDA) and antioxidant enzymes activities (catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx)) were measured. Subjects with CAD had significant lower plasma coenzyme Q10, CAT and GPx activities and higher MDA and SOD levels compared to those of the control group. The plasma coenzyme Q10 was positively correlated with CAT and GPx activities and negatively correlated with MDA and SOD. However, the correlations were not significant after adjusting for the potential confounders of CAD with the exception of SOD. A higher level of plasma coenzyme Q10 (≥0.52 μmol/L) was significantly associated with reducing the risk of CAD. Our results support the potential cardioprotective impact of coenzyme Q10. PMID:22645453

  16. Catalytically active tissue transglutaminase colocalises with Aβ pathology in Alzheimer’s disease mouse models

    PubMed Central

    Wilhelmus, Micha M. M.; de Jager, Mieke; Smit, August B.; van der Loo, Rolinka J.; Drukarch, Benjamin

    2016-01-01

    Alzheimer’s disease (AD) is characterised by amyloid-beta (Aβ) protein deposition in the brain. Posttranslational modifications in Aβ play an important role in Aβ deposition. Tissue transglutaminase (tTG) is an enzyme involved in posttranslational cross-linking of proteins. tTG levels and activity are increased in AD brains, and tTG is associated with Aβ deposits and lesion-associated astrocytes in AD cases. Furthermore, Aβ is a substrate of tTG-catalysed cross-linking. To study the role of tTG in Aβ pathology, we compared tTG distribution and activity in both the APPSWE/PS1ΔE9 and APP23 mice models with human AD. Using immunohistochemistry, we found association of both tTG and in situ active tTG with Aβ plaques and vascular Aβ, in early and late stages of Aβ deposition. In addition, tTG staining colocalised with Aβ-associated reactive astrocytes. Thus, alike human AD cases, tTG was associated with Aβ depositions in these AD models. Although, distribution pattern and spatial overlay of both tTG and its activity with Aβ pathology was substantially different from human AD cases, our findings provide evidence for an early role of tTG in Aβ pathology. Yet, species differences should be taken into account when using these models to study the role of tTG in Aβ pathology. PMID:26837469

  17. Newcastle disease virus infection induces activation of the NLRP3 inflammasome.

    PubMed

    Wang, Binbin; Zhu, Jie; Li, Dandan; Wang, Yang; Zhan, Yuan; Tan, Lei; Qiu, Xusheng; Sun, Yingjie; Song, Cuiping; Meng, Chunchun; Ying, Liao; Xiang, Mao; Meng, Guangxun; Ding, Chan

    2016-09-01

    Inflammatory responses are important aspects of the innate immune system during virus infection. We found that Newcastle disease virus can induce inflammasome activation in the human macrophage-like cell line THP-1. Viral replication was required for inflammasome activation, and small hairpin RNA knockdown experiments indicated that IL-1β secretion was mediated by the NLRP3 inflammasome. We also verified the results in LPS-primed bone marrow-derived macrophages (BMDMs) from NLRP3-deficient and wild type mice. NDV is considered to be a promising oncolytic virus. Stimulating the immune system has been proposed as a key mechanism of oncolytic specificity, and the inflammasome appears to be an important mechanism by which NDV is controlled. Knockdown of inflammasome components or chemical inhibition of caspase-1 activity shows that cell survival was augmented and benefited NDV replication. This study shows that NLRP3 inflammasome activation is an innate cellular response to NDV infection and offers insights into the oncolytic specificity of NDV. PMID:27269659

  18. Hydrogel scaffolds as in vitro models to study fibroblast activation in wound healing and disease

    PubMed Central

    Smithmyer, Megan E.; Sawicki, Lisa A.

    2014-01-01

    Wound healing results from complex signaling between cells and their environment in response to injury. Fibroblasts residing within the extracellular matrix (ECM) of various connective tissues are critical for matrix synthesis and repair. Upon injury or chronic insult, these cells activate into wound-healing cells, called myofibroblasts, and repair the damaged tissue through enzyme and protein secretion. However, misregulation and persistence of myofibroblasts can lead to uncontrolled accumulation of matrix proteins, tissue stiffening, and ultimately disease. Extracellular cues are important regulators of fibroblast activation and have been implicated in their persistence. Hydrogel-based culture models have emerged as useful tools to examine fibroblast response to ECM cues presented during these complex processes. In this Mini-Review, we will provide an overview of these model systems, which are built upon naturally-derived or synthetic materials, and mimic relevant biophysical and biochemical properties of the native ECM with different levels of control. Additionally, we will discuss the application of these hydrogel-based systems for the examination of fibroblast function and fate, including adhesion, migration, and activation, as well as approaches for mimicking both static and temporal aspects of extracellular environments. Specifically, we will highlight hydrogels that have been used to investigate the effects of matrix rigidity, protein binding, and cytokine signaling on fibroblast activation. Last, we will describe future directions for the design of hydrogels to develop improved synthetic models that mimic the complex extracellular environment. PMID:25379176

  19. Activation of mTOR: a culprit of Alzheimer’s disease?

    PubMed Central

    Cai, Zhiyou; Chen, Guanghui; He, Wenbo; Xiao, Ming; Yan, Liang-Jun

    2015-01-01

    Alzheimer’s disease (AD) is characterized by cognitive impairment in clinical presentation, and by β-amyloid (Aβ) production and the hyper-phosphorylation of tau in basic research. More highlights demonstrate that the activation of the mammalian target of rapamycin (mTOR) enhances Aβ generation and deposition by modulating amyloid precursor protein (APP) metabolism and upregulating β- and γ-secretases. mTOR, an inhibitor of autophagy, decreases Aβ clearance by scissoring autophagy function. mTOR regulates Aβ generation or Aβ clearance by regulating several key signaling pathways, including phosphoinositide 3-kinase (PI3-K)/protein kinase B (Akt), glycogen synthase kinase 3 [GSK-3], AMP-activated protein kinase (AMPK), and insulin/insulin-like growth factor 1 (IGF-1). The activation of mTOR is also a contributor to aberrant hyperphosphorylated tau. Rapamycin, the inhibitor of mTOR, may mitigate cognitive impairment and inhibit the pathologies associated with amyloid plaques and neurofibrillary tangles by promoting autophagy. Furthermore, the upstream and downstream components of mTOR signaling are involved in the pathogenesis and progression of AD. Hence, inhibiting the activation of mTOR may be an important therapeutic target for AD. PMID:25914534

  20. Predicting Disease-Related Subnetworks for Type 1 Diabetes Using a New Network Activity Score

    PubMed Central

    Gao, Shouguo; Jia, Shuang; Hessner, Martin J.

    2012-01-01

    Abstract In this study we investigated the advantage of including network information in prioritizing disease genes of type 1 diabetes (T1D). First, a naïve Bayesian network (NBN) model was developed to integrate information from multiple data sources and to define a T1D-involvement probability score (PS) for each individual gene. The algorithm was validated using known functional candidate genes as a benchmark. Genes with higher PS were found to be more likely to appear in T1D-related publications. Next a new network activity metric was proposed to evaluate the T1D relevance of protein-protein interaction (PPI) subnetworks. The metric considered the contribution both from individual genes and from network topological characteristics. The predictions were confirmed by several independent datasets, including a genome wide association study (GWAS), and two large-scale human gene expression studies. We found that novel candidate genes in the T1D subnetworks showed more significant associations with T1D than genes predicted using PS alone. Interestingly, most novel candidates were not encoded within the human leukocyte antigen (HLA) region, and their expression levels showed correlation with disease only in cohorts with low-risk HLA genotypes. The results suggested the importance of mapping disease gene networks in dissecting the genetics of complex diseases, and offered a general approach to network-based disease gene prioritization from multiple data sources. PMID:22917479

  1. Crosstalk between mitogen-activated protein kinases and mitochondria in cardiac diseases: therapeutic perspectives

    PubMed Central

    Javadov, Sabzali; Jang, Sehwan; Agostini, Bryan

    2014-01-01

    Cardiovascular diseases cause more mortality and morbidity worldwide than any other diseases. Although many intracellular signaling pathways influence cardiac physiology and pathology, the mitogen-activated protein kinase (MAPK) family has garnered significant attention because of its vast implications in signaling and cross-talk with other signaling networks. The extensively studied MAPKs ERK1/2, p38, JNK, and ERK5, demonstrate unique intracellular signaling mechanisms, responding to a myriad of mitogens and stressors and influencing the signaling of cardiac development, metabolism, performance, and pathogenesis. Definitive relationships between MAPK signaling and cardiac dysfunction remain elusive, despite 30 years of extensive clinical studies and basic research of various animal/cell models, severities of stress, and types of stimuli. Still, several studies have proven the importance of MAPK cross-talk with mitochondria, powerhouses of the cell that provide over 80% of ATP for normal cardiomyocyte function and play a crucial role in cell death. Although many questions remain unanswered, there exists enough evidence to consider the possibility of targeting MAPK-mitochondria interactions in the prevention and treatment of heart disease. The goal of this review is to integrate previous studies into a discussion of MAPKs and MAPK-mitochondria signaling in cardiac diseases, such as myocardial infarction (ischemia), hypertrophy and heart failure. A comprehensive understanding of relevant molecular mechanisms, as well as challenges for studies in this area, will facilitate the development of new pharmacological agents and genetic manipulations for therapy of cardiovascular diseases. PMID:24924700

  2. ADENOSINE DEAMINASE ACTIVITY AND SERUM C-REACTIVE PROTEIN AS PROGNOSTIC MARKERS OF CHAGAS DISEASE SEVERITY

    PubMed Central

    BRAVO-TOBAR, Iván Darío; NELLO-PÉREZ, Carlota; FERNÁNDEZ, Alí; MOGOLLÓN, Nora; PÉREZ, Mary Carmen; VERDE, Juan; CONCEPCIÓN, Juan Luis; RODRIGUEZ-BONFANTE, Claudina; BONFANTE-CABARCAS, Rafael

    2015-01-01

    SUMMARY Chagas disease is a public health problem worldwide. The availability of diagnostic tools to predict the development of chronic Chagas cardiomyopathy is crucial to reduce morbidity and mortality. Here we analyze the prognostic value of adenosine deaminase serum activity (ADA) and C-reactive protein serum levels (CRP) in chagasic individuals. One hundred and ten individuals, 28 healthy and 82 chagasic patients were divided according to disease severity in phase I (n = 35), II (n = 29), and III (n = 18). A complete medical history, 12-lead electrocardiogram, chest X-ray, and M-mode echocardiogram were performed on each individual. Diagnosis of Chagas disease was confirmed by ELISA and MABA using recombinant antigens; ADA was determined spectrophotometrically and CRP by ELISA. The results have shown that CRP and ADA increased linearly in relation to disease phase, CRP being significantly higher in phase III and ADA at all phases. Also, CRP and ADA were positively correlated with echocardiographic parameters of cardiac remodeling and with electrocardiographic abnormalities, and negatively with ejection fraction. CRP and ADA were higher in patients with cardiothoracic index ≥ 50%, while ADA was higher in patients with ventricular repolarization disturbances. Finally, CRP was positively correlated with ADA. In conclusion, ADA and CRP are prognostic markers of cardiac dysfunction and remodeling in Chagas disease. PMID:26603224

  3. ADENOSINE DEAMINASE ACTIVITY AND SERUM C-REACTIVE PROTEIN AS PROGNOSTIC MARKERS OF CHAGAS DISEASE SEVERITY.

    PubMed

    Bravo-Tobar, Iván Darío; Nello-Pérez, Carlota; Fernández, Alí; Mogollón, Nora; Pérez, Mary Carmen; Verde, Juan; Concepción, Juan Luis; Rodriguez-Bonfante, Claudina; Bonfante-Cabarcas, Rafael

    2015-01-01

    Chagas disease is a public health problem worldwide. The availability of diagnostic tools to predict the development of chronic Chagas cardiomyopathy is crucial to reduce morbidity and mortality. Here we analyze the prognostic value of adenosine deaminase serum activity (ADA) and C-reactive protein serum levels (CRP) in chagasic individuals. One hundred and ten individuals, 28 healthy and 82 chagasic patients were divided according to disease severity in phase I (n = 35), II (n = 29), and III (n = 18). A complete medical history, 12-lead electrocardiogram, chest X-ray, and M-mode echocardiogram were performed on each individual. Diagnosis of Chagas disease was confirmed by ELISA and MABA using recombinant antigens; ADA was determined spectrophotometrically and CRP by ELISA. The results have shown that CRP and ADA increased linearly in relation to disease phase, CRP being significantly higher in phase III and ADA at all phases. Also, CRP and ADA were positively correlated with echocardiographic parameters of cardiac remodeling and with electrocardiographic abnormalities, and negatively with ejection fraction. CRP and ADA were higher in patients with cardiothoracic index ≥ 50%, while ADA was higher in patients with ventricular repolarization disturbances. Finally, CRP was positively correlated with ADA. In conclusion, ADA and CRP are prognostic markers of cardiac dysfunction and remodeling in Chagas disease. PMID:26603224

  4. 7α, 25-dihydroxycholesterol-mediated activation of EBI2 in immune regulation and diseases

    PubMed Central

    Sun, Siquan; Liu, Changlu

    2015-01-01

    EBI2, aka GPR183, is a G-couple receptor originally identified in 1993 as one of main genes induced in Burkitt’s lymphoma cell line BL41 by Epstein–Barr virus (EBV) infection. After it was reported in 2009 that the receptor played a key role in regulating B cell migration and responses, we initiated an effort in looking for its endogenous ligand. In 2011 we and another group reported the identification of 7α, 25-dihydroxyxcholesterol (7α, 25-OHC), an oxysterol, as the likely physiological ligand of EBI2. A few subsequently published studies further elucidated how 7α, 25-OHC bound to EBI2, and how a gradient of 7α, 25-OHC could be generated in vivo and regulated migration, activation, and functions of B cells, T cells, dendritic cells (DCs), monocytes/macrophages, and astrocytes. The identification of 7α, 25-OHC as a G protein-coupled receptor ligand revealed a previously unknown signaling system of oxysterols, a class of molecules which exert profound biological functions. Dysregulation of the synthesis or functions of these molecules is believed to contribute to inflammation and autoimmune diseases, cardiovascular diseases, neurodegenerative diseases, cancer as well as metabolic diseases such as diabetes, obesity, and dyslipidemia. Therefore EBI2 may represent a promising target for therapeutic interventions for human diseases. PMID:25852561

  5. Value of commonly measured laboratory tests as biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis

    PubMed Central

    Grayson, Peter C.; Monach, Paul A.; Pagnoux, Christian; Cuthbertson, David; Carette, Simon; Hoffman, Gary S.; Khalidi, Nader A.; Koening, Curry L.; Langford, Carol A.; Maksimowicz-McKinnon, Kathleen; Seo, Philip; Specks, Ulrich; Ytterberg, Steven R.

    2015-01-01

    Objective. The aim of this study was to assess the clinical value of absolute eosinophil count, serum IgE, ESR and CRP as longitudinal biomarkers of disease activity and predictors of relapse in eosinophilic granulomatosis with polyangiitis (Churg-Strauss, EGPA). Methods. Patients were selected from an observational EGPA cohort. Absolute eosinophil count, IgE, ESR and CRP were measured quarterly. Disease activity was defined by validated assessment tools. The association of tests with disease activity was assessed via regression models, adjusting for repeated measures and treatment status. Survival analysis was used to determine if laboratory tests were predictive of the 3 month future flare risk. Results. Seventy-four per cent of 892 study visits in 141 patients occurred while patients were on treatment, mostly during remission or mild disease activity, defined as a BVAS for Wegener’s granulomatosis (BVAS/WG) of 1 or 2. Correlations between absolute eosinophil count, IgE, ESR and CRP were mostly low or non-significant (r = −0.08 to 0.44). There were few weak associations with disease activity [absolute eosinophil count: OR) 1.01/100 U (95% CI 1.01, 1.02); ESR: OR 1.15/10 mg/l increase (95% CI 1.04, 1.27)]. When BVAS/WG ≥1 defined active disease, the absolute eosinophil count [hazard ratio (HR) 1.01/100 U (95% CI 1.01, 1.02)] was weakly predictive of flare. When BVAS/WG ≥3 defined active disease, ESR was weakly predictive of flare [HR 1.52/10 mm/h increase (95% CI 1.17, 1.67)]. Conclusion. The absolute eosinophil count, IgE, ESR and CRP have limitations as longitudinal biomarkers of disease activity or predictors of flare in EGPA. These findings suggest that novel biomarkers of disease activity for EGPA are needed. PMID:25406357

  6. Antibacterial activity of extracts from Zostera marina against pathogens of Apostichopus japonicus skin ulceration disease

    NASA Astrophysics Data System (ADS)

    Liu, Yang; Jiang, Guoliang; Wu, Zhiqiang

    2010-03-01

    The purpose of this study was to investigate the antibacterial activity of extracts from Zostera marina against the pathogens of Apostichopus japonicus skin ulceration disease. When 95% ethanol (v/v) solvent was used to extract Zostera marina at 50°C, aqueous extract (ZA) showed obvious bacteriostatic effects on the tested bacterial strains (inhibition halo diameters between 8.23 mm and 13.62 mm), whereas the ethyl acetate extract (ZE) was almost inactive. The minimal inhibitory concentration (MIC) of ZA against four pathogens were homogeneous at 12.8 g L-1. ZA components were analyzed by thin layer chromatography (TLC) assay and six fractions were obtained. In another study, the six fractions showed inhibitory effects against the tested bacteria while their functions seemed to counteract the ZA activity.

