WorldWideScience

Sample records for chronic neurodegeneration models

  1. Insights into Mechanisms of Chronic Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Abigail B. Diack

    2016-01-01

    Full Text Available Chronic neurodegenerative diseases such as Alzheimer’s disease (AD, Parkinson’s disease (PD, and prion diseases are characterised by the accumulation of abnormal conformers of a host encoded protein in the central nervous system. The process leading to neurodegeneration is still poorly defined and thus development of early intervention strategies is challenging. Unique amongst these diseases are Transmissible Spongiform Encephalopathies (TSEs or prion diseases, which have the ability to transmit between individuals. The infectious nature of these diseases has permitted in vivo and in vitro modelling of the time course of the disease process in a highly reproducible manner, thus early events can be defined. Recent evidence has demonstrated that the cell-to-cell spread of protein aggregates by a “prion-like mechanism” is common among the protein misfolding diseases. Thus, the TSE models may provide insights into disease mechanisms and testable hypotheses for disease intervention, applicable to a number of these chronic neurodegenerative diseases.

  2. Neurodegeneration severity can be predicted from early microglia alterations monitored in vivo in a mouse model of chronic glaucoma

    Directory of Open Access Journals (Sweden)

    Alejandra Bosco

    2015-05-01

    Full Text Available Microglia serve key homeostatic roles, and respond to neuronal perturbation and decline with a high spatiotemporal resolution. The course of all chronic CNS pathologies is thus paralleled by local microgliosis and microglia activation, which begin at early stages of the disease. However, the possibility of using live monitoring of microglia during early disease progression to predict the severity of neurodegeneration has not been explored. Because the retina allows live tracking of fluorescent microglia in their intact niche, here we investigated their early changes in relation to later optic nerve neurodegeneration. To achieve this, we used the DBA/2J mouse model of inherited glaucoma, which develops progressive retinal ganglion cell degeneration of variable severity during aging, and represents a useful model to study pathogenic mechanisms of retinal ganglion cell decline that are similar to those in human glaucoma. We imaged CX3CR1+/GFP microglial cells in vivo at ages ranging from 1 to 5 months by confocal scanning laser ophthalmoscopy (cSLO and quantified cell density and morphological activation. We detected early microgliosis at the optic nerve head (ONH, where axonopathy first manifests, and could track attenuation of this microgliosis induced by minocycline. We also observed heterogeneous and dynamic patterns of early microglia activation in the retina. When the same animals were aged and analyzed for the severity of optic nerve pathology at 10 months of age, we found a strong correlation with the levels of ONH microgliosis at 3 to 4 months. Our findings indicate that live imaging and monitoring the time course and levels of early retinal microgliosis and microglia activation in glaucoma could serve as indicators of future neurodegeneration severity.

  3. Neuroprotective effects and mechanisms of exercise in a chronic mouse model of Parkinson’s disease with moderate neurodegeneration

    OpenAIRE

    Lau, Yuen-Sum; Patki, Gaurav; Das-Panja, Kaberi; Le, Wei-dong; Ahmad, S. Omar

    2011-01-01

    The protective impact of exercise on neurodegenerative processes has not been confirmed, and the mechanisms underlying the benefit of exercise have not been determined in human Parkinson’s disease or in chronic animal disease models. This research examined the long-term neurological, behavioral, and mechanistic consequences of endurance exercise in experimental chronic parkinsonism. We used a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of Parkinson’s disease with ...

  4. Restorative effect of endurance exercise on behavioral deficits in the chronic mouse model of Parkinson's disease with severe neurodegeneration

    Directory of Open Access Journals (Sweden)

    Lau Yuen-Sum

    2009-01-01

    Full Text Available Abstract Background Animal models of Parkinson's disease have been widely used for investigating the mechanisms of neurodegenerative process and for discovering alternative strategies for treating the disease. Following 10 injections with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 25 mg/kg and probenecid (250 mg/kg over 5 weeks in mice, we have established and characterized a chronic mouse model of Parkinson's disease (MPD, which displays severe long-term neurological and pathological defects resembling that of the human Parkinson's disease in the advanced stage. The behavioral manifestations in this chronic mouse model of Parkinson's syndrome remain uninvestigated. The health benefit of exercise in aging and in neurodegenerative disorders including the Parkinson's disease has been implicated; however, clinical and laboratory studies in this area are limited. In this research with the chronic MPD, we first conducted a series of behavioral tests and then investigated the impact of endurance exercise on the identified Parkinsonian behavioral deficits. Results We report here that the severe chronic MPD mice showed significant deficits in their gait pattern consistency and in learning the cued version of the Morris water maze. Their performances on the challenging beam and walking grid were considerably attenuated suggesting the lack of balance and motor coordination. Furthermore, their spontaneous and amphetamine-stimulated locomotor activities in the open field were significantly suppressed. The behavioral deficits in the chronic MPD lasted for at least 8 weeks after MPTP/probenecid treatment. When the chronic MPD mice were exercise-trained on a motorized treadmill 1 week before, 5 weeks during, and 8–12 weeks after MPTP/probenecid treatment, the behavioral deficits in gait pattern, spontaneous ambulatory movement, and balance performance were reversed; whereas neuronal loss and impairment in cognitive skill, motor coordination, and

  5. Restorative effect of endurance exercise on behavioral deficits in the chronic mouse model of Parkinson's disease with severe neurodegeneration

    OpenAIRE

    Lau Yuen-Sum; Kurz Max J; Pothakos Konstantinos

    2009-01-01

    Abstract Background Animal models of Parkinson's disease have been widely used for investigating the mechanisms of neurodegenerative process and for discovering alternative strategies for treating the disease. Following 10 injections with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 25 mg/kg) and probenecid (250 mg/kg) over 5 weeks in mice, we have established and characterized a chronic mouse model of Parkinson's disease (MPD), which displays severe long-term neurological and patholog...

  6. ENDURANCE EXERCISE PROMOTES CARDIORESPIRATORY REHABILITATION WITHOUT NEURORESTORATION IN THE CHRONIC MOUSE MODEL OF PARKINSONISM WITH SEVERE NEURODEGENERATION

    OpenAIRE

    Al-Jarrah, Muhammed; Pothakos, Konstantinos; Novikova, Lesya; Smirnova, Irina V; Kurz, Max J.; Stehno-Bittel, Lisa; Lau, Yuen-Sum

    2007-01-01

    Physical rehabilitation with endurance exercise for patients with Parkinson's disease has not been well established, although some clinical and laboratory reports suggest that exercise may produce neuroprotective effect and restore dopaminergic and motor functions. In this study, we used a chronic mouse model of Parkinsonism, which was induced by injecting male C57BL/6 mice with 10 doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (25 mg/kg) and probenecid (250 mg/kg) over five weeks. Thi...

  7. Neurodegeneration in an Animal Model of Chronic Amyloid-beta Oligomer Infusion Is Counteracted by Antibody Treatment Infused with Osmotic Pumps.

    Science.gov (United States)

    Sajadi, Ahmadali; Provost, Chloé; Pham, Brendon; Brouillette, Jonathan

    2016-01-01

    Decline in hippocampal-dependent explicit memory (memory for facts and events) is one of the earliest clinical symptom of Alzheimer's disease (AD). It is well established that synapse loss and ensuing neurodegeneration are the best predictors for memory impairments in AD. Latest studies have emphasized the neurotoxic role of soluble amyloid-beta oligomers (Aβo) that begin to accumulate in the human brain approximately 10 to 15 yr before the clinical symptoms become apparent. Many reports indicate that soluble Aβo correlate with memory deficits in AD models and humans. The Aβo-induced neurodegeneration observed in neuronal and brain slice cultures has been more challenging to reproduce in many animal models. The model of repeated Aβo infusions shown here overcome this issue and allow addressing two key domains for developing new disease modifying therapies: identify biological markers to diagnose early AD, and determine the molecular mechanisms underpinning Aβo-induced memory deficits at the onset of AD. Since soluble Aβo aggregate relatively fast into insoluble Aβ fibrils that correlate poorly with the clinical state of patients, soluble Aβo are prepared freshly and injected once per day during six days to produce marked cell death in the hippocampus. We used cannula specially design for simultaneous infusions of Aβo and continuous infusion of Aβo antibody (6E10) in the hippocampus using osmotic pumps. This innovative in vivo method can now be used in preclinical studies to validate the efficiency of new AD therapies that might prevent the deposition and neurotoxicity of Aβo in pre-dementia patients. PMID:27585306

  8. Chronic Stress and Glucocorticoids: From Neuronal Plasticity to Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Sheela Vyas

    2016-01-01

    Full Text Available Stress and stress hormones, glucocorticoids (GCs, exert widespread actions in central nervous system, ranging from the regulation of gene transcription, cellular signaling, modulation of synaptic structure, and transmission and glial function to behavior. Their actions are mediated by glucocorticoid and mineralocorticoid receptors which are nuclear receptors/transcription factors. While GCs primarily act to maintain homeostasis by inducing physiological and behavioral adaptation, prolonged exposure to stress and elevated GC levels may result in neuro- and psychopathology. There is now ample evidence for cause-effect relationships between prolonged stress, elevated GC levels, and cognitive and mood disorders while the evidence for a link between chronic stress/GC and neurodegenerative disorders such as Alzheimer’s (AD and Parkinson’s (PD diseases is growing. This brief review considers some of the cellular mechanisms through which stress and GC may contribute to the pathogenesis of AD and PD.

  9. Neurodegeneration after mild and repetitive traumatic brain injury: Chronic traumatic encepalopathy

    Directory of Open Access Journals (Sweden)

    Stanescu Ioana

    2015-09-01

    Full Text Available Repetitive brain trauma is associated with a progressive neurological deterioration, now termed as chronic traumatic encephalopathy (CTE. Although research on the long-term effects of TBI is advancing quickly, the incidence and prevalence of post-traumatic neurodegeneration and CTE are unknown. The incidence and prevalence of chronic traumatic encephalopathy and the genetic risk factors critical to its development are currently under research. CTE can be diagnosed only by post mortem neuropathological examination of the brain. Great efforts are being made to better understand the clinical signs and symptoms of CTE, obtained in most cases retrospectively from families of affected persons.Patients with CTE are described as having behavioral, mood, cognitive and motor impairments, occurring after a long latency from the traumatic events. Recent pathogenetic studies have provided new insights to CTE mechanisms, offering important clues in understanding neurodegenerative process and relations between physical factors and pathologic protein deposition. Further research is needed to better identify the genetic and environmental risk factors for CTE, as well as rehabilitation and treatment strategies.

  10. Chromosome 13 dementia syndromes as models of neurodegeneration

    DEFF Research Database (Denmark)

    Ghiso, J.; Revesz, T.; Holton, J.;

    2001-01-01

    Two hereditary conditions, familial British dementia (FBD) and familial Danish dementia (FDD), are associated with amyloid deposition in the central nervous system and neurodegeneration. The two amyloid proteins, ABri and ADan, are degradation products of the same precursor molecule BriPP bearing...

  11. Aging and Neurodegeneration: A Tangle of Models and Mechanisms.

    Science.gov (United States)

    Chakrabarti, Sasanka; Mohanakumar, Kochupurackal P

    2016-03-01

    The research on aging and age-related diseases, especially the neurodegenerative diseases, is on the fast track. However, the results have so far not been translated to actual benefit for the patients in terms of treatment or diagnosis of age-related degenerative diseases including those of the CNS. As far as the prevention of the cognitive decline during non-pathological aging is concerned, there is nothing much to offer other than calorie restriction and physical exercise. Needless to say, the benefits are not up to our expectations. However, over the years at the experimental level it has been possible to identify several cellular and molecular mechanisms that are intricately associated with aging in general and neurodegenerative diseases in particular. These include oxidative stress and altered redox-signaling, mitochondrial dysfunction, inflammation, proteotoxicity and altered gene expressions. These inter-dependent pathways mediate cellular senescence and often culminate in programmed cell death like apoptosis and autophagy, and in the context of brain these changes are manifested clinically as cognitive decline and pathologically as neurodegeneration. This special issue provides the readers with glimpses of this complex scenario from different angles primarily in the context of brain and also attempts to identify the potential drug targets against neurodegenerative diseases. PMID:27114843

  12. Correlated Inflammatory Responses and Neurodegeneration in Peptide-Injected Animal Models of Alzheimer’s Disease

    OpenAIRE

    McLarnon, James G

    2014-01-01

    Animal models of Alzheimer's disease (AD) which emphasize activation of microglia may have particular utility in correlating proinflammatory activity with neurodegeneration. This paper reviews injection of amyloid- β (A β ) into rat brain as an alternative AD animal model to the use of transgenic animals. In particular, intrahippocampal injection of Aβ 1-42 peptide demonstrates prominent microglial mobilization and activation accompanied by a significant loss of granule cell neurons. Furtherm...

  13. Mitochondrial optic neuropathy: In vivo model of neurodegeneration and neuroprotective strategies

    Directory of Open Access Journals (Sweden)

    Julio C Rojas

    2010-03-01

    Full Text Available Julio C Rojas, Francisco Gonzalez-LimaDepartments of Psychology, Pharmacology and Toxicology, University of Texas at Austin, Austin, TX, USAAbstract: This review summarizes the characteristics of a rodent toxicologic model of optic neuropathy induced by the mitochondrial complex I inhibitor rotenone. This model has been developed to fulfill the demand for a drug-screening tool providing a sound mechanistic context to address the role of mitochondrial dysfunction in the pathogenesis of neurodegenerative disorders. It features biochemical, structural, and functional retinal deficits that resemble those of patients with Leber’s hereditary optic neuropathy, a mitochondrial disease characterized by selective degeneration of retinal ganglion cells, and for which an environmental component is believed to play a major triggering role. The available data support the efficiency, sensitivity, and versatility of the model for providing insights into the mechanisms of neurodegeneration, including mitochondrial dysfunction, oxidative stress and excitotoxicity. Screening work with this model has provided proof-of-principle that interventions targeting the electron transport chain, such as USP methylene blue and near-infrared light therapy, are effective at preventing neurodegeneration induced by mitochondrial dysfunction in vivo. Prospective developments of this model include the use of neuronal reporter genes for in vivo non-invasive assessment of retinal degeneration at different time points, and its combination with genetic approaches to elucidate the synergism of environmental and genetic factors in neurodegeneration.Keywords: animal model, neuroprotection, mitochondrial dysfunction, visual function, oxidative stress, cytochrome oxidase

  14. Pantethine rescues a Drosophila model for pantothenate kinase–associated neurodegeneration

    OpenAIRE

    Rana, Anil; Seinen, Erwin; Siudeja, Katarzyna; Muntendam, Remco; Srinivasan, Balaji; Van der Want, Johannes J.; Hayflick, Susan; Reijngoud, Dirk-Jan; Kayser, Oliver; Sibon, Ody C.M

    2010-01-01

    Pantothenate kinase–associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired f...

  15. The db/db mouse: a useful model for the study of diabetic retinal neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Patricia Bogdanov

    Full Text Available BACKGROUND: To characterize the sequential events that are taking place in retinal neurodegeneration in a murine model of spontaneous type 2 diabetes (db/db mouse. METHODS: C57BLKsJ-db/db mice were used as spontaneous type 2 diabetic animal model, and C57BLKsJ-db/+ mice served as the control group. To assess the chronological sequence of the abnormalities the analysis was performed at different ages (8, 16 and 24 weeks. The retinas were evaluated in terms of morphological and functional abnormalities [electroretinography (ERG]. Histological markers of neurodegeneration (glial activation and apoptosis were evaluated by immunohistochemistry. In addition glutamate levels and glutamate/aspartate transporter (GLAST expression were assessed. Furthermore, to define gene expression changes associated with early diabetic retinopathy a transcriptome analyses was performed at 8 week. Furthermore, an additional interventional study to lower blood glucose levels was performed. RESULTS: Glial activation was higher in diabetic than in non diabetic mice in all the stages (p<0.01. In addition, a progressive loss of ganglion cells and a significant reduction of neuroretinal thickness were also observed in diabetic mice. All these histological hallmarks of neurodegeneration were less pronounced at week 8 than at week 16 and 24. Significant ERG abnormalities were present in diabetic mice at weeks 16 and 24 but not at week 8. Moreover, we observed a progressive accumulation of glutamate in diabetic mice associated with an early downregulation of GLAST. Morphological and ERG abnormalities were abrogated by lowering blood glucose levels. Finally, a dysregulation of several genes related to neurotransmission and oxidative stress such as UCP2 were found at week 8. CONCLUSIONS: Our results suggest that db/db mouse reproduce the features of the neurodegenerative process that occurs in the human diabetic eye. Therefore, it seems an appropriate model for investigating the

  16. Neuroprotective Effects of Citicoline in in Vitro Models of Retinal Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Andrea Matteucci

    2014-04-01

    Full Text Available In recent years, citicoline has been the object of remarkable interest as a possible neuroprotectant. The aim of this study was to investigate if citicoline affected cell survival in primary retinal cultures and if it exerted neuroprotective activity in conditions modeling retinal neurodegeneration. Primary retinal cultures, obtained from rat embryos, were first treated with increasing concentrations of citicoline (up to 1000 µM and analyzed in terms of apoptosis and caspase activation and characterized by immunocytochemistry to identify neuronal and glial cells. Subsequently, excitotoxic concentration of glutamate or High Glucose-containing cell culture medium (HG was administered as well-known conditions modeling neurodegeneration. Glutamate or HG treatments were performed in the presence or not of citicoline. Neuronal degeneration was evaluated in terms of apoptosis and loss of synapses. The results showed that citicoline did not cause any damage to the retinal neuroglial population up to 1000 µM. At the concentration of 100 µM, it was able to counteract neuronal cell damage both in glutamate- and HG-treated retinal cultures by decreasing proapoptotic effects and contrasting synapse loss. These data confirm that citicoline can efficiently exert a neuroprotective activity. In addition, the results suggest that primary retinal cultures, under conditions inducing neurodegeneration, may represent a useful system to investigate citicoline neuroprotective mechanisms.

  17. Ku70 alleviates neurodegeneration in Drosophila models of Huntington's disease.

    Directory of Open Access Journals (Sweden)

    Takuya Tamura

    Full Text Available DNA damage accumulates in genome DNA during the long life of neurons, thus DNA damage repair is indispensable to keep normal functions of neurons. We previously reported that Ku70, a critical molecule for DNA double strand break (DSB repair, is involved in the pathology of Huntington's disease (HD. Mutant huntingtin (Htt impaired Ku70 function via direct interaction, and Ku70 supplementation recovered phenotypes of a mouse HD model. In this study, we generate multiple Drosophila HD models that express mutant huntingtin (Htt in eye or motor neuron by different drivers and show various phenotypes. In such fly models, Ku70 co-expression recovers lifespan, locomotive activity and eye degeneration. In contrast, Ku70 reduction by heterozygous null mutation or siRNA-mediated knock down accelerates lifespan shortening and locomotion disability. These results collectively support that Ku70 is a critical mediator of the HD pathology and a candidate therapeutic target in HD.

  18. Implanted neural electrodes cause chronic, local inflammation that is correlated with local neurodegeneration

    Science.gov (United States)

    McConnell, George C.; Rees, Howard D.; Levey, Allan I.; Gutekunst, Claire-Anne; Gross, Robert E.; Bellamkonda, Ravi V.

    2009-10-01

    Prosthetic devices that are controlled by intracortical electrodes recording one's 'thoughts' are a reality today, and no longer merely in the realm of science fiction. However, widespread clinical use of implanted electrodes is hampered by a lack of reliability in chronic recordings, independent of the type of electrodes used. One major hypothesis has been that astroglial scar electrically impedes the electrodes. However, there is a temporal discrepancy between stabilization of scar's electrical properties and recording failure with recording failure lagging by 1 month. In this study, we test a possible explanation for this discrepancy: the hypothesis that chronic inflammation, due to the persistent presence of the electrode, causes a local neurodegenerative state in the immediate vicinity of the electrode. Through modulation of chronic inflammation via stab wound, electrode geometry and age-matched control, we found that after 16 weeks, animals with an increased level of chronic inflammation were associated with increased neuronal and dendritic, but not axonal, loss. We observed increased neuronal and dendritic loss 16 weeks after implantation compared to 8 weeks after implantation, suggesting that the local neurodegenerative state is progressive. After 16 weeks, we observed axonal pathology in the form of hyperphosphorylation of the protein tau in the immediate vicinity of the microelectrodes (as observed in Alzheimer's disease and other tauopathies). The results of this study suggest that a local, late onset neurodegenerative disease-like state surrounds the chronic electrodes and is a potential cause for chronic recording failure. These results also inform strategies to enhance our capability to attain reliable long-term recordings from implantable electrodes in the CNS.

  19. The db/db Mouse: A Useful Model for the Study of Diabetic Retinal Neurodegeneration

    OpenAIRE

    Bogdanov, Patricia; Corraliza, Lidia; A. Villena, Josep; Carvalho, Andrea R.; Garcia-Arumí, José; Ramos, David; Ruberte, Jesús; Simó, Rafael; Hernández, Cristina

    2014-01-01

    Background To characterize the sequential events that are taking place in retinal neurodegeneration in a murine model of spontaneous type 2 diabetes (db/db mouse). Methods C57BLKsJ-db/db mice were used as spontaneous type 2 diabetic animal model, and C57BLKsJ-db/+ mice served as the control group. To assess the chronological sequence of the abnormalities the analysis was performed at different ages (8, 16 and 24 weeks). The retinas were evaluated in terms of morphological and functional abnor...

  20. Chronic expression of H-ferritin in dopaminergic midbrain neurons results in an age-related expansion of the labile iron pool and subsequent neurodegeneration: implications for Parkinson’s disease

    OpenAIRE

    Kaur, Deepinder; Rajagopalan, Subramanian; Andersen, Julie K.

    2009-01-01

    While ferritin elevation within dopaminergic (DA) neurons of the substantia nigra (SN) is protective against neurodegeneration elicited by two toxin models of Parkinson’s disease (PD), MPTP and paraquat, in young animals, its prolonged elevation results in a selective age-related neurodegeneration. A similar age-related neurodegeneration has been reported in iron regulatory protein 2-deficient (IRP2 −/−) mice coinciding with increased ferritin levels within degenerating neurons. This has been...

  1. Correlated Inflammatory Responses and Neurodegeneration in Peptide-Injected Animal Models of Alzheimer’s Disease

    Directory of Open Access Journals (Sweden)

    James G. McLarnon

    2014-01-01

    Full Text Available Animal models of Alzheimer’s disease (AD which emphasize activation of microglia may have particular utility in correlating proinflammatory activity with neurodegeneration. This paper reviews injection of amyloid-β (Aβ into rat brain as an alternative AD animal model to the use of transgenic animals. In particular, intrahippocampal injection of Aβ1-42 peptide demonstrates prominent microglial mobilization and activation accompanied by a significant loss of granule cell neurons. Furthermore, pharmacological inhibition of inflammatory reactivity is demonstrated by a broad spectrum of drugs with a common endpoint in conferring neuroprotection in peptide-injected animals. Peptide-injection models provide a focus on glial cell responses to direct peptide injection in rat brain and offer advantages in the study of the mechanisms underlying neuroinflammation in AD brain.

  2. Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration

    NARCIS (Netherlands)

    Siudeja, Katarzyna; Srinivasan, Balaji; Xu, Lanjun; Rana, Anil; de Jong, Jannie; Nollen, Ellen A. A.; Jackowski, Suzanne; Sanford, Lynn; Hayflick, Susan; Sibon, Ody C. M.

    2011-01-01

    Pantothenate kinase-associated neurodegeneration (PKAN is a neurodegenerative disease with unresolved pathophysiology. Previously, we observed reduced Coenzyme A levels in a Drosophila model for PKAN. Coenzyme A is required for acetyl-Coenzyme A synthesis and acyl groups from the latter are transfer

  3. Chronic Intraventricular Administration of 1-Methyl-4-Phenylpyridinium as a Progressive Model of Parkinson’s Disease

    OpenAIRE

    Sonsalla, Patricia K.; Zeevalk, Gail D.; German, Dwight C.

    2008-01-01

    Animal models of Parkinson’s disease (PD) that more closely exhibit the chronic neuropathology seen in the human condition are needed in order to reveal processes involved with progressive neurodegeneration and for testing potential interventions for retarding dopamine (DA) neuronal loss. Here we describe the recently developed chronic rat model of PD in which 1-methyl-4-phenylpyridinium ion (MPP+) is infused chronically into the lateral cerebral ventricle. We review features of this model th...

  4. Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration.

    Science.gov (United States)

    Rana, Anil; Seinen, Erwin; Siudeja, Katarzyna; Muntendam, Remco; Srinivasan, Balaji; van der Want, Johannes J; Hayflick, Susan; Reijngoud, Dirk-Jan; Kayser, Oliver; Sibon, Ody C M

    2010-04-13

    Pantothenate kinase-associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired function of pantothenate kinase induces a neurodegenerative phenotype and a reduced lifespan. We have explored this Drosophila model further and have demonstrated that impairment of pantothenate kinase is associated with decreased levels of CoA, mitochondrial dysfunction, and increased protein oxidation. Furthermore, we searched for compounds that can rescue pertinent phenotypes of the Drosophila PKAN model and identified pantethine. Pantethine feeding restores CoA levels, improves mitochondrial function, rescues brain degeneration, enhances locomotor abilities, and increases lifespan. We show evidence for the presence of a de novo CoA biosynthesis pathway in which pantethine is used as a precursor compound. Importantly, this pathway is effective in the presence of disrupted pantothenate kinase function. Our data suggest that pantethine may serve as a starting point to develop a possible treatment for PKAN. PMID:20351285

  5. Pantethine rescues a Drosophila model for pantothenate kinase–associated neurodegeneration

    Science.gov (United States)

    Rana, Anil; Seinen, Erwin; Siudeja, Katarzyna; Muntendam, Remco; Srinivasan, Balaji; van der Want, Johannes J.; Hayflick, Susan; Reijngoud, Dirk-Jan; Kayser, Oliver; Sibon, Ody C. M.

    2010-01-01

    Pantothenate kinase–associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKAN is not understood, and there is no cure to halt or reverse the symptoms of this devastating disease. Recently, we and others presented a PKAN Drosophila model, and we demonstrated that impaired function of pantothenate kinase induces a neurodegenerative phenotype and a reduced lifespan. We have explored this Drosophila model further and have demonstrated that impairment of pantothenate kinase is associated with decreased levels of CoA, mitochondrial dysfunction, and increased protein oxidation. Furthermore, we searched for compounds that can rescue pertinent phenotypes of the Drosophila PKAN model and identified pantethine. Pantethine feeding restores CoA levels, improves mitochondrial function, rescues brain degeneration, enhances locomotor abilities, and increases lifespan. We show evidence for the presence of a de novo CoA biosynthesis pathway in which pantethine is used as a precursor compound. Importantly, this pathway is effective in the presence of disrupted pantothenate kinase function. Our data suggest that pantethine may serve as a starting point to develop a possible treatment for PKAN. PMID:20351285

  6. Neurodegeneration and motor dysfunction in a conditional model of Parkinson's disease.

    Science.gov (United States)

    Nuber, Silke; Petrasch-Parwez, Elisabeth; Winner, Beate; Winkler, Jürgen; von Hörsten, Stephan; Schmidt, Thorsten; Boy, Jana; Kuhn, Melanie; Nguyen, Huu P; Teismann, Peter; Schulz, Jörg B; Neumann, Manuela; Pichler, Bernd J; Reischl, Gerald; Holzmann, Carsten; Schmitt, Ina; Bornemann, Antje; Kuhn, Wilfried; Zimmermann, Frank; Servadio, Antonio; Riess, Olaf

    2008-03-01

    Alpha-synuclein (alpha-syn) has been implicated in the pathogenesis of many neurodegenerative disorders, including Parkinson's disease. These disorders are characterized by various neurological and psychiatric symptoms based on progressive neuropathological alterations. Whether the neurodegenerative process might be halted or even reversed is presently unknown. Therefore, conditional mouse models are powerful tools to analyze the relationship between transgene expression and progression of the disease. To explore whether alpha-syn solely originates and further incites these alterations, we generated conditional mouse models by using the tet-regulatable system. Mice expressing high levels of human wild-type alpha-syn in midbrain and forebrain regions developed nigral and hippocampal neuropathology, including reduced neurogenesis and neurodegeneration in absence of fibrillary inclusions, leading to cognitive impairment and progressive motor decline. Turning off transgene expression in symptomatic mice halted progression but did not reverse the symptoms. Thus, our data suggest that approaches targeting alpha-syn-induced pathological pathways might be of benefit rather in early disease stages. Furthermore, alpha-syn-associated cytotoxicity is independent of filamentous inclusion body formation in our conditional mouse model. PMID:18322092

  7. Oral microbiome link to neurodegeneration in glaucoma.

    Directory of Open Access Journals (Sweden)

    Konstantin Astafurov

    Full Text Available BACKGROUND: Glaucoma is a progressive optic nerve degenerative disease that often leads to blindness. Local inflammatory responses are implicated in the pathology of glaucoma. Although inflammatory episodes outside the CNS, such as those due to acute systemic infections, have been linked to central neurodegeneration, they do not appear to be relevant to glaucoma. Based on clinical observations, we hypothesized that chronic subclinical peripheral inflammation contributes to neurodegeneration in glaucoma. METHODS: Mouthwash specimens from patients with glaucoma and control subjects were analyzed for the amount of bacteria. To determine a possible pathogenic mechanism, low-dose subcutaneous lipopolysaccharide (LPS was administered in two separate animal models of glaucoma. Glaucomatous neurodegeneration was assessed in the retina and optic nerve two months later. Changes in gene expression of toll-like receptor 4 (TLR4 signaling pathway and complement as well as changes in microglial numbers and morphology were analyzed in the retina and optic nerve. The effect of pharmacologic blockade of TLR4 with naloxone was determined. FINDINGS: Patients with glaucoma had higher bacterial oral counts compared to control subjects (p<0.017. Low-dose LPS administration in glaucoma animal models resulted in enhancement of axonal degeneration and neuronal loss. Microglial activation in the optic nerve and retina as well as upregulation of TLR4 signaling and complement system were observed. Pharmacologic blockade of TLR4 partially ameliorated the enhanced damage. CONCLUSIONS: The above findings suggest that the oral microbiome contributes to glaucoma pathophysiology. A plausible mechanism by which increased bacterial loads can lead to neurodegeneration is provided by experiments in animal models of the disease and involves activation of microglia in the retina and optic nerve, mediated through TLR4 signaling and complement upregulation. The finding that commensal

  8. Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration

    OpenAIRE

    Siudeja, Katarzyna; Srinivasan, Balaji; Xu, Lanjun; Rana, Anil; de Jong, Jannie; Nollen, Ellen A. A.; Jackowski, Suzanne; Sanford, Lynn; Hayflick, Susan; Sibon, Ody C.M

    2011-01-01

    Pantothenate kinase-associated neurodegeneration (PKAN is a neurodegenerative disease with unresolved pathophysiology. Previously, we observed reduced Coenzyme A levels in a Drosophila model for PKAN. Coenzyme A is required for acetyl-Coenzyme A synthesis and acyl groups from the latter are transferred to lysine residues of proteins, in a reaction regulated by acetyltransferases. The tight balance between acetyltransferases and their antagonistic counterparts histone deacetylases is a well-kn...

  9. Yeast proteinopathy models: a robust tool for deciphering the basis of neurodegeneration

    Directory of Open Access Journals (Sweden)

    Amit Shrestha

    2015-11-01

    Full Text Available Protein quality control or proteostasis is an essential determinant of basic cell health and aging. Eukaryotic cells have evolved a number of proteostatic mechanisms to ensure that proteins retain functional conformation, or are rapidly degraded when proteins misfold or self-aggregate. Disruption of proteostasis is now widely recognized as a key feature of aging related illness, specifically neurodegenerative disease. For example, Alzheimer’s disease, Huntington’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis (ALS each target and afflict distinct neuronal cell subtypes, yet this diverse array of human pathologies share the defining feature of aberrant protein aggregation within the affected cell population. Here, we review the use of budding yeast as a robust proxy to study the intersection between proteostasis and neurodegenerative disease. The humanized yeast model has proven to be an amenable platform to identify both, conserved proteostatic mechanisms across eukaryotic phyla and novel disease specific molecular dysfunction. Moreover, we discuss the intriguing concept that yeast specific proteins may be utilized as bona fide therapeutic agents, to correct proteostasis errors across various forms of neurodegeneration.

  10. Moringa oleifera Mitigates Memory Impairment and Neurodegeneration in Animal Model of Age-Related Dementia

    Directory of Open Access Journals (Sweden)

    Chatchada Sutalangka

    2013-01-01

    Full Text Available To date, the preventive strategy against dementia is still essential due to the rapid growth of its prevalence and the limited therapeutic efficacy. Based on the crucial role of oxidative stress in age-related dementia and the antioxidant and nootropic activities of Moringa oleifera, the enhancement of spatial memory and neuroprotection of M. oleifera leaves extract in animal model of age-related dementia was determined. The possible underlying mechanism was also investigated. Male Wistar rats, weighing 180–220 g, were orally given M. oleifera leaves extract at doses of 100, 200, and 400 mg/kg at a period of 7 days before and 7 days after the intracerebroventricular administration of AF64A bilaterally. Then, they were assessed memory, neuron density, MDA level, and the activities of SOD, CAT, GSH-Px, and AChE in hippocampus. The results showed that the extract improved spatial memory and neurodegeneration in CA1, CA2, CA3, and dentate gyrus of hippocampus together with the decreased MDA level and AChE activity but increased SOD and CAT activities. Therefore, our data suggest that M. oleifera leaves extract is the potential cognitive enhancer and neuroprotectant. The possible mechanism might occur partly via the decreased oxidative stress and the enhanced cholinergic function. However, further explorations concerning active ingredient(s are still required.

  11. Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson's Disease.

    Science.gov (United States)

    Ghosh, Anamitra; Langley, Monica R; Harischandra, Dilshan S; Neal, Matthew L; Jin, Huajun; Anantharam, Vellareddy; Joseph, Joy; Brenza, Timothy; Narasimhan, Balaji; Kanthasamy, Arthi; Kalyanaraman, Balaraman; Kanthasamy, Anumantha G

    2016-06-01

    Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson's disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP(+))-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP(+)-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in

  12. Pantethine rescues a Drosophila model for pantothenate kinase-associated neurodegeneration

    NARCIS (Netherlands)

    Rana, Anil; Seinen, Erwin; Siudeja, Katarzyna; Muntendam, Remco; Srinivasan, Balaji; van der Want, Johannes J.; Hayflick, Susan; Reijngoud, Dirk-Jan; Kayser, Oliver; Sibon, Ody C. M.

    2010-01-01

    Pantothenate kinase-associated neurodegeneration (PKAN), a progressive neurodegenerative disorder, is associated with impairment of pantothenate kinase function. Pantothenate kinase is the first enzyme required for de novo synthesis of CoA, an essential metabolic cofactor. The pathophysiology of PKA

  13. Protein kinase Cδ upregulation in microglia drives neuroinflammatory responses and dopaminergic neurodegeneration in experimental models of Parkinson's disease.

    Science.gov (United States)

    Gordon, Richard; Singh, Neeraj; Lawana, Vivek; Ghosh, Anamitra; Harischandra, Dilshan S; Jin, Huajun; Hogan, Colleen; Sarkar, Souvarish; Rokad, Dharmin; Panicker, Nikhil; Anantharam, Vellareddy; Kanthasamy, Anumantha G; Kanthasamy, Arthi

    2016-09-01

    at Ser536. Furthermore, both genetic ablation and siRNA-mediated knockdown of PKCδ attenuated NFκB activation, suggesting that PKCδ regulates NFκB activation subsequent to microglial exposure to inflammatory stimuli. To further investigate the pivotal role of PKCδ in microglial activation in vivo, we utilized pre-clinical models of PD. We found that PKCδ deficiency attenuated the proinflammatory response in the mouse substantia nigra, reduced locomotor deficits and recovered mice from sickness behavior in an LPS-induced neuroinflammation model of PD. Likewise, we found that PKCδ knockout mice treated with MPTP displayed a dampened microglial inflammatory response. Moreover, PKCδ knockout mice exhibited reduced susceptibility to the neurotoxin-induced dopaminergic neurodegeneration and associated motor impairments. Taken together, our studies propose a pivotal role for PKCδ in PD pathology, whereby sustained PKCδ activation drives sustained microglial inflammatory responses and concomitant dopaminergic neurotoxicity consequently leading to neurobehavioral deficits. We conclude that inhibiting PKCδ activation may represent a novel therapeutic strategy in PD treatment. PMID:27151770

  14. Neurodegeneration progresses despite complete elimination of clinical relapses in a mouse model of multiple sclerosis

    OpenAIRE

    Hampton, David W; Serio, Andrea; Pryce, Gareth; Al-Izki, Sarah; Franklin, Robin Jm; Giovannoni, Gavin; Baker, David; Chandran, Siddharthan

    2013-01-01

    BackgoundMultiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered qu...

  15. Modeling and imaging cardiac sympathetic neurodegeneration in Parkinson’s disease

    OpenAIRE

    Joers, Valerie; Emborg, Marina E.

    2014-01-01

    Parkinson’s disease (PD) is currently recognized as a multisystem disorder affecting several components of the central and peripheral nervous system. This new understanding of PD helps explain the complexity of the patients’ symptoms while challenges researchers to identify new diagnostic and therapeutic strategies. Cardiac neurodegeneration and dysautonomia affect PD patients and are associated with orthostatic hypotension, fatigue, and abnormal control of electrical heart activity. They can...

  16. Nasal Administration of Quercetin Liposomes Improves Memory Impairment and Neurodegeneration in Animal Model of Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Terdthai Tong-un

    2010-01-01

    Full Text Available Problem statement: At present, the development of protective strategy against Alzheimer’s Disease (AD is increasing its importance due to the high prevalence of AD, a limitation of therapeutic efficacy and its high impacts on economic and social aspects. The development of the preventive and therapeutic strategy to protect against the path physiology induced by free radicals in AD from antioxidant has gained very much concentration. Quercetin, one of the flavonoids in fruits and vegetables, has a powerful antioxidant activity both in vitro and in vivo. However, poor absorption, rapid metabolism and limited ability to cross the blood-brain-barrier are obstacles to its use for treatment of AD. Liposome’s have been used as an effective delivery system to the brain. Advantages associated with the nasal administration over oral route include higher bioavailability due to no first pass hepatic metabolism and rapid absorption leading to shorter time to onset of effect. Based on all these points, the possible effects of quercetin liposomes via nasal route on improving cognitive behavior and neurodegeneration in animal model of Alzheimer’s disease were investigated. Approach: Male Wistar rats were pretreated with quercetin liposome’s, containing 0.5 mg of quercetin in 20 μL (dose = 20 μg, via intranasal route once daily continually for 2 weeks before and 1 week after AF64A administration. Learning and memory was evaluated using the Morris water maze test at 7 days after the AF64A administration and then the rats were sacrificed for determining the density of neurons and cholinergic neurons in hippocampus using histological and immunohistochemical techniques. Results: Nasal administration of quercetin liposome’s significantly prevented changes of spatial memory of AF64A treated rats. The cognitive enhancement of quercetin liposome’s was found to be related to its ability to inhibit the degeneration of neurons and cholinergic neurons in hippocampus

  17. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model.

    Science.gov (United States)

    Brunetti, Dario; Dusi, Sabrina; Giordano, Carla; Lamperti, Costanza; Morbin, Michela; Fugnanesi, Valeria; Marchet, Silvia; Fagiolari, Gigliola; Sibon, Ody; Moggio, Maurizio; d'Amati, Giulia; Tiranti, Valeria

    2014-01-01

    Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2(-/-)) mouse model did not recapitulate the human disease but showed azoospermia and mitochondrial dysfunctions. We challenged this mouse model with a low glucose and high lipid content diet (ketogenic diet) to stimulate lipid use by mitochondrial beta-oxidation. In the presence of a shortage of co-enzyme A, this diet could evoke a general impairment of bioenergetic metabolism. Only Pank2(-/-) mice fed with a ketogenic diet developed a pantothenate kinase-associated neurodegeneration-like syndrome characterized by severe motor dysfunction, neurodegeneration and severely altered mitochondria in the central and peripheral nervous systems. These mice also showed structural alteration of muscle morphology, which was comparable with that observed in a patient with pantothenate kinase-associated neurodegeneration. We here demonstrate that pantethine administration can prevent the onset of the neuromuscular phenotype in mice suggesting the possibility of experimental treatment in patients with pantothenate kinase-associated neurodegeneration. PMID:24316510

  18. Pantothenate kinase-associated neurodegeneration: altered mitochondria membrane potential and defective respiration in Pank2 knock-out mouse model.

    Science.gov (United States)

    Brunetti, Dario; Dusi, Sabrina; Morbin, Michela; Uggetti, Andrea; Moda, Fabio; D'Amato, Ilaria; Giordano, Carla; d'Amati, Giulia; Cozzi, Anna; Levi, Sonia; Hayflick, Susan; Tiranti, Valeria

    2012-12-15

    Neurodegeneration with brain iron accumulation (NBIA) comprises a group of neurodegenerative disorders characterized by high brain content of iron and presence of axonal spheroids. Mutations in the PANK2 gene, which encodes pantothenate kinase 2, underlie an autosomal recessive inborn error of coenzyme A metabolism, called pantothenate kinase-associated neurodegeneration (PKAN). PKAN is characterized by dystonia, dysarthria, rigidity and pigmentary retinal degeneration. The pathogenesis of this disorder is poorly understood and, although PANK2 is a mitochondrial protein, perturbations in mitochondrial bioenergetics have not been reported. A knock-out (KO) mouse model of PKAN exhibits retinal degeneration and azoospermia, but lacks any neurological phenotype. The absence of a clinical phenotype has partially been explained by the different cellular localization of the human and murine PANK2 proteins. Here we demonstrate that the mouse Pank2 protein localizes to mitochondria, similar to its human orthologue. Moreover, we show that Pank2-defective neurons derived from KO mice have an altered mitochondrial membrane potential, a defect further corroborated by the observations of swollen mitochondria at the ultra-structural level and by the presence of defective respiration. PMID:22983956

  19. Apolipoprotein E-mimetics inhibit neurodegeneration and restore cognitive functions in a transgenic Drosophila model of Alzheimer's disease.

    Directory of Open Access Journals (Sweden)

    Svetlana Sarantseva

    Full Text Available BACKGROUND: Mutations of the amyloid precursor protein gene (APP are found in familial forms of Alzheimer's disease (AD and some lead to the elevated production of amyloid-beta-protein (Abeta. While Abeta has been implicated in the causation of AD, the exact role played by Abeta and its APP precursor are still unclear. PRINCIPAL FINDINGS: In our study, Drosophila melanogaster transgenics were established as a model to analyze AD-like pathology caused by APP overexpression. We demonstrated that age related changes in the levels and pattern of synaptic proteins accompanied progressive neurodegeneration and impairment of cognitive functions in APP transgenic flies, but that these changes may be independent from the generation of Abeta. Using novel peptide mimetics of Apolipoprotein-E, COG112 or COG133 proved to be neuroprotective and significantly improved the learning and memory of APP transgenic flies. CONCLUSIONS: The development of neurodegeneration and cognitive deficits was corrected by injections of COG112 or COG133, novel mimetics of apolipoprotein-E (apoE with neuroprotective activities.

  20. The Neuron-Astrocyte-Microglia Triad in a Rat Model of Chronic Cerebral Hypoperfusion: Protective Effect of Dipyridamole

    OpenAIRE

    Daniele Lana; Felicita Pedata; Maria Grazia Giovannini

    2014-01-01

    Chronic cerebral hypoperfusion during aging may cause progressive neurodegeneration as ischemic conditions persist. Proper functioning of the interplay between neurons and glia is fundamental for the functional organization of the brain. The aim of our research was to study the pathophysiological mechanisms, and particularly the derangement of the interplay between neurons and astrocytes-microglia with the formation of “triads,” in a model of chronic cerebral hypoperfusion induced by the two-...

  1. A new in vivo model of pantothenate kinase-associated neurodegeneration reveals a surprising role for transcriptional regulation in pathogenesis.

    Directory of Open Access Journals (Sweden)

    Varun ePandey

    2013-09-01

    Full Text Available Pantothenate Kinase-Associated Neurodegeneration (PKAN is a neurodegenerative disorder with a poorly understood molecular mechanism. It is caused by mutations in Pantothenate Kinase, the first enzyme in the Coenzyme A (CoA biosynthetic pathway. Here, we developed a Drosophila model of PKAN (tim-fbl flies that allows us to continuously monitor the modeled disease in the brain. In tim-fbl flies, downregulation of fumble, the Drosophila PanK homologue in the cells containing a circadian clock results in characteristic features of PKAN such as developmental lethality, hypersensitivity to oxidative stress, and diminished life span. Despite quasi-normal circadian transcriptional rhythms, tim-fbl flies display brain-specific aberrant circadian locomotor rhythms, and a unique transcriptional signature. Comparison with expression data from flies exposed to paraquat demonstrates that, as previously suggested, pathways others than oxidative stress are affected by PANK downregulation. Surprisingly we found a significant decrease in the expression of key components of the photoreceptor recycling pathways, which could lead to retinal degeneration, a hallmark of PKAN. Importantly, these defects are not accompanied by changes in structural components in eye genes suggesting that changes in gene expression in the eye precede and may cause the retinal degeneration. Indeed tim-fbl flies have diminished response to light transitions, and their altered day/night patterns of activity demonstrates defects in light perception. This suggest that retinal lesions are not solely due to oxidative stress and demonstrates a role for the transcriptional response to CoA deficiency underlying the defects observed in dPanK deficient flies. Moreover, in the present study we developed a new fly model that can be applied to other diseases and that allows the assessment of neurodegeneration in the brains of living flies.

  2. Isolated spinal cord contusion in rats induces chronic brain neuroinflammation, neurodegeneration, and cognitive impairment: Involvement of cell cycle activation

    OpenAIRE

    Wu, Junfang; Stoica, Bogdan A.; Luo, Tao; Sabirzhanov, Boris; Zhao, Zaorui; Guanciale, Kelsey; Nayar, Suresh K.; Foss, Catherine A.; Pomper, Martin G.; Faden, Alan I.

    2014-01-01

    Cognitive dysfunction has been reported in patients with spinal cord injury (SCI), but it has been questioned whether such changes may reflect concurrent head injury, and the issue has not been addressed mechanistically or in a well-controlled experimental model. Our recent rodent studies examining SCI-induced hyperesthesia revealed neuroinflammatory changes not only in supratentorial pain-regulatory sites, but also in other brain regions, suggesting that additional brain functions may be imp...

  3. Impaired Coenzyme A metabolism affects histone and tubulin acetylation in Drosophila and human cell models of pantothenate kinase associated neurodegeneration.

    Science.gov (United States)

    Siudeja, Katarzyna; Srinivasan, Balaji; Xu, Lanjun; Rana, Anil; de Jong, Jannie; Nollen, Ellen A A; Jackowski, Suzanne; Sanford, Lynn; Hayflick, Susan; Sibon, Ody C M

    2011-12-01

    Pantothenate kinase-associated neurodegeneration (PKAN is a neurodegenerative disease with unresolved pathophysiology. Previously, we observed reduced Coenzyme A levels in a Drosophila model for PKAN. Coenzyme A is required for acetyl-Coenzyme A synthesis and acyl groups from the latter are transferred to lysine residues of proteins, in a reaction regulated by acetyltransferases. The tight balance between acetyltransferases and their antagonistic counterparts histone deacetylases is a well-known determining factor for the acetylation status of proteins. However, the influence of Coenzyme A levels on protein acetylation is unknown. Here we investigate whether decreased levels of the central metabolite Coenzyme A induce alterations in protein acetylation and whether this correlates with specific phenotypes of PKAN models. We show that in various organisms proper Coenzyme A metabolism is required for maintenance of histone- and tubulin acetylation, and decreased acetylation of these proteins is associated with an impaired DNA damage response, decreased locomotor function and decreased survival. Decreased protein acetylation and the concurrent phenotypes are partly rescued by pantethine and HDAC inhibitors, suggesting possible directions for future PKAN therapy development. PMID:21998097

  4. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

    OpenAIRE

    Brunetti, D.; Dusi, S.; C. Giordano; Lamperti, C; Morbin, M; Fugnanesi, V.; Marchet, S.; Fagiolari, G.; Sibon, O.; Moggio, M.; d'Amati, G.; TIRANTI, V.

    2013-01-01

    Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2, responsible for the phosphorylation of pantothenate or vitamin B5 in the biosynthesis of co-enzyme A. A Pank2 knockout (Pank2−/− ) mouse model did not recapitulate the human disease but showed azo...

  5. Mitoapocynin Treatment Protects Against Neuroinflammation and Dopaminergic Neurodegeneration in a Preclinical Animal Model of Parkinson’s Disease

    Science.gov (United States)

    Ghosh, Anamitra; Langley, Monica R; Harischandra, Dilshan; Neal, Matthew L; Jin, Huajun; Anantharam, Vellareddy; Joseph, Joy; Brenza, Timothy; Narasimhan, Balaji; Kanthasamy, Arthi; Kalyanaraman, Balaraman; Kanthasamy, Anumantha G.

    2016-01-01

    Mitochondrial dysfunction, oxidative stress and neuroinflammation have been implicated as key mediators contributing to the progressive degeneration of dopaminergic neurons in Parkinson’s disease (PD). Currently, we lack a pharmacological agent that can intervene in all key pathological mechanisms, which would offer better neuroprotective efficacy than a compound that targets a single degenerative mechanism. Herein, we investigated whether mito-apocynin (Mito-Apo), a newly-synthesized and orally available derivative of apocynin that targets mitochondria, protects against oxidative damage, glial-mediated inflammation and nigrostriatal neurodegeneration in cellular and animal models of PD. Mito-Apo treatment in primary mesencephalic cultures significantly attenuated the 1-methyl-4-phenylpyridinium (MPP+)-induced loss of tyrosine hydroxylase (TH)-positive neuronal cells and neurites. Mito-Apo also diminished MPP+-induced increases in glial cell activation and inducible nitric oxide synthase (iNOS) expression. Additionally, Mito-Apo decreased nitrotyrosine (3-NT) and 4-hydroxynonenol (4-HNE) levels in primary mesencephalic cultures. Importantly, we assessed the neuroprotective property of Mito-Apo in the MPTP mouse model of PD, wherein it restored the behavioral performance of MPTP-treated mice. Immunohistological analysis of nigral dopaminergic neurons and monoamine measurement further confirmed the neuroprotective effect of Mito-Apo against MPTP-induced nigrostriatal dopaminergic neuronal loss. Mito-Apo showed excellent brain bioavailability and also markedly attenuated MPTP-induced oxidative markers in the substantia nigra (SN). Furthermore, oral administration of Mito-Apo significantly suppressed MPTP-induced glial cell activation, upregulation of proinflammatory cytokines, iNOS and gp91phox in IBA1-positive cells of SN. Collectively, these results demonstrate that the novel mitochondria-targeted compound Mito-Apo exhibits profound neuroprotective effects in

  6. Histone deacetylases suppress CGG repeat-induced neurodegeneration via transcriptional silencing in models of fragile X tremor ataxia syndrome.

    Directory of Open Access Journals (Sweden)

    Peter K Todd

    Full Text Available Fragile X Tremor Ataxia Syndrome (FXTAS is a common inherited neurodegenerative disorder caused by expansion of a CGG trinucleotide repeat in the 5'UTR of the fragile X syndrome (FXS gene, FMR1. The expanded CGG repeat is thought to induce toxicity as RNA, and in FXTAS patients mRNA levels for FMR1 are markedly increased. Despite the critical role of FMR1 mRNA in disease pathogenesis, the basis for the increase in FMR1 mRNA expression is unknown. Here we show that overexpressing any of three histone deacetylases (HDACs 3, 6, or 11 suppresses CGG repeat-induced neurodegeneration in a Drosophila model of FXTAS. This suppression results from selective transcriptional repression of the CGG repeat-containing transgene. These findings led us to evaluate the acetylation state of histones at the human FMR1 locus. In patient-derived lymphoblasts and fibroblasts, we determined by chromatin immunoprecipitation that there is increased acetylation of histones at the FMR1 locus in pre-mutation carriers compared to control or FXS derived cell lines. These epigenetic changes correlate with elevated FMR1 mRNA expression in pre-mutation cell lines. Consistent with this finding, histone acetyltransferase (HAT inhibitors repress FMR1 mRNA expression to control levels in pre-mutation carrier cell lines and extend lifespan in CGG repeat-expressing Drosophila. These findings support a disease model whereby the CGG repeat expansion in FXTAS promotes chromatin remodeling in cis, which in turn increases expression of the toxic FMR1 mRNA. Moreover, these results provide proof of principle that HAT inhibitors or HDAC activators might be used to selectively repress transcription at the FMR1 locus.

  7. Experimental models for the study of neurodegeneration in amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Tapia Ricardo

    2009-07-01

    Full Text Available Abstract Amyotrophic lateral sclerosis (ALS is a fatal neurodegenerative disease of unknown cause, characterized by the selective and progressive death of both upper and lower motoneurons, leading to a progressive paralysis. Experimental animal models of the disease may provide knowledge of the pathophysiological mechanisms and allow the design and testing of therapeutic strategies, provided that they mimic as close as possible the symptoms and temporal progression of the human disease. The principal hypotheses proposed to explain the mechanisms of motoneuron degeneration have been studied mostly in models in vitro, such as primary cultures of fetal motoneurons, organotypic cultures of spinal cord sections from postnatal rodents and the motoneuron-like hybridoma cell line NSC-34. However, these models are flawed in the sense that they do not allow a direct correlation between motoneuron death and its physical consequences like paralysis. In vivo, the most widely used model is the transgenic mouse that bears a human mutant superoxide dismutase 1, the only known cause of ALS. The major disadvantage of this model is that it represents about 2%–3% of human ALS. In addition, there is a growing concern on the accuracy of these transgenic models and the extrapolations of the findings made in these animals to the clinics. Models of spontaneous motoneuron disease, like the wobbler and pmn mice, have been used aiming to understand the basic cellular mechanisms of motoneuron diseases, but these abnormalities are probably different from those occurring in ALS. Therefore, the design and testing of in vivo models of sporadic ALS, which accounts for >90% of the disease, is necessary. The main models of this type are based on the excitotoxic death of spinal motoneurons and might be useful even when there is no definitive demonstration that excitotoxicity is a cause of human ALS. Despite their difficulties, these models offer the best possibility to establish

  8. Neurodegeneration in an animal model of Parkinson's disease is exacerbated by a high-fat diet

    OpenAIRE

    Morris, Jill K.; Bomhoff, Gregory L.; Stanford, John A.; Geiger, Paige C.

    2010-01-01

    Despite numerous clinical studies supporting a link between type 2 diabetes (T2D) and Parkinson's disease (PD), the clinical literature remains equivocal. We, therefore, sought to address the relationship between insulin resistance and nigrostriatal dopamine (DA) in a preclinical animal model. High-fat feeding in rodents is an established model of insulin resistance, characterized by increased adiposity, systemic oxidative stress, and hyperglycemia. We subjected rats to a normal chow or high-...

  9. Connectivity mapping uncovers small molecules that modulate neurodegeneration in Huntington’s disease models

    OpenAIRE

    Joshua L Smalley; Breda, Carlo; Mason, Robert P.; Kooner, Gurdeep; Luthi-Carter, Ruth; Gant, Timothy W.; Giorgini, Flaviano

    2015-01-01

    Abstract Huntington’s disease (HD) is a genetic disease caused by a CAG trinucleotide repeat expansion encoding a polyglutamine tract in the huntingtin (HTT) protein, ultimately leading to neuronal loss and consequent cognitive decline and death. As no treatments for HD currently exist, several chemical screens have been performed using cell-based models of mutant HTT toxicity. These screens measured single disease-related endpoints, such as cell death, but had low ‘hit rates’ and limited dim...

  10. Moringa oleifera Mitigates Memory Impairment and Neurodegeneration in Animal Model of Age-Related Dementia

    OpenAIRE

    Chatchada Sutalangka; Jintanaporn Wattanathorn; Supaporn Muchimapura; Wipawee Thukham-mee

    2013-01-01

    To date, the preventive strategy against dementia is still essential due to the rapid growth of its prevalence and the limited therapeutic efficacy. Based on the crucial role of oxidative stress in age-related dementia and the antioxidant and nootropic activities of Moringa oleifera, the enhancement of spatial memory and neuroprotection of M. oleifera leaves extract in animal model of age-related dementia was determined. The possible underlying mechanism was also investigated. Male Wistar rat...

  11. Neurodegeneration and Epilepsy in a Zebrafish Model of CLN3 Disease (Batten Disease).

    Science.gov (United States)

    Wager, Kim; Zdebik, Anselm A; Fu, Sonia; Cooper, Jonathan D; Harvey, Robert J; Russell, Claire

    2016-01-01

    The neuronal ceroid lipofuscinoses are a group of lysosomal storage disorders that comprise the most common, genetically heterogeneous, fatal neurodegenerative disorders of children. They are characterised by childhood onset, visual failure, epileptic seizures, psychomotor retardation and dementia. CLN3 disease, also known as Batten disease, is caused by autosomal recessive mutations in the CLN3 gene, 80-85% of which are a ~1 kb deletion. Currently no treatments exist, and after much suffering, the disease inevitably results in premature death. The aim of this study was to generate a zebrafish model of CLN3 disease using antisense morpholino injection, and characterise the pathological and functional consequences of Cln3 deficiency, thereby providing a tool for future drug discovery. The model was shown to faithfully recapitulate the pathological signs of CLN3 disease, including reduced survival, neuronal loss, retinopathy, axonopathy, loss of motor function, lysosomal storage of subunit c of mitochondrial ATP synthase, and epileptic seizures, albeit with an earlier onset and faster progression than the human disease. Our study provides proof of principle that the advantages of the zebrafish over other model systems can be utilised to further our understanding of the pathogenesis of CLN3 disease and accelerate drug discovery. PMID:27327661

  12. Towards a Pathway Inventory of the Human Brain for Modeling Disease Mechanisms Underlying Neurodegeneration.

    Science.gov (United States)

    Iyappan, Anandhi; Gündel, Michaela; Shahid, Mohammad; Wang, Jiali; Li, Hui; Mevissen, Heinz-Theodor; Müller, Bernd; Fluck, Juliane; Jirsa, Viktor; Domide, Lia; Younesi, Erfan; Hofmann-Apitius, Martin

    2016-04-12

    Molecular signaling pathways have been long used to demonstrate interactions among upstream causal molecules and downstream biological effects. They show the signal flow between cell compartments, the majority of which are represented as cartoons. These are often drawn manually by scanning through the literature, which is time-consuming, static, and non-interoperable. Moreover, these pathways are often devoid of context (condition and tissue) and biased toward certain disease conditions. Mining the scientific literature creates new possibilities to retrieve pathway information at higher contextual resolution and specificity. To address this challenge, we have created a pathway terminology system by combining signaling pathways and biological events to ensure a broad coverage of the entire pathway knowledge domain. This terminology was applied to mining biomedical papers and patents about neurodegenerative diseases with focus on Alzheimer's disease. We demonstrate the power of our approach by mapping literature-derived signaling pathways onto their corresponding anatomical regions in the human brain under healthy and Alzheimer's disease states. We demonstrate how this knowledge resource can be used to identify a putative mechanism explaining the mode-of-action of the approved drug Rasagiline, and show how this resource can be used for fingerprinting patents to support the discovery of pathway knowledge for Alzheimer's disease. Finally, we propose that based on next-generation cause-and-effect pathway models, a dedicated inventory of computer-processable pathway models specific to neurodegenerative diseases can be established, which hopefully accelerates context-specific enrichment analysis of experimental data with higher resolution and richer annotations. PMID:27079715

  13. Inflammatory mechanisms of neurodegeneration in toxin-based models of Parkinson's disease.

    Science.gov (United States)

    Litteljohn, Darcy; Mangano, Emily; Clarke, Melanie; Bobyn, Jessica; Moloney, Kerry; Hayley, Shawn

    2010-01-01

    Parkinson's disease (PD) has been associated with exposure to a variety of environmental agents, including pesticides, heavy metals, and organic pollutants; and inflammatory processes appear to constitute a common mechanistic link among these insults. Indeed, toxin exposure has been repeatedly demonstrated to induce the release of oxidative and inflammatory factors from immunocompetent microglia, leading to damage and death of midbrain dopamine (DA) neurons. In particular, proinflammatory cytokines such as tumor necrosis factor-α and interferon-γ, which are produced locally within the brain by microglia, have been implicated in the loss of DA neurons in toxin-based models of PD; and mounting evidence suggests a contributory role of the inflammatory enzyme, cyclooxygenase-2. Likewise, immune-activating bacterial and viral agents were reported to have neurodegenerative effects themselves and to augment the deleterious impact of chemical toxins upon DA neurons. The present paper will focus upon the evidence linking microglia and their inflammatory processes to the death of DA neurons following toxin exposure. Particular attention will be devoted to the possibility that environmental toxins can activate microglia, resulting in these cells adopting a "sensitized" state that favors the production of proinflammatory cytokines and damaging oxidative radicals. PMID:21234362

  14. Inflammatory Mechanisms of Neurodegeneration in Toxin-Based Models of Parkinson's Disease

    Directory of Open Access Journals (Sweden)

    Darcy Litteljohn

    2011-01-01

    Full Text Available Parkinson's disease (PD has been associated with exposure to a variety of environmental agents, including pesticides, heavy metals, and organic pollutants; and inflammatory processes appear to constitute a common mechanistic link among these insults. Indeed, toxin exposure has been repeatedly demonstrated to induce the release of oxidative and inflammatory factors from immunocompetent microglia, leading to damage and death of midbrain dopamine (DA neurons. In particular, proinflammatory cytokines such as tumor necrosis factor-α and interferon-γ, which are produced locally within the brain by microglia, have been implicated in the loss of DA neurons in toxin-based models of PD; and mounting evidence suggests a contributory role of the inflammatory enzyme, cyclooxygenase-2. Likewise, immune-activating bacterial and viral agents were reported to have neurodegenerative effects themselves and to augment the deleterious impact of chemical toxins upon DA neurons. The present paper will focus upon the evidence linking microglia and their inflammatory processes to the death of DA neurons following toxin exposure. Particular attention will be devoted to the possibility that environmental toxins can activate microglia, resulting in these cells adopting a “sensitized” state that favors the production of proinflammatory cytokines and damaging oxidative radicals.

  15. Silencing mutant SOD1 using RNAi protects against neurodegeneration and extends survival in an ALS model.

    Science.gov (United States)

    Ralph, G Scott; Radcliffe, Pippa A; Day, Denise M; Carthy, Janine M; Leroux, Marie A; Lee, Debbie C P; Wong, Liang-Fong; Bilsland, Lynsey G; Greensmith, Linda; Kingsman, Susan M; Mitrophanous, Kyriacos A; Mazarakis, Nicholas D; Azzouz, Mimoun

    2005-04-01

    Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the selective death of motor neurons in the brain and spinal cord. Some familial cases of ALS are caused by dominant mutations in the gene encoding superoxide dismutase (SOD1). The emergence of interfering RNA (RNAi) for specific gene silencing could be therapeutically beneficial for the treatment of such dominantly inherited diseases. We generated a lentiviral vector to mediate expression of RNAi molecules specifically targeting the human SOD1 gene (SOD1). Injection of this vector into various muscle groups of mice engineered to overexpress a mutated form of human SOD1 (SOD1(G93A)) resulted in an efficient and specific reduction of SOD1 expression and improved survival of vulnerable motor neurons in the brainstem and spinal cord. Furthermore, SOD1 silencing mediated an improved motor performance in these animals, resulting in a considerable delay in the onset of ALS symptoms by more than 100% and an extension in survival by nearly 80% of their normal life span. These data are the first to show a substantial extension of survival in an animal model of a fatal, dominantly inherited neurodegenerative condition using RNAi and provide the highest therapeutic efficacy observed in this field to date. PMID:15768029

  16. Induction of Neuron-Specific Degradation of Coenzyme A Models Pantothenate Kinase-Associated Neurodegeneration by Reducing Motor Coordination in Mice.

    Directory of Open Access Journals (Sweden)

    Stephanie A Shumar

    Full Text Available Pantothenate kinase-associated neurodegeneration, PKAN, is an inherited disorder characterized by progressive impairment in motor coordination and caused by mutations in PANK2, a human gene that encodes one of four pantothenate kinase (PanK isoforms. PanK initiates the synthesis of coenzyme A (CoA, an essential cofactor that plays a key role in energy metabolism and lipid synthesis. Most of the mutations in PANK2 reduce or abolish the activity of the enzyme. This evidence has led to the hypothesis that lower CoA might be the underlying cause of the neurodegeneration in PKAN patients; however, no mouse model of the disease is currently available to investigate the connection between neuronal CoA levels and neurodegeneration. Indeed, genetic and/or dietary manipulations aimed at reducing whole-body CoA synthesis have not produced a desirable PKAN model, and this has greatly hindered the discovery of a treatment for the disease.Cellular CoA levels are tightly regulated by a balance between synthesis and degradation. CoA degradation is catalyzed by two peroxisomal nudix hydrolases, Nudt7 and Nudt19. In this study we sought to reduce neuronal CoA in mice through the alternative approach of increasing Nudt7-mediated CoA degradation. This was achieved by combining the use of an adeno-associated virus-based expression system with the synapsin (Syn promoter. We show that mice with neuronal overexpression of a cytosolic version of Nudt7 (scAAV9-Syn-Nudt7cyt exhibit a significant decrease in brain CoA levels in conjunction with a reduction in motor coordination. These results strongly support the existence of a link between CoA levels and neuronal function and show that scAAV9-Syn-Nudt7cyt mice can be used to model PKAN.

  17. The mTOR Inhibitor Rapamycin Mitigates Perforant Pathway Neurodegeneration and Synapse Loss in a Mouse Model of Early-Stage Alzheimer-Type Tauopathy.

    Directory of Open Access Journals (Sweden)

    Robert Siman

    Full Text Available The perforant pathway projection from layer II of the entorhinal cortex to the hippocampal dentate gyrus is especially important for long-term memory formation, and is preferentially vulnerable to developing a degenerative tauopathy early in Alzheimer's disease (AD that may spread over time trans-synaptically. Despite the importance of the perforant pathway to the clinical onset and progression of AD, a therapeutic has not been identified yet that protects it from tau-mediated toxicity. Here, we used an adeno-associated viral vector-based mouse model of early-stage AD-type tauopathy to investigate effects of the mTOR inhibitor and autophagy stimulator rapamycin on the tau-driven loss of perforant pathway neurons and synapses. Focal expression of human tau carrying a P301L mutation but not eGFP as a control in layer II of the lateral entorhinal cortex triggered rapid degeneration of these neurons, loss of lateral perforant pathway synapses in the dentate gyrus outer molecular layer, and activation of neuroinflammatory microglia and astroglia in the two locations. Chronic systemic rapamycin treatment partially inhibited phosphorylation of a mechanistic target of rapamycin substrate in brain and stimulated LC3 cleavage, a marker of autophagic flux. Compared with vehicle-treated controls, rapamycin protected against the tau-induced neuronal loss, synaptotoxicity, reactive microgliosis and astrogliosis, and activation of innate neuroimmunity. It did not alter human tau mRNA or total protein levels. Finally, rapamycin inhibited trans-synaptic transfer of human tau expression to the dentate granule neuron targets for the perforant pathway, likely by preventing the synaptic spread of the AAV vector in response to pathway degeneration. These results identify systemic rapamycin as a treatment that protects the entorhinal cortex and perforant pathway projection from tau-mediated neurodegeneration, axonal and synapse loss, and neuroinflammatory reactive

  18. Repulsive Guidance Molecule-a Is Involved in Th17-Cell-Induced Neurodegeneration in Autoimmune Encephalomyelitis

    Directory of Open Access Journals (Sweden)

    Shogo Tanabe

    2014-11-01

    Full Text Available Multiple sclerosis (MS is a chronic autoimmune disease characterized by inflammation, demyelination, and neurodegeneration in the CNS. Although it is important to prevent neurodegeneration for alleviating neurological disability, the molecular mechanism of neurodegeneration remains largely unknown. Here, we report that repulsive guidance molecule-a (RGMa, known to regulate axonal growth, is associated with neurodegeneration in experimental autoimmune encephalomyelitis (EAE, a mouse model of MS. RGMa is highly expressed in interleukin-17-producing CD4+ T cells (Th17 cells. We induced EAE by adoptive transfer of myelin oligodendrocyte glycoprotein (MOG-specific Th17 cells and then inhibited RGMa with a neutralizing antibody. Inhibition of RGMa improves EAE scores and reduces neuronal degeneration without altering immune or glial responses. Th17 cells induce cultured cortical neuron death through RGMa-neogenin and Akt dephosphorylation. Our results demonstrate that RGMa is involved in Th17-cell-mediated neurodegeneration and that RGMa-specific antibody may have a therapeutic effect in MS.

  19. Oxidative Stress in Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Varsha Shukla

    2011-01-01

    Full Text Available It has been demonstrated that oxidative stress has a ubiquitous role in neurodegenerative diseases. Major source of oxidative stress due to reactive oxygen species (ROS is related to mitochondria as an endogenous source. Although there is ample evidence from tissues of patients with neurodegenerative disorders of morphological, biochemical, and molecular abnormalities in mitochondria, it is still not very clear whether the oxidative stress itself contributes to the onset of neurodegeneration or it is part of the neurodegenerative process as secondary manifestation. This paper begins with an overview of how oxidative stress occurs, discussing various oxidants and antioxidants, and role of oxidative stress in diseases in general. It highlights the role of oxidative stress in neurodegenerative diseases like Alzheimer's, Parkinson's, and Huntington's diseases and amyotrophic lateral sclerosis. The last part of the paper describes the role of oxidative stress causing deregulation of cyclin-dependent kinase 5 (Cdk5 hyperactivity associated with neurodegeneration.

  20. Pantothenate kinase-associated neurodegeneration.

    Science.gov (United States)

    Hartig, Monika B; Prokisch, Holger; Meitinger, Thomas; Klopstock, Thomas

    2012-08-01

    Pantothenate kinase-associated neurodegeneration (PKAN) is a hereditary progressive disorder and the most frequent form of neurodegeneration with brain iron accumulation (NBIA). PKAN patients present with a progressive movement disorder, dysarthria, cognitive impairment and retinitis pigmentosa. In magnetic resonance imaging, PKAN patients exhibit the pathognonomic "eye of the tiger" sign in the globus pallidus which corresponds to iron accumulation and gliosis as shown in neuropathological examinations. The discovery of the disease causing mutations in PANK2 has linked the disorder to coenzyme A (CoA) metabolism. PANK2 is the only one out of four PANK genes encoding an isoform which localizes to mitochondria. At least two other NBIA genes (PLA2G6, C19orf12) encode proteins that share with PANK2 a mitochondrial localization and all are suggested to play a role in lipid homeostasis. With no causal therapy available for PKAN until now, only symptomatic treatment is possible. A multi-centre retrospective study with bilateral pallidal deep brain stimulation in patients with NBIA revealed a significant improvement of dystonia. Recently, studies in the PANK Drosophila model "fumble" revealed improvement by the compound pantethine which is hypothesized to feed an alternate CoA biosynthesis pathway. In addition, pilot studies with the iron chelator deferiprone that crosses the blood brain barrier showed a good safety profile and some indication of efficacy. An adequately powered randomized clinical trial will start in 2012. This review summarizes clinical presentation, neuropathology and pathogenesis of PKAN. PMID:22515741

  1. Synaptic deficits are rescued in the p25/Cdk5 model of neurodegeneration by the reduction of β-secretase (BACE1)

    Science.gov (United States)

    Giusti-Rodríguez, Paola; Gao, Jun; Gräff, Johannes; Rei, Damien; Soda, Takahiro; Tsai, Li-Huei

    2011-01-01

    Alzheimer’s disease (AD) is the most common cause of dementia, and is characterized by memory loss and cognitive decline, as well as amyloid β (Aβ) accumulation, and progressive neurodegeneration. Cdk5 is a proline-directed serine/threonine kinase whose activation by the p25 protein has been implicated in a number of neurodegenerative disorders. The CK-p25 inducible mouse model exhibits progressive neuronal death, elevated Aβ, reduced synaptic plasticity, and impaired learning following p25 overexpression in forebrain neurons. Levels of Aβ, as well as the amyloid precursor protein (APP) processing enzyme, β-secretase (BACE1), are also increased in CK-p25 mice. It is unknown what role increased Aβ plays in the cognitive and neurodegenerative phenotype of the CK-p25 mouse. In the current work, we restored Aβ levels in the CK-p25 mouse to those of wildtype mice via the partial genetic deletion of BACE1, allowing us to examine the Aβ-independent phenotype of this mouse model. We show that, in the CK-p25 mouse, normalization of Aβ levels led to a rescue of synaptic and cognitive deficits. Conversely, neuronal loss was not ameliorated. Our findings indicate that increases in p25/Cdk5 activity may mediate cognitive and synaptic impairment via an Aβ-dependent pathway in the CK-p25 mouse. These findings explore the impact of targeting Aβ production in a mouse model of neurodegeneration and cognitive impairment, and how this may translate into therapeutic approaches for sporadic AD. PMID:22049418

  2. Mitochondrial dysfunction in the striatum of aged chronic mouse model of Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Gaurav Patki

    2009-12-01

    Full Text Available Mitochondrial oxidative stress and dysfunction has been implicated as a possible mechanism for the onset and progression of Parkinson-like neurodegeneration. However, long-term mitochondrial defects in chronic animal neurodegenerative models have not been demonstrated. In this study, we investigated the function of striatal mitochondria 6 weeks after the induction of a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP mouse model of Parkinson’s disease (MPD. Although severe depression of mitochondrial respiration was observed immediately after acute administrations of MPTP, we failed to detect a significant mitochondrial inhibition in presence of striatal dopamine deficit 6 weeks after the chronic MPD induction in young adult mice. In contrast, when aged mice were chronically treated with MPTP and at 6 weeks post-treatment, these animals suffered an inhibition of the basal (state 4 and ADP-stimulated (state 3 respiration and a fall in ATP level in the striatal mitochondria. The aged chronic MPD also brought about a sustained diminution of striatal anti-oxidant enzyme levels including that of superoxide dismutases and cytochrome c. The mitochondrial deficits in the striatum of aged chronic MPD 6 weeks after treatment were further correlated with significant losses of striatal dopamine, tyrosine hydroxylase, dopamine uptake transporter, and with impaired movement when tested on a challenging beam. Our findings suggest that MPTP may trigger the neurodegenerative process by obstructing the mitochondrial function; however, striatal mitochondria in young animals may potentially rejuvenate, whereas mitochondrial dysfunction is sustained in the aged chronic MPD. Therefore, the aged chronic MPD may serve as a suitable investigative model for further elucidating the integral relationship between mitochondrial dysfunction and neurodegenerative disorder, and for assessing the therapeutic efficacy of mitochondrial protective agents as potential

  3. The Quest to Model Chronic Traumatic Encephalopathy: A Multiple Model & Injury Paradigm Experience

    Directory of Open Access Journals (Sweden)

    Ryan C. Turner

    2015-10-01

    Full Text Available Chronic neurodegeneration following a history of neurotrauma is frequently associated with neuropsychiatric and cognitive symptoms. In order to enhance understanding about the underlying pathophysiology linking neurotrauma to neurodegeneration, a multi-model pre-clinical approach must be established to account for the different injury paradigms and pathophysiologic mechanisms. We investigated the development of tau pathology and behavioral changes using a multi-model and multi-institutional approach, comparing the pre-clinical results to tauopathy patterns seen in post-mortem human samples from athletes diagnosed with chronic traumatic encephalopathy (CTE. We utilized a scaled and validated blast-induced traumatic brain injury model in rats and a modified pneumatic closed-head impact model in mice. Tau hyperphosphorylation was evaluated by western blot and immunohistochemistry. Elevated plus maze and Morris water maze were employed to measure impulsive-like behavior and cognitive deficits respectively. Animals exposed to single blast (~50 PSI reflected peak overpressure exhibited elevated AT8 immunoreactivity in the contralateral hippocampus at 1 month compared to controls (q = 3.96, p < 0.05. Animals exposed to repeat blast (6 blasts over 2 weeks had increased AT8 (q = 8.12, p < 0.001 and AT270 (q = 4.03, p < 0.05 in the contralateral hippocampus at 1 month post-injury compared to controls. In the modified controlled closed-head impact mouse model, no significant difference in AT8 was seen at 7 days, however a significant elevation was detected at 1 month following injury in the ipsilateral hippocampus compared to control (q = 4.34, p < 0.05. Elevated plus maze data revealed that rats exposed to single blast (q = 3.53, p < 0.05 and repeat blast (q = 4.21, p < 0.05 spent more time in seconds exploring the open arms compared to controls. Morris water maze testing revealed a significant difference between groups in acquisition times on days 22

  4. Peroxiredoxins and Neurodegeneration

    Directory of Open Access Journals (Sweden)

    S.H. Lee

    2006-01-01

    Full Text Available Peroxiredoxins (Prxs are a family of novel antioxidant proteins that are found in a variety of species and participate in a number of vital biological processes such as proliferation, differentiation, response to oxidative stress and intracellular signaling. It has been proposed that they might participate in these cellular processes by playing a role in eliminating or regulating the intracellular concentration of peroxides produced during metabolism as well as in the signaling cascades of growth factors and cytokines. Mammalian cells express six isoforms of Prx (Prx I to VI, which are classified into three subgroups (typical 2-Cys, atypical 2-Cys and 1-Cys based on the number and position of cysteine (Cys residues that participate in catalysis and on amino acid sequences and the immunological reactivity. Members of the typical 2-Cys subgroup include Prx I through Prx IV and contain an additional conserved cysteine in the carboxyl-terminal region, whereas Prx V and Prx VI, members of the atypical 2-Cys and 1-Cys subgroups, respectively, do not contain this second conserved Cys. On the other hand, Prxs activity can be regulated by phosphorylation and proteolysis processes in addition to overoxidation. Taken together, this study suggest that the generation of the oxidative stress which caused neurodegeneration may couple with produced Prxs and the reverse is true. However, this argument is still unclear on account of the difficulties of the direct observation of the reactive oxygen species due to their biological lifetime is short. Thus, experiments will be required to solve these problems and to comprehend the actual role of Prxs in neurodegeneration.

  5. Pantethine treatment is effective in recovering the disease phenotype induced by ketogenic diet in a pantothenate kinase-associated neurodegeneration mouse model

    NARCIS (Netherlands)

    Brunetti, Dario; Dusi, Sabrina; Giordano, Carla; Lamperti, Costanza; Morbin, Michela; Fugnanesi, Valeria; Marchet, Silvia; Fagiolari, Gigliola; Sibon, Ody; Moggio, Maurizio; d'Amati, Giulia; Tiranti, Valeria

    2014-01-01

    Pantothenate kinase-associated neurodegeneration, caused by mutations in the PANK2 gene, is an autosomal recessive disorder characterized by dystonia, dysarthria, rigidity, pigmentary retinal degeneration and brain iron accumulation. PANK2 encodes the mitochondrial enzyme pantothenate kinase type 2,

  6. Animal models for investigating chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    Aghdassi Alexander A

    2011-12-01

    Full Text Available Abstract Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed.

  7. Animal models for investigating chronic pancreatitis.

    Science.gov (United States)

    Aghdassi, Alexander A; Mayerle, Julia; Christochowitz, Sandra; Weiss, Frank U; Sendler, Matthias; Lerch, Markus M

    2011-01-01

    Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in the course of the disease a progressive loss of endocrine and exocrine function occurs. Despite advances in understanding the pathogenesis no causal treatment for chronic pancreatitis is presently available. Thus, there is a need for well characterized animal models for further investigations that allow translation to the human situation. This review summarizes existing experimental models and distinguishes them according to the type of pathological stimulus used for induction of pancreatitis. There is a special focus on pancreatic duct ligation, repetitive overstimulation with caerulein and chronic alcohol feeding. Secondly, attention is drawn to genetic models that have recently been generated and which mimic features of chronic pancreatitis in man. Each technique will be supplemented with data on the pathophysiological background of the model and their limitations will be discussed. PMID:22133269

  8. Linking aβ42-induced hyperexcitability to neurodegeneration, learning and motor deficits, and a shorter lifespan in an Alzheimer's model.

    Directory of Open Access Journals (Sweden)

    Yong Ping

    2015-03-01

    Full Text Available Alzheimer's disease (AD is the most prevalent form of dementia in the elderly. β-amyloid (Aβ accumulation in the brain is thought to be a primary event leading to eventual cognitive and motor dysfunction in AD. Aβ has been shown to promote neuronal hyperactivity, which is consistent with enhanced seizure activity in mouse models and AD patients. Little, however, is known about whether, and how, increased excitability contributes to downstream pathologies of AD. Here, we show that overexpression of human Aβ42 in a Drosophila model indeed induces increased neuronal activity. We found that the underlying mechanism involves the selective degradation of the A-type K+ channel, Kv4. An age-dependent loss of Kv4 leads to an increased probability of AP firing. Interestingly, we find that loss of Kv4 alone results in learning and locomotion defects, as well as a shortened lifespan. To test whether the Aβ42-induced increase in neuronal excitability contributes to, or exacerbates, downstream pathologies, we transgenically over-expressed Kv4 to near wild-type levels in Aβ42-expressing animals. We show that restoration of Kv4 attenuated age-dependent learning and locomotor deficits, slowed the onset of neurodegeneration, and partially rescued premature death seen in Aβ42-expressing animals. We conclude that Aβ42-induced hyperactivity plays a critical role in the age-dependent cognitive and motor decline of this Aβ42-Drosophila model, and possibly in AD.

  9. Trimethyltin-induced hippocampal neurodegeneration: A mechanism-based review.

    Science.gov (United States)

    Lee, Sueun; Yang, Miyoung; Kim, Jinwook; Kang, Sohi; Kim, Juhwan; Kim, Jong-Choon; Jung, Chaeyong; Shin, Taekyun; Kim, Sung-Ho; Moon, Changjong

    2016-07-01

    Trimethyltin (TMT), a toxic organotin compound, induces neurodegeneration selectively involving the limbic system and especially prominent in the hippocampus. Neurodegeneration-associated behavioral abnormalities, such as hyperactivity, aggression, cognitive deficits, and epileptic seizures, occur in both exposed humans and experimental animal models. Previously, TMT had been used generally in industry and agriculture, but the use of TMT has been limited because of its dangers to people. TMT has also been used to make a promising in vivo rodent model of neurodegeneration because of its region-specific characteristics. Several studies have demonstrated that TMT-treated animal models of epileptic seizures can be used as tools for researching hippocampus-specific neurotoxicity as well as the molecular mechanisms leading to hippocampal neurodegeneration. This review summarizes the in vivo and in vitro underlying mechanisms of TMT-induced hippocampal neurodegeneration (oxidative stress, inflammatory responses, and neuronal death/survival). Thus, the present review may be helpful to provide general insights into TMT-induced neurodegeneration and approaches to therapeutic interventions for neurodegenerative diseases, including temporal lobe epilepsy. PMID:27450702

  10. Pantothenate Kinase-Associated Neurodegeneration

    OpenAIRE

    Meitinger, Thomas; Prokisch, Holger; Hartig, Monika B.; Klopstock, Thomas

    2012-01-01

    Pantothenate kinase-associated neurodegeneration (PKAN) is a hereditary progressive disorder and the most frequent form of neurodegeneration with brain iron accumulation (NBIA). PKAN patients present with a progressive movement disorder, dysarthria, cognitive impairment and retinitis pigmentosa. In magnetic resonance imaging, PKAN patients exhibit the pathognonomic "eye of the tiger" sign in the globus pallidus which corresponds to iron accumulation and gliosis as shown in neuropathological e...

  11. The role of tau in neurodegeneration

    Directory of Open Access Journals (Sweden)

    Petrucelli Leonard

    2009-03-01

    Full Text Available Abstract Since the identification of tau as the main component of neurofibrillary tangles in Alzheimer's disease and related tauopathies, and the discovery that mutations in the tau gene cause frontotemporal dementia, much effort has been directed towards determining how the aggregation of tau into fibrillar inclusions causes neuronal death. As evidence emerges that tau-mediated neuronal death can occur even in the absence of tangle formation, a growing number of studies are focusing on understanding how abnormalities in tau (e.g. aberrant phosphorylation, glycosylation or truncation confer toxicity. Though data obtained from experimental models of tauopathies strongly support the involvement of pathologically modified tau and tau aggregates in neurodegeneration, the exact neurotoxic species remain unclear, as do the mechanism(s by which they cause neuronal death. Nonetheless, it is believed that tau-mediated neurodegeneration is likely to result from a combination of toxic gains of function as well as from the loss of normal tau function. To truly appreciate the detrimental consequences of aberrant tau function, a better understanding of all functions carried out by tau, including but not limited to the role of tau in microtubule assembly and stabilization, is required. This review will summarize what is currently known regarding the involvement of tau in the initiation and development of neurodegeneration in tauopathies, and will also highlight some of the remaining questions in need of further investigation.

  12. Chronic bacterial infection models for BRM screening.

    Science.gov (United States)

    Dickneite, G; Schorlemmer, H U; Sedlacek, H H

    1984-05-01

    Models of chronic infections have been established to test the therapeutic and prophylactic potency of biological response modifiers (BRM). As an example for a BRM the immunostimulating drug Bestatin was tested. It is of dipeptide nature and was purified from culture supernatants of Streptomyces olivoreticuli. In two chronic bacterial infection models, induced by the inoculation of NRMI mice with Salmonella typhimurium or with a nephropathogenic strain of Escherichia coli, Bestatin acted prophylactically as well as therapeutically. This could be seen from the reduction of bacterial organ colonization and the inhibition of organ lesion formation. Bestatin could be shown to stimulate macrophage activity and to potentiate delayed type hypersensitivity, but not be effective on the humoral immune response. PMID:6383323

  13. Neurotrophic effects of a cyanine dye via the PI3K-Akt pathway: attenuation of motor discoordination and neurodegeneration in an ataxic animal model.

    Directory of Open Access Journals (Sweden)

    Hitomi Ohta

    Full Text Available BACKGROUND: Neurotrophic factors may be future therapeutic agents for neurodegenerative disease. In the screening of biologically active molecules for neurotrophic potency, we found that a photosensitizing cyanine dye, NK-4, had remarkable neurotrophic activities and was a potent radical scavenger. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we evaluated the effect of NK-4 on the protection of neurons against oxidative damage and investigated the associated intracellular signaling pathways. Subsequently, we evaluated the effect of NK-4 in an animal model of neurodegeneration. In vitro, NK-4 showed dose-dependent protection of PC12 cells from toxicity induced by oxidative stress caused by hydrogen peroxide (H(2O(2 or 6-hydroxydopamine (6-OHDA. Comparison of extracellular signal-regulated kinase signaling pathways between treatment with NK-4 and nerve growth factor (NGF using K252a, an inhibitor of the NGF receptor TrkA, revealed that NK-4 activity occurs independently of NGF receptors. LY294002, a phosphatidylinositol 3-kinase (PI3K inhibitor, blocked the protective effect of NK-4, and NK-4 caused activation of Akt/protein kinase B, a downstream effector of PI3K. These results suggest that the neuroprotective effects of NK-4 are mediated by the PI3K-Akt signaling pathway. NK-4 treatment also attenuated stress-induced activation of SAPK/JNK, which suggests that NK-4 activates a survival signaling pathway and inhibits stress-activated apoptotic pathways independently of the TrkA receptor in neuronal cells. In vivo, administration of NK-4 improved motor coordination in genetic ataxic hamsters, as assessed by rota-rod testing. Histological analysis showed that cerebellar atrophy was significantly attenuated by NK-4 treatment. Notably, the Purkinje cell count in the treated group was threefold higher than that in the vehicle group. CONCLUSIONS/SIGNIFICANCE: These results suggest that NK-4 is a potential agent for therapy for neurodegenerative

  14. Neurodegeneration in a Drosophila model of adrenoleukodystrophy: the roles of the Bubblegum and Double bubble acyl-CoA synthetases

    Directory of Open Access Journals (Sweden)

    Anna Sivachenko

    2016-04-01

    Full Text Available Debilitating neurodegenerative conditions with metabolic origins affect millions of individuals worldwide. Still, for most of these neurometabolic disorders there are neither cures nor disease-modifying therapies, and novel animal models are needed for elucidation of disease pathology and identification of potential therapeutic agents. To date, metabolic neurodegenerative disease has been modeled in animals with only limited success, in part because existing models constitute analyses of single mutants and have thus overlooked potential redundancy within metabolic gene pathways associated with disease. Here, we present the first analysis of a very-long-chain acyl-CoA synthetase (ACS double mutant. We show that the Drosophila bubblegum (bgm and double bubble (dbb genes have overlapping functions, and that the consequences of double knockout of both bubblegum and double bubble in the fly brain are profound, affecting behavior and brain morphology, and providing the best paradigm to date for an animal model of adrenoleukodystrophy (ALD, a fatal childhood neurodegenerative disease associated with the accumulation of very-long-chain fatty acids. Using this more fully penetrant model of disease to interrogate brain morphology at the level of electron microscopy, we show that dysregulation of fatty acid metabolism via disruption of ACS function in vivo is causal of neurodegenerative pathologies that are evident in both neuronal cells and their supporting cell populations, and leads ultimately to lytic cell death in affected areas of the brain. Finally, in an extension of our model system to the study of human disease, we describe our identification of an individual with leukodystrophy who harbors a rare mutation in SLC27a6 (encoding a very-long-chain ACS, a human homolog of bgm and dbb.

  15. Biopsychosocial model of chronic recurrent pain

    Directory of Open Access Journals (Sweden)

    Zlatka Rakovec-Felser

    2009-07-01

    Full Text Available Pain is not merely a symptom of disease but a complex independent phenomenon where psychological factors are always present (Sternberg, 1973. Especially by chronic, recurrent pain it's more constructive to think of chronic pain as a syndrome that evolves over time, involving a complex interaction of physiological/organic, psychological, and behavioural processes. Study of chronic recurrent functional pain covers tension form of headache. 50 suffering persons were accidentally chosen among those who had been seeking medical help over more than year ago. We tested their pain intensity and duration, extent of subjective experience of accommodation efforts, temperament characteristics, coping strategies, personal traits, the role of pain in intra- and interpersonal communication. At the end we compared this group with control group (without any manifest physical disorders and with analyse of variance (MANOVA. The typical person who suffers and expects medical help is mostly a woman, married, has elementary or secondary education, is about 40. Pain, seems to appear in the phase of stress-induced psychophysical fatigue, by persons with lower constitutional resistance to different influences, greater irritability and number of physiologic correlates of emotional tensions. Because of their ineffective style of coping, it seems they quickly exhausted their adaptation potential too. Through their higher level of social–field dependence, reactions of other persons (doctor, spouse could be important factors of reinforcement and social learning processes. In managing of chronic pain, especially such as tension headache is, it's very important to involve bio-psychosocial model of pain and integrative model of treatment. Intra- and inter-subjective psychological functions of pain must be recognised as soon as possible.

  16. Neurodegeneration in the diabetic eye

    DEFF Research Database (Denmark)

    Simó, Rafael; Hernández, Cristina; Bandello, F; Burks, D; Cunha-Vaz, J; Egan, C; Garcia-Arumi, J; Gibson, J; Harding, S; Karadeniz, S; Lang, G; Massin, P; Midena, E; Pontasi, B; Porta, M; Scanlon, P; Grauslund, Jakob; Valverde, AM

    2014-01-01

    Diabetic retinopathy (DR), one of the leading causes of preventable blindness, has been considered a microcirculatory disease of the retina. However, there is emerging evidence to suggest that retinal neurodegeneration is an early event in the pathogenesis of DR, which participates in the develop...

  17. Optimization of a 3D Dynamic Culturing System for In Vitro Modeling of Frontotemporal Neurodegeneration-Relevant Pathologic Features

    Science.gov (United States)

    Tunesi, Marta; Fusco, Federica; Fiordaliso, Fabio; Corbelli, Alessandro; Biella, Gloria; Raimondi, Manuela T.

    2016-01-01

    Frontotemporal lobar degeneration (FTLD) is a severe neurodegenerative disorder that is diagnosed with increasing frequency in clinical setting. Currently, no therapy is available and in addition the molecular basis of the disease are far from being elucidated. Consequently, it is of pivotal importance to develop reliable and cost-effective in vitro models for basic research purposes and drug screening. To this respect, recent results in the field of Alzheimer’s disease have suggested that a tridimensional (3D) environment is an added value to better model key pathologic features of the disease. Here, we have tried to add complexity to the 3D cell culturing concept by using a microfluidic bioreactor, where cells are cultured under a continuous flow of medium, thus mimicking the interstitial fluid movement that actually perfuses the body tissues, including the brain. We have implemented this model using a neuronal-like cell line (SH-SY5Y), a widely exploited cell model for neurodegenerative disorders that shows some basic features relevant for FTLD modeling, such as the release of the FTLD-related protein progranulin (PRGN) in specific vesicles (exosomes). We have efficiently seeded the cells on 3D scaffolds, optimized a disease-relevant oxidative stress experiment (by targeting mitochondrial function that is one of the possible FTLD-involved pathological mechanisms) and evaluated cell metabolic activity in dynamic culture in comparison to static conditions, finding that SH-SY5Y cells cultured in 3D scaffold are susceptible to the oxidative damage triggered by a mitochondrial-targeting toxin (6-OHDA) and that the same cells cultured in dynamic conditions kept their basic capacity to secrete PRGN in exosomes once recovered from the bioreactor and plated in standard 2D conditions. We think that a further improvement of our microfluidic system may help in providing a full device where assessing basic FTLD-related features (including PRGN dynamic secretion) that may

  18. Senescence-accelerated mouse (SAM) with special references to neurodegeneration models, SAMP8 and SAMP10 mice.

    Science.gov (United States)

    Takeda, Toshio

    2009-04-01

    The SAM strains, a group of related inbred strains consisting of senescence-prone inbred strains (SAMP) and senescence-resistant inbred strains (SAMR), have been successfully developed by selective inbreeding of the AKR/J strain of mice donated by the Jackson laboratory in 1968. The characteristic feature of aging common to the SAMP and SAMR is accelerated senescence and normal aging, respectively. Furthermore, SAMP and SAMR strains of mice manifest various pathobiological phenotypes spontaneously. Among SAMP strains, SAMP8 and SAMP10 mice show age-related behavioral deterioration such as deficits in learning and memory, emotional disorders (reduced anxiety-like behavior and depressive behavior) and altered circadian rhythm associated with certain pathological, biochemical and pharmacological changes. Here, the previous and recent literature on SAM mice are reviewed with an emphasis on SAMP8 and SAMP10 mice. A spontaneous model like SAM with distinct advantages over the gene-modified model is hoped by investigators to be used more widely as a biogerontological resource to explore the etiopathogenesis of accelerated senescence and neurodegenerative disorders. PMID:19199030

  19. Deleterious effects of lymphocytes at the early stage of neurodegeneration in an animal model of amyotrophic lateral sclerosis

    Directory of Open Access Journals (Sweden)

    Nakatsuji Yuji

    2011-02-01

    Full Text Available Abstract Background Non-neuronal cells, such as microglia and lymphocytes, are thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS. Previous studies have demonstrated neuroprotective effects of lymphocytes at the end stage of ALS, partly through induction of alternatively activated microglia (M2 microglia, which are neuroprotective. In this study, we investigated the role of lymphocytes in the early stage of the disease using an animal model of inherited ALS. Methods We established a transgenic mouse line overexpressing the familial ALS-associated G93A-SOD1 mutation (harboring a single amino acid substitution of glycine to alanine at codon 93 with depletion of the Rag2 gene (mSOD1/RAG2-/- mice, an animal model of inherited ALS lacking mature lymphocytes. Body weights, clinical scores and motor performance (hanging wire test of mSOD1/RAG2-/- mice were compared to those of mutant human SOD1 transgenic mice (mSOD1/RAG2+/+ mice. Activation of glial cells in the spinal cords of these mice was determined immunohistochemically, and the expression of mRNA for various inflammatory and anti-inflammatory molecules was evaluated. Results Clinical onset in mSOD1/RAG2-/- mice was significantly delayed, and the number of lectin-positive cells in spinal cord was increased at the early stage of disease when compared to mSOD1/RAG2+/+ mice. Quantitative RT-PCR confirmed that mRNA for Ym1, an M2 microglial-related molecule, was significantly increased in mSOD1/RAG2-/- mouse spinal cords at the early disease stage. Conclusions Compared with mSOD1/RAG2+/+ mice, mSOD1/RAG2-/- mice displayed delayed onset and increased M2 microglial activation at the early stage of disease. Thus, lymphocytes at the early pathological phase of ALS display a deleterious effect via inhibition of M2 microglial activation.

  20. Reducing C-terminal-truncated alpha-synuclein by immunotherapy attenuates neurodegeneration and propagation in Parkinson's disease-like models.

    Science.gov (United States)

    Games, Dora; Valera, Elvira; Spencer, Brian; Rockenstein, Edward; Mante, Michael; Adame, Anthony; Patrick, Christina; Ubhi, Kiren; Nuber, Silke; Sacayon, Patricia; Zago, Wagner; Seubert, Peter; Barbour, Robin; Schenk, Dale; Masliah, Eliezer

    2014-07-01

    Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are common neurodegenerative disorders of the aging population, characterized by progressive and abnormal accumulation of α-synuclein (α-syn). Recent studies have shown that C-terminus (CT) truncation and propagation of α-syn play a role in the pathogenesis of PD/DLB. Therefore, we explored the effect of passive immunization against the CT of α-syn in the mThy1-α-syn transgenic (tg) mouse model, which resembles the striato-nigral and motor deficits of PD. Mice were immunized with the new monoclonal antibodies 1H7, 5C1, or 5D12, all directed against the CT of α-syn. CT α-syn antibodies attenuated synaptic and axonal pathology, reduced the accumulation of CT-truncated α-syn (CT-α-syn) in axons, rescued the loss of tyrosine hydroxylase fibers in striatum, and improved motor and memory deficits. Among them, 1H7 and 5C1 were most effective at decreasing levels of CT-α-syn and higher-molecular-weight aggregates. Furthermore, in vitro studies showed that preincubation of recombinant α-syn with 1H7 and 5C1 prevented CT cleavage of α-syn. In a cell-based system, CT antibodies reduced cell-to-cell propagation of full-length α-syn, but not of the CT-α-syn that lacked the 118-126 aa recognition site needed for antibody binding. Furthermore, the results obtained after lentiviral expression of α-syn suggest that antibodies might be blocking the extracellular truncation of α-syn by calpain-1. Together, these results demonstrate that antibodies against the CT of α-syn reduce levels of CT-truncated fragments of the protein and its propagation, thus ameliorating PD-like pathology and improving behavioral and motor functions in a mouse model of this disease. PMID:25009275

  1. Ceftriaxone prevents the neurodegeneration and decreased neurogenesis seen in a Parkinson's disease rat model: An immunohistochemical and MRI study.

    Science.gov (United States)

    Weng, Jun-Cheng; Tikhonova, Maria A; Chen, Jian-Horng; Shen, Mei-Shiuan; Meng, Wan-Yun; Chang, Yen-Ting; Chen, Ke-Hsin; Liang, Keng-Chen; Hung, Ching-Sui; Amstislavskaya, Tamara G; Ho, Ying-Jui

    2016-05-15

    Manganese-enhanced magnetic resonance imaging (MEMRI) is a widely used technique for detecting neuronal activity in the brain of a living animal. Ceftriaxone (CEF) has been shown to have neuroprotective effects in neurodegenerative diseases. The present study was aimed at clarifying whether, in an 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced Parkinson's disease (PD) rat model, the known CEF-induced neuronal protection was accompanied by neurogenesis and decreased loss of neuronal activity. After MPTP lesioning (day 0), the rats were treated with CEF (100mg/kg/day, i.p.) or saline for 15 days. They were then injected with MnCl2 (40mg/kg, i.p.) on day 13 and underwent a brain MRI scan on day 14, then the brain was taken for histological evaluation on day 15. The results showed that MPTP lesioning resulted in decreased neuronal activity and density in the nigrostriatal dopaminergic (DAergic) system and the hippocampal CA1, CA3, and dentate gyrus (DG) areas and reduced neurogenesis in the DG, but in hyperactivity in the subthalamic nucleus (STN). These neuronal changes were prevented by CEF treatment. Positive correlations between MEMRI R1 values and neuronal density in the hippocampus were evidenced. Neuronal densities in the hippocampus and SNc were positively correlated. In addition, the R1 value of the STN showed a positive correlation with its neuronal activity but showed a negative correlation with the density of DAergic neurons in the SNc. Therefore, MEMRI R1 value may serve as a good indicator for PD severity and the effect of treatment. To our knowledge, this is the first study showing that CEF prevents loss of neuronal activity and neurogenesis in the brain of PD rats. CEF may therefore have clinical potential in the treatment of PD. PMID:26940602

  2. Diabetic Retinal Neurodegeneration Is Associated With Mitochondrial Oxidative Stress and Is Improved by an Angiotensin Receptor Blocker in a Model Combining Hypertension and Diabetes

    OpenAIRE

    Silva, Kamila C.; Rosales, Mariana A.B.; Biswas, Subrata K.; Lopes de Faria, Jose B.; Lopes de Faria, Jacqueline M.

    2009-01-01

    OBJECTIVE Diabetic retinopathy displays the features of a neurodegenerative disease. Oxidative stress is involved in the pathogenesis of diabetic retinopathy. This investigation sought to determine whether hypertension exacerbates the oxidative stress, neurodegeneration, and mitochondrial dysfunction that exists in diabetic retinopathy and whether these changes could be minimized by the angiotensin II type 1 (AT1) receptor blocker (ARB) losartan. RESEARCH DESIGN AND METHODS Diabetes was induc...

  3. Neurogenesis, Neurodegeneration, Interneuron Vulnerability, and Amyloid-β in the Olfactory Bulb of APP/PS1 Mouse Model of Alzheimer's Disease

    Science.gov (United States)

    De la Rosa-Prieto, Carlos; Saiz-Sanchez, Daniel; Ubeda-Banon, Isabel; Flores-Cuadrado, Alicia; Martinez-Marcos, Alino

    2016-01-01

    Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, mostly idiopathic and with palliative treatment. Neuropathologically, it is characterized by intracellular neurofibrillary tangles of tau protein and extracellular plaques of amyloid β peptides. The relationship between AD and neurogenesis is unknown, but two facts are particularly relevant. First, early aggregation sites of both proteinopathies include the hippocampal formation and the olfactory bulb (OB), which have been correlated to memory and olfactory deficits, respectively. These areas are well-recognized integration zones of newly-born neurons in the adult brain. Second, molecules, such as amyloid precursor protein (APP) and presenilin-1 are common to both AD etiology and neurogenic development. Adult neurogenesis in AD models has been studied in the hippocampus, but only occasionally addressed in the OB and results are contradictory. To gain insight on the relationship between adult neurogenesis and AD, this work analyzes neurogenesis, neurodegeneration, interneuron vulnerability, and amyloid-β involvement in the OB of an AD model. Control and double-transgenic mice carrying the APP and the presenilin-1 genes, which give rise amyloid β plaques have been used. BrdU-treated animals have been studied at 16, 30, 43, and 56 weeks of age. New-born cell survival (BrdU), neuronal loss (using neuronal markers NeuN and PGP9.5), differential interneuron (calbindin-, parvalbumin-, calretinin- and somatostatin-expressing populations) vulnerability, and involvement by amyloid β have been analyzed. Neurogenesis increases with aging in the granule cell layer of control animals from 16 to 43 weeks. No neuronal loss has been observed after quantifying NeuN or PGP9.5. Regarding interneuron population vulnerability: calbindin-expressing neurons remains unchanged; parvalbumin-expressing neurons trend to increase with aging in transgenic animals; calretinin-expressing neurons increase with aging in

  4. The Neuron-Astrocyte-Microglia Triad in a Rat Model of Chronic Cerebral Hypoperfusion: Protective Effect of Dipyridamole

    Directory of Open Access Journals (Sweden)

    Daniele Lana

    2014-11-01

    Full Text Available Chronic cerebral hypoperfusion during aging may cause progressive neurodegeneration as ischemic conditions persist. Proper functioning of the interplay between neurons and glia is fundamental for the functional organization of the brain. The aim of our research was to study the pathophysiological mechanisms, and particularly the derangement of the interplay between neurons and astrocytes-microglia with the formation of “triads”, in a model of chronic cerebral hypoperfusion induced by the 2-vessel occlusion (2VO in adult Wistar rats (n=15. The protective effect of dipyridamole given during the early phases after 2VO (4 mg/kg/day i.v., the first 7 days after 2VO was verified (n=15. Sham-operated rats (n=15 were used as controls. Immunofluorescent triple staining of neurons (NeuN, astrocytes (GFAP and microglia (IBA1 was performed 90 days after 2VO. We found significantly higher amount of “ectopic” neurons, neuronal debris and apoptotic neurons in CA1 Str. Radiatum and Str. Pyramidale of 2VO rats. In CA1 Str. Radiatum of 2VO rats the amount of astrocytes (cells/mm2 did not increase. In some instances several astrocytes surrounded ectopic neurons and formed a “micro scar” around them. Astrocyte branches could infiltrate the cell body of ectopic neurons, and, together with activated microglia cells formed the “triads”. In the triad, significantly more numerous in CA1 Str. Radiatum of 2VO than in sham rats, astrocytes and microglia cooperated in the phagocytosis of ectopic neurons. These events might be common mechanisms underlying many neurodegenerative processes. The frequency to which they appear might depend upon, or might be the cause of, the burden and severity of neurodegeneration. Dypiridamole significantly reverted all the above described events. The protective effect of chronic administration of dipyridamole might be a consequence of its vasodilatory, antioxidant and anti-inflammatory role during the early phases after 2VO.

  5. Parkinson's disease managing reversible neurodegeneration.

    Science.gov (United States)

    Hinz, Marty; Stein, Alvin; Cole, Ted; McDougall, Beth; Westaway, Mark

    2016-01-01

    Traditionally, the Parkinson's disease (PD) symptom course has been classified as an irreversible progressive neurodegenerative disease. This paper documents 29 PD and treatment-induced systemic depletion etiologies which cause and/or exacerbate the seven novel primary relative nutritional deficiencies associated with PD. These reversible relative nutritional deficiencies (RNDs) may facilitate and accelerate irreversible progressive neurodegeneration, while other reversible RNDs may induce previously undocumented reversible pseudo-neurodegeneration that is hiding in plain sight since the symptoms are identical to the symptoms being experienced by the PD patient. Documented herein is a novel nutritional approach for reversible processes management which may slow or halt irreversible progressive neurodegenerative disease and correct reversible RNDs whose symptoms are identical to the patient's PD symptoms. PMID:27103805

  6. Unconventional neurotransmitters, neurodegeneration and neuroprotection

    OpenAIRE

    M. Leonelli; A.S. Torrão; L.R.G. Britto

    2009-01-01

    Neurotransmitters are also involved in functions other than conventional signal transfer between nerve cells, such as development, plasticity, neurodegeneration, and neuroprotection. For example, there is a considerable amount of data indicating developmental roles for the glutamatergic, cholinergic, dopaminergic, GABA-ergic, and ATP/adenosine systems. In this review, we discuss the existing literature on these "new" functions of neurotransmitters in relation to some unconventional neurotrans...

  7. Early limited nitrosamine exposures exacerbate high fat diet-mediated type 2 diabetes and neurodegeneration

    Directory of Open Access Journals (Sweden)

    Longato Lisa

    2010-03-01

    Full Text Available Abstract Background Type 2 diabetes mellitus (T2DM and several types of neurodegeneration, including Alzheimer's, are linked to insulin-resistance, and chronic high dietary fat intake causes T2DM with mild neurodegeneration. Intra-cerebral Streptozotocin, a nitrosamine-related compound, causes neurodegeneration, whereas peripheral treatment causes DM. Hypothesis Limited early exposures to nitrosamines that are widely present in the environment, enhance the deleterious effects of high fat intake in promoting T2DM and neurodegeneration. Methods Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA by i.p. injection, and upon weaning, they were fed with high fat (60%; HFD or low fat (5%; LFD chow for 8 weeks. Cerebella were harvested to assess gene expression, and insulin and insulin-like growth factor (IGF deficiency and resistance in the context of neurodegeneration. Results HFD ± NDEA caused T2DM, neurodegeneration with impairments in brain insulin, insulin receptor, IGF-2 receptor, or insulin receptor substrate gene expression, and reduced expression of tau and choline acetyltransferase (ChAT, which are regulated by insulin and IGF-1. In addition, increased levels of 4-hydroxynonenal and nitrotyrosine were measured in cerebella of HFD ± NDEA treated rats, and overall, NDEA+HFD treatment reduced brain levels of Tau, phospho-GSK-3β (reflecting increased GSK-3β activity, glial fibrillary acidic protein, and ChAT to greater degrees than either treatment alone. Finally, pro-ceramide genes, examined because ceramides cause insulin resistance, oxidative stress, and neurodegeneration, were significantly up-regulated by HFD and/or NDEA exposure, but the highest levels were generally present in brains of HFD+NDEA treated rats. Conclusions Early limited exposure to nitrosamines exacerbates the adverse effects of later chronic high dietary fat intake in promoting T2DM and neurodegeneration. The mechanism involves increased generation of

  8. Phagocytic Clearance in Neurodegeneration

    OpenAIRE

    Sokolowski, Jennifer D.; Mandell, James W.

    2011-01-01

    The cellular and molecular mechanisms of phagocytic clearance of apoptotic cells and debris have been intensely studied in invertebrate model organisms and in the mammalian immune system. This evolutionarily conserved process serves multiple purposes. Uncleared debris from dying cells or aggregated proteins can be toxic and may trigger exaggerated inflammatory responses. Even though apoptotic cell death and debris accumulation are key features of neurodegenerative diseases, relatively little ...

  9. Neurodegeneration and Identity.

    Science.gov (United States)

    Strohminger, Nina; Nichols, Shaun

    2015-09-01

    There is a widespread notion, both within the sciences and among the general public, that mental deterioration can rob individuals of their identity. Yet there have been no systematic investigations of what types of cognitive damage lead people to appear to no longer be themselves. We measured perceived identity change in patients with three kinds of neurodegenerative disease: frontotemporal dementia, Alzheimer's disease, and amyotrophic lateral sclerosis. Structural equation models revealed that injury to the moral faculty plays the primary role in identity discontinuity. Other cognitive deficits, including amnesia, have no measurable impact on identity persistence. Accordingly, frontotemporal dementia has the greatest effect on perceived identity, and amyotrophic lateral sclerosis has the least. We further demonstrated that perceived identity change fully mediates the impact of neurodegenerative disease on relationship deterioration between patient and caregiver. Our results mark a departure from theories that ground personal identity in memory, distinctiveness, dispositional emotion, or global mental function. PMID:26270072

  10. Animal models for investigating chronic pancreatitis

    OpenAIRE

    Aghdassi Alexander A; Mayerle Julia; Christochowitz Sandra; Weiss Frank U; Sendler Matthias; Lerch Markus M

    2011-01-01

    Abstract Chronic pancreatitis is defined as a continuous or recurrent inflammatory disease of the pancreas characterized by progressive and irreversible morphological changes. It typically causes pain and permanent impairment of pancreatic function. In chronic pancreatitis areas of focal necrosis are followed by perilobular and intralobular fibrosis of the parenchyma, by stone formation in the pancreatic duct, calcifications in the parenchyma as well as the formation of pseudocysts. Late in t...

  11. Chronic pain: Model of psychosomatic disorder (review

    Directory of Open Access Journals (Sweden)

    Chernus N.P.

    2011-12-01

    Full Text Available The article presents a detailed review on epidemiology, pathogenesis and interrelation of serotonin neuromedia-tor metabolism in the central nervous system in state of chronic pain and depression. It has been demonstrated that neurophysiological conditions serve as psychological defense of an individual. That mechanism has been proved to «transform» serious emotions onto the inner level (body and it assists in the development of psychosomatic disorders — chronic pain syndrome

  12. The Chemistry of Neurodegeneration: Kinetic Data and Their Implications.

    Science.gov (United States)

    Pavlin, Matic; Repič, Matej; Vianello, Robert; Mavri, Janez

    2016-07-01

    kinetic molecular model of neurodegeneration itself. PMID:26081152

  13. DNA repair deficiency in neurodegeneration

    DEFF Research Database (Denmark)

    Jeppesen, Dennis Kjølhede; Bohr, Vilhelm A; Stevnsner, Tinna V.

    2011-01-01

    Deficiency in repair of nuclear and mitochondrial DNA damage has been linked to several neurodegenerative disorders. Many recent experimental results indicate that the post-mitotic neurons are particularly prone to accumulation of unrepaired DNA lesions potentially leading to progressive...... neurodegeneration. Nucleotide excision repair is the cellular pathway responsible for removing helix-distorting DNA damage and deficiency in such repair is found in a number of diseases with neurodegenerative phenotypes, including Xeroderma Pigmentosum and Cockayne syndrome. The main pathway for repairing oxidative...... base lesions is base excision repair, and such repair is crucial for neurons given their high rates of oxygen metabolism. Mismatch repair corrects base mispairs generated during replication and evidence indicates that oxidative DNA damage can cause this pathway to expand trinucleotide repeats, thereby...

  14. Human Interleukin-10 Gene Transfer Is Protective in a Rat Model of Parkinson’s Disease

    OpenAIRE

    Johnston, Louisa C; Su, Xiaomin; Maguire-Zeiss, Kathleen; Horovitz, Karen; Ankoudinova, Irina; Guschin, Dmitry; Hadaczek, Piotr; Federoff, Howard J.; Bankiewicz, Krystof; Forsayeth, John

    2008-01-01

    In Parkinson’s disease (PD) chronic inflammation occurs in the substantia nigra (SNc) concurrently with dop-aminergic neurodegeneration. In models of PD, microglial activation precedes neurodegeneration in the SNc, suggesting that the underlying pathogenesis involves a complex response in the nigrostriatal pathway, and that the innate immune system plays a significant role. We have investigated the neuroprotective effect of an ade-no-associated viral type-2 (AAV2) vector containing the comple...

  15. A Customizable Model for Chronic Disease Coordination: Lessons Learned From the Coordinated Chronic Disease Program

    Science.gov (United States)

    Sequeira, Sonia; Chavez, Amy Holmes

    2016-01-01

    In 2012, the Centers for Disease Control and Prevention provided funding and technical assistance to all states and territories to implement the Coordinated Chronic Disease Program, marking the first time that all state health departments had federal resources to coordinate chronic disease prevention and control programs. This article describes lessons learned from this initiative and identifies key elements of a coordinated approach. We analyzed 80 programmatic documents from 21 states and conducted semistructured interviews with 7 chronic disease directors. Six overarching themes emerged: 1) focused agenda, 2) identification of functions, 3) comprehensive planning, 4) collaborative leadership and expertise, 5) managed resources, and 6) relationship building. These elements supported 4 essential activities: 1) evidence-based interventions, 2) strategic use of staff, 3) consistent communication, and 4) strong program infrastructure. On the basis of these elements and activities, we propose a conceptual model that frames overarching concepts, skills, and strategies needed to coordinate state chronic disease prevention and control programs. PMID:27032986

  16. A Customizable Model for Chronic Disease Coordination: Lessons Learned From the Coordinated Chronic Disease Program.

    Science.gov (United States)

    Voetsch, Karen; Sequeira, Sonia; Chavez, Amy Holmes

    2016-01-01

    In 2012, the Centers for Disease Control and Prevention provided funding and technical assistance to all states and territories to implement the Coordinated Chronic Disease Program, marking the first time that all state health departments had federal resources to coordinate chronic disease prevention and control programs. This article describes lessons learned from this initiative and identifies key elements of a coordinated approach. We analyzed 80 programmatic documents from 21 states and conducted semistructured interviews with 7 chronic disease directors. Six overarching themes emerged: 1) focused agenda, 2) identification of functions, 3) comprehensive planning, 4) collaborative leadership and expertise, 5) managed resources, and 6) relationship building. These elements supported 4 essential activities: 1) evidence-based interventions, 2) strategic use of staff, 3) consistent communication, and 4) strong program infrastructure. On the basis of these elements and activities, we propose a conceptual model that frames overarching concepts, skills, and strategies needed to coordinate state chronic disease prevention and control programs. PMID:27032986

  17. Genetics and inflammation in nerve injury-induced neurodegeneration

    OpenAIRE

    Lidman, Olle

    2003-01-01

    Neurodegeneration and inflammation are characteristic of many diseases of the central nervous system (CNS) and understanding the molecular networks that regulate these processes is of central importance for the development of effective therapies. Although the CNS has traditionally been regarded as an immuno privileged organ, immune reactions, including components of both local innate and systemic immunity, do occur in this tissue. Animal models can provide powerful tools for...

  18. Neurodegeneration in Autoimmune Optic Neuritis Is Associated with Altered APP Cleavage in Neurons and Up-Regulation of p53.

    Directory of Open Access Journals (Sweden)

    Sabine Herold

    Full Text Available Multiple Sclerosis (MS is a chronic autoimmune inflammatory disease of the central nervous system (CNS. Histopathological and radiological analysis revealed that neurodegeneration occurs early in the disease course. However, the pathological mechanisms involved in neurodegeneration are poorly understood. Myelin oligodendrocyte glycoprotein (MOG-induced experimental autoimmune encephalomyelitis (EAE in Brown Norway rats (BN-rats is a well-established animal model, especially of the neurodegenerative aspects of MS. Previous studies in this animal model indicated that loss of retinal ganglion cells (RGCs, the neurons that form the axons of the optic nerve, occurs in the preclinical phase of the disease and is in part independent of overt histopathological changes of the optic nerve. Therefore, the aim of this study was to identify genes which are involved in neuronal cell loss at different disease stages of EAE. Furthermore, genes that are highly specific for autoimmune-driven neurodegeneration were compared to those regulated in RGCs after optic nerve axotomy at corresponding time points. Using laser capture micro dissection we isolated RNA from unfixed RGCs and performed global transcriptome analysis of retinal neurons. In total, we detected 582 genes sequentially expressed in the preclinical phase and 1150 genes in the clinical manifest EAE (P 1.5. Furthermore, using ingenuity pathway analysis (IPA, we identified amyloid precursor protein (APP as a potential upstream regulator of changes in gene expression in the preclinical EAE but neither in clinical EAE, nor at any time point after optic nerve transection. Therefore, the gene pathway analysis lead to the hypothesis that altered cleavage of APP in neurons in the preclinical phase of EAE leads to the enhanced production of APP intracellular domain (AICD, which in turn acts as a transcriptional regulator and thereby initiates an apoptotic signaling cascade via up-regulation of the target gene p

  19. A Model of Chronic Nutrient Infusion in the Rat

    OpenAIRE

    Fergusson, Grace; Ethier, Mélanie; Zarrouki, Bader; Fontés, Ghislaine; Poitout, Vincent

    2013-01-01

    Chronic exposure to excessive levels of nutrients is postulated to affect the function of several organs and tissues and to contribute to the development of the many complications associated with obesity and the metabolic syndrome, including type 2 diabetes. To study the mechanisms by which excessive levels of glucose and fatty acids affect the pancreatic beta-cell and the secretion of insulin, we have established a chronic nutrient infusion model in the rat. The procedure consists of cathete...

  20. Nucleotide Salvage Deficiencies, DNA Damage and Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Michael Fasullo

    2015-04-01

    Full Text Available Nucleotide balance is critically important not only in replicating cells but also in quiescent cells. This is especially true in the nervous system, where there is a high demand for adenosine triphosphate (ATP produced from mitochondria. Mitochondria are particularly prone to oxidative stress-associated DNA damage because nucleotide imbalance can lead to mitochondrial depletion due to low replication fidelity. Failure to maintain nucleotide balance due to genetic defects can result in infantile death; however there is great variability in clinical presentation for particular diseases. This review compares genetic diseases that result from defects in specific nucleotide salvage enzymes and a signaling kinase that activates nucleotide salvage after DNA damage exposure. These diseases include Lesch-Nyhan syndrome, mitochondrial depletion syndromes, and ataxia telangiectasia. Although treatment options are available to palliate symptoms of these diseases, there is no cure. The conclusions drawn from this review include the critical role of guanine nucleotides in preventing neurodegeneration, the limitations of animals as disease models, and the need to further understand nucleotide imbalances in treatment regimens. Such knowledge will hopefully guide future studies into clinical therapies for genetic diseases.

  1. Effects of hypothalamic neurodegeneration on energy balance.

    Directory of Open Access Journals (Sweden)

    Allison Wanting Xu

    2005-12-01

    Full Text Available Normal aging in humans and rodents is accompanied by a progressive increase in adiposity. To investigate the role of hypothalamic neuronal circuits in this process, we used a Cre-lox strategy to create mice with specific and progressive degeneration of hypothalamic neurons that express agouti-related protein (Agrp or proopiomelanocortin (Pomc, neuropeptides that promote positive or negative energy balance, respectively, through their opposing effects on melanocortin receptor signaling. In previous studies, Pomc mutant mice became obese, but Agrp mutant mice were surprisingly normal, suggesting potential compensation by neuronal circuits or genetic redundancy. Here we find that Pomc-ablation mice develop obesity similar to that described for Pomc knockout mice, but also exhibit defects in compensatory hyperphagia similar to what occurs during normal aging. Agrp-ablation female mice exhibit reduced adiposity with normal compensatory hyperphagia, while animals ablated for both Pomc and Agrp neurons exhibit an additive interaction phenotype. These findings provide new insight into the roles of hypothalamic neurons in energy balance regulation, and provide a model for understanding defects in human energy balance associated with neurodegeneration and aging.

  2. A chronic ulcerative colitis model in rats

    Institute of Scientific and Technical Information of China (English)

    Li Zheng; Zhen Qiang Gao; Shu Xian Wang

    2000-01-01

    @@ INTRODUCTION In recent years, there have been many reports about animal model to investigate drugs for inflammatory bowel diseases (IBD). The experimental animal model often used is acetic acid-induced damage of colonic muscosa. In the present study, this animal model was investigated by administering various concentrations of TNBS.

  3. Chronic subordinate colony housing (CSC as a model of chronic psychosocial stress in male rats.

    Directory of Open Access Journals (Sweden)

    Kewir D Nyuyki

    Full Text Available Chronic subordinate colony housing (CSC is an adequate and reliable mouse model of chronic psychosocial stress, resulting in reduced body weight gain, reduced thymus and increased adrenal weight, long-lasting anxiety-like behaviour, and spontaneous colitis. Furthermore, CSC mice show increased corticotrophin (ACTH responsiveness to acute heterotypic stressors, suggesting a general mechanism which allows a chronically-stressed organism to adequately respond to a novel threat. Therefore, the aim of the present study was to extend the CSC model to another rodent species, namely male Wistar rats, and to characterize relevant physiological, immunological, and behavioural consequences; placing particular emphasis on changes in hypothalamo-pituitary-adrenal (HPA axis responsiveness to an acute heterotypic stressor. In line with previous mouse data, exposure of Wistar rats to 19 days of CSC resulted in a decrease in body weight gain and absolute thymus mass, mild colonic barrier defects and intestinal immune activation. Moreover, no changes in stress-coping behaviour or social preference were seen; again in agreement with the mouse paradigm. Most importantly, CSC rats showed an increased plasma corticosterone response to an acute heterotypic stressor (open arm, 5 min despite displaying similar basal levels and similar basal and stressor-induced plasma ACTH levels. In contrast to CSC mice, anxiety-related behaviour and absolute, as well as relative adrenal weights remained unchanged in CSC rats. In summary, the CSC paradigm could be established as an adequate model of chronic psychosocial stress in male rats. Our data further support the initial hypothesis that adrenal hyper-responsiveness to ACTH during acute heterotypic stressors represents a general adaptation, which enables a chronically-stressed organism to adequately respond to novel challenges.