  7. Activation of brain histaminergic neurotransmission: a mechanism for cognitive effects of memantine in Alzheimer's disease.

    PubMed

    Motawaj, M; Burban, A; Davenas, E; Arrang, J-M

    2011-02-01

    We previously reported that some N-methyl-D-aspartate (NMDA)-receptor antagonists enhanced histamine neuron activity in rodents. Here, we have investigated the effects of memantine, an NMDA-receptor antagonist used for the treatment of Alzheimer's disease, on histaminergic neurotransmission. In vitro, memantine antagonized native NMDA receptors with a micromolar potency but had no effect at recombinant human histamine receptors. In vivo, a single administration of memantine increased histamine neuron activity, as shown by the 60% increase of tele-methylhistamine (t-MeHA) levels observed in the brain of mice. This increase occurred with an ED(50) of 0.3 ± 0.1 mg/kg, similar to that found on inhibition of ex vivo [(3)H]dizocilpine maleate (MK-801) binding (1.8 ± 1.3 mg/kg). Two days after pretreatment of mice with memantine at 5 mg/kg twice daily for 5 days, t-MeHA levels were enhanced by 50 ± 7% (p < 0.001), indicating a long-lasting activation of histamine neurons. Quantitative polymerase chain reaction analysis was used to explore genes involved in this persistent effect. H(3) receptor mRNAs were strongly increased, but the density of H(3) receptor binding sites was increased solely in hypothalamus (by 141 ± 24%). Up-regulations of brain-derived neurotrophic factor and NMDA-receptor 1 subunit mRNAs were also found but were restricted to hippocampus. mRNA expression of α7-nicotinic receptors remained unchanged in any region. Considering the well established cognitive effects of histamine neurons, the increase in brain t-MeHA levels after single or repeated administration of therapeutic doses of memantine suggests that the drug exerts its beneficial effects on cognitive deficits of Alzheimer's disease, at least partly, by activating histamine neurons. PMID:21057059

  8. Longitudinal Changes in the Motor Learning-Related Brain Activation Response in Presymptomatic Huntington's Disease

    PubMed Central

    Holtbernd, Florian; Tang, Chris C.; Feigin, Andrew; Dhawan, Vijay; Ghilardi, Maria Felice; Paulsen, Jane S.; Guttman, Mark; Eidelberg, David

    2016-01-01

    Neurocognitive decline, including deficits in motor learning, occurs in the presymptomatic phase of Huntington’s disease (HD) and precedes the onset of motor symptoms. Findings from recent neuroimaging studies have linked these deficits to alterations in fronto-striatal and fronto-parietal brain networks. However, little is known about the temporal dynamics of these networks when subjects approach phenoconversion. Here, 10 subjects with presymptomatic HD were scanned with 15O-labeled water at baseline and again 1.5 years later while performing a motor sequence learning task and a kinematically matched control task. Spatial covariance analysis was utilized to characterize patterns of change in learning-related neural activation occurring over time in these individuals. Pattern expression was compared to corresponding values in 10 age-matched healthy control subjects. Spatial covariance analysis revealed significant longitudinal changes in the expression of a specific learning-related activation pattern characterized by increasing activity in the right orbitofrontal cortex, with concurrent reductions in the right medial prefrontal and posterior cingulate regions, the left insula, left precuneus, and left cerebellum. Changes in the expression of this pattern over time correlated with baseline measurements of disease burden and learning performance. The network changes were accompanied by modest improvement in learning performance that took place concurrently in the gene carriers. The presence of increased network activity in the setting of stable task performance is consistent with a discrete compensatory mechanism. The findings suggest that this effect is most pronounced in the late presymptomatic phase of HD, as subjects approach clinical onset. PMID:27192167

  9. Next-generation active immunization approach for synucleinopathies - implications for Parkinson’s Disease clinical trials

    PubMed Central

    Mandler, Markus; Valera, Elvira; Rockenstein, Edward; Weninger, Harald; Patrick, Christina; Adame, Anthony; Santic, Radmila; Meindl, Stefanie; Vigl, Benjamin; Smrzka, Oskar; Schneeberger, Achim; Mattner, Frank; Masliah, Eliezer

    2014-01-01

    Immunotherapeutic approaches are currently in the spotlight for their potential as disease-modifying treatments for neurodegenerative disorders. The discovery that α-synuclein (α-syn) can transmit from cell to cell in a prion-like fashion suggests that immunization might be a viable option for the treatment of synucleinopathies. This possibility has been bolstered by the development of next-generation active vaccination technology with short peptides-AFFITOPEs® (AFF) that do not elicit a α-syn specific T-cell response. This approach allows the generation of long-term sustained, more specific, non-cross reacting antibodies suitable for the treatment of synucleinopathies such as Parkinson’s disease (PD). In this context, we screened a large library of peptides that mimic the c-terminus region of α-syn and discovered a novel set of AFF that identified α-syn oligomers. Next, the peptide that elicited the most specific response against α-syn (AFF 1) was selected for immunizing two different transgenic mouse models of PD and Dementia with Lewy bodies (DLB), the PDGF- and the mThy1-α-syn tg mice. Vaccination with AFF 1 resulted in high antibody titers in CSF and plasma, which crossed into the CNS and recognized α-syn aggregates. Active vaccination with AFF 1 resulted in decreased accumulation of α-syn oligomers in axons and synapses that was accompanied by reduced degeneration of TH fibers in the caudo-putamen nucleus and by improvements in motor and memory deficits in both in vivo models. Clearance of α-syn involved activation of microglia and increased anti-inflammatory cytokine expression, further supporting the efficacy of this novel active vaccination approach for synucleinopathies. PMID:24525765

  10. Effects of hemodialysis on ventricular activation time in children with end-stage renal disease.

    PubMed

    Laszki-Szcząchor, Krystyna; Polak-Jonkisz, Dorota; Zwolińska, Danuta; Makulska, Irena; Rehan, Leopold; Sobieszczańska, Małgorzata

    2015-01-01

    Patients with end-stage renal disease are affected by cardiovascular complications, including disturbances of the heart intraventricular conduction. Body surface potential mapping is a non-invasive electrocardiographic detection method of initial disturbances in heart activation propagation. A goal of the study was to analyze the effects of single hemodialysis (HD) session on ventricular activation time (VAT) maps obtained from hemodialyzed children. The study group consisted of 13 hemodialyzed children (age: 6-18 years). The control group is composed of 26 healthy subjects. In each HD patient, 12-lead electrocardiogram and echocardiography examinations were performed. Isochrone heart maps, reflecting body surface distribution of VAT isolines, were recorded from an 87-electrode HPM-7100 system for body surface potential mapping, before (group B) and after HD session (group A). The distribution of isochrones and VAT values, as recorded in the HD patients, differed significantly from the reference VAT map for controls. The highest VAT maximal value was noted in group B (Me: 110 vs. 62 ms in the control group; P < 0.001), becoming significantly lower after HD session (Me: 98 ms for group A vs. 110 ms for group B; P < 0.001). Ventricular activation time maps, recorded before HD session, showed significant VAT delays with isochrone arrangement specific for the left bundle branch block. After HD session, VAT maps presented significant changes, suggesting a normalization process. Ventricular activation time maps in children with end-stage renal disease exhibited disturbances of intraventricular conduction within the left bundle branch block, undetectable on standard electrocardiogram. A single HD session resulted in VAT map improvement related to overall HD treatment duration. PMID:24992701

  11. Underlying Mechanism of Antimicrobial Activity of Chitosan Microparticles and Implications for the Treatment of Infectious Diseases

    PubMed Central

    Jeon, Soo Jin; Oh, Manhwan; Yeo, Won-Sik; Galvão, Klibs N.; Jeong, Kwang Cheol

    2014-01-01

    The emergence of antibiotic resistant microorganisms is a great public health concern and has triggered an urgent need to develop alternative antibiotics. Chitosan microparticles (CM), derived from chitosan, have been shown to reduce E. coli O157:H7 shedding in a cattle model, indicating potential use as an alternative antimicrobial agent. However, the underlying mechanism of CM on reducing the shedding of this pathogen remains unclear. To understand the mode of action, we studied molecular mechanisms of antimicrobial activity of CM using in vitro and in vivo methods. We report that CM are an effective bactericidal agent with capability to disrupt cell membranes. Binding assays and genetic studies with an ompA mutant strain demonstrated that outer membrane protein OmpA of E. coli O157:H7 is critical for CM binding, and this binding activity is coupled with a bactericidal effect of CM. This activity was also demonstrated in an animal model using cows with uterine diseases. CM treatment effectively reduced shedding of intrauterine pathogenic E. coli (IUPEC) in the uterus compared to antibiotic treatment. Since Shiga-toxins encoded in the genome of bacteriophage is often overexpressed during antibiotic treatment, antibiotic therapy is generally not recommended because of high risk of hemolytic uremic syndrome. However, CM treatment did not induce bacteriophage or Shiga-toxins in E. coli O157:H7; suggesting that CM can be a potential candidate to treat infections caused by this pathogen. This work establishes an underlying mechanism whereby CM exert antimicrobial activity in vitro and in vivo, providing significant insight for the treatment of diseases caused by a broad spectrum of pathogens including antibiotic resistant microorganisms. PMID:24658463

  12. Low Molecular Weight Antagonists of Plasminogen Activator Inhibitor-1: Therapeutic Potential in Cardiovascular Disease.

    PubMed

    Simone, Tessa M; Higgins, Paul J

    2012-08-01

    Plasminogen activator inhibitor-1 (PAI-1; SERPINE1) is the major physiologic regulator of the plasmin-based pericellular proteolytic cascade, a modulator of vascular smooth muscle cell (VSMC) migration and a causative factor in cardiovascular disease and restenosis, particularly in the context of increased vessel transforming growth factor- β1 (TGF-β1) levels. PAI-1 limits conversion of plasminogen to plasmin (and, thereby, fibrin degradation) by inhibiting its protease targets urokinase and tissue-type plasminogen activators (uPA, tPA). PAI-1 also has signaling functions and binds to the low density lipoprotein receptor-related protein 1 (LRP1) to regulate LRP1-dependent cell motility that, in turn, contributes to neointima formation. PAI-1/uPA/uPA receptor/LRPI/integrin complexes are endocytosed with subsequent uPAR/LRP1/integrin redistribution to the leading edge, initiating an "adhesion-detachment-readhesion" cycle to promote cell migration. PAI-1 also interacts with LRP1 in a uPA/uPAR-independent manner triggering Jak/Stat1 pathway activation to stimulate cell motility. PAI-1 itself is a substrate for extracellular proteases and exists in a "cleaved" form which, while unable to interact with uPA and tPA, retains LRP1-binding and migratory activity. These findings suggest that there are multiple mechanisms through which inhibition of PAI-1 may promote cardiovascular health. Several studies have focused on the design, synthesis and preclinical assessment of PAI-1 antagonists including monoclonal antibodies, peptides and low molecular weight (LMW) antagonists. This review discusses the translational impact of LMW PAI-1 antagonists on cardiovascular disease addressing PAI-1-initiated signaling, PAI-1 structure, the design and characteristics of PAI-1-targeting drugs, results of in vitro and in vivo studies, and their clinical implications. PMID:23936868

  13. Phosphotidylserine exposure and neutrophil extracellular traps enhance procoagulant activity in patients with inflammatory bowel disease.

    PubMed

    He, Zhangxiu; Si, Yu; Jiang, Tao; Ma, Ruishuang; Zhang, Yan; Cao, Muhua; Li, Tao; Yao, Zhipeng; Zhao, Lu; Fang, Shaohong; Yu, Bo; Dong, Zengxiang; Thatte, Hemant S; Bi, Yayan; Kou, Junjie; Yang, Shufen; Piao, Daxun; Hao, Lirong; Zhou, Jin; Shi, Jialan

    2016-04-01

    Inflammatory bowel disease (IBD)-associated thromboembolic event often lacks precise aetiology. The aim of this study was to investigate the contribution of phosphatidylserine (PS) exposure and neutrophil extracellular traps (NETs) towards the hypercoagulable state in IBD. We demonstrated that the levels of PS exposed MPs and the sources of MP-origin, platelets, erythrocytes, leukocytes and cultured endothelial cells (ECs) were higher in IBD groups than in healthy controls using flow cytometry and confocal microscopy. Wright-Giemsa and immunofluorescence staining demonstrated that the elevated NETs were released by activated IBD neutrophils or by control neutrophils treated with IBD sera obtained from patients with the active disease. MPs and MP-origin cells in IBD groups, especially in active stage, markedly shortened coagulation time and had increased levels of fibrin, thrombin and FXa production as assessed by coagulation function assays. Importantly, we found that on stimulated ECs, PS rich membranes provided binding sites for FXa and FVa, promoting fibrin formation while TNF blockage or IgG depletion attenuated this effect. Treatment of control neutrophils with TNF and isolated IgG from PR3-ANCA-positive active IBD patients also resulted in the release of NETs. Blockade of PS with lactadherin prolonged coagulation time, decreased fibrin formation to control levels, and inhibited the procoagulant enzymes production in the MPs and MP-origin cells. NET cleavage by DNase I partly decreased PCA in IBD or stimulated neutrophils. Our study reveals a previously unrecognised link between hypercoagulable state and PS exposure or NETs, and may further explain the epidemiological association of thrombosis within IBD patients. PMID:26660948

  14. Therapeutic Role of Rifaximin in Inflammatory Bowel Disease: Clinical Implication of Human Pregnane X Receptor Activation

    PubMed Central

    Cheng, Jie; Shah, Yatrik M.; Ma, Xiaochao; Pang, Xiaoyan; Tanaka, Toshiya; Kodama, Tatsuhiko; Krausz, Kristopher W.

    2010-01-01

    Human pregnane X receptor (PXR) has been implicated in the pathogenesis of inflammatory bowel disease (IBD). Rifaximin, a human PXR activator, is in clinical trials for treatment of IBD and has demonstrated efficacy in Crohn's disease and active ulcerative colitis. In the current study, the protective and therapeutic role of rifaximin in IBD and its respective mechanism were investigated. PXR-humanized (hPXR), wild-type, and Pxr-null mice were treated with rifaximin in the dextran sulfate sodium (DSS)-induced and trinitrobenzene sulfonic acid (TNBS)-induced IBD models to determine the protective function of human PXR activation in IBD. The therapeutic role of rifaximin was further evaluated in DSS-treated hPXR and Pxr-null mice. Results demonstrated that preadministration of rifaximin ameliorated the clinical hallmarks of colitis in DSS- and TNBS-treated hPXR mice as determined by body weight loss and assessment of diarrhea, rectal bleeding, colon length, and histology. In addition, higher survival rates and recovery from colitis symptoms were observed in hPXR mice, but not in Pxr-null mice, when rifaximin was administered after the onset of symptoms. Nuclear factor κB (NF-κB) target genes were markedly down-regulated in hPXR mice by rifaximin treatment. In vitro NF-κB reporter assays demonstrated inhibition of NF-κB activity after rifaximin treatment in colon-derived cell lines expressing hPXR. These findings demonstrated the preventive and therapeutic role of rifaximin on IBD through human PXR-mediated inhibition of the NF-κB signaling cascade, thus suggesting that human PXR may be an effective target for the treatment of IBD. PMID:20627999

  15. Indium 111-granulocyte scanning in the assessment of disease extent and disease activity in inflammatory bowel disease. A comparison with colonoscopy, histology, and fecal indium 111-granulocyte excretion

    SciTech Connect

    Saverymuttu, S.H.; Camilleri, M.; Rees, H.; Lavender, J.P.; Hodgson, H.J.; Chadwick, V.S.

    1986-05-01

    Indium 111-leukocyte scanning has recently been introduced as a new method for imaging inflammatory bowel disease. The technique has recently been made more specific for acute inflammation by labeling a pure granulocyte fraction rather than the conventional mixed leukocyte preparation. We now report a prospective study comparing 111In-granulocyte scanning with endoscopy, histology, and fecal 111In-granulocyte excretion for the assessment of disease extent and severity in colonic inflammatory bowel disease. In 52 patients with Crohn's disease or ulcerative colitis, disease extent and severity were assessed macroscopically, histologically, or by scanning using a numerical grading system. Excellent correlations were found between both endoscopy and histology and 111In scans (r = 0.90 (endoscopy) and r = 0.90 (histology) for extent; r = 0.86 and r = 0.91 for disease activity). Severity graded by scanning also showed a close correlation with fecal 111In-granulocyte excretion (r = 0.90). Indium 111-granulocyte scans are a rapid, accurate, noninvasive means of assessing both disease extent and severity of colonic involvement in inflammatory bowel disease.

  16. Evaluation of high density lipoprotein as a circulating biomarker of Gaucher disease activity

    PubMed Central

    Stein, Philip; Yang, Ruhua; Liu, Jun; Pastores, Gregory M.; Mistry, Pramod K.

    2011-01-01

    Circulating biomarkers are important surrogates for monitoring disease activity in type I Gaucher disease (GD1). We and others have reported low high-density lipoprotein (HDL) in GD1. We assessed HDL cholesterol as a biomarker of GD1, with respect to its correlation with indicators of disease severity and its response to imiglucerase enzyme replacement therapy (ERT). In 278 consecutively evaluated GD1 patients, we correlated HDL cholesterol, chitotriosidase, and angiotensin-converting enzyme (ACE) with indicators of disease severity. Additionally, we measured the response of these biomarkers to ERT. HDL cholesterol was negatively correlated with spleen volume, liver volume, and GD severity score index; the magnitude of this association of disease severity with HDL cholesterol was similar to that for ACE and for chitotriosidase. Within individual patients monitored over many years, there was a strikingly strong correlation of HDL with liver and spleen volumes; there was a similarly strong correlation of chitotriosidase and ACE with disease severity in individual patients monitored serially over many years (chitotriosidase r=0.96 to 0.98, ACE r =0.88 to 0.94, and HDL r=−0.84 to −0.94, p<0.001). ERT for 3 years resulted in a striking increase of HDL while serum levels of chitotriosidase and ACE decreased. Our results reveal markedly low HDL cholesterol in untreated GD1, a correlation with indicators of disease severity in GD1, and a rise towards normal after ERT. These findings suggest HDL cholesterol merits inclusion within the “biomarker basket” for monitoring of patients with GD1. PMID:21290183

  17. The relationship between enthesitis indices and disease activity parameters in patients with ankylosing spondylitis.

    PubMed

    Sivas, Filiz; Mermerci Başkan, Bedriye; Erkol Inal, Esra; Akbulut Aktekin, Lale; Barça, Nurdan; Ozoran, Kürşat; Bodur, Hatice

    2009-03-01

    In this study, patients with ankylosing spondylitis (AS) were assessed both by patient and physician using two enthesitis indices and the relationship between these indices and disease activity parameters was investigated. The study involved 100 AS patients. The patients were evaluated with 10-cm visual analog scale (VAS) for spinal pain (VAS-S), peripheral joint pain (VAS-P), global assessment of patient, and global assessment of doctor. In the laboratory evaluations, the erythrocyte sedimentation rates (ESR) and serum C-reactive protein levels of the patients were determined. Bath AS disease activity index (BASDAI), Bath AS functional index (BASFI), Bath AS metrology index, and Bath AS radiology index were calculated. The severity of enthesitis was evaluated according to Mander enthesitis index (MEI) and Maastricht ankylosing spondylitis enthesitis score applied by both the patient (MASES-P) him/herself and the physician (MASES-D). There was a correlation between BASDAI and BASFI as well as MEI, MASES-D, and MASES-P indices (r = 0.447, r = 0.342, r = 0.663, r = 0.530, r = 0.464, and r = 0.435, respectively). No correlation between the laboratory parameters and enthesitis indices were detected. In multiple linear regression analysis, BASFI, VAS-S, and female gender (41.3%) were the best predictors of MEI-D, whereas BASFI, VAS-S, female gender, and ESR (32.5%) were the best predictors for MASES-D and BASFI (18.9%) was the best predictor of MASES-P. The assessment of simple and easily applicable MASES score by a patient may be expected to help the physician in clinical practice. When the disease activity of the patients with AS are evaluated, both BASDAI, the clinical importance of which has been confirmed in numerous studies and which is recommended by ASAS, and BASFI, which is valued by patients, should be considered. PMID:18953622

  18. Innate mucosal-associated invariant T (MAIT) cells are activated in inflammatory bowel diseases.

    PubMed

    Serriari, N-E; Eoche, M; Lamotte, L; Lion, J; Fumery, M; Marcelo, P; Chatelain, D; Barre, A; Nguyen-Khac, E; Lantz, O; Dupas, J-L; Treiner, E

    2014-05-01

    Inflammatory bowel diseases are characterized by a deregulated immune response targeting the gut bacterial flora. Mucosal-associated invariant T (MAIT) cells are major histocompatibility complex (MHC) class Ib-restricted innate-like lymphocytes with anti-bacterial functions. They display an effector/memory phenotype and are found in large numbers in the blood, mucosae and liver. They have also been implicated in inflammatory diseases such as multiple sclerosis. Therefore, we aimed to analyse the possible involvement of MAIT cells in Crohn's disease (CD) and ulcerative colitis (UC). To this end, a phenotypical and functional analysis of MAIT cells isolated from the blood of healthy subjects, CD and UC patients was undertaken. MAIT cells were also quantified in ileal biopsies of CD patients. The frequency of blood MAIT cells was specifically reduced in IBD patients compared with healthy donors, whereas it was dramatically greater in the inflamed versus healthy tissue. MAIT cells were activated as they expressed significantly more the Ki67 antigen, and this was accompanied by phenotypical changes such as increased expression of natural killer (NK)G2D and B and T lymphocyte attenuator (BTLA). Finally, in-vitro-activated MAIT cells from CD and UC patients secreted significantly more interleukin (IL)-17, together with a decreased interferon (IFN)-γ in CD but an increased IL-22 in UC. These data show that MAIT cells are activated in IBD, which results in an increased recruitment towards the inflamed tissues, an altered phenotype and a switch in the pattern of cytokine secretion. This is the first demonstration that MAIT cells are immune players in IBD, whose precise functions in this context need to be addressed. PMID:24450998

  19. Activating Transcription Factor 6 Is Necessary and Sufficient for Alcoholic Fatty Liver Disease in Zebrafish

    PubMed Central

    Howarth, Deanna L.; Lindtner, Claudia; Vacaru, Ana M.; Sachidanandam, Ravi; Tsedensodnom, Orkhontuya; Vasilkova, Taisa; Buettner, Christoph; Sadler, Kirsten C.

    2014-01-01

    Fatty liver disease (FLD) is characterized by lipid accumulation in hepatocytes and is accompanied by secretory pathway dysfunction, resulting in induction of the unfolded protein response (UPR). Activating transcription factor 6 (ATF6), one of three main UPR sensors, functions to both promote FLD during acute stress and reduce FLD during chronic stress. There is little mechanistic understanding of how ATF6, or any other UPR factor, regulates hepatic lipid metabolism to cause disease. We addressed this using zebrafish genetics and biochemical analyses and demonstrate that Atf6 is necessary and sufficient for FLD. atf6 transcription is significantly upregulated in the liver of zebrafish with alcoholic FLD and morpholino-mediated atf6 depletion significantly reduced steatosis incidence caused by alcohol. Moreover, overexpression of active, nuclear Atf6 (nAtf6) in hepatocytes caused FLD in the absence of stress. mRNA-Seq and qPCR analyses of livers from five day old nAtf6 transgenic larvae revealed upregulation of genes promoting glyceroneogenesis and fatty acid elongation, including fatty acid synthase (fasn), and nAtf6 overexpression in both zebrafish larvae and human hepatoma cells increased the incorporation of 14C-acetate into lipids. Srebp transcription factors are key regulators of lipogenic enzymes, but reducing Srebp activation by scap morpholino injection neither prevented FLD in nAtf6 transgenics nor synergized with atf6 knockdown to reduce alcohol-induced FLD. In contrast, fasn morpholino injection reduced FLD in nAtf6 transgenic larvae and synergistically interacted with atf6 to reduce alcoholic FLD. Thus, our data demonstrate that Atf6 is required for alcoholic FLD and epistatically interacts with fasn to cause this disease, suggesting triglyceride biogenesis as the mechanism of UPR induced FLD. PMID:24874946

  20. Progranulin Is Associated with Disease Activity in Patients with Rheumatoid Arthritis

    PubMed Central

    Andrés Cerezo, Lucie; Kuklová, Markéta; Hulejová, Hana; Vernerová, Zdeňka; Kaspříková, Nikola; Veigl, David; Pavelka, Karel; Vencovský, Jiří; Šenolt, Ladislav

    2015-01-01

    Objective. Progranulin (PGRN) is implicated in the pathogenesis of rheumatoid arthritis (RA). The aim of this study was to assess the relationship between PGRN and disease activity in RA. Methods. PGRN levels were evaluated in patients with RA (n = 47) and OA (n = 42) and healthy controls (n = 41). Immunohistochemical analysis of PGRN in synovial tissues was performed. The association between PGRN and C-reactive protein (CRP), disease activity score (DAS28-CRP), and health assessment questionnaire (HAQ) was studied. Results. Circulating PGRN was elevated in patients with RA and OA compared to healthy controls (227.1 ± 100.2 and 221.5 ± 102.5 versus 128.1 ± 34.7 ng/mL; P < 0.001). Synovial fluid levels of PGRN were higher in patients with RA compared to OA (384.5 ± 275.3 versus 241.4 ± 165.2 ng/mL; P = 0.002). PGRN expression was significantly upregulated in the synovial tissue of RA patients particularly in the inflammatory infiltrates. Serum PGRN levels correlated with DAS28 (r = 0.327, P = 0.049) and HAQ score (r = 0.323, P = 0.032), while synovial fluid PGRN correlated only with HAQ (r = 0.310, P = 0.043) in patients with RA. PGRN levels were not associated with CRP or autoantibodies. Conclusions. This study demonstrates increased PGRN expression at local sites of inflammation and association between PGRN levels, disease activity, and functional impairment in patients with RA. PMID:26339140

  1. Symmetric dimethylarginine (SDMA) serum levels in rheumatoid arthritis: correlations with insulin resistance and disease activity scores.

    PubMed

    Dimitroulas, Theodoros; Hodson, James; Sandoo, Aamer; Smith, Jacqueline; Kitas, George D

    2015-09-01

    Vascular abnormalities predisposing to atherosclerosis are present in patients with rheumatoid arthritis (RA) and associate with excess cardiovascular risk. Symmetric dimethylarginine (SDMA), an endogenous inhibitor of nitric oxide (NO) synthase activity, has been recognised as novel risk factor for endothelial dysfunction and cardiovascular disease. We aimed to compare SDMA levels in RA patients and controls and to investigate whether they are influenced by demographic, inflammatory or metabolic factors. Serum SDMA levels were measured in 197 RA individuals [median age: 67 years (quartiles: 59-3), 153 (78 %) females] and 82 controls [median age: 44 years [quartiles: 33-55, 50 (61 %) females]. Routine biochemistry tests, lipid profile, glycemic profile [glucose, insulin, homeostasis model assessment (HOMA-IR), quantitative insulin sensitivity check index (QUICKI)], as well as inflammatory markers were measured in all patients. Paired analysis was employed for the comparison of SDMA in two groups and multivariable regression models were performed to identify predictors of SDMA in the RA cohort. SDMA was significantly lower in RA than control patients in both unpaired and paired analyses (P < 0.001 and P = 0.005, respectively), with the magnitude of the difference being similar in both models. QUICKI (P = 0.005) and disease activity score-28 (P = 0.007) were positively related to SDMA in the RA cohort, whilst a negative correlation with renal function (eGFR) was detected (P = 0.005). The molecular explanation of lower serum SDMA is unclear, but the established relationships with indices of disease activity and insulin resistance, may underline the pathogenetic role of the L-arginine/NO pathway dysregulation in the development of atherosclerosis in RA. The biological and clinical importance of SDMA in RA remains to be evaluated in clinical and experimental studies. PMID:25772817

  2. Does body mass index (BMI) influence the Ankylosing Spondylitis Disease Activity Score in axial spondyloarthritis?

    PubMed Central

    Rubio Vargas, Roxana; van den Berg, Rosaline; van Lunteren, Miranda; Ez-Zaitouni, Zineb; Bakker, Pauline A C; Dagfinrud, Hanne; Ramonda, Roberta; Landewé, Robert; Molenaar, Esmeralda; van Gaalen, Floris A; van der Heijde, Désirée

    2016-01-01

    Objective Obesity is associated with elevated C reactive protein (CRP) levels. The Ankylosing Spondylitis Disease Activity Score (ASDAS) combines patient-reported outcomes (PROs) and CRP. We evaluated the effect of body mass index (BMI) on CRP and on ASDAS, and studied if ASDAS can be used in obese axial spondyloarthritis (axSpA) patients to assess disease activity. Methods Baseline data of patients with chronic back pain of short duration included in the SPondyloArthritis Caught Early (SPACE) cohort were used. Collected data included BMI and ASDAS. Patients were classified according to the ASAS axSpA classification criteria and BMI (overweight ≥25 and obese ≥30). Correlation and linear regression analyses were performed to assess the relation between BMI and ASDAS. Linear regression models were performed to assess if age or gender were effect modifiers in the relation between BMI and CRP, and between BMI and ASDAS. Results In total, 428 patients were analysed (n=168 axSpA; n=260 no-axSpA). The mean age was 31.1 years, 36.9% were male, 26.4% were overweight and 13.3% obese, median CRP was 3 mg/L and the mean ASDAS was 2.6. Gender was the only factor modifying the relationship between BMI and CRP as BMI had an influence on CRP only in females (β=0.35; p<0.001). Correlations between BMI and CRP or PROs were generally weak, and only significant for CRP in female patients. BMI was not related to ASDAS in axSpA patients. Conclusions ASDAS is not affected by BMI in axSpA patients. Therefore, based on our data it is not necessary to take BMI in consideration when assessing disease activity using ASDAS in axSpA patients. PMID:27403336

  3. Associations of Smoking and Alcohol Consumption With Disease Activity and Functional Status in Rheumatoid Arthritis

    PubMed Central

    Lu, Bing; Rho, Young Hee; Cui, Jing; Iannaccone, Christine K.; Frits, Michelle L.; Karlson, Elizabeth W.; Shadick, Nancy A.

    2014-01-01

    Objective To investigate the associations of smoking and alcohol consumption with disease activity and functional status in rheumatoid arthritis (RA). Methods We conducted a prospective study consisting of 662 RA patients followed up to 7 years from the Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study. Smoking and alcohol consumption were assessed through yearly questionnaires. The disease activity and functional status were measured by the Disease Activity Score examined in 28 commonly affected joints (DAS28-CRP3) and Modified Health Assessment Questionnaire (MHAQ) assessed annually. Linear mixed models were developed to assess the longitudinal effects of smoking and alcohol consumption on DAS28-CRP3 and MHAQ after adjustment for potential confounders. The HLA-DRB1 shared epitope (HLA-SE) by smoking and alcohol interactions were also evaluated in the analysis. Results The median follow-up time of the cohort was 4 years. Current smoking was not associated with DAS28-CRP3 in this study, but was associated with a higher MHAQ than non-smokers in seropositive RA (p=0.05). Alcohol consumption showed an approximate J-shaped relationship with MHAQ, with the minima occurring at 5.1–10.0 grams/day. Compared to no alcohol use, alcohol consumption of 5.1–10.0 grams/day was associated with a significant decrease of MHAQ (P=0.02). When stratified by HLA-SE, the effect of alcohol consumption appeared to be stronger in HLA-SE positive RA than HLA-SE negative RA. Conclusion We found that current smoking was associated with a worse functional status, while moderate alcohol consumption was associated with a better functional status in RA. Replications of these findings in other prospective studies are needed. PMID:24293566

  4. Active theater as a complementary therapy for Parkinson's disease rehabilitation: a pilot study.

    PubMed

    Modugno, Nicola; Iaconelli, Sara; Fiorlli, Mariagrazia; Lena, Francesco; Kusch, Imogen; Mirabella, Giovanni

    2010-01-01

    Most medical treatments of Parkinson's disease (PD) are aimed at the reduction of motor symptoms. However, even when motor improvements are evident, patients often report a deterioration of their daily lives. Thus, to achieve a global improvement in personal well-being, not only drugs, but also complementary therapies, such as physical exercise, occupational and speech therapy, and active music therapy, have been used. We hypothesized that theater could reduce clinical disability and improve the quality of life of PD patients (primary end points) more efficiently than other complementary therapies because (1) in order to impersonate a character, patients are forced to regain the control of their bodies; and (2) while being part of a group, patients have a high degree of social interaction. The need to regain the control of their bodies and their social functioning is very likely to deeply motivate patients. To assess this hypothesis, we ran a randomized, controlled, and single-blinded study that lasted 3 years, on 20 subjects affected by a moderate form of idiopathic PD, in stable treatment with L-dopa and L-dopa agonists, and without severe sensory deficits. Ten patients were randomly assigned to an active theater program (in which patients were required to participate), while the others underwent physiotherapy (control group), the most common nonpharmacological treatment for PD rehabilitation. Patients of both groups were evaluated at the beginning of each year, using five clinical rating scales (Unified Parkinson's Disease Rating Scale [UPDRS], Schwab and England Scale, Parkinson's Disease Quality of Life [PDQ39] Scale, Epworth Sleepiness Scale, and Hamilton Depression Rating Scale). The theater patients showed progressive improvements and, at the end of the third year, they showed significant improvements in all clinical scales. Conversely, the control patients did not exhibit significant ameliorations with time. Thus, the present study provides the first

  5. Platelet phospholipase A(2) activity in Alzheimer's disease and mild cognitive impairment.

    PubMed

    Gattaz, W F; Forlenza, O V; Talib, L L; Barbosa, N R; Bottino, C M C

    2004-05-01

    Phospholipase A(2) (PLA(2)) controls the metabolism of phospholipids in cell membranes. In the brain, PLA(2) influences the processing of the amyloid precursor protein (APP) and thus the production of the amyloid-beta peptides (Abeta), which are the major components of the senile plaques in Alzheimer's disease (AD). Reduced PLA(2) activity has been reported in brain and in platelets of AD patients. In the present study we investigated PLA(2) activity in platelets from 21 AD patients as compared to 17 healthy elderly controls and 11 individuals with mild cognitive impairment (MCI). Subjects were cognitively assessed by the Mini-Mental State Examination (MMSE) and the CAMDEX schedule. Platelet PLA(2) activity was determined by radio-enzymatic assay, which mainly detected a calcium-independent form of the enzyme present also in the brain (iPLA(2)). PLA(2) activity was significantly lower in AD than in controls (p < 0.001). Mean PLA(2) activity in MCI individuals was between the values of AD patients and controls, with a subgroup showing PLA as low as the lowest AD patients, but the differences from MCI were not significant from AD and control groups. Lower PLA(2) activity was significantly correlated with a worse cognitive performance both at the MMSE (p = 0.001) and the cognitive sub-scale of the CAMDEX inventory (p = 0.002). Our data replicate previous findings of reduced platelet PLA(2) activity in AD. Both reduced PLA(2) activity and the correlation with impaired cognition were also reported in brain tissue of AD patients, suggesting thus that the present determinations in platelets may be related to a reduction in the brain. In the brain the inhibition of PLA(2) inhibits the physiological secretion of the APP, a mechanism that increases Abeta formation. Further longitudinal studies should investigate whether those MCI individuals with the lowest PLA(2) values in platelets would be at a higher risk to develop AD during a longitudinal follow up. PMID:15088152