  4. Predictive validity of behavioural animal models for chronic pain

    OpenAIRE

    Berge, Odd-Geir

    2011-01-01

    Rodent models of chronic pain may elucidate pathophysiological mechanisms and identify potential drug targets, but whether they predict clinical efficacy of novel compounds is controversial. Several potential analgesics have failed in clinical trials, in spite of strong animal modelling support for efficacy, but there are also examples of successful modelling. Significant differences in how methods are implemented and results are reported means that a literature-based comparison between precl...

  5. Sex differences in the chronic mild stress model of depression.

    Science.gov (United States)

    Franceschelli, Anthony; Herchick, Samantha; Thelen, Connor; Papadopoulou-Daifoti, Zeta; Pitychoutis, Pothitos M

    2014-09-01

    A large volume of clinical and experimental evidence documents sex differences in brain anatomy, chemistry, and function, as well as in stress and drug responses. The chronic mild stress model (CMS) is one of the most extensively investigated animal models of chronic stress. However, only a limited number of studies have been conducted in female rodents despite the markedly higher prevalence of major depression among women. Herein, we review CMS studies conducted in rats and mice of both sexes and further discuss intriguing sex-dependent behavioral and neurobiological findings. The PubMed literature search engine was used to find and collect all relevant articles analyzed in this review. Specifically, a multitermed search was performed with 'chronic mild stress', 'chronic unpredictable stress' and 'chronic variable stress' as base terms and 'sex', 'gender', 'females' and 'depression' as secondary terms in various combinations. Male and female rodents appear to be differentially affected by CMS application, depending on the behavioral, physiological, and neurobiological indices that are being measured. Importantly, the CMS paradigm, despite its limitations, has been successfully used to assess a constellation of interdisciplinary research questions in the sex differences field and has served as a 'silver bullet' in assessing the role of sex in the neurobiology of major depression. PMID:25025701

  6. Models for Reactive and Chronic Depression in Infancy.

    Science.gov (United States)

    Field, Tiffany

    1986-01-01

    Presents studies on primates and human infants suggesting that maternal depression may predispose the infant to chronic depression. Findings also suggest that the effect of early separations from the mother may provide a model for reactive depression in the infant. (Author/BB)

  7. Sonic hedgehog expression in a rat model of chronic pancreatitis

    Science.gov (United States)

    Wang, Luo-Wei; Lin, Han; Lu, Yi; Xia, Wei; Gao, Jun; Li, Zhao-Shen

    2014-01-01

    AIM: To analyze the activation of sonic hedgehog (SHh) signaling pathways in a rat model of chronic pancreatitis. METHODS: Forty Wistar rats were randomly divided into 2 groups: experimental group and control group (20 rats in each group). Dibutyltin dichloride was infused into the tail vein of the rats to induce chronic pancreatitis in the experimental group. The same volume of ethanol and glycerol mixture was infused in the control group. The expression of Ptch, Smo and Gli were analyzed using immunohistochemistry, and real-time reverse transcription polymerase chain reaction (RT-PCR). RESULTS: Compared with the control group, significant histological changes in terms of the areas of abnormal architecture, glandular atrophy, fibrosis, pseudo tubular complexes, and edema were observed at week 4 in the experimental group. The expression of Ptch1, Smo and Gli1 in the pancreatic tissue increased significantly in the experimental group. Using RT-PCR, mRNA levels of Ptch, Smo and Gli in the experimental group increased significantly compared with the control group. CONCLUSION: The SHh signaling pathway is aberrantly activated in rats with chronic pancreatitis. The SHh signaling pathway plays an important role in the development of chronic pancreatitis. These results may be helpful in studies focusing on the relationship between chronic pancreatitis and pancreatic cancer. PMID:24782623

  8. Traumatic stress, oxidative stress and posttraumatic stress disorder: neurodegeneration and the accelerated-aging hypothesis

    OpenAIRE

    Miller, Mark W.; Sadeh, Naomi

    2014-01-01

    Posttraumatic stress disorder (PTSD) is associated with elevated risk for a variety of age-related diseases and neurodegeneration. In this paper, we review evidence relevant to the hypothesis that chronic PTSD constitutes a form of persistent life stress that potentiates oxidative stress (OXS) and accelerates cellular aging. We provide an overview of empirical studies that have examined the effects of psychological stress on OXS, discuss the stress-perpetuating characteristics of PTSD, and th...

  9. Traumatization and chronic pain: a further model of interaction.

    Science.gov (United States)

    Egloff, Niklaus; Hirschi, Anna; von Känel, Roland

    2013-01-01

    Up to 80% of patients with severe posttraumatic stress disorder are suffering from "unexplained" chronic pain. Theories about the links between traumatization and chronic pain have become the subject of increased interest over the last several years. We will give a short summary about the existing interaction models that emphasize particularly psychological and behavioral aspects of this interaction. After a synopsis of the most important psychoneurobiological mechanisms of pain in the context of traumatization, we introduce the hypermnesia-hyperarousal model, which focuses on two psychoneurobiological aspects of the physiology of learning. This hypothesis provides an answer to the hitherto open question about the origin of pain persistence and pain sensitization following a traumatic event and also provides a straightforward explanatory model for educational purposes. PMID:24231792

  10. Chronic gastritis rat model and role of inducing factors

    Institute of Scientific and Technical Information of China (English)

    Zun Xiang; Jian-Min Si; Huai-De Huang

    2004-01-01

    AIM: To establish an experimental animal model of chronic gastritis in a short term and to investigate the effects of several potential inflammation-inducing factors on rat gastric mucosa.METHODS: Twenty-four healthy, male SD rats were treated with intragastric administration of 600 mL/L alcohol, 20mmol/L sodium deoxycholate and 0.5 g/L ammonia (factor A), forage containing low levels of vitamins (factor B), and/or indomethacin (factor C), according to an L8(27)orthogonal design. After 12 wk, gastric antral and body mucosae were pathologically examined.RESULTS: Chronic gastritis model was successfully induced in rats treated with factor A for 12 wk. After the treatment of animals, the gastric mucosal inflammation was significantly different from that in controls, and the number of pyloric glands at antrum and parietal cells at body were obviously reduced (P<0.01). Indomethacin induced gastritis but without atrophy, and short-term vitamin deficiency failed to induce chronic gastritis and gastric atrophy, In addition,indomethacin and vitamin deficiency had no synergistic effect in inducing gastritis with the factor A. No atypical hyperplasia and intestinal metaplasia in the gastric antrum and body were observed in all rats studied.CONCLUSION: Combined intragastric administration of 600 mL/L alcohol, 20 mmol/L sodium deoxycholate and 0.5 g/L ammonia induces chronic gastritis and gastric atrophy in rats. Indomethacin induces chronic gastritis only.The long-term roles of these factors in gastric inflammation and carcinogenesis need to be further elucidated.

  11. Huntingtin interacting proteins are genetic modifiers of neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Linda S Kaltenbach

    2007-05-01

    Full Text Available Huntington's disease (HD is a fatal neurodegenerative condition caused by expansion of the polyglutamine tract in the huntingtin (Htt protein. Neuronal toxicity in HD is thought to be, at least in part, a consequence of protein interactions involving mutant Htt. We therefore hypothesized that genetic modifiers of HD neurodegeneration should be enriched among Htt protein interactors. To test this idea, we identified a comprehensive set of Htt interactors using two complementary approaches: high-throughput yeast two-hybrid screening and affinity pull down followed by mass spectrometry. This effort led to the identification of 234 high-confidence Htt-associated proteins, 104 of which were found with the yeast method and 130 with the pull downs. We then tested an arbitrary set of 60 genes encoding interacting proteins for their ability to behave as genetic modifiers of neurodegeneration in a Drosophila model of HD. This high-content validation assay showed that 27 of 60 orthologs tested were high-confidence genetic modifiers, as modification was observed with more than one allele. The 45% hit rate for genetic modifiers seen among the interactors is an order of magnitude higher than the 1%-4% typically observed in unbiased genetic screens. Genetic modifiers were similarly represented among proteins discovered using yeast two-hybrid and pull-down/mass spectrometry methods, supporting the notion that these complementary technologies are equally useful in identifying biologically relevant proteins. Interacting proteins confirmed as modifiers of the neurodegeneration phenotype represent a diverse array of biological functions, including synaptic transmission, cytoskeletal organization, signal transduction, and transcription. Among the modifiers were 17 loss-of-function suppressors of neurodegeneration, which can be considered potential targets for therapeutic intervention. Finally, we show that seven interacting proteins from among 11 tested were able to

  12. Supramolecular Inhibition of Neurodegeneration by a Synthetic Receptor.

    Science.gov (United States)

    Li, Shengke; Chen, Huanxian; Yang, Xue; Bardelang, David; Wyman, Ian W; Wan, Jianbo; Lee, Simon M Y; Wang, Ruibing

    2015-12-10

    Cucurbit[7]uril (CB[7]) was found in vitro to sequester the neurotoxins MPTP (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) and MPP(+) (N-methyl-4-phenylpyridine). The CB[7]/neurotoxin host-guest complexes were studied in detail with (1)H NMR, electrospray ionization mass spectrometry, UV-visible spectroscopic titration, and molecular modeling by density functional theory. The results supported the macrocyclic encapsulation of MPTP and MPP(+), respectively, by CB[7] in aqueous solutions with relatively strong affinities and 1:1 host-guest binding stoichiometries in both cases. More importantly, the progression of MPTP/MPP(+) induced neurodegeneration (often referred to as a Parkinson's disease model) was observed to be strongly inhibited in vivo by the synthetic CB[7] receptor, as shown in zebrafish models. These results show that a supramolecular approach could lead to a new preventive and/or therapeutic strategy for counteracting the deleterious effects of some neurotoxins leading to neurodegeneration. PMID:26713100

  13. Resveratrol Neuroprotection in a Chronic Mouse Model of Multiple Sclerosis

    OpenAIRE

    Zoe eFonseca-Kelly; Mayssa eNassrallah; Jorge eUribe; Khan, Reas S.; Kimberly eDine; Mahasweta eDutt; Shindler, Kenneth S.

    2012-01-01

    Resveratrol is a naturally-occurring polyphenol that activates SIRT1, an NAD-dependent deacetylase. SRT501, a pharmaceutical formulation of resveratrol with enhanced systemic absorption, prevents neuronal loss without suppressing inflammation in mice with relapsing experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. In contrast, resveratrol has been reported to suppress inflammation in chronic EAE, although neuroprotective effects were not evaluated. The current st...

  14. Establishing a cat model of chronic optic nerve compression injury

    Institute of Scientific and Technical Information of China (English)

    Feng Yu; Shaoji Yuan; Rongwei Zhang; Yicheng Lu; Meiqing Lou

    2009-01-01

    BACKGROUND:An animal model of chronic optic nerve injury is necessary to further understand the pathological mechanisms involved.OBJECTIVE:To establish a stabilized,chronic,optic nerve crush model,which is similar to the clinical situation to explore histopathological and optic electrophysiological changes involved in this injury.DESIGN,TIME AND SETTING:A randomized and controlled animal trial was performed at Shanghai Institute of Neurosurgery from May to October 2004.MATERIALS:A BAL3XRAY undetachable balloon and Magic-BD catheter were provided by BLAT,France;JX-2000 biological signal processing system by Second Military Medical University of Chinese PLA,China;inverted phase contrast microscopy by Olympus,Japan.METHODS:A total of twenty normal adult cats were randomly assigned to control (n = 5) and model (n = 15) groups,according to different doses of contrast agent injected through balloons as follows:0.2 mL injection,0.25 mL injection,and 0.35 mL injection,with each group containing 5 animals.Imitating the clinical pterion approach,the optic nerves were exposed using micro-surgical methods.An engorged undetachable balloon was implanted beneath the nerve and connected to a catheter.Balloon size was controlled with a contrast agent injection (0.1 mL/10 min) to form an occupying lesion model similar to sellar tumors.MAIN OUTCOME MEASURES:The visually evoked potential examination was used to study optical electrophysiology changes in pre-post chronic optical nerve injury.Ultrastructural pathological changes to the optic nerve were analyzed by electron microscopy.RESULTS:During the early period (day 11 after modeling),visually evoked potential demonstrated no significant changes.In the late period (day 51 after modeling),recorded VEP demonstrated that P1 wave latency was prolonged and P1 wave amplitude was obviously reduced.Following injury,the endoneurium,myelin sheath,lamella,axolemma,and axon appeared disordered.CONCLUSION:Results demonstrated that the chronic

  15. Cause or Effect: Misregulation of MicroRNA Pathways in Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Fen-BiaoGao

    2012-04-01

    Full Text Available During normal aging or neurodegenerative diseases, neuronal survival and function depend on protein homeostasis, which is regulated by multiple mechanisms, including the microRNA (miRNA pathway. In different cells types, the absence of Dicer, a key miRNA processing enzyme, leads to neurodegeneration through cell-autonomous and non-cell-autonomous mechanisms. Loss of certain miRNAs also causes neurodegeneration in some model organisms. On the other hand, miRNA expression is misregulated in patients with different neurodegenerative diseases. Thus, the miRNA pathway appears to be essential in the pathogenesis of several age-dependent neurodegenerative conditions; however, our understanding of the underlying mechanism remains rudimentary. The precise causal relationships between specific miRNAs and neurodegeneration in humans need to be further investigated.

  16. Traumatization and chronic pain: a further model of interaction

    Directory of Open Access Journals (Sweden)

    Egloff N

    2013-11-01

    Full Text Available Niklaus Egloff,1 Anna Hirschi,2 Roland von Känel1 1Department of General Internal Medicine, Division of Psychosomatic Medicine, Inselspital, University Hospital, Bern, Switzerland; 2Outpatient Clinic for Victims of Torture and War, Swiss Red Cross, Bern-Wabern, Switzerland Abstract: Up to 80% of patients with severe posttraumatic stress disorder are suffering from “unexplained” chronic pain. Theories about the links between traumatization and chronic pain have become the subject of increased interest over the last several years. We will give a short summary about the existing interaction models that emphasize particularly psychological and behavioral aspects of this interaction. After a synopsis of the most important psychoneurobiological mechanisms of pain in the context of traumatization, we introduce the hypermnesia–hyperarousal model, which focuses on two psychoneurobiological aspects of the physiology of learning. This hypothesis provides an answer to the hitherto open question about the origin of pain persistence and pain sensitization following a traumatic event and also provides a straightforward explanatory model for educational purposes. Keywords: posttraumatic stress disorder, chronic pain, hypermnesia, hypersensitivity, traumatization

  17. Attitudes of Doctors and Nurses toward the Chronic Care Model

    Directory of Open Access Journals (Sweden)

    Rolando Bonal Ruiz

    2015-06-01

    Full Text Available Background: the fact that chronic diseases replace traditional causes of morbidity and mortality in a country, or are on a par with major common health problems, demands the development of new strategies to address them. Objective: to explore attitudes of doctors and nurses from the Rolando López Peña Polyclinic toward the Chronic Care Model. Methods: a quantitative and qualitative cross-sectional study was conducted including the 22 family physicians and 26 nurses who provide care to patients with chronic diseases and were at the polyclinic at the time of the study. All were administered a 5 point Likert scale and a focus group interview, which was taped, transcribed and analyzed. Results: the attitudinal results correspond with the actions assessed in each component of the model, being the most common barriers: the lack of awareness and training on the new approaches to care of these patients, work overload created by other programs such as the maternal-child and vector control programs, uncertainties on the effectiveness of patient education and ignorance of the practice guidelines. Conclusions: favorable attitudes toward the introduction of the model to the practice of the family physician and nurse predominated as long as organizational changes are made and the suggestions of these service providers are put into practice with the support of the decision makers of the health sector.

  18. Mathematical model of gas plasma applied to chronic wounds

    Energy Technology Data Exchange (ETDEWEB)

    Wang, J. G.; Liu, X. Y.; Liu, D. W.; Lu, X. P. [State Key Lab of Advanced Electromagnetic Engineering and Technology, Huazhong University of Science and Technology, WuHan, HuBei 430074 (China); Zhang, Y. T. [Shandong Provincial Key Lab of UHV Technology and Gas Discharge Physics, School of Electrical Engineering, Shandong University, Jinan, Shandong Province 250061 (China)

    2013-11-15

    Chronic wounds are a major burden for worldwide health care systems, and patients suffer pain and discomfort from this type of wound. Recently gas plasmas have been shown to safely speed chronic wounds healing. In this paper, we develop a deterministic mathematical model formulated by eight-species reaction-diffusion equations, and use it to analyze the plasma treatment process. The model follows spatial and temporal concentration within the wound of oxygen, chemoattractants, capillary sprouts, blood vessels, fibroblasts, extracellular matrix material, nitric oxide (NO), and inflammatory cell. Two effects of plasma, increasing NO concentration and reducing bacteria load, are considered in this model. The plasma treatment decreases the complete healing time from 25 days (normal wound healing) to 17 days, and the contributions of increasing NO concentration and reducing bacteria load are about 1/4 and 3/4, respectively. Increasing plasma treatment frequency from twice to three times per day accelerates healing process. Finally, the response of chronic wounds of different etiologies to treatment with gas plasmas is analyzed.

  19. Parkinson’s disease managing reversible neurodegeneration

    Science.gov (United States)

    Hinz, Marty; Stein, Alvin; Cole, Ted; McDougall, Beth; Westaway, Mark

    2016-01-01

    Traditionally, the Parkinson’s disease (PD) symptom course has been classified as an irreversible progressive neurodegenerative disease. This paper documents 29 PD and treatment-induced systemic depletion etiologies which cause and/or exacerbate the seven novel primary relative nutritional deficiencies associated with PD. These reversible relative nutritional deficiencies (RNDs) may facilitate and accelerate irreversible progressive neurodegeneration, while other reversible RNDs may induce previously undocumented reversible pseudo-neurodegeneration that is hiding in plain sight since the symptoms are identical to the symptoms being experienced by the PD patient. Documented herein is a novel nutritional approach for reversible processes management which may slow or halt irreversible progressive neurodegenerative disease and correct reversible RNDs whose symptoms are identical to the patient’s PD symptoms. PMID:27103805

  20. A novel model of chronic wounds: importance of redox imbalance and biofilm-forming bacteria for establishment of chronicity.

    Directory of Open Access Journals (Sweden)

    Sandeep Dhall

    Full Text Available Chronic wounds have a large impact on health, affecting ∼6.5 M people and costing ∼$25B/year in the US alone. We previously discovered that a genetically modified mouse model displays impaired healing similar to problematic wounds in humans and that sometimes the wounds become chronic. Here we show how and why these impaired wounds become chronic, describe a way whereby we can drive impaired wounds to chronicity at will and propose that the same processes are involved in chronic wound development in humans. We hypothesize that exacerbated levels of oxidative stress are critical for initiation of chronicity. We show that, very early after injury, wounds with impaired healing contain elevated levels of reactive oxygen and nitrogen species and, much like in humans, these levels increase with age. Moreover, the activity of anti-oxidant enzymes is not elevated, leading to buildup of oxidative stress in the wound environment. To induce chronicity, we exacerbated the redox imbalance by further inhibiting the antioxidant enzymes and by infecting the wounds with biofilm-forming bacteria isolated from the chronic wounds that developed naturally in these mice. These wounds do not re-epithelialize, the granulation tissue lacks vascularization and interstitial collagen fibers, they contain an antibiotic-resistant mixed bioflora with biofilm-forming capacity, and they stay open for several weeks. These findings are highly significant because they show for the first time that chronic wounds can be generated in an animal model effectively and consistently. The availability of such a model will significantly propel the field forward because it can be used to develop strategies to regain redox balance that may result in inhibition of biofilm formation and result in restoration of healthy wound tissue. Furthermore, the model can lead to the understanding of other fundamental mechanisms of chronic wound development that can potentially lead to novel therapies.

  1. Does a loss of TDP-43 function cause neurodegeneration?

    Directory of Open Access Journals (Sweden)

    Xu Zuo-Shang

    2012-06-01

    Full Text Available Abstract In 2006, TAR-DNA binding protein 43 kDa (TDP-43 was discovered to be in the intracellular aggregates in the degenerating cells in amyotrophic lateral sclerosis (ALS and frontotemporal lobar degeneration (FTLD, two fatal neurodegenerative diseases [1,2]. ALS causes motor neuron degeneration leading to paralysis [3,4]. FTLD causes neuronal degeneration in the frontal and temporal cortices leading to personality changes and a loss of executive function [5]. The discovery triggered a flurry of research activity that led to the discovery of TDP-43 mutations in ALS patients and the widespread presence of TDP-43 aggregates in numerous neurodegenerative diseases. A key question regarding the role of TDP-43 is whether it causes neurotoxicity by a gain of function or a loss of function. The gain-of-function hypothesis has received much attention primarily based on the striking neurodegenerative phenotypes in numerous TDP-43-overexpression models. In this review, I will draw attention to the loss-of-function hypothesis, which postulates that mutant TDP-43 causes neurodegeneration by a loss of function, and in addition, by exerting a dominant-negative effect on the wild-type TDP-43 allele. Furthermore, I will discuss how a loss of function can cause neurodegeneration in patients where TDP-43 is not mutated, review the literature in model systems to discuss how the current data support the loss-of-function mechanism and highlight some key questions for testing this hypothesis in the future.

  2. In Vitro Metabolomic Approach to Hippocampal Neurodegeneration Induced by Trimethyltin.

    Science.gov (United States)

    Gasparova, Zdenka; Pronayova, Nada; Stara, Veronika; Liptaj, Tibor

    2016-04-01

    Search for indicators of neurodegenerative disorders is a hot topic where much research remains to be done. Our aim was to determine proton nuclear magnetic resonance ((1)H-NMR) spectra of brain metabolites in the trimethyltin (TMT) model of neurodegeneration. Male Wistar rats were subjected to TMT or saline and were sacrificed on day 3 or 24 after administration. (1)H-NMR spectrum was measured on the 600 MHz Varian VNMRS spectrometer in nano-probe in the volume of 40 μl of hippocampal extracts. TMT administration resulted in reduction of the hippocampal weight on day 24. Of the sixteen identified metabolite spectra, decreased aspartate and increased glutamine contents were observed in the initial asymptomatic stage of neurodegeneration on day 3 in hippocampal extracts of TMT exposed rats compared to sham animals. Increased myo-inositol content was observed on day 24. The presented data provide further knowledge about this experimental model and putative indicators of neuronal damage. PMID:26482153

  3. Biology and Genetics of Prions Causing Neurodegeneration

    OpenAIRE

    Prusiner, SB

    2013-01-01

    Prions are proteins that acquire alternative conformations that become self-propagating. Transformation of proteins into prions is generally accompanied by an increase in β-sheet structure and a propensity to aggregate into oligomers. Some prions are beneficial and perform cellular functions, whereas others cause neurodegeneration. In mammals, more than a dozen proteins that become prions have been identified, and a similar number has been found in fungi. In both mammals and fungi, variations...

  4. Alcohol-Related Neurodegeneration and Recovery

    OpenAIRE

    Crews, Fulton T.

    2008-01-01

    Human studies have found alcoholics to have a smaller brain size than moderate drinkers; however, these studies are complicated by many uncontrollable factors, including timing and amount of alcohol use. Animal experiments, which can control many factors, have established that alcohol can cause damage to brain cells (i.e., neurons), which results in their loss of structure or function (i.e., neurodegeneration) in multiple brain regions, similar to the damage found in human alcoholics. In addi...

  5. Hypersensitivity of the hippocampal CA3 region to stress-induced neurodegeneration and amyloidogenesis in a rat model of surgical menopause

    OpenAIRE

    Zhang, Quan-guang; Wang, Rui-Min; Scott, Erin; Han, Dong; Dong, Yan; Tu, Jing-yi; Yang, Fang; Reddy Sareddy, Gangadhara; Ratna K. Vadlamudi; Brann, Darrell W.

    2013-01-01

    Females who enter menopause prematurely via bilateral ovariectomy (surgical menopause) have a significantly increased risk for cognitive decline and dementia. To help elucidate the mechanisms underlying this phenomenon, we used an animal model of surgical menopause, long-term (10-week) bilateral ovariectomy in female rats. Herein, we demonstrate that long-term oestrogen deprivation dramatically increases sensitivity of the normally resistant hippocampal CA3 region to ischaemic stress, an effe...

  6. Parkinson’s disease managing reversible neurodegeneration

    Directory of Open Access Journals (Sweden)

    Hinz M

    2016-04-01

    Full Text Available Marty Hinz,1 Alvin Stein,2 Ted Cole,3 Beth McDougall,4 Mark Westaway5 1Clinical Research, NeuroResearch Clinics, Inc., Cape Coral, FL, 2Stein Orthopedic Associates, Plantation, FL, 3Cole Center for Healing, Cincinnati, OH, 4CLEARCenter of Health, Mill Valley, CA, USA; 5Four Pillars Health, Brendale, QLD, Australia Abstract: Traditionally, the Parkinson’s disease (PD symptom course has been classified as an irreversible progressive neurodegenerative disease. This paper documents 29 PD and treatment-induced systemic depletion etiologies which cause and/or exacerbate the seven novel primary relative nutritional deficiencies associated with PD. These reversible relative nutritional deficiencies (RNDs may facilitate and accelerate irreversible progressive neurodegeneration, while other reversible RNDs may induce previously undocumented reversible pseudo-neurodegeneration that is hiding in plain sight since the symptoms are identical to the symptoms being experienced by the PD patient. Documented herein is a novel nutritional approach for reversible processes management which may slow or halt irreversible progressive neurodegenerative disease and correct reversible RNDs whose symptoms are identical to the patient’s PD symptoms. Keywords: Parkinson’s disease, L-dopa, carbidopa, B6, neurodegeneration

  7. Neurodegeneration with Brain Iron Accumulation: An Overview

    Directory of Open Access Journals (Sweden)

    Seyed Hassan TONEKABONI*

    2014-12-01

    Full Text Available How to Cite This Article: Tonekaboni SH, Mollamohammadi M. Neurodegeneration with Brain Iron Accumulation: An Overview. Iran J Child Neurol. 2014 Autumn;8(4: 1-8.AbstractObjectiveNeurodegeneration with brain iron accumulation (NBIA is a group of neurodegenerative disorder with deposition of iron in the brain (mainly Basal Ganglia leading to a progressive Parkinsonism, spasticity, dystonia, retinal degeneration, optic atrophy often accompanied by psychiatric manifestations and cognitive decline. 8 of the 10 genetically defined NBIA types are inherited as autosomal recessive and the remaining two by autosomal dominant and X-linked dominant manner. Brain MRI findings are almost specific and show abnormal brain iron deposition in basal ganglia some other related anatomicallocations. In some types of NBIA cerebellar atrophy is the major finding in MRI.ReferencesShevel M. Racial hygiene, activeeuthanasia, and Julius Hallervorden. Neurology 1992;42:2214-2219.HayflickSJ. Neurodegeneration with brain Iron accumulation: from genes to pathogenesis.Semin Pediatr Neurol 2006;13:182-185.Zhou B, Westawy SK, Levinson B, et al. A novel pantothenate kinase gene(PANK2 is defective in Hallervorden-Spatzsyndrome. Nat Genet 2001;28:345- 349.www.ncbi.nlm.nihgov/NBK111Y/university of Washington, seattle. Allison Gregory and Susan Hayflick.Paisan-Ruiz C, Li A, Schneider SA, et al. Widesread Levy body and tau accumulation in childhood and adult onset dystonia-parkinsonism cases with PLA2G6 mutations. Neurobiol Aging 2012;33:814-823.Dick KJ, Eckhardt M, Paison-Ruiz C, et al. Mutation of FA2H underlies a complicated form of hereditary spastic paraplegia(SPG 35. Hum Mutat 31: E1251-E1260.Edvardson S, Hama H, Shaag A, et al. Mutation in the fatty acid 2-Hydroxylase gene are associated with leukodystrophy with spastic paraparesis and dystonia. Am I Hum Genet 2008;83:647-648.Schneider SA, Aggarwal A, Bhatt m, et al. Severe tongue protrusion dystonia: clinical syndromes

  8. Advanced Glycation End-Products and Their Receptors: Related Pathologies, Recent Therapeutic Strategies, and a Potential Model for Future Neurodegeneration Studies.

    Science.gov (United States)

    Pinkas, Adi; Aschner, Michael

    2016-05-16

    Advanced glycation end products (AGEs) are the result of a nonenzymatic reaction between sugars and proteins, lipids, or nucleic acids. AGEs are both consumed and endogenously formed; their accumulation is accelerated under hyperglycemic and oxidative stress conditions, and they are associated with the onset and complication of many diseases, such as cardiovascular diseases, diabetes, and Alzheimer's disease. AGEs exert their deleterious effects by either accumulating in the circulation and tissues or by receptor-mediated signal transduction. Several receptors bind AGEs: some are specific and contribute to clearance of AGEs, whereas others, like the RAGE receptor, are nonspecific, associated with inflammation and oxidative stress, and considered to be mediators of the aforementioned AGE-related diseases. Although several anti-AGE compounds have been studied, understanding the underlying mechanisms of RAGE and targeting it as a therapeutic strategy is becoming increasingly desirable. For achieving these goals efficiently and expeditiously, the C. elegans model has been suggested. This model is already used for studying several human diseases and, by expressing RAGE, could also be used to study RAGE-related pathways and pathologies to facilitate the development of novel therapeutic strategies. PMID:27054356

  9. Mortality model based on delays in progression of chronic diseases: alternative to cause elimination model.

    OpenAIRE

    Manton, K G; Patrick, C H; Stallard, E

    1980-01-01

    For the analysis of the impact of major chronic diseases on a population, a life table model is proposed in which the age at death due to specific cause (chronic disease) is postponed. Even though many of the major causes of death related to intrinsic aging processes are impossible to eliminate, these causes might be significantly delayed or retarded. To illustrate the use of this model, the effects of a delay of 5, 10, and 15 years in deaths due to three chronic degenerative diseases (cancer...

  10. Progressive Neurodegeneration in Aspartylglycosaminuria Mice

    OpenAIRE

    Gonzalez-Gomez, Ignacio; Mononen, Ilkka; Heisterkamp, Nora; Groffen, John; Kaartinen, Vesa

    1998-01-01

    Aspartylglycosaminuria (AGU) is one of the most common lysosomal storage disorders in humans. A mouse model for AGU has been recently generated through targeted disruption of the glycosylasparaginase gene, and at a young age the glycosyl asparaginase-deficient mice demonstrated many pathological changes found in human AGU patients (Kaartinen V, Mononen I, Voncken J-W, Gonzalez-Gomez I, Heisterkamp N, Groffen J: A mouse model for aspartylglycosaminuria. Nat Med 1996, 2:1375–1378). Our current ...

  11. Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease.

    Science.gov (United States)

    Nelson, Amy R; Sweeney, Melanie D; Sagare, Abhay P; Zlokovic, Berislav V

    2016-05-01

    Vascular insults can initiate a cascade of molecular events leading to neurodegeneration, cognitive impairment, and dementia. Here, we review the cellular and molecular mechanisms in cerebral blood vessels and the pathophysiological events leading to cerebral blood flow dysregulation and disruption of the neurovascular unit and the blood-brain barrier, which all may contribute to the onset and progression of dementia and Alzheimer's disease (AD). Particularly, we examine the link between neurovascular dysfunction and neurodegeneration including the effects of AD genetic risk factors on cerebrovascular functions and clearance of Alzheimer's amyloid-β peptide toxin, and the impact of vascular risk factors, environment, and lifestyle on cerebral blood vessels, which in turn may affect synaptic, neuronal, and cognitive functions. Finally, we examine potential experimental treatments for dementia and AD based on the neurovascular model, and discuss some critical questions to be addressed by future studies. This article is part of a Special Issue entitled: Vascular Contributions to Cognitive Impairment and Dementia edited by M. Paul Murphy, Roderick A. Corriveau and Donna M. Wilcock. PMID:26705676

  12. Bioimpedance modeling to monitor astrocytic response to chronically implanted electrodes

    Science.gov (United States)

    McConnell, G. C.; Butera, R. J.; Bellamkonda, R. V.

    2009-10-01

    The widespread adoption of neural prosthetic devices is currently hindered by our inability to reliably record neural signals from chronically implanted electrodes. The extent to which the local tissue response to implanted electrodes influences recording failure is not well understood. To investigate this phenomenon, impedance spectroscopy has shown promise for use as a non-invasive tool to estimate the local tissue response to microelectrodes. Here, we model impedance spectra from chronically implanted rats using the well-established Cole model, and perform a correlation analysis of modeled parameters with histological markers of astroglial scar, including glial fibrillary acid protein (GFAP) and 4',6-diamidino-2- phenylindole (DAPI). Correlations between modeled parameters and GFAP were significant for three parameters studied: Py value, Ro and |Z|1 kHz, and in all cases were confined to the first 100 µm from the interface. Py value was the only parameter also correlated with DAPI in the first 100 µm. Our experimental results, along with computer simulations, suggest that astrocytes are a predominant cellular player affecting electrical impedance spectra. The results also suggest that the largest contribution from reactive astrocytes on impedance spectra occurs in the first 100 µm from the interface, where electrodes are most likely to record electrical signals. These results form the basis for future approaches where impedance spectroscopy can be used to evaluate neural implants, evaluate strategies to minimize scar and potentially develop closed-loop prosthetic devices.

  13. Do telemonitoring projects of heart failure fit the Chronic Care Model?

    OpenAIRE

    Willemse, Evi; Adriaenssens, Jef; Dilles, Tinne; Remmen, Roy

    2014-01-01

    This study describes the characteristics of extramural and transmural telemonitoring projects on chronic heart failure in Belgium. It describes to what extent these telemonitoring projects coincide with the Chronic Care Model of Wagner.Background: The Chronic Care Model describes essential components for high-quality health care. Telemonitoring can be used to optimise home care for chronic heart failure. It provides a potential prospective to change the current care organisation.Methods: This...

  14. Impact of exercise on mitochondrial transcription factor expression and damage in the striatum of a chronic mouse model of Parkinson’s disease

    OpenAIRE

    Patki, Gaurav; Lau, Yuen-Sum

    2011-01-01

    The etiology of neurodegenerative disorders like Parkinson’s disease remains unknown, although many genetic and environmental factors are suggested as likely causes. Neuronal oxidative stress and mitochondrial dysfunction have been implicated as possible triggers for the onset and progression of Parkinson’s neurodegeneration. We have recently shown that long-term treadmill exercise prevented neurological, mitochondrial and locomotor deficits in a chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropy...

  15. Early neurodegeneration progresses independently of microglial activation by heparan sulfate in the brain of mucopolysaccharidosis IIIB mice.

    Directory of Open Access Journals (Sweden)

    Jérôme Ausseil

    Full Text Available BACKGROUND: In mucopolysaccharidosis type IIIB, a lysosomal storage disease causing early onset mental retardation in children, the production of abnormal oligosaccharidic fragments of heparan sulfate is associated with severe neuropathology and chronic brain inflammation. We addressed causative links between the biochemical, pathological and inflammatory disorders in a mouse model of this disease. METHODOLOGY/PRINCIPAL FINDINGS: In cell culture, heparan sulfate oligosaccharides activated microglial cells by signaling through the Toll-like receptor 4 and the adaptor protein MyD88. CD11b positive microglial cells and three-fold increased expression of mRNAs coding for the chemokine MIP1alpha were observed at 10 days in the brain cortex of MPSIIIB mice, but not in MPSIIIB mice deleted for the expression of Toll-like receptor 4 or the adaptor protein MyD88, indicating early priming of microglial cells by heparan sulfate oligosaccharides in the MPSIIIB mouse brain. Whereas the onset of brain inflammation was delayed for several months in doubly mutant versus MPSIIIB mice, the onset of disease markers expression was unchanged, indicating similar progression of the neurodegenerative process in the absence of microglial cell priming by heparan sulfate oligosaccharides. In contrast to younger mice, inflammation in aged MPSIIIB mice was not affected by TLR4/MyD88 deficiency. CONCLUSIONS/SIGNIFICANCE: These results indicate priming of microglia by HS oligosaccharides through the TLR4/MyD88 pathway. Although intrinsic to the disease, this phenomenon is not a major determinant of the neurodegenerative process. Inflammation may still contribute to neurodegeneration in late stages of the disease, albeit independent of TLR4/MyD88. The results support the view that neurodegeneration is primarily cell autonomous in this pediatric disease.

  16. Toll-like receptors in neurodegeneration

    DEFF Research Database (Denmark)

    Owens, Trevor

    2009-01-01

    Innate pattern recognition receptors are implicated in first-line defense against pathogens but also participate in maintenance of tissue homeostasis and response to injury. This chapter reviews the role of Toll-like receptors (TLRs) in neuronal and glial responses that are associated with...... neurodegeneration. Accompanying roles for infection and inflammation, involvement in clinical neurodegenerative disorders, and heterogeneity of glial response are discussed. A "strength of signal" hypothesis is advanced in an attempt to reconcile evolutionarily selected and therefore likely beneficial effects of...... TLR signaling in the nervous system with capability for neurotoxocity and gliotoxicity....

  17. On the global dynamics of a chronic myelogenous leukemia model

    Science.gov (United States)

    Krishchenko, Alexander P.; Starkov, Konstantin E.

    2016-04-01

    In this paper we analyze some features of global dynamics of a three-dimensional chronic myelogenous leukemia (CML) model with the help of the stability analysis and the localization method of compact invariant sets. The behavior of CML model is defined by concentrations of three cellpopulations circulating in the blood: naive T cells, effector T cells specific to CML and CML cancer cells. We prove that the dynamics of the CML system around the tumor-free equilibrium point is unstable. Further, we compute ultimate upper bounds for all three cell populations and provide the existence conditions of the positively invariant polytope. One ultimate lower bound is obtained as well. Moreover, we describe the iterative localization procedure for refining localization bounds; this procedure is based on cyclic using of localizing functions. Applying this procedure we obtain conditions under which the internal tumor equilibrium point is globally asymptotically stable. Our theoretical analyses are supplied by results of the numerical simulation.

  18. Activation of mTOR ameliorates fragile X premutation rCGG repeat-mediated neurodegeneration.

    Directory of Open Access Journals (Sweden)

    Yunting Lin

    Full Text Available Fragile X associated tremor/ataxia syndrome (FXTAS is a late onset neurodegenerative disorder caused by aberrant expansion of CGG repeats in 5' UTR of FMR1 gene. The elevated mRNA confers a toxic gain-of-function thought to be the critical event of pathogenesis. Expressing rCGG90 repeats of the human FMR1 5'UTR in Drosophila is sufficient to induce neurodegeneration. Rapamycin has been demonstrated to attenuate neurotoxicity by inducing autophagy in various animal models of neurodegenerative diseases. Surprisingly, we observed rapamycin exacerbated rCGG90-induced neurodegenerative phenotypes through an autophagy-independent mechanism. CGG90 expression levels of FXTAS flies exposed to rapamycin presented no significant differences. We further demonstrated that activation of the mammalian target of rapamycin (mTOR signaling could suppress neurodegeneration of FXTAS. These findings indicate that rapamycin will exacerbate neurodegeneration, and that enhancing autophagy is insufficient to alleviate neurotoxicity in FXTAS. Moreover, these results suggest mTOR and its downstream molecules as new therapeutic targets for FXTAS by showing significant protection against neurodegeneration.

  19. Automated medical diagnosis with fuzzy stochastic models: monitoring chronic diseases.

    Science.gov (United States)

    Jeanpierre, Laurent; Charpillet, François

    2004-01-01

    As the world population ages, the patients per physician ratio keeps on increasing. This is even more important in the domain of chronic pathologies where people are usually monitored for years and need regular consultations. To address this problem, we propose an automated system to monitor a patient population, detecting anomalies in instantaneous data and in their temporal evolution, so that it could alert physicians. By handling the population of healthy patients autonomously and by drawing the physicians' attention to the patients-at-risk, the system allows physicians to spend comparatively more time with patients who need their services. In such a system, the interaction between the patients, the diagnosis module, and the physicians is very important. We have based this system on a combination of stochastic models, fuzzy filters, and strong medical semantics. We particularly focused on a particular tele-medicine application: the Diatelic Project. Its objective is to monitor chronic kidney-insufficient patients and to detect hydration troubles. During two years, physicians from the ALTIR have conducted a prospective randomized study of the system. This experiment clearly shows that the proposed system is really beneficial to the patients' health. PMID:15520535

  20. Modeling of radiation doses from chronic aqueous releases

    International Nuclear Information System (INIS)

    A general model and corresponding computer code were developed to calculate personnel dose estimates from chronic releases via aqueous pathways. Potential internal dose pathways are consumption of water, fish, crustacean, and mollusk. Dose prediction from consumption of fish, crustacean, or mollusk is based on the calculated radionuclide content of the water and applicable bioaccumulation factor. 70-year dose commitments are calculated for whole body, bone, lower large intestine of the gastrointestinal tract, and six internal organs. In addition, the code identifies the largest dose contributor and the dose percentages for each organ-radionuclide combination in the source term. The 1974 radionuclide release data from the Savannah River Plant were used to evaluate the dose models. The dose predicted from the model was compared to the dose calculated from radiometric analysis of water and fish samples. The whole body dose from water consumption was 0.45 mrem calculated from monitoring data and 0.61 mrem predicted from the model. Tritium contributed 99 percent of this dose. The whole body dose from fish consumption was 0.20 mrem calculated from monitoring data and 0.14 mrem from the model. Cesium-134,137 was the principal contributor to the 70-year whole body dose from fish consumption

  1. Protection of MPTP-induced neuroinflammation and neurodegeneration by Pycnogenol.

    Science.gov (United States)

    Khan, Mohammad Moshahid; Kempuraj, Duraisamy; Thangavel, Ramasamy; Zaheer, Asgar

    2013-03-01

    Oxidative stress and inflammation play a crucial role in Parkinson's disease (PD) pathogenesis and may represent a target for treatment. Current PD drugs provide only symptomatic relief and have limitations in terms of adverse effects and inability to prevent neurodegeneration. Flavonoids have been suggested to exert human health benefits by its anti-oxidant and anti-inflammatory properties. Therefore, in the present study, using 1-methyl-4-phenyl-1,2,3,6-tetrahydro pyridine (MPTP)-induced mouse model of Parkinsonism, we investigated the neuroprotective potential of bioflavonoid compound Pycnogenol® (PYC), an extract of Pinus maritime bark. MPTP injected mice developed significantly severe oxidative stress and impaired motor coordination at day 1 and day 7 postinjection. This was associated with significantly increased inflammatory responses of astrocyte and microglia as assessed by ionized calcium binding adaptor molecule 1 (Iba 1) and glial fibrillary acidic protein (GFAP) immunohistochemistry, and nuclear transcription factor-κB (NF-κB), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in the striata by Western blot. Additionally, there was significant upregulation of tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β) expression in the striata of MPTP injected mice compared to saline controls. The MPTP-induced neuroinflammation, neurodegeneration and behavioral impairments were markedly repudiated by treatment with PYC. These results suggest that PYC protects dopaminergic neurons from MPTP-induced toxicity in the mouse model of PD. Thus, the present finding of PYC-induced adaptation to oxidative stress and inflammation could suggest a novel avenue for clinical intervention in neurodegenerative diseases including PD. PMID:23391521

  2. Adapting chronic care models for diabetes care delivery inlow-and-middle-income countries: A review

    Institute of Scientific and Technical Information of China (English)

    2015-01-01

    A contextual review of models for chronic care was doneto develop a context-adapted chronic care model-basedservice delivery model for chronic conditions includingdiabetes. The Philippines was used as the setting ofa low-to-middle-income country. A context-basednarrative review of existing models for chronic carewas conducted. A situational analysis was done at thegrassroots level, involving the leaders and members ofthe community, the patients, the local health system andthe healthcare providers. A second analysis making useof certain organizational theories was done to explore onimproving feasibility and acceptability of organizing carefor chronic conditions. The analyses indicated that carefor chronic conditions may be introduced, consideringthe needs of people with diabetes in particular andthe community in general as recipients of care, andthe issues and factors that may affect the healthcareworkers and the health system as providers of thiscare. The context-adapted chronic care model-basedservice delivery model was constructed accordingly.Key features are incorporation of chronic care in thehealth system's services; assimilation of chronic caredelivery with the other responsibilities of the healthcareworkers but with redistribution of certain tasks; andensuring that the recipients of care experience thewhole spectrum of basic chronic care that includes educationand promotion in the general population, riskidentification, screening, counseling including self-caredevelopment, and clinical management of the chroniccondition and any co-morbidities, regardless of level ofcontrol of the condition. This way, low-to-middle incomecountries can introduce and improve care for chronicconditions without entailing much additional demand ontheir limited resources.

  3. Emerging targets in neurodegeneration: new opportunities for Alzheimer's disease treatment?

    Science.gov (United States)

    Rampa, Angela; Gobbi, Silvia; Belluti, Federica; Bisi, Alessandra

    2013-01-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder of the brain associated with memory impairment, progressive cognitive decline and changes in personality and behavior, with rising incidence among elderly people. Reflecting the world population ageing, the scenario is expected to worsen in the next decades if novel drugs or mechanisms that help to counteract neurodegeneration will not be identified. The complex neuropathology of AD is characterized by cholinergic loss, extracellular deposition of amyloid-β plaques, formation of intracellular neurofibrillary tangles, chronic brain inflammation and oxidative damage. To date, there are no effective treatments that can slow or halt the disease, and currently approved drugs only seem to act as palliative by temporary ameliorating cognitive impairment. On the other hand, the role played by other biological systems in the pathogenetic process is now clearly growing and, as knowledge on how AD develops and triggers brain damage proceeds, drug discovery attempts to identify new potential therapeutic targets. This review will focus on these emerging strategies, some of which could open new therapeutic perspectives in Alzheimer's disease, adding new elements for the medicinal chemist to handle and combine for the design of novel multi-target-directed ligands able to simultaneously modulate 'old classic' and newly identified targets. PMID:23931436

  4. Analysis of axonal transport and molecular chaperones during neurodegeneration in drosophila

    OpenAIRE

    Sinadinos, Christopher

    2010-01-01

    Neuronal dysfunction and cell death occurs during neurodegeneration. Animal models that express human disease genes and show neurodegenerative-like pathologies are widely used to study particular molecular systems in early neurodegenerative changes. Axonal transport (AT) is perturbed in several prevalent neurodegenerative diseases. The development of a Huntington’s Disease (HD) model in Drosophila melanogaster larvae is described, in which disease gene expression is directed to motor neurons ...

  5. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

    OpenAIRE

    Li Li; Meng Xu; Bo Shen; Man Li; Qian Gao; Shou-gang Wei

    2016-01-01

    D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected ...

  6. Oxidative Stress Mechanisms Underlying Parkinson’s Disease-Associated Neurodegeneration in C. elegans

    OpenAIRE

    Sudipta Chakraborty; Julia Bornhorst; Nguyen, Thuy T; Michael Aschner

    2013-01-01

    Oxidative stress is thought to play a significant role in the development and progression of neurodegenerative diseases. Although it is currently considered a hallmark of such processes, the interweaving of a multitude of signaling cascades hinders complete understanding of the direct role of oxidative stress in neurodegeneration. In addition to its extensive use as an aging model, some researchers have turned to the invertebrate model Caenorhabditis elegans (C. elegans) in order to further i...

  7. Inflammatory and Remodeling Events in Asthma with Chronic Exposure to House Dust Mites: A Murine Model

    OpenAIRE

    Ahn, Joong Hyun; Kim, Chi Hong; Kim, Yong Hyun; Kim, Seung Joon; Lee, Sook-Young; Kim, Young Kyoon; Kim, Kwan Hyoung; Moon, Hwa Sik; Song, Jeong Sup; Park, Sung Hak; Kwon, Soon Seog

    2007-01-01

    Although animal models with ovalbumin have been used to study chronic asthma, there are difficulties in inducing recurrence as well as in maintaining chronic inflammation in this system. Using a murine model of house dust mite (HDM)-induced bronchial asthma, we examined the airway remodeling process in response to the chronic exposure to HDM. During the seventh and twelfth weeks of study, HDM were inhaled through the nose for three consecutive days and airway responsiveness was measured. Twen...

  8. Tryptase - PAR2 axis in Experimental Autoimmune Prostatitis, a model for Chronic Pelvic Pain Syndrome

    OpenAIRE

    Roman, Kenny; Done, Joseph D.; Schaeffer, Anthony J.; Murphy, Stephen F.; Thumbikat, Praveen

    2014-01-01

    Chronic prostatitis/Chronic pelvic pain syndrome (CP/CPPS) affects up to 15% of the male population and is characterized by pelvic pain. Mast cells are implicated in the murine experimental autoimmune prostatitis (EAP) model as key to chronic pelvic pain development. The mast cell mediator tryptase-β and its cognate receptor protease-activated receptor 2 (PAR2) are involved in mediating pain in other visceral disease models. Prostatic secretions and urines from CP/CPPS patients were examined ...

  9. Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment

    DEFF Research Database (Denmark)

    Larsen, Marianne H; Mikkelsen, Jens D; Hay-Schmidt, Anders;

    2010-01-01

    Chronic unpredictable stress (CUS) is a widely used animal model of depression. The present study was undertaken to investigate behavioral, physiological and molecular effects of CUS and/or chronic antidepressant treatment (venlafaxine or imipramine) in the same set of animals. Anhedonia, a core ...... of the dorsal hippocampus correlated with chronic antidepressant treatment emphasizing a role for BDNF in the mechanisms underlying antidepressant activity....

  10. Neurodegeneration and Cancer: Where the Disorder Prevails.

    Science.gov (United States)

    Klus, Petr; Cirillo, Davide; Botta Orfila, Teresa; Gaetano Tartaglia, Gian

    2015-01-01

    It has been reported that genes up-regulated in cancer are often down-regulated in neurodegenerative disorders and vice versa. The fact that apparently unrelated diseases share functional pathways suggests a link between their etiopathogenesis and the properties of molecules involved. Are there specific features that explain the exclusive association of proteins with either cancer or neurodegeneration? We performed a large-scale analysis of physico-chemical properties to understand what characteristics differentiate classes of diseases. We found that structural disorder significantly distinguishes proteins up-regulated in neurodegenerative diseases from those linked to cancer. We also observed high correlation between structural disorder and age of onset in Frontotemporal Dementia, Parkinson's and Alzheimer's diseases, which strongly supports the role of protein unfolding in neurodegenerative processes. PMID:26493371

  11. The relationship between hyperhomocysteinemia and neurodegeneration.

    Science.gov (United States)

    Bonetti, Francesco; Brombo, Gloria; Zuliani, Giovanni

    2016-04-01

    Homocysteine (Hcy) is a key junction in methionine metabolism. In inherited forms of hyperhomocysteinemia patients develop early vascular damage and cognitive decline. Hyperhomocysteinemia is a common consequence of dietary, behavioral and pathological conditions and is epidemiologically related to different diseases, among them neurodegenerative ones are receiving progressively more attention in the last years. Several detrimental mechanisms that see in Hcy a possible promoter seem to be implicated in neurodegeneration (protein structural and functional modifications, oxidative stress, cellular metabolic derangements, epigenetic modifications, pathological aggregates deposition, endothelial damage and atherothrombosis). Interventional studies exploring B group vitamins administration in terms of prevention of Hcy-related cognitive decline and cerebrovascular involvement have shown scant results. In this review, current and possible alternative/complementary approaches are discussed. PMID:27033101

  12. Chronic Myeloid Leukemia (CML) Mouse Model in Translational Research.

    Science.gov (United States)

    Peng, Cong; Li, Shaoguang

    2016-01-01

    Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by increased proliferation of granulocytic cells without the loss of their capability to differentiate. CML is a clonal disease, originated at the level of Hematopoietic Stem Cells with the Philadelphia chromosome resulting from a reciprocal translocation between the chromosomes 9 and 22t(9;22)-(q34;q11). This translocation produces a fusion gene known as BCR-ABL which acquires uncontrolled tyrosine kinase activity, constantly turning on its downstream signaling molecules/pathways, and promoting proliferation of leukemia cell through anti-apoptosis and acquisition of additional mutations. To evaluate the role of each critical downstream signaling molecule of BCR-ABL and test therapeutic drugs in vivo, it is important to use physiological mouse disease models. Here, we describe a mouse model of CML induced by BCR-ABL retrovirus (MSCV-BCR-ABL-GFP; MIG-BCR-ABL) and how to use this model in translational research.Moreover, to expand the application of this retrovirus induced CML model in a lot of conditional knockout mouse strain, we modified this vector to a triple gene coexpression vector in which we can co-express BCR-ABL, GFP, and a third gene which will be tested in different systems. To apply this triple gene system in conditional gene knockout strains, we can validate the CML development in the knockout mice and trace the leukemia cell following the GFP marker. In this protocol, we also describe how we utilize this triple gene system to prove the function of Pten as a tumor suppressor in leukemogenesis. Overall, this triple gene system expands our research spectrum in current conditional gene knockout strains and benefits our CML translational research. PMID:27150093

  13. Enhanced itch elicited by capsaicin in a chronic itch model.

    Science.gov (United States)

    Yu, Guang; Yang, Niuniu; Li, Fengxian; Chen, Meijuan; Guo, Changxiong J; Wang, Changming; Hu, Danyou; Yang, Yan; Zhu, Chan; Wang, Zhongli; Shi, Hao; Gegen, Tana; Tang, Ming; He, Qian; Liu, Qin; Tang, Zongxiang

    2016-01-01

    Chronic itch (pruritus) is an important clinical problem. However, the underlying molecular basis has yet to be understood. The Transient Receptor Potential Vanilloid 1 channel is a heat-sensitive cation channel expressed in primary sensory neurons and involved in both thermosensation and pain, but its role in chronic itch remains elusive. Here, we for the first time revealed an increased innervation density of Transient Receptor Potential Vanilloid 1-expressing sensory fibers in the skin afflicted with chronic itch. Further analysis indicated that this phenomenon is due to an expansion of Transient Receptor Potential Vanilloid 1-expressing sensory neurons under chronic itch conditions. As a functional correlates of this neuronal expansion, we observed an enhanced neuronal responsiveness to capsaicin under the dry skin conditions. Importantly, the neuronal hypersensitivity to capsaicin results in itch, rather than pain sensation, suggesting that the up-regulated Transient Receptor Potential Vanilloid 1 underlies the pain-to-itch switch under chronic itchy conditions. The study shows that there are different mechanisms of chronic pain and itching, and Transient Receptor Potential Vanilloid 1 plays an important role in chronic itch. PMID:27118771

  14. Managing painful chronic wounds: the Wound Pain Management Model

    DEFF Research Database (Denmark)

    Price, Patricia; Fogh, Karsten; Glynn, Chris;

    2007-01-01

    the wound should be handled as one of the main priorities in chronic wound management together with addressing the cause. Management of pain in chronic wounds depends on proper assessment, reporting and documenting patient experiences of pain. Assessment should be based on six critical dimensions of...... document persistent wound pain and not to develop a treatment and monitoring strategy to improve the lives of persons with chronic wounds. Unless wound pain is optimally managed, patient suffering and costs to health care systems will increase. Udgivelsesdato: 2007-Apr...

  15. Kainic Acid-Induced Excitotoxicity Experimental Model: Protective Merits of Natural Products and Plant Extracts

    Directory of Open Access Journals (Sweden)

    Nur Shafika Mohd Sairazi

    2015-01-01

    Full Text Available Excitotoxicity is well recognized as a major pathological process of neuronal death in neurodegenerative diseases involving the central nervous system (CNS. In the animal models of neurodegeneration, excitotoxicity is commonly induced experimentally by chemical convulsants, particularly kainic acid (KA. KA-induced excitotoxicity in rodent models has been shown to result in seizures, behavioral changes, oxidative stress, glial activation, inflammatory mediator production, endoplasmic reticulum stress, mitochondrial dysfunction, and selective neurodegeneration in the brain upon KA administration. Recently, there is an emerging trend to search for natural sources to combat against excitotoxicity-associated neurodegenerative diseases. Natural products and plant extracts had attracted a considerable amount of attention because of their reported beneficial effects on the CNS, particularly their neuroprotective effect against excitotoxicity. They provide significant reduction and/or protection against the development and progression of acute and chronic neurodegeneration. This indicates that natural products and plants extracts may be useful in protecting against excitotoxicity-associated neurodegeneration. Thus, targeting of multiple pathways simultaneously may be the strategy to maximize the neuroprotection effect. This review summarizes the mechanisms involved in KA-induced excitotoxicity and attempts to collate the various researches related to the protective effect of natural products and plant extracts in the KA model of neurodegeneration.

  16. Pediatric Fear-Avoidance Model of Chronic Pain: Foundation, Application and Future Directions

    Directory of Open Access Journals (Sweden)

    Gordon JG Asmundson

    2012-01-01

    Full Text Available The fear-avoidance model of chronic musculoskeletal pain has become an increasingly popular conceptualization of the processes and mechanisms through which acute pain can become chronic. Despite rapidly growing interest and research regarding the influence of fear-avoidance constructs on pain-related disability in children and adolescents, there have been no amendments to the model to account for unique aspects of pediatric chronic pain. A comprehensive understanding of the role of fear-avoidance in pediatric chronic pain necessitates understanding of both child/adolescent and parent factors implicated in its development and maintenance. The primary purpose of the present article is to propose an empirically-based pediatric fear-avoidance model of chronic pain that accounts for both child/adolescent and parent factors as well as their potential interactive effects. To accomplish this goal, the present article will define important fear-avoidance constructs, provide a summary of the general fear-avoidance model and review the growing empirical literature regarding the role of fear-avoidance constructs in pediatric chronic pain. Assessment and treatment options for children with chronic pain will also be described in the context of the proposed pediatric fear-avoidance model of chronic pain. Finally, avenues for future investigation will be proposed.

  17. Traumatization and chronic pain: a further model of interaction

    OpenAIRE

    Egloff, Niklaus

    2013-01-01

    Niklaus Egloff,1 Anna Hirschi,2 Roland von Känel1 1Department of General Internal Medicine, Division of Psychosomatic Medicine, Inselspital, University Hospital, Bern, Switzerland; 2Outpatient Clinic for Victims of Torture and War, Swiss Red Cross, Bern-Wabern, Switzerland Abstract: Up to 80% of patients with severe posttraumatic stress disorder are suffering from “unexplained” chronic pain. Theories about the links between traumatization and chronic pain have be...

  18. Traumatization and chronic pain: a further model of interaction.

    OpenAIRE

    Egloff N; Hirschi A; von Känel R

    2013-01-01

    Niklaus Egloff,1 Anna Hirschi,2 Roland von Känel1 1Department of General Internal Medicine, Division of Psychosomatic Medicine, Inselspital, University Hospital, Bern, Switzerland; 2Outpatient Clinic for Victims of Torture and War, Swiss Red Cross, Bern-Wabern, Switzerland Abstract: Up to 80% of patients with severe posttraumatic stress disorder are suffering from “unexplained” chronic pain. Theories about the links between traumatization and chronic pain have become the subj...

  19. Oxidative and nitrative stress in neurodegeneration.

    Science.gov (United States)

    Cobb, Catherine A; Cole, Marsha P

    2015-12-01

    Aerobes require oxygen for metabolism and normal free radical formation. As a result, maintaining the redox homeostasis is essential for brain cell survival due to their high metabolic energy requirement to sustain electrochemical gradients, neurotransmitter release, and membrane lipid stability. Further, brain antioxidant levels are limited compared to other organs and less able to compensate for reactive oxygen and nitrogen species (ROS/RNS) generation which contribute oxidative/nitrative stress (OS/NS). Antioxidant treatments such as vitamin E, minocycline, and resveratrol mediate neuroprotection by prolonging the incidence of or reversing OS and NS conditions. Redox imbalance occurs when the antioxidant capacity is overwhelmed, consequently leading to activation of alternate pathways that remain quiescent under normal conditions. If OS/NS fails to lead to adaptation, tissue damage and injury ensue, resulting in cell death and/or disease. The progression of OS/NS-mediated neurodegeneration along with contributions from microglial activation, dopamine metabolism, and diabetes comprise a detailed interconnected pathway. This review proposes a significant role for OS/NS and more specifically, lipid peroxidation (LPO) and other lipid modifications, by triggering microglial activation to elicit a neuroinflammatory state potentiated by diabetes or abnormal dopamine metabolism. Subsequently, sustained stress in the neuroinflammatory state overwhelms cellular defenses and prompts neurotoxicity resulting in the onset or amplification of brain damage. PMID:26024962

  20. Methylenedioxymethamphetamine (MDMA, 'Ecstasy': Neurodegeneration versus Neuromodulation

    Directory of Open Access Journals (Sweden)

    Elena Puerta

    2011-07-01

    Full Text Available The amphetamine analogue 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’ is widely abused as a recreational drug due to its unique psychological effects. Of interest, MDMA causes long-lasting deficits in neurochemical and histological markers of the serotonergic neurons in the brain of different animal species. Such deficits include the decline in the activity of tryptophan hydroxylase in parallel with the loss of 5-HT and its main metabolite 5-hydoxyindoleacetic acid (5-HIAA along with a lower binding of specific ligands to the 5-HT transporters (SERT. Of concern, reduced 5-HIAA levels in the CSF and SERT density have also been reported in human ecstasy users, what has been interpreted to reflect the loss of serotonergic fibers and terminals. The neurotoxic potential of MDMA has been questioned in recent years based on studies that failed to show the loss of the SERT protein by western blot or the lack of reactive astrogliosis after MDMA exposure. In addition, MDMA produces a long-lasting down-regulation of SERT gene expression; which, on the whole, has been used to invoke neuromodulatory mechanisms as an explanation to MDMA-induced 5-HT deficits. While decreased protein levels do not necessarily reflect neurodegeneration, the opposite is also true, that is, neuroregulatory mechanisms do not preclude the existence of 5-HT terminal degeneration.