  6. Subthalamic stimulation modulates cortical motor network activity and synchronization in Parkinson's disease.

    PubMed

    Weiss, Daniel; Klotz, Rosa; Govindan, Rathinaswamy B; Scholten, Marlieke; Naros, Georgios; Ramos-Murguialday, Ander; Bunjes, Friedemann; Meisner, Christoph; Plewnia, Christian; Krüger, Rejko; Gharabaghi, Alireza

    2015-03-01

    Dynamic modulations of large-scale network activity and synchronization are inherent to a broad spectrum of cognitive processes and are disturbed in neuropsychiatric conditions including Parkinson's disease. Here, we set out to address the motor network activity and synchronization in Parkinson's disease and its modulation with subthalamic stimulation. To this end, 20 patients with idiopathic Parkinson's disease with subthalamic nucleus stimulation were analysed on externally cued right hand finger movements with 1.5-s interstimulus interval. Simultaneous recordings were obtained from electromyography on antagonistic muscles (right flexor digitorum and extensor digitorum) together with 64-channel electroencephalography. Time-frequency event-related spectral perturbations were assessed to determine cortical and muscular activity. Next, cross-spectra in the time-frequency domain were analysed to explore the cortico-cortical synchronization. The time-frequency modulations enabled us to select a time-frequency range relevant for motor processing. On these time-frequency windows, we developed an extension of the phase synchronization index to quantify the global cortico-cortical synchronization and to obtain topographic differentiations of distinct electrode sites with respect to their contributions to the global phase synchronization index. The spectral measures were used to predict clinical and reaction time outcome using regression analysis. We found that movement-related desynchronization of cortical activity in the upper alpha and beta range was significantly facilitated with 'stimulation on' compared to 'stimulation off' on electrodes over the bilateral parietal, sensorimotor, premotor, supplementary-motor, and prefrontal areas, including the bilateral inferior prefrontal areas. These spectral modulations enabled us to predict both clinical and reaction time improvement from subthalamic stimulation. With 'stimulation on', interhemispheric cortico

  7. Circulating interferon-α2 levels are increased in the majority of patients with systemic lupus erythematosus and are associated with disease activity and multiple cytokine activation.

    PubMed

    Becker-Merok, A; Østli-Eilersten, G; Lester, S; Nossent, Jc

    2013-02-01

    Mutations in interferon (IFN) regulatory factor genes and the biological activity of type I IFN on expression of specific genes that are induced by IFN have been associated with various aspects of systemic lupus erythematosus (SLE). Circulating levels of IFN-α in SLE has not been extensively studied because of limited sensitivity of available ELISA assays. We performed a cross-sectional case-control study where circulating levels of IFN-α2 were measured by a highly sensitive, solution phase multiplex magnetized bead assay and investigated the relation of IFN-α2 with autoantibody profiles, clinical disease activity and levels of inflammatory cytokines in SLE patients (n = 87). Cytokine levels were determined on stored sera aliquots with cut-off levels determined by the geometric mean + 2SD in healthy controls (n = 27). IFN-α2 levels were increased in 64% of SLE patients, who displayed more renal disease and higher disease activity (p = 0.06) and had a significantly higher sum of activated cytokines (median 4.5, range 7) compared to patients with normal IFN-α2 (median one, range 3; p < 0.001). Solution phase micro-bead assay thus identified increased IFN-α2 levels in two-thirds of SLE patients with longstanding disease. The association with clinical disease and activation of multiple inflammatory cytokines supports a role for IFN-α2 in disease perpetuation in a large subset of SLE patients. PMID:23213068

  8. Peroxisome proliferator-activated receptor α, a potential therapeutic target for alcoholic liver disease

    PubMed Central

    Nan, Yue-Min; Wang, Rong-Qi; Fu, Na

    2014-01-01

    Alcoholic liver injury represents a progressive process with a range of consequences including hepatic steatosis, steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma. Targeting key molecular regulators involved in the development of alcoholic liver injury may be of great value in the prevention of liver injury. Peroxisome proliferator-activated receptor α (PPARα) plays a pivotal role in modulation of hepatic lipid metabolism, oxidative stress, inflammatory response and fibrogenesis. As such, PPARα may be a potential therapeutic target for the treatment of alcoholic liver disease. PMID:25009377

  9. Characterization of peripartum rumination and activity of cows diagnosed with metabolic and uterine diseases.

    PubMed

    Liboreiro, Daniela N; Machado, Karine S; Silva, Paula R B; Maturana, Milton M; Nishimura, Thiago K; Brandão, Alice P; Endres, Márcia I; Chebel, Ricardo C

    2015-10-01

    delivering live calves (499.3 ± 16.2 vs. 461.3 ± 4.1 arbitrary unit). Occurrence of retained fetal membrane tended to and was associated with reduced prepartum (444.3 ± 11.0 vs. 466.5 ± 4.3 arbitrary unit) and postpartum (488.2 ± 14.5 vs. 538.8 ± 5.7 arbitrary unit) activity, respectively. Cows diagnosed with metritis had reduced postpartum DRT (415.9 ± 10.1 vs. 441.0 ± 5.2 min/d) and activity (512.5 ± 11.5 vs. 539.2 ± 6.0 arbitrary unit). Postpartum activity was reduced among cows that were diagnosed with subclinical ketosis (502.20 ± 16.5 vs. 536.6 ± 6.2 arbitrary unit). Although differences in DRT and activity between populations of cows that developed periparturient diseases and healthy cows were observed, further experiments are necessary to determine how DRT and activity data may be used to precociously diagnose individuals that will develop such periparturient diseases. PMID:26233440

  10. Low-grade disease activity in early life precedes childhood asthma and allergy.

    PubMed

    Chawes, Bo Lund Krogsgaard

    2016-08-01

    Asthma and allergies are today the most common chronic diseases in children and the leading causes of school absences, chronic medication usage, emergency department visits and hospitalizations, which affect all members of the family and represent a significant societal and scientific challenge. These highly prevalent disorders are thought to originate from immune distortion in early childhood, but the etiology and heterogeneity of the disease mechanisms are not understood, which hampers preventive initiatives and makes treatment inadequate. The objective of this thesis is to investigate the presence of an early life disease activity prior to clinical symptoms to understand the anteceding pathophysiological steps towards childhood asthma and allergy. The thesis is built on seven studies from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC2000) birth cohort examining biomarkers of disease activity in 411 asymptomatic neonates in cord blood (I-II), urine (III), exhaled breath (IV-V) and infant lung function (VI-VII) in relation to the subsequent development of asthma and allergy during the first seven years of life. In papers I-II, we studied cord blood chemokines and 25(OH)-vitamin D, which represent a proxy of the inborn immature immune system, the intrauterine milieu, and the maternal immune health during pregnancy. High levels of the Th2-related chemokine CCL22 and high CCL22/CXCL11 ratio were positively correlated with total IgE level during preschool age (II). This suggests an inborn Th2 skewing of the immune system in healthy newborns subsequently developing elevated total IgE antibodies, which is considered to increase the risk of asthma and allergies later in life. Additionally, deficient cord blood 25(OH)-vitamin D levels were associated with a 2.7-fold increased risk of recurrent wheeze at age 0-7 years (I). Together, these findings support the concept that early life immune programming in the pre-symptomatic era plays an essential role

  11. Incidence of gastroesophageal reflux disease (GERD), active component, U.S. Armed Forces, 2005-2014.

    PubMed

    Daniele, Denise O; Oh, Gi-Taik; O'Donnell, Francis L; Clark, Leslie L

    2015-07-01

    Gastroesophageal reflux disease (GERD) is a common condition among adults that can cause symptoms such as frequent heartburn, substernal chest pain, and regurgitation of food. During 2005-2014, a total of 137,081 active component service members had an incident (first-ever) diagnosis of GERD (incidence rate: 101.3 per 10,000 person-years). Incidence rates were higher than their respective counterparts among females, black and white non-Hispanics, service members in the Coast Guard and Air Force, officers, and those in healthcare occupations. Rates increased monotonically with increasing age groups. Most GERD cases (79.2%) were uncomplicated GERD; however, 20.8% were identified as having a symptom or complication linked to their GERD diagnosis. Lifestyle changes, medication, and prevention of serious complications should be emphasized among individuals diagnosed with GERD, particularly those at risk for severe disease. PMID:26207411

  12. Activation of glycolysis and apoptosis in glycogen storage disease type Ia.

    PubMed

    Sun, Baodong; Li, Songtao; Yang, Liu; Damodaran, Tirupapuliyur; Desai, Dev; Diehl, Anna Mae; Alzate, Oscar; Koeberl, Dwight D

    2009-08-01

    The deficiency of glucose-6-phosphatase (G6Pase) underlies glycogen storage disease type Ia (GSD-Ia, von Gierke disease; MIM 232200), an autosomal recessive disorder of metabolism associated with life-threatening hypoglycemia, growth retardation, renal failure, hepatic adenomas, and hepatocellular carcinoma. Liver involvement includes the massive accumulation of glycogen and lipids due to accumulated glucose-6-phosphate and glycolytic intermediates. Proteomic analysis revealed elevations in glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and other enzymes involved in glycolysis. GAPDH was markedly increased in murine G6Pase-deficient hepatocytes. The moonlighting role of GAPDH includes increasing apoptosis, which was demonstrated by increased TUNEL assay positivity and caspase 3 activation in the murine GSD-Ia liver. These analyses of hepatic involvement in GSD-Ia mice have implicated the induction of apoptosis in the pathobiology of GSD-Ia. PMID:19419892

  13. Alternative pathway activation in sickle cell disease and beta-thalassemia major.

    PubMed

    deCiutiis, A C; Peterson, C M; Polley, M J; Metakis, L J

    1978-07-01

    Total hemolytic complement activity (CH50), immuno-electrophoretic conversion of Factor B (C3PA), and of C3 were studied in 16 patients with sickle cell disease in a steady state, eight patients in crisis, and ten patients with β-thalassemia major anemia maintained on a constant transfusion regimen. Patients with sickle cell disease in a steady state have moderatley 56 (percent) depressed conversion of Factor B in addition to markedly decreased conversion of C3 in four of ten patients. One of the three sickle cell patients and two of the four thalassemia patients with low C3 conversion levels have died subsequent to the studies. The combination of chronically decreased Factor B conversion in the face of markedly decreased C3 conversion may make these patients occasionally vulnerable to overwhelming infection analagous to the situation seen in postsplenectomy cases. PMID:702579

  14. Modelling Rift Valley fever (RVF) disease vector habitats using active and passive remote sensing systems

    NASA Technical Reports Server (NTRS)

    Ambrosia, Vincent G.; Linthicum, K. G.; Bailey, C. L.; Sebesta, P.

    1989-01-01

    The NASA Ames Ecosystem Science and Technology Branch and the U.S. Army Medical Research Institute of Infectious Diseases are conducting research to detect Rift Valley fever (RVF) vector habitats in eastern Africa using active and passive remote-sensing. The normalized difference vegetation index (NDVI) calculated from Landsat TM and SPOT data is used to characterize the vegetation common to the Aedes mosquito. Relationships have been found between the highest NDVI and the 'dambo' habitat areas near Riuru, Kenya on both wet and dry data. High NDVI values, when combined with the vegetation classifications, are clearly related to the areas of vector habitats. SAR data have been proposed for use during the rainy season when optical systems are of minimal use and the short frequency and duration of the optimum RVF mosquito habitat conditions necessitate rapid evaluation of the vegetation/moisture conditions; only then can disease potential be stemmed and eradication efforts initiated.

  15. Kalanchoe pinnata inhibits mast cell activation and prevents allergic airway disease.

    PubMed

    Cruz, E A; Reuter, S; Martin, H; Dehzad, N; Muzitano, M F; Costa, S S; Rossi-Bergmann, B; Buhl, R; Stassen, M; Taube, C

    2012-01-15

    Aqueous extract of Kalanchoe pinnata (Kp) have been found effective in models to reduce acute anaphylactic reactions. In the present study, we investigate the effect of Kp and the flavonoid quercetin (QE) and quercitrin (QI) on mast cell activation in vitro and in a model of allergic airway disease in vivo. Treatment with Kp and QE in vitro inhibited degranulation and cytokine production of bone marrow-derived mast cells following IgE/FcɛRI crosslinking, whereas treatment with QI had no effect. Similarly, in vivo treatment with Kp and QE decreased development of airway hyperresponsiveness, airway inflammation, goblet cell metaplasia and production of IL-5, IL-13 and TNF. In contrast, treatment with QI had no effect on these parameters. These findings demonstrate that treatment with Kp or QE is effective in treatment of allergic airway disease, providing new insights to the immunomodulatory functions of this plant. PMID:21802918

  16. Active turbulence in active nematics

    NASA Astrophysics Data System (ADS)

    Thampi, S. P.; Yeomans, J. M.

    2016-07-01

    Dense, active systems show active turbulence, a state characterised by flow fields that are chaotic, with continually changing velocity jets and swirls. Here we review our current understanding of active turbulence. The development is primarily based on the theory and simulations of active liquid crystals, but with accompanying summaries of related literature.

  17. Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease.

    PubMed

    Flores, Alyssa M; Casey, Scott D; Felix, Christian M; Phuan, Puay W; Verkman, A S; Levin, Marc H

    2016-05-01

    Dry eye disorders, including Sjögren's syndrome, constitute a common problem in the aging population, with limited effective therapeutic options available. The cAMP-activated Cl(-) channel cystic fibrosis transmembrane conductance regulator (CFTR) is a major prosecretory channel at the ocular surface. We investigated whether compounds that target CFTR can correct the abnormal tear film in dry eye. Small-molecule activators of human wild-type CFTR identified by high-throughput screening were evaluated in cell culture and in vivo assays, to select compounds that stimulate Cl(-)-driven fluid secretion across the ocular surface in mice. An aminophenyl-1,3,5-triazine, CFTRact-K089, fully activated CFTR in cell cultures with EC50 ∼250 nM and produced an ∼8.5 mV hyperpolarization in ocular surface potential difference. When delivered topically, CFTRact-K089 doubled basal tear volume for 4 h and had no effect in CF mice. CFTRact-K089 showed sustained tear film bioavailability without detectable systemic absorption. In a mouse model of aqueous-deficient dry eye produced by lacrimal ablation, topical administration of 0.1 nmol CFTRact-K089 3 times daily restored tear volume to basal levels, preventing corneal epithelial disruption when initiated at the time of surgery and reversing it when started after development of dry eye. Our results support the potential utility of CFTR-targeted activators as a novel prosecretory treatment for dry eye.-Flores, A. M., Casey, S. D., Felix, C. M., Phuan, P. W., Verkman, A. S., Levin, M. H. Small-molecule CFTR activators increase tear secretion and prevent experimental dry eye disease. PMID:26842854

  18. Direct conscious telemetry recordings demonstrate increased renal sympathetic nerve activity in rats with chronic kidney disease

    PubMed Central

    Salman, Ibrahim M.; Sarma Kandukuri, Divya; Harrison, Joanne L.; Hildreth, Cara M.; Phillips, Jacqueline K.