  1. Post-translational modifications in neurodegeneration

    Directory of Open Access Journals (Sweden)

    Federico Benetti

    2015-12-01

    Full Text Available Post-translational modifications increase proteome functionality for managing all aspects of normal cell biology. They are based on the covalent attachment of functional groups, leading to phosphorylation, acetylation, glycosylation, acylation, ubiquitination, SUMOylation and oxidation of protein targets. Post-translational modifications occur at any step of protein life cycle, modulating in time and space protein folding, subcellular localization and activity. Aberrant post-translational modifications of one or more culprit proteins may lead to neurodegeneration, as shown in paradigmatic neurological disorders such as Alzheimer’s, Parkinson’s and prion diseases. In this review, we report the most important post-translational modifications found in neurodegenerative disorders, illustrating the pathophysiological mechanisms in which they are involved. This work highlights the lack of a global framework of post-translational modifications in terms of complexity and regulation. Therefore, in the next future many efforts are required to describe the interplay existing between post-translational modifications and their combinatorial patterns on protein targets.

  2. Challenges of Change: A Qualitative Study of Chronic Care Model Implementation

    OpenAIRE

    Hroscikoski, Mary C.; Solberg, Leif I.; Sperl-Hillen, JoAnn M.; Harper, Peter G.; McGrail, Michael P.; Crabtree, Benjamin F.

    2006-01-01

    PURPOSE The Chronic Care Model (CCM) provides a conceptual framework for transforming health care for patients with chronic conditions; however, little is known about how to best design and implement its specifics. One large health care organization that tried to implement the CCM in primary care provided an opportunity to study these issues.

  3. Recruitment bias in chronic pain research: whiplash as a model.

    Science.gov (United States)

    Nijs, Jo; Inghelbrecht, Els; Daenen, Liesbeth; Hachimi-Idrissi, Said; Hens, Luc; Willems, Bert; Roussel, Nathalie; Cras, Patrick; Wouters, Kristien; Bernheim, Jan

    2011-11-01

    In science findings which cannot be extrapolated to other settings are of little value. Recruitment methods vary widely across chronic whiplash studies, but it remains unclear whether this generates recruitment bias. The present study aimed to examine whether the recruitment method accounts for differences in health status, social support, and personality traits in patients with chronic whiplash-associated disorders (WAD). Two different recruitment methods were compared: recruiting patients through a local whiplash patient support group (group 1) and local hospital emergency department (group 2). The participants (n=118) filled in a set of questionnaires: the Neck Disability Index, Medical Outcome Study Short-Form General Health Survey, Anamnestic Comparative Self-Assessment measure of overall well-being, Symptom Checklist-90, Dutch Personality Questionnaire, and the Social Support List. The recruitment method (either through the local emergency department or patient support group) accounted for the differences in insufficiency, somatization, disability, quality of life, self-satisfaction, and dominance (all p values recruitment methods generated chronic WAD patients comparable for psychoneurotism, social support, self-sufficiency, (social) inadequacy, rigidity, and resentment (p>.01). The recruitment of chronic WAD patients solely through patient support groups generates bias with respect to the various aspects of health status and personality, but not social support. In order to enhance the external validity of study findings, chronic WAD studies should combine a variety of recruitment procedures. PMID:21853277

  4. Long non-coding RNA MALAT1 regulates retinal neurodegeneration through CREB signaling.

    Science.gov (United States)

    Yao, Jin; Wang, Xiao-Qun; Li, Yu-Jie; Shan, Kun; Yang, Hong; Wang, Yang-Ning-Zhi; Yao, Mu-Di; Liu, Chang; Li, Xiu-Miao; Shen, Yi; Liu, Jing-Yu; Cheng, Hong; Yuan, Jun; Zhang, Yang-Yang; Jiang, Qin; Yan, Biao

    2016-01-01

    The nervous and vascular systems, although functionally different, share many common regulators of function maintenance. Long non-coding RNAs (lncRNAs) are important players in many biological processes and human disorders. We previously identified a role of MALAT1 in microvascular dysfunction. However, its role in neurodegeneration is still unknown. Here, we used the eye as the model to investigate the role of MALAT1 in retinal neurodegeneration. We show that MALAT1 expression is significantly up-regulated in the retinas, Müller cells, and primary retinal ganglion cells (RGCs) upon stress. MALAT1 knockdown reduces reactive gliosis, Müller cell activation, and RGC survival in vivo and in vitro MALAT1-CREB binding maintains CREB phosphorylation by inhibiting PP2A-mediated dephosphorylation, which leads to continuous CREB signaling activation. Clinical and animal experimentation suggests that MALAT1 dysfunction is implicated in neurodegenerative processes and several human disorders. Collectively, this study reveals that MALAT1 might regulate the development of retinal neurodegeneration through CREB signaling. PMID:26964565

  5. Metal and Microelement Biomarkers of Neurodegeneration in Early Life Permethrin-Treated Rats

    Directory of Open Access Journals (Sweden)

    Cinzia Nasuti

    2016-01-01

    Full Text Available Hair is a non-invasive biological material useful in the biomonitoring of trace elements because it is a vehicle for substance excretion from the body, and it permits evaluating long-term metal exposure. Here, hair from an animal model of neurodegeneration, induced by early life permethrin treatment from the sixth to 21th day of life, has been analyzed with the aim to assess if metal and microelement content could be used as biomarkers. A hair trace element assay was performed by the ICP-MS technique in six- and 12-month-old rats. A significant increase of As, Mg, S and Zn was measured in the permethrin-treated group at 12 months compared to six months, while Si and Cu/Zn were decreased. K, Cu/Zn and S were increased in the treated group compared to age-matched controls at six and 12 months, respectively. Cr significantly decreased in the treated group at 12 months. PCA analysis showed both a best difference between treated and age-matched control groups at six months. The present findings support the evidence that the Cu/Zn ratio and K, measured at six months, are the best biomarkers for neurodegeneration. This study supports the use of hair analysis to identify biomarkers of neurodegeneration induced by early life permethrin pesticide exposure.

  6. Neurodegeneration and Neuroprotection in Diabetic Retinopathy

    Directory of Open Access Journals (Sweden)

    Abdullah S. Alhomida

    2013-01-01

    Full Text Available Diabetic retinopathy is widely considered to be a neurovascular disease. This is in contrast to its previous identity as solely a vascular disease. Early in the disease progression of diabetes, the major cells in the neuronal component of the retina consist of retinal ganglion cells and glial cells, both of which have been found to be compromised. A number of retinal function tests also indicated a functional deficit in diabetic retina, which further supports dysfunction of neuronal cells. As an endocrinological disorder, diabetes alters metabolism both systemically and locally in several body organs, including the retina. A growing body of evidences indicates increased levels of excitotoxic metabolites, including glutamate, branched chain amino acids and homocysteine in cases of diabetic retinopathy. Also present, early in the disease, are decreased levels of folic acid and vitamin-B12, which are potential metabolites capable of damaging neurons. These altered levels of metabolites are found to activate several metabolic pathways, leading to increases in oxidative stress and decreases in the level of neurotrophic factors. As a consequence, they may damage retinal neurons in diabetic patients. In this review, we have discussed those potential excitotoxic metabolites and their implications in neuronal damage. Possible therapeutic targets to protect neurons are also discussed. However, further research is needed to understand the exact molecular mechanism of neurodegeneration so that effective neuroprotection strategies can be developed. By protecting retinal neurons early in diabetic retinopathy cases, damage of retinal vessels can be protected, thereby helping to ameliorate the progression of diabetic retinopathy, a leading cause of blindness worldwide.

  7. Chronic Low Back Pain: Toward an Integrated Psychosocial Assessment Model.

    Science.gov (United States)

    Strong, Jenny; And Others

    1994-01-01

    Integrated six dimensions of chronic low back pain (pain intensity, functional disability, attitudes toward pain, pain coping strategies, depression, illness behavior) to provide multidimensional patient profile. Data from 100 patients revealed presence of three distinct patient groups: patients who were in control, patients who were depressed and…

  8. The role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases

    DEFF Research Database (Denmark)

    Brandt, Claus; Pedersen, Bente K

    2010-01-01

    Chronic inflammation is involved in the pathogenesis of insulin resistance, atherosclerosis, neurodegeneration, and tumour growth. Regular exercise offers protection against type 2 diabetes, cardiovascular diseases, colon cancer, breast cancer, and dementia. Evidence suggests that the protective ...

  9. A dietary regimen of caloric restriction or pharmacological activation of SIRT1 to delay the onset of neurodegeneration

    Science.gov (United States)

    Gräff, Johannes; Kahn, Martin; Samiei, Alireza; Gao, Jun; Ota, Kristie T.; Rei, Damien; Tsai, Li-Huei

    2013-01-01

    Caloric restriction (CR) is a dietary regimen known to promote lifespan by slowing down the occurrence of age-dependent diseases. The greatest risk factor for neurodegeneration in the brain is age, from which follows that CR might also attenuate the progressive loss of neurons that is often associated with impaired cognitive capacities. In this study, we used a transgenic mouse model that allows for a temporally and spatially controlled onset of neurodegeneration to test the potentially beneficial effects of CR. We found that in this model, CR significantly delayed the onset of neurodegeneration, synaptic loss and dysfunction, and thereby preserved cognitive capacities. Mechanistically, CR induced the expression of the known lifespan-regulating protein SIRT1, prompting us to test whether a pharmacological activation of SIRT1 might recapitulate CR. We found that oral administration of a SIRT1-activating compound essentially replicated the beneficial effects of CR. Thus, SIRT1-activating compounds might provide a pharmacological alternative to the regimen of CR against neurodegeneration and its associated ailments. PMID:23699506

  10. Clinical challenges of chronic wounds: searching for an optimal animal model to recapitulate their complexity

    Directory of Open Access Journals (Sweden)

    Robert Nunan

    2014-11-01

    Full Text Available The efficient healing of a skin wound is something that most of us take for granted but is essential for surviving day-to-day knocks and cuts, and is absolutely relied on clinically whenever a patient receives surgical intervention. However, the management of a chronic wound – defined as a barrier defect that has not healed in 3 months – has become a major therapeutic challenge throughout the Western world, and it is a problem that will only escalate with the increasing incidence of conditions that impede wound healing, such as diabetes, obesity and vascular disorders. Despite being clinically and molecularly heterogeneous, all chronic wounds are generally assigned to one of three major clinical categories: leg ulcers, diabetic foot ulcers or pressure ulcers. Although we have gleaned much knowledge about the fundamental cellular and molecular mechanisms that underpin healthy, acute wound healing from various animal models, we have learned much less about chronic wound repair pathology from these models. This might largely be because the animal models being used in this field of research have failed to recapitulate the clinical features of chronic wounds. In this Clinical Puzzle article, we discuss the clinical complexity of chronic wounds and describe the best currently available models for investigating chronic wound pathology. We also assess how such models could be optimised to become more useful tools for uncovering pathological mechanisms and potential therapeutic treatments.

  11. Le «Chronic care model» en médecine de famille en Suisse

    OpenAIRE

    Steurer-Stey, C.; Frei, A; Rosemann, T

    2010-01-01

    The Chronic care model in Swiss primary care The care of patients with chronic disease is one of the most urgent medical challenges of actual society. The chronic care model (CCM) is an organizational, proactive approach for chronic disease in primary care. The system creates practical, supportive, evidence-based interactions between an informed, activated patient and a proactive practice team. CCM identifies six essential elements of high-quality health care : community ; heal...

  12. Holistic interaction model for peoble living with a chronic disease

    OpenAIRE

    Villalba Mora, Elena

    2008-01-01

    Ambient Intelligence (AmI) allows the intelligent and natural interaction between the context and individuals. This paradigm will facilitate user support through novel medical protocol design for chronic disease treatment, based on the healthy lifestyle promotion. Cardiovascular Diseases (CVD) account for 45% of all deaths in the western world according to the 2004 World Health Organization statistic report. Heart Failure (HF), CVD’s primary paradigm, mainly affects people older than 65. The ...

  13. Changes in erectile organ structure and function in a rat model of chronic prostatitis/chronic pelvic pain syndrome.

    Science.gov (United States)

    Wang, X-J; Xia, L-L; Xu, T-Y; Zhang, X-H; Zhu, Z-W; Zhang, M-G; Liu, Y; Xu, C; Zhong, S; Shen, Z-J

    2016-04-01

    There is a growing recognition of the association between chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) and erectile dysfunction (ED); however, most of the reports are based on questionnaires which cannot distinguish between organic and functional ED. The purpose of this study was to determine the exact relationship between CP/CPPS and ED, and to investigate the changes in erectile organ structure and function in a rat model of CP/CPPS. We established a rat model of experimental autoimmune prostatitis (EAP), which is a valid model for CP/CPPS. Erectile function in EAP and normal rats was comparable after cavernous nerve electrostimulation. The serum testosterone and oestradiol levels, ultrastructure of the corpus cavernosum and expression of endothelial nitric oxide synthase and neuronal nitric oxide synthase in the two groups were similar; however, there was a decrease in smooth muscle-to-collagen ratio and alpha-smooth muscle actin expression and an increase in transforming growth factor-beta 1 expression was observed in EAP rats. Thus, organic ED may not exist in EAP rats. We speculate that ED complained by patients with CP/CPPS may be psychological, which could be caused by impairment in the quality of life; however, further studies are needed to fully understand the potential mechanisms underlying the penile fibrosis in EAP rats. PMID:25990367

  14. An α2-Na/K ATPase/α-adducin complex in astrocytes triggers non–cell autonomous neurodegeneration

    Science.gov (United States)

    Gallardo, Gilbert; Barowski, Jessica; Ravits, John; Siddique, Teepu; Lingrel, Jerry B; Robertson, Janice; Steen, Hanno; Bonni, Azad

    2015-01-01

    Perturbations of astrocytes trigger neurodegeneration in several diseases, but the glial cell–intrinsic mechanisms that induce neurodegeneration remain poorly understood. We found that a protein complex of α2-Na/K ATPase and α-adducin was enriched in astrocytes expressing mutant superoxide dismutase 1 (SOD1), which causes familial amyotrophic lateral sclerosis (ALS). Knockdown of α2-Na/K ATPase or α-adducin in mutant SOD1 astrocytes protected motor neurons from degeneration, including in mutant SOD1 mice in vivo. Heterozygous disruption of the α2-Na/K ATPase gene suppressed degeneration in vivo and increased the lifespan of mutant SOD1 mice. The pharmacological agent digoxin, which inhibits Na/K ATPase activity, protected motor neurons from mutant SOD1 astrocyte–induced degeneration. Notably, α2-Na/K ATPase and α-adducin were upregulated in spinal cord of sporadic and familial ALS patients. Collectively, our findings define chronic activation of the α2-Na/K ATPase/α-adducin complex as a critical glial cell–intrinsic mechanism of non–cell autonomous neurodegeneration, with implications for potential therapies for neurodegenerative diseases. PMID:25344630

  15. L-tyrosine improves neuroendocrine function in a mouse model of chronic stress

    Institute of Scientific and Technical Information of China (English)

    Zhihua Wang; Jinghua Li; Zhiming Wang; Lingyan Xue; Yi Zhang; Yingjie Chen; Jun Su; Zhongming Li

    2012-01-01

    Adult BALB/c mice, individually housed, were stimulated with nine different stressors, arranged randomly, for 4 continuous weeks to generate an animal model of chronic stress. In chronically stressed mice, spontaneous locomotor activity was significantly decreased, escape latency in the Morris water maze test was prolonged, serum levels of total thyrotropin and total triiodothyronine were significantly decreased, and dopamine and norepinephrine content in the pallium, hippocampus and hypothalamus were significantly reduced. All of these changes were suppressed, to varying degrees, by L-tyrosine supplementation. These findings indicate that the neuroendocrine network plays an important role in chronic stress, and that L-tyrosine supplementation has therapeutic effects.

  16. Endovascular middle cerebral arterial occlusion in a nonhuman primate model of chronic stroke

    Institute of Scientific and Technical Information of China (English)

    Qiang Wang; Tong Zhang; Chunyu Zhao; Bin Du; Feng Gao; Mei Wen; Weijian Jiang

    2011-01-01

    No study has reported the safety, effectiveness, and consistency of endovascular middle cerebral artery occlusion in a chronic cerebral ischemia model. Nor have studies verified the safest and most effective segment, or branch, in the embolic middle cerebral artery. In this experiment, cerebral infarction models were established at M1, and on the upper and lower trunks on the contralateral side of the handedness of rhesus monkeys by using endovascular intervention. The results confirmed a high animal survival rate in stroke models of middle cerebral artery upper trunk occlusion. There was pronounced paralysis at the acute phase, long-term upper extremity dysfunction at the chronic phase, and the models showed good repeatability and consistency. Thus, this study describes a safe and effective model of chronic stroke.

  17. Facilitators and barriers of implementing the chronic care model in primary care: a systematic review

    OpenAIRE

    Kadu, Mudathira K; Stolee, Paul

    2015-01-01

    Background The Chronic Care Model (CCM) is a framework developed to redesign care delivery for individuals living with chronic diseases in primary care. The CCM and its various components have been widely adopted and evaluated, however, little is known about different primary care experiences with its implementation, and the factors that influence its successful uptake. The purpose of this review is to synthesize findings of studies that implemented the CCM in primary care, in order to identi...

  18. Using Mobile Health to Support the Chronic Care Model: Developing an Institutional Initiative

    OpenAIRE

    Shantanu Nundy; Jonathan J. Dick; Goddu, Anna P.; Patrick Hogan; Lu, Chen-Yuan E.; Solomon, Marla C; Arnell Bussie; Chin, Marshall H; Peek, Monica E.

    2012-01-01

    Background. Self-management support and team-based care are essential elements of the Chronic Care Model but are often limited by staff availability and reimbursement. Mobile phones are a promising platform for improving chronic care but there are few examples of successful health system implementation. Program Development. An iterative process of program design was built upon a pilot study and engaged multiple institutional stakeholders. Patients identified having a “human face” to the pilot...

  19. Effects of chronic administration of drugs of abuse on impulsive choice (delay discounting) in animal models

    OpenAIRE

    Setlow, Barry; Mendez, Ian A.; Mitchell, Marci R; Simon, Nicholas W.

    2009-01-01

    Drug addicted individuals demonstrate high levels of impulsive choice, characterized by preference for small immediate over larger but delayed rewards. Although the causal relationship between chronic drug use and elevated impulsive choice in humans has been unclear, a small but growing body of literature over the past decade has shown that chronic drug administration in animal models can cause increases in impulsive choice, suggesting that a similar causal relationship may exist in human dru...

  20. In vivo functional chronic imaging of a small animal model using optical-resolution photoacoustic microscopy

    OpenAIRE

    Hu, Song; Maslov, Konstantin; Wang, Lihong V.

    2009-01-01

    Optical-resolution photoacoustic microscopy (OR-PAM) has been validated as a valuable tool for label-free volumetric microvascular imaging. More importantly, the advantages of noninvasiveness and measurement consistency suggest the use of OR-PAM for chronic imaging of intact microcirculation. Here, such chronic imaging is demonstrated for the first time by monitoring the healing process of laser-induced microvascular lesions in a small animal model in vivo. The central part of a 1 mm by 1 mm ...

  1. L-tyrosine improves neuroendocrine function in a mouse model of chronic stress

    OpenAIRE

    Wang, Zhihua; Li, Jinghua; Wang, Zhiming; Xue, Lingyan; Zhang, Yi; Chen, Yingjie; Su, Jun; Li, Zhongming

    2012-01-01

    Adult BALB/c mice, individually housed, were stimulated with nine different stressors, arranged randomly, for 4 continuous weeks to generate an animal model of chronic stress. In chronically stressed mice, spontaneous locomotor activity was significantly decreased, escape latency in the Morris water maze test was prolonged, serum levels of total thyrotropin and total triiodothyronine were significantly decreased, and dopamine and norepinephrine content in the pallium, hippocampus and hypothal...

  2. Biological Analysis of Human CML Stem Cells; Xenograft Model of Chronic Phase Human Chronic Myeloid Leukemia.

    Science.gov (United States)

    Abraham, Sheela A

    2016-01-01

    Xenograft mouse models have been instrumental in expanding our knowledge of hematopoiesis and can provide a functional description of stem cells that possess engrafting potential. Here we describe methodology outlining one way of analyzing human malignant cells that are able to engraft immune compromised mice. Using models such as these will allow researchers to gain valuable insight into the primitive leukemic subtypes that evade current therapy regimes and are critical to understand, in order to eradicate malignancy. PMID:27581148

  3. Murine Model Imitating Chronic Wound Infections for Evaluation of Antimicrobial Photodynamic Therapy Efficacy

    Science.gov (United States)

    Fila, Grzegorz; Kasimova, Kamola; Arenas, Yaxal; Nakonieczna, Joanna; Grinholc, Mariusz; Bielawski, Krzysztof P.; Lilge, Lothar

    2016-01-01

    It is generally acknowledged that the age of antibiotics could come to an end, due to their widespread, and inappropriate use. Particularly for chronic wounds alternatives are being thought. Antimicrobial Photodynamic Therapy (APDT) is a potential candidate, and while approved for some indications, such as periodontitis, chronic sinusitis and other niche indications, its use in chronic wounds is not established. To further facilitate the development of APDT in chronic wounds we present an easy to use animal model exhibiting the key hallmarks of chronic wounds, based on full-thickness skin wounds paired with an optically transparent cover. The moisture-retaining wound exhibited rapid expansion of pathogen colonies up to 8 days while not jeopardizing the host survival. Use of two bioluminescent pathogens; methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa permits real time monitoring of the pathogens. The murine model was employed to evaluate the performance of four different photosensitizers as mediators in Photodynamic Therapy. While all four photosensitizers, Rose Bengal, porphyrin TMPyP, New Methylene Blue, and TLD1411 demonstrated good to excellent antimicrobial efficacy in planktonic solutions at 1 to 50 μM concentrations, whereas in in vivo the growth delay was limited with 24–48 h delay in pathogen expansion for MRSA, and we noticed longer growth suppression of P. aeruginosa with TLD1411 mediated Photodynamic Therapy. The murine model will enable developing new strategies for enhancement of APDT for chronic wound infections. PMID:27555843

  4. Murine Model Imitating Chronic Wound Infections for Evaluation of Antimicrobial Photodynamic Therapy Efficacy.

    Science.gov (United States)

    Fila, Grzegorz; Kasimova, Kamola; Arenas, Yaxal; Nakonieczna, Joanna; Grinholc, Mariusz; Bielawski, Krzysztof P; Lilge, Lothar

    2016-01-01

    It is generally acknowledged that the age of antibiotics could come to an end, due to their widespread, and inappropriate use. Particularly for chronic wounds alternatives are being thought. Antimicrobial Photodynamic Therapy (APDT) is a potential candidate, and while approved for some indications, such as periodontitis, chronic sinusitis and other niche indications, its use in chronic wounds is not established. To further facilitate the development of APDT in chronic wounds we present an easy to use animal model exhibiting the key hallmarks of chronic wounds, based on full-thickness skin wounds paired with an optically transparent cover. The moisture-retaining wound exhibited rapid expansion of pathogen colonies up to 8 days while not jeopardizing the host survival. Use of two bioluminescent pathogens; methicillin resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa permits real time monitoring of the pathogens. The murine model was employed to evaluate the performance of four different photosensitizers as mediators in Photodynamic Therapy. While all four photosensitizers, Rose Bengal, porphyrin TMPyP, New Methylene Blue, and TLD1411 demonstrated good to excellent antimicrobial efficacy in planktonic solutions at 1 to 50 μM concentrations, whereas in in vivo the growth delay was limited with 24-48 h delay in pathogen expansion for MRSA, and we noticed longer growth suppression of P. aeruginosa with TLD1411 mediated Photodynamic Therapy. The murine model will enable developing new strategies for enhancement of APDT for chronic wound infections. PMID:27555843

  5. Electron Transport Disturbances and Neurodegeneration: From Albert Szent-Györgyi's Concept (Szeged) till Novel Approaches to Boost Mitochondrial Bioenergetics

    OpenAIRE

    Levente Szalárdy; Dénes Zádori; Péter Klivényi; József Toldi; László Vécsei

    2015-01-01

    Impaired function of certain mitochondrial respiratory complexes has long been linked to the pathogenesis of chronic neurodegenerative disorders such as Parkinson’s and Huntington’s diseases. Furthermore, genetic alterations of mitochondrial genome or nuclear genes encoding proteins playing essential roles in maintaining proper mitochondrial function can lead to the development of severe systemic diseases associated with neurodegeneration and vacuolar myelinopathy. At present, all of these di...

  6. A Logic Model for the Integration of Mental Health Into Chronic Disease Prevention and Health Promotion

    Directory of Open Access Journals (Sweden)

    James Lando, MD, MPH

    2006-03-01

    Full Text Available Mental illnesses such as depression or anxiety affect an individual’s ability to undertake health-promoting behaviors. Chronic diseases can have a profound impact on an individual’s mental health; in turn, mental health status affects an individual’s ability to participate in treatment and recovery. A group of mental health and public health professionals convened to develop a logic model for addressing mental health as it relates to chronic disease prevention and health promotion. The model provides details on inputs, activities, and desired outcomes, and the designers of the model welcome input from other mental health and public health practitioners.

  7. Chronic ethanol exposure inhibits distraction osteogenesis in a mouse model: Role of the TNF signaling axis

    International Nuclear Information System (INIS)

    Tumor necrosis factor-alpha (TNF-α) is an inflammatory cytokine that modulates osteoblastogenesis. In addition, the demonstrated inhibitory effects of chronic ethanol exposure on direct bone formation in rats are hypothetically mediated by TNF-α signaling. The effects in mice are unreported. Therefore, we hypothesized that in mice (1) administration of a soluble TNF receptor 1 derivative (sTNF-R1) would protect direct bone formation during chronic ethanol exposure, and (2) administration of recombinant mouse TNF-α (rmTNF-α) to ethanol naive mice would inhibit direct bone formation. We utilized a unique model of limb lengthening (distraction osteogenesis, DO) combined with liquid diets to measure chronic ethanol's effects on direct bone formation. Chronic ethanol exposure resulted in increased marrow TNF, IL-1, and CYP 2E1 RNA levels in ethanol-treated vs. control mice, while no significant weight differences were noted. Systemic administration of sTNF-R1 during DO (8.0 mg/kg/2 days) to chronic ethanol-exposed mice resulted in enhanced direct bone formation as measured radiologically and histologically. Systemic rmTNF-α (10 μg/kg/day) administration decreased direct bone formation measures, while no significant weight differences were noted. We conclude that chronic ethanol-associated inhibition of direct bone formation is mediated to a significant extent by the TNF signaling axis in a mouse model

  8. The Relevance of Value Net Integrator and Shared Infrastructure Business Models in Managing Chronic Conditions

    Directory of Open Access Journals (Sweden)

    Susan Lambert

    2005-11-01

    Full Text Available There is widespread support for chronic condition management (CCM programs that require a multi-disciplinary, care-team approach. Implementation of such programs represents a paradigm shift in primary care service delivery and has significant resource implications for the general practice. Integral to the widespread uptake of care-team based CCM is information collection, storage and dissemination amongst the care-team members. This paper looks to ebusiness models for assistance in understanding the requirements of general practitioners (GPs in providing multi-disciplinary team care to patients with chronic conditions. The role required of GPs in chronic condition management is compared to that of a value net integrator. The essential characteristics of value net integrators are identified and compared to those of GPs providing multi-disciplinary team care to patients with chronic conditions. It is further suggested that a shared infrastructure is required.

  9. Telmisartan attenuates chronic ciclosporin A nephrotoxicity in a pig model

    DEFF Research Database (Denmark)

    Cibulskyte, Donata; pedersen, michael; Hørlyck, Arne;

    2007-01-01

    BACKGROUND: We have previously demonstrated renal enlargement in pigs treated with ciclosporin A (CsA) 10 mg/kg/day orally for 6 months. The aim of the study was to investigate the effect of oral CsA (10 mg/kg/day) for 12 months on kidney structure and function and the potential renoprotective role...... of angiotensin II (Ang II) receptor blocker telmisartan on chronic CsA nephrotoxicity in pigs. METHODS: Fourteen Göttingen minipigs aged 12-14 months were included: pigs received either CsA 10 mg/kg/day (n = 7) or CsA 10 mg/kg/day + telmisartan 40 mg/day (n = 7) orally for 12 months. At week 0, 12...

  10. A Biopsychosocial Model of the Development of Chronic Conduct Problems in Adolescence.

    Science.gov (United States)

    Dodge, Kenneth A.; Pettit, Gregory S.

    2003-01-01

    A biopsychosocial model of the development of adolescent chronic conduct problems is presented and supported through a review of empirical findings. The model posits that biological dispositions and sociocultural contexts place certain children at risk in early life but that life experiences with parents, peers, and social institutions increment…

  11. Dimethyl fumarate attenuates intracerebroventricular streptozotocin-induced spatial memory impairment and hippocampal neurodegeneration in rats.

    Science.gov (United States)

    Majkutewicz, Irena; Kurowska, Ewelina; Podlacha, Magdalena; Myślińska, Dorota; Grembecka, Beata; Ruciński, Jan; Plucińska, Karolina; Jerzemowska, Grażyna; Wrona, Danuta

    2016-07-15

    Intracerebroventricular (ICV) injection of streptozotocin (STZ) is a widely-accepted animal model of sporadic Alzheimer's disease (sAD). The present study evaluated the ability of dimethyl fumarate (DMF), an agent with antioxidant and anti-inflammatory properties, to prevent spatial memory impairments and hippocampal neurodegeneration mediated by ICV injection of STZ in 4-month-old rats. Rodent chow containing DMF (0.4%) or standard rodent chow was made available on day 0. Rat body weight and food intake were measured daily for whole the experiment (21days). STZ or vehicle (SHAM) ICV injections were performed on days 2 and 4. Spatial reference and working memory were evaluated using the Morris water maze on days 14-21. Cells containing Fluoro-Jade B (neurodegeneration marker), IL-6, IL-10 were quantified in the hippocampus and choline acetyltransferase (ChAT) in the basal forebrain. The disruption of spatial memory and a high density of hippocampal CA1-3 cells labeled with Fluoro-Jade B or containing IL-6 or IL-10 were observed in the STZ group but not in the STZ+DMF group, as compared to the SHAM or SHAM+DMF groups. STZ vs. STZ+DMF differences were found: worse reference memory acquisition, fewer ChAT-positive neurons in the medial septum (Ch1), more Fluoro-Jade-positive CA1 hippocampal cells in STZ rats. DMF therapy in a rodent model of sAD prevented the disruption of spatial reference and working memory, loss of Ch1 cholinergic cells and hippocampal neurodegeneration as well as the induction of IL-6 and IL-10 in CA1. These beneficial cognitive and molecular effects validate the anti-inflammatory and neuroprotective properties of DMF in the hippocampus. PMID:27083302

  12. The Chronic Kidney Disease Model: A General Purpose Model of Disease Progression and Treatment

    Directory of Open Access Journals (Sweden)

    Patel Uptal D

    2011-06-01

    Full Text Available Abstract Background Chronic kidney disease (CKD is the focus of recent national policy efforts; however, decision makers must account for multiple therapeutic options, comorbidities and complications. The objective of the Chronic Kidney Disease model is to provide guidance to decision makers. We describe this model and give an example of how it can inform clinical and policy decisions. Methods Monte Carlo simulation of CKD natural history and treatment. Health states include myocardial infarction, stroke with and without disability, congestive heart failure, CKD stages 1-5, bone disease, dialysis, transplant and death. Each cycle is 1 month. Projections account for race, age, gender, diabetes, proteinuria, hypertension, cardiac disease, and CKD stage. Treatment strategies include hypertension control, diabetes control, use of HMG-CoA reductase inhibitors, use of angiotensin converting enzyme inhibitors, nephrology specialty care, CKD screening, and a combination of these. The model architecture is flexible permitting updates as new data become available. The primary outcome is quality adjusted life years (QALYs. Secondary outcomes include health state events and CKD progression rate. Results The model was validated for GFR change/year -3.0 ± 1.9 vs. -1.7 ± 3.4 (in the AASK trial, and annual myocardial infarction and mortality rates 3.6 ± 0.9% and 1.6 ± 0.5% vs. 4.4% and 1.6% in the Go study. To illustrate the model's utility we estimated lifetime impact of a hypothetical treatment for primary prevention of vascular disease. As vascular risk declined, QALY improved but risk of dialysis increased. At baseline, 20% and 60% reduction: QALYs = 17.6, 18.2, and 19.0 and dialysis = 7.7%, 8.1%, and 10.4%, respectively. Conclusions The CKD Model is a valid, general purpose model intended as a resource to inform clinical and policy decisions improving CKD care. Its value as a tool is illustrated in our example which projects a relationship between

  13. Unique Hippocampal Changes and Allodynia in a Model of Chronic Stress

    OpenAIRE

    Kim, Seong-Ho; Moon, Il Soo; Park, In-Sick

    2013-01-01

    Sustained stress can have numerous pathologic effects. There have been several animal models for chronic stress. We tried to identify the changes of pain threshold and hippocampus in a model of chronic stress. Male Sprague-Dawley rats were kept in a cage filled with 23℃ water to a height of 2.2 cm for 7 days. Nociceptive thresholds, expressed in grams, were measured with a Dynamic Plantar Aesthesiometer. Golgi staining was used to identify hippocampal changes. To demonstrate how long allodyni...

  14. Tryptophan-2,3-dioxygenase (TDO) inhibition ameliorates neurodegeneration by modulation of kynurenine pathway metabolites.

    Science.gov (United States)

    Breda, Carlo; Sathyasaikumar, Korrapati V; Sograte Idrissi, Shama; Notarangelo, Francesca M; Estranero, Jasper G; Moore, Gareth G L; Green, Edward W; Kyriacou, Charalambos P; Schwarcz, Robert; Giorgini, Flaviano

    2016-05-10

    Metabolites of the kynurenine pathway (KP) of tryptophan (TRP) degradation have been closely linked to the pathogenesis of several neurodegenerative disorders. Recent work has highlighted the therapeutic potential of inhibiting two critical regulatory enzymes in this pathway-kynurenine-3-monooxygenase (KMO) and tryptophan-2,3-dioxygenase (TDO). Much evidence indicates that the efficacy of KMO inhibition arises from normalizing an imbalance between neurotoxic [3-hydroxykynurenine (3-HK); quinolinic acid (QUIN)] and neuroprotective [kynurenic acid (KYNA)] KP metabolites. However, it is not clear if TDO inhibition is protective via a similar mechanism or if this is instead due to increased levels of TRP-the substrate of TDO. Here, we find that increased levels of KYNA relative to 3-HK are likely central to the protection conferred by TDO inhibition in a fruit fly model of Huntington's disease and that TRP treatment strongly reduces neurodegeneration by shifting KP flux toward KYNA synthesis. In fly models of Alzheimer's and Parkinson's disease, we provide genetic evidence that inhibition of TDO or KMO improves locomotor performance and ameliorates shortened life span, as well as reducing neurodegeneration in Alzheimer's model flies. Critically, we find that treatment with a chemical TDO inhibitor is robustly protective in these models. Consequently, our work strongly supports targeting of the KP as a potential treatment strategy for several major neurodegenerative disorders and suggests that alterations in the levels of neuroactive KP metabolites could underlie several therapeutic benefits. PMID:27114543

  15. Gender differences in a Drosophila transcriptomic model of chronic pentylenetetrazole induced behavioral deficit.

    Directory of Open Access Journals (Sweden)

    Abhay Sharma

    Full Text Available A male Drosophila model of locomotor deficit induced by chronic pentylenetetrazole (PTZ, a proconvulsant used to model epileptogenesis in rodents, has recently been described. Antiepileptic drugs (AEDs ameliorate development of this behavioral abnormality. Time-series of microarray profiling of heads of male flies treated with PTZ has shown epileptogenesis-like transcriptomic perturbation in the fly model. Gender differences are known to exist in neurological and psychiatric conditions including epileptogenesis. We describe here the effects of chronic PTZ in Drosophila females, and compare the results with the male model. As in males, chronic PTZ was found to cause a decreased climbing speed in females. In males, overrepresentation of Wnt, MAPK, TGF-beta, JAK-STAT, Cell communication, and Dorso-Ventral axis formation pathways in downregulated genes was previously described. Of these, female genes showed enrichment only for Dorso-Ventral axis formation. Surprisingly, the ribosomal pathway was uniquely overrepresented in genes downregulated in females. Gender differences thus exist in the Drosophila model. Gender neutral, the developmental pathway Dorso-Ventral axis formation may be considered as the candidate causal pathway in chronic pentylenetetrazole induced behavioral deficit. Prior evidence of developmental mechanisms in epileptogenesis may support potential usefulness of the fly model. Given this, gender specific pathways identified here may provide a lead for further understanding brain dimorphism in neuropsychiatric disorders.

  16. Exacerbation of CNS inflammation and neurodegeneration by systemic LPS treatment is independent of circulating IL-1 beta and IL-6

    LENUS (Irish Health Repository)

    Murray, Carol L

    2011-05-17

    Abstract Background Chronic neurodegeneration comprises an inflammatory response but its contribution to the progression of disease remains unclear. We have previously shown that microglial cells are primed by chronic neurodegeneration, induced by the ME7 strain of prion disease, to synthesize limited pro-inflammatory cytokines but to produce exaggerated responses to subsequent systemic inflammatory insults. The consequences of this primed response include exaggerated hypothermic and sickness behavioural responses, acute neuronal death and accelerated progression of disease. Here we investigated whether inhibition of systemic cytokine synthesis using the anti-inflammatory steroid dexamethasone-21-phosphate was sufficient to block any or all of these responses. Methods ME7 animals, at 18-19 weeks post-inoculation, were challenged with LPS (500 μg\\/kg) in the presence or absence of dexamethasone-21-phosphate (2 mg\\/kg) and effects on core-body temperature and systemic and CNS cytokine production and apoptosis were examined. Results LPS induced hypothermia and decreased exploratory activity. Dexamethasone-21-phosphate prevented this hypothermia, markedly suppressed systemic IL-1β and IL-6 secretion but did not prevent decreased exploration. Furthermore, robust transcription of cytokine mRNA occurred in the hippocampus of both ME7 and NBH (normal brain homogenate) control animals despite the effective blocking of systemic cytokine synthesis. Microglia primed by neurodegeneration were not blocked from the robust synthesis of IL-1β protein and endothelial COX-2 was also robustly synthesized. We injected biotinylated LPS at 100 μg\\/kg and even at this lower dose this could be detected in blood plasma. Apoptosis was acutely induced by LPS, despite the inhibition of the systemic cytokine response. Conclusions These data suggest that LPS can directly activate the brain endothelium even at relatively low doses, obviating the need for systemic cytokine stimulation to

  17. 慢性咽炎模型探讨%To explore the model of chronic pharyngitis

    Institute of Scientific and Technical Information of China (English)

    涂小红; 黄玉婷; 蔡粤川; 何跃; 彭顺林

    2013-01-01

    慢性咽炎是耳鼻喉科的一种常见病,多发病,对于慢性咽炎的发病机理、临床症状及治疗等研究较多,但实验动物的选择及造模方法却很少,导师彭顺林教授所创彭氏造模法成为慢性咽炎的经典造模方法,其后的研究者们大多沿用此法。%Chronic pharyngitis is a common disease ,frequently occurring in the Department of ENT , research the pathogenesis ,clinical symptoms and treatment of chronic pharyngitis ,but few and modeling methods of the choice of the experimental animal ,Professor Peng Shunlin created the Peng's molding become chronic pharyngitis of the classical modeling methods ,the most researchers use this method .

  18. Eugenia jambolana Lam. Increases lifespan and ameliorates experimentally induced neurodegeneration in C. elegans

    Directory of Open Access Journals (Sweden)

    Maria de Fátima Bezerra

    2014-09-01

    Full Text Available Summary. Type-2 diabetes mellitus (T2DM, dyslipidemia (DL and inflammation (IF are associated with reduced lifespan (LS and increased risk of neurodegenerative diseases (NDG. Dysregulation in insulin/insulin-like growth factor-1 (IGF-1 (IIS signaling, forkhead box O transcription factor (FOXO and Silent Information Regulators or Sirtuins (SIRT may be responsible. We investigated the effect of spray dried Jambolan (Eugenia jambolana Lam. fruit in Caenorhabditis elegans model for lifespan, amyloid b1-42 (Ab1-42 aggregation induced paralysis and MPP+ (1-methyl-4-phenylpyridinium induced neurodegeneration. Effect on modulating critical genes involved signaling pathways important in IIS, LS and NDG were also studied in C. elegans. Results show suggest statistically significant increase in lifespan (9-22.7% coupled with a delay in Ab1-42 induced paralysis (11.5% and MPP+ induced paralysis (38-43%. Gene expression studies indicated a significant upregulation in expression of  C. elegans homologs of foxo, sirt1, dopamine D1 receptor and suggested a non-FOXO mediated mechanism of action.Industrial relevance. Jambolan is a bioactive-rich tropical fruit with high colorant potential. Despite this fact, its perishability has hampered its market and industrial use beyond the countries where it is cultivated. Considering that drying is a popular technique able to extend fruits shelf life and concentrate their natural bioactive compounds, this research investigates the health relevance of spray dried jambolan. Here we addressed the potential of dried Jambolan fruit to extend lifespan and inhibit the progression of experimentally induced neurodegeneration using the C. elegans model. We demonstrated that this convenient fruit product was able to increase the lifespan of C. elegans. The jambolan extracts also influenced some critical genes of signaling pathways relevant to metabolic diseases, aging and neurodegeneration. Based on our results, some insight about

  19. Establishment of a chronic left ventricular aneurysm model in rabbit

    Institute of Scientific and Technical Information of China (English)

    Cang-Song XIAO; Chang-Qing GAO; Li-Bing LI; Yao WANG; Tao ZHAO; Wei-Hua YE; Chong-Lei REN; Zhi-Yong LIU; Yang WU

    2014-01-01

    Objectives To establish a cost-effective and reproducible procedure for induction of chronic left ventricular aneurysm (LVA) in rabbits. Methods Acute myocardial infarction (AMI) was induced in 35 rabbits via concomitant ligation of the left anterior descending (LAD) coronary artery and the circumflex (Cx) branch at the middle portion. Development of AMI was co n-firmed by ST segment elevation and akinesis of the occluded area. Echocardiography, pathological evaluation, and agar i n-tra-chamber casting were utilized to validate the formation of LVA four weeks after the surgery. Left ventricular end systolic pressure (LVESP) and diastolic pressure (LVEDP) were measured before, immediately after and four weeks after ligation. D i-mensions of the ventricular chamber, thickness of the interventricular septum (IVS) and the left ventricular posterior wall (LVPW) left ventricular end diastolic volume (LVEDV) and systolic volume (LVESV), and ejection fraction (EF) were recorded by echo-cardiography. Results Thirty one (88.6%) rabbits survived myocardial infarction and 26 of them developed aneurysm (83.9%). The mean area of aneurysm was 33.4% ± 2.4% of the left ventricle. LVEF markedly decreased after LVA formation, whereas LVEDV, LVESV and the thickness of IVS as well as the dimension of ventricular chamber from apex to mitral valve annulus significantly increased. LVESP immediately dropped after ligation and recovered to a small extent after LVA formation. LVEDP progressively increased after ligation till LVA formation. Areas in the left ventricle (LV) that underwent fibrosis included the apex, anterior wall and lateral wall but not IVS. Agar intra-chamber cast showed that the bulging of LV wall was prominent in the area of aneurysm. Conclusions Ligation of LAD and Cx at the middle portion could induce develo pment of LVA at a mean area ratio of 33.4%±2.4%which involves the apex, anterior wall and lateral wall of the LV.

  20. Complement is dispensable for neurodegeneration in Niemann-Pick disease type C

    Directory of Open Access Journals (Sweden)

    Lopez Manuel E

    2012-09-01

    Full Text Available Abstract Background The immune system has been implicated in neurodegeneration during development and disease. In various studies, the absence of complement (that is, C1q deficiency impeded the elimination of apoptotic neurons, allowing survival. In the genetic lysosomal storage disease Niemann-Pick C (NPC, caused by loss of NPC1 function, the expression of complement system components, C1q especially, is elevated in degenerating brain regions of Npc1-/- mice. Here we test whether complement is mediating neurodegeneration in NPC disease. Findings In normal mature mice, C1q mRNA was found in neurons, particularly cerebellar Purkinje neurons (PNs. In Npc1-/- mice, C1q mRNA was additionally found in activated microglia, which accumulate during disease progression and PN loss. Interestingly, C1q was not enriched on or near degenerating neurons. Instead, C1q was concentrated in other brain regions, where it partially co-localized with a potential C1q inhibitor, chondroitin sulfate proteoglycan (CSPG. Genetic deletion of C1q, or of the downstream complement pathway component C3, did not significantly alter patterned neuron loss or disease progression. Deletion of other immune response factors, a Toll-like receptor, a matrix metalloprotease, or the apoptosis facilitator BIM, also failed to alter neuron loss. Conclusion We conclude that complement is not involved in the death and clearance of neurons in NPC disease. This study supports a view of neuroinflammation as a secondary response with non-causal relationship to neuron injury in the disease. This disease model may prove useful for understanding the conditions in which complement and immunity do contribute to neurodegeneration in other disorders.

  1. Cardiometabolic Effects of Chronic Hyperandrogenemia in a New Model of Postmenopausal Polycystic Ovary Syndrome.

    Science.gov (United States)

    Dalmasso, Carolina; Maranon, Rodrigo; Patil, Chetan; Bui, Elizabeth; Moulana, Mohadetheh; Zhang, Howei; Smith, Andrew; Yanes Cardozo, Licy L; Reckelhoff, Jane F

    2016-07-01

    Postmenopausal women who have had polycystic ovary syndrome (PCOS) and chronic hyperandrogenemia may be at a greater risk for cardiovascular disease than normoandrogenemic postmenopausal women. The cardiometabolic effect of chronic hyperandrogenemia in women with PCOS after menopause is unclear. The present study was performed to test the hypothesis that chronic hyperandrogenemia in aging female rats would have more deleterious effects on metabolic function, blood pressure, and renal function than in normoandrogenemic age-matched females. Female Sprague Dawley were implanted continuously, beginning at 4-5 weeks, with dihydrotestosterone (postmenopausal hyperandrogenemic female [PMHAF]) or placebo pellets (controls), and were studied at 13 months of age. Plasma DHT was 3-fold higher, and estradiol was 90% lower in PMHAF than controls. Body weights were higher; EchoMRI showed greater fat and lean mass; and computed tomography showed more sc and visceral adiposity in PMHAF, but with similar femur length compared with controls. Insulin resistance was present in PMHAF with higher plasma insulin, normal fasting blood glucose, abnormal oral glucose tolerance test, and higher nonfasting blood glucose. Blood pressure (radiotelemetry) was significantly higher and heart rate was lower, and renal function (glomerular filtration rate) was reduced by 40% in PMHAF. Thus the aging chronically hyperandrogenemic female rat is a new model of postmenopausal PCOS, which exhibits insulin resistance and visceral obesity, hypertension, and impairment in renal function. This new model provides a unique tool to study the deleterious effects of chronic androgen excess in postmenopausal females rats. PMID:27145003

  2. Group Medical Visits Using an Empowerment-based Model as Treatment for Women With Chronic Pain in an Underserved Community

    OpenAIRE

    Geller, Jeffrey S.; Kulla, Jill; Shoemaker, Alena

    2015-01-01

    Background: Over the past decade, group medical visits have become more prevalent. Group medical visits may have some advantages in treating chronic illnesses such as chronic pain as they can be more patient centered. The empowerment model is a novel approach used to provide support, education, and healthy activities guided by participants. Objective: To evaluate the early stages of a chronic pain group medical visit program based on the empowerment model. Methods: This prospective cohort stu...

  3. Traumatic brain injury, neuroimaging, and neurodegeneration

    Directory of Open Access Journals (Sweden)

    Erin D. Bigler

    2013-08-01

    Full Text Available Depending on severity, traumatic brain injury (TBI induces immediate neuropathological effects that in the mildest form may be transient but as severity increases results in neural damage and degeneration. The first phase of neural degeneration is explainable by the primary acute and secondary neuropathological effects initiated by the injury; however, neuroimaging studies demonstrate a prolonged period of pathological changes that progressively occur even during the chronic phase. This review examines how neuroimaging may be used in TBI to understand (1 the dynamic changes that occur in brain development relevant to understanding the effects of TBI and how these relate to developmental stage when the brain is injured, (2 how TBI interferes with age-typical brain development and the effects of aging thereafter, and (3 how TBI results in greater frontotemporolimbic damage, results in cerebral atrophy, and is more disruptive to white matter neural connectivity. Neuroimaging quantification in TBI demonstrates degenerative effects from brain injury over time. An adverse synergistic influence of TBI with aging may predispose the brain injured individual for the development of neuropsychiatric and neurodegenerative disorders long after surviving the brain injury.

  4. Stress in adolescents with a chronically ill parent: inspiration from Rolland's Family Systems-Illness model

    NARCIS (Netherlands)

    D.S. Sieh; A.L.C. Dikkers; J.M.A. Visser-Meily; A.M. Meijer

    2012-01-01

    This article was inspired by Rolland’s Family Systems-Illness (FSI) model, aiming to predict adolescent stress as a function of parental illness type. Ninety-nine parents with a chronic medical condition, 82 partners, and 158 adolescent children (51 % girls; mean age = 15.1 years) participated in th

  5. Disease management projects and the Chronic CareModel in action: Baseline qualitative research

    NARCIS (Netherlands)

    B. Hipple-Walters (Bethany); S.A. Adams (Samantha); A.P. Nieboer (Anna); R.A. Bal (Roland)

    2012-01-01

    textabstractBackground: Disease management programs, especially those based on the Chronic Care Model (CCM),are increasingly common in the Netherlands. While disease management programs have beenwell-researched quantitatively and economically, less qualitative research has been done. Theoverall aim

  6. The relation between inflammation and neurodegeneration in multiple sclerosis brains

    DEFF Research Database (Denmark)

    Frischer, J.M.; Bramow, S.; Dal-Bianco, A.;

    2009-01-01

    Some recent studies suggest that in progressive multiple sclerosis, neurodegeneration may occur independently from inflammation. The aim of our study was to analyse the interdependence of inflammation, neurodegeneration and disease progression in various multiple sclerosis stages in relation to...... disease or brain lesions. We found that pronounced inflammation in the brain is not only present in acute and relapsing multiple sclerosis but also in the secondary and primary progressive disease. T- and B-cell infiltrates correlated with the activity of demyelinating lesions, while plasma cell...... infiltrates were most pronounced in patients with secondary progressive multiple sclerosis (SPMS) and primary progressive multiple sclerosis (PPMS) and even persisted, when T- and B-cell infiltrates declined to levels seen in age matched controls. A highly significant association between inflammation and...

  7. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice

    Institute of Scientific and Technical Information of China (English)

    Li Li; Meng Xu; Bo Shen; Man Li; Qian Gao; Shou-gang Wei

    2016-01-01

    D-galactose has been widely used in aging research because of its efifcacy in inducing senescence and accelerating aging in animal models. The present study investigated the beneifts of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-ga-lactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apop-tosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice.

  8. Moderate exercise prevents neurodegeneration in D-galactose-induced aging mice.

    Science.gov (United States)

    Li, Li; Xu, Meng; Shen, Bo; Li, Man; Gao, Qian; Wei, Shou-Gang

    2016-05-01

    D-galactose has been widely used in aging research because of its efficacy in inducing senescence and accelerating aging in animal models. The present study investigated the benefits of exercise for preventing neurodegeneration, such as synaptic plasticity, spatial learning and memory abilities, in mouse models of aging. D-galactose-induced aging mice were administered daily subcutaneous injections of D-galactose at the base of the neck for 10 consecutive weeks. Then, the mice were subjected to exercise training by running on a treadmill for 6 days a week. Shortened escape latency in a Morris water maze test indicated that exercise improved learning and memory in aging mice. The ameliorative changes were likely induced by an upregulation of Bcl-2 and brain-derived neurotrophic factor, the repression of apoptosis factors such as Fas and Bax, and an increase in the activity of glucose transporters-1 and 4. The data suggest moderate exercise may retard or inhibit neurodegeneration in D-galactose-induced aging mice. PMID:27335566

  9. Microglial AGE-albumin is critical in promoting alcohol-induced neurodegeneration in rats and humans.

    Science.gov (United States)

    Byun, Kyunghee; Bayarsaikhan, Delger; Bayarsaikhan, Enkhjargal; Son, Myeongjoo; Oh, Seyeon; Lee, Jaesuk; Son, Hye-In; Won, Moo-Ho; Kim, Seung U; Song, Byoung-Joon; Lee, Bonghee

    2014-01-01

    Alcohol is a neurotoxic agent, since long-term heavy ingestion of alcohol can cause various neural diseases including fetal alcohol syndrome, cerebellar degeneracy and alcoholic dementia. However, the molecular mechanisms of alcohol-induced neurotoxicity are still poorly understood despite numerous studies. Thus, we hypothesized that activated microglial cells with elevated AGE-albumin levels play an important role in promoting alcohol-induced neurodegeneration. Our results revealed that microglial activation and neuronal damage were found in the hippocampus and entorhinal cortex following alcohol treatment in a rat model. Increased AGE-albumin synthesis and secretion were also observed in activated microglial cells after alcohol exposure. The expressed levels of receptor for AGE (RAGE)-positive neurons and RAGE-dependent neuronal death were markedly elevated by AGE-albumin through the mitogen activated protein kinase pathway. Treatment with soluble RAGE or AGE inhibitors significantly diminished neuronal damage in the animal model. Furthermore, the levels of activated microglial cells, AGE-albumin and neuronal loss were significantly elevated in human brains from alcoholic indivisuals compared to normal controls. Taken together, our data suggest that increased AGE-albumin from activated microglial cells induces neuronal death, and that efficient regulation of its synthesis and secretion is a therapeutic target for preventing alcohol-induced neurodegeneration. PMID:25140518

  10. Salt-induced changes in cardiac phosphoproteome in a rat model of chronic renal failure.

    Directory of Open Access Journals (Sweden)

    Zhengxiu Su

    Full Text Available Heart damage is widely present in patients with chronic kidney disease. Salt diet is the most important environmental factor affecting development of chronic renal failure and cardiovascular diseases. The proteins involved in chronic kidney disease -induced heart damage, especially their posttranslational modifications, remain largely unknown to date. Sprague-Dawley rats underwent 5/6 nephrectomy (chronic renal failure model or sham operation were treated for 2 weeks with a normal-(0.4% NaCl, or high-salt (4% NaCl diet. We employed TiO2 enrichment, iTRAQ labeling and liquid-chromatography tandem mass spectrometry strategy for phosphoproteomic profiling of left ventricular free walls in these animals. A total of 1724 unique phosphopeptides representing 2551 non-redundant phosphorylation sites corresponding to 763 phosphoproteins were identified. During normal salt feeding, 89 (54% phosphopeptides upregulated and 76 (46% phosphopeptides downregulated in chronic renal failure rats relative to sham rats. In chronic renal failure rats, high salt intake induced upregulation of 84 (49% phosphopeptides and downregulation of 88 (51% phosphopeptides. Database searches revealed that most of the identified phospholproteins were important signaling molecules such as protein kinases, receptors and phosphatases. These phospholproteins were involved in energy metabolism, cell communication, cell differentiation, cell death and other biological processes. The Search Tool for the Retrieval of Interacting Genes analysis revealed functional links among 15 significantly regulated phosphoproteins in chronic renal failure rats compared to sham group, and 23 altered phosphoproteins induced by high salt intake. The altered phosphorylation levels of two proteins involved in heart damage, lamin A and phospholamban were validated. Expression of the downstream genes of these two proteins, desmin and SERCA2a, were also analyzed.

  11. Strain Differences in the Chronic Mild Stress Animal Model of Depression and Anxiety in Mice

    OpenAIRE

    Jung, Yang-Hee; Hong, Sa-Ik; Ma, Shi-Xun; Hwang, Ji-Young; Kim, Jun-Sup; lee, Ju-hyun; Seo, Jee-Yeon; Lee, Seok-Yong; Jang, Choon-Gon

    2014-01-01

    Chronic mild stress (CMS) has been reported to induce an anhedonic-like state in mice that resembles some of the symptoms of human depression. In the present study, we used a chronic mild stress animal model of depression and anxiety to examine the responses of two strains of mice that have different behavioral responsiveness. An outbred ICR and an inbred C57BL/6 strain of mice were selected because they are widely used strains in behavioral tests. The results showed that the inbred C57BL/6 a...

  12. Protective Action of Acupuncture and Moxibustion on Gastric Mucosa in Model Rats with Chronic Atrophic Gastritis

    Institute of Scientific and Technical Information of China (English)

    高希言; 饶红; 王燕; 孟丹; 魏玉龙

    2005-01-01

    Objective: To probe the mechanism of acupuncture and moxibustion in atrophic gastritis so as to provide a basis for clinical treatment. Method: Observe the effects of acupuncture and moxibustion at the points of Zusanli, Zhongwan and Tianshu on gastric mucosa in model rats with chronic atrophic gastritis. Results:Acupuncture and moxibustion can increase the contents of PGE2α, PGF2α and cAMP, and decrease the content of cGMP in the tissue of gastric mucosa. Conclusion: Acupuncture and moxibustion shows cytoprotection on gastric mucosa, so it is an effective method for treating chronic atrophic gastritis.

  13. Microglial cell dysregulation in brain aging and neurodegeneration

    OpenAIRE

    von Bernhardi, Rommy; Eugenín-von Bernhardi, Laura; Eugenín, Jaime

    2015-01-01

    Aging is the main risk factor for neurodegenerative diseases. In aging, microglia undergoes phenotypic changes compatible with their activation. Glial activation can lead to neuroinflammation, which is increasingly accepted as part of the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD). We hypothesize that in aging, aberrant microglia activation leads to a deleterious environment and neurodegeneration. In aged mice, microglia exhibit an increased expression of c...

  14. Protection of MPTP-induced neuroinflammation and neurodegeneration by Pycnogenol

    OpenAIRE

    Khan, Mohammad Moshahid; Kempuraj, Duraisamy; Thangavel, Ramasamy; Zaheer, Asgar

    2013-01-01

    Oxidative stress and inflammation play a crucial role in Parkinson’s disease (PD) pathogenesis and may represent a target for treatment. Current PD drugs provide only symptomatic relief and have limitations in terms of adverse effects and inability to prevent neurodegeneration. Flavonoids have been suggested to exert human health benefits by its anti-oxidant and anti-inflammatory properties. Therefore, in the present study, using 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydro pyridine (MPTP)-induced...

  15. Neurodegeneration in Schizophrenia: Evidence from In Vivo Neuroimaging Studies

    OpenAIRE

    Csernansky, John G.

    2007-01-01

    Although schizophrenia is primarily considered to be a neurodevelopmental disorder, there is a growing consensus that the disorder may also involve neurodegeneration. Recent research using non-invasive neuroimaging techniques, such as magnetic resonance imaging, suggests that some patients with schizophrenia show progressive losses of gray matter in the frontal and temporal lobes of the brain. The cellular mechanisms responsible for such gray matter losses are unknown, but have been hypothesi...

  16. Emerging nexus between RAB GTPases, autophagy and neurodegeneration.

    Science.gov (United States)

    Jain, Navodita; Ganesh, Subramaniam

    2016-05-01

    The RAB class of small GTPases includes the major regulators of intracellular communication, which are involved in vesicle generation through fusion and fission, and vesicular trafficking. RAB proteins also play an imperative role in neuronal maintenance and survival. Recent studies in the field of neurodegeneration have also highlighted the process of autophagy as being essential for neuronal maintenance. Here we review the emerging roles of RAB proteins in regulating macroautophagy and its impact in the context of neurodegenerative diseases. PMID:26985808

  17. Neurodegeneration in Schizophrenia: Evidence from In Vivo Neuroimaging Studies

    Directory of Open Access Journals (Sweden)

    John G. Csernansky

    2007-01-01

    Full Text Available Although schizophrenia is primarily considered to be a neurodevelopmental disorder, there is a growing consensus that the disorder may also involve neurodegeneration. Recent research using non-invasive neuroimaging techniques, such as magnetic resonance imaging, suggests that some patients with schizophrenia show progressive losses of gray matter in the frontal and temporal lobes of the brain. The cellular mechanisms responsible for such gray matter losses are unknown, but have been hypothesized to involve abnormal increases in apoptosis.

  18. TDP-43 Aggregation In Neurodegeneration: Are Stress Granules The Key?

    OpenAIRE

    Dewey, Colleen M.; Cenik, Basar; Sephton, Chantelle F.; Johnson, Brett A.; Herz, Joachim; Yu, Gang

    2012-01-01

    The RNA-binding protein TDP-43 is strongly linked to neurodegeneration. Not only are mutations in the gene encoding TDP-43 associated with ALS and FTLD, but this protein is also a major constituent of pathological intracellular inclusions in these diseases. Recent studies have significantly expanded our understanding of TDP-43 physiology. TDP-43 is now known to play important roles in neuronal RNA metabolism. It binds to and regulates the splicing and stability of numerous RNAs encoding prote...

  19. The multiple sclerosis visual pathway cohort: understanding neurodegeneration in MS

    OpenAIRE

    Martínez-Lapiscina, Elena H; Fraga-Pumar, Elena; Gabilondo, Iñigo; Martínez-Heras, Eloy; Torres-Torres, Ruben; Ortiz-Pérez, Santiago; Llufriu, Sara; Tercero, Ana; Andorra, Magi; Roca, Marc Figueras; Lampert, Erika; Zubizarreta, Irati; Saiz, Albert; Sanchez-Dalmau, Bernardo; Villoslada, Pablo

    2014-01-01

    Background Multiple Sclerosis (MS) is an immune-mediated disease of the Central Nervous System with two major underlying etiopathogenic processes: inflammation and neurodegeneration. The latter determines the prognosis of this disease. MS is the main cause of non-traumatic disability in middle-aged populations. Findings The MS-VisualPath Cohort was set up to study the neurodegenerative component of MS using advanced imaging techniques by focusing on analysis of the visual pathway in a middle-...