    2015-01-01

    Chronic kidney disease (CKD) is associated with sympathetic hyperactivity and impaired blood pressure control reflex responses, yet direct evidence demonstrating these features of autonomic dysfunction in conscious animals is still lacking. Here we measured renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) using telemetry-based recordings in a rat model of CKD, the Lewis Polycystic Kidney (LPK) rat, and assessed responses to chemoreflex activation and acute stress. Male LPK and Lewis control animals (total n = 16) were instrumented for telemetric recording of RSNA and MAP. At 12–13 weeks-of-age, resting RSNA and MAP, sympathetic and haemodynamic responses to both peripheral (hypoxia: 10% O2) and central chemoreflex (hypercapnia: 7% CO2) activation and acute stress (open-field exposure), were measured. As indicators of renal function, urinary protein (UPro) and creatinine (UCr) levels were assessed. LPK rats had higher resting RSNA (1.2 ± 0.1 vs. 0.6 ± 0.1 μV, p < 0.05) and MAP (151 ± 8 vs. 97 ± 2 mmHg, p < 0.05) compared to Lewis. MAP was negatively correlated with UCr (r = −0.80, p = 0.002) and positively correlated with RSNA (r = 0.66, p = 0.014), with multiple linear regression modeling indicating the strongest correlation was with Ucr. RSNA and MAP responses to activation of the central chemoreflex and open-field stress were reduced in the LPK relative to the Lewis (all p < 0.05). This is the first description of dual conscious telemetry recording of RSNA and MAP in a genetic rodent model of CKD. Elevated RSNA is likely a key contributor to the marked hypertension in this model, while attenuated RSNA and MAP responses to central chemoreflex activation and acute stress in the LPK indicate possible deficits in the neural processing of autonomic outflows evoked by these sympathoexcitatory pathways. PMID:26300784

  19. Physical Activity, Health Status and Risk of Hospitalization in Patients with Severe Chronic Obstructive Pulmonary Disease

    PubMed Central

    Benzo, Roberto P.; Chang, Chung-Chou H.; Farrell, Max H.; Kaplan, Robert; Ries, Andrew; Martinez, Fernando J.; Wise, Robert; Make, Barry; Sciurba, Frank

    2010-01-01

    Background Chronic obstructive pulmonary disease (COPD) is a leading cause of death and 70% of the cost of COPD is due to hospitalizations. Self-reported daily physical activity and health status have been reported as predictors of a hospitalization in COPD but are not routinely assessed. Objectives We tested the hypothesis that self-reported daily physical activity and health status assessed by a simple question were predictors of a hospitalization in a well-characterized cohort of patients with severe emphysema. Methods Investigators gathered daily physical activity and health status data assessed by a simple question in 597 patients with severe emphysema and tested the association of those patient-reported outcomes to the occurrence of a hospitalization in the following year. Multiple logistic regression analyses were used to determine predictors of hospitalization during the first 12 months after randomization. Results The two variables tested in the hypothesis were significant predictors of a hospitalization after adjusting for all univariable significant predictors: >2 h of physical activity per week had a protective effect [odds ratio (OR) 0.60; 95% confidence interval (95% CI) 0.41–0.88] and self-reported health status as fair or poor had a deleterious effect (OR 1.57; 95% CI 1.10–2.23). In addition, two other variables became significant in the multivariate model: total lung capacity (every 10% increase) had a protective effect (OR 0.88; 95% CI 0.78–0.99) and self-reported anxiety had a deleterious effect (OR 1.75; 95% CI 1.13–2.70). Conclusion Self-reported daily physical activity and health status are independently associated with COPD hospitalizations. Our findings, assessed by simple questions, suggest the value of patient-reported outcomes in developing risk assessment tools that are easy to use. PMID:20234126

  20. Increased Complement C1q Level Marks Active Disease in Human Tuberculosis

    PubMed Central

    Zhang, Mingxia; Liu, Haiying; Zhang, Guoliang; Deng, Qunyi; Huang, Jian; Gao, Zhiliang; Zhou, Boping; Feng, Carl G.; Chen, Xinchun

    2014-01-01

    Background Complement functions as an important host defense system and complement C5 and C7 have been implicated in immunopathology of tuberculosis. However, little is known about the role of other complement components in tuberculosis. Methods Complement gene expression in peripheral blood mononuclear cells of tuberculosis patients and controls were determined using whole genome transcriptional microarray assays. The mRNA and protein levels of three C1q components, C1qA, C1qB, and C1qC, were further validated by qRT-PCR and enzyme-linked immunosorbent assay, respectively. The percentages of C1q expression in CD14 positive cells were determined by flow cytometry. Finally, C1qC protein level was quantified in the pleural fluid of tuberculosis and non-tuberculosis pleurisy. Results C1q expression increases significantly in the peripheral blood of patients with active tuberculosis compared to healthy controls and individuals with latent TB infection. The percentage of C1q-expressing CD14 positive cells is significantly increased in active TB patients. C1q expression in the peripheral blood correlates with sputum smear positivity in tuberculosis patients and is reduced after anti-tuberculosis chemotherapy. Notably, receiver operating characteristic analysis showed that C1qC mRNA levels in peripheral blood efficiently discriminate active from latent tuberculosis infection and healthy controls. Additionally, C1qC protein level in pleural effusion shows improved power in discriminating tuberculosis from non-tuberculosis pleurisy when compared to other inflammatory markers, such as IL-6 and TNF-α. Conclusions C1q expression correlates with active disease in human tuberculosis. C1q could be a potential diagnostic marker to discriminate active tuberculosis from latent tuberculosis infection as well as tuberculosis pleurisy from non-tuberculosis pleurisy. PMID:24647646

  1. Childhood-onset systemic lupus erythematosus in Singapore: clinical phenotypes, disease activity, damage, and autoantibody profiles.

    PubMed

    Tan, J H T; Hoh, S F; Win, M T M; Chan, Y H; Das, L; Arkachaisri, T

    2015-08-01

    Childhood-onset systemic lupus erythematosus (cSLE) is a multisystem autoimmune disease characterized by immune dysregulation affecting patients less than 18 years old. One-fifth of SLE cases are diagnosed during childhood. cSLE presents differently from adults and has a more severe and aggressive course. We describe the clinical and antibody profiles in our cSLE Singapore cohort. All cSLE patients who satisfied the 1997 American College of Rheumatology diagnostic criteria were captured in our lupus registry from January 2009 to January 2014. Data including demographic, cumulative clinical, serologic data, and damage indices were collected. Adjusted mean SLEDAI-2K (AMS) was used to summarize disease activity over multiple visits. Cluster analysis using non-hierarchical K-means procedure was performed on eight selected antibodies. The 64 patients (female:male ratio 5:1; Chinese 45.3%, Malay 28.1%, Indian 9.4%, and other races 17.2%) had a mean onset age of 11.5 years (range 2.1-16.7) and mean age at diagnosis was 11.9 years (range 2.6-18.0). Our study demonstrated differences in clinical manifestations for which hematologic involvement was the most common manifestation with less renal disease and uncommon neurologic manifestation as compared to other cSLE cohorts reported in our region. Antibody clusters were identified in our cohort but their clinical association/discrimination and outcome prediction required further validation study. Outcomes of our cohort in regard to disease activity after therapy and organ damages were comparable if not better to other cSLE cohorts elsewhere. Steroid-related damage, including symptomatic multifocal avascular necrosis and cataract, were not uncommon locally. Infection remains the major cause of death for the continent. Nevertheless, the five year survival rate of our cohort (98.4%) was high. PMID:25926055

  2. Is mean platelet volume a new activity criteria in Behçet's disease?

    PubMed

    Uzkeser, Hulya; Haliloglu, Sema; Cayir, Yasemin; Bilen, Nurhan; Karaaslan, Yasar; Kosar, Ali; Carlioglu, Ayse

    2015-10-01

    The aim of this study was to assess mean platelet volume (MPV) and its relationship with disease activity in patients with Behçet's disease. Thirty-six patients with an age of 38.9 ± 11 (mean ± SD) years and 40 controls aged 36.5 ± 12 (mean ± SD) years were enrolled the study. Demographic data, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), MPV, clinical findings such as oral aphthae, genital aphthae, erythema nodosum, acne, central nervous system involvement, uveitis, arthritis and arthralgia were all recorded. The MPV value in patients with Behçet's disease was 8.06 ± 1.0 (mean ± SD) and the MPV value of the control participants was 7.45 ± 0.6 (mean ± SD). MPV was statistically higher in patients with Behçet's disease than in the controls (P = 0.003). There were also significant differences between patients and controls according to ESR and CRP values (P < 0.001 and P = 0.001, respectively). MPV was positively correlated with arthralgia (P < 0.001, r = 0.438), arthritis (P = 0.008, r = 0.307), erythema nodosum (P = 0.002, r =  0.354), central nervous system involvement (P = 0.002, r = 0.357), acne (P = 0.008, r = 0.312), genital aphthae (P < 0.001, r = 0.401) and oral aphthae (P = 0.001 r = 0.377). MPV can be easily obtained from the patients. It was a cheap and practical method. In the future, MPV may be used as a new marker to detect the activation of BD. PMID:26196194

  3. What are the evidences of solar activity influence on coronary heart disease?

    NASA Astrophysics Data System (ADS)

    Gurfinkel, Yury; Breus, Tamara

    Researches of last two decades have shown that the cardiovascular system represents the most probable target for influence of helio - and geomagnetic activity. Both cardiovascular system and blood connect very closely: one system cannot exist without another. For the same reason the effects perceived by one system, are easily transferred to another. Laboratory tests as blood coagulation, platelet aggregation, and capillary blood velocity performed in our hospital in patients suffering from coronary heart disease (CHD) revealed a high their dependence on a level of geomagnetic activity (Gurfinkel et al., 1995, 1998). Later Gmitrov and Ohkubo (2002) in experiments on animals also found a significant negative correlation between geomagnetic field disturbances and capillary blood velocity. The analyzing data collected by the Moscow ambulance services covering more then one million observations over three years, cleaned up by seasonal effects of meteorological and social causes, showed that the number of cases of myocardial infarction increased during geomagnetic storms (Breus et al., 1995). During 14 years we collected more than 25000 cases of acute myocardial infarction and brain stroke at seven medical hospitals located in Russia, China and some other countries. We used only cases with established date of acute attack of diseases. Undated cases were excluded from the analysis. Average numbers of patients on geomagnetic active days and days with quiet geomagnetic condition were compared. It was shown statistically that during geomagnetic disturbances the frequency of myocardial infarction and brain stroke cases increased on the average by a factor of two in comparison with quiet geomagnetic conditions. These results are close to results obtained by (Stoupel, 1999), for patients suffering with acute cardiological pathology. Our recent study (with L.Parfeonova) revealed the relation between heart ventricular ectopic activity (VEA) and geomagnetic conditions in patients

  4. Effect of the pituitary adenylate cyclase-activating polypeptide on the autophagic activation observed in in vitro and in vivo models of Parkinson's disease.

    PubMed

    Lamine-Ajili, Asma; Fahmy, Ahmed M; Létourneau, Myriam; Chatenet, David; Labonté, Patrick; Vaudry, David; Fournier, Alain

    2016-04-01

    Parkinson's disease (PD) is a neurodegenerative disorder that leads to destruction of the midbrain dopaminergic (DA) neurons. This phenomenon is related to apoptosis and its activation can be blocked by the pituitary adenylate cyclase-activating polypeptide (PACAP). Growing evidence indicates that autophagy, a self-degradation activity that cleans up the cell, is induced during the course of neurodegenerative diseases. However, the role of autophagy in the pathogenesis of neuronal disorders is yet poorly understood and the potential ability of PACAP to modulate the related autophagic activation has never been significantly investigated. Hence, we explored the putative autophagy-modulating properties of PACAP in in vitro and in vivo models of PD, using the neurotoxic agents 1-methyl-4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), respectively, to trigger alterations of DA neurons. In both models, following the toxin exposure, PACAP reduced the autophagic activity as evaluated by the production of LC3 II, the modulation of the p62 protein levels, and the formation of autophagic vacuoles. The ability of PACAP to inhibit autophagy was also observed in an in vitro cell assay by the blocking of the p62-sequestration activity produced with the autophagy inducer rapamycin. Thus, the results demonstrated that autophagy is induced in PD experimental models and that PACAP exhibits not only anti-apoptotic but also anti-autophagic properties. PMID:26769362

  5. Interval shifts in basophil measures correlate with disease activity in chronic spontaneous urticaria.

    PubMed

    Oliver, E T; Sterba, P M; Saini, S S

    2015-05-01

    Chronic spontaneous urticaria (CSU) significantly impacts the quality of life of those affected through symptoms of pruritus and recurrent skin lesions. In active CSU disease, reduced IgE-mediated basophil histamine release (HR) and basopenia are observed. We sought to examine the relationship between interval changes in basophil measures and shifts in patient-reported disease impairment. Simultaneous symptom and basophil evaluations were completed at two sequential study visits, and interval changes in measures were compared between visits for each subject (n = 38). These measures included Skindex-29, current itch and hives scores, total leukocyte histamine content (an indirect measure of blood basophil presence), and basophil HR in response to anti-IgE and formyl-methionine-leucine-phenylalanine. Overall, interval improvements in disease measures in CSU subjects were associated with increased basophil numbers (total leukocyte histamine content) and IgE-mediated HR. This suggests these measures are potential biomarkers for CSU disease improvement and further implicates a role for basophils in CSU. PMID:25631394

  6. SEMA4D compromises blood-brain barrier, activates microglia, and inhibits remyelination in neurodegenerative disease.

    PubMed

    Smith, Ernest S; Jonason, Alan; Reilly, Christine; Veeraraghavan, Janaki; Fisher, Terrence; Doherty, Michael; Klimatcheva, Ekaterina; Mallow, Crystal; Cornelius, Chad; Leonard, John E; Marchi, Nicola; Janigro, Damir; Argaw, Azeb Tadesse; Pham, Trinh; Seils, Jennifer; Bussler, Holm; Torno, Sebold; Kirk, Renee; Howell, Alan; Evans, Elizabeth E; Paris, Mark; Bowers, William J; John, Gareth; Zauderer, Maurice

    2015-01-01

    Multiple sclerosis (MS) is a chronic neuroinflammatory disease characterized by immune cell infiltration of CNS, blood-brain barrier (BBB) breakdown, localized myelin destruction, and progressive neuronal degeneration. There exists a significant need to identify novel therapeutic targets and strategies that effectively and safely disrupt and even reverse disease pathophysiology. Signaling cascades initiated by semaphorin 4D (SEMA4D) induce glial activation, neuronal process collapse, inhibit migration and differentiation of oligodendrocyte precursor cells (OPCs), and disrupt endothelial tight junctions forming the BBB. To target SEMA4D, we generated a monoclonal antibody that recognizes mouse, rat, monkey and human SEMA4D with high affinity and blocks interaction between SEMA4D and its cognate receptors. In vitro, anti-SEMA4D reverses the inhibitory effects of recombinant SEMA4D on OPC survival and differentiation. In vivo, anti-SEMA4D significantly attenuates experimental autoimmune encephalomyelitis in multiple rodent models by preserving BBB integrity and axonal myelination and can be shown to promote migration of OPC to the site of lesions and improve myelin status following chemically-induced demyelination. Our study underscores SEMA4D as a key factor in CNS disease and supports the further development of antibody-based inhibition of SEMA4D as a novel therapeutic strategy for MS and other neurologic diseases with evidence of demyelination and/or compromise to the neurovascular unit. PMID:25461192

  7. Physical Activity Level of Korean Adults with Chronic Diseases: The Korean National Health and Nutritional Examination Survey, 2010-2012

    PubMed Central

    Jin, Ho-Seong; An, Ah-Reum; Choi, Ho-Chun; Lee, Sang-Hyun; Shin, Dong-Heon; Oh, Seung-Min; Seo, Young-Gyun

    2015-01-01

    Background Proper physical activities are known to be helpful in the prevention and management of chronic diseases. However, the physical activity level of patients with chronic diseases is low. Therefore, this study aimed to investigate the physical activity compliance of patients with hypertension, diabetes, and dyslipidemia in Korea. Methods This study analyzed the 2010-2012 Fifth Korean National Health and Nutrition Examination Survey data. We included 13,873 individuals in the analysis. The level of physical activity compliance was measured by performing multivariate logistic regression analyses. Results In the univariate analysis, the subjects with hypertension or diabetes tended to comply with the physical activity guidelines less faithfully than their healthy counterparts. The proportion of subjects with hypertension who were insufficiently physically active was 65.4% among the men and 75.8% among the women. For diabetes, the proportions were 66.7% and 76.8%, respectively. No significant difference was found between the subjects with dyslipidemia and their healthy counterparts. In the multivariate logistic regression analysis, no significant difference in physical activity compliance was observed between the subjects with hypertension, diabetes, or dyslipidemia and their healthy counterparts for both sexes. Conclusion The patients with hypertension or diabetes tended to have lower physical activity prevlaence than their healthy counterparts. However, for dyslipidemia, no significant difference was found between the two groups. Given the significance of physical activities in the management of chronic diseases, the physical activities of these patients need to be improved. PMID:26634091

  8. Early Components of the Complement Classical Activation Pathway in Human Systemic Autoimmune Diseases

    PubMed Central

    Lintner, Katherine E.; Wu, Yee Ling; Yang, Yan; Spencer, Charles H.; Hauptmann, Georges; Hebert, Lee A.; Atkinson, John P.; Yu, C. Yung

    2016-01-01

    The complement system consists of effector proteins, regulators, and receptors that participate in host defense against pathogens. Activation of the complement system, via the classical pathway (CP), has long been recognized in immune complex-mediated tissue injury, most notably systemic lupus erythematosus (SLE). Paradoxically, a complete deficiency of an early component of the CP, as evidenced by homozygous genetic deficiencies reported in human, are strongly associated with the risk of developing SLE or a lupus-like disease. Similarly, isotype deficiency attributable to a gene copy-number (GCN) variation and/or the presence of autoantibodies directed against a CP component or a regulatory protein that result in an acquired deficiency are relatively common in SLE patients. Applying accurate assay methodologies with rigorous data validations, low GCNs of total C4, and heterozygous and homozygous deficiencies of C4A have been shown as medium to large effect size risk factors, while high copy numbers of total C4 or C4A as prevalent protective factors, of European and East-Asian SLE. Here, we summarize the current knowledge related to genetic deficiency and insufficiency, and acquired protein deficiencies for C1q, C1r, C1s, C4A/C4B, and C2 in disease pathogenesis and prognosis of SLE, and, briefly, for other systemic autoimmune diseases. As the complement system is increasingly found to be associated with autoimmune diseases and immune-mediated diseases, it has become an attractive therapeutic target. We highlight the recent developments and offer a balanced perspective concerning future investigations and therapeutic applications with a focus on early components of the CP in human systemic autoimmune diseases. PMID:26913032

  9. Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment

    PubMed Central

    Rech, Juergen; Hueber, Axel J; Finzel, Stephanie; Englbrecht, Matthias; Haschka, Judith; Manger, Bernhard; Kleyer, Arnd; Reiser, Michaela; Cobra, Jayme Fogagnolo; Figueiredo, Camille; Tony, Hans-Peter; Kleinert, Stefan; Wendler, Joerg; Schuch, Florian; Ronneberger, Monika; Feuchtenberger, Martin; Fleck, Martin; Manger, Karin; Ochs, Wolfgang; Schmitt-Haendle, Matthias; Lorenz, Hanns-Martin; Nuesslein, Hubert; Alten, Rieke; Henes, Joerg; Krueger, Klaus; Schett, Georg

    2016-01-01

    Objective To analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial. Methods MBDA scores (scale 1–100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse. Results Moderate-to-high MBDA scores were found in 33% of patients with RA overall. Twice as many patients who relapsed (58%) had moderate/high MBDA compared with patients who remained in remission (21%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13%) in patients who were MBDA−/ACPA−, moderate in patients who were MBDA+/ACPA− (33.3%) and MBDA−ACPA+ (31.8%) and high in patients who were MBDA+/ACPA+ (76.4%). Conclusions MBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80% of the patients. Trial registration number EudraCT 2009-015740-42. PMID:26483255

  10. Serum matrix metalloproteinase‐3 levels correlate with disease activity in relapsing‐remitting multiple sclerosis

    PubMed Central

    Kanesaka, T; Mori, M; Hattori, T; Oki, T; Kuwabara, S

    2006-01-01

    Background Adhesion molecules and matrix metalloproteinases (MMPs) are known to be relevant to the ongoing development and disappearance of areas of demyelination in the white matter of the CNS of multiple sclerosis (MS) patients. This study examined whether serum matrix metalloproteinase‐3 (MMP‐3) levels correlate with disease activity in MS. Methods Serum MMP‐3 levels in 47 consecutive patients with relapsing‐remitting MS were measured by immunoassay every 4 weeks over a 15 month period. Results During the study period, 48 clinical relapses occurred. Serum MMP‐3 levels within 1 month of relapse were significantly higher than during the remission phase. Sequential analysis showed that serum MMP‐3 levels had increased transiently at the time of clinical relapse but returned to the normal range within a month. Conclusions Circulatory MMP‐3 levels are correlated with disease activity in relapsing‐remitting MS. This may contribute to the breakdown of the blood‐brain barrier at the time of relapse. PMID:16421119

  11. ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease.

    PubMed

    Letronne, Florent; Laumet, Geoffroy; Ayral, Anne-Marie; Chapuis, Julien; Demiautte, Florie; Laga, Mathias; Vandenberghe, Michel E; Malmanche, Nicolas; Leroux, Florence; Eysert, Fanny; Sottejeau, Yoann; Chami, Linda; Flaig, Amandine; Bauer, Charlotte; Dourlen, Pierre; Lesaffre, Marie; Delay, Charlotte; Huot, Ludovic; Dumont, Julie; Werkmeister, Elisabeth; Lafont, Franck; Mendes, Tiago; Hansmannel, Franck; Dermaut, Bart; Deprez, Benoit; Hérard, Anne-Sophie; Dhenain, Marc; Souedet, Nicolas; Pasquier, Florence; Tulasne, David; Berr, Claudine; Hauw, Jean-Jacques; Lemoine, Yves; Amouyel, Philippe; Mann, David; Déprez, Rebecca; Checler, Frédéric; Hot, David; Delzescaux, Thierry; Gevaert, Kris; Lambert, Jean-Charles

    2016-07-01

    Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amyloid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inversely correlates with amyloid load in Alzheimer's disease brains. Accordingly, in vitro down- or up-regulation of ADAM30 expression triggered an increase/decrease in Aβ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30(mut)) did not affect Aβ secretion. Proteomics/cell-based experiments showed that ADAM30-dependent regulation of APP metabolism required both cathepsin D (CTSD) activation and APP sorting to lysosomes. Accordingly, in Alzheimer-like transgenic mice, neuronal ADAM30 over-expression lowered Aβ42 secretion in neuron primary cultures, soluble Aβ42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation alterations. Our data thus indicate that lowering ADAM30 expression may favor Aβ production, thereby contributing to Alzheimer's disease development. PMID:27333034

  12. Serum Thiols as a Biomarker of Disease Activity in Lupus Nephritis

    PubMed Central

    Lalwani, Pritesh; de Souza, Giselle Katiane Bonfim Bacelar; de Lima, Domingos Savio Nunes; Passos, Luiz Fernando Souza; Boechat, Antonio Luiz; Lima, Emerson Silva

    2015-01-01

    Lupus Nephritis (LN) develops in more than half of the Systemic Lupus Erythematous (SLE) patients. However, lack of reliable, specific biomarkers for LN hampers clinical management of patients and impedes development of new therapeutics. The goal of this study was to investigate whether oxidative stress biomarkers in patients with SLE is predictive of renal pathology. Serum biochemical and oxidative stress markers were measured in patients with inactive lupus, active lupus with and without nephritis and compared to healthy control group. To assess the predictive performance of biomarkers, Receiver Operating Characteristic (ROC) curves were constructed and cut-offs were used to identify SLE patients with nephritis. We observed an increased oxidative stress response in all SLE patients compared to healthy controls. Among the several biomarkers tested, serum thiols had a significant inverse association with SLE Disease Activity Index (SLEDAI). Interestingly, thiols were able too aptly differentiate between SLE patients with and without renal pathology, and serum thiol levels were not affected by immunosuppressive drug therapy. The decreased thiols in SLE correlated significantly with serum creatinine and serum C3 levels. Further retrospective evaluation using serum creatinine or C3 levels in combination with thiol’s cutoff values from ROC analysis, we could positively predict chronicity of renal pathology in SLE patients. In summary, serum thiols emerge as an inexpensive and reliable indicator of LN, which may not only help in early identification of renal pathology but also aid in the therapeutic management of the disease, in developing countries with resource poor settings. PMID:25799079

  13. Physical Activity and Brain Function in Older Adults at Increased Risk for Alzheimer’s Disease

    PubMed Central

    Smith, J. Carson; Nielson, Kristy A.; Woodard, John L.; Seidenberg, Michael; Rao, Stephen M.

    2013-01-01

    Leisure-time physical activity (PA) and exercise training are known to help maintain cognitive function in healthy older adults. However, relatively little is known about the effects of PA on cognitive function or brain function in those at increased risk for Alzheimer’s disease through the presence of the apolipoproteinE epsilon4 (APOE-ε4) allele, diagnosis of mild cognitive impairment (MCI), or the presence of metabolic disease. Here, we examine the question of whether PA and exercise interventions may differentially impact cognitive trajectory, clinical outcomes, and brain structure and function among individuals at the greatest risk for AD. The literature suggests that the protective effects of PA on risk for future dementia appear to be larger in those at increased genetic risk for AD. Exercise training is also effective at helping to promote stable cognitive function in MCI patients, and greater cardiorespiratory fitness is associated with greater brain volume in early-stage AD patients. In APOE-ε4 allele carriers compared to non-carriers, greater levels of PA may be more effective in reducing amyloid burden and are associated with greater activation of semantic memory-related neural circuits. A greater research emphasis should be placed on randomized clinical trials for exercise, with clinical, behavioral, and neuroimaging outcomes in people at increased risk for AD. PMID:24961307

  14. Repurposing of the Open Access Malaria Box for Kinetoplastid Diseases Identifies Novel Active Scaffolds against Trypanosomatids.

    PubMed

    Kaiser, Marcel; Maes, Louis; Tadoori, Leela Pavan; Spangenberg, Thomas; Ioset, Jean-Robert

    2015-06-01

    Phenotypic screening had successfully been used for hit generation, especially in the field of neglected diseases, in which feeding the drug pipeline with new chemotypes remains a constant challenge. Here, we catalyze drug discovery research using a publicly available screening tool to boost drug discovery. The Malaria Box, assembled by the Medicines for Malaria Venture, is a structurally diverse set of 200 druglike and 200 probelike compounds distilled from more than 20,000 antimalarial hits from corporate and academic libraries. Repurposing such compounds has already identified new scaffolds against cryptosporidiosis and schistosomiasis. In addition to initiating new hit-to-lead activities, screening the Malaria Box against a plethora of other parasites would enable the community to better understand the similarities and differences between them. We describe the screening of the Malaria Box and triaging of the identified hits against kinetoplastids responsible for human African trypanosomiasis (Trypanosoma brucei), Chagas disease (Trypanosoma cruzi), and visceral leishmaniasis (Leishmania donovani and Leishmania infantum). The in vitro and in vivo profiling of the most promising active compounds with respect to efficacy, toxicity, pharmacokinetics, and complementary druggable properties are presented and a collaborative model used as a way to accelerate the discovery process discussed. PMID:25690568

  15. In vivo neutron activation analysis: body composition studies in health and disease

    SciTech Connect

    Ellis, K.J.; Cohn, S.H.

    1984-01-01

    In vivo analysis of body elements by neutron activation is an important tool in medical research. It has provided a direct quantitative measure of body composition of human beings in vivo. Basic physiological differences related to age, sex, race, and body size have been assessed by this noninvasive technique. The diagnosis and management of patients with various metabolic disorders and diseases has also been demonstrated. Two major facilities at Brookhaven are being utilized exclusively for in vivo neutron activation analysis (IVNAA) of calcium, phosphorus, sodium, chlorine, nitrogen, hydrogen, and potassium. These elements serve as the basis for a four compartment model of body composition: protein, water, mineral ash, and fat. Variations in these compartments are demonstrated in clinical research programs investigating obesity, anorexia, cancer, renal failure, osteoporosis, and normal aging. IVNAA continues to provide a unique approach to the evaluation of clinical diagnosis, efficacy of therapeutic regimens, and monitoring of the aging process. Classical balance studies usually require the patient to be admitted to a hospital for extended periods of confinement. IVNAA, however, allows for clinical management of the patient on an out-patient basis, an important aspect for treatment of chronic diseases. 25 references, 3 figures, 5 tables.

  16. Physical activity in the prevention of coronary heart disease: implications for the clinician.

    PubMed

    Varghese, Tina; Schultz, William M; McCue, Andrew A; Lambert, Cameron T; Sandesara, Pratik B; Eapen, Danny J; Gordon, Neil F; Franklin, Barry A; Sperling, Laurence S

    2016-06-15

    Cardiovascular disease (CVD) continues to be a leading cause of death worldwide. Because regular physical activity (PA) independently decreases the risk of coronary heart disease (CHD) while also having a positive, dose-related impact on other cardiovascular (CV) risk factors, it has increasingly become a focus of CHD prevention. Current guidelines recommend 30 min of moderate-intensity PA 5 days a week, but exercise regimens remain underused. PA adherence can be fostered with a multilevel approach that involves active individual participation, physician counselling and health coaching, community involvement, and policy change, with incorporation of cardiac rehabilitation for patients requiring secondary prevention. Viewing exercise quantity as a vital sign, prescribing PA like a medication, and using technology, such as smartphone applications, encourage a global shift in focus from CVD treatment to prevention. Community-wide, home-based and internet-based prevention initiatives may also offer a developing pool of resources that can be tapped into to promote education and PA compliance. This review summarises the underlying rationale, current guidelines for and recommendations to cultivate a comprehensive focus in the endorsement of PA in the primary and secondary prevention of CHD. PMID:26941396

  17. Celastrol increases glucocerebrosidase activity in Gaucher disease by modulating molecular chaperones

    PubMed Central

    Yang, Chunzhang; Swallows, Cody L.; Zhang, Chao; Lu, Jie; Xiao, Hongbin; Brady, Roscoe O.; Zhuang, Zhengping

    2014-01-01

    Gaucher disease is caused by mutations in the glucosidase, beta, acid gene that encodes glucocerebrosidase (GCase). Glucosidase, beta, acid mutations often cause protein misfolding and quantitative loss of GCase. In the present study, we found that celastrol, an herb derivative with known anticancer, anti-inflammatory, and antioxidant activity, significantly increased the quantity and catalytic activity of GCase. Celastrol interfered with the establishment of the heat-shock protein 90/Hsp90 cochaperone Cdc37/Hsp90-Hsp70-organizing protein chaperone complex with mutant GCase and reduced heat-shock protein 90-associated protein degradation. In addition, celastrol modulated the expression of molecular chaperones. Bcl2-associated athanogene 3 and heat shock 70kDa proteins 1A and 1B were significantly increased by celastrol. Furthermore, BAG family molecular chaperone regulator 3 assisted protein folding and maturation of mutant GCase. These findings provide insight into a therapeutic strategy for Gaucher disease and other human disorders that are associated with protein misfolding. PMID:24351928

  18. Protocatechuic acid and human disease prevention: biological activities and molecular mechanisms.

    PubMed

    Masella, R; Santangelo, C; D'Archivio, M; Li Volti, G; Giovannini, C; Galvano, F

    2012-01-01

    Epidemiological evidence has shown that a high dietary intake of vegetables and fruit rich in polyphenols is associated with a reduction of cancer incidence and mortality from coronary heart disease. The healthy effects associated with polyphenol consumption have made the study of the mechanisms of action a matter of great importance. In particular, the hydroxybenzoic acid protocatechuic acid (PCA) has been eliciting a growing interest for several reasons. Firstly, PCA is one of the main metabolites of complex polyphenols such as anthocyanins and procyanidins that are normally found at high concentrations in vegetables and fruit, and are absorbed by animals and humans. Since the daily intake of anthocyanins has been estimated to be much higher than that of other polyphenols, the nutritional value of PCA is increasingly recognized. Secondly, a growing body of evidence supports the concept that PCA can exert a variety of biological effects by acting on different molecular targets. It has been shown that PCA possesses antioxidant, anti-inflammatory as well as antihyperglycemic and neuroprotective activities. Furthermore, PCA seems to have chemopreventive potential because it inhibits the in vitro chemical carcinogenesis and exerts pro-apoptotic and anti-proliferative effects in different tissues. This review is aimed at providing an up-dated and comprehensive report on PCA giving a special emphasis on its biological activities and the molecular mechanisms of action most likely responsible for a beneficial role in human disease prevention. PMID:22519395

  19. Activation of sigma-1 receptor chaperone in the treatment of neuropsychiatric diseases and its clinical implication.

    PubMed

    Hashimoto, Kenji

    2015-01-01

    Endoplasmic reticulum (ER) protein sigma-1 receptor represents unique chaperone activity in the central nervous system, and it exerts a potent influence on a number of neurotransmitter systems. Several lines of evidence suggest that activation of sigma-1 receptor plays a role in the pathophysiology of neuropsychiatric diseases, as well as in the mechanisms of some therapeutic drugs and neurosteroids. Preclinical studies showed that some selective serotonin reuptake inhibitors (SSRIs; fluvoxamine, fluoxetine, excitalopram), donepezil, and ifenprodil act as sigma-1 receptor agonists. Furthermore, sigma-1 receptor agonists could improve the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP)-induced cognitive deficits in mice. A study using positron emission tomography have demonstrated that an oral administration of fluvoxamine or donepezil could bind to sigma-1 receptor in the healthy human brain, suggesting that sigma-1 receptor might be involved in the therapeutic mechanisms of these drugs. Moreover, case reports suggest that sigma-1 receptor agonists, including fluvoxamine, and ifenprodil, may be effective in the treatment of cognitive impairment in schizophrenia, delirium in elderly people, and flashbacks in post-traumatic stress disorder. In this review article, the author would like to discuss the clinical implication of sigma-1 receptor agonists, including endogenous neurosteroids, in the neuropsychiatric diseases. PMID:25704012

  20. Peroxisome Proliferator-Activated Receptor Targets for the Treatment of Metabolic Diseases

    PubMed Central

    Monsalve, Francisco A.; Pyarasani, Radha D.; Delgado-Lopez, Fernando; Moore-Carrasco, Rodrigo

    2013-01-01

    Metabolic syndrome is estimated to affect more than one in five adults, and its prevalence is growing in the adult and pediatric populations. The most widely recognized metabolic risk factors are atherogenic dyslipidemia, elevated blood pressure, and elevated plasma glucose. Individuals with these characteristics commonly manifest a prothrombotic state and a proinflammatory state as well. Peroxisome proliferator-activated receptors (PPARs) may serve as potential therapeutic targets for treating the metabolic syndrome and its related risk factors. The PPARs are transcriptional factors belonging to the ligand-activated nuclear receptor superfamily. So far, three isoforms of PPARs have been identified, namely, PPAR-α, PPAR-β/δ, and PPAR-γ. Various endogenous and exogenous ligands of PPARs have been identified. PPAR-α and PPAR-γ are mainly involved in regulating lipid metabolism, insulin sensitivity, and glucose homeostasis, and their agonists are used in the treatment of hyperlipidemia and T2DM. Whereas PPAR-β/δ function is to regulate lipid metabolism, glucose homeostasis, anti-inflammation, and fatty acid oxidation and its agonists are used in the treatment of metabolic syndrome and cardiovascular diseases. This review mainly focuses on the biological role of PPARs in gene regulation and metabolic diseases, with particular focus on the therapeutic potential of PPAR modulators in the treatment of thrombosis. PMID:23781121

  1. Structure–activity relationship of memapsin 2: implications on physiological functions and Alzheimer's disease

    PubMed Central

    Li, Xiaoman; Hong, Lin; Coughlan, Kathleen; Wang, Liang; Cao, Liu; Tang, Jordan

    2013-01-01

    Memapsin 2 (BACE1, β-secretase), a membrane aspartic protease, functions in the cleavage of the type I transmembrane protein, β-amyloid precursor protein (APP), leading to the production of amyloid β (Aβ) in the brain. Since Aβ is closely associated with the pathogenesis of Alzheimer's disease, understanding the biological function, particularly the catalytic activities of memapsin 2, would assist in a better understanding of the disease and the development of its inhibitors. The transmembrane and cytosolic domains of memapsin 2 function in cellular transport and localization, which are important regulatory mechanisms for its activity. The catalytic ectodomain contains a long substrate cleft that is responsible for substrate recognition, specificity, and peptide bond hydrolysis. The substrate cleft accommodates 11 residues of the substrate in separate binding subsites. Besides APP, a number of membrane proteins have been reported to be substrates of memapsin 2. The elucidation for the specificity of these subsites and the amino acid sequences surrounding the memapsin 2 cleavage site in these proteins has led to the establishment of a predictive model that can quantitatively estimate the efficiency of cleavage for any potential substrates. Such tools may be employed for future studies of memapsin 2 about its biological function. Herein, we review the current knowledge on the structure–function relationship of memapsin 2 and its relationship in the biological function. PMID:23676825

  2. Exercise and Physical Activity

    MedlinePlus

    Alzheimer ’s Caregiving Tips Exercise and Physical Activity Being active and getting exercise helps people with Alzheimer’s disease feel better. Exercise helps keep their muscles, joints, and heart in ...