  20. Maintaining the Brain: Insight into Human Neurodegeneration From Drosophila Mutants

    OpenAIRE

    Lessing, Derek; Bonini, Nancy M.

    2009-01-01

    The fruit fly Drosophila melanogaster has brought significant advances to research in neurodegenerative disease, notably in the identification of genes that are required to maintain the structural integrity of the brain, defined by recessive mutations that cause adult-onset neurodegeneration. Here, we survey these genes in the fly and classify them according to five key cell biological processes. Over half of these genes have counterparts in mouse or human that are also associated with neurod...

  1. Mechanisms of neurodegeneration in Alzheimer’s disease

    OpenAIRE

    Jovanović Zorica

    2012-01-01

    Introduction. Recent research into mechanisms of neurodegeneration in Alzheimer’s disease has lead to a dramatic increase in our understanding of the mechanisms of cell death and neuroprotection. Alzheimer’s disease is a complex disease with multiple etiological factors involved in disease pathogenesis. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Amyloid-β peptide toxicity is mediated at least in part by oxidative stress. Amyloid-β peptide directly generates r...

  2. Ninjin'yoeito and ginseng extract prevent oxaliplatin-induced neurodegeneration in PC12 cells.

    Science.gov (United States)

    Suzuki, Toshiaki; Yamamoto, Ayano; Ohsawa, Masahiro; Motoo, Yoshiharu; Mizukami, Hajime; Makino, Toshiaki

    2015-10-01

    Ninjin'yoeito (NYT) is a formula of Japanese traditional kampo medicine composed of 12 crude drugs, and is designed to improve the decline in constitution after recovery from disease, fatigue, anemia, anorexia, perspiration during sleep, cold limbs, slight fever, chills, persistent cough, malaise, mental disequilibrium, insomnia, and constipation. Oxaliplatin (L-OHP) is a platinum-based anticancer drug used to treat colorectal, pancreatic, and stomach cancers. However, it often causes acute and chronic peripheral neuropathies including cold allodynia and mechanical hyperalgesia. In this study, we investigated the preventive effects of NYT on neuronal degeneration caused by L-OHP using PC12 cells, which are derived from the rat adrenal medulla and differentiate into nerve-like cells after exposure to nerve growth factor. L-OHP treatment decreased the elongation of neurite-like projection outgrowths in differentiated PC12 cells. When PC12 cells were treated with NYT hot water extract, neurodegeneration caused by L-OHP was significantly prevented in a concentration-dependent manner. Among the 12 crude drugs composing NYT, the extract of Ginseng (the root of Panax ginseng) exhibited the strongest preventive effects on neurodegeneration in differentiated PC12 cells. By activity-guided fractionation, we found that the fraction containing ginsenosides displayed preventive activity and, among several ginsenosides, ginsenoside F2 exhibited significant preventive effects on L-OHP-induced decreases in neurite-like outgrowths in differentiated PC12 cells. These results suggest that NYT and ginseng are promising agents for preventing L-OHP-induced neuropathies and present ginsenoside F2 as one of the active ingredients in ginseng. PMID:26014046

  3. One in vitro model for visceral adipose-derived fibroblasts in chronic inflammation

    International Nuclear Information System (INIS)

    One pathogenesis of the obesity-associated complications is that consistent with increased body fat mass, the elevation of adipose tissue-derived cytokines inflicts a low-grade chronic inflammation, which ultimately leads to metabolic disorders. Adipocytes and macrophages in visceral adipose (VA) have been confirmed to contribute to the chronic inflammation; however, the role of the resident fibroblasts is still unknown. We established one VA fibroblast cell line, termed VAFC. Morphological analysis indicated that there were large numbers of pits at the cell plasma membrane. In vitro VAFC cells promoted bone marrow cells to differentiate into macrophages and protected them from apoptosis in the serum-free conditions. Additionally, they also interfered in lymphocytes proliferation. On the basis of these results, this cell line might be an in vitro model for understanding the role of adipose-derived fibroblasts in obesity-associated chronic inflammation

  4. Diffusion-weighted MRI and quantitative biophysical modeling of hippocampal neurite loss in chronic stress.

    Directory of Open Access Journals (Sweden)

    Peter Vestergaard-Poulsen

    Full Text Available Chronic stress has detrimental effects on physiology, learning and memory and is involved in the development of anxiety and depressive disorders. Besides changes in synaptic formation and neurogenesis, chronic stress also induces dendritic remodeling in the hippocampus, amygdala and the prefrontal cortex. Investigations of dendritic remodeling during development and treatment of stress are currently limited by the invasive nature of histological and stereological methods. Here we show that high field diffusion-weighted MRI combined with quantitative biophysical modeling of the hippocampal dendritic loss in 21 day restraint stressed rats highly correlates with former histological findings. Our study strongly indicates that diffusion-weighted MRI is sensitive to regional dendritic loss and thus a promising candidate for non-invasive studies of dendritic plasticity in chronic stress and stress-related disorders.

  5. Phage therapy of staphylococcal chronic osteomyelitis in experimental animal model

    OpenAIRE

    Chandan Kishor; Raghvendra Raman Mishra; Saraf, Shyam K.; Mohan Kumar; Arvind K Srivastav; Gopal Nath

    2016-01-01

    Background & objectives: Methicillin resistant Staphylococcus aureus (MRSA) are the commonest cause of osteomyelitis. The aim of this study was to evaluate the role of an alternative therapy i.e. application of S. aureus specific bacteriophages in cases of osteomyelitis caused by MRSA in animal model. Methods: Twenty two rabbits were included in this study. The first two rabbits were used to test the safety of phage cocktail while the remaining 20 rabbits were divided into three groups; g...

  6. Program Implementation in the Prison System: An Organizational Study of the Chronic Care Model Program

    OpenAIRE

    Robinson, Greg

    2013-01-01

    This study provides evidence of a successful implementation of a not-for-profit operational model within a public setting. The federal government placed a receiver in charge of improving health care within the California Department of Corrections and Rehabilitation. To achieve the receivership's goals, a chronic care model from the not-for-profit sector was selected and implemented to improve the delivery of health care to inmates. The data suggest that operational programs developed outsi...

  7. Diet-related chronic disease in the northeastern United States: a model-based clustering approach

    OpenAIRE

    Flynt, Abby; Daepp, Madeleine I. G.

    2015-01-01

    Background Obesity and diabetes are global public health concerns. Studies indicate a relationship between socioeconomic, demographic and environmental variables and the spatial patterns of diet-related chronic disease. In this paper, we propose a methodology using model-based clustering and variable selection to predict rates of obesity and diabetes. We test this method through an application in the northeastern United States. Methods We use model-based clustering, an unsupervised learning a...

  8. Biomarkers of Disease and Treatment in Murine and Cynomolgus Models of Chronic Asthma

    OpenAIRE

    Jennifer Louten,; Mattson, Jeanine D.; Maria-Christina Malinao; Ying Li; Claire Emson; Felix Vega; Robert L. Wardle; Scott, Michael R.; Fick, Robert B.; McClanahan, Terrill K.; Rene de Waal Malefyt; Maribel Beaumont

    2012-01-01

    Background Biomarkers facilitate early detection of disease and measurement of therapeutic efficacy, both at clinical and experimental levels. Recent advances in analytics and disease models allow comprehensive screening for biomarkers in complex diseases, such as asthma, that was previously not feasible. Objective Using murine and nonhuman primate (NHP) models of asthma, identify biomarkers associated with early and chronic stages of asthma and responses to steroid treatment. Methods The tot...

  9. Validation of two prediction models of undiagnosed chronic kidney disease in mixed-ancestry South Africans

    OpenAIRE

    Mogueo, Amelie; Echouffo-Tcheugui, Justin B; Matsha, Tandi E.; Erasmus, Rajiv T; Kengne, Andre P.

    2015-01-01

    Background Chronic kidney disease (CKD) is a global challenge. Risk models to predict prevalent undiagnosed CKD have been published. However, none was developed or validated in an African population. We validated the Korean and Thai CKD prediction model in mixed-ancestry South Africans. Methods Discrimination and calibration were assessed overall and by major subgroups. CKD was defined as ‘estimated glomerular filtration rate (eGFR)

  10. Stochastic modelling to evaluate the economic efficiency of treatment of chronic subclinical mastitis

    OpenAIRE

    Steeneveld, W.; Hogeveen, H; Borne, van den, D Dirk; Swinkels, J.M.

    2006-01-01

    Treatment of subclinical mastitis is traditionally no common practice. However, some veterinarians regard treatment of some types of subclinical mastitis to be effective. The goal of this research was to develop a stochastic Monte Carlo simulation model to support decisions around treatment of chronic subclinical mastitis caused by Streptococcus uberis. Factors in the model include, amongst others, the probability of spontaneous cure, probability of the cow becoming clinically diseased, trans...

  11. Prognostic factors for chronic severe hepatitis and construction of a prognostic model

    Institute of Scientific and Technical Information of China (English)

    Qian Li; Gui-Yu Yuan; Ke-Cheng Tang; Guo-Wang Liu; Rui Wang; Wu-Kui Cao

    2008-01-01

    BACKGROUND:Chronic severe hepatitis is a serious illness with a high mortality rate. Discussion of prognostic judgment criteria for chronic severe hepatitis is of great value in clinical guidance. This study was designed to investigate the clinical and laboratory indices affecting the prognosis of chronic severe hepatitis and construct a prognostic model. METHODS: The clinical and laboratory indices of 213 patients with chronic severe hepatitis within 24 hours after diagnosis were analyzed retrospectively. Death or survival was limited to within 3 months after diagnosis. RESULTS: The mortality of all patients was 47.42%. Compared with the survival group, the age, basis of hepatocirrhosis, infection, degree of hepatic encephalopathy (HE) and the levels of total bilirubin (TBil), total cholesterol (CHO), cholinesterase (CHE), blood urea nitrogen (BUN), blood creatinine (Cr), blood sodium ion (Na), peripheral blood leukocytes (WBC), alpha-fetoprotein (AFP), international normalized ratio (INR) of blood coagulation and prothrombin time (PT) were signiifcantly different in the group who died, but the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin (ALB) and hemoglobin (HGB) were not different between the two groups. At the same time, a regression model, Logit (P)=1.573×Age+1.338× HE-1.608×CHO+0.011×Cr-0.109×Na+1.298×INR+11.057, was constructed by logistic regression analysis and the prognostic value of the model was higher than that of the MELD score. CONCLUSIONS:Multivariate analysis excels univariate anlysis in the prognosis of chronic severe hepatitis, and the regression model is of signiifcant value in the prognosis of this disease.

  12. CGG repeat-associated translation mediates neurodegeneration in fragile X tremor ataxia syndrome.

    Science.gov (United States)

    Todd, Peter K; Oh, Seok Yoon; Krans, Amy; He, Fang; Sellier, Chantal; Frazer, Michelle; Renoux, Abigail J; Chen, Kai-chun; Scaglione, K Matthew; Basrur, Venkatesha; Elenitoba-Johnson, Kojo; Vonsattel, Jean P; Louis, Elan D; Sutton, Michael A; Taylor, J Paul; Mills, Ryan E; Charlet-Berguerand, Nicholas; Paulson, Henry L

    2013-05-01

    Fragile X-associated tremor ataxia syndrome (FXTAS) results from a CGG repeat expansion in the 5' UTR of FMR1. This repeat is thought to elicit toxicity as RNA, yet disease brains contain ubiquitin-positive neuronal inclusions, a pathologic hallmark of protein-mediated neurodegeneration. We explain this paradox by demonstrating that CGG repeats trigger repeat-associated non-AUG-initiated (RAN) translation of a cryptic polyglycine-containing protein, FMRpolyG. FMRpolyG accumulates in ubiquitin-positive inclusions in Drosophila, cell culture, mouse disease models, and FXTAS patient brains. CGG RAN translation occurs in at least two of three possible reading frames at repeat sizes ranging from normal (25) to pathogenic (90), but inclusion formation only occurs with expanded repeats. In Drosophila, CGG repeat toxicity is suppressed by eliminating RAN translation and enhanced by increased polyglycine protein production. These studies expand the growing list of nucleotide repeat disorders in which RAN translation occurs and provide evidence that RAN translation contributes to neurodegeneration. PMID:23602499

  13. The P66Shc/Mitochondrial Permeability Transition Pore Pathway Determines Neurodegeneration

    Directory of Open Access Journals (Sweden)

    Costanza Savino

    2013-01-01

    Full Text Available Mitochondrial-mediated oxidative stress and apoptosis play a crucial role in neurodegenerative disease and aging. Both mitochondrial permeability transition (PT and swelling of mitochondria have been involved in neurodegeneration. Indeed, knockout mice for cyclophilin-D (Cyc-D, a key regulatory component of the PT pore (PTP that triggers mitochondrial swelling, resulted to be protected in preclinical models of multiple sclerosis (MS, Parkinson’s disease (PD, and amyotrophic lateral sclerosis (ALS. However, how neuronal stress is transduced into mitochondrial oxidative stress and swelling is unclear. Recently, the aging determinant p66Shc that generates H2O2 reacting with cytochrome c and induces oxidation of PTP and mitochondrial swelling was found to be involved in MS and ALS. To investigate the role of p66Shc/PTP pathway in neurodegeneration, we performed experimental autoimmune encephalomyelitis (EAE experiments in p66Shc knockout mice (p66Shc−/−, knock out mice for cyclophilin-D (Cyc-D−/−, and p66Shc Cyc-D double knock out (p66Shc/Cyc-D−/− mice. Results confirm that deletion of p66Shc protects from EAE without affecting immune response, whereas it is not epistatic to the Cyc-D mutation. These findings demonstrate that p66Shc contributes to EAE induced neuronal damage most likely through the opening of PTP suggesting that p66Shc/PTP pathway transduces neurodegenerative stresses.

  14. Modelling the effects of ionizing radiation on survival of animal population: acute versus chronic exposure.

    Science.gov (United States)

    Kryshev, A I; Sazykina, T G

    2015-03-01

    The objective of the present paper was application of a model, which was originally developed to simulate chronic ionizing radiation effects in a generic isolated population, to the case of acute exposure, and comparison of the dynamic features of radiation effects on the population survival in cases of acute and chronic exposure. Two modes of exposure were considered: acute exposure (2-35 Gy) and chronic lifetime exposure with the same integrated dose. Calculations were made for a generic mice population; however, the model can be applied for other animals with proper selection of parameter values. In case of acute exposure, in the range 2-11 Gy, the population response was in two phases. During a first phase, there was a depletion in population survival; the second phase was a recovery period due to reparation of damage and biosynthesis of new biomass. Model predictions indicate that a generic mice population, living in ideal conditions, has the potential for recovery (within a mouse lifetime period) from acute exposure with dose up to 10-11 Gy, i.e., the population may recover from doses above an LD50 (6.2 Gy). Following acute doses above 14 Gy, however, the mice population went to extinction without recovery. In contrast, under chronic lifetime exposures (500 days), radiation had little effect on population survival up to integrated doses of 14-15 Gy, so the survival of a population subjected to chronic exposure was much better compared with that after an acute exposure with the same dose. Due to the effect of "wasted radiation", the integrated dose of chronic exposure could be about two times higher than acute dose, producing the same effect on survival. It is concluded that the developed generic population model including the repair of radiation damage can be applied both to acute and chronic modes of exposure; results of calculations for generic mice population are in qualitative agreement with published data on radiation effects in mice. PMID

  15. A model of hemo-immunopoietic system adaptation to chronic low and intermediate radiation doses

    International Nuclear Information System (INIS)

    In this paper radiobiological conformities to natural laws of mice's hemoimmunopoiesis systems (lines CBA and C57 Bl/6) were investigated upon chronic internal with lowering power doses of β- irradiation 90Sr and external γ-irradiation with constant power. It was shown that determinative effects of long chronic irradiation become apparent upon development of chronic radioactive effect for experimental animals were observed upon γ-irradiation with power 6 cGy/day and more or under internal with lowering power dose of β-irradiation 90Sr introduced in concentration above 1.1 c Bq/g, that is correlated with appreciations of other author's made before, concerning 'critical' level of power doses for hemopoietic system. It was shown that reduction of medium length of animals' life correlates with dis-balance into a system and between systems' links of immuno- and hemopoiesis. Physiological balance of those systems was supplied genetically by determinative systems of sanogenesis, responded for forming adaptive processes in organism. Characteristics of positive and negative inter and outward systems' links, induced by additional radiation exposure and noticeably modified constitutive regulative mechanisms being before were made more exact. A model for adaptation of hemoimmunopoiesis system to chronic radiation exposure in a rate of low and intermediate power doses was modeled. A possibility of full or part regeneration of hemopoiesis depending on power dose and kind of irradiation was experimentally substantiated. (author)

  16. Individualizing Opioid Use Disorder (OUD Treatment: Time to Fully Embrace a Chronic Disease Model

    Directory of Open Access Journals (Sweden)

    Richard Gustin

    2015-02-01

    Full Text Available The current opioid epidemic in the United States is changing our perceptions of the face of addiction. Opioid Use Disorder (OUD has become pervasive and is affecting all ethnicities, races, socioeconomic classes, the young and the old. In 2015, 46 people will lose their life each day to a chronic brain disease that is going unnoticed and undertreated. Over the last five decades, numerous scientific and clinical breakthroughs have allowed for a better understanding of the mechanisms underlying addiction, and the development of medications that can help support a patient’s long-term recovery. All of those that have contributed to these advancements have aided in redefining addiction as a primary, chronic disease of the brain reward, motivation, memory and related circuitry; however, our treatment strategies have not necessarily advanced to the same extent as our current understanding of the disease. This commentary will explore how personal philosophies can bias treatments strategies and definitions of treatment success, and prevent adoption of chronic disease treatment models that would significantly improve the quality of life of those suffering with OUD. This is a challenge to consider how our views and stigma can impact a patient’s recovery. We are currently losing a battle with a disease that is taking the lives of 46 individuals daily; it is time to fully embrace a chronic disease model which comprises an integrated pharmacopsychosocial approach for treating the biopsychosocial disorder that is addiction to reverse these trends.

  17. Combined Population Dynamics and Entropy Modelling Supports Patient Stratification in Chronic Myeloid Leukemia

    Science.gov (United States)

    Brehme, Marc; Koschmieder, Steffen; Montazeri, Maryam; Copland, Mhairi; Oehler, Vivian G.; Radich, Jerald P.; Brümmendorf, Tim H.; Schuppert, Andreas

    2016-04-01

    Modelling the parameters of multistep carcinogenesis is key for a better understanding of cancer progression, biomarker identification and the design of individualized therapies. Using chronic myeloid leukemia (CML) as a paradigm for hierarchical disease evolution we show that combined population dynamic modelling and CML patient biopsy genomic analysis enables patient stratification at unprecedented resolution. Linking CD34+ similarity as a disease progression marker to patient-derived gene expression entropy separated established CML progression stages and uncovered additional heterogeneity within disease stages. Importantly, our patient data informed model enables quantitative approximation of individual patients’ disease history within chronic phase (CP) and significantly separates “early” from “late” CP. Our findings provide a novel rationale for personalized and genome-informed disease progression risk assessment that is independent and complementary to conventional measures of CML disease burden and prognosis.

  18. Meeting report: 2009 international conference on molecular neurodegeneration May 18-20, 2009, Xiamen, China

    OpenAIRE

    Owens Lisa; Zhang Yunwu; Bu Guojun

    2009-01-01

    Abstract Age-related neurodegenerative diseases are great challenges as the aging population grows. To promote neurodegeneration research and to share recent progress in understanding molecular mechanisms underlying these devastating diseases, the journal Molecular Neurodegeneration and Institute for Biomedical Research, Xiamen University co-organized the 2009 International Conference on Molecular Neurodegeneration in Xiamen, China on May 18-20, 2009. The objectives of this meeting were to (1...

  19. Treatment of severe chronic hypotonic hyponatremia: a new treatment model

    Directory of Open Access Journals (Sweden)

    Antonio Burgio

    2013-03-01

    Full Text Available Recommended treatment of severe hypotonic hyponatremia is based on the infusion of 3% sodium chloride solution, with a daily correction rate below 10 mEq/L of sodium concentration, according to the Adrogué and Madias formula that includes the current desired change in sodium concentrations. However, such treatment needs close monitoring of the rate of infusion and does not take into account the body weight or age of the patient. This may result in hypercorrection and neurological damage. We made an inverse calculation using the same algorithms of the Adrogué and Madias formula to estimate the number of vials of sodium chloride needed to reach a correction rate of the serum sodium concentration below 0.4 mEq/h, taking into account the body weight and age of the patient. Three tables have been produced, each containing the number of vials to be infused, according to the patient’s age and body weight, the serum sodium concentration, and the rate of correction over 24 h to avoid the risk of brain damage. We propose a new practical model to calculate the need of sodium chloride infusate to safely correct the hyponatremia. The tables make treatment easier to manage in daily clinical practice in a wide range of patient ages and body weights.

  20. Phage therapy of staphylococcal chronic osteomyelitis in experimental animal model

    Directory of Open Access Journals (Sweden)

    Chandan Kishor

    2016-01-01

    Full Text Available Background & objectives: Methicillin resistant Staphylococcus aureus (MRSA are the commonest cause of osteomyelitis. The aim of this study was to evaluate the role of an alternative therapy i.e. application of S. aureus specific bacteriophages in cases of osteomyelitis caused by MRSA in animal model. Methods: Twenty two rabbits were included in this study. The first two rabbits were used to test the safety of phage cocktail while the remaining 20 rabbits were divided into three groups; group A (n=4 to assess the establishment of osteomyelitis; group B (n=4 osteomyelitis developed but therapy started only after six weeks; and group C (n=12 osteomyelitis developed and therapy started after three weeks. Groups B and C rabbits were treated with four doses of cocktail of seven virulent bacteriophages at the interval of 48 h. Comparison between three groups was made on the basis of observation of clinical, radiological, microbiological, and histopathological examinations. Results: Experimental group rabbits recovered from the illness in the subsequent two weeks of the therapy. Appetite and activity of the rabbits improved, local oedema, erythema and induration subsided. There were minimal changes associated with osteomyelitis in X-ray and histopathology also showed no signs of infection with new bone formation. Control B group rabbits also recovered well from the infection. Interpretation & conclusions: The present study shows a potential of phage therapy to treat difficult infections caused by multidrug resistant bacteria.

  1. Describing and analysing primary health care system support for chronic illness care in Indigenous communities in Australia's Northern Territory – use of the Chronic Care Model

    Directory of Open Access Journals (Sweden)

    Stewart Allison

    2008-05-01

    Full Text Available Abstract Background Indigenous Australians experience disproportionately high prevalence of, and morbidity and mortality from chronic illness such as diabetes, renal disease and cardiovascular disease. Improving the understanding of how Indigenous primary care systems are organised to deliver chronic illness care will inform efforts to improve the quality of care for Indigenous people. Methods This cross-sectional study was conducted in 12 Indigenous communities in Australia's Northern Territory. Using the Chronic Care Model as a framework, we carried out a mail-out survey to collect information on material, financial and human resources relating to chronic illness care in participating health centres. Follow up face-to-face interviews with health centre staff were conducted to identify successes and difficulties in the systems in relation to providing chronic illness care to community members. Results Participating health centres had distinct areas of strength and weakness in each component of systems: 1 organisational influence – strengthened by inclusion of chronic illness goals in business plans, appointment of designated chronic disease coordinators and introduction of external clinical audits, but weakened by lack of training in disease prevention and health promotion and limited access to Medicare funding; 2 community linkages – facilitated by working together with community organisations (e.g. local stores and running community-based programs (e.g. "health week", but detracted by a shortage of staff especially of Aboriginal health workers working in the community; 3 self management – promoted through patient education and goal setting with clients, but impeded by limited focus on family and community-based activities due to understaffing; 4 decision support – facilitated by distribution of clinical guidelines and their integration with daily care, but limited by inadequate access to and support from specialists; 5 delivery system

  2. Regulated protein aggregation: stress granules and neurodegeneration

    OpenAIRE

    Wolozin Benjamin

    2012-01-01

    Abstract The protein aggregation that occurs in neurodegenerative diseases is classically thought to occur as an undesirable, nonfunctional byproduct of protein misfolding. This model contrasts with the biology of RNA binding proteins, many of which are linked to neurodegenerative diseases. RNA binding proteins use protein aggregation as part of a normal regulated, physiological mechanism controlling protein synthesis. The process of regulated protein aggregation is most evident in formation ...

  3. Stability Analysis of a Simplified Yet Complete Model for Chronic Myelegenous Leukemia

    CERN Document Server

    Jauffret, Marie Doumic; Perthame, Benoît

    2009-01-01

    We analyze the asymptotic behavior of a partial differential equation (PDE) model for hematopoiesis. This PDE model is derived from the original agent-based model formulated by (Roeder et al., Nat. Med., 2006), and it describes the progression of blood cell development from the stem cell to the terminally differentiated state. To conduct our analysis, we start with the PDE model of (Kim et al, JTB, 2007), which coincides very well with the simulation results obtained by Roeder et al. We simplify the PDE model to make it amenable to analysis and justify our approximations using numerical simulations. An analysis of the simplified PDE model proves to exhibit very similar properties to those of the original agent-based model, even if for slightly different parameters. Hence, the simplified model is of value in understanding the dynamics of hematopoiesis and of chronic myelogenous leukemia, and it presents the advantage of having fewer parameters, which makes comparison with both experimental data and alternative...

  4. The phenomenological-existential comprehension of chronic pain: going beyond the standing healthcare models.

    Science.gov (United States)

    Lima, Daniela Dantas; Alves, Vera Lucia Pereira; Turato, Egberto Ribeiro

    2014-01-01

    A distinguishing characteristic of the biomedical model is its compartmentalized view of man. This way of seeing human beings has its origin in Greek thought; it was stated by Descartes and to this day it still considers humans as beings composed of distinct entities combined into a certain form. Because of this observation, one began to believe that the focus of a health treatment could be exclusively on the affected area of the body, without the need to pay attention to patient's subjectivity. By seeing pain as a merely sensory response, this model was not capable of encompassing chronic pain, since the latter is a complex process that can occur independently of tissue damage. As of the second half of the twentieth century, when it became impossible to deny the relationship between psyche and soma, the current understanding of chronic pain emerges: that of chronic pain as an individual experience, the result of a sum of physical, psychological, and social factors that, for this reason, cannot be approached separately from the individual who expresses pain. This understanding has allowed a significant improvement in perspective, emphasizing the characteristic of pain as an individual experience. However, the understanding of chronic pain as a sum of factors corresponds to the current way of seeing the process of falling ill, for its conception holds a Cartesian duality and the positivist premise of a single reality. For phenomenology, on the other hand, the individual in his/her unity is more than a simple sum of parts. Phenomenology sees a human being as an intending entity, in which body, mind, and the world are intertwined and constitute each other mutually, thus establishing the human being's integral functioning. Therefore, a real understanding of the chronic pain process would only be possible from a phenomenological point of view at the experience lived by the individual who expresses and communicates pain. PMID:24410937

  5. Economic evaluation in chronic pain: a systematic review and de novo flexible economic model.

    Science.gov (United States)

    Sullivan, W; Hirst, M; Beard, S; Gladwell, D; Fagnani, F; López Bastida, J; Phillips, C; Dunlop, W C N

    2016-07-01

    There is unmet need in patients suffering from chronic pain, yet innovation may be impeded by the difficulty of justifying economic value in a field beset by data limitations and methodological variability. A systematic review was conducted to identify and summarise the key areas of variability and limitations in modelling approaches in the economic evaluation of treatments for chronic pain. The results of the literature review were then used to support the development of a fully flexible open-source economic model structure, designed to test structural and data assumptions and act as a reference for future modelling practice. The key model design themes identified from the systematic review included: time horizon; titration and stabilisation; number of treatment lines; choice/ordering of treatment; and the impact of parameter uncertainty (given reliance on expert opinion). Exploratory analyses using the model to compare a hypothetical novel therapy versus morphine as first-line treatments showed cost-effectiveness results to be sensitive to structural and data assumptions. Assumptions about the treatment pathway and choice of time horizon were key model drivers. Our results suggest structural model design and data assumptions may have driven previous cost-effectiveness results and ultimately decisions based on economic value. We therefore conclude that it is vital that future economic models in chronic pain are designed to be fully transparent and hope our open-source code is useful in order to aspire to a common approach to modelling pain that includes robust sensitivity analyses to test structural and parameter uncertainty. PMID:26377997

  6. The p47phox mouse knock-out model of chronic granulomatous disease

    OpenAIRE

    1995-01-01

    Chronic granulomatous disease (CGD) is caused by a congenital defect in phagocyte reduced nicotinamide dinucleotide phosphate (NADPH) oxidase production of superoxide and related species. It is characterized by recurrent life-threatening bacterial and fungal infections and tissue granuloma formation. We have created a mouse model of CGD by targeted disruption of p47phox, one of the genes in which mutations cause human CGD. Identical to the case in human CGD, leukocytes from p47phox-/- mice pr...

  7. The Chronic Care Model and Diabetes Management in US Primary Care Settings: A Systematic Review

    OpenAIRE

    Stellefson, Michael; Dipnarine, Krishna; Stopka, Christine

    2013-01-01

    Introduction The Chronic Care Model (CCM) uses a systematic approach to restructuring medical care to create partnerships between health systems and communities. The objective of this study was to describe how researchers have applied CCM in US primary care settings to provide care for people who have diabetes and to describe outcomes of CCM implementation. Methods We conducted a literature review by using the Cochrane database of systematic reviews, CINAHL, and Health Source: Nursing/Academi...

  8. Chronic antioxidant therapy reduces oxidative stress in a mouse model of Alzheimer’s disease

    OpenAIRE

    Siedlak, Sandra L.; Casadesus, Gemma; Webber, Kate M; Pappolla, Miguel A.; Atwood, Craig S.; Smith, Mark A.; Perry, George

    2009-01-01

    Oxidative modifications are a hallmark of oxidative imbalance in the brains of individuals with Alzheimer’s, Parkinson’s and prion diseases and their respective animal models. While the causes of oxidative stress are relatively well-documented, the effects of chronically reducing oxidative stress on cognition, pathology and biochemistry require further clarification. To address this, young and aged control and amyloid-β protein precursor-over-expressing mice were fed a diet with added R-alpha...

  9. Quantitative Modeling of Microbial Population Responses to Chronic Irradiation Combined with Other Stressors

    OpenAIRE

    Shuryak, Igor; Dadachova, Ekaterina

    2016-01-01

    Microbial population responses to combined effects of chronic irradiation and other stressors (chemical contaminants, other sub-optimal conditions) are important for ecosystem functioning and bioremediation in radionuclide-contaminated areas. Quantitative mathematical modeling can improve our understanding of these phenomena. To identify general patterns of microbial responses to multiple stressors in radioactive environments, we analyzed three data sets on: (1) bacteria isolated from soil co...

  10. Degeneration in Arousal Neurons in Chronic Sleep Disruption Modeling Sleep Apnea

    OpenAIRE

    Zhu, Yan; Fenik, Polina; Zhan, Guanxia; Xin, Ryan; Veasey, Sigrid C.

    2015-01-01

    Chronic sleep disruption (CSD) is a cardinal feature of sleep apnea that predicts impaired wakefulness. Despite effective treatment of apneas and sleep disruption, patients with sleep apnea may have persistent somnolence. Lasting wake disturbances in treated sleep apnea raise the possibility that CSD may induce sufficient degeneration in wake-activated neurons (WAN) to cause irreversible wake impairments. Implementing a stereological approach in a murine model of CSD, we found reduced neurona...

  11. Modeling PD pathogenesis in mice: advantages of a chronic MPTP protocol

    OpenAIRE

    Meredith, Gloria E.; Totterdell, Susan; Potashkin, Judith A.; Surmeier, D. James

    2008-01-01

    Formidable challenges for Parkinson's disease (PD) research are to understand the processes underlying nigrostriatal degeneration and how to protect the dopamine neurons. Fundamental research relies on good animal models that demonstrate the pathological hallmarks and motor deficits of PD. Using a chronic regimen of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and probenecid (MPTP/p) in mice, dopamine cell loss exceeds 60%, extracellular glutamate is elevated, cytoplasmic inclusions are forme...

  12. An animal model of panic vulnerability with chronic disinhibition of the dorsomedial/perifornical hypothalamus

    OpenAIRE

    Johnson, Philip L.; Shekhar, Anantha

    2012-01-01

    Panic disorder (PD) is a severe anxiety disorder characterized by susceptibility to induction of panic attacks by subthreshold interoceptive stimuli such as sodium lactate infusions or hypercapnia induction. Here we review a model of panic vulnerability in rats involving chronic inhibition of GABAergic tone in the dorsomedial/ perifornical hypothalamic (DMH/PeF) region that produces enhanced anxiety and freezing responses in fearful situations, as well as a vulnerability to displaying acute p...

  13. The Biopsychosocial Model of Treatment the Patients with Inflammatory Chronic Bowel Disease

    OpenAIRE

    Rakovec-Felser, Zlatka

    2011-01-01

    We present the organised psychological group interventions for persons with inflammatory bowel disease (ulcerose colitis, Morbus Crohn). The actual bio-psychosocial model of health and illness is used to explain the situation of chronically ill patient as stressful life position and their ways of coping with such, health-related problems. Considering that numerous psychological factors can lead to insufficient illness adaptation and (non) adherence to treatment – and all those – t...

  14. Care production for tuberculosis cases:analysis according to the elements of the Chronic Care Model

    OpenAIRE

    Daiane Medeiros da Silva; Hérika Brito Gomes de Farias; Tereza Cristina Scatena Villa; Lenilde Duarte de Sá; Maria Eugênia Firmino Brunello; Jordana Almeida Nogueira

    2016-01-01

    Abstract OBJECTIVE: To analyze the care provided to tuberculosis cases in primary health care services according to the elements of the Chronic Care Model. METHOD: Cross-sectional study conducted in a capital city of the northeastern region of Brazil involving 83 Family Health Strategy professionals.A structured tool adapted to tuberculosis-related care in Brazil was applied.Analysis was based on the development of indicators with capacity to produce care varying between limited and optimum...

  15. Disease management projects and the Chronic CareModel in action: Baseline qualitative research

    OpenAIRE

    Hipple-Walters, Bethany; Adams, Samantha; Nieboer, Anna; Bal, Roland

    2012-01-01

    textabstractBackground: Disease management programs, especially those based on the Chronic Care Model (CCM),are increasingly common in the Netherlands. While disease management programs have beenwell-researched quantitatively and economically, less qualitative research has been done. Theoverall aim of the study is to explore how disease management programs are implementedwithin primary care settings in the Netherlands; this paper focuses on the early developmentand implementation stages of fi...

  16. Disease management projects and the Chronic Care Model in action: baseline qualitative research

    OpenAIRE

    Walters Bethany; Adams Samantha A; Nieboer Anna P; Bal Roland

    2012-01-01

    Abstract Background Disease management programs, especially those based on the Chronic Care Model (CCM), are increasingly common in the Netherlands. While disease management programs have been well-researched quantitatively and economically, less qualitative research has been done. The overall aim of the study is to explore how disease management programs are implemented within primary care settings in the Netherlands; this paper focuses on the early development and implementation stages of f...

  17. An optimised mouse model of chronic pancreatitis with a combination of ethanol and cerulein

    Science.gov (United States)

    Ahmadi, Abbas; Nikkhoo, Bahram; Mokarizadeh, Aram; Rahmani, Mohammad-Reza; Fakhari, Shohreh; Mohammadi, Mehdi

    2016-01-01

    Introduction Chronic pancreatitis (CP) is an intractable and multi-factorial disorder. Developing appropriate animal models is an essential step in pancreatitis research, and the best ones are those which mimic the human disorder both aetiologically and pathophysiologically. The current study presents an optimised protocol for creating a murine model of CP, which mimics the initial steps of chronic pancreatitis in alcohol chronic pancreatitis and compares it with two other mouse models treated with cerulein or ethanol alone. Material and methods Thirty-two male C57BL/6 mice were randomly selected, divided into four groups, and treated intraperitoneally with saline (10 ml/kg, control group), ethanol (3 g/kg; 30% v/v), cerulein (50 µg/kg), or ethanol + cerulein, for six weeks. Histopathological and immunohistochemical assays for chronic pancreatitis index along with real-time PCR assessments for mRNA levels of inflammatory cytokines and fibrogenic markers were conducted to verify the CP induction. Results The results indicated that CP index (CPI) was significantly increased in ethanol-cerulein mice compared to the saline, ethanol, and cerulein groups (p < 0.001). Interleukin 1β (IL-1β), tumor necrosis factor α (TNF-α), transforming growth factor β (TGF-β), α-smooth muscle actin (α-SMA), and myeloperoxidase activity were also significantly greater in both cerulein and ethanol-cerulein groups than in the saline treated animals (p < 0.001). Immunohistochemical analysis revealed enhanced expression of TGF-β and α-SMA in ethanol-cerulein mice compared to the saline group. Conclusions Intraperitoneal (IP) injections of ethanol and cerulein could successfully induce CP in mice. IP injections of ethanol provide higher reproducibility compared to ethanol feeding. The model is simple, non-invasive, reproducible, and time-saving. Since the protocol mimics the initial phases of CP development in alcoholics, it can be used for investigating basic mechanisms and testing

  18. Hemodynamic and Histologic Characterization of a Swine (Sus scrofa domestica) Model of Chronic Pulmonary Arterial Hypertension

    OpenAIRE

    Rothman, Abraham; Wiencek, Robert G; Davidson, Stephanie; William N. Evans; Restrepo, Humberto; Sarukhanov, Valeri; Rivera-Begeman, Amanda; Mann, David

    2011-01-01

    The purpose of this work was to develop and characterize an aortopulmonary shunt model of chronic pulmonary hypertension in swine and provide sequential hemodynamic, angiographic, and histologic data by using an experimental endoarterial biopsy catheter. Nine Yucatan female microswine (Sus scrofa domestica) underwent surgical anastomosis of the left pulmonary artery to the descending aorta. Sequential hemodynamic, angiographic, and pulmonary vascular samples were obtained. Six pigs (mean weig...

  19. Enzymology of Pyrimidine Metabolism and Neurodegeneration.

    Science.gov (United States)

    Vincenzetti, Silvia; Polzonetti, Valeria; Micozzi, Daniela; Pucciarelli, Stefania

    2016-01-01

    It is well known that disorders of pyrimidine pathways may lead to neurological, hematological, immunological diseases, renal impairments, and association with malignancies. Nucleotide homeostasis depends on the three stages of pyrimidine metabolism: de novo synthesis, catabolism and recycling of these metabolites. Cytidine and uridine, in addition to be used as substrates for pyrimidine nucleotide salvaging, also act as the precursors of cytidine triphosphate used in the biosynthetic pathway of both brain's phosphatidylcholine and phosphatidylethanolamine via the Kennedy cycle. The synthesis in the brain of phosphatidylcholine and other membrane phosphatides can utilize, in addition to glucose, three compounds present in the blood stream: choline, uridine, and a polyunsaturated fatty acids like docosahexaenoic acid. Some authors, using rat models, found that oral administration of two phospholipid precursors such as uridine and omega-3 fatty acids, along with choline from the diet, can increase the amount of synaptic membrane generated by surviving striatal neurons in rats with induced Parkinson's disease. Other authors found that in hypertensive rat fed with uridine and choline, cognitive deficit resulted improved. Uridine has also been recently considered as a neuroactive molecule, because of its involvement in important neurological functions by improving memory, sleep disorders, anti-epileptic effects, as well as neuronal plasticity. Cytidine and uridine are uptaken by the brain via specific receptors and successively salvaged to the corresponding nucleotides. The present review is devoted to the enzymology of pyrimidine pathways whose importance has attracted the attention of several researchers investigating on the mechanisms underlying the physiopathology of brain. PMID:27063261

  20. Sporadic ALS/MND: a global neurodegeneration with retroviral involvement?

    Science.gov (United States)

    Westarp, M E; Ferrante, P; Perron, H; Bartmann, P; Kornhuber, H H

    1995-05-01

    Sporadic amyotrophic lateral sclerosis may be an aetiologically heterogenous disease. We confirmed elevated circulating IgG immune complexes, and altered IgG seroreactivities against human retroviral antigens (HIV-2 and HTLV immunoblots) in overlapping subgroups of patients. Together with preliminary findings of a positive polymerase chain reactivity for human T-lymphotropic virus (HTLV.tax/rex) in blood leukocytes of 5 out of 14 sALS patients, we interpret this as evidence for a retroviral involvement in this relentlessly progressive, often asymmetrically spreading neurodegeneration. The possibility of a secondary phenomenon seems unlikely, yet cannot be completely ruled out. PMID:7595609

  1. Neurodegeneration with Brain Iron Accumulation: Diagnosis and Management

    Directory of Open Access Journals (Sweden)

    Penelope Hogarth

    2015-01-01

    Full Text Available Neurodegeneration with brain iron accumulation (NBIA encompasses a group of inherited disorders that share the clinical features of an extrapyramidal movement disorder accompanied by varying degrees of intellectual disability and abnormal iron deposition in the basal ganglia. The genetic basis of ten forms of NBIA is now known. The clinical features of NBIA range from rapid global neurodevelopmental regression in infancy to mild parkinsonism with minimal cognitive impairment in adulthood, with wide variation seen between and within the specific NBIA sub-type. This review describes the clinical presentations, imaging findings, pathologic features, and treatment considerations for this heterogeneous group of disorders.

  2. Multiple sclerosis and fatigue: A review on the contribution of inflammation and immune-mediated neurodegeneration.

    Science.gov (United States)

    Patejdl, Robert; Penner, Iris K; Noack, Thomas K; Zettl, Uwe K

    2016-03-01

    Multiple sclerosis (MS) is an immune mediated disease of the central nervous system (CNS) and the leading cause of non-traumatic disability among young and middle-aged adults in the western world. One of its most prevalent and debilitating symptoms is fatigue. Despite the general acceptance of the idea of an immune pathogenesis of MS itself, the role of autoimmunity in the course of MS-fatigue is a matter of debate. Both immune-related processes (acute inflammation, chronic inflammation, immune-mediated neurodegeneration, immune-mediated alterations of endocrine functions related to fatigue) and presumably non-immune-mediated disturbances and factors (sleep disturbances, depression, cognitive alterations, chronic infections, adverse effects of medications) contribute to the clinical picture. Data from in vitro and animal experiments has provided evidence for a role of cytokines as IL-1 and TNF-alpha. This association could not be verified directly in blood samples from humans whereas whole blood stimulation protocols gave some indirect evidence for a role of cytokines in MS-fatigue. MRI being able to detect acute and chronic immune mediated damage to the CNS could depict that global atrophy of gray or white matter does not correlate with fatigue. Rather, distinctive clusters of lesions and atrophy at different locations, mostly bifrontal or in subcortical structures, correlate specifically with fatigue. Regardless of the difficulties in pinpointing the immunogenesis of MS-fatigue, an important role of autoimmunity is strongly supported by an indirect route: A growing amount of data shows that the highly effective immunotherapeutics which have been introduced to MS-treatment over the last years effectively and sustainably stabilize and ameliorate fatigue in parallel to their dampening effects on the neuroinflammatory process. This review summarizes the existing data on the relation between inflammation, patterns of CNS-lesions and the effects of immunotherapeutics

  3. A microsimulation model for the development and progression of chronic obstructive pulmonary disease.

    Science.gov (United States)

    Tan, Emma; Boessen, Ruud; Fishwick, David; Klein Entink, Rinke; Meijster, Tim; Pronk, Anjoeka; van Duuren-Stuurman, Birgit; Warren, Nick

    2015-12-01

    Chronic obstructive pulmonary disease (COPD) is a chronic lung disease that is thought to affect over one million people in Great Britain. The main factor contributing to the development of COPD is tobacco smoke. This paper presents a microsimulation model for the development of COPD, incorporating population dynamics and trends in smoking. The model simulates a population longitudinally throughout their lifetimes, providing projections of future COPD prevalence and evaluation of the effects of changes in risk factor prevalence such as smoking. Sensitivity analysis provides information on the most influential model parameters. The model-predicted prevalence of COPD in 2040 was 17% in males over the age of 35 years (13% amongst non-smokers and 22% amongst smokers), and a modest decline over the next 25 years due to recent trends in smoking rates. The simulation model provides us with valuable information on current and future trends in COPD in Great Britain. It was developed primarily to enable easy extension to evaluate the effects of occupational and environmental exposures on lung function and the prevalence of COPD and to allow evaluation of interventions, such as introducing health surveillance or policy changes. As longitudinal studies for investigating COPD are difficult due to the lengthy follow-up time required and the potentially large number of drop-outs, we anticipate that the model will provide a valuable tool for health impact assessment. An extended model for occupational exposures is under development and will be presented in a subsequent paper. PMID:26499910

  4. Hypericum perforatum treatment: effect on behaviour and neurogenesis in a chronic stress model in mice

    Directory of Open Access Journals (Sweden)

    Cuzzocrea Salvatore

    2011-01-01

    Full Text Available Abstract Background Extracts of Hypericum perforatum (St. John's wort have been traditionally recommended for a wide range of medical conditions, in particular mild-to-moderate depression. The present study was designed to investigate the effect of Hypericum perforatum treatment in a mouse model of anxiety/depressive-like behavior, induced by chronic corticosterone administration. Methods CD1 mice were submitted to 7 weeks corticosterone administration and then behavioral tests as Open Field (OF, Novelty-Suppressed Feeding (NSF, Forced Swim Test (FST were performed. Cell proliferation in hippocampal dentate gyrus (DG was investigated by both 5-bromo-2'-deoxyuridine (BrdU and doublecortin (DCX immunohistochemistry techniques and stereological procedure was used to quantify labeled cells. Golgi-impregnation method was used to evaluate changes in dendritic spines in DG. Hypericum perforatum (30 mg/Kg has been administered for 3 weeks and then neural development in the adult hippocampus and behavioral changes have been examined. Results The anxiety/depressive-like state due to chronic corticosterone treatment was reversed by exogenous administration of Hypericum perforatum; the proliferation of progenitor cells in mice hippocampus was significantly reduced under chronic corticosterone treatment, whereas a long term treatment with Hypericum perforatum prevented the corticosterone-induced decrease in hippocampal cell proliferation. Corticosterone-treated mice exhibited a reduced spine density that was ameliorated by Hypericum perforatum administration. Conclusion These results provide evidence of morphological adaptations occurring in mature hippocampal neurons that might underlie resilient responses to chronic stress and contribute to the therapeutic effects of chronic Hypericum perforatum treatment.

  5. Application of transtheoretical model to assess the compliance of chronic periodontitis patients to periodontal therapy

    Directory of Open Access Journals (Sweden)

    Shilpa Emani

    2016-01-01

    Full Text Available Background: The present cross-sectional survey study was conducted to assess whether the transtheoretical model for oral hygiene behavior was interrelated in theoretically consistent directions in chronic periodontitis patients and its applicability to assess the compliance of the chronic periodontitis patients to the treatment suggested. Materials and Methods: A total of 150 chronic periodontitis patients were selected for the proposed study. The selected patients were given four questionnaires that were constructed based on transtheoretical model (TTM, and the patients were divided subsequently into five different groups (precontemplation, contemplation, preparation, action, and maintenance groups based on their answers to the questionnaires. Then, each patient was given four appointments for their periodontal treatment spaced with a time gap of 10 days. The patients visit for each appointments scheduled to them was documented. The results obtained were assessed using TTM. Results: Higher mean pro scores of decisional balance, self-efficacy, and process of change scores was recorded in maintenance group followed by action group, preparation group, contemplation group, and precontemplation group, respectively, whereas higher mean cons score was recorded in precontemplation group followed by contemplation group, preparation group, action group, and maintenance group, respectively. The difference scores of TTM constructs were statistically highly significant between all the five groups. Furthermore, the number of appointment attended in were significantly more than maintenance group followed by action group, preparation group, contemplation group, and precontemplation group. Conclusion: Within the limitations of this study, it can be concluded that transtheoretical model can be successfully applied to chronic periodontitis patients to assess their compliance to the suggested periodontal treatment.

  6. Application of transtheoretical model to assess the compliance of chronic periodontitis patients to periodontal therapy

    Science.gov (United States)

    Emani, Shilpa; Thomas, Raison; Shah, Rucha; Mehta, Dhoom Singh

    2016-01-01

    Background: The present cross-sectional survey study was conducted to assess whether the transtheoretical model for oral hygiene behavior was interrelated in theoretically consistent directions in chronic periodontitis patients and its applicability to assess the compliance of the chronic periodontitis patients to the treatment suggested. Materials and Methods: A total of 150 chronic periodontitis patients were selected for the proposed study. The selected patients were given four questionnaires that were constructed based on transtheoretical model (TTM), and the patients were divided subsequently into five different groups (precontemplation, contemplation, preparation, action, and maintenance groups) based on their answers to the questionnaires. Then, each patient was given four appointments for their periodontal treatment spaced with a time gap of 10 days. The patients visit for each appointments scheduled to them was documented. The results obtained were assessed using TTM. Results: Higher mean pro scores of decisional balance, self-efficacy, and process of change scores was recorded in maintenance group followed by action group, preparation group, contemplation group, and precontemplation group, respectively, whereas higher mean cons score was recorded in precontemplation group followed by contemplation group, preparation group, action group, and maintenance group, respectively. The difference scores of TTM constructs were statistically highly significant between all the five groups. Furthermore, the number of appointment attended in were significantly more than maintenance group followed by action group, preparation group, contemplation group, and precontemplation group. Conclusion: Within the limitations of this study, it can be concluded that transtheoretical model can be successfully applied to chronic periodontitis patients to assess their compliance to the suggested periodontal treatment. PMID:27307663

  7. Development and validation of a chronic copper biotic ligand model for Ceriodaphnia dubia

    International Nuclear Information System (INIS)

    A biotic ligand model (BLM) to predict chronic Cu toxicity to Ceriodaphnia dubia was developed and tested. The effect of cationic competition, pH and natural organic matter complexation of Cu was examined to develop the model. There was no effect of cationic competition using increasing Ca and Na concentrations in our exposures. However, we did see a significant regression of decreasing toxicity (measured as the IC25; concentration at which there was a 25% inhibition of reproduction) as Mg concentration increased. However, taking into account the actual variability of the IC25 and since the relative increase in IC25 due to additional Mg was small (1.5-fold) Mg competition was not included in the model. Changes in pH had a significant effect on Cu IC25, which is consistent with proton competition as often suggested for acute BLMs. Finally, natural organic matter (NOM) was added to exposures resulting in significant decreases in toxicity. Therefore, our predictive model for chronic Cu toxicity to C. dubia includes the effect of pH and NOM complexation. The model was validated with Cu IC25 data generated in six natural surface waters collected from across Canada. Using WHAM VI, we calculated Cu speciation in each natural water and using our model, we generated 'predicted' IC25 data. We successfully predicted all Cu IC25 within a factor of 3 for the six waters used for validation

  8. Development of Toxicological Risk Assessment Models for Acute and Chronic Exposure to Pollutants.

    Science.gov (United States)

    Reichwaldt, Elke S; Stone, Daniel; Barrington, Dani J; Sinang, Som C; Ghadouani, Anas

    2016-01-01

    Alert level frameworks advise agencies on a sequence of monitoring and management actions, and are implemented so as to reduce the risk of the public coming into contact with hazardous substances. Their effectiveness relies on the detection of the hazard, but with many systems not receiving any regular monitoring, pollution events often go undetected. We developed toxicological risk assessment models for acute and chronic exposure to pollutants that incorporate the probabilities that the public will come into contact with undetected pollution events, to identify the level of risk a system poses in regards to the pollutant. As a proof of concept, we successfully demonstrated that the models could be applied to determine probabilities of acute and chronic illness types related to recreational activities in waterbodies containing cyanotoxins. Using the acute model, we identified lakes that present a 'high' risk to develop Day Away From Work illness, and lakes that present a 'low' or 'medium' risk to develop First Aid Cases when used for swimming. The developed risk models succeeded in categorising lakes according to their risk level to the public in an objective way. Modelling by how much the probability of public exposure has to decrease to lower the risks to acceptable levels will enable authorities to identify suitable control measures and monitoring strategies. We suggest broadening the application of these models to other contaminants. PMID:27589798

  9. Mesenchymal stem cells ameliorate the histopathological changes in a murine model of chronic asthma.

    Science.gov (United States)

    Firinci, Fatih; Karaman, Meral; Baran, Yusuf; Bagriyanik, Alper; Ayyildiz, Zeynep Arikan; Kiray, Muge; Kozanoglu, Ilknur; Yilmaz, Osman; Uzuner, Nevin; Karaman, Ozkan

    2011-08-01

    Asthma therapies are effective in reducing inflammation but airway remodeling is poorly responsive to these agents. New therapeutic options that have fewer side effects and reverse chronic changes in the lungs are essential. Mesenchymal stem cells (MSCs) are promising for the development of novel therapies in regenerative medicine. This study aimed to examine the efficacy of MSCs on lung histopathology in a murine model of chronic asthma. BALB/c mice were divided into four groups: Group 1 (control group, n=6), Group 2 (ovalbumin induced asthma only, n=10), Group 3 (ovalbumin induced asthma + MSCs, n=10), and Group 4 (MSCs only, n=10). Histological findings (basement membrane, epithelium, subepithelial smooth muscle thickness, numbers of goblet and mast cells) of the airways and MSC migration were evaluated by light, electron, and confocal microscopes. In Group 3, all early histopathological changes except epithelial thickness and all of the chronic changes were significantly ameliorated when compared with Group 2. Evaluation with confocal microscopy showed that no noteworthy amount of MSCs were present in the lung tissues of Group 4 while significant amount of MSCs was detected in Group 3. Serum NO levels in Group 3, were significantly lower than Group 2. The results of this study revealed that MSCs migrated to lung tissue and ameliorated bronchial asthma in murine model. Further studies are needed to evaluate the efficacy of MSCs for the treatment of asthma. PMID:21439399

  10. Complementary therapy in chronic wound management: a holistic caring case study and praxis model.

    Science.gov (United States)

    Popoola, Mercy Mammah

    2003-01-01

    Holistic caring consists of providing care to each aspect of a patient's life through the use of therapeutic caring and complementary or alternative healing modalities. Since nursing consists of caring for the whole person and not just the disease process, consideration of a patient's physical, emotional, social, economic, spiritual, and cultural needs is necessary in dealing with any chronic health problem such as chronic wounds. In this model case studies presentation, the purpose of this article is to discuss the importance of the holistic caring approach and the use of complementary and alternative medicine or therapeutic modalities in chronic wound management. The use or role of theory in practice will also be discussed to emphasize the holistic caring praxis model used in the holistic assessment and holistic plan of care for the cases presented. This article also presents a framework that will help wound care and holistic nurses move from simply the positivist-modernist philosophy to begin to embrace the postmodernist philosophy. PMID:12784899

  11. Mild systemic thermal therapy ameliorates renal dysfunction in a rodent model of chronic kidney disease.

    Science.gov (United States)

    Iwashita, Yoshihiro; Kuwabara, Takashige; Hayata, Manabu; Kakizoe, Yutaka; Izumi, Yuichiro; Iiyama, Junichi; Kitamura, Kenichiro; Mukoyama, Masashi

    2016-06-01

    Thermal therapy has become a nonpharmacological therapy in clinical settings, especially for cardiovascular diseases. However, the practical role of thermal therapy on chronic kidney disease remains elusive. We performed the present study to investigate whether a modified thermal protocol, repeated mild thermal stimulation (MTS), could affect renal damages in chronic kidney disease using a mouse renal ablation model. Mice were subjected to MTS or room temperature (RT) treatment once daily for 4 wk after subtotal nephrectomy (Nx) or sham operation (Sh). We revealed that MTS alleviated renal impairment as indicated by serum creatinine and albuminuria in Nx groups. In addition, the Nx + MTS group showed attenuated tubular histological changes and reduced urinary neutrophil gelatinase-associated lipocalin excretion approximately by half compared with the Nx + RT group. Increased apoptotic signaling, such as TUNEL-positive cell count and cleavage of caspase 3, as well as enhanced oxidative stress were significantly reduced in the Nx + MTS group compared with the Nx + RT group. These changes were accompanied with the restoration of kidney Mn-SOD levels by MTS. Heat shock protein 27, a key molecular chaperone, was phosphorylated by MTS only in Nx kidneys rather than in Sh kidneys. MTS also tended to increase the phosphorylation of p38 MAPK and Akt in Nx kidneys, possibly associated with the activation of heat shock protein 27. Taken together, these results suggest that modified MTS can protect against renal injury in a rodent model of chronic kidney disease. PMID:27029428

  12. Review of the chronic exposure pathways models in MACCS [MELCOR Accident Consequence Code System] and several other well-known probabilistic risk assessment models

    International Nuclear Information System (INIS)

    The purpose of this report is to document the results of the work performed by the author in connection with the following task, performed for US Nuclear Regulatory Commission, (USNRC) Office of Nuclear Regulatory Research, Division of Systems Research: MACCS Chronic Exposure Pathway Models: Review the chronic exposure pathway models implemented in the MELCOR Accident Consequence Code System (MACCS) and compare those models to the chronic exposure pathway models implemented in similar codes developed in countries that are members of the OECD. The chronic exposures concerned are via: the terrestrial food pathways, the water pathways, the long-term groundshine pathway, and the inhalation of resuspended radionuclides pathway. The USNRC has indicated during discussions of the task that the major effort should be spent on the terrestrial food pathways. There is one chapter for each of the categories of chronic exposure pathways listed above

  13. Resistance to Recombinant Human Erythropoietin Therapy in a Rat Model of Chronic Kidney Disease Associated Anemia

    OpenAIRE

    Patrícia Garrido; Sandra Ribeiro; João Fernandes; Helena Vala; Petronila Rocha-Pereira; Elsa Bronze-da-Rocha; Luís Belo; Elísio Costa; Alice Santos-Silva; Flávio Reis

    2016-01-01

    This study aimed to elucidate the mechanisms explaining the persistence of anemia and resistance to recombinant human erythropoietin (rHuEPO) therapy in a rat model of chronic kidney disease (CKD)-associated anemia with formation of anti-rHuEPO antibodies. The remnant kidney rat model of CKD induced by 5/6 nephrectomy was used to test a long-term (nine weeks) high dose of rHuEPO (200 UI/kg bw/week) treatment. Hematological and biochemical parameters were evaluated as well as serum and tissue ...

  14. Therapeutic activity of two xanthones in a xenograft murine model of human chronic lymphocytic leukemia

    Directory of Open Access Journals (Sweden)

    Berthou Christian

    2010-12-01

    Full Text Available Abstract Background We previously reported that allanxanthone C and macluraxanthone, two xanthones purified from Guttiferae trees, display in vitro antiproliferative and proapoptotic activities in leukemic cells from chronic lymphocytic leukemia (CLL and leukemia B cell lines. Results Here, we investigated the in vivo therapeutic effects of the two xanthones in a xenograft murine model of human CLL, developed by engrafting CD5-transfected chronic leukemia B cells into SCID mice. Treatment of the animals with five daily injections of either allanxanthone C or macluraxanthone resulted in a significant prolongation of their survival as compared to control animals injected with the solvent alone (p = 0.0006 and p = 0.0141, respectively. The same treatment of mice which were not xenografted induced no mortality. Conclusion These data show for the first time the in vivo antileukemic activities of two plant-derived xanthones, and confirm their potential interest for CLL therapy.

  15. Disease management projects and the Chronic Care Model in action: baseline qualitative research

    Directory of Open Access Journals (Sweden)

    Walters Bethany

    2012-05-01

    Full Text Available Abstract Background Disease management programs, especially those based on the Chronic Care Model (CCM, are increasingly common in the Netherlands. While disease management programs have been well-researched quantitatively and economically, less qualitative research has been done. The overall aim of the study is to explore how disease management programs are implemented within primary care settings in the Netherlands; this paper focuses on the early development and implementation stages of five disease management programs in the primary care setting, based on interviews with project leadership teams. Methods Eleven semi-structured interviews were conducted at the five selected sites with sixteen professionals interviewed; all project directors and managers were interviewed. The interviews focused on each project’s chosen chronic illness (diabetes, eating disorders, COPD, multi-morbidity, CVRM and project plan, barriers to development and implementation, the project leaders’ action and reactions, as well as their roles and responsibilities, and disease management strategies. Analysis was inductive and interpretive, based on the content of the interviews. After analysis, the results of this research on disease management programs and the Chronic Care Model are viewed from a traveling technology framework. Results This analysis uncovered four themes that can be mapped to disease management and the Chronic Care Model: (1 changing the health care system, (2 patient-centered care, (3 technological systems and barriers, and (4 integrating projects into the larger system. Project leaders discussed the paths, both direct and indirect, for transforming the health care system to one that addresses chronic illness. Patient-centered care was highlighted as needed and a paradigm shift for many. Challenges with technological systems were pervasive. Project leaders managed the expenses of a traveling technology, including the social, financial, and

  16. Sensitization of the Hypothalamic-Pituitary-Adrenal Axis in a Male Rat Chronic Stress Model.

    Science.gov (United States)

    Franco, Alier J; Chen, Chun; Scullen, Tyler; Zsombok, Andrea; Salahudeen, Ahmed A; Di, Shi; Herman, James P; Tasker, Jeffrey G

    2016-06-01

    Stress activation of the hypothalamic-pituitary-adrenal (HPA) axis is regulated by rapid glucocorticoid negative feedback. Chronic unpredictable stress animal models recapitulate certain aspects of major depression in humans, which have been attributed to impaired glucocorticoid negative feedback. We tested for an attenuated HPA sensitivity to fast glucocorticoid feedback inhibition in male rats exposed to a chronic variable stress (CVS) paradigm. In vitro, parvocellular neuroendocrine cells of the hypothalamic paraventricular nucleus recorded in slices from CVS rats showed an increase in basal excitatory synaptic inputs and a decrease in basal inhibitory synaptic inputs compared with neurons from control rats. There was no difference between control and CVS-treated rats in the rapid glucocorticoid suppression of excitatory synaptic inputs, a fast feedback mechanism. In vivo, CVS-treated rats showed an increase in ACTH secretion at baseline and after both iv CRH and acute stress and no impairment of the corticosterone suppression of the ACTH response, compared with controls. In an in vitro pituitary preparation, an increase in basal ACTH release, a small increase in CRH-induced ACTH release, and no decrement in the glucocorticoid suppression of ACTH release were seen in pituitaries from CVS rats. Thus, CVS does not suppress rapid glucocorticoid negative feedback at the hypothalamus or pituitary, but increases the synaptic excitability of paraventricular nucleus CRH neurons and the CRH sensitivity of the pituitary. Therefore, increased HPA activity in chronically stressed male rats is due to sensitization of the HPA axis, rather than to desensitization to rapid glucocorticoid feedback. PMID:27054552

  17. Neural Stem Cell Grafting in an Animal Model of Chronic Temporal Lobe Epilepsy

    Science.gov (United States)

    Hattiangady, Bharathi; Shetty, Ashok K.

    2016-01-01

    Neural stem cell (NSC) transplantation into the hippocampus could offer an alternative therapy to hippocampal resection in patients with drug-resistant chronic epilepsy, which afflicts ~30% of mesial temporal lobe epilepsy (TLE) cases. Multipotent, self-renewing NSCs could be expanded from multiple regions of the developing and adult brain, human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs). However, to provide a comprehensive methodology involved in testing the efficacy of transplantation of NSCs in a rat model of chronic TLE, NSCs derived from the embryonic medial ganglionic eminence (MGE) are taken as an example in this article. The topics comprise description of the required materials, reagents and equipment, and protocols for expanding MGE-NSCs in culture, generating chronically epileptic rats, the intrahippocampal grafting, the post-grafting evaluation of the effects of NSC grafts on spontaneous recurrent seizures and cognitive impairments, analyses of the yield and the fate of graft-derived cells, and the effects of NSC grafts on the host hippocampus. PMID:21913169

  18. Montelukast versus Dexamethasone Treatment in a Guinea Pig Model of Chronic Pulmonary Neutrophilic Inflammation.

    Science.gov (United States)

    Abdel Kawy, Hala S

    2016-08-01

    Airway inflammation in chronic obstructive pulmonary disease (COPD) is refractory to corticosteroids and hence COPD treatment is hindered and insufficient. This study assessed the effects of oral treatment with Montelukast (10 and 30 mg/kg) or dexamethasone (20 mg/kg) for 20 days on COPD model induced by chronic exposure to lipopolysaccharide (LPS). Six groups of male guinea pigs were studied. Group 1: naïve group, group 2: exposed to saline nebulization. Groups 3, 4, 5, and 6: exposed to 9 nebulizations of LPS (30 μg/ml) for 1 hour, 48 hours apart with or without treatment with Montelukast or dexamethasone. Airway hyperreactivity (AHR) to methacholine (MCh), histopathological study and bronchoalveolar lavage fluid (BALF) as well as lung tissue analyses were performed 48 hours after the final exposure to LPS (day 20). LPS-induced pulmonary dysfunction was associated with increased neutrophil count, leukotriene (LT) B4, and tumor necrosis factor (TNF)-α in BALF. Moreover, there was an increase in malondialdehyde (MDA) level and a decrease in histone deacetylases(HDAC) activity in the lung tissue. Both Montelukast (10 or 30 mg /kg) and dexamethasone significantly reduced neutrophil count in BALF and inflammatory cells in lung parenchyma as well as TNF-α, and MDA levels. However, dexamethasone was more effective (p dexamethasone. These results suggest that treatment with Montelukast can be useful in chronic airway inflammatory diseases including COPD poorly responsive to glucocorticoids. PMID:26751767

  19. Modeling methodology for the accurate and prompt prediction of symptomatic events in chronic diseases.

    Science.gov (United States)

    Pagán, Josué; Risco-Martín, José L; Moya, José M; Ayala, José L

    2016-08-01

    Prediction of symptomatic crises in chronic diseases allows to take decisions before the symptoms occur, such as the intake of drugs to avoid the symptoms or the activation of medical alarms. The prediction horizon is in this case an important parameter in order to fulfill the pharmacokinetics of medications, or the time response of medical services. This paper presents a study about the prediction limits of a chronic disease with symptomatic crises: the migraine. For that purpose, this work develops a methodology to build predictive migraine models and to improve these predictions beyond the limits of the initial models. The maximum prediction horizon is analyzed, and its dependency on the selected features is studied. A strategy for model selection is proposed to tackle the trade off between conservative but robust predictive models, with respect to less accurate predictions with higher horizons. The obtained results show a prediction horizon close to 40min, which is in the time range of the drug pharmacokinetics. Experiments have been performed in a realistic scenario where input data have been acquired in an ambulatory clinical study by the deployment of a non-intrusive Wireless Body Sensor Network. Our results provide an effective methodology for the selection of the future horizon in the development of prediction algorithms for diseases experiencing symptomatic crises. PMID:27260782

  20. Caring, chronicity and community: an emergent model of community health services provision for people living with chronic illness

    OpenAIRE

    Ryan, Denis

    2008-01-01

    Purpose An evaluation of an Integrated Care approach with the aim of exploring the components of the service which contributed to its functioning. Theory There is growing recognition internationally that conventional approaches to the management of chronic illness are not adequately meeting the needs of people with such conditions. This concern is also shared in Ireland and a pilot programme to provide an alternative community based approach was established in Callan, Co. Kilkennny, Ireland f...

  1. Predictive models for ocular chronic graft-versus-host disease diagnosis and disease activity in transplant clinical practice.

    Science.gov (United States)

    Curtis, Lauren M; Datiles, Manuel B; Steinberg, Seth M; Mitchell, Sandra A; Bishop, Rachel J; Cowen, Edward W; Mays, Jacqueline; McCarty, John M; Kuzmina, Zoya; Pirsl, Filip; Fowler, Daniel H; Gress, Ronald E; Pavletic, Steven Z

    2015-09-01

    Ocular chronic graft-versus-host disease is one of the most bothersome common complications following allogeneic hematopoietic stem cell transplantation. The National Institutes of Health Chronic Graft-versus-Host Disease Consensus Project provided expert recommendations for diagnosis and organ severity scoring. However, ocular chronic graft-versus-host disease can be diagnosed only after examination by an ophthalmologist. There are no currently accepted definitions of ocular chronic graft-versus-host disease activity. The goal of this study was to identify predictive models of diagnosis and activity for use in clinical transplant practice. A total of 210 patients with moderate or severe chronic graft-versus-host disease were enrolled in a prospective, cross-sectional, observational study (clinicaltrials.gov identifier: 00092235). Experienced ophthalmologists determined presence of ocular chronic graft-versus-host disease, diagnosis and activity. Measures gathered by the transplant clinician included Schirmer's tear test and National Institutes of Health 0-3 Eye Score. Patient-reported outcome measures were the ocular subscale of the Lee Chronic Graft-versus-Host Disease Symptom Scale and Chief Eye Symptom Intensity Score. Altogether, 157 (75%) patients were diagnosed with ocular chronic graft-versus-host disease; 133 of 157 patients (85%) had active disease. In a multivariable model, the National Institutes of Health Eye Score (Pscore (P=0.027). These results support the use of selected transplant clinician- and patient-reported outcome measures for ocular chronic graft-versus-host disease screening when providing care to allogeneic hematopoietic stem cell transplantation survivors with moderate to severe chronic graft-versus-host disease. Prospective studies are needed to determine if the Lee ocular subscale demonstrates adequate responsiveness as a disease activity outcome measure. PMID:26088932

  2. Characterization of the innate immune response to chronic aspiration in a novel rodent model

    Directory of Open Access Journals (Sweden)

    Lin Shu S

    2007-11-01

    Full Text Available Abstract Background Although chronic aspiration has been associated with several pulmonary diseases, the inflammatory response has not been characterized. A novel rodent model of chronic aspiration was therefore developed in order to investigate the resulting innate immune response in the lung. Methods Gastric fluid or normal saline was instilled into the left lung of rats (n = 48 weekly for 4, 8, 12, or 16 weeks (n = 6 each group. Thereafter, bronchoalveolar lavage specimens were collected and cellular phenotypes and cytokine concentrations of IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, GM-CSF, IFN-gamma, TNF-alpha, and TGF-beta were determined. Results Following the administration of gastric fluid but not normal saline, histologic specimens exhibited prominent evidence of giant cells, fibrosis, lymphocytic bronchiolitis, and obliterative bronchiolitis. Bronchoalveolar lavage specimens from the left (treated lungs exhibited consistently higher macrophages and T cells with an increased CD4:CD8 T cell ratio after treatment with gastric fluid compared to normal saline. The concentrations of IL-1alpha, IL-1beta, IL-2, TNF-alpha and TGF-beta were increased in bronchoalveolar lavage specimens following gastric fluid aspiration compared to normal saline. Conclusion This represents the first description of the pulmonary inflammatory response that results from chronic aspiration. Repetitive aspiration events can initiate an inflammatory response consisting of macrophages and T cells that is associated with increased TGF-beta, TNF-alpha, IL-1alpha, IL-1beta, IL-2 and fibrosis in the lung. Combined with the observation of gastric fluid-induced lymphocyitic bronchiolitis and obliterative bronchiolitis, these findings further support an association between chronic aspiration and pulmonary diseases, such as obliterative bronchiolitis, pulmonary fibrosis, and asthma.

  3. Interleukins in chronic liver disease: lessons learned from experimental mouse models

    Directory of Open Access Journals (Sweden)

    Hammerich L

    2014-09-01

    Full Text Available Linda Hammerich, Frank Tacke Department of Medicine III, University Hospital Aachen, Aachen, Germany Abstract: Interleukins represent a class of immunomodulatory cytokines, small intercellular signaling proteins, that are critically involved in the regulation of immune responses. They are produced in large amounts by various cell types during inflammatory reactions, and the balance of cytokines determines the outcome of an immune response. Therefore, cytokines are regarded as interesting therapeutic targets for the treatment of patients with liver diseases. Mouse models provide a good tool for in vivo studies on cytokine function, as human and mouse cytokines share many homologies. Sophisticated mouse models either mimicking distinct pathological conditions or targeting cytokines and cytokine-signaling pathways in the liver or even in distinct cellular compartments have provided enormous insight into the different functions of interleukins during hepatic inflammation. Interleukins may have pro- as well as anti-inflammatory functions in chronic liver diseases, some interleukins even both, dependent on the inflammatory stimulus, the producing and the responding cell type. IL-17, for example, promotes hepatic fibrogenesis through activation of hepatic stellate cells and facilitates development of liver cancer through recruitment of myeloid-derived suppressor cells. IL-22, on the other hand, protects from development of fibrosis or steatohepatitis. IL-12 balances T-helper (Th-1 and Th2 cell responses in infectious disease models. IL-13 and IL-33, two cytokines related to Th2 cells and innate lymphoid cells, promote fibrotic responses in the liver. IL-10 is the prototypic anti-inflammatory interleukin with tissue-protective functions during chronic liver injury and fibrogenesis. Despite its critical role for inducing the acute-phase response in the liver, IL-6 signaling is protective during fibrosis progression, but promotes hepatocellular carcinoma

  4. Antidepressant-like effects of BCEF0083 in the chronic unpredictable stress models in mice

    Institute of Scientific and Technical Information of China (English)

    ZHOU Lan-lan; MING Liang; MA Chuan-geng; CHENG Yan; JIANG Qin

    2005-01-01

    Background Up to now there have been no satisfactory drugs to treat psychiatric disorders, and now bioactive compound from entomagenous fungi (BCEF0083) is a new type of bioactive compound from entomopathogenic fungi. Our previous investigations have shown that BCEF has an inhibition effect on monoamine oxidase. So, BCEF may be a latent antidepressant. This study aimed at observing the antidepressant effects and its mechanism of BCEF in the chronic unpredictable stress models in mice. Methods The antidepressant effects of BCEF were examined on the chronic unpredictable stress models in mice. Sixty mice were randomly divided to six groups. Animals were housed and isolated except saline group. Mice were exposed to different stressors per day randomly from day 1 to day 21. Body weight were weighed on day 1,day 10 and on day 21 during the 21-day stress procedure. Awarding response was detected by using method of calculating the 24-hour consumption of saccharum water. Step through test was used to evaluate the behavioral response. AVP contents in plasma were also detected by using radioimmunoassays. Results Chronic unpredictable stress resulted in a significant decrease of the body weight and could apparently cause escape behavior disturbance and gradual reduction of sensitivity to reward in animal models. Drug treatment (BCEF 25, 50, 100 mg/kg) could significantly ameliorate the decreased body weight and effectively reverse the escape behavior disturbance. The gradual reduction of sensitivity to reward, the anhedonic state, was also effectively reversed by BCEF. BCEF (50, 100 mg/kg) could also effectively restore the AVP content in the plasma.Conclusions This evidence suggests that BCEF can effectively inhibit the depression behavior and show strong antidepressant effect. BCEF can effectively restore the plasma AVP release and this may be an important mechanism of its antidepressant effect.

  5. Modeling the oxygen uptake kinetics during exercise testing of patients with chronic obstructive pulmonary diseases using nonlinear mixed models

    DEFF Research Database (Denmark)

    Baty, Florent; Ritz, Christian; van Gestel, Arnoldus;

    2016-01-01

    regression. Simultaneous modeling of multiple kinetics requires nonlinear mixed models methodology. To the best of our knowledge, no such curve-fitting approach has been used to analyze multiple [Formula: see text]O2 kinetics in both research and clinical practice so far. METHODS: In the present study, we...... describe functionality of the R package medrc that extends the framework of the commonly used packages drc and nlme and allows fitting nonlinear mixed effects models for automated nonlinear regression modeling. The methodology was applied to a data set including 6MWT [Formula: see text]O2 kinetics from 61...... patients with chronic obstructive pulmonary disease (disease severity stage II to IV). The mixed effects approach was compared to a traditional curve-by-curve approach. RESULTS: A six-parameter nonlinear regression model was jointly fitted to the set of [Formula: see text]O2 kinetics. Significant...

  6. Nonapoptotic neurodegeneration in a transgenic mouse model of Huntington's disease

    OpenAIRE

    Turmaine, Mark; Raza, Aysha; Mahal, Amarbirpal; Mangiarini, Laura; Bates, Gillian P.; Davies, Stephen W.

    2000-01-01

    Huntington's disease (HD) is a fatal inherited neurodegenerative disorder characterized by personality changes, motor impairment, and subcortical dementia. HD is one of a number of diseases caused by expression of an expanded polyglutamine repeat. We have developed several lines of mice that are transgenic for exon 1 of the HD gene containing an expanded CAG sequence. These mice exhibit a defined neurological phenotype along with neuronal changes that are pathognomonic for the disease. We hav...

  7. Therapeutic strategies in an animal model of neurodegeneration

    NARCIS (Netherlands)

    Borre, Y.E.

    2013-01-01

    Neurodegenerative diseases have complex and multifactorial etiologies, creating an enormous burden on society without an effective treatment. This thesis utilized olfactory bulbectomized rats to investigate therapeutic approaches to neurodegenerative disorders. Removal of the olfactory bulbs, leads

  8. Hormetic Effect of Chronic Hypergravity in a Mouse Model of Allergic Asthma and Rhinitis

    OpenAIRE

    Tae Young Jang; Ah-Yeoun Jung; Young Hyo Kim

    2016-01-01

    We aimed to evaluate the effect of chronic hypergravity in a mouse model of allergic asthma and rhinitis. Forty BALB/c mice were divided as: group A (n = 10, control) sensitized and challenged with saline, group B (n = 10, asthma) challenged by intraperitoneal and intranasal ovalbumin (OVA) to induce allergic asthma and rhinitis, and groups C (n = 10, asthma/rotatory control) and D (n = 10, asthma/hypergravity) exposed to 4 weeks of rotation with normogravity (1G) or hypergravity (5G) during ...

  9. Association between endothelial dysfunction and depression-like symptoms in chronic mild stress model of depression

    DEFF Research Database (Denmark)

    Bouzinova, Elena; Bødtkjer, Donna Marie Briggs; Kudryavtseva, Olga;

    2014-01-01

    OBJECTIVE: Cardiovascular diseases have high comorbidity with major depression. Endothelial dysfunction may explain the adverse cardiovascular outcome in depression; therefore, we analyzed it in vitro. In the chronic mild stress model, some rats develop depression-like symptoms (including......-dependent hyperpolarization-like response) was reduced in anhedonic rats (p < .001). This was associated with decreased transcription of intermediate-conductance Ca-activated K channels. CONCLUSIONS: Our findings demonstrate that depression-like symptoms are associated with reduced endothelium-dependent relaxation due to...

  10. The model of rat lipid metabolism disorder induced by chronic stress accompanying high-fat-diet

    OpenAIRE

    Shaodong Chen; Jing Li; Haihong Zhou; Manting Lin; Yihua Liu

    2011-01-01

    Abstract Objective To develop an animal model of Lipid Metabolism Disorder, which conforms to human clinical characteristic. Methods: There were 24 male Wistar rats that were randomly divided into 3 groups with 8 rats in each. They were group A (normal diet), group B (high-fat-diet), group C (chronic stress+ high-fat-diet). Group A was fed with normal diet, while group B and C were fed with high-fat-diet, going on for 55 days. From the 35th day, group B and C received one time of daily chroni...

  11. Differential effects of Smad3 targeting in a murine model of chronic kidney disease

    DEFF Research Database (Denmark)

    Kellenberger, Terese; Krag, Søren; Danielsen, Carl Christian;

    2013-01-01

    genes involved in extracellular matrix (ECM) metabolism. This study analyzes the hypothesis that blockade of Smad3 attenuates the development of TGF-β1-driven renal fibrosis. This was examined in vivo in a transgenic model of TGF-β1-induced chronic kidney disease with Smad3 or without Smad3 expression......Transforming growth factor (TGF)-β1 has a pivotal role in the pathogenesis of progressive kidney diseases that are characterized by fibrosis. The main intracellular signaling pathway of TGF-β1 is the Smad system, where Smad2 and Smad3 play a central role in transcriptional regulation of target...... in the kidney....

  12. Quercetin attenuates neuronal death against aluminum-induced neurodegeneration in the rat hippocampus.

    Science.gov (United States)

    Sharma, D R; Wani, W Y; Sunkaria, A; Kandimalla, R J; Sharma, R K; Verma, D; Bal, A; Gill, K D

    2016-06-01

    Aluminum is a light weight and toxic metal present ubiquitously on earth, which has gained considerable attention due to its neurotoxic effects. It also has been linked ecologically and epidemiologically to several neurological disorders, including Alzheimer's disease (AD), Parkinson's disease (PD), Guamanian-Parkinsonian complex and Amyotrophic lateral sclerosis (ALS). The mechanism of aluminum neurotoxicity is poorly understood, but it is well documented that aluminum generates reactive oxygen species (ROS). Enhanced ROS production leads to disruption of cellular antioxidant defense systems and release of cytochrome c (cyt-c) from mitochondria to cytosol resulting in apoptotic cell death. Quercetin (a natural flavonoid) protects it from oxidative damage and has been shown to decrease mitochondrial damage in various animal models of oxidative stress. We hypothesized that if oxidative damage to mitochondria does play a significant role in aluminum-induced neurodegeneration, and then quercetin should ameliorate neuronal apoptosis. Administration of quercetin (10mg/kg body wt/day) reduced aluminum (10mg/kg body wt/day)-induced oxidative stress (decreased ROS production, increased mitochondrial superoxide dismutase (MnSOD) activity). In addition, quercetin also prevents aluminum-induced translocation of cyt-c, and up-regulates Bcl-2, down-regulates Bax, p53, caspase-3 activation and reduces DNA fragmentation. Quercetin also obstructs aluminum-induced neurodegenerative changes in aluminum-treated rats as seen by Hematoxylin and Eosin (H&E) staining. Further electron microscopic studies revealed that quercetin attenuates aluminum-induced mitochondrial swelling, loss of cristae and chromatin condensation. These results indicate that treatment with quercetin may represent a therapeutic strategy to attenuate the neuronal death against aluminum-induced neurodegeneration. PMID:26944603

  13. Conditional Expression of Parkinson's Disease-Related R1441C LRRK2 in Midbrain Dopaminergic Neurons of Mice Causes Nuclear Abnormalities without Neurodegeneration

    OpenAIRE

    Tsika, Elpida; Kannan, Meghna; Foo, Caroline Shi-Yan; Dikeman, Dustin; Glauser, Liliane; Gellhaar, Sandra; Galter, Dagmar; Knott, Graham W.; Ted M Dawson; Dawson, Valina L.; Moore, Darren J.

    2014-01-01

    Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene cause late-onset, autosomal dominant Parkinson's disease (PD). The clinical and neurochemical features of LRRK2-linked PD are similar to idiopathic disease although neuropathology is somewhat heterogeneous. Dominant mutations in LRRK2 precipitate neurodegeneration through a toxic gain-of-function mechanism which can be modeled in transgenic mice overexpressing human LRRK2 variants. A number of LRRK2 transgenic mouse models have been d...

  14. Challenge models to assess new therapies in chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    van der Merwe R

    2012-09-01

    Full Text Available René van der Merwe,1 Nestor A Molfino2,31Respiratory Clinical Development, MedImmune Ltd, Cambridge, UK; 2Respiratory Clinical Development, MedImmune, LLC, Gaithersburg, MD, USA, 3KaloBios Pharmaceuticals, South San Francisco, CA, USAAbstract: Chronic obstructive pulmonary disease (COPD is a major cause of morbidity and mortality. Current therapies confer partial benefits either by incompletely improving airflow limitation or by reducing acute exacerbations, hence new therapies are desirable. In the absence of robust early predictors of clinical efficacy, the potential success of novel therapeutic agents in COPD will not entirely be known until the drugs enter relatively large and costly clinical trials. New predictive models in humans, and new study designs are being sought to allow for confirmation of pharmacodynamic and potentially clinically meaningful effects in early development. This review focuses on human challenge models with lipopolysaccharide endotoxin, ozone, and rhinovirus, in the early clinical development phases of novel therapeutic agents for the treatment and reduction of exacerbations in COPD.Keywords: chronic obstructive pulmonary disease, challenge models, therapy assessment

  15. Autophagy in retinal ganglion cells in a rhesus monkey chronic hypertensive glaucoma model.

    Directory of Open Access Journals (Sweden)

    Shuifeng Deng

    Full Text Available Primary open angle glaucoma (POAG is a neurodegenerative disease characterized by physiological intraocular hypertension that causes damage to the retinal ganglion cells (RGCs. In the past, RGC damage in POAG was suggested to have been attributed to RGC apoptosis. However, in the present study, we applied a model closer to human POAG through the use of a chronic hypertensive glaucoma model in rhesus monkeys to investigate whether another mode of progressive cell death, autophagy, was activated in the glaucomatous retinas. First, in the glaucomatous retinas, the levels of LC3B-II, LC3B-II/LC3B-I and Beclin 1 increased as demonstrated by Western blot analyses, whereas early or initial autophagic vacuoles (AVi and late or degraded autophagic vacuoles (AVd accumulated in the ganglion cell layer (GCL and in the inner plexiform layer (IPL as determined by transmission electron microscopy (TEM analysis. Second, lysosome activity and autophagosome-lysosomal fusion increased in the RGCs of the glaucomatous retinas, as demonstrated by Western blotting against lysosome associated membrane protein-1 (LAMP1 and double labeling against LC3B and LAMP1. Third, apoptosis was activated in the glaucomatous eyes with increased levels of caspase-3 and cleaved caspase-3 and an increased number of TUNEL-positive RGCs. Our results suggested that autophagy was activated in RGCs in the chronic hypertensive glaucoma model of rhesus monkeys and that autophagy may have potential as a new target for intervention in glaucoma treatment.

  16. The effect of pH on chronic aquatic nickel toxicity is dependent on the pH itself: Extending the chronic nickel bioavailability models.

    Science.gov (United States)

    Nys, Charlotte; Janssen, Colin R; Van Sprang, Patrick; De Schamphelaere, Karel A C

    2016-05-01

    The environmental quality standard for Ni in the European Commission's Water Framework Directive is bioavailability based. Although some of the available chronic Ni bioavailability models are validated only for pH ≤ 8.2, a considerable fraction of European surface waters has a pH > 8.2. Therefore, the authors investigated the effect of a change in pH from 8.2 to 8.7 on chronic Ni toxicity in 3 invertebrate (Daphnia magna, Lymnaea stagnalis, and Brachionus calyciflorus) and 2 plant species (Pseudokirchneriella subcapitata and Lemna minor). Nickel toxicity was almost always significantly higher at pH 8.7 than at pH 8.2. To test whether the existing chronic Ni bioavailability models developed for pH ≤ 8.2 can be used at higher pH levels, Ni toxicity at pH 8.7 was predicted based on Ni toxicity observed at pH 8.2. This resulted in a consistent underestimation of toxicity. The results suggest that the effect of pH on Ni(2+) toxicity is dependent on the pH itself: the slope of the pH effect is steeper above than below pH 8.2 for species for which a species-specific bioavailability model exists. Therefore, the existing chronic Ni bioavailability models were modified to allow predictions of chronic Ni toxicity to invertebrates and plants in the pH range of 8.2 to 8.7 by applying a pH slope (SpH ) dependent on the pH of the target water. These modified Ni bioavailability models resulted in more accurate predictions of Ni toxicity to all 5 species (within 2-fold error), without the bias observed using the bioavailability models developed for pH ≤ 8.2. The results of the present study can decrease the uncertainty in implementing the bioavailability-based environmental quality standard under the Water Framework Directive for high-pH regions in Europe. PMID:26335781

  17. Strategies for clinical approach to neurodegeneration in Amyotrophic lateral sclerosis.

    Science.gov (United States)

    Carlesi, Cecilia; Pasquali, Livia; Piazza, Selina; Lo Gerfo, Annalisa; Caldarazzo Ienco, Elena; Alessi, Rosaria; Fornai, Francesco; Siciliano, Gabriele

    2011-03-01

    Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and ultimately fatal neurodegenerative disorder of unknown aetiology that involves the loss of upper and lower motor neurons in the cerebral cortex, brainstem and spinal cord. Significant progress in understanding the cellular mechanisms of motor neuron degeneration in ALS has not been matched with the development of therapeutic strategies to prevent disease progression, and riluzole remains the only available therapy, with only marginal effects on disease survival. More recently alterations of mRNA processing in genetically defined forms of ALS, as those related to TDP-43 and FUS-TLS gene mutations have provided important insights into the molecular networks implicated in the disease pathogenesis. Here we review some of the recent progress in promoting therapeutic strategies for neurodegeneration. PMID:21412722

  18. Self-mutilation in neurodegeneration with brain iron accumulation

    Directory of Open Access Journals (Sweden)

    Sadanandavalli Retnaswami Chandra

    2015-01-01

    Full Text Available Neurodegeneration with brain iron accumulation (NBIA is the term applied to a heterogeneous group of disorders resulting in iron deposition in the basal ganglia. Well-known phenotypic features are progressive regression with extra pyramidal involvement and a variable course. A 10-year-old child born to consanguineous parents presented with progressive generalized opisthotonic dystonia, retrocollis, oromandibular dyskinesias, apraxia for swallowing, optic atrophy and severe self-mutilation of lips. MR imaging showed brain iron accumulation. Other causes of self-mutilation were excluded. Early infantile onset, ophisthotonic dystonia with oromandibular dyskinesias and characteristic MR images are suggestive of NBIA. There is only one case reported in the literature of self-mutilation in this condition.

  19. Implications of mitochondrial dynamics on neurodegeneration and on hypothalamic dysfunction

    Directory of Open Access Journals (Sweden)

    Antonio eZorzano

    2015-06-01

    Full Text Available Mitochondrial dynamics is a term that encompasses the movement of mitochondria along the cytoskeleton, regulation of their architecture, and connectivity mediated by tethering and fusion/fission. The importance of these events in cell physiology and pathology has been partially unraveled with the identification of the genes responsible for the catalysis of mitochondrial fusion and fission. Mutations in two mitochondrial fusion genes (MFN2 and OPA1 cause neurodegenerative diseases, namely Charcot-Marie Tooth type 2A and autosomal dominant optic atrophy. Alterations in mitochondrial dynamics may be involved in the pathophysiology of prevalent neurodegenerative conditions. Moreover, impairment of the activity of mitochondrial fusion proteins dysregulates the function of hypothalamic neurons, leading to alterations in food intake and in energy homeostasis. Here we review selected findings in the field of mitochondrial dynamics and their relevance for neurodegeneration and hypothalamic dysfunction.

  20. Effects of Exercise on Behavior and Peripheral Blood Lymphocyte Apoptosis in a Rat Model of Chronic Fatigue Syndrome

    Institute of Scientific and Technical Information of China (English)

    邹军; 苑建齐; 吕爽; 屠嘉衡

    2010-01-01

    This study examined the effects of exercise on behavior and peripheral blood leukocyte apoptosis in a rat model of chronic fatigue syndrome(CFS).Thirty-six healthy male Sprague-Dawley rats were equally randomized into 3 groups:the control group,CFS model group and the exercise group in terms of body weight.A total of 25 rats entered the final statistical analysis due to 11 deaths during the study.CFS model was established by subjecting the rats in CFS model group and exercise group to electric shock,chronic...

  1. Chronic pancreatitis

    Science.gov (United States)

    Chronic pancreatitis - chronic; Pancreatitis - chronic - discharge; Pancreatic insufficiency - chronic; Acute pancreatitis - chronic ... abuse over many years. Repeated episodes of acute pancreatitis can lead to chronic pancreatitis. Genetics may be ...

  2. Linking pathways in the developing and aging brain with neurodegeneration.

    Science.gov (United States)

    Kovacs, G G; Adle-Biassette, H; Milenkovic, I; Cipriani, S; van Scheppingen, J; Aronica, E

    2014-06-01

    The molecular and cellular mechanisms, which coordinate the critical stages of brain development to reach a normal structural organization with appropriate networks, are progressively being elucidated. Experimental and clinical studies provide evidence of the occurrence of developmental alterations induced by genetic or environmental factors leading to the formation of aberrant networks associated with learning disabilities. Moreover, evidence is accumulating that suggests that also late-onset neurological disorders, even Alzheimer's disease, might be considered disorders of aberrant neural development with pathological changes that are set up at early stages of development before the appearance of the symptoms. Thus, evaluating proteins and pathways that are important in age-related neurodegeneration in the developing brain together with the characterization of mechanisms important during brain development with relevance to brain aging are of crucial importance. In the present review we focus on (1) aspects of neurogenesis with relevance to aging; (2) neurodegenerative disease (NDD)-associated proteins/pathways in the developing brain; and (3) further pathways of the developing or neurodegenerating brains that show commonalities. Elucidation of complex pathogenetic routes characterizing the earliest stage of the detrimental processes that result in pathological aging represents an essential first step toward a therapeutic intervention which is able to reverse these pathological processes and prevent the onset of the disease. Based on the shared features between pathways, we conclude that prevention of NDDs of the elderly might begin during the fetal and childhood life by providing the mothers and their children a healthy environment for the fetal and childhood development. PMID:24699227

  3. Path analysis of the chronicity of depression using the comprehensive developmental model framework.

    Science.gov (United States)

    Fandiño-Losada, Andrés; Bangdiwala, Shrikant I; Lavebratt, Catharina; Forsell, Yvonne

    2016-07-01

    Background Depressive disorder is recognized as recurrent or chronic in the majority of affected individuals; but literature is not consistent about determinants of the disorder course. Aims To analyse the relationships between familial, personal and environmental characteristics in different life phases and their effects on the chronicity of depression in a population-based sample. Methods It was a longitudinal panel study with three waves (W1-W3) for 651 adult men and women with diagnosis of minor/major depression or dysthymia at W1 of the Swedish PART (mental health, work and relations) study. Risk factors and co-morbidities were assessed with questionnaires. The main outcome was an episode of minor/major depression or dysthymia at 10-12 years of follow-up (W3). Liability for depressive episodes was determined using exploratory structural equation modelling (SEM), following a path approach with step-wise specification searches. Results Most of the risk factors determined, directly or indirectly, depression severity at W3. Somatic trait anxiety, partner loss and other negative life events at W1, depressive symptoms at W2, and life difficulties and other dependent life events at W3 had direct effects on the outcome. Conclusions SEM model revealed complex and intertwined psychopathological pathways leading to chronicity of depression, given previous episodes, which could be assembled in two main mechanisms: a depressive-internalizing path and an adversity path comprised of life events. Pathways are simpler than those of depression occurrence, emphasizing the relevance of personality factors as depression determinants, and excluding disability levels, co-morbidities and social support. These novel findings need to be replicated in future studies. PMID:26925597

  4. Effects of Ginseng Treatment on Neutrophil Chemiluminescence and Immunoglobulin G Subclasses in a Rat Model of Chronic Pseudomonas aeruginosa Pneumonia

    OpenAIRE

    Song, Zhijun; Kharazmi, Arsalan; Wu,Hong; Faber, Viggo; Moser, Claus; Krogh Johansen, Helle; Rygaard, Jørgen; Høiby, Niels

    1998-01-01

    Chronic Pseudomonas aeruginosa lung infection in cystic fibrosis (CF) patients is almost impossible to eradicate with antibiotic treatment. In the present study, the effects of treatment with the Chinese herbal medicine ginseng on blood polymorphonuclear leukocyte (PMN) chemiluminescence and serum specific antibody responses were studied in a rat model of chronic P. aeruginosa pneumonia mimicking CF. An aqueous extract of ginseng was administered by subcutaneous injection at a dosage of 25 mg...

  5. Structural Equation Modeling Highlights the Potential of Kim-1 as a Biomarker for Chronic Kidney Disease

    Science.gov (United States)

    Gardiner, Lesley; Akintola, Adebayo; Chen, Gang; Catania, Jeffrey M.; Vaidya, Vishal; Burghardt, Robert C.; Bonventre, Joseph V.; Trzeciakowski, Jerome; Parrish, Alan R.

    2012-01-01

    Background Chronic kidney disease (CKD) is a major public health problem, and despite continued research in the field, there is still a need to identify both biomarkers of risk and progression, as well as potential therapeutic targets. Structural equation modeling (SEM) is a family of statistical techniques that has been utilized in the fields of sociology and psychology for many years; however, its utilization in the biological sciences is relatively novel. SEM's ability to investigate complex relationships in an efficient, single model could be utilized to understand the progression of CKD, as well as to develop a predictive model to assess kidney status in the patient. Methods Fischer 344 rats were fed either an ad libitum diet or a calorically restricted diet, and a time-course study of kidney structure and function was performed. EQS, a SEM software package, was utilized to generate five CKD models of the Fisher 344 rat and identify relationships between measured variables and estimates of kidney damage and kidney function. Results All models identified strong relationships between a biomarker for CKD, kidney injury molecule-1 (Kim-1) and kidney damage, in the Fischer 344 rat CKD model. Models also indicate a strong relationship between age and renal damage and dysfunction. Conclusion SEM can be used to model CKD and could be useful to examine biomarkers in CKD patients. PMID:22269876

  6. An organotypic slice culture model of chronic white matter injury with maturation arrest of oligodendrocyte progenitors

    Directory of Open Access Journals (Sweden)

    Sherman Larry S

    2011-07-01

    Full Text Available Abstract Background CNS myelination disturbances commonly occur in chronic white matter lesions in neurodevelopmental and adult neurological disorders. Recent studies support that myelination failure can involve a disrupted cellular repair mechanism where oligodendrocyte (OL progenitor cells (OPCs proliferate in lesions with diffuse astrogliosis, but fail to fully differentiate to mature myelinating OLs. There are no in vitro models that reproduce these features of myelination failure. Results Forebrain coronal slices from postnatal day (P 0.5/1 rat pups were cultured for 1, 5, or 9 days in vitro (DIV. Slices rapidly exhibited diffuse astrogliosis and accumulation of the extracellular matrix glycosaminoglycan hyaluronan (HA, an inhibitor of OPC differentiation and re-myelination. At 1 DIV ~1.5% of Olig2+ OLs displayed caspase-3 activation, which increased to ~11.5% by 9 DIV. At 1 DIV the density of PDGFRα+ and PDGFRα+/Ki67+ OPCs were significantly elevated compared to 0 DIV (P P + OLs at 9 DIV compared to controls (217 ± 16 vs. 328 ± 17 cells/mm2, respectively; P = 0.0003, supporting an inhibitory role of HA in OL lineage progression in chronic lesions. Conclusions Diffuse white matter astrogliosis and early OPC proliferation with impaired OL maturation were reproduced in this model of myelination failure. This system may be used to define mechanisms of OPC maturation arrest and myelination failure related to astrogliosis and HA accumulation.

  7. Pharmacological characterisation of anti-inflammatory compounds in acute and chronic mouse models of cigarette smoke-induced inflammation

    Directory of Open Access Journals (Sweden)

    Mok Joanie

    2010-09-01

    Full Text Available Abstract Background Candidate compounds being developed to treat chronic obstructive pulmonary disease are typically assessed using either acute or chronic mouse smoking models; however, in both systems compounds have almost always been administered prophylactically. Our aim was to determine whether the prophylactic effects of reference anti-inflammatory compounds in acute mouse smoking models reflected their therapeutic effects in (more clinically relevant chronic systems. Methods To do this, we started by examining the type of inflammatory cell infiltrate which occurred after acute (3 days or chronic (12 weeks cigarette smoke exposure (CSE using female, C57BL/6 mice (n = 7-10. To compare the effects of anti-inflammatory compounds in these models, mice were exposed to either 3 days of CSE concomitant with compound dosing or 14 weeks of CSE with dosing beginning after week 12. Budesonide (1 mg kg-1; i.n., q.d., roflumilast (3 mg kg-1; p.o., q.d. and fluvastatin (2 mg kg-1; p.o., b.i.d. were dosed 1 h before (and 5 h after for fluvastatin CSE. These dose levels were selected because they have previously been shown to be efficacious in mouse models of lung inflammation. Bronchoalveolar lavage fluid (BALF leukocyte number was the primary endpoint in both models as this is also a primary endpoint in early clinical studies. Results To start, we confirmed that the inflammatory phenotypes were different after acute (3 days versus chronic (12 weeks CSE. The inflammation in the acute systems was predominantly neutrophilic, while in the more chronic CSE systems BALF neutrophils (PMNs, macrophage and lymphocyte numbers were all increased (p Conclusions These results demonstrate that the acute, prophylactic systems can be used to identify compounds with therapeutic potential, but may not predict a compound's efficacy in chronic smoke exposure models.

  8. Gene Expression Profiling as a Tool to Investigate the Molecular Machinery Activated during Hippocampal Neurodegeneration Induced by Trimethyltin (TMT Administration

    Directory of Open Access Journals (Sweden)

    Maria Concetta Geloso

    2013-08-01

    Full Text Available Trimethyltin (TMT is an organotin compound exhibiting neurotoxicant effects selectively localized in the limbic system and especially marked in the hippocampus, in both experimental animal models and accidentally exposed humans. TMT administration causes selective neuronal death involving either the granular neurons of the dentate gyrus or the pyramidal cells of the Cornu Ammonis, with a different pattern of localization depending on the different species studied or the dosage schedule. TMT is broadly used to realize experimental models of hippocampal neurodegeneration associated with cognitive impairment and temporal lobe epilepsy, though the molecular mechanisms underlying the associated selective neuronal death are still not conclusively clarified. Experimental evidence indicates that TMT-induced neurodegeneration is a complex event involving different pathogenetic mechanisms, probably acting differently in animal and cell models, which include neuroinflammation, intracellular calcium overload, and oxidative stress. Microarray-based, genome-wide expression analysis has been used to investigate the molecular scenario occurring in the TMT-injured brain in different in vivo and in vitro models, producing an overwhelming amount of data. The aim of this review is to discuss and rationalize the state-of-the-art on TMT-associated genome wide expression profiles in order to identify comparable and reproducible data that may allow focusing on significantly involved pathways.

  9. A STUDY OF ANTI - INFLAMMATORY ACTIVITY OF PLANT “TRIANTHEMA PORTULACASTRUM” IN CHRONIC MODELS OF INFLAMMATION

    Directory of Open Access Journals (Sweden)

    Suresh. S

    2015-06-01

    Full Text Available BACKGROUND: Trianthema portulacastrum is being used in Ayurveda since centuries for its medicinal values , hence this study was done to know if it has got anti - inflammatory activity in chronic models of inflammation, MATERIALS AND METHODS: Wistar albino rats were treated with whole plant ethanolic extract of trianthema portulacastrum 100mg \\ kg orally with 2% gum acacia , as suspending agent and indomethacin 20mg \\ kg as standard. And the effects were observed in chronic model of inflammation namely, rexin pellet induced granuloma model, RESULT: This study demon - strated that trianthema portulacastrum reduced significantly the dry weight of granuloma that was formed after rexin pellet implantation, CONCLUSION: Trianthema po rtulacastrum has got significant anti - inflammatory activity in chronic models of inflammation.

  10. Curative haploidentical BMT in a murine model of X-linked chronic granulomatous disease.

    Science.gov (United States)

    Takeuchi, Yasuo; Takeuchi, Emiko; Ishida, Takashi; Onodera, Masafumi; Nakauchi, Hiromitsu; Otsu, Makoto

    2015-07-01

    Chronic granulomatous disease (CGD) is a primary immunodeficiency disorder characterized by defective microbial killing in phagocytes. Long-term prognosis for CGD patients is generally poor, highlighting the need to develop minimally toxic, curative therapeutic approaches. We here describe the establishment of a mouse model in which X-linked CGD can be cured by allogeneic bone marrow transplantation. Using a combination of non-myeloablative-dose total body irradiation and a single injection of anti-CD40 ligand monoclonal antibody, transplantation of whole bone marrow cells achieved long-lasting mixed chimerism in X-linked CGD mice in a haploidentical transplantation setting. Stable mixed chimerism was maintained for up to 1 year even at a low range (CGD models. These results warrant future development of a simplified allogeneic hematopoietic cell transplantation regimen that would benefit CGD patients by allowing the use of haploidentical donor grafts without serious concerns of severe treatment-related toxicity. PMID:25921405

  11. Modelling management of chronic illness in everyday life: A common-sense approach

    Directory of Open Access Journals (Sweden)

    Howard Leventhal

    2016-04-01

    Full Text Available The Commonsense Model of Self-Regulation (CSM has a history of over 50 years as a theoretical framework that explicates the processes by which individuals form cognitive, affective, and behavioral representations of health threats. This article summarizes the major components of individuals' "commonsense models", the underlying assumptions of the CSM as a theory of dynamic behavior change, and the major empirical evidence that have developed these aspects of the CSM since its inception. We also discuss ongoing changes to the theory itself as well as its use in medical practice for optimizing patients' self-management of chronic health threats. The final section focuses on future directions for the theory and its application.

  12. Psychosocial Adaptation to Chronic Illness and Disability: A Virtue Based Model.

    Science.gov (United States)

    Kim, Jeong Han; McMahon, Brian T; Hawley, Carolyn; Brickham, Dana; Gonzalez, Rene; Lee, Dong-Hun

    2016-03-01

    Purpose Psychosocial adaptation to chronic illness and disability (CID) is an area of study where a positive psychology perspective, especially the study of virtues and character strengths, can be implemented within the rehabilitation framework. A carefully developed theory to guide future interdisciplinary research is now timely. Methods A traditional literature review between philosophy and rehabilitation psychology was conducted in order to develop a virtue-based psychosocial adaptation theory, merging important perspectives from the fields of rehabilitation and positive psychology. Results The virtue-based psychosocial adaptation model (V-PAM) to CID is proposed in the present study. Conclusions The model involves five qualities or constructs: courage, practical wisdom, commitment to action, integrity and emotional transcendence. Each of these components of virtue contributes to an understanding of psychosocial adaptation. The present study addresses the implications and applications of V-PAM that will advance this understanding. PMID:26781509

  13. DISTURBANCES OF BIOLOGICAL RHYTHMS IN A RAT CHRONIC MILD STRESS MODEL OF DEPRESSION

    DEFF Research Database (Denmark)

    Christiansen, Sofie; Wiborg, Ove; Bouzinova, Elena

    Aim: The focus of this project is to identify biomarkers related to circadian disturbances in major depressive disorder. Background: A large body of clinical data from depressed individuals showed that sleep, temperature, hormones, physiological states and moodchanges are consistent with...... validated animal model of depression, the chronic mild stress model (CMS). Depression-like and control rats were killed by decapitation within 24 h. Trunk blood, brain and liver tissue were collected. The quantitative amount of plasma corticosterone and melatonin were measured using an ELISA and RIA kit...... that depression-like animals showed an abnormal circadian rhythm in the liver and in subregions of the rat brains related to depression. However, the SCN was partly protected against stress. We found an increased level of corticosteron and melatonin, in the depression-like animals as well as a shifted...

  14. Cytokine and Chemokine Expression in Kidneys during Chronic Leptospirosis in Reservoir and Susceptible Animal Models

    Science.gov (United States)

    Matsui, Mariko; Roche, Louise; Geroult, Sophie; Soupé-Gilbert, Marie-Estelle; Monchy, Didier; Huerre, Michel; Goarant, Cyrille

    2016-01-01

    Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. Humans can be infected after exposure to contaminated urine of reservoir animals, usually rodents, regarded as typical asymptomatic carriers of leptospires. In contrast, accidental hosts may present an acute form of leptospirosis with a range of clinical symptoms including the development of Acute Kidney Injury (AKI). Chronic Kidney Disease (CKD) is considered as a possible AKI-residual sequela but little is known about the renal pathophysiology consequent to leptospirosis infection. Herein, we studied the renal morphological alterations in relation with the regulation of inflammatory cytokines and chemokines, comparing two experimental models of chronic leptospirosis, the golden Syrian hamster that survived the infection, becoming carrier of virulent leptospires, and the OF1 mouse, a usual reservoir of the bacteria. Animals were monitored until 28 days after injection with a virulent L. borgpetersenii serogroup Ballum to assess chronic infection. Hamsters developed morphological alterations in the kidneys with tubulointerstitial nephritis and fibrosis. Grading of lesions revealed higher scores in hamsters compared to the slight alterations observed in the mouse kidneys, irrespective of the bacterial load. Interestingly, pro-fibrotic TGF-β was downregulated in mouse kidneys. Moreover, cytokines IL-1β and IL-10, and chemokines MIP-1α/CCL3 and IP-10/CXCL-10 were significantly upregulated in hamster kidneys compared to mice. These results suggest a possible maintenance of inflammatory processes in the hamster kidneys with the infiltration of inflammatory cells in response to bacterial carriage, resulting in alterations of renal tissues. In contrast, lower expression levels in mouse kidneys indicated a better regulation of the inflammatory response and possible resolution processes likely related to resistance mechanisms. PMID:27219334

  15. Copper balance and ceruloplasmin in chronic hepatitis in a Wilson disease animal model, LEC rats

    Energy Technology Data Exchange (ETDEWEB)

    Komatsu, Yutaka; Ogra, Yasumitsu; Suzuki, Kazuo T. [Graduate School of Pharmaceutical Sciences, Chiba University, Inage, Chiba 263-8522 (Japan)

    2002-09-01

    In an animal model of Wilson disease, Long-Evans rats with cinnamon-colored coat (LEC rats), copper (Cu) accumulates in the liver with age up to the onset of acute hepatitis owing to a hereditary defective transporter for the efflux of Cu, ATP7B. The plasma Cu concentration is low in LEC rats because of the excretion of apo-ceruloplasmin (apo-Cp). However, toward and after the onset of chronic hepatitis, plasma Cu concentration increases in the form of holo-Cp, while the liver Cu concentration is maintained at a constant level without the occurrence of fulminant hepatitis. In the present study, the material balance of Cu was studied in LEC rats with chronic hepatitis in order to elucidate the mechanisms underlying the increase of holo-Cp in plasma and the maintenance of Cu at a constant level in the liver. The relationship between the Cu concentration and ferroxidase activity of Cp was analyzed in the plasma of LEC rats of different ages and of Wistar rats fed a Cu-deficient diet for different durations. Cu was suggested to be delivered to Cp in an all-or-nothing manner, resulting in the excretion of fully Cu-occupied holo-Cp (Cu{sub 6}-Cp) or totally Cu-unoccupied Cu{sub 0}-Cp (apo-Cp), but not partially Cu-occupied Cu{sub n}-Cp (where n=1-5). The increase of holo-Cp in acute and chronic hepatitis in LEC rats was explained by the delivery of Cu, accumulating in the non-metallothionein-bound form, to Cp outside the Golgi apparatus of the liver. The plasma Cu concentration and ferroxidase activity were proposed to be specific indicators of the appearance of non-metallothionein-bound Cu in the liver of LEC rats. (orig.)

  16. Micturition in rats: a chronic model for study of bladder function and effect of anesthetics.

    Science.gov (United States)

    Yaksh, T L; Durant, P A; Brent, C R

    1986-12-01

    The volume-evoked micturition reflex (VEMR) and the effects of anesthetics on the VEMR were studied in a chronic unanesthetized rat model. The bladder catheter was implanted chronically through a laparotomy and externalized percutaneously. An intrathecal (IT) catheter was implanted chronically in animals scheduled for an IT injection. By 2 days after implantation, infusion of saline (200 microliter/min) in the bladder reliably resulted in a low base-line pressure (BP) followed by a transient increase in bladder pressure, an opening of the sphincter (bladder opening pressure, BOP) corresponding to expression of urine (volume of urination, V), then a further rise in pressure (peak pressure, PP) and a subsequent return to base line. Seven days after implantation, values (means +/- SE) for BP, BOP, PP, and V were 10 +/- 0.3, 30 +/- 2, 67 +/- 6 cmH2O, and 1.0 +/- 0.1 ml, respectively. Residual volumes were reliably less than 2-4% of the expressed volume. The VEMR was reliably evoked up to 28 days after implantation. V values in unimplanted and implanted animals were not different. In implanted animals, VEMR parameters were not different during infusion or during spontaneous urination after oral fluid load. Administration of pentobarbital sodium (50 mg/kg ip), alpha-chloralose (130 mg/kg ip), ketamine (100 mg/kg im), halothane (in air 2%), and local anesthetics (2-chloroprocaine 3% or bupivacaine 0.75%, 10 microliter IT) produced a complete blockade of the VEMR and overflow incontinence at pressures significantly higher than BOP values. To compare overflow pressures and passive compliance of the bladder, unanesthetized animals were decapitated.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3789199

  17. Cytokine and Chemokine Expression in Kidneys during Chronic Leptospirosis in Reservoir and Susceptible Animal Models.

    Science.gov (United States)

    Matsui, Mariko; Roche, Louise; Geroult, Sophie; Soupé-Gilbert, Marie-Estelle; Monchy, Didier; Huerre, Michel; Goarant, Cyrille

    2016-01-01

    Leptospirosis is caused by pathogenic spirochetes of the genus Leptospira. Humans can be infected after exposure to contaminated urine of reservoir animals, usually rodents, regarded as typical asymptomatic carriers of leptospires. In contrast, accidental hosts may present an acute form of leptospirosis with a range of clinical symptoms including the development of Acute Kidney Injury (AKI). Chronic Kidney Disease (CKD) is considered as a possible AKI-residual sequela but little is known about the renal pathophysiology consequent to leptospirosis infection. Herein, we studied the renal morphological alterations in relation with the regulation of inflammatory cytokines and chemokines, comparing two experimental models of chronic leptospirosis, the golden Syrian hamster that survived the infection, becoming carrier of virulent leptospires, and the OF1 mouse, a usual reservoir of the bacteria. Animals were monitored until 28 days after injection with a virulent L. borgpetersenii serogroup Ballum to assess chronic infection. Hamsters developed morphological alterations in the kidneys with tubulointerstitial nephritis and fibrosis. Grading of lesions revealed higher scores in hamsters compared to the slight alterations observed in the mouse kidneys, irrespective of the bacterial load. Interestingly, pro-fibrotic TGF-β was downregulated in mouse kidneys. Moreover, cytokines IL-1β and IL-10, and chemokines MIP-1α/CCL3 and IP-10/CXCL-10 were significantly upregulated in hamster kidneys compared to mice. These results suggest a possible maintenance of inflammatory processes in the hamster kidneys with the infiltration of inflammatory cells in response to bacterial carriage, resulting in alterations of renal tissues. In contrast, lower expression levels in mouse kidneys indicated a better regulation of the inflammatory response and possible resolution processes likely related to resistance mechanisms. PMID:27219334

  18. Diabetes and overexpression of proNGF cause retinal neurodegeneration via activation of RhoA pathway.

    Directory of Open Access Journals (Sweden)

    Mohammed M H Al-Gayyar

    Full Text Available Our previous studies showed positive correlation between accumulation of proNGF, activation of RhoA and neuronal death in diabetic models. Here, we examined the neuroprotective effects of selective inhibition of RhoA kinase in the diabetic rat retina and in a model that stably overexpressed the cleavage-resistance proNGF plasmid in the retina. Male Sprague-Dawley rats were rendered diabetic using streptozotocin or stably express cleavage-resistant proNGF plasmid. The neuroprotective effects of the intravitreal injection of RhoA kinase inhibitor Y27632 were examined in vivo. Effects of proNGF were examined in freshly isolated primary retinal ganglion cell (RGC cultures and RGC-5 cell line. Retinal neurodegeneration was assessed by counting TUNEL-positive and Brn-3a positive retinal ganglion cells. Expression of proNGF, p75(NTR, cleaved-PARP, caspase-3 and p38MAPK/JNK were examined by Western-blot. Activation of RhoA was assessed by pull-down assay and G-LISA. Diabetes and overexpression of proNGF resulted in retinal neurodegeneration as indicated by 9- and 6-fold increase in TUNEL-positive cells, respectively. In vitro, proNGF induced 5-fold cell death in RGC-5 cell line, and it induced >10-fold cell death in primary RGC cultures. These effects were associated with significant upregulation of p75(NTR and activation of RhoA. While proNGF induced TNF-α expression in vivo, it selectively activated RhoA in primary RGC cultures and RGC-5 cell line. Inhibiting RhoA kinase with Y27632 significantly reduced diabetes- and proNGF-induced activation of proapoptotic p38MAPK/JNK, expression of cleaved-PARP and caspase-3 and prevented retinal neurodegeneration in vivo and in vitro. Taken together, these results provide compelling evidence for a causal role of proNGF in diabetes-induced retinal neurodegeneration through enhancing p75(NTR expression and direct activation of RhoA and p38MAPK/JNK apoptotic pathways.

  19. A partial hearing animal model for chronic electro-acoustic stimulation

    Science.gov (United States)

    Irving, S.; Wise, A. K.; Millard, R. E.; Shepherd, R. K.; Fallon, J. B.

    2014-08-01

    Objective. Cochlear implants (CIs) have provided some auditory function to hundreds of thousands of people around the world. Although traditionally carried out only in profoundly deaf patients, the eligibility criteria for implantation have recently been relaxed to include many partially-deaf patients with useful levels of hearing. These patients receive both electrical stimulation from their implant and acoustic stimulation via their residual hearing (electro-acoustic stimulation; EAS) and perform very well. It is unclear how EAS improves speech perception over electrical stimulation alone, and little evidence exists about the nature of the interactions between electric and acoustic stimuli. Furthermore, clinical results suggest that some patients that undergo cochlear implantation lose some, if not all, of their residual hearing, reducing the advantages of EAS over electrical stimulation alone. A reliable animal model with clinically-relevant partial deafness combined with clinical CIs is important to enable these issues to be studied. This paper outlines such a model that has been successfully used in our laboratory. Approach. This paper outlines a battery of techniques used in our laboratory to generate, validate and examine an animal model of partial deafness and chronic CI use. Main results. Ototoxic deafening produced bilaterally symmetrical hearing thresholds in neonatal and adult animals. Electrical activation of the auditory system was confirmed, and all animals were chronically stimulated via adapted clinical CIs. Acoustic compound action potentials (CAPs) were obtained from partially-hearing cochleae, using the CI amplifier. Immunohistochemical analysis allows the effects of deafness and electrical stimulation on cell survival to be studied. Significance. This animal model has applications in EAS research, including investigating the functional interactions between electric and acoustic stimulation, and the development of techniques to maintain residual

  20. Mitochondrial defects and neurodegeneration in mice overexpressing wild-type or G399S mutant HtrA2.

    Science.gov (United States)

    Casadei, Nicolas; Sood, Poonam; Ulrich, Thomas; Fallier-Becker, Petra; Kieper, Nicole; Helling, Stefan; May, Caroline; Glaab, Enrico; Chen, Jing; Nuber, Silke; Marcus, Katrin; Rapaport, Doron; Ott, Thomas; Riess, Olaf; Krüger, Rejko; Fitzgerald, Julia C

    2016-02-01

    The protease HtrA2 has a protective role inside mitochondria, but promotes apoptosis under stress. We previously identified the G399S HtrA2 mutation in Parkinson's disease (PD) patients and reported mitochondrial dysfunction in vitro. Mitochondrial dysfunction is a common feature of PD and related to neurodegeneration. Complete loss of HtrA2 has been shown to cause neurodegeneration in mice. However, the full impact of HtrA2 overexpression or the G399S mutation is still to be determined in vivo. Here, we report the first HtrA2 G399S transgenic mouse model. Our data suggest that the mutation has a dominant-negative effect. We also describe a toxic effect of wild-type (WT) HtrA2 overexpression. Only low overexpression of the G399S mutation allowed viable animals and we suggest that the mutant protein is likely unstable. This is accompanied by reduced mitochondrial respiratory capacity and sensitivity to apoptotic cell death. Mice overexpressing WT HtrA2 were viable, yet these animals have inhibited mitochondrial respiration and significant induction of apoptosis in the brain leading to motor dysfunction, highlighting the opposing roles of HtrA2. Our data further underscore the importance of HtrA2 as a key mediator of mitochondrial function and its fine regulatory role in cell fate. The location and abundance of HtrA2 is tightly controlled and, therefore, human mutations leading to gain- or loss of function could provide significant risk for PD-related neurodegeneration. PMID:26604148

  1. Pseudomonas aeruginosa biofilm aggravates skin inflammatory response in BALB/c mice in a novel chronic wound model

    DEFF Research Database (Denmark)

    Trøstrup, Hannah; Thomsen, Kim; Christophersen, Lars J;

    2013-01-01

    Chronic wounds are presumed to persist in the inflammatory state, preventing healing. Emerging evidence indicates a clinical impact of bacterial biofilms in soft tissues, including Pseudomonas aeruginosa (PA) biofilms. To further investigate this, we developed a chronic PA biofilm wound infection...... model in C3H/HeN and BALB/c mice. The chronic wound was established by an injection of seaweed alginate-embedded P. aeruginosa PAO1 beneath a third-degree thermal lesion providing full thickness skin necrosis, as in human chronic wounds. Cultures revealed growth of PA, and both alginate with or without...... PAO1 generated a polymorphonuclear-dominated inflammation early after infection. However, both at days 4 and 7, there were a more acute polymorphonuclear-dominated and higher degree of inflammation in the PAO1 containing group (p <0.05). Furthermore, PNA-FISH and supplemented DAPI staining showed...

  2. Social and economic determinants of pediatric health inequalities: the model of chronic kidney disease.

    Science.gov (United States)

    Sereni, Fabio; Edefonti, Alberto; Lepore, Marta; Agostoni, Carlo; Sandoval Diaz, Mabel; Silva Galan, Yajaira; Montini, Giovanni; Tognoni, Gianni

    2016-01-01

    Purpose of this review is to deal with priorities and strategies to significantly tackle inequalities in the management of pediatric diseases in low-middle-income countries. This issue has become a focal point of epidemiological and public health, with special reference to chronic nontransmissible diseases. We will provide our readership with an essential overview of the cultural, institutional, and political events, which have occurred over the last 20 y and which have produced the current general framework for epidemiology and public health. Then the most recent epidemiological data will be evaluated, in order to quantify the interaction between the medical components of the disease profiles and their socioeconomic determinants. Finally, a focus will be added on models of pediatric chronic kidney diseases, which are in our opinion amongst the most sensitive markers of the interplay between health and society. Collaborative, pediatrician-initiated, multicentre projects in these fields should be given priority in calls for grants supported by public agencies. The involvement of a critical mass of those working in the "fringes" of pediatric care is a final, essential mean by which significant results can be produced under the sole responsibility and research interest of centers of excellence. PMID:26466076

  3. Evaluation of protective effect of Aegle marmelos Corr. in an animal model of chronic fatigue syndrome

    Directory of Open Access Journals (Sweden)

    Vanphawng Lalremruta

    2012-01-01

    Full Text Available Objective: To evaluate ethanolic extract of leaves of Aegle marmelos in an experimental animal model of chronic fatigue syndrome for potential therapeutic benefit. Materials and Methods: Age/weight-matched female Wistar albino rats were grouped into five groups. (Group I- V (n = 8. Group I served as naïve control and II served as stress control. Except for group I animals, other group animals were subjected to forced swimming every day for 15 minutes to induce a state of chronic fatigue and simultaneously treated with ethanolic extract of Aegle marmelos (EEAM 150 and 250 mg/kg b.w. and Imipramine (20 mg.kg b.w., respectively. Duration of immobility, anxiety level and locomotor activity were assessed on day 1, 7, 14 and 21 followed by biochemical estimation of oxidative biomarkers at the end of the study. Results: Treatment with EEAM (150 and 250 mg/kg b.w. resulted in a statistically significant and dose dependent reduction (P <0.001 in the duration of immobility, reduction in anxiety and increase in locomotor activity. Dose dependent and significant reduction in LPO level and increase in CAT and SOD was observed in extract treated animals. Conclusion: The results are suggestive of potential protective effect of A. marmelos against experimentally induced CFS.