  3. Nerve Growth Factor Gene Therapy Activates Neuronal Responses in Alzheimer’s Disease

    PubMed Central

    Tuszynski, Mark H.; Yang, Jennifer H.; Barba, David; U, H S.; Bakay, Roy; Pay, Mary M.; Masliah, Eliezer; Conner, James M.; Kobalka, Peter; Roy, Subhojit; Nagahara, Alan H.

    2016-01-01

    IMPORTANCE Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and lacks effective disease modifying therapies. In 2001 we initiated a clinical trial of Nerve Growth Factor (NGF) gene therapy in AD, the first effort at gene delivery in an adult neurodegenerative disorder. This program aimed to determine whether a nervous system growth factor prevents or reduces cholinergic neuronal degeneration in AD patients. We present post-mortem findings in 10 subjects with survival times ranging from 1 to 10 years post-treatment. OBJECTIVE To determine whether degenerating neurons in AD retain an ability to respond to a nervous system growth factor delivered after disease onset. DESIGN, SETTING, AND PARTICIPANTS 10 patients with early AD underwent NGF gene therapy using either ex vivo or in vivo gene transfer. The brains of all eight patients in the first Phase 1 ex vivo trial and two patients in a subsequent Phase 1 in vivo trial were examined. MAIN OUTCOME MEASURES Brains were immunolabeled to evaluate in vivo gene expression, cholinergic neuronal responses to NGF, and activation of NGF-related cell signaling. In two cases, NGF protein levels were measured by ELISA. RESULTS Degenerating neurons in the AD brain respond to NGF. All patients exhibited a trophic response to NGF, in the form of axonal sprouting toward the NGF source. Comparing treated and non-treated sides of the brain in three patients that underwent unilateral gene transfer, cholinergic neuronal hypertrophy occurred on the NGF-treated side (P>0.05). Activation of cellular signaling and functional markers were present in two patients that underwent AAV2-mediated NGF gene transfer. Neurons exhibiting tau pathology as well as neurons free of tau expressed NGF, indicating that degenerating cells can be infected with therapeutic genes with resulting activation of cell signaling. No adverse pathological effects related to NGF were observed. CONCLUSIONS AND RELEVANCE These findings indicate that

  4. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS.

    PubMed

    Park, Yong Hwan; Wood, Geryl; Kastner, Daniel L; Chae, Jae Jin

    2016-08-01

    Mutations in the genes encoding pyrin and mevalonate kinase (MVK) cause distinct interleukin-1β (IL-1β)-mediated autoinflammatory diseases: familial Mediterranean fever (FMF) and hyperimmunoglobulinemia D syndrome (HIDS). Pyrin forms an inflammasome when mutant or in response to bacterial modification of the GTPase RhoA. We found that RhoA activated the serine-threonine kinases PKN1 and PKN2 that bind and phosphorylate pyrin. Phosphorylated pyrin bound to 14-3-3 proteins, regulatory proteins that in turn blocked the pyrin inflammasome. The binding of 14-3-3 and PKN proteins to FMF-associated mutant pyrin was substantially decreased, and the constitutive IL-1β release from peripheral blood mononuclear cells of patients with FMF or HIDS was attenuated by activation of PKN1 and PKN2. Defects in prenylation, seen in HIDS, led to RhoA inactivation and consequent pyrin inflammasome activation. These data suggest a previously unsuspected fundamental molecular connection between two seemingly distinct autoinflammatory disorders. PMID:27270401

  5. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3.

    PubMed

    Haapaniemi, Emma M; Kaustio, Meri; Rajala, Hanna L M; van Adrichem, Arjan J; Kainulainen, Leena; Glumoff, Virpi; Doffinger, Rainer; Kuusanmäki, Heikki; Heiskanen-Kosma, Tarja; Trotta, Luca; Chiang, Samuel; Kulmala, Petri; Eldfors, Samuli; Katainen, Riku; Siitonen, Sanna; Karjalainen-Lindsberg, Marja-Liisa; Kovanen, Panu E; Otonkoski, Timo; Porkka, Kimmo; Heiskanen, Kaarina; Hänninen, Arno; Bryceson, Yenan T; Uusitalo-Seppälä, Raija; Saarela, Janna; Seppänen, Mikko; Mustjoki, Satu; Kere, Juha

    2015-01-22

    The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked-like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4(-)CD8(-)) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity. PMID:25349174

  6. Activation Mechanism of LRRK2 and Its Cellular Functions in Parkinson's Disease

    PubMed Central

    Rosenbusch, Katharina E.; Kortholt, Arjan

    2016-01-01

    Human LRRK2 (Leucine-Rich Repeat Kinase 2) has been associated with both familial and idiopathic Parkinson's disease (PD). Although several LRRK2 mediated pathways and interaction partners have been identified, the cellular functions of LRRK2 and LRRK2 mediated progression of PD are still only partially understood. LRRK2 belongs to the group of Roco proteins which are characterized by the presence of a Ras-like G-domain (Roc), a C-terminal of Roc domain (COR), a kinase, and several protein-protein interaction domains. Roco proteins exhibit a complex activation mechanism involving intramolecular signaling, dimerization, and substrate/effector binding. Importantly, PD mutations in LRRK2 have been linked to a decreased GTPase and impaired kinase activity, thus providing putative therapeutic targets. To fully explore these potential targets it will be crucial to understand the function and identify the pathways responsible for LRRK2-linked PD. Here, we review the recent progress in elucidating the complex LRRK2 activation mechanism, describe the accumulating evidence that link LRRK2-mediated PD to mitochondrial dysfunction and aberrant autophagy, and discuss possible ways for therapeutically targeting LRRK2. PMID:27293958

  7. Autoimmunity, hypogammaglobulinemia, lymphoproliferation, and mycobacterial disease in patients with activating mutations in STAT3

    PubMed Central

    Haapaniemi, Emma M.; Kaustio, Meri; Rajala, Hanna L. M.; van Adrichem, Arjan J.; Kainulainen, Leena; Glumoff, Virpi; Doffinger, Rainer; Kuusanmäki, Heikki; Heiskanen-Kosma, Tarja; Trotta, Luca; Chiang, Samuel; Kulmala, Petri; Eldfors, Samuli; Katainen, Riku; Siitonen, Sanna; Karjalainen-Lindsberg, Marja-Liisa; Kovanen, Panu E.; Otonkoski, Timo; Porkka, Kimmo; Heiskanen, Kaarina; Hänninen, Arno; Bryceson, Yenan T.; Uusitalo-Seppälä, Raija; Saarela, Janna; Seppänen, Mikko; Kere, Juha

    2015-01-01

    The signal transducer and activator of transcription (STAT) family of transcription factors orchestrate hematopoietic cell differentiation. Recently, mutations in STAT1, STAT5B, and STAT3 have been linked to development of immunodysregulation polyendocrinopathy enteropathy X-linked–like syndrome. Here, we immunologically characterized 3 patients with de novo activating mutations in the DNA binding or dimerization domains of STAT3 (p.K392R, p.M394T, and p.K658N, respectively). The patients displayed multiorgan autoimmunity, lymphoproliferation, and delayed-onset mycobacterial disease. Immunologically, we noted hypogammaglobulinemia with terminal B-cell maturation arrest, dendritic cell deficiency, peripheral eosinopenia, increased double-negative (CD4−CD8−) T cells, and decreased natural killer, T helper 17, and regulatory T-cell numbers. Notably, the patient harboring the K392R mutation developed T-cell large granular lymphocytic leukemia at age 14 years. Our results broaden the spectrum of phenotypes caused by activating STAT3 mutations, highlight the role of STAT3 in the development and differentiation of multiple immune cell lineages, and strengthen the link between the STAT family of transcription factors and autoimmunity. PMID:25349174

  8. A Novel Pyrimidin-Like Plant Activator Stimulates Plant Disease Resistance and Promotes Growth

    PubMed Central

    Sun, Tie-Jun; Lu, Yun; Narusaka, Mari; Shi, Chao; Yang, Yu-Bing; Wu, Jian-Xin; Zeng, Hong-Yun; Narusaka, Yoshihiro; Yao, Nan

    2015-01-01

    Plant activators are chemicals that induce plant defense responses to a broad spectrum of pathogens. Here, we identified a new potential plant activator, 5-(cyclopropylmethyl)-6-methyl-2-(2-pyridyl)pyrimidin-4-ol, named PPA (pyrimidin-type plant activator). Compared with benzothiadiazole S-methyl ester (BTH), a functional analog of salicylic acid (SA), PPA was fully soluble in water and increased fresh weight of rice (Oryza sativa) and Arabidopsis plants at low concentrations. In addition, PPA also promoted lateral root development. Microarray data and real-time PCR revealed that PPA-treated leaves not challenged with pathogen showed up-regulation of genes related to reactive oxygen species (ROS), defenses and SA. During bacterial infection, Arabidopsis plants pretreated with PPA showed dramatically decreased disease symptoms and an earlier and stronger ROS burst, compared with plants pretreated with BTH. Microscopy revealed that H2O2 accumulated in the cytosol, plasma membrane and cell wall around intracellular bacteria, and also on the bacterial cell wall, indicating that H2O2 was directly involved in killing bacteria. The increase in ROS-related gene expression also supported this observation. Our results indicate that PPA enhances plant defenses against pathogen invasion through the plant redox system, and as a water-soluble compound that can promote plant growth, has broad potential applications in agriculture. PMID:25849038

  9. Activation of AMPK-induced autophagy ameliorates Huntington disease pathology in vitro.

    PubMed

    Walter, Carolin; Clemens, Laura E; Müller, Amelie J; Fallier-Becker, Petra; Proikas-Cezanne, Tassula; Riess, Olaf; Metzger, Silke; Nguyen, Huu Phuc

    2016-09-01

    The expansion of a polyglutamine repeat in huntingtin (HTT) causes Huntington disease (HD). Although the exact pathogenesis is not entirely understood, mutant huntingtin (mHTT) causes disruption of various cellular functions, formation of aggregates and ultimately cell death. The process of autophagy is the main degradation pathway for mHTT, and various studies have demonstrated that the induction of autophagy leads to an amelioration of aggregate formation and an increase in cell viability. Commonly, this is achieved by inhibition of the mammalian target of rapamycin (mTOR), a prominent regulator of cell metabolism. Alternatively, non-canonical AMPK or mTOR-independent autophagy regulation has been recognized. Given mTOR's involvement in major cellular pathways besides autophagy, its inhibition may come with potentially detrimental effects. Here, we investigated if AMPK activation may provide a target for the induction of autophagy in an mTOR-independent manner. We demonstrate that activation of AMPK by A769662 and overexpression of a constitutively active form of AMPKα in STHdh cells and mouse embryonic fibroblasts (MEFs), leads to increased expression of the autophagosomal markers LC3 and p62, suggesting efficient autophagy induction. The induction of autophagy was independent of mTOR, and accompanied by a decrease of mHTT-containing aggregates as well as improved cell viability. Therefore, we validated AMPK as a promising therapeutic target to treat HD, and identified A769662 as a potential therapeutic compound to facilitate the clearance of mHTT. PMID:27133377

  10. Physical activity delays hippocampal neurodegeneration and rescues memory deficits in an Alzheimer disease mouse model.

    PubMed

    Hüttenrauch, M; Brauß, A; Kurdakova, A; Borgers, H; Klinker, F; Liebetanz, D; Salinas-Riester, G; Wiltfang, J; Klafki, H W; Wirths, O

    2016-01-01

    The evidence for a protective role of physical activity on the risk and progression of Alzheimer's disease (AD) has been growing in the last years. Here we studied the influence of a prolonged physical and cognitive stimulation on neurodegeneration, with special emphasis on hippocampal neuron loss and associated behavioral impairment in the Tg4-42 mouse model of AD. Tg4-42 mice overexpress Aβ4-42 without any mutations, and develop an age-dependent hippocampal neuron loss associated with a severe memory decline. We demonstrate that long-term voluntary exercise diminishes CA1 neuron loss and completely rescues spatial memory deficits in different experimental settings. This was accompanied by changes in the gene expression profile of Tg4-42 mice. Deep sequencing analysis revealed an upregulation of chaperones involved in endoplasmatic reticulum protein processing, which might be intimately linked to the beneficial effects seen upon long-term exercise. We believe that we provide evidence for the first time that enhanced physical activity counteracts neuron loss and behavioral deficits in a transgenic AD mouse model. The present findings underscore the relevance of increased physical activity as a potential strategy in the prevention of dementia. PMID:27138799

  11. SIRT2- and NRF2-Targeting Thiazole-Containing Compound with Therapeutic Activity in Huntington's Disease Models.

    PubMed

    Quinti, Luisa; Casale, Malcolm; Moniot, Sébastien; Pais, Teresa F; Van Kanegan, Michael J; Kaltenbach, Linda S; Pallos, Judit; Lim, Ryan G; Naidu, Sharadha Dayalan; Runne, Heike; Meisel, Lisa; Rauf, Nazifa Abdul; Leyfer, Dmitriy; Maxwell, Michele M; Saiah, Eddine; Landers, John E; Luthi-Carter, Ruth; Abagyan, Ruben; Dinkova-Kostova, Albena T; Steegborn, Clemens; Marsh, J Lawrence; Lo, Donald C; Thompson, Leslie M; Kazantsev, Aleksey G

    2016-07-21

    There are currently no disease-modifying therapies for the neurodegenerative disorder Huntington's disease (HD). This study identified novel thiazole-containing inhibitors of the deacetylase sirtuin-2 (SIRT2) with neuroprotective activity in ex vivo brain slice and Drosophila models of HD. A systems biology approach revealed an additional SIRT2-independent property of the lead-compound, MIND4, as an inducer of cytoprotective NRF2 (nuclear factor-erythroid 2 p45-derived factor 2) activity. Structure-activity relationship studies further identified a potent NRF2 activator (MIND4-17) lacking SIRT2 inhibitory activity. MIND compounds induced NRF2 activation responses in neuronal and non-neuronal cells and reduced production of reactive oxygen species and nitrogen intermediates. These drug-like thiazole-containing compounds represent an exciting opportunity for development of multi-targeted agents with potentially synergistic therapeutic benefits in HD and related disorders. PMID:27427231

  12. Physical activity

    MedlinePlus

    ... time they spend watching TV and using a computer and other electronic devices. All of these activities ... U.S. Department of Health and Human Services. Physical Activity Guidelines for Americans: Recommendation ... Page last updated: ...

  13. Elastic Scattering Spectroscopy as an Optical Marker of Inflammatory Bowel Disease Activity and Subtypes

    PubMed Central

    Rodriguez-Diaz, Eladio; Atkinson, Christopher; Jepeal, Lisa I.; Berg, Adam; Huang, Christopher S.; Cerda, Sandra R.; O’Brien, Michael J.; Bigio, Irving J.; Farraye, Francis A.; Singh, Satish K.