  4. Using Mobile Health to Support the Chronic Care Model: Developing an Institutional Initiative

    Directory of Open Access Journals (Sweden)

    Shantanu Nundy

    2012-01-01

    Full Text Available Background. Self-management support and team-based care are essential elements of the Chronic Care Model but are often limited by staff availability and reimbursement. Mobile phones are a promising platform for improving chronic care but there are few examples of successful health system implementation. Program Development. An iterative process of program design was built upon a pilot study and engaged multiple institutional stakeholders. Patients identified having a “human face” to the pilot program as essential. Stakeholders recognized the need to integrate the program with primary and specialty care but voiced concerns about competing demands on clinician time. Program Description. Nurse administrators at a university-affiliated health plan use automated text messaging to provide personalized self-management support for member patients with diabetes and facilitate care coordination with the primary care team. For example, when a patient texts a request to meet with a dietitian, a nurse-administrator coordinates with the primary care team to provide a referral. Conclusion. Our innovative program enables the existing health system to support a de novo care management program by leveraging mobile technology. The program supports self-management and team-based care in a way that we believe engages patients yet meets the limited availability of providers and needs of health plan administrators.

  5. Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain.

    Science.gov (United States)

    de Araujo, Aline Dantas; Mobli, Mehdi; Castro, Joel; Harrington, Andrea M; Vetter, Irina; Dekan, Zoltan; Muttenthaler, Markus; Wan, JingJing; Lewis, Richard J; King, Glenn F; Brierley, Stuart M; Alewood, Paul F

    2014-01-01

    Poor oral availability and susceptibility to reduction and protease degradation is a major hurdle in peptide drug development. However, drugable receptors in the gut present an attractive niche for peptide therapeutics. Here we demonstrate, in a mouse model of chronic abdominal pain, that oxytocin receptors are significantly upregulated in nociceptors innervating the colon. Correspondingly, we develop chemical strategies to engineer non-reducible and therefore more stable oxytocin analogues. Chemoselective selenide macrocyclization yields stabilized analogues equipotent to native oxytocin. Ultra-high-field nuclear magnetic resonance structural analysis of native oxytocin and the seleno-oxytocin derivatives reveals that oxytocin has a pre-organized structure in solution, in marked contrast to earlier X-ray crystallography studies. Finally, we show that these seleno-oxytocin analogues potently inhibit colonic nociceptors both in vitro and in vivo in mice with chronic visceral hypersensitivity. Our findings have potentially important implications for clinical use of oxytocin analogues and disulphide-rich peptides in general. PMID:24476666

  6. Physical activity: benefit or weakness in metabolic adaptations in a mouse model of chronic food restriction?

    Science.gov (United States)

    Méquinion, Mathieu; Caron, Emilie; Zgheib, Sara; Stievenard, Aliçia; Zizzari, Philippe; Tolle, Virginie; Cortet, Bernard; Lucas, Stéphanie; Prévot, Vincent; Chauveau, Christophe; Viltart, Odile

    2015-02-01

    In restrictive-type anorexia nervosa (AN) patients, physical activity is usually associated with food restriction, but its physiological consequences remain poorly characterized. In female mice, we evaluated the impact of voluntary physical activity with/without chronic food restriction on metabolic and endocrine parameters that might contribute to AN. In this protocol, FRW mice (i.e., food restriction with running wheel) reached a crucial point of body weight loss (especially fat mass) faster than FR mice (i.e., food restriction only). However, in contrast to FR mice, their body weight stabilized, demonstrating a protective effect of a moderate, regular physical activity. Exercise delayed meal initiation and duration. FRW mice displayed food anticipatory activity compared with FR mice, which was strongly diminished with the prolongation of the protocol. The long-term nature of the protocol enabled assessment of bone parameters similar to those observed in AN patients. Both restricted groups adapted their energy metabolism differentially in the short and long term, with less fat oxidation in FRW mice and a preferential use of glucose to compensate for the chronic energy imbalance. Finally, like restrictive AN patients, FRW mice exhibited low leptin levels, high plasma concentrations of corticosterone and ghrelin, and a disruption of the estrous cycle. In conclusion, our model suggests that physical activity has beneficial effects on the adaptation to the severe condition of food restriction despite the absence of any protective effect on lean and bone mass. PMID:25465889

  7. Behavioural and EEG effects of chronic rapamycin treatment in a mouse model of tuberous sclerosis complex.

    Science.gov (United States)

    Cambiaghi, Marco; Cursi, Marco; Magri, Laura; Castoldi, Valerio; Comi, Giancarlo; Minicucci, Fabio; Galli, Rossella; Leocani, Letizia

    2013-04-01

    Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder caused by mutation in either Tsc1 or Tsc2 genes that leads to the hyper activation of the mTOR pathway, a key signalling pathway for synaptic plasticity. TSC is characterized by benign tumors arising in different organs and severe neuropsychiatric symptoms, such as epilepsy, intellectual disability, autism, anxiety and depressive behaviour. Rapamycin is a potent inhibitor of mTOR and its efficacy in treating epilepsy and neurological symptoms remains elusive. In a mouse model in which Tsc1 has been deleted in embryonic telencephalic neural stem cells, we analyzed anxiety- and depression-like behaviour by elevated-plus maze (EPM), open-field test (OFT), forced-swim test (FST) and tail-suspension test (TST), after chronic administration of rapamycin. In addition, spectral analysis of background EEG was performed. Rapamycin-treated mutant mice displayed a reduction in anxiety- and depression-like phenotype, as shown by the EPM/OFT and FST, respectively. These results were inline with EEG power spectra outcomes. The same effects of rapamycin were observed in wild-type mice. Notably, in heterozygous animals we did not observe any EEG and/or behavioural variation after rapamycin treatment. Together these results suggest that both TSC1 deletion and chronic rapamycin treatment might have a role in modulating behaviour and brain activity, and point out to the potential usefulness of background EEG analysis in tracking brain dysfunction in parallel with behavioural testing. PMID:23159330

  8. Optic neuritis and retinal ganglion cell loss in a chronic murine model of multiple sclerosis

    Directory of Open Access Journals (Sweden)

    KennethS.Shindler

    2011-08-01

    Full Text Available Multiple sclerosis (MS and its animal model experimental autoimmune encephalomyelitis (EAE are neurodegenerative diseases with characteristic inflammatory demyelination in the central nervous system, including the optic nerve. Neuronal and axonal damage is considered to be the main cause of long-term disability in patients with MS. Neuronal loss, including retinal ganglion cell (RGC apoptosis in eyes with optic neuritis, also occurs in EAE. However, there is significant variability in the clinical course and level of neuronal damage in MS and EAE. The current studies examine the mechanisms and kinetics of RGC loss in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein to induce a chronic EAE disease. Clinical progression of EAE was scored daily and vision was assessed by optokinetic responses. At various time points, RGCs were counted and optic nerves were examined for inflammatory cell infiltration. Almost all EAE mice develop optic neuritis by day 15 post-immunization; however, RGC loss is delayed in these mice. No RGC loss is detected 25 days post-immunization, whereas RGC numbers in EAE mice significantly and progressively decrease compared to controls from 35-50 days post-immunization. The delayed time course of RGC loss is in stark contrast to that reported in relapsing EAE, as well as in rats with chronic EAE. Results suggest that different clinical disease courses of optic nerve inflammation may trigger distinct mechanisms of neuronal damage, or RGCs in different rodent strains may have variable resistance to neuronal degeneration.

  9. Downregulated GABA and BDNF-TrkB Pathway in Chronic Cyclothiazide Seizure Model

    Directory of Open Access Journals (Sweden)

    Shuzhen Kong

    2014-01-01

    Full Text Available Cyclothiazide (CTZ has been reported to simultaneously enhance glutamate receptor excitation and inhibit GABAA receptor inhibition, and in turn it evokes epileptiform activities in hippocampal neurons. It has also been shown to acutely induce epileptic seizure behavior in freely moving rats. However, whether CTZ induced seizure rats could develop to have recurrent seizure still remains unknown. In the current study, we demonstrated that 46% of the CTZ induced seizure rats developed to have recurrent seizure behavior as well as epileptic EEG with a starting latency between 2 weeks and several months. In those chronic seizure rats 6 months after the seizure induction by the CTZ, our immunohistochemistry results showed that both GAD and GAT-1 were significantly decreased across CA1, CA3, and dentate gyrus area of the hippocampus studied. In addition, both BDNF and its receptor TrkB were also decreased in hippocampus of the chronic CTZ seizure rats. Our results indicate that CTZ induced seizure is capable of developing to have recurrent seizure, and the decreased GABA synthesis and transport as well as the impaired BDNF-TrkB signaling pathway may contribute to the development of the recurrent seizure. Thus, CTZ seizure rats may provide a novel animal model for epilepsy study and anticonvulsant drug testing in the future.

  10. Hormetic Effect of Chronic Hypergravity in a Mouse Model of Allergic Asthma and Rhinitis

    Science.gov (United States)

    Jang, Tae Young; Jung, Ah-Yeoun; Kim, Young Hyo

    2016-06-01

    We aimed to evaluate the effect of chronic hypergravity in a mouse model of allergic asthma and rhinitis. Forty BALB/c mice were divided as: group A (n = 10, control) sensitized and challenged with saline, group B (n = 10, asthma) challenged by intraperitoneal and intranasal ovalbumin (OVA) to induce allergic asthma and rhinitis, and groups C (n = 10, asthma/rotatory control) and D (n = 10, asthma/hypergravity) exposed to 4 weeks of rotation with normogravity (1G) or hypergravity (5G) during induction of asthma/rhinitis. Group D showed significantly decreased eosinophils, neutrophils, and lymphocytes in their BAL fluid compared with groups B and C (p < 0.05). In real-time polymerase chain reaction using lung homogenate, the expression of IL-1β was significantly upregulated (p < 0.001) and IL-4 and IL-10 significantly downregulated (p < 0.05) in group D. Infiltration of inflammatory cells into lung parenchyma and turbinate, and the thickness of respiratory epithelium was significantly reduced in group D (p < 0.05). The expression of Bcl-2 and heme oxygenase-1 were significantly downregulated, Bax and extracellular dismutase significantly upregulated in Group D. Therefore, chronic hypergravity could have a hormetic effect for allergic asthma and rhinitis via regulation of genes involved in antioxidative and proapoptotic pathways. It is possible that we could use hypergravity machinery for treating allergic respiratory disorders.

  11. Human mesenchymal stem cells suppress chronic airway inflammation in the murine ovalbumin asthma model.

    Science.gov (United States)

    Bonfield, Tracey L; Koloze, Mary; Lennon, Donald P; Zuchowski, Brandon; Yang, Sung Eun; Caplan, Arnold I

    2010-12-01

    Allogeneic human mesenchymal stem cells (hMSCs) introduced intravenously can have profound anti-inflammatory activity resulting in suppression of graft vs. host disease as well as regenerative events in the case of stroke, infarct, spinal cord injury, meniscus regeneration, tendinitis, acute renal failure, and heart disease in human and animal models of these diseases. hMSCs produce bioactive factors that provide molecular cuing for: 1) immunosuppression of T cells; 2) antiscarring; 3) angiogenesis; 4) antiapoptosis; and 5) regeneration (i.e., mitotic for host-derived progenitor cells). Studies have shown that hMSCs have profound effects on the immune system and are well-tolerated and therapeutically active in immunocompetent rodent models of multiple sclerosis and stroke. Furthermore, intravenous administration of MSCs results in pulmonary localization. Asthma is a major debilitating pulmonary disease that impacts in excess of 150 million people in the world with uncontrolled asthma potentially leading to death. In addition, the socioeconomic impact of asthma-associated illnesses at the pediatric and adult level are in the millions of dollars in healthcare costs and lost days of work. hMSCs may provide a viable multiaction therapeutic for this inflammatory lung disease by secreting bioactive factors or directing cellular activity. Our studies show the effectiveness and specificity of the hMSCs on decreasing chronic airway inflammation associated with the murine ovalbumin model of asthma. In addition, the results from these studies verify the in vivo immunoeffectiveness of hMSCs in rodents and support the potential therapeutic use of hMSCs for the treatment of airway inflammation associated with chronic asthma. PMID:20817776

  12. New Mouse Models to Investigate the Efficacy of Drug Combinations in Human Chronic Myeloid Leukemia.

    Science.gov (United States)

    Lin, Hanyang; Woolfson, Adrian; Jiang, Xiaoyan

    2016-01-01

    Chronic myeloid leukemia (CML) comprises a simple and effective paradigm for generating new insights into the cellular origin, pathogenesis, and treatment of many types of human cancer. In particular, mouse models of CML have greatly facilitated the understanding of the underlying molecular mechanisms and pathogenesis of this disease and have led to the identification of new drug targets that in some cases offer the possibility of functional cure. There are currently three established CML mouse models: the BCR-ABL transgenic model, the BCR-ABL retroviral transduction/transplantation model, and the xenotransplant immunodeficient model. Each has its own unique advantages and disadvantages. Depending on the question of interest, some models may be more appropriate than others. In this chapter, we describe a newly developed xenotransplant mouse model to determine the efficacy of novel therapeutic agents, either alone or in combination. The model facilitates the evaluation of the frequency of leukemic stem cells with long-term leukemia-initiating activity, a critical subcellular population that causes disease relapse and progression, through the utilization of primary CD34(+) CML stem/progenitor cells obtained from CML patients at diagnosis and prior to drug treatment. We have also investigated the effectiveness of new combination treatment strategies designed to prevent the development of leukemia in vivo using BCR-ABL (+) blast crisis cells as a model system. These types of in vivo studies are important for the prediction of individual patient responses to drug therapy, and have the potential to facilitate the design of personalized combination therapy strategies. PMID:27581149

  13. White Matter Integrity on DTI, Amyloid Load, and Neurodegeneration in Non-demented Elderly

    Science.gov (United States)

    Kantarci, Kejal; Schwarz, Christopher G.; Reid, Robert; Przybelski, Scott A.; Lesnick, Timothy; Zuk, Samantha M.; Senjem, Matthew L.; Gunter, Jeffrey L.; Lowe, Val; Machulda, Mary M.; Knopman, David S.; Petersen, Ronald C.; Jack, Clifford R.

    2016-01-01

    Importance Pathophysiologic mechanisms leading to loss of white matter (WM) integrity and the temporal positioning of biomarkers of WM integrity relative to the biomarkers of gray matter (GM) neurodegeneration and amyloid load in the course of AD are poorly understood. Objective To investigate the effects of Alzheimer’s disease (AD)-related GM neurodegeneration and high β-amyloid on white matter (WM) microstructure in non-demented older adults. Design Longitudinal cohort study Setting Population-based Mayo Clinic Study of Aging. Participants Participants (n=701) with MRI/DTI and PET studies diagnosed as cognitively normal (CN; n=570) or mild cognitive impairment (MCI; n=131) were included. CN and MCI subjects were divided into biomarker-negative, amyloid- positive only, neurodegeneration- positive only, and amyloid plus neurodegeneration-positive groups based on their amyloid load on 11C-Pittsburgh compound-B PET, AD hypometabolic pattern on 18F-fluorodeoxyglucose PET and/or hippocampal atrophy on MRI. Main Outcome Measure Fractional anisotrophy (FA) from diffusion tensor imaging (DTI) Results No FA alterations were observed in biomarker-negative MCI, and amyloid-positive only CN and MCI groups. Conversely, neurodegeneration-positive only and amyloid plus neurodegeneration- positive CN and MCI groups consistently had decreased FA in the fornix, which correlated with cognitive performance (Rho=0.38; pPatients with MCI had more extensive WM involvement than CN subjects, and greatest FA decreases were observed in the amyloid plus neurodegeneration-positive MCI group. Conclusions and Relevance High amyloid load does not influence DTI-based measures of WM integrity in the absence of co-existent GM neurodegeneration in non-demented older adults. PMID:25347157

  14. Chronic Diarrhea

    Science.gov (United States)

    ... infections that cause chronic diarrhea be prevented? Chronic Diarrhea What is chronic diarrhea? Diarrhea that lasts for more than 2-4 ... represent a life-threatening illness. What causes chronic diarrhea? Chronic diarrhea has many different causes; these causes ...

  15. Skeletal growth and long-term bone turnover after enterocystoplasty in a chronic rat model

    DEFF Research Database (Denmark)

    Gerharz, E.W.; Gasser, J.A.; Mosekilde, Li.;

    2003-01-01

    differences in bone length and volume. Loss of bone mass was almost exclusively in rats with ileocystoplasty and resection of the ileocaecal segment (-37.5%, pQCT, P < 0.01). There was no hyperchloraemic metabolic acidosis or gross impairment of renal function. Hypomagnesaemia, hypocalcaemia and decreased......OBJECTIVE: To investigate skeletal growth and bone metabolism in a chronic animal model of urinary diversion.MATERIALS AND METHODS: Young male Wistar rats (120) were allocated randomly to four groups undergoing: ileocystoplasty, ileocystoplasty and resection of the ileocaecal segment...... significant loss of bone mass when combined with resection of the ileocaecal segment. Rarefaction of the trabecular network is confined to the metabolically highly active cancellous compartment, most likely as a consequence of intestinal malabsorption....

  16. Genetic design of pigs as experimental models in the combat between chronic diseases and healthy aging

    DEFF Research Database (Denmark)

    Bolund, Lars

    2012-01-01

    necessary. The pig is an excellent model for medical research as well as for testing of new methods and drugs for disease prevention and treatment. Its size and longevity makes it especially useful for the study of chronic disease processes that can be monitored and repeatedly biopsied for long periods with...... and without intervention. The genome of different pig breeds have been sequenced, revealing that the pig is genetically more similar to man than conventional laboratory animals - in agreement with the similarities in organ development, physiology and metabolism. Genetically designed minipigs...... (Göttingen and Yucatan) are obtained by genetic engineering of somatic cells and animal cloning by somatic cell nuclear transfer. Primary minipig fibroblasts are genetically modified in culture by transposon-based transgenesis and/or homologous recombination with AAV-transduced constructs. The designed pig...

  17. Hormetic Effect of Chronic Hypergravity in a Mouse Model of Allergic Asthma and Rhinitis.

    Science.gov (United States)

    Jang, Tae Young; Jung, Ah-Yeoun; Kim, Young Hyo

    2016-01-01

    We aimed to evaluate the effect of chronic hypergravity in a mouse model of allergic asthma and rhinitis. Forty BALB/c mice were divided as: group A (n = 10, control) sensitized and challenged with saline, group B (n = 10, asthma) challenged by intraperitoneal and intranasal ovalbumin (OVA) to induce allergic asthma and rhinitis, and groups C (n = 10, asthma/rotatory control) and D (n = 10, asthma/hypergravity) exposed to 4 weeks of rotation with normogravity (1G) or hypergravity (5G) during induction of asthma/rhinitis. Group D showed significantly decreased eosinophils, neutrophils, and lymphocytes in their BAL fluid compared with groups B and C (p asthma and rhinitis via regulation of genes involved in antioxidative and proapoptotic pathways. It is possible that we could use hypergravity machinery for treating allergic respiratory disorders. PMID:27251783

  18. L-Tetrahydropalmatine alleviates mechanical hyperalgesia in models of chronic inflammatory and neuropathic pain in mice.

    Science.gov (United States)

    Zhou, Hai-Hui; Wu, Dan-Lian; Gao, Li-Yan; Fang, Yun; Ge, Wei-Hong

    2016-05-01

    Chronic pain is categorized as inflammatory and neuropathic, and there are common mechanisms underlying the generation of each pain state. Such pain is difficult to treat and the treatment at present is inadequate. Corydalis yanhusuo is a traditional Chinese medicine with demonstrated analgesic efficacy in humans. The potential antihyperalgesic effect of its active component is L-tetrahydropalmatine (L-THP). L-THP has been used for the treatment of headache and other mild pain. However, little is known about its analgesic effect on chronic pain and its mechanism. Here, we report that L-THP exerts remarkable antihyperalgesic effects on neuropathic and inflammatory pain in animal models. Neuropathic hypersensitivity was induced by segmental spinal nerve ligation and inflammatory hypersensitivity was induced by an intraplantar injection of complete Freund's adjuvant. To determine the receptor mechanism underlying the antihyperalgesic actions of L-THP, we used SCH23390, an antagonist of a dopamine D1 receptor, in an attempt to block the antihyperalgesic effects of L-THP. We found that L-THP (1-4 mg/kg, i.p.) produced a dose-dependent antihyperalgesic effect in spinal nerve ligation and complete Freund's adjuvant models. The antihyperalgesic effects of L-THP were abolished by a dopamine D1 receptor antagonist SCH23390 (0.02 mg/kg). Furthermore, L-THP (4 mg/kg, i.p.) did not influence motor function. These findings suggest that L-THP may ameliorate mechanical hyperalgesia by enhancing dopamine D1 receptor-mediated dopaminergic transmission. PMID:26981712

  19. Characterization of right ventricular remodeling and failure in a chronic pulmonary hypertension model

    Science.gov (United States)

    Ishikawa, Kiyotake; Hadri, Lahouaria; Santos-Gallego, Carlos; Fish, Kenneth; Hammoudi, Nadjib; Chaanine, Antoine; Torquato, Samantha; Naim, Charbel; Ibanez, Borja; Pereda, Daniel; García-Alvarez, Ana; Fuster, Valentin; Sengupta, Partho P.; Leopold, Jane A.; Hajjar, Roger J.

    2014-01-01

    In pulmonary hypertension (PH), right ventricular (RV) dysfunction and failure is the main determinant of a poor prognosis. We aimed to characterize RV structural and functional differences during adaptive RV remodeling and progression to RV failure in a large animal model of chronic PH. Postcapillary PH was created surgically in swine (n = 21). After an 8- to 14-wk follow-up, two groups were identified based on the development of overt heart failure (HF): PH-NF (nonfailing, n = 12) and PH-HF (n = 8). In both groups, invasive hemodynamics, pressure-volume relationships, and echocardiography confirmed a significant increase in pulmonary pressures and vascular resistance consistent with PH. Histological analysis also demonstrated distal pulmonary arterial (PA) remodeling in both groups. Diastolic dysfunction, defined by a steeper RV end-diastolic pressure-volume relationship and longitudinal strain, was found in the absence of HF as an early marker of RV remodeling. RV contractility was increased in both groups, and RV-PA coupling was preserved in PH-NF animals but impaired in the PH-HF group. RV hypertrophy was present in PH-HF, although there was evidence of increased RV fibrosis in both PH groups. In the PH-HF group, RV sarcoplasmic reticulum Ca2+-ATPase2a expression was decreased, and endoplasmic reticulum stress was increased. Aldosterone levels were also elevated in PH-HF. Thus, in the swine pulmonary vein banding model of chronic postcapillary PH, RV remodeling occurs at the structural, histological, and molecular level. Diastolic dysfunction and fibrosis are present in adaptive RV remodeling, whereas the onset of RV failure is associated with RV-PA uncoupling, defective calcium handling, and hyperaldosteronism. PMID:25158063

  20. Modelling the propagation of effects of chronic exposure to ionising radiation from individuals to populations

    Energy Technology Data Exchange (ETDEWEB)

    Alonzo, F. [Laboratory of Environmental Modelling, DEI/SECRE/LME, Institute of Radioprotection and Nuclear Safety (IRSN), Cadarache, Building 159, BP3, 13115 St-Paul-lez-Durance Cedex (France); Laboratory of Radioecology and Ecotoxicology, DEI/SECRE/LRE, Institute of Radioprotection and Nuclear Safety (IRSN), Cadarache Building 186, BP3, 13115 St-Paul-lez-Durance Cedex (France)], E-mail: frederic.alonzo@irsn.fr; Hertel-Aas, T. [Department of Plant and Environmental Sciences, P.O. Box 5003, Norwegian University of Life Sciences, 1432 Aas (Norway); Gilek, M. [School of Life Sciences, Soedertoern University College, 14189 Huddinge (Sweden); Gilbin, R. [Laboratory of Radioecology and Ecotoxicology, DEI/SECRE/LRE, Institute of Radioprotection and Nuclear Safety (IRSN), Cadarache Building 186, BP3, 13115 St-Paul-lez-Durance Cedex (France); Oughton, D.H. [Department of Plant and Environmental Sciences, P.O. Box 5003, Norwegian University of Life Sciences, 1432 Aas (Norway); Garnier-Laplace, J. [Laboratory of Radioecology and Ecotoxicology, DEI/SECRE/LRE, Institute of Radioprotection and Nuclear Safety (IRSN), Cadarache Building 186, BP3, 13115 St-Paul-lez-Durance Cedex (France)

    2008-09-15

    This study evaluated the potential effect of ionising radiation on population growth using simple population models and parameter values derived from chronic exposure experiments in two invertebrate species with contrasting life-history strategies. In the earthworm Eisenia fetida, models predicted increasing delay in population growth with increasing gamma dose rate (up to 0.6 generation times at 11 mGy h{sup -1}). Population extinction was predicted at 43 mGy h{sup -1}. In the microcrustacean Daphnia magna, models predicted increasing delay in population growth with increasing alpha dose rate (up to 0.8 generation times at 15.0 mGy h{sup -1}), only after two successive generations were exposed. The study examined population effects of changes in different individual endpoints (including survival, number of offspring produced and time to first reproduction). Models showed that the two species did not respond equally to equivalent levels of change, the fast growing daphnids being more susceptible to reduction in fecundity or delay in reproduction than the slow growing earthworms. This suggested that susceptibility of a population to ionising radiation cannot be considered independent of the species' life history.

  1. Modeled concentrations in rice and ingestion doses from chronic atmospheric releases of tritium

    International Nuclear Information System (INIS)

    The expansion of nuclear power programs in Asia has stimulated interest in the improved modeling of concentrations of tritium in rice, a staple crop grown throughout the far east. Normally, the specific activity model is used to calculate concentrations of tritium in the tissue water of edible plants to assess ingestion dose from chronic releases. However, because rice, like other grains, has much lower water content than most crops, the calculation must also account for organically bound tritium. This paper reviews ways to calculate steady-state concentrations of tritium in rice, including the methods of Canadian and US regulatory models, and the assumptions behind them. Concentrations in rice and resulting ingestion doses are compared for the various methods, and equations for calculating concentrations are recommended. The regulatory models underestimate doses received from ingestion of rice contaminated with tritium since they do not account explicitly for organically bound tritium. The importance of including organically bound tritium is illustrated in a comparison of doses from rice, leafy vegetables and milk for an Asian diet. Dose factors from tritium for these foods are estimated to be 135, 47, and 20 nSv y-1/(Bq m-3), respectively. Assuming known air concentrations, tritium concentrations in rice, calculated with the recommended equations, are uncertain by less than a factor 2 when tritium concentrations in the rice paddy water are known, and by less than a factor of 2.3 when concentrations in paddy water are unknown

  2. Microglia and regulation of inflammation-mediated neurodegeneration: Prevention and treatment by phytochemicals and metabolic nutrients

    Directory of Open Access Journals (Sweden)

    Rajagopal Shanmuga Sundaram

    2012-01-01

    Full Text Available Inflammation, a common denominator among the diverse list of neurodegenerative diseases, has recently been implicated as a critical mechanism responsible for the progressive nature of neurodegeneration. Microglias are the resident innate immune cells in the central nervous system and produce a barrage of factors (ILs, TNF α, NO, PGs, SOD that are toxic to neurons. Evidence supports that the unregulated activation of microglia, in response to environmental toxins, endogenous proteins and neuronal death, results in the production of toxic factors that propagate neuronal injury. Herbal medicine has long been used to treat neural symptoms. Although the precise mechanisms of action of herbal drugs have yet to be determined, some of them have been shown to exert anti-inflammatory and / or antioxidant effects in a variety of peripheral systems. Now, as increasing evidence indicates that neuroglia-derived chronic inflammatory responses play a pathological role in the central nervous system, anti-inflammatory herbal medicine and its constituents are being proved to be potent neuroprotectors against various brain pathologies. Structural diversity of medicinal herbs makes them a valuable source of novel lead compounds against therapeutic targets that are newly discovered by genomics, proteomics and high-throughput screening. In the following review, we discuss the common thread of microglial activation across numerous neurodegenerative diseases, define current perceptions of how microglia are damaging neurons and explain how the microglial response to neuronal damage results in a self-propelling cycle of neuron death. This article synthesizes what we know about these destructive processes, while offering an insight into a new avenue of treatment involving phytochemicals and other nutrients.

  3. The effects of soluble Aβ oligomers on neurodegeneration in Alzheimer's disease.

    Science.gov (United States)

    Brouillette, Jonathan

    2014-01-01

    The neurodegenerative process that defines Alzheimer''s disease (AD) is initially characterized by synaptic alterations followed by synapse loss and ultimately cell death. Decreased synaptic density that precedes neuronal death is the strongest pathological correlate of cognitive deficits observed in AD. Substantial synapse and neuron loss occur early in disease progression in the entorhinal cortex (EC) and the CA1 region of the hippocampus, when memory deficits become clinically detectable. Mounting evidence suggests that soluble amyloid-β (Aβ) oligomers trigger synapse dysfunction both in vitro and in vivo. However, the neurodegenerative effect of Aβ species observed on neuronal culture or organotypic brain slice culture has been more challenging to mimic in animal models. While most of the transgenic mice that overexpress Aβ show abundant amyloid plaque pathology and early synaptic alterations, these models have been less successful in recapitulating the spatiotemporal pattern of cell loss observed in AD. Recently we developed a novel animal model that revealed the neurodegenerative effect of soluble low-molecular-weight Aβ oligomers in vivo. This new approach may now serve to determine the molecular and cellular mechanisms linking soluble Aβ species to neurodegeneration in animals. In light of the low efficiency of AD therapies based on the amyloid cascade hypothesis, a novel framework, the aging factor cascade hypothesis, is proposed in an attempt to integrate the new data and concepts that emerged from recent research to develop disease modifying therapies. PMID:23859546

  4. Molecular Mechanisms of Neurodegeneration in Spinal Muscular Atrophy

    Science.gov (United States)

    Ahmad, Saif; Bhatia, Kanchan; Kannan, Annapoorna; Gangwani, Laxman

    2016-01-01

    Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. SMA is primarily characterized by degeneration of the spinal motor neurons that leads to skeletal muscle atrophy followed by symmetric limb paralysis, respiratory failure, and death. In humans, mutation of the Survival Motor Neuron 1 (SMN1) gene shifts the load of expression of SMN protein to the SMN2 gene that produces low levels of full-length SMN protein because of alternative splicing, which are sufficient for embryonic development and survival but result in SMA. The molecular mechanisms of the (a) regulation of SMN gene expression and (b) degeneration of motor neurons caused by low levels of SMN are unclear. However, some progress has been made in recent years that have provided new insights into understanding of the cellular and molecular basis of SMA pathogenesis. In this review, we have briefly summarized recent advances toward understanding of the molecular mechanisms of regulation of SMN levels and signaling mechanisms that mediate neurodegeneration in SMA. PMID:27042141

  5. Selective neurodegeneration, neuropathology and symptom profiles in Huntington's disease.

    Science.gov (United States)

    Waldvogel, Henry J; Thu, Doris; Hogg, Virginia; Tippett, Lynette; Faull, Richard L M

    2012-01-01

    Huntington's disease (HD) is an autosomal dominant inherited neurodegenerative disease caused by a CAG repeat expansion in exon 1 of the Huntington gene (HD) also known as IT15. Despite the disease being caused by dysfunction ofa single gene, expressed as an expanded polyglutamine in the huntingtin protein, there is a major variability in the symptom profile of patients with Huntington's disease as well as great variability in the neuropathology. The symptoms vary throughout the course of the disease and vary greatly between cases. These symptoms present as varying degrees of involuntary movements, mood, personality changes, cognitive changes and dementia. To determine whether there is a morphological basis for this symptom variability, recent studies have investigated the cellular and neurochemical changes in the striatum and cerebral cortex in the human brain to determine whether there is a link between the pathology in these regions and the symptomatology shown by individual cases. These studies together revealed that cases showing mainly mood symptom profiles correlated with marked degeneration in the striosomal compartment of the striatum, or in the anterior cingulate gyrus of the cerebral cortex. In contrast, in cases with mainly motor symptoms neurodegeneration was especially marked in the primary motor cortex with variable degeneration in both the striosomes and matrix compartments of the striatum. These studies suggest that the variable degeneration of the striatum and cerebral cortex correlates with the variable profiles of Huntington's disease. PMID:23560309

  6. Application of medical cannabis in patients with the neurodegeneration disorders

    Directory of Open Access Journals (Sweden)

    Lidia Kotuła

    2014-04-01

    Full Text Available Medical cannabis is the dried flowers of the female Cannabis sativa L. plant. Cannabis contains a number of active elements, including dronabinol (THC and cannabidiol (CBD. Dronabinol is usually the main ingredient. The body’s own cannabinoid system has been identified. The discovery of this system, which comprises endocannabinoids and receptors, confirmed that cannabis has a positive effect on certain illnesses and conditions. Two types of cannabinoid receptors have been identified: CB1 and CB2 receptors. The first type CB1 is mostly found in the central nervous system, modulate pain. It also has an anti-emetic effect, and has influence on the memory and the motor system. The second type of receptors CB2 is peripheral, and it is primarily found in immune system cells and it is responsible for the immunomodulatory effects of cannabinoids. Medical cannabis can help in cases of the neurodegeneration disorders, for example Parkinson’s disease, Huntington’s Disease, Amyotrophic Lateral Sclerosis. Patients generally tolerate medical cannabis well.

  7. Oxidative damage and neurodegeneration in manganese-induced neurotoxicity

    International Nuclear Information System (INIS)

    Exposure to excessive manganese (Mn) levels results in neurotoxicity to the extrapyramidal system and the development of Parkinson's disease (PD)-like movement disorder, referred to as manganism. Although the mechanisms by which Mn induces neuronal damage are not well defined, its neurotoxicity appears to be regulated by a number of factors, including oxidative injury, mitochondrial dysfunction and neuroinflammation. To investigate the mechanisms underlying Mn neurotoxicity, we studied the effects of Mn on reactive oxygen species (ROS) formation, changes in high-energy phosphates (HEP), neuroinflammation mediators and associated neuronal dysfunctions both in vitro and in vivo. Primary cortical neuronal cultures showed concentration-dependent alterations in biomarkers of oxidative damage, F2-isoprostanes (F2-IsoPs) and mitochondrial dysfunction (ATP), as early as 2 h following Mn exposure. Treatment of neurons with 500 μM Mn also resulted in time-dependent increases in the levels of the inflammatory biomarker, prostaglandin E2 (PGE2). In vivo analyses corroborated these findings, establishing that either a single or three (100 mg/kg, s.c.) Mn injections (days 1, 4 and 7) induced significant increases in F2-IsoPs and PGE2 in adult mouse brain 24 h following the last injection. Quantitative morphometric analyses of Golgi-impregnated striatal sections from mice exposed to single or three Mn injections revealed progressive spine degeneration and dendritic damage of medium spiny neurons (MSNs). These findings suggest that oxidative stress, mitochondrial dysfunction and neuroinflammation are underlying mechanisms in Mn-induced neurodegeneration.

  8. Chronic ibuprofen administration worsens cognitive outcome following traumatic brain injury in rats.

    Science.gov (United States)

    Browne, Kevin D; Iwata, Akira; Putt, M E; Smith, Douglas H

    2006-10-01

    Traumatic brain injury (TBI) can induce progressive neurodegeneration in association with chronic inflammation. Since chronic treatment with the non-steroidal anti-inflammatory drug (NSAID), ibuprofen, improves functional and histopathologic outcome in a mouse model of Alzheimer's disease (AD), we investigated whether it would also improve long-term outcome following TBI. Anesthetized adult rats were subjected to fluid percussion brain injury. Over the following 4 months the injured animals received ibuprofen per os (formulated in feed) at the approximate doses of 20 mg/kg body wt/day (n=13), 40 mg/kg body wt/day (n=13), or control (feed only, n=12). Sham animals underwent surgery without injury or ibuprofen treatment (n=9). At 4 months post-injury, a Morris water maze task revealed a profound learning dysfunction in all three injured groups compared to the sham group. Surprisingly, the learning ability of injured animals treated with either chronic ibuprofen regimen was significantly worsened compared to non-treated injured animals. However, there was no difference in the extent of progressive atrophy of the cortex or hippocampus between treated and non-treated injured animals. These data may have important implications for TBI patients who are often prescribed NSAIDs for chronic pain. PMID:16764859

  9. Estimation of progression of multi-state chronic disease using the Markov model and prevalence pool concept

    OpenAIRE

    Liu Chi-Ming; Chou Pesus; Shih Hui-Chuan; Tung Tao-Hsin

    2007-01-01

    Abstract Background We propose a simple new method for estimating progression of a chronic disease with multi-state properties by unifying the prevalence pool concept with the Markov process model. Methods Estimation of progression rates in the multi-state model is performed using the E-M algorithm. This approach is applied to data on Type 2 diabetes screening. Results Good convergence of estimations is demonstrated. In contrast to previous Markov models, the major advantage of our proposed m...

  10. Novel promising therapeutics against chronic neuroinflammation and neurodegeneration in Alzheimer's disease.

    Science.gov (United States)

    Venigalla, Madhuri; Sonego, Sandra; Gyengesi, Erika; Sharman, Matthew J; Münch, Gerald

    2016-05-01

    Alzheimer's disease (AD) is a progressive neurodegenerative disorder, characterized by deposition of amyloid plaques and neurofibrillary tangles, as well as microglial and astroglial activation, and, finally, leading to neuronal dysfunction and death. Current treatments for AD primarily focus on enhancement of cholinergic transmission. However, these treatments are only symptomatic, and no disease-modifying drug is available for the treatment of AD patients. This review will provide an overview of the antioxidant, anti-inflammatory, anti-amyloidogenic, neuroprotective, and cognition-enhancing effects of a variety of nutraceuticals including curcumin, apigenin, docosahexaenoic acid, epigallocatechin gallate, α-lipoic acid and resveratrol and their potential for AD prevention and treatment. We suggest that therapeutic use of these compounds might lead to a safe strategy to delay the onset of AD or slow down its progression. The continuing investigation of the potential of these substances is necessary as they are promising compounds to yield a possible remedy for this pervasive disease. PMID:26529297

  11. Excisional wound healing is delayed in a murine model of chronic kidney disease.

    Directory of Open Access Journals (Sweden)

    Akhil K Seth

    Full Text Available BACKGROUND: Approximately 15% of the United States population suffers from chronic kidney disease (CKD, often demonstrating an associated impairment in wound healing. This study outlines the development of a surgical murine model of CKD in order to investigate the mechanisms underlying this impairment. METHODS: CKD was induced in mice by partial cauterization of one kidney cortex and contralateral nephrectomy, modifying a previously published technique. After a minimum of 6-weeks, splinted, dorsal excisional wounds were created to permit assessment of wound healing parameters. Wounds were harvested on postoperative days (POD 0, 3, 7, and 14 for histological, immunofluorescent, and quantitative PCR (qPCR. RESULTS: CKD mice exhibited deranged blood chemistry and hematology profiles, including profound uremia and anemia. Significant decreases in re-epithelialization and granulation tissue deposition rates were found in uremic mice wounds relative to controls. On immunofluorescent analysis, uremic mice demonstrated significant reductions in cellular proliferation (BrdU and angiogenesis (CD31, with a concurrent increase in inflammation (CD45 as compared to controls. CKD mice also displayed differential expression of wound healing-related genes (VEGF, IL-1β, eNOS, iNOS on qPCR. CONCLUSIONS: These findings represent the first reported investigation of cutaneous healing in a CKD animal model. Ongoing studies of this significantly delayed wound healing phenotype include the establishment of renal failure model in diabetic strains to study the combined effects of CKD and diabetes.

  12. Probability Prediction in Multistate Survival Models for Patients with Chronic Myeloid Leukaemia

    Institute of Scientific and Technical Information of China (English)

    FANG Ya; Hein Putter

    2005-01-01

    In order to find an appropriate model suitable for a multistate survival experiment, 634 patients with chronic myeloid leukaemia (CML) were selected to illustrate the method of analysis.After transplantation, there were 4 possible situations for a patient: disease free, relapse but still alive, death before relapse, and death after relapse. The last 3 events were considered as treatment failure. The results showed that the risk of death before relapse was higher than that of the relapse,especially in the first year after transplantation with competing-risk method. The result of patients with relapse time less than 12 months was much poor by the Kaplan-Meier method. And the multistate survival models were developed, which were detailed and informative based on the analysis of competing risks and Kaplan-Meier analysis. With the multistate survival models, a further analysis on conditional probability was made for patients who were disease free and still alive at month 12 after transplantation. It was concluded that it was possible for an individual patient to predict the 4 possible probabilities at any time. Also the prognoses for relapse either death or not and death either before or afterrelapse may be given. Furthermore, the conditional probabilities for patients who were disease free and still alive in a given time after transplantation can be predicted.

  13. Implementation of an active aging model in Mexico for prevention and control of chronic diseases in the elderly

    Directory of Open Access Journals (Sweden)

    Correa-Muñoz Elsa

    2009-08-01

    Full Text Available Abstract Background World Health Organization cites among the main challenges of populational aging the dual disease burden: the greater risk of disability, and the need for care. In this sense, the most frequent chronic diseases during old age worldwide are high blood pressure, type 2 diabetes mellitus, cancer, arthritis, osteoporosis, depression, and dementia. Chronic disease-associated dependency represents an onerous sanitary and financial burden for the older adult, the family, and the health care system. Thus, it is necessary to propose community-level models for chronic disease prevention and control in old age. The aim of the present work is to show our experience in the development and implementation of a model for chronic disease prevention and control in old age at the community level under the active aging paradigm. Methods/Design A longitudinal study will be carried out in a sample of 400 elderly urban and rural-dwelling individuals residing in Hidalgo State, Mexico during five years. All participants will be enrolled in the model active aging. This establishes the formation of 40 gerontological promoters (GPs from among the older adults themselves. The GPs function as mutual-help group coordinators (gerontological nuclei and establish self-care and self-promotion actions for elderly well-being and social development. It will be conformed a big-net of social network of 40 mutual-help groups of ten elderly adults each one, in which self-care is a daily practice for chronic disease prevention and control, as well as for achieving maximal well-being and life quality in old age. Indicators of the model's impact will be (i therapeutic adherence; (ii the incidence of the main chronic diseases in old age; (iii life expectancy without chronic diseases at 60 years of age; (iv disability adjusted life years lost; (v years of life lost due to premature mortality, and (vi years lived with disability. Discussion We propose that the

  14. Cytosolic caspases mediate mislocalised SOD2 depletion in an in vitro model of chronic prion infection

    Directory of Open Access Journals (Sweden)

    Layla Sinclair

    2013-07-01

    Oxidative stress as a contributor to neuronal death during prion infection is supported by the fact that various oxidative damage markers accumulate in the brain during the course of this disease. The normal cellular substrate of the causative agent, the prion protein, is also linked with protective functions against oxidative stress. Our previous work has found that, in chronic prion infection, an apoptotic subpopulation of cells exhibit oxidative stress and the accumulation of oxidised lipid and protein aggregates with caspase recruitment. Given the likely failure of antioxidant defence mechanisms within apoptotic prion-infected cells, we aimed to investigate the role of the crucial antioxidant pathway components, superoxide dismutases (SOD 1 and 2, in an in vitro model of chronic prion infection. Increased total SOD activity, attributable to SOD1, was found in the overall population coincident with a decrease in SOD2 protein levels. When apoptotic cells were separated from the total population, the induction of SOD activity in the infected apoptotic cells was lost, with activity reduced back to levels seen in mock-infected control cells. In addition, mitochondrial superoxide production was increased and mitochondrial numbers decreased in the infected apoptotic subpopulation. Furthermore, a pan-caspase probe colocalised with SOD2 outside of mitochondria within cytosolic aggregates in infected cells and inhibition of caspase activity was able to restore cellular levels of SOD2 in the whole unseparated infected population to those of mock-infected control cells. Our results suggest that prion propagation exacerbates an apoptotic pathway whereby mitochondrial dysfunction follows mislocalisation of SOD2 to cytosolic caspases, permitting its degradation. Eventually, cellular capacity to maintain oxidative homeostasis is overwhelmed, thus resulting in cell death.

  15. EFFECTS OF RADIX ANGELICAE SINENSIS AND SHUANGHUANGLIAN ON A RAT MODEL OF CHRONIC PSEUDOMONAS AERUGINOSA PNEUMONIA

    Institute of Scientific and Technical Information of China (English)

    H.K.Johansen; C.Moser; V.Faber; A.Khamzmi; J.Rygaard; N.Hφiby; Z.J.Song

    2000-01-01

    Objective. To study the effects of two kinds of Chinese herbal medicine, Radix angelicae sinensis(RAS) (当归)and Shuanghuanglian(SHL)(双黄连) on chronic Pseudomortas aerug/nosa(PA)lung infection in a rat model mimicking cystic fibrosis(CF).Methods. Rats were divided into RAS, SIlL and control groups. All rats were challenged intratracheally with alginate embedded PA and the trealments with herbal medicine started on the same day of challenge. The drugs were administered subcutaneously once a day for ten days and the control group was treated with sterile saline. The rats were sacrificed two weeks after challenge. Results. Significantly improved lung bacterial clearance(P <0.05, P < 0.01) and milder macroecopic lung pathology (P<0.005) were found in the two treated groups compared to the control group. In tbe SHL treated group, the neutrophil percent in the peripheral blood leukocytes(P < 0.05), the anti-PA IgG level in serum (P < 0.05), the incidence of lung abscesses(P < 0.005) and the incidence of acnte lung inflammafion(P < 0.05) were signitlcanfly lower than in the control group. The RAS treatment reduced fever(P < 0.05), decreased the incidence of lung abscesses(P <0.005) and lung mast cell number (P< 0.05), and lowered anti-PA IgG1 level in serum(P< 0.05) when compared to the control group. The anti-PA bacterial activity test in SHL was weakly positive whereas in RAS it was negative. Conclusion. The treatment with both herbal medicines could increase the resistance of the rats against PA lung infection and they therefore might be potential premising drugs for stimulation of the immtme system in CF patients with chronic PA lung infection.

  16. A modified collagen gel dressing promotes angiogenesis in a preclinical swine model of chronic ischemic wounds.

    Science.gov (United States)

    Elgharably, Haytham; Ganesh, Kasturi; Dickerson, Jennifer; Khanna, Savita; Abas, Motaz; Ghatak, Piya Das; Dixit, Sriteja; Bergdall, Valerie; Roy, Sashwati; Sen, Chandan K

    2014-01-01

    We recently performed proteomic characterization of a modified collagen gel (MCG) dressing and reported promising effects of the gel in healing full-thickness excisional wounds. In this work, we test the translational relevance of our aforesaid findings by testing the dressing in a swine model of chronic ischemic wounds recently reported by our laboratory. Full-thickness excisional wounds were established in the center of bipedicle ischemic skin flaps on the backs of animals. Ischemia was verified by laser Doppler imaging, and MCG was applied to the test group of wounds. Seven days post wounding, macrophage recruitment to the wound was significantly higher in MCG-treated ischemic wounds. In vitro, MCG up-regulated expression of Mrc-1 (a reparative M2 macrophage marker) and induced the expression of anti-inflammatory cytokine interleukin (IL)-10 and of fibroblast growth factor-basic (β-FGF). An increased expression of CCR2, an M2 macrophage marker, was noted in the macrophages from MCG treated wounds. Furthermore, analyses of wound tissues 7 days post wounding showed up-regulation of transforming growth factor-β, vascular endothelial growth factor, von Willebrand's factor, and collagen type I expression in MCG-treated ischemic wounds. At 21 days post wounding, MCG-treated ischemic wounds displayed higher abundance of proliferating endothelial cells that formed mature vascular structures and increased blood flow to the wound. Fibroblast count was markedly higher in MCG-treated ischemic wound-edge tissue. In addition, MCG-treated wound-edge tissues displayed higher abundance of mature collagen with increased collagen type I : III deposition. Taken together, MCG helped mount a more robust inflammatory response that resolved in a timely manner, followed by an enhanced proliferative phase, angiogenic outcome, and postwound tissue remodeling. Findings of the current study warrant clinical testing of MCG in a setting of ischemic chronic wounds. PMID:25224310

  17. Bone Marrow Stromal Cells Attenuate Lung Injury in a Murine Model of Neonatal Chronic Lung Disease

    OpenAIRE

    Aslam, Muhammad; Baveja, Rajiv; Liang, Olin D.; Fernandez-Gonzalez, Angeles; Lee, Changjin; Mitsialis, S. Alex; Kourembanas, Stella

    2009-01-01

    Rationale: Neonatal chronic lung disease, known as bronchopulmonary dysplasia (BPD), remains a serious complication of prematurity despite advances in the treatment of extremely low birth weight infants.

  18. Assessment of a primary and tertiary care integrated management model for chronic obstructive pulmonary disease

    Directory of Open Access Journals (Sweden)

    Peiro Meritxell

    2009-02-01

    Full Text Available Abstract Background The diagnosis and treatment of patients with chronic obstructive pulmonary disease (COPD in Spain continues to present challenges, and problems are exacerbated when there is a lack of coordinated follow-up between levels of care. This paper sets out the protocol for assessing the impact of an integrated management model for the care of patients with COPD. The new model will be evaluated in terms of 1 improvement in the rational utilization of health-care services and 2 benefits reflected in improved health status and quality of life for patients. Methods/Design A quasi-experimental study of the effectiveness of a COPD management model called COPD PROCESS. The patients in the study cohorts will be residents of neighborhoods served by two referral hospitals in Barcelona, Spain. One area comprises the intervention group (n = 32,248 patients and the other the control group (n = 32,114 patients. The study will include pre- and post-intervention assessment 18 months after the program goes into effect. Analyses will be on two datasets: clinical and administrative data available for all patients, and clinical assessment information for a cohort of 440 patients sampled randomly from the intervention and control areas. The main endpoints will be the hospitalization rates in the two health-care areas and quality-of-life measures in the two cohorts. Discussion The COPD PROCESS model foresees the integrated multidisciplinary management of interventions at different levels of the health-care system through coordinated routine clinical practice. It will put into practice diagnostic and treatment procedures that are based on current evidence, multidisciplinary consensus, and efficient use of available resources. Care pathways in this model are defined in terms of patient characteristics, level of disease severity and the presence or absence of exacerbation. The protocol covers the full range of care from primary prevention to treatment of

  19. Protective effects of triptolide on retinal ganglion cells in a rat model of chronic glaucoma

    Directory of Open Access Journals (Sweden)

    Yang F

    2015-11-01

    Full Text Available Fan Yang, Dongmei Wang, Lingling Wu, Ying Li Ophthalmology Department, Peking University Third Hospital, Beijing, People’s Republic of China Purpose: To study the effects of triptolide, a Chinese herb extract, on retinal ganglion cells (RGCs in a rat model of chronic glaucoma.Methods: Eighty Wistar rats were randomly divided into triptolide group (n=40 and normal saline (NS group (n=40. Angle photocoagulation was used to establish the model of glaucoma, with right eye as laser treated eye and left eye as control eye. Triptolide group received triptolide intraperitoneally daily, while NS group received NS. Intraocular pressure (IOP, anti-CD11b immunofluorescent stain in retina and optic nerve, RGCs count with Nissel stain and microglia count with anti-CD11b immunofluorescence stain in retina flat mounts, retinal tumor necrosis factor (TNF-α mRNA detection by reverse transcription–polymerase chain reaction, and double immunofluorescent labeling with anti-TNF-α and anti-CD11b in retinal frozen section were performed.Results: Mean IOP of the laser treated eyes significantly increased 3 weeks after photocoagulation (P<0.05, with no statistical difference between the two groups (P>0.05. RGCs survival in the laser treated eyes was significantly improved in the triptolide group than the NS group (P<0.05. Microglia count in superficial retina of the laser treated eyes was significantly less in the triptolide group (30.40±4.90 than the NS group (35.06±7.59 (P<0.05. TNF-α mRNA expression in the retina of the laser treated eyes in the triptolide group decreased by 60% compared with that in the NS group (P<0.01. The double immunofluorescent labeling showed that TNF-α was mainly distributed around the microglia.Conclusion: Triptolide improved RGCs survival in this rat model of chronic glaucoma, which did not depend on IOP decrease but might be exerted by inhibiting microglia activities and reducing TNF-α secretion. Keywords: glaucoma, triptolide

  20. Effectiveness of the introduction of a Chronic Care Model-based program for type 2 diabetes in Belgium

    OpenAIRE

    De Maeseneer Jan; Vermeire Etienne; Verbeke Geert; Feyen Luc; Nobels Frank; Bastiaens Hilde; Sunaert Patricia; Willems Sara; De Sutter An

    2010-01-01

    Abstract Background During a four-year action research project (2003-2007), a program targeting all type 2 diabetes patients was implemented in a well-defined geographical region in Belgium. The implementation of the program resulted in an increase of the overall Assessment of Chronic Illness Care (ACIC) score from 1.45 in 2003 to 5.5 in 2007. The aim of the follow-up study in 2008 was to assess the effect of the implementation of Chronic Care Model (CCM) elements on the quality of diabetes c...

  1. Cerebrospinal Fluid Markers of Neurodegeneration and Rates of Brain Atrophy in Early Alzheimer Disease

    Science.gov (United States)

    Tarawneh, Rawan; Head, Denise; Allison, Samantha; Buckles, Virginia; Fagan, Anne M.; Ladenson, Jack H.; Morris, John C.; Holtzman, David M.

    2015-01-01

    IMPORTANCE Measures of neuronal loss are likely good surrogates for clinical and radiological disease progression in Alzheimer disease (AD). Cerebrospinal fluid (CSF) markers of neuronal injury or neurodegeneration may offer usefulness in predicting disease progression and guiding outcome assessments and prognostic decisions in clinical trials of disease-modifying therapies. Visinin-like protein 1 (VILIP-1) has demonstrated potential usefulness as a marker of neuronal injury in AD. OBJECTIVE To investigate the usefulness of CSF VILIP-1, tau, p-tau181, and Aβ42 levels in predicting rates of whole-brain and regional atrophy in early AD and cognitively normal control subjects over time. DESIGN, SETTING, AND PARTICIPANTS Longitudinal observational study of brain atrophy in participants with early AD and cognitively normal controls. Study participants had baseline CSF biomarker measurements and longitudinal magnetic resonance imaging assessments for a mean follow-up period of 2 to 3 years. Mixed linear models assessed the ability of standardized baseline CSF biomarker measures to predict rates of whole-brain and regional atrophy over the follow-up period. The setting was The Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine in St Louis. Participants (mean age, 72.6 years) were individuals with a clinical diagnosis of very mild AD (n = 23) and cognitively normal controls (n = 64) who were enrolled in longitudinal studies of healthy aging and dementia. The study dates were 2000 to 2010. MAIN OUTCOMES AND MEASURES Correlations between baseline CSF biomarker measures and rates of whole-brain or regional atrophy in the AD and control cohorts over the follow-up period. RESULTS Baseline CSF VILIP-1, tau, and p-tau181 levels (but not Aβ42 levels) predicted rates of whole-brain and regional atrophy in AD over the follow-up period. Baseline CSF VILIP-1 levels predicted whole-brain (P = .006), hippocampal (P = .01), and

  2. Protective effect of naringin on 3-nitropropionic acid-induced neurodegeneration through the modulation of matrix metalloproteinases and glial fibrillary acidic protein.

    Science.gov (United States)

    Gopinath, Kulasekaran; Sudhandiran, Ganapasam

    2016-01-01

    Naringin (4',5,7-trihydroxy-flavonone-7-rhamnoglucoside), a flavonone present in grapefruit, has recently been reported to protect against neurodegeration, induced with 3-nitropropionic acid (3-NP), through its antioxidant, anti-inflammatory, and antiapoptotic properties. This study used a rat model of 3-NP-induced neurodegeneration to investigate the neuroprotective effects of naringin exerted by modulating the expression of matrix metalloproteinases and glial fibrillary acidic protein. Neurodegeneration was induced with 3-NP (10 mg/kg body mass, by intraperitoneal injection) once a day for 2 weeks, and induced rats were treated with naringin (80 mg/kg body mass, by oral gavage, once a day for 2 weeks). Naringin ameliorated the motor abnormalities caused by 3-NP, and reduced blood-brain barrier dysfunction by decreasing the expression of matrix metalloproteinases 2 and 9, along with increasing the expression of the tissue inhibitors of metalloproteinases 1 and 2 in 3-NP-induced rats. Further, naringin reduced 3-NP-induced neuroinflammation by decreasing the expression of nuclear factor-kappa B and glial fibrillary acidic protein. Thus, naringin exerts protective effects against 3-NP-induced neurodegeneration by ameliorating the expressions of matrix metalloproteinases and glial fibrillary acidic protein. PMID:26544788

  3. Hypertension exacerbates predisposition to neurodegeneration and memory impairment in the presence of a neuroinflammatory stimulus: Protection by angiotensin converting enzyme inhibition.

    Science.gov (United States)

    Goel, Ruby; Bhat, Shahnawaz Ali; Rajasekar, N; Hanif, Kashif; Nath, Chandishwar; Shukla, Rakesh

    2015-06-01

    Hypertension is a risk factor for cognitive impairment. Furthermore, neuroinflammation and neurodegeneration are intricately associated with memory impairment. Therefore, the present study aimed to explore the involvement of hypertension and angiotensin system in neurodegeneration and memory dysfunction in the presence of neuroinflammatory stimulus. Memory impairment was induced by chronic neuroinflammation that was developed by repeated intracerebroventricular (ICV) injections of lipopolysaccharide (LPS) on the 1st, 4th, 7th, and 10th day. Memory functions were evaluated by the Morris water maze (MWM) test on days 13-15, followed by biochemical and molecular studies in the cortex and hippocampus regions of rat brain. LPS at the dose of 25μg ICV caused memory impairment in spontaneously hypertensive rats (SHRs) but not in normotensive Wistar rats (NWRs). Memory deficit was obtained with 50μg of LPS (ICV) in NWRs. Control SHRs already exhibited increased angiotensin converting enzyme (ACE) activity and expression, neuroinflammation (increased TNF-α, GFAP, COX-2 and NF-kB), oxidative stress (increased iNOS, ROS and nitrite levels), TLR-4 expression and TUNEL positive cells as compared to control NWRs. Further, LPS (25μg ICV) exaggerated inflammatory response, oxidative stress and apoptosis in SHRs but similar effects were witnessed at 50μg of LPS (ICV) in NWRs. Oral administration of perindopril (ACE inhibitor), at non-antihypertensive dose (0.1mg/kg), for 15days attenuated LPS induced deleterious changes in both NWRs and SHRs. Our data suggest that susceptibility of the brain for neurodegeneration and memory impairment induced by neuroinflammation is enhanced in hypertension, and that can be protected by ACE inhibition. PMID:25869103

  4. Resistance to Recombinant Human Erythropoietin Therapy in a Rat Model of Chronic Kidney Disease Associated Anemia

    Directory of Open Access Journals (Sweden)

    Patrícia Garrido

    2015-12-01

    Full Text Available This study aimed to elucidate the mechanisms explaining the persistence of anemia and resistance to recombinant human erythropoietin (rHuEPO therapy in a rat model of chronic kidney disease (CKD-associated anemia with formation of anti-rHuEPO antibodies. The remnant kidney rat model of CKD induced by 5/6 nephrectomy was used to test a long-term (nine weeks high dose of rHuEPO (200 UI/kg bw/week treatment. Hematological and biochemical parameters were evaluated as well as serum and tissue (kidney, liver and/or duodenum protein and/or gene expression of mediators of erythropoiesis, iron metabolism and tissue hypoxia, inflammation, and fibrosis. Long-term treatment with a high rHuEPO dose is associated with development of resistance to therapy as a result of antibodies formation. In this condition, serum EPO levels are not deficient and iron availability is recovered by increased duodenal absorption. However, erythropoiesis is not stimulated, and the resistance to endogenous EPO effect and to rHuEPO therapy results from the development of a hypoxic, inflammatory and fibrotic milieu in the kidney tissue. This study provides new insights that could be important to ameliorate the current therapeutic strategies used to treat patients with CKD-associated anemia, in particular those that become resistant to rHuEPO therapy.

  5. Brain mitochondrial dysfunction in aging, neurodegeneration and Parkinson's disease

    Directory of Open Access Journals (Sweden)

    Ana Navarro

    2010-09-01

    Full Text Available Brain senescence and neurodegeneration occur with a mitochondrial dysfunction characterized by impaired electron transfer and by oxidative damage. Brain mitochondria of old animals show decreased rates of electron transfer in complexes I and IV, decreased membrane potential, increased content of the oxidation products of phospholipids and proteins and increased size and fragility. This impairment, with complex I inactivation and oxidative damage, is named “complex I syndrome” and is recognized as characteristic of mammalian brain aging and of neurodegenerative diseases. Mitochondrial dysfunction is more marked in brain areas as rat hippocampus and frontal cortex, in human cortex in Parkinson’s disease and dementia with Lewy bodies, and in substantia nigra in Parkinson’s disease. The molecular mechanisms involved in complex I inactivation include the synergistic inactivations produced by ONOO- mediated reactions, by reactions with free radical intermediates of lipid peroxidation and by amine-aldehyde adduction reactions. The accumulation of oxidation products prompts the idea of antioxidant therapies. High doses of vitamin E produce a significant protection of complex I activity and mitochondrial function in rats and mice, and with improvement of neurological functions and increased median life span in mice. Mitochondria-targeted antioxidants, as the Skulachev cations covalently attached to vitamin E, ubiquinone and PBN and the SS tetrapeptides, are negatively charged and accumulate in mitochondria where they exert their antioxidant effects. Activation of the cellular mechanisms that regulate mitochondrial biogenesis is another potential therapeutic strategy, since the process generates organelles devoid of oxidation products and with full enzymatic activity and capacity for ATP production.