    2016-01-01

    Background In 10% to 15% of individuals, inflammatory bowel disease (IBD) is difficult to classify as ulcerative colitis (UC) or Crohn’s disease (CD). Previous work has demonstrated that probe-based elastic scattering spectroscopy (ESS) can produce spectra, informed by parameters like tissue ultrastructure and hemoglobin content, capable of differentiating pathologies. This study investigates whether ESS is an in vivo optical biomarker for the presence, activity, and type of IBD in the colon. Methods Pilot study, a retrospective data analysis. ESS spectra of endoscopically normal and inflamed colon were obtained from 48 patients with IBD and 46 non-IBD controls. Measurements from patients with IBD were categorized as CD or UC based on clinical diagnosis. Spectra were analyzed using high-dimensional methods. Leave-one-patient-out cross-validation was used to obtain diagnostic performance estimates. Results Patients with IBD were distinguishable from non-IBD controls with a sensitivity of 0.93 and specificity of 0.91 based on readings from endoscopically normal mucosa, and 0.94 and 0.93 from inflamed mucosa. In patients with IBD, histologically normal and inflamed colon were distinguishable with per-class accuracies of 0.83 and 0.89, respectively; histologically normal from inactive inflammation with accuracies of 0.73 and 0.89, respectively; and inactive from active colitis with accuracies of 0.87 and 0.84, respectively. The diagnosis of CD versus UC was made with per-class accuracies of 0.92 and 0.87 in normal and 0.87 and 0.85 in inflamed mucosa, respectively. Conclusions ESS, a simple, low-cost clinically friendly optical biopsy modality, has the potential to enhance the endoscopic assessment of IBD and its activity in real time and may help to distinguish CD from UC. PMID:24798637

  14. Peroxisome proliferator-activated receptors in cardiac energy metabolism and cardiovascular disease.

    PubMed

    Ajith, Thekkuttuparambil Ananthanarayanan; Jayakumar, Thankamani Gopinathan

    2016-07-01

    Cardiomyocytes mainly depend on energy produced from the oxidation of fatty acids and mitochondrial oxidative phosphorylation. Shortage of energy or excessive fat accumulation can lead to cardiac disorders. High saturated fat intake and a sedentary life style have a major influence in the development of cardiovascular disease (CVD). Peroxisome proliferator-activated receptors (PPARs), one of the nuclear receptor super family members, play critical role in the metabolism of lipids by regulating their oxidation and storage. Furthermore, they are involved in glucose homeostasis as well. PPARs, mainly alpha (α) and beta/delta (β/δ), have a significant effect on the lipid metabolism and anti-inflammation in endothelial cells (ECs), vascular smooth muscle cells, and also in cardiomyocytes. Pro-inflammatory cytokines, mainly tumour necrosis factor-α, released at the site of inflammation in the sub-ECs of coronary arteries can inactivate the PPARs which can eventually lead to decreased energy production in the myocardium. Various synthetic ligands of PPAR-α and β/δ have many favourable effects in modulating the vascular diseases and heart failure. Despite the adverse effects from therapy using PPAR- gamma ligands, several laboratories are now focused on synthesizing partial activators which may combine their beneficial effects with lowering of undesirable side effects. This review discusses the role of isoforms of PPAR in the cardiomyocytes energy balance and CVD. The knowledge will help in the synthesis of ligands for their partial activation in order to render energy balance and protection from CVD. PMID:27115677

  15. Carbon Nanotube-Induced Pulmonary Granulomatous Disease: Twist1 and Alveolar Macrophage M1 Activation

    PubMed Central

    Barna, Barbara P.; Huizar, Isham; Malur, Anagha; McPeek, Matthew; Marshall, Irene; Jacob, Mark; Dobbs, Larry; Kavuru, Mani S.; Thomassen, Mary Jane

    2013-01-01

    Sarcoidosis, a chronic granulomatous disease of unknown cause, has been linked to several environmental risk factors, among which are some that may favor carbon nanotube formation. Using gene array data, we initially observed that bronchoalveolar lavage (BAL) cells from sarcoidosis patients displayed elevated mRNA of the transcription factor, Twist1, among many M1-associated genes compared to healthy controls. Based on this observation we hypothesized that Twist1 mRNA and protein expression might become elevated in alveolar macrophages from animals bearing granulomas induced by carbon nanotube instillation. To address this hypothesis, wild-type and macrophage-specific peroxisome proliferator-activated receptor gamma (PPARγ) knock out mice were given oropharyngeal instillation of multiwall carbon nanotubes (MWCNT). BAL cells obtained 60 days later exhibited significantly elevated Twist1 mRNA expression in granuloma-bearing wild-type or PPARγ knock out alveolar macrophages compared to sham controls. Overall, Twist1 expression levels in PPARγ knock out mice were higher than those of wild-type. Concurrently, BAL cells obtained from sarcoidosis patients and healthy controls validated gene array data: qPCR and protein analysis showed significantly elevated Twist1 in sarcoidosis compared to healthy controls. In vitro studies of alveolar macrophages from healthy controls indicated that Twist1 was inducible by classical (M1) macrophage activation stimuli (LPS, TNFα) but not by IL-4, an inducer of alternative (M2) macrophage activation. Findings suggest that Twist1 represents a PPARγ-sensitive alveolar macrophage M1 biomarker which is induced by inflammatory granulomatous disease in the MWCNT model and in human sarcoidosis. PMID:24322444

  16. Patients with active inflammatory bowel disease lack immature peripheral blood plasmacytoid and myeloid dendritic cells

    PubMed Central

    Baumgart, D C; Metzke, D; Schmitz, J; Scheffold, A; Sturm, A; Wiedenmann, B; Dignass, A U

    2005-01-01

    Background: Breakdown of tolerance against the commensal microflora is believed to be a major factor in the pathogenesis of inflammatory bowel disease (IBD). Dendritic cells (DC) have been implicated in this process in various animal models, but data on human DC in IBD are very limited. Aim: To characterise plasmacytoid DC (PDC) and myeloid DC (MDC) in patients with active versus inactive IBD and healthy controls. Patients and Methods: Peripheral blood was obtained from 106 patients (Crohn’s disease (CD) n = 49, ulcerative colitis (UC) n = 57) and healthy controls (n = 19). Disease activity was scored using the modified Truelove Witts (MTWSI) for UC and the Harvey Bradshaw severity indices (HBSI) for CD. Four colour flow cytometric analysis was used to identify, enumerate, and phenotype DC. DC from patients with acute flare ups and healthy controls were cultured and stimulated with CpG ODN 2006 or lipopolysaccharide (LPS). Results: IBD patients in remission (PDC UC, 0.39%; CD, 0.35%; MDC-1 UC, 0.23%; CD, 0.22% of PBMC) have slightly lower numbers of circulating DC compared with healthy controls (PDC 0.41%, MDC-1 0.25% of PBMC). In acute flare ups IBD patients experience a significant drop of DC (PDC UC, 0.04%; CD, 0.11%; MDC-1 UC, 0.11%; CD, 0.14% of PBMC) that correlates with disease activity (correlation coefficients: PDC MTWSI, 0.93; HBSI, 0.79; MDC-1 MTWSI, 0.75; HBSI, 0.81). Moreover, both express α4β7 integrin and display an immature phenotype. Freshly isolated PDC and MDC-1 from untreated flaring IBD patients express higher baseline levels of CD86 which increases further in culture and upon stimulation compared with healthy controls. Conclusion: IBD patients lack immature blood DC during flare ups which possibly migrate to the gut. An aberrant response to microbial surrogate stimuli suggests a disturbed interaction with commensals. PMID:15647187

  17. History of falls in Parkinson disease is associated with reduced cholinergic activity

    PubMed Central

    Bohnen, N I.; Müller, M L.T.M.; Koeppe, R A.; Studenski, S A.; Kilbourn, M A.; Frey, K A.; Albin, R L.

    2009-01-01

    Objective: To investigate the relationships between history of falls and cholinergic vs dopaminergic denervation in patients with Parkinson disease (PD). Background: There is a need to explore nondopaminergic mechanisms of gait control as the majority of motor impairments associated with falls in PD are resistant to dopaminergic treatment. Alterations in cholinergic neurotransmission in PD may be implicated because of evidence that gait control depends on cholinergic system–mediated higher-level cortical and subcortical processing, including pedunculopontine nucleus (PPN) function. Methods: In this cross-sectional study, 44 patients with PD (Hoehn & Yahr stages I–III) without dementia and 15 control subjects underwent a clinical assessment and [11C]methyl-4-piperidinyl propionate (PMP) acetylcholinesterase (AChE) and [11C]dihydrotetrabenazine (DTBZ) vesicular monoamine transporter type 2 (VMAT2) brain PET imaging. Results: Seventeen patients (38.6%) reported a history of falls and 27 patients had no falls. Analysis of covariance of the cortical AChE hydrolysis rates demonstrated reduced cortical AChE in the PD fallers group (−12.3%) followed by the PD nonfallers (−6.6%) compared to control subjects (F = 7.22, p = 0.0004). Thalamic AChE activity was lower only in the PD fallers group (−11.8%; F = 4.36, p = 0.008). There was no significant difference in nigrostriatal dopaminergic activity between PD fallers and nonfallers. Conclusions: Unlike nigrostriatal dopaminergic denervation, cholinergic hypofunction is associated with fall status in Parkinson disease (PD). Thalamic AChE activity in part represents cholinergic output of the pedunculopontine nucleus (PPN), a key node for gait control. Our results are consistent with other data indicating that PPN degeneration is a major factor leading to impaired postural control and gait dysfunction in PD. GLOSSARY AChE = acetylcholinesterase; ANCOVA = analysis of covariance; MMSE = Mini-Mental State Examination; PD

  18. Evidence for the absence of cerebral glucose-6-phosphatase activity in glycogen storage disease type I (Von Gierke's disease)

    SciTech Connect

    Phelps, M.E.; Mazziotta, J.C.; Hawkins, R.A.; Philippart, M.

    1981-01-01

    Glycogen storage disease type I (GSD-I) is characterized by a functional deficit in glucose-6-phosphatase that normally hydrolyzes glucose-6-PO/sub 4/ to glucose. This enzyme is primarily found in liver, kidney, and muscle but it is also present in brain, where it appears to participate in the regulation of cerebral tissue glucose. Since most neurological symptoms in GSD-I patients involve systemic hypoglycemia, previous reports have not examined possible deficiencies in phosphatase activity in the brain. Positron computed tomography, F-18-labeled 2-fluorodeoxyglucose (FDG) and a tracer kinetic model for FDG were used to measure the cortical plasma/tissue forward and reverse transport, phosphorylation and dephosphorylation rate constants, tissue/plasma concentration gradient, tissue concentration turnover rate for this competitive analog of glucose, and the cortical metabolic rates for glucose. Studies were carried out in age-matched normals (N = 13) and a single GSD-I patient. The dephosphorylation rate constant in the GSD-I patient was about one tenth the normal value indicating a low level of cerebral phosphatase activity. The other measured parameters were within normal limits except for the rate of glucose phosphorylation which reflected a cortical glucose metabolic rate one half the normal value. Since glucose transport and tissue glucose concentration was normal, the reduced cortical glucose metabolism probably results from the use of alternative substrates (..beta..-hydroxybutyrate and acetoacetate) which are consistently elevated in the plasma of GSD-I patients.

  19. The Importance of Physical Fitness versus Physical Activity for Coronary Artery Disease Risk Factors: A Cross-Sectional Analysis.

    ERIC Educational Resources Information Center

    Young, Deborah Rohm; Steinhardt, Mary A.

    1993-01-01

    This cross-sectional study examined relationships among physical fitness, physical activity, and risk factors for coronary artery disease (CAD) in male police officers. Data from screenings and physical fitness assessments indicated physical activity must be sufficient to influence fitness before obtaining statistically significant risk-reducing…

  20. Technology-Aided Verbal Instructions to Help Persons with Mild or Moderate Alzheimer's Disease Perform Daily Activities

    ERIC Educational Resources Information Center

    Lancioni, Giulio E.; Singh, Nirbhay N.; O'Reilly, Mark F.; Sigafoos, Jeff; Tatulli, Emanuela; Rigante, Valeria; Zonno, Nadia; Perilli, Viviana; Pinto, Katia; Minervini, Mauro G.

    2010-01-01

    These two studies extended previous research on the use of verbal instructions and support technology for helping persons with mild or moderate Alzheimer's disease perform daily activities. Study I included seven participants who were to carry out one of two previously targeted activities (i.e., either coffee preparation or table setting). Study…

  1. "What I Wish You Knew": Social Barriers toward Physical Activity in Youth with Congenital Heart Disease (CHD)

    ERIC Educational Resources Information Center

    Moola, Fiona; Fusco, Caroline; Kirsh, Joel A.

    2011-01-01

    Despite the benefits of physical activity for youth with congenital heart disease (CHD), most patients are inactive. Although literature has addressed medical and psychological barriers to participation, little is known about the social barriers that youth encounter. This qualitative study explored sociocultural barriers to physical activity from…

  2. Assessing Activity Limitations in Patients with Neuromuscular Diseases: Is the ACTIVLIM Questionnaire Linked to ICF and ICF-CY?

    ERIC Educational Resources Information Center

    Raggi, Alberto; Leonardi, Matilde

    2009-01-01

    The objective of this study was to explore to what extent the ACTIVLIM questionnaire, designed to evaluate limitations in activities involving upper and lower limbs in adults and children with neuromuscular diseases, is linked to the domains of the Activities and Participation of the International Classification of Functioning, Disability and…

  3. Activity Scale.

    ERIC Educational Resources Information Center

    Kerpelman, Larry C.; Weiner, Michael J.

    This twenty-four item scale assesses students' actual and desired political-social activism in terms of physical participation, communication activities, and information-gathering activities. About ten minutes are required to complete the instrument. The scale is divided into two subscales. The first twelve items (ACT-A) question respondents on…

  4. Dietary Fiber Intake is Associated with Increased Colonic Mucosal GPR43+ Polymorphonuclear Infiltration in Active Crohn’s Disease

    PubMed Central

    Zhao, Mingli; Zhu, Weiming; Gong, Jianfeng; Zuo, Lugen; Zhao, Jie; Sun, Jing; Li, Ning; Li, Jieshou

    2015-01-01

    G protein-coupled receptor 43/free fatty acid receptor 2 (GPR43/FFAR2) is essential for polymorphonuclear (PMN) recruitment. We investigated the expression of GPR43/FFAR2 in the colon from Crohn’s disease patients and whether dietary fiber in enteral nutrition increases GPR43+ polymorphonuclear infiltration in mucosa. Segments of ascending colon and white blood cells from peripheral blood were obtained from 46 Crohn’s disease patients and 10 colon cancer patients. The Crohn’s disease patients were grouped by the activity of disease (active or remission) and enteral nutrition with or without dietary fiber. Histological feature, expression and location of GPR43/FFAR2 and level of tumor necrosis factor-α (TNF-α), interleukine-6 (IL-6) and myeloperoxidase were assessed. The results of hematoxylin-eosin and immunohistochemistry staining revealed that the infiltration of immune cells, including GPR43+ PMN, was more severe in active Crohn’s disease patients who consumed normal food or enteral nutrition with dietary fiber than in remission patients and colon cancer patients. This finding was supported by the results of GPR43 and myeloperoxidase expression. Active Crohn’s disease (CD) patients who consumed enteral nutrition without dietary fiber exhibited severe immune cell infiltration similar to the other active CD patients, but GPR43+ PMNs were rarely observed. The level of TNF-α mRNA in active Crohn’s disease patients was higher than those of the other patients. In conclusion, the use of dietary fiber in enteral nutrition by active Crohn’s disease patients might increase GPR43+ PMNs infiltration in colon mucosa. This effect was not observed in Crohn’s disease patients in remission. PMID:26140540

  5. Basophil phenotypes in chronic idiopathic urticaria in relation to disease activity and autoantibodies.

    PubMed

    Eckman, John A; Hamilton, Robert G; Gober, Laura M; Sterba, Patricia M; Saini, Sarbjit S

    2008-08-01

    Potentially pathogenic IgG autoantibodies to IgE or its receptor, Fc epsilonRIalpha, have been detected in approximately 40% of chronic idiopathic urticaria (CIU) patients. CIU patients' basophils display distinct altered Fc epsilonRIalpha-mediated degranulation. CIU patients with basophil histamine release in response to polyclonal goat anti-human IgE > or = 10% are classified as CIU responders (CIU-R) and < 10% are CIU non-responders (CIU-NR). We compared the presence of autoantibodies to basophil degranulation phenotypes and to disease status (active or inactive). Sera were collected from non-CIU subjects and CIU subjects who participated in a longitudinal study of disease severity and had defined basophil degranulation phenotypes. Immunoenzymetric assays (IEMA) quantified IgG anti-Fc epsilonRIalpha and anti-IgE. IgG anti-Fc epsilonRIalpha antibody was detected in 57% of CIU-R (n=35), 55% of CIU-NR (n=29), and 57% of non-CIU subjects (n=23), whereas IgG anti-IgE was present in 43% of CIU-R, 45% of CIU-NR, and 30% of non-CIU subjects. Both the autoantibody levels and the functional basophil phenotype remained stable in subjects with active disease (n=16), whereas there was an enhancement in basophil function as subjects evolved into a state of remission (n=6), which appears independent of the presence of autoantibody. IEMAs detected a similar frequency of autoantibodies in CIU-R, CIU-NR, and non-CIU subjects. Basophil function may be independent of IEMA-detected autoantibodies. PMID:18356810

  6. [Vitamin D levels in ankylosing spondylitis: does deficiency correspond to disease activity?].

    PubMed

    Pokhai, Gabriel G; Bandagi, Sabiha; Abrudescu, Adriana

    2014-01-01

    Ankylosing spondylitis (AS) is an inflammatory disorder that presents with arthritis of the axial skeleton, including sacroiliac joints. Vitamin D is a secosteroid hormone with a long-established role in calcium and phosphate homeostasis, and in the regulation of bone formation and resorption. It is now known that vitamin D plays an immunosuppressive role in the body, and there is interest of late in the role of vitamin D in autoimmune diseases. Inflammation may be responsible for some of the loss of bone mineral density seen in AS. We reviewed the literature for studies assessing vitamin D level as a marker of AS disease activity and those examining vitamin D levels in AS in comparison to healthy controls. Four of 7 studies found a significant negative correlation between vitamin D levels and Bath Ankylosing Spondylitis Index (BASDAI), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). In a review of 8 case-control studies,