  6. Mechanisms of neurodegeneration in Alzheimer’s disease

    Directory of Open Access Journals (Sweden)

    Jovanović Zorica

    2012-01-01

    Full Text Available Introduction. Recent research into mechanisms of neurodegeneration in Alzheimer’s disease has lead to a dramatic increase in our understanding of the mechanisms of cell death and neuroprotection. Alzheimer’s disease is a complex disease with multiple etiological factors involved in disease pathogenesis. Oxidative stress and mitochondrial dysfunction in Alzheimer’s disease. Amyloid-β peptide toxicity is mediated at least in part by oxidative stress. Amyloid-β peptide directly generates reactive oxygen species in the presence of redox-active metal ions. In Alzheimer’s disease, oxidative stress is present early in pathogenesis and contributes to disease pathogenesis. Unlike other organs, the brain is especially vulnerable to reactive oxygen species due to neurons having relatively low levels of endogenous antioxidants. Overly abundant oxygen radicals cause the destruction of cellular macromolecules and participate in signaling mechanisms that result in apoptotic cell death. Microglial activation and nicotinamide adenine dinucleotide phosphate oxidase in Alzheimer’s disease. There is a wealth of evidence demonstrating that microglia, the resident innate immune cells in the brain, can become deleterious and damage neurons. Microglial activation causes neuron damage through the production of neurotoxic factors, such as reactive oxygen species and cytokines that are toxic to neurons. The neuron also has strong homeostatic mechanisms that can delay or prevent activation of apoptosis and necrosis. Insulin resistance and Alzheimer’s disease. Insulin plays a role in Alzheimer’s disease, as it is involved in the metabolism of β-amyloid. Hyperinsulinemia and type-2 diabetes mellitus results in an increased risk of developing Alzheimer’s disease, but its implications when the disease is already well established remain unknown. Treatment of central insulin resistance may be a promising avenue, not only in metabolic syndrom, but also in

  7. PROVANN: Model System for Chronic Exposure of Larval and Adult Fish to Releases from Offshore Petroleum Platforms

    International Nuclear Information System (INIS)

    Produced water from offshore oil and gas production platforms contains a variety of hydrocarbons, heavy metals, and production chemicals. Vertical and horizontal mixing generally brings concentrations in discharge plumes below level associated with acute effects within 500 or 1000 m of the source. Chronic effects outside this region remain a potential problem. The purpose of PROVANN, the system of models described in this paper, is to assess the potential for chronic effects from produced water. The preliminary focus is on potential bioaccumulation and boimagnification of produced water constituents in the marine food web. Other possible types of chronic effects, such as reduced fecundity, or pheromone response interference, can also be assessed to the extent that such effects may be correlated with exposure. PROVANN simulates 3-dimensional transport, dilution, and degradation of chemicals released into the water, from one or more simultaneous sources. 8 refs., 10 figs., 3 tabs

  8. Establishing a predictive model for aspirin resistance in elderly Chinese patients with chronic cardiovascular disease

    Science.gov (United States)

    Cao, Jian; Hao, Wei-Jun; Gao, Ling-Gen; Chen, Tian-Meng; Liu, Lin; Sun, Yu-Fa; Hu, Guo-Liang; Hu, Yi-Xin; Fan, Li

    2016-01-01

    Background Resistance to anti-platelet therapy is detrimental to patients. Our aim was to establish a predictive model for aspirin resistance to identify high-risk patients and to propose appropriate intervention. Methods Elderly patients (n = 1130) with stable chronic coronary heart disease who were taking aspirin (75 mg) for > 2 months were included. Details of their basic characteristics, laboratory test results, and medications were collected. Logistic regression analysis was performed to establish a predictive model for aspirin resistance. Risk score was finally established according to coefficient B and type of variables in logistic regression. The Hosmer–Lemeshow (HL) test and receiver operating characteristic curves were performed to respectively test the calibration and discrimination of the model. Results Seven risk factors were included in our risk score. They were serum creatinine (> 110 μmol/L, score of 1); fasting blood glucose (> 7.0 mmol/L, score of 1); hyperlipidemia (score of 1); number of coronary arteries (2 branches, score of 2; ≥ 3 branches, score of 4); body mass index (20–25 kg/m2, score of 2; > 25 kg/m2, score of 4); percutaneous coronary intervention (score of 2); and smoking (score of 3). The HL test showed P ≥ 0.05 and area under the receiver operating characteristic curve ≥ 0.70. Conclusions We explored and quantified the risk factors for aspirin resistance. Our predictive model showed good calibration and discriminative power and therefore a good foundation for the further study of patients undergoing anti-platelet therapy. PMID:27594876

  9. Chronic graft-versus-host disease in the rat radiation chimera. III. Immunology and immunopathology in rapidly induced models

    International Nuclear Information System (INIS)

    Although chronic graft-versus-host disease (GVHD) frequently develops in the long-term rat radiation chimera, we present three additional models in which a histologically similar disease is rapidly induced. These include adoptive transfer of spleen and bone marrow from rats with spontaneous chronic GVHD into lethally irradiated rats of the primary host strain; sublethal irradiation of stable chimeras followed by a booster transplant; and transfer of spleen cells of chimeras recovering from acute GVHD into second-party (primary recipient strain) or third-party hosts. Some immunopathologic and immune abnormalities associated with spontaneous chronic GVHD were not observed in one or more of the induced models. Thus, IgM deposition in the skin, antinuclear antibodies, and vasculitis appear to be paraphenomena. On the other hand, lymphoid hypocellularity of the thymic medulla, immaturity of splenic follicles, and nonspecific suppressor cells were consistently present in the long term chimeras, and in all models. These abnormalities therefore may be pathogenetically important, or closely related to the development of chronic GVHD

  10. Acute and chronic nociceptive phases observed in a rat hind paw ischemia/reperfusion model depend on different mechanisms.

    Science.gov (United States)

    Klafke, J Z; da Silva, M A; Rossato, M F; de Prá, S Dal Toé; Rigo, F K; Walker, C I B; Bochi, G V; Moresco, R N; Ferreira, J; Trevisan, G

    2016-02-01

    Complex regional pain syndrome type 1 (CRPS1) may be evoked by ischemia/reperfusion, eliciting acute and chronic pain that is difficult to treat. Despite this, the underlying mechanism of CRPS1 has not been fully elucidated. Therefore, the goal of this study is to evaluate the involvement of inflammation, oxidative stress, and the transient receptor potential ankyrin 1 (TRPA1) channel, a chemosensor of inflammation and oxidative substances, in an animal model of chronic post-ischemia pain (CPIP). Male Wistar rats were subjected to 3 h hind paw ischemia/reperfusion (CPIP model). Different parameters of nociception, inflammation, ischemia, and oxidative stress were evaluated at 1 (acute) and 14 (chronic) days after CPIP. The effect of a TRPA1 antagonist and the TRPA1 immunoreactivity were also observed after CPIP. In the CPIP acute phase, we observed mechanical and cold allodynia; increased levels of tumor necrosis factor-α (hind paw), ischemia-modified albumin (IMA) (serum), protein carbonyl (hind paw and spinal cord), lactate (serum), and 4-hydroxy-2-nonenal (4-HNE, hind paw and spinal cord); and higher myeloperoxidase (MPO) and N-acetyl-β-D-glucosaminidase (NAGase) activities (hind paw). In the CPIP chronic phase, we detected mechanical and cold allodynia and increased levels of IMA (serum), protein carbonyl (hind paw and spinal cord), and 4-HNE (hind paw and spinal cord). TRPA1 antagonism reduced mechanical and cold allodynia 1 and 14 days after CPIP, but no change in TRPA1 immunoreactivity was observed. Different mechanisms underlie acute (inflammation and oxidative stress) and chronic (oxidative stress) phases of CPIP. TRPA1 activation may be relevant for CRPS1/CPIP-induced acute and chronic pain. PMID:26490459

  11. Neuroprotective Effect of Compound Anisodine in a Mouse Model with Chronic Ocular Hypertension

    Institute of Scientific and Technical Information of China (English)

    Wen-Dong Liu; Lan-Lan Chen; Ce-Ying Shen; Li-Bin Jiang

    2015-01-01

    Background:Compound anisodine (CA) is a compound preparation made from hydrobromide anisodine and procaine hydrochloride.The former is an M-choline receptor blocker with the function of regulating the vegetative nervous system,improving microcirculation,and so on.The latter is an antioxidant with the activities ofneuroprotection.This study aimed to investigate the potential neuroprotection of CA,which affects the degeneration of the retinal ganglion cells (RGCs) in an animal model with chronic ocular hypertension.Methods:Female C57BL/6J mice (n =24) were divided randomly into four groups:Normal control group without any treatment (Group A,n =6);CA control group with feeding the CA solution (Group B,n =6);microbeads (MBs) control group with injecting MB into the anterior chamber (Group C,n =6);CA study group with MB injection and with feeding the CA solution (Group D,n =6).Intraocular pressure (IOP) was measured every 3 days after MB injection.At the 21st day,neurons were retrograde-labeled by Fluoro-Gold (FG).Animals were sacrificed on the 27th day.Retinal flat mounts were stained immunohistologically by β-Ⅲ-tubulin.FG-retrograde-labeled RGCs,β-Ⅲ-tubulin-positive RGCs,and β-Ⅲ-tubulin-positive nerve fibers were quantified.Results:Mice of Groups C and D expressed the incidence of consistent IOP elevation,which is above the IOP level of Group A with the normal one.There is no significant difference in IOP between Groups A and B (P > 0.05).On the 27th day,there were distinct loss in stained RGCs and nerve fibers from Groups C and D compared with Group A (all P < 0.00l).The quantity was significantly higher in Group D as compared to Group C (all P < 0.00l) but lower than Group A (all P < 0.001).There was no significant difference in the quantity of RGCs and nerve fibers between Groups A and B (all P > 0.05).Conclusions:These findings suggest that CA plays an importantly neuroprotective role on RGCs in a mouse model with chronic ocular hypertension.

  12. Modelling population-level consequences of chronic external gamma irradiation in aquatic invertebrates under laboratory conditions

    International Nuclear Information System (INIS)

    We modelled population-level consequences of chronic external gamma irradiation in aquatic invertebrates under laboratory conditions. We used Leslie matrices to combine life-history characteristics (duration of life stages, survival and fecundity rates) and dose rate-response curves for hatching, survival and reproduction fitted on effect data from the FREDERICA database. Changes in net reproductive rate R0 (offspring per individual) and asymptotic population growth rate λ (dimensionless) were calculated over a range of dose rates in two marine polychaetes (Neanthes arenaceodentata and Ophryotrocha diadema) and a freshwater gastropod (Physa heterostropha). Sensitivities in R0 and λ to changes in life-history traits were analysed in each species. Results showed that fecundity has the strongest influence on R0. A delay in age at first reproduction is most critical for λ independent of the species. Fast growing species were proportionally more sensitive to changes in individual endpoints than slow growing species. Reduction of 10% in population λ were predicted at dose rates of 6918, 5012 and 74,131 μGy·h−1 in N. arenaceodentata, O. diadema and P. heterostropha respectively, resulting from a combination of strong effects on several individual endpoints in each species. These observations made 10%-reduction in λ a poor criterion for population protection. The lowest significant changes in R0 and λ were respectively predicted at a same dose rate of 1412 μGy h−1 in N. arenaceodentata, at 760 and 716 μGy h−1 in O. diadema and at 12,767 and 13,759 μGy h−1 in P. heterostropha. These values resulted from a combination of slight but significant changes in several measured endpoints and were lower than effective dose rates calculated for the individual level in O. diadema and P. heterostropha. The relevance of the experimental dataset (external irradiation rather than contamination, exposure over one generation only, effects on survival and reproduction only

  13. Development of a Chronic Kidney Disease Model in C57BL/6 Mice with Relevance to Human Pathology

    OpenAIRE

    Huang, Linghong; Scarpellini, Alessandra; Funck, Muriel; Verderio, Elisabetta A. M.; Johnson, Timothy S.

    2013-01-01

    Background Genetically modified mice are used to investigate disease and assess potential interventions. However, research into kidney fibrosis is hampered by a lack of models of chronic kidney disease (CKD) in mice. Recently, aristolochic acid nephropathy (AAN), characterised by severe tubulointerstitial fibrosis, has been identified as a cause of end stage kidney disease and proposed as a model of CKD. Published studies have used various dosing regimens, species and strains, with variable o...

  14. Integrated palliative care in Europe: a qualitative systematic literature review of empirically-tested models in cancer and chronic disease

    OpenAIRE

    Siouta, Naouma; Beek, K.; van der Eerden, M. E.; Preston, N.; Hasselaar, J.G.; Hughes, S; GARRALDA, E.; Centeno, C. (Carlos); Csikos, A.; Groot, M. de; Radbruch, L.; Payne, S; Menten, J.

    2016-01-01

    Background Integrated Palliative Care (PC) strategies are often implemented following models, namely standardized designs that provide frameworks for the organization of care for people with a progressive life-threatening illness and/or for their (in)formal caregivers. The aim of this qualitative systematic review is to identify empirically-evaluated models of PC in cancer and chronic disease in Europe. Further, develop a generic framework that will consist of the basis for the design of futu...

  15. Validation of Ten Noninvasive Diagnostic Models for Prediction of Liver Fibrosis in Patients with Chronic Hepatitis B

    OpenAIRE

    Cheng, Jieyao; Hou, Jinlin; Ding, Huiguo; Chen, Guofeng; Xie, Qing; Wang, Yuming; Zeng, Minde; Ou, Xiaojuan; Ma, Hong; Jia, Jidong

    2015-01-01

    Background and Aims Noninvasive models have been developed for fibrosis assessment in patients with chronic hepatitis B. However, the sensitivity, specificity and diagnostic accuracy in evaluating liver fibrosis of these methods have not been validated and compared in the same group of patients. The aim of this study was to verify the diagnostic performance and reproducibility of ten reported noninvasive models in a large cohort of Asian CHB patients. Methods The diagnostic performance of ten...

  16. The Use of Amnion-Derived Cellular Cytokine Solution to Improve Healing in Acute and Chronic Wound Models

    OpenAIRE

    Franz, Michael G.; Payne, Wyatt G.; Xing, Liyu; Naidu, D. K; Salas, R. E; Marshall, Vivienne S.; Trumpower, C. J; Smith, Charlotte A; Steed, David L.; Robson, M. C.

    2008-01-01

    Objective: Growth factors demonstrate mixed results improving wound healing. Amnion-derived multipotent cells release physiologic levels of growth factors and tissue inhibitors of metalloproteinases. This solution was tested in models of acute and chronic wound healing. Methods: Acute model: Sprague-Dawley rats underwent laparotomy incisions. The midline fascia was primed with phosphate-buffered saline, unconditioned media, or amnion-derived cellular cytokine suspension prior to incision. Bre...

  17. The effect of sulindac, a non-steroidal anti-inflammatory drug, attenuates inflammation and fibrosis in a mouse model of chronic pancreatitis

    Directory of Open Access Journals (Sweden)

    Bai Han

    2012-08-01

    Full Text Available Abstract Background Chronic pancreatitis is characterized by progressive fibrosis, pain and loss of exocrine and endocrine functions. The long-standing chronic pancreatitis and its associated pancreatic fibrosis are the most common pathogenic events involved in human pancreatic carcinogenesis, but the therapeutic strategies to chronic pancreatitis and the chemoprevention of pancreatic carcinogenesis are very limited. Methods We investigated the effect of sulindac, a non-steroidal anti-inflammatory drug (NSAID, on inhibition of chronic pancreatitis in a caerulein induced chronic pancreatitis mouse model. Results Sulindac significantly reduced the severity of chronic pancreatitis including the extent of acini loss, inflammatory cell infiltration and stromal fibrosis. The protein expression of phosphorylation of MEK/ERK was inhibited in the chronic pancreatic tissues by sulindac treatment as measured by Western blot assay. The levels of inflammatory cytokines including TNF-α and MCP-1 were also significantly decreased with sulindac treatment, as well as the expression of TGF-β, PDGF-β, SHH and Gli in the chronic pancreatic tissue detected by qPCR assay and confirmed by western blot assay. The activation of pancreatic satellet cells was also inhibited by sulindac as measured by the activity of α-smooth muscle actin (α-SMA in the pancreatic tissue of chronic pancreatitis. Conclusions Sulindac is a promising reagent for the treatment of chronic pancreatitis via inhibition of inflammatory cell infiltration and stromal fibrosis, the inhibitory effect of sulindac on chronic pancreatitis may through targeting the activation ERK/MAPK signaling pathway.

  18. Intrathecal morphine therapy in the management of status dystonicus in neurodegeneration brain iron accumulation type 1.

    Science.gov (United States)

    Lopez, William Omar Contreras; Kluge Schroeder, Humberto; Santana Neville, Iuri; Jacobsen Teixeira, Manoel; Costa Barbosa, Danilo; Assumpçao de Mônaco, Bernardo; Talamoni Fonoff, Erich

    2015-01-01

    Neurodegeneration with brain iron accumulation type 1 (NBIA-1) is a rare disorder characterized by progressive extrapyramidal dysfunction and dementia. NBIA-1 encompasses typical iron brain accumulation, mostly in the globus pallidus with secondary dementia, spasticity, rigidity, dystonia, and choreoathetosis. Treatment remains mostly symptomatic and is challenging. We present the case of a 14-year-old boy diagnosed with NBIA-1, presenting intractable progressive generalized dystonia leading to unresponsive status dystonicus (SD). The patient received a SynchroMed II (model 8637) programmable system pump (Medtronic®, Inc.) implant with an Ascenda intrathecal catheter for intrathecal morphine therapy (IMT). The initial dose of morphine was 1.0 mg/day. Overall, we observed no complications with IMT treatment and important improvement of the patient's motor function with stabilization of his incapacitating dystonia and his quality of life. On the Global Dystonia Severity Rating Scale, he presented 52% improvement, 30% improvement on the Unified Dystonia Rating Scale, and 38% improvement on the Fahn-Marsden Rating Scale after 10 months, when the dose was 1.7 mg/day. IMT should be considered as a potential palliative treatment in the management of intractable dystonia and SD secondary to NBIA-1. PMID:25896138

  19. ROS effects on neurodegeneration in Alzheimer's disease and related disorders: on environmental stresses of ionizing radiation.

    Science.gov (United States)

    Manton, Kenneth G; Volovik, Serge; Kulminski, Alexander

    2004-11-01

    Neurodegenerative processes associated with Alzheimer's disease are complex and involve many CNS tissue types, structures and biochemical processes. Factors believed involved in these processes are generation of Reactive Oxygen Species (ROS), associated inflammatory responses, and the bio-molecular and genetic damage they produce. Since oxidative processes are essential to energy production, and to other biological functions, such as cell signaling, the process is not one of risk exposure, as for cigarettes and cancer, but one where normal physiological processes operate out of normal ranges and without adequate control. Thus, it is necessary to study the ambiphilicity that allows the same molecule (e.g., beta amyloid) to behave in contradictory ways depending upon the physiological microenvironment. To determine ways to study this in human populations we review evidence on the effects of an exogenous generator of ROS, ionizing radiation, in major population events with radionuclides (e.g., Hiroshima and Nagasaki; Chernobyl Reactor accident; environmental contamination in Chelyabinsk (South Urals) where plutonium was produced, and in the nuclear weapons test area in Semipalatinsk, Kazakhstan). The age evolution, and traits, of neurodegenerative processes in human populations in these areas, may help us understand how IR affects the CNS. After reviewing human population evidence, we propose a model of neurodegeneration based upon the complexity of CNS functions. PMID:15975057

  20. Retinal neurodegeneration may precede microvascular changes characteristic of diabetic retinopathy in diabetes mellitus.

    Science.gov (United States)

    Sohn, Elliott H; van Dijk, Hille W; Jiao, Chunhua; Kok, Pauline H B; Jeong, Woojin; Demirkaya, Nazli; Garmager, Allison; Wit, Ferdinand; Kucukevcilioglu, Murat; van Velthoven, Mirjam E J; DeVries, J Hans; Mullins, Robert F; Kuehn, Markus H; Schlingemann, Reinier Otto; Sonka, Milan; Verbraak, Frank D; Abràmoff, Michael David

    2016-05-10

    Diabetic retinopathy (DR) has long been recognized as a microvasculopathy, but retinal diabetic neuropathy (RDN), characterized by inner retinal neurodegeneration, also occurs in people with diabetes mellitus (DM). We report that in 45 people with DM and no to minimal DR there was significant, progressive loss of the nerve fiber layer (NFL) (0.25 μm/y) and the ganglion cell (GC)/inner plexiform layer (0.29 μm/y) on optical coherence tomography analysis (OCT) over a 4-y period, independent of glycated hemoglobin, age, and sex. The NFL was significantly thinner (17.3 μm) in the eyes of six donors with DM than in the eyes of six similarly aged control donors (30.4 μm), although retinal capillary density did not differ in the two groups. We confirmed significant, progressive inner retinal thinning in streptozotocin-induced "type 1" and B6.BKS(D)-Lepr(db)/J "type 2" diabetic mouse models on OCT; immunohistochemistry in type 1 mice showed GC loss but no difference in pericyte density or acellular capillaries. The results suggest that RDN may precede the established clinical and morphometric vascular changes caused by DM and represent a paradigm shift in our understanding of ocular diabetic complications. PMID:27114552

  1. Retinal Vascular Fractals Correlate With Early Neurodegeneration in Patients With Type 2 Diabetes Mellitus

    DEFF Research Database (Denmark)

    Frydkjaer-Olsen, Ulrik; Soegaard Hansen, Rasmus; Pedersen, Knud;

    2015-01-01

    . In a randomly selected eye of each patient, Fd was calculated using SIVA-Fractal, a specialized semiautomatic software. Retinal neurodegeneration was evaluated by Topcon 3D OCT-2000 spectral-domain optical coherence tomography (OCT) and by a RETI-scan multifocal ERG (mf-ERG) system in rings one to...... ETDRS levels were 10 (42.7%), 20 (35.0%), and 35 (22.3%), respectively. Fd correlated inversely with mf-ERG implicit time of ring one (r = -0.25, P = 0.01) and present diabetic neuropathy (P = 0.02), and positively with OCT ganglion cell layer (GCL) thickness (r = 0.20, P = 0.04). In a multivariable...... linear regression model, Fd was associated with mf-ERG implicit time of ring one (coefficient -0.0021/ms, P = 0.040) and the presence of diabetic neuropathy (coefficient -0.0209 for neuropathy present versus absent, P = 0.041). Conclusions: In patients with T2DM and no or minimal DR, independent...

  2. Functional modulation of G-protein coupled receptors during Parkinson disease-like neurodegeneration.

    Science.gov (United States)

    Jenkins, Bruce G; Zhu, Aijun; Poutiainen, Pekka; Choi, Ji-Kyung; Kil, Kun-Eek; Zhang, Zhaoda; Kuruppu, Darshini; Aytan, Nurgul; Dedeoglu, Alpaslan; Brownell, Anna-Liisa

    2016-09-01

    G-protein coupled dopamine and metabotropic glutamate receptors (mGlu) can modulate neurotransmission during Parkinson's disease (PD)-like neurodegeneration. PET imaging studies in a unilateral dopamine denervation model (6-OHDA) showed a significant inverse correlation of presynaptic mGlu4 and postsynaptic mGlu5 expression in the striatum and rapidly declining mGlu4 and enhanced mGlu5 expression in the hippocampus during progressive degeneration over time. Immunohistochemical studies verified the decreased mGlu4 expression in the hippocampus on the lesion side but did not show difference in mGlu5 expression between lesion and control side. Pharmacological MRI studies showed enhanced hemodynamic response in several brain areas on the lesion side compared to the control side after challenge with mGlu4 positive allosteric modulator or mGlu5 negative allosteric modulator. However, mGlu4 response was biphasic having short enhancement followed by negative response on both sides of brain. Studies in mGlu4 expressing cells demonstrated that glutamate induces cooperative increase in binding of mGlu4 ligands - especially at high glutamate levels consistent with in vivo concentration. This suggests that mGlu allosteric modulators as drug candidates will be highly sensitive to changes in glutamate concentration and hence metabolic state. These experiments demonstrate the importance of the longitudinal imaging studies to investigate temporal changes in receptor functions to obtain individual response for experimental drugs. PMID:26581500

  3. Phosphatidylinositol-glycan-phospholipase D is involved in neurodegeneration in prion disease.

    Directory of Open Access Journals (Sweden)

    Jae-Kwang Jin

    Full Text Available PrPSc is formed from a normal glycosylphosphatidylinositol (GPI-anchored prion protein (PrPC by a posttranslational modification. Most GPI-anchored proteins have been shown to be cleaved by GPI phospholipases. Recently, GPI-phospholipase D (GPI-PLD was shown to be a strictly specific enzyme for GPI anchors. To investigate the involvement of GPI-PLD in the processes of neurodegeneration in prion diseases, we examined the mRNA and protein expression levels of GPI-PLD in the brains of a prion animal model (scrapie, and in both the brains and cerebrospinal fluids (CSF of sporadic and familial Creutzfeldt-Jakob disease (CJD patients. We found that compared with controls, the expression of GPI-PLD was dramatically down-regulated in the brains of scrapie-infected mice, especially in the caveolin-enriched membrane fractions. Interestingly, the observed decrease in GPI-PLD expression levels began at the same time that PrPSc began to accumulate in the infected brains and this decrease was also observed in both the brain and CSF of CJD patients; however, no differences in expression were observed in either the brains or CSF specimens from Alzheimer's disease patients. Taken together, these results suggest that the down-regulation of GPI-PLD protein may be involved in prion propagation in the brains of prion diseases.

  4. Role of bile acids, prostaglandins and COX inhibitors in chronic esophagitis in a mouse model

    Institute of Scientific and Technical Information of China (English)

    C Poplawski; D Sosnowski; A Szaflarska-Poplawska; J Sarosiek; R McCallum; Z Bartuzi

    2006-01-01

    33 %). In HCl/P/BA/INDO group the esophagitis surface was larger than that in not treated group (33%). In HCL/P group the surface of esophagus with ulceration was significantly larger (10-fold) than that in HCl/P/BA group. The PGE2 concentration was significantly higher in HCl/P group than in HCl/P/BA group.The PGE2 concentration in lower part of esophagus was also significantly higher in middle than those in HCl and HCl/P/BA groups. In upper part of esophagus the PGE2 concentration was significantly higher in HCl/P/BA group than that in group treated with indometacine (46%). We also observed higher PGE2 concentration in middle part of esophagus in HCl/P/BA group than those in group treated with indometacine and in group treated with indometacin and NS-398 (by 52% and 43% respectively).CONCLUSION: Pepsin is the pivotal factor in the development of chronic esophageal injury. Bile acids diminish chronic esophageal injury induced by HCl/P, indicating its potential negative impact on pepsin proteolytic potential,pivotal for mucosal injury in low pH. The role of selective COX inhibitors is still unclear, and needs more investigations. This novel chronic experimental esophagitis is an excellent model for further study on the role of cytokines in genetically modified animals.

  5. Is unpredictable chronic mild stress (UCMS) a reliable model to study depression-induced neuroinflammation?

    Science.gov (United States)

    Farooq, Rai Khalid; Isingrini, Elsa; Tanti, Arnaud; Le Guisquet, Anne-Marie; Arlicot, Nicolas; Minier, Frederic; Leman, Samuel; Chalon, Sylvie; Belzung, Catherine; Camus, Vincent

    2012-05-16

    Unipolar depression is one of the leading causes of disability. The pathophysiology of depression is poorly understood. Evidence suggests that inflammation is associated with depression. For instance, pro-inflammatory cytokines are found to be elevated in the peripheral blood of depressed subjects. Cytokine immunotherapy itself is known to induce depressive symptoms. While the epidemiological and biochemical relationship between inflammation and depression is strong, little is known about the possible existence of neuroinflammation in depression. The use of animal models of depression such as the Unpredictable Chronic Mild Stress (UCMS) has already contributed to the elucidation of the pathophysiological mechanisms of depression such as decreased neurogenesis and HPA axis alterations. We used this model to explore the association of depressive-like behavior in mice with changes in peripheral pro-inflammatory cytokines IL-1β, TNFα and IL-6 level as well as the neuroinflammation by quantifying CD11b expression in brain areas known to be involved in the pathophysiology of depression. These areas include the cerebral cortex, the nucleus accumbens, the bed nucleus of the stria terminalis, the caudate putamen, the amygdala and the hippocampus. The results indicate that microglial activation is significantly increased in the infralimbic, cingulate and medial orbital cortices, nucleus accumbens, caudate putamen, amygdala and hippocampus of the mouse brain as a function of UCMS, while levels of pro-inflammatory cytokines did not differ among the groups. This finding suggests that neuroinflammation occurs in depression and may be implicated in the subject's behavioral response. They also suggest that UCMS could be a potentially reliable model to study depression-induced neuroinflammation. PMID:22465167

  6. Modeling routes of chronic wasting disease transmission: Environmental prion persistence promotes deer population decline and extinction

    Science.gov (United States)

    Almberg, Emily S.; Cross, Paul C.; Johnson, Christopher J.; Heisey, Dennis M.; Richards, Bryan J.

    2011-01-01

    Chronic wasting disease (CWD) is a fatal disease of deer, elk, and moose transmitted through direct, animal-to-animal contact, and indirectly, via environmental contamination. Considerable attention has been paid to modeling direct transmission, but despite the fact that CWD prions can remain infectious in the environment for years, relatively little information exists about the potential effects of indirect transmission on CWD dynamics. In the present study, we use simulation models to demonstrate how indirect transmission and the duration of environmental prion persistence may affect epidemics of CWD and populations of North American deer. Existing data from Colorado, Wyoming, and Wisconsin's CWD epidemics were used to define plausible short-term outcomes and associated parameter spaces. Resulting long-term outcomes range from relatively low disease prevalence and limited host-population decline to host-population collapse and extinction. Our models suggest that disease prevalence and the severity of population decline is driven by the duration that prions remain infectious in the environment. Despite relatively low epidemic growth rates, the basic reproductive number, R0, may be much larger than expected under the direct-transmission paradigm because the infectious period can vastly exceed the host's life span. High prion persistence is expected to lead to an increasing environmental pool of prions during the early phases (i.e. approximately during the first 50 years) of the epidemic. As a consequence, over this period of time, disease dynamics will become more heavily influenced by indirect transmission, which may explain some of the observed regional differences in age and sex-specific disease patterns. This suggests management interventions, such as culling or vaccination, will become increasingly less effective as CWD epidemics progress.

  7. Repeated mild traumatic brain injury causes chronic neuroinflammation, changes in hippocampal synaptic plasticity, and associated cognitive deficits

    Science.gov (United States)

    Aungst, Stephanie L; Kabadi, Shruti V; Thompson, Scott M; Stoica, Bogdan A; Faden, Alan I

    2014-01-01

    Repeated mild traumatic brain injury (mTBI) can cause sustained cognitive and psychiatric changes, as well as neurodegeneration, but the underlying mechanisms remain unclear. We examined histologic, neurophysiological, and cognitive changes after single or repeated (three injuries) mTBI using the rat lateral fluid percussion (LFP) model. Repeated mTBI caused substantial neuronal cell loss and significantly increased numbers of activated microglia in both ipsilateral and contralateral hippocampus on post-injury day (PID) 28. Long-term potentiation (LTP) could not be induced on PID 28 after repeated mTBI in ex vivo hippocampal slices from either hemisphere. N-Methyl-D-aspartate (NMDA) receptor-mediated responses were significantly attenuated after repeated mTBI, with no significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated responses. Long-term potentiation was elicited in slices after single mTBI, with potentiation significantly increased in ipsilateral versus contralateral hippocampus. After repeated mTBI, rats displayed cognitive impairments in the Morris water maze (MWM) and novel object recognition (NOR) tests. Thus, repeated mTBI causes deficits in the hippocampal function and changes in excitatory synaptic neurotransmission, which are associated with chronic neuroinflammation and neurodegeneration. PMID:24756076

  8. Repeated mild traumatic brain injury causes chronic neuroinflammation, changes in hippocampal synaptic plasticity, and associated cognitive deficits.

    Science.gov (United States)

    Aungst, Stephanie L; Kabadi, Shruti V; Thompson, Scott M; Stoica, Bogdan A; Faden, Alan I

    2014-07-01

    Repeated mild traumatic brain injury (mTBI) can cause sustained cognitive and psychiatric changes, as well as neurodegeneration, but the underlying mechanisms remain unclear. We examined histologic, neurophysiological, and cognitive changes after single or repeated (three injuries) mTBI using the rat lateral fluid percussion (LFP) model. Repeated mTBI caused substantial neuronal cell loss and significantly increased numbers of activated microglia in both ipsilateral and contralateral hippocampus on post-injury day (PID) 28. Long-term potentiation (LTP) could not be induced on PID 28 after repeated mTBI in ex vivo hippocampal slices from either hemisphere. N-Methyl-D-aspartate (NMDA) receptor-mediated responses were significantly attenuated after repeated mTBI, with no significant changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated responses. Long-term potentiation was elicited in slices after single mTBI, with potentiation significantly increased in ipsilateral versus contralateral hippocampus. After repeated mTBI, rats displayed cognitive impairments in the Morris water maze (MWM) and novel object recognition (NOR) tests. Thus, repeated mTBI causes deficits in the hippocampal function and changes in excitatory synaptic neurotransmission, which are associated with chronic neuroinflammation and neurodegeneration. PMID:24756076

  9. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration

    Directory of Open Access Journals (Sweden)

    Maria Emilia Figueiredo-Pereira

    2015-01-01

    Full Text Available The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia and prion diseases. Cyclooxygenases (COX -1 and COX-2, which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1 exert their actions, (2 potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3 disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4 contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury, and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects.

  10. Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration.

    Science.gov (United States)

    Figueiredo-Pereira, Maria E; Rockwell, Patricia; Schmidt-Glenewinkel, Thomas; Serrano, Peter

    2014-01-01

    The immune response of the CNS is a defense mechanism activated upon injury to initiate repair mechanisms while chronic over-activation of the CNS immune system (termed neuroinflammation) may exacerbate injury. The latter is implicated in a variety of neurological and neurodegenerative disorders such as Alzheimer and Parkinson diseases, amyotrophic lateral sclerosis, multiple sclerosis, traumatic brain injury, HIV dementia, and prion diseases. Cyclooxygenases (COX-1 and COX-2), which are key enzymes in the conversion of arachidonic acid into bioactive prostanoids, play a central role in the inflammatory cascade. J2 prostaglandins are endogenous toxic products of cyclooxygenases, and because their levels are significantly increased upon brain injury, they are actively involved in neuronal dysfunction induced by pro-inflammatory stimuli. In this review, we highlight the mechanisms by which J2 prostaglandins (1) exert their actions, (2) potentially contribute to the transition from acute to chronic inflammation and to the spreading of neuropathology, (3) disturb the ubiquitin-proteasome pathway and mitochondrial function, and (4) contribute to neurodegenerative disorders such as Alzheimer and Parkinson diseases, and amyotrophic lateral sclerosis, as well as stroke, traumatic brain injury (TBI), and demyelination in Krabbe disease. We conclude by discussing the therapeutic potential of targeting the J2 prostaglandin pathway to prevent/delay neurodegeneration associated with neuroinflammation. In this context, we suggest a shift from the traditional view that cyclooxygenases are the most appropriate targets to treat neuroinflammation, to the notion that J2 prostaglandin pathways and other neurotoxic prostaglandins downstream from cyclooxygenases, would offer significant benefits as more effective therapeutic targets to treat chronic neurodegenerative diseases, while minimizing adverse side effects. PMID:25628533

  11. The experimental study of 32P-colloid perfusion therapy in the animal-models of chronic maxillary sinusitis

    International Nuclear Information System (INIS)

    Objective: To search for the mechanism of 32P-colloid perfusion therapy in the animal models of chronic maxillary sinusitis. Methods: 32P-colloid were injected into the male sheep maxillary sinuses of the animal-models of chronic maxillary sinusitis in different dosage group. The changes of bacteria and mucosael pathomorphology were observed by periodic germiculture and pathology in 1,3,6 months after injection. Results: After 32P-colloid perfusion therapy, the amounts of bacterial species and chronic phlogistic cells were remarkable reduced, and the structure of cilia cells did not change. The curable rate was 83.3% in 6 months. There were remarkable difference in groups. Conclusions: 32P-colloid was provided with antibiosis and reducing chronic phlogistic responses. The authors had found the optimal dose of 32P-colloid perfusion in the maxillary sinuses through the study. The curable rate of single dose of 32P-colloid perfusion in the maxillary sinuses was higher than other therapy, 32P-colloid perfusion was simple and convenient. There was high selectivity of 32P in the target organ, when there was no effect on other important organs through radiobiological measurement. (authors)

  12. Effects of Shuyusan on monoamine neurotransmitters expression in a rat model of chronic stress-induced depression

    Institute of Scientific and Technical Information of China (English)

    Yuanyuan Zhang; Jianjun Jia; Liping Chen; Zhitao Han; Yulan Zhao; Honghong Zhang; Yazhuo Hu

    2011-01-01

    Shuyusan, a traditional Chinese medicine, was shown to improve depression symptoms and behavioral scores, as well as increase 5-hydroxytryptamine (5-HT), 5-hydroxyindoleacetic acid, and 5-hydroxytryptophan levels, in a rat model of chronic stress-induced depression. However, dopamine, noradrenalin, and 3-methoxy-4-hydroxyphenylglycol expressions remained unchanged following Shuyusan treatment. Compared with the model group, the number of 5-HT-positive neurons in layers 4-5 of the frontal cortex, as well as hippocampal CA1 and CA3 regions, significantly increased following Shuyusan treatment. These results suggested that Shuyusan improved symptoms in a rat model of chronic stress-induced depression with mechanisms that involved 5-HT, 5-HT metabolite, 5-HT precursor expressions.

  13. Chronic lymphocytic leukaemia induces an exhausted T cell phenotype in the TCL1 transgenic mouse model.

    Science.gov (United States)

    Gassner, Franz J; Zaborsky, Nadja; Catakovic, Kemal; Rebhandl, Stefan; Huemer, Michael; Egle, Alexander; Hartmann, Tanja N; Greil, Richard; Geisberger, Roland

    2015-08-01

    Although chronic lymphocytic leukaemia (CLL) is a B cell malignancy, earlier studies have indicated a role of T cells in tumour growth and disease progression. In particular, the functional silencing of antigen-experienced T cells, called T cell exhaustion, has become implicated in immune evasion in CLL. In this study, we tested whether T cell exhaustion is recapitulated in the TCL1(tg) mouse model for CLL. We show that T cells express high levels of the inhibitory exhaustion markers programmed cell death 1 (PDCD1, also termed PD-1) and lymphocyte-activation gene 3 (LAG3), whereas CLL cells express high levels of CD274 (also termed PD-ligand 1). In addition, the fraction of exhausted T cells increases with CLL progression. Finally, we demonstrate that exhausted T cells are reinvigorated towards CLL cytotoxicity by inhibition of PDCD1/CD274 interaction in vivo. These results suggest that T cell exhaustion contributes to CLL pathogenesis and that interference with PDCD1/CD274 signalling holds high potential for therapeutic approaches. PMID:25940792

  14. Complement protein C3 exacerbates prion disease in a mouse model of chronic wasting disease.

    Science.gov (United States)

    Michel, Brady; Ferguson, Adam; Johnson, Theodore; Bender, Heather; Meyerett-Reid, Crystal; Wyckoff, A Christy; Pulford, Bruce; Telling, Glenn C; Zabel, Mark D

    2013-12-01

    Accumulating evidence shows a critical role of the complement system in facilitating attachment of prions to both B cells and follicular dendritic cells and assisting in prion replication. Complement activation intensifies disease in prion-infected animals, and elimination of complement components inhibits prion accumulation, replication and pathogenesis. Chronic wasting disease (CWD) is a highly infectious prion disease of captive and free-ranging cervid populations that utilizes the complement system for efficient peripheral prion replication and most likely efficient horizontal transmission. Here we show that complete genetic or transient pharmacological depletion of C3 prolongs incubation times and significantly delays splenic accumulation in a CWD transgenic mouse model. Using a semi-quantitative prion amplification scoring system we show that C3 impacts disease progression in the early stages of disease by slowing the rate of prion accumulation and/or replication. The delayed kinetics in prion replication correlate with delayed disease kinetics in mice deficient in C3. Taken together, these data support a critical role of C3 in peripheral CWD prion pathogenesis. PMID:24038599

  15. Protective role of hydrogen sulfide against noise-induced cochlear damage: a chronic intracochlear infusion model.

    Directory of Open Access Journals (Sweden)

    Xu Li

    Full Text Available BACKGROUND: A reduction in cochlear blood flow plays an essential role in noise-induced hearing loss (NIHL. The timely regulation of cochlear perfusion determines the progression and prognosis of NIHL. Hydrogen sulfide (H(2S has attracted increasing interest as a vasodilator in cardiovascular systems. This study identified the role of H(2S in cochlear blood flow regulation and noise protection. METHODOLOGY/PRINCIPAL FINDINGS: The gene and protein expression of the H(2S synthetase cystathionine-γ-lyase (CSE in the rat cochlea was examined using immunofluorescence and real-time PCR. Cochlear CSE mRNA levels varied according to the duration of noise exposure. A chronic intracochlear infusion model was built and artificial perilymph (AP, NaHS or DL-propargylglycine (PPG were locally administered. Local sodium hydrosulfide (NaHS significantly increased cochlear perfusion post-noise exposure. Cochlear morphological damage and hearing loss were alleviated in the NaHS group as measured by conventional auditory brainstem response (ABR, cochlear scanning electron microscope (SEM and outer hair cell (OHC count. The highest percentage of OHC loss occurred in the PPG group. CONCLUSIONS/SIGNIFICANCE: Our results suggest that H(2S plays an important role in the regulation of cochlear blood flow and the protection against noise. Further studies may identify a new preventive and therapeutic perspective on NIHL and other blood supply-related inner ear diseases.

  16. Examination of the interaction of different lighting conditions and chronic mild stress in animal model.

    Science.gov (United States)

    Muller, A; Gal, N; Betlehem, J; Fuller, N; Acs, P; Kovacs, G L; Fusz, K; Jozsa, R; Olah, A

    2015-09-01

    We examined the effects of different shift work schedules and chronic mild stress (CMS) on mood using animal model. The most common international shift work schedules in nursing were applied by three groups of Wistar-rats and a control group with normal light-dark cycle. One subgroup from each group was subjected to CMS. Levels of anxiety and emotional life were evaluated in light-dark box. Differences between the groups according to independent and dependent variables were examined with one- and two-way analysis of variance, with a significance level defined at p examination confirm that the changes of lighting conditions evocate anxiety more prominently than CMS. No significant differences were found between the results of the low rotating group and the control group, supposing that this schedule is the least harmful to health. Our results on the association between the use of lighting regimens and the level of CMS provide evidence that the fast rotating shift work schedule puts the heaviest load on the organism of animals. PMID:26551746

  17. Strain differences in the chronic mild stress animal model of depression.

    Science.gov (United States)

    Wu, Hsiao Hua; Wang, Sabrina

    2010-11-12

    Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has been implicated in depression pathology. In the present study, we used a chronic mild stress (CMS) animal model of depression to examine the responses of three strains of rats that have different HPA axis responsiveness; and whether the behavioral changes observed are correlated with changes in hippocampal cell proliferation and survival. In addition, in most of the CMS experiments the rats are kept in singly housed condition. Since rats are social animals we also examined whether prolonged single housing condition affects the behavior of the rats. The results showed that rats with a hyperactive HPA axis, the inbred Fischer (F344) rat, were the most responsive to CMS. The inbred Lewis (LEW) rat, which has a hypoactive HPA axis, did not show anhedonia after CMS treatment but showed other signs of distress. The responses of the outbred Sprague-Dawley (SD) rats were variable; this strain was very sensitive to the single housing condition. Prolonged single housing condition itself could induce helplessness behavior in the rats. The results from hippocampal cell proliferation of the three strains indicated that cell proliferation was not related to anhedonia induced by CMS. We conclude that F344 rat is the strain most sensitive to CMS treatment and is probably the stain of choice for CMS experiments. PMID:20438768

  18. Optical coherence tomography (OCT) of a murine model of chronic kidney disease

    Science.gov (United States)

    Wang, Hsing-Wen; Guo, Hengchang; Andrews, Peter M.; Anderson, Erik; Chen, Y.

    2015-03-01

    Chronic Kidney Disease (CKD) is characterized by a progressive loss in renal function over time. Pathology can provide valuable insights into the progression of CKD by analyzing the status of glomeruli and the uriniferous tubules over time. Optical coherence tomography (OCT) is a new procedure that can analyze the microscopic structure of the kidney in a non-invasive manner. This is especially important because there are significant artifacts associated with excision biopsies and immersion fixation procedures. Recently, we have shown that OCT can provide real time images of kidney microstructure and Doppler OCT (DOCT) can image glomerular renal blood flow in vivo without administrating exogenous contrast agents. In this study, we used OCT to evaluate CKD in a model induced by intravenous Adriamycin injection into Munich-Wistar rats. We evaluated tubular density and tubular diameter from OCT images at several post- Adriamycin induction time points and compared them with conventional light microscopic histological imaging. Proteinurea and serum creatinine were used as physiological markers of the extent of CKD. Preliminary OCT results revealed changes in tubular density due to tubular necrosis and interstitial fibrosis within the first 4 weeks following Adriamycin injection. From week 4 to 8 after Adriamycin induction, changes in tubular density and diameter occurred due to both tubular loss and tubular dilation. The results suggest OCT can provide additional information about kidney histopathology in CKD. DOCT revealed reduced blood flow in some glomeruli probably as a consequence of focal glomerularsclerosis.

  19. Effects of melatonin in experimental stroke models in acute, sub-acute, and chronic stages

    Directory of Open Access Journals (Sweden)

    Hsiao-Wen Lin

    2009-03-01

    Full Text Available Hsiao-Wen Lin, E-Jian LeeNeurophysiology Laboratory, Neurosurgical Service, Department of Surgery, National Cheng Kung University Medical Center and Medical School, Tainan, TaiwanAbstract: Melatonin (N-acetyl-5-methoxy-tryptamine, a naturally occurring indole produced mainly by the pineal gland, is a well known antioxidant. Stroke (cerebral ischemia is the second leading cause of death worldwide. To date, however, effective and safe treatment for stroke remains unavailable. Melatonin is both lipid- and water-soluble and readily crosses the blood–brain barrier (BBB. Increasing evidence has shown that, in animal stroke models, administering melatonin significantly reduces infarct volume, edema, and oxidative damage and improves electrophysiological and behavioral performance. Here, we reviewed studies that assess effects of melatonin on cerebral ischemia in acute, sub-acute, and chronic stages. In addition to its potent antioxidant properties, melatonin exerts antiapoptotic, antiexcitotoxic, anti-inflammatory effects and promotes mitochondrial functions in animals with cerebral ischemia. Given that melatonin shows almost no toxicity to humans and possesses multifaceted protective capacity against cerebral ischemia, it is valuable to consider using melatonin in clinical trials on patients suffering from stroke.Keywords: cerebral ischemia, melatonin, stroke, neuroprotection

  20. An in-vivo model to interrogate the transition from acute to chronic inflammation

    Directory of Open Access Journals (Sweden)

    Lickorish D.

    2004-09-01

    Full Text Available This study describes the modulation of the rodent foreign body giant cell (FBGC response to subcutaneously implanted, biodegradable poly(lactide-co-glycolide/calcium phosphate (PLGA/CaP composites by application of a thin surface coat of calcium phosphate. Macroporous PLGA/CaP composite scaffolds, with interconnecting macroporosity, were half coated with a 3mm thick layer of CaP by immersion in simulated body fluid. Half-coated scaffolds were implanted subcutaneously in the dorsum of male Wistar rats for 1, 4 and 8 weeks. Specimens were embedded in paraffin and tissue sections evaluated by light microscopy with particular reference to the FBGC response. Histomorphometry revealed that FBGCs were in contact with 6% (± 3.5% of the uncoated half, at 1 week, but no FBGCs were seen on the coated half. By 4 weeks, FBGCs were seen on both the uncoated and coated halves of the scaffolds with 87% (±10% and 36% (±4% FBGC/polymer contact respectively. By 8 weeks these FBGC contact percentages had risen to 97% (±0.45% in the case of the uncoated halves of scaffolds, but decreased to 22% (±4% in the case of the CaP-coated halves. Thus the CaP coating abrogated the FBGC response to the underlying polymer. Such a model may prove useful in providing an experimental system whereby both the mechanisms of biocompatibility and the transition from acute to chronic inflammation could be interrogated.

  1. Behavioral Abnormalities in a Mouse Model of Chronic Toxoplasmosis Are Associated with MAG1 Antibody Levels and Cyst Burden.

    Science.gov (United States)

    Xiao, Jianchun; Li, Ye; Prandovszky, Emese; Kannan, Geetha; Viscidi, Raphael P; Pletnikov, Mikhail V; Yolken, Robert H

    2016-04-01

    There is marked variation in the human response to Toxoplasma gondii infection. Epidemiological studies indicate associations between strain virulence and severity of toxoplasmosis. Animal studies on the pathogenic effect of chronic infection focused on relatively avirulent strains (e.g. type II) because they can easily establish latent infections in mice, defined by the presence of bradyzoite-containing cysts. To provide insight into virulent strain-related severity of human toxoplasmosis, we established a chronic model of the virulent type I strain using outbred mice. We found that type I-exposed mice displayed variable outcomes ranging from aborted to severe infections. According to antibody profiles, we found that most of mice generated antibodies against T. gondii organism but varied greatly in the production of antibodies against matrix antigen MAG1. There was a strong correlation between MAG1 antibody level and brain cyst burden in chronically infected mice (r = 0.82, p = 0.0021). We found that mice with high MAG1 antibody level displayed lower weight, behavioral changes, altered levels of gene expression and immune activation. The most striking change in behavior we discovered was a blunted response to amphetamine-trigged locomotor activity. The extent of most changes was directly correlated with levels of MAG1 antibody. These changes were not found in mice with less cyst burden or mice that were acutely but not chronically infected. Our finding highlights the critical role of cyst burden in a range of disease severity during chronic infection, the predictive value of MAG1 antibody level to brain cyst burden and to changes in behavior or other pathology in chronically infected mice. Our finding may have important implications for understanding the heterogeneous effects of T. gondii infections in human. PMID:27124472

  2. Vascular Changes and Neurodegeneration in the Early Stages of Diabetic Retinopathy

    DEFF Research Database (Denmark)

    Jonsson, Karoline Boegeberg; Frydkjaer-Olsen, Ulrik; Grauslund, Jakob

    2016-01-01

    patients without or with early DR, and to examine whether neurodegeneration precedes visible vasculopathy in the pathogenesis of DR. METHODS: A systematic literature search was performed to identify studies which used optical coherence tomography (OCT) or multifocal electroretinography (mfERG) to detect...... neurodegeneration in patients with no or mild DR as compared to healthy controls. Outcome measures were mean retinal thickness (RT), mean retinal nerve fiber layer (RNFL) thickness and ganglion cell layer (GCL) thickness. Also, mfERG amplitude and implicit time were analyzed. RESULTS: Eleven studies which used mfERG...... and/or OCT to detect neurodegeneration were included. Two OCT studies found significant thinning of RT, 2 found thinning of RNFL, whereas 1 found thickening of RT, RNFL and GCL in patients without DR. Two mfERG studies found a significant delay of implicit time in the same patient group. Retinal...

  3. The minipig as a new model for the evaluation of doxorubicin-induced chronic toxicity.

    Science.gov (United States)

    Manno, Rosa Anna; Grassetti, Andrea; Oberto, Germano; Nyska, Abraham; Ramot, Yuval

    2016-08-01

    Doxorubicin can cause life-threatening toxic effects in several organs, with cardiotoxicity being the major concern. Although a large number of animal models have been utilized to study doxorubicin toxicity, several restrictions limit their use. Since the Göttingen minipig is an accepted species for non-clinical safety assessment and translation to man, we aimed at exploring its use as a non-rodent animal model for safety assessment and regulatory toxicity studies using doxorubicin. Three groups of three males and three females adult Göttingen minipigs received 1.5 mg kg(-1) , 3/2.3 mg kg(-1) or vehicle at intervals of 3 weeks for 7 cycles. Doxorubicin treatment resulted in a dose-related decrease in the erythrocytes, hemoglobin and hematocrit count, accompanied by leukopenia and thrombocytopenia. Bone marrow smears revealed dose-related hypocellularity. Urea and creatinine levels were elevated in treated animals, associated with proteinuria and hematuria. Histopathological evaluation detected nephropathy and atrophy of hematopoietic tissues/organs, mucosa of the intestinal tract and male genital tract. Cardiac lesions including chronic inflammation, endocardial hyperplasia, hemorrhage and myxomatous changes were evident in hematoxylin and eosin stains, and evaluation of semi-thin sections showed the presence of dose-related vacuolation in the atrial and ventricular cardiomyocytes. Cardiac troponin levels were increased in the high-dose group, but there was no direct correlation to the severity of the histopathological lesions. This study confirms that the Göttingen minipig has a comparable toxicity profile to humans and considering its anatomical, physiological, genetic and biochemical resemblance to humans, it should be considered as the non-rodent species of choice for studies on doxorubicin toxicity. Copyright © 2015 John Wiley & Sons, Ltd. PMID:26614124

  4. The treatment of Uygur medicine Dracocephalum moldavica L on chronic mountain sickness rat model

    Directory of Open Access Journals (Sweden)

    Dilinuer Maimaitiyiming

    2014-01-01

    Full Text Available Aim: Dracocephalum moldavica L, a traditional Uygur medicine, possesses some key cardiac activities. However, till date, no reports are available on the use of D. moldavica against chronic mountain sickness (CMS, which is a medical condition that affects the residents of high altitude. The present study was designed to explore the treatment efficacy of D. moldavica on CMS. Materials and Methods: 80 of the 100 Sprague Dawley rats enrolled were bred in simulated high altitude environment and the remaining 20 rats were kept in the plains. Water and alcohol extracts of D. moldavica were prepared. CMS rat model was prepared, and the rat hearts were removed for histopathological analysis. Blood samples were taken for hematological and biochemical analyses. Rat pulmonary artery pressure was determined to study the treatment efficacy. Results: In the CMS model group, the levels of interleukin-6 (IL-6, C-reactive protein (CRP, and malondialdehyde (MDA were found to be significantly higher than the control group; while the concentrations of SOD and GSH-Px decreased. D. moldavica could improve these levels, decrease pulmonary artery pressure, and improve the cardiac pathological state. Conclusions: The study results show that IL-6, CRP, MDA, SOD and GSH-Px participate and mediate the formation of CMS and D. moldavica is found to possess noticeable effects on CMS. The present study explored the basics of high altitude sickness and laid the foundation for further progress of Uygur medicines on the treatment of altitude sickness. Further preclinical and clinical studies with more sample size are recommended.

  5. Chronic Exposure to Beta-Blockers Attenuates Inflammation and Mucin Content in a Murine Asthma Model

    OpenAIRE

    Nguyen, Long P.; Omoluabi, Ozozoma; Parra, Sergio; Frieske, Joanna M.; Clement, Cecilia; Ammar-Aouchiche, Zoulikha; Ho, Samuel B.; Ehre, Camille; Kesimer, Mehmet; Knoll, Brian J.; Tuvim, Michael J; Dickey, Burton F.; Bond, Richard A.

    2007-01-01

    Single-dose administration of beta-adrenoceptor agonists produces bronchodilation and inhibits airway hyperresponsiveness (AHR), and is the standard treatment for the acute relief of asthma. However, chronic repetitive administration of beta-adrenoceptor agonists may increase AHR, airway inflammation, and risk of death. Based upon the paradigm shift that occurred with the use of beta-blockers in congestive heart failure, we previously determined that chronic administration of beta-blockers de...

  6. Protective mechanisms of garlic and wolfberry derivatives on acute and chronic liver injury animal models

    OpenAIRE

    Xiao, Jia; 肖佳

    2012-01-01

    Liver is one of the most important organs in the body that maintains the homeostasis of metabolism, immunity, detoxification and hematopoiesis. A large number of acute and chronic intoxications and diseases can influence the normal functions of the liver, leading to irreversible liver damage and even cancer. Currently, applying herbs or herbal derivatives in the prevention and therapy of acute and chronic liver injury receive numerous attentions since they hold great potentials as food supple...

  7. Pain catastrophizing, physiological indexes, and chronic pain severity: tests of mediation and moderation models

    OpenAIRE

    Wolff, Brandy; Burns, John W.; Quartana, Phillip J.; Lofland, Kenneth; Bruehl, Stephen; Chung, Ok Y.

    2008-01-01

    Catastrophizing about pain is related to elevated pain severity and poor adjustment among chronic pain patients, but few physiological mechanisms by which pain catastrophizing maintains and exacerbates pain have been explored. We hypothesized that resting levels of lower paraspinal muscle tension and/or lower paraspinal and cardiovascular reactivity to emotional arousal may: (a) mediate links between pain catastrophizing and chronic pain intensity; (b) moderate these links such that only pati...

  8. A comparative study of matrix remodeling in chronic models for COPD; mechanistic insights into the role of TNF-α.

    Science.gov (United States)

    Eurlings, Irene M J; Dentener, Mieke A; Mercken, Evi M; de Cabo, Rafael; Bracke, Ken R; Vernooy, Juanita H J; Wouters, Emiel F M; Reynaert, Niki L

    2014-10-01

    Remodeling in chronic obstructive pulmonary disease (COPD) has at least two dimensions: small airway wall thickening and destruction of alveolar walls. Recently we showed comparable alterations of the extracellular matrix (ECM) compounds collagen, hyaluoran, and elastin in alveolar and small airway walls of COPD patients. The aim of this study was to characterize and assess similarities in alveolar and small airway wall matrix remodeling in chronic COPD models. From this comparative characterization of matrix remodeling we derived and elaborated underlying mechanisms to the matrix changes reported in COPD. Lung tissue sections of chronic models for COPD, either induced by exposure to cigarette smoke, chronic intratracheal lipopolysaccharide instillation, or local tumor necrosis factor (TNF) expression [surfactant protein C (SPC)-TNFα mice], were stained for elastin, collagen, and hyaluronan. Furthermore TNF-α matrix metalloproteinase (MMP)-2, -9, and -12 mRNA expression was analyzed using qPCR and localized using immunohistochemistry. Both collagen and hyaluronan were increased in alveolar and small airway walls of all three models. Interestingly, elastin contents were differentially affected, with a decrease in both alveolar and airway walls in SPC-TNFα mice. Furthermore TNF-α and MMP-2 and -9 mRNA and protein levels were found to be increased in alveolar walls and around airway walls only in SPC-TNFα mice. We show that only SPC-TNFα mice show changes in elastin remodeling that are comparable to what has been observed in COPD patients. This reveals that the SPC-TNFα model is a suitable model to study processes underlying matrix remodeling and in particular elastin breakdown as seen in COPD. Furthermore we indicate a possible role for MMP-2 and MMP-9 in the breakdown of elastin in airways and alveoli of SPC-TNFα mice. PMID:25106431

  9. Development of Quantitative Structure-Activity Relationship Models for Predicting Chronic Toxicity of Substituted Benzenes to Daphnia Magna.

    Science.gov (United States)

    Fan, Deling; Liu, Jining; Wang, Lei; Yang, Xianhai; Zhang, Shenghu; Zhang, Yan; Shi, Lili

    2016-05-01

    The chronic toxicity of anthropogenic molecules such as substituted benzenes to Daphnia magna is a basic eco-toxicity parameter employed to assess their environmental risk. As the experimental methods are laborious, costly, and time-consuming, development in silico models for predicting the chronic toxicity is vitally important. In this study, on the basis of five molecular descriptors and 48 compounds, a quantitative structure-property relationship model that can predict the chronic toxicity of substituted benzenes were developed by employing multiple linear regressions. The correlation coefficient (R (2)) and root-mean square error (RMSE) for the training set were 0.836 and 0.390, respectively. The developed model was validated by employing 10 compounds tested in our lab. The R EXT (2) and RMSE EXT for the validation set were 0.736 and 0.490, respectively. To further characterizing the toxicity mechanism of anthropogenic molecules to Daphnia, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models were developed. PMID:27016939

  10. Development of a chronic fish toxicity model for predicting sub-lethal NOEC values for non-polar narcotics.

    Science.gov (United States)

    Austin, T J; Eadsforth, C V

    2014-01-01

    To comply with the REACH (Registration, Evaluation, Authorisation and restriction of Chemicals) regulations, the generation of chronic fish toxicity data is required for chemicals produced or imported within or into the EU in quantities greater than 100 tonnes per year. This comes at a great cost to industry and consumers alike and requires the sacrifice of many vertebrates. In acknowledgment of these issues the REACH regulations encourage the use of non-testing methods (NTM). These include read-across, weight-of-evidence and QSAR (quantitative structure-activity relationship) techniques. There are many QSAR tools available to generate predictive values for a number of physico-chemical properties, as well as human and environmental health end points; however, close analysis of the currently available chronic fish models identified room for improvement in both the selection of data used and in its application in model creation. In light of this a model was developed using only sub-lethal no-observed-effect concentration (NOEC) end-point data according to best practice QSAR development. Only the lowest value was taken for each compound, in line with the conservative approach taken by the European Chemicals Agency (ECHA). The model developed meets the Organisation for Economic Co-operation and Development (OECD) principles, has strong internal and external validation statistics, and can reliably predict sub-lethal chronic NOEC values for fish within its defined applicability domain. PMID:24635482

  11. Performances of models for predicting mercury concentrations in fresh-water fish after chronic releases into rivers

    International Nuclear Information System (INIS)

    The performances of assessment models for estimating the transfer and bioaccumulation of mercury in fresh-water ecosystems were tested by being applied to a test scenario proposed in an international cooperative study BIOMOVS. Two kinds of models have been developed to estimate mercury concentrations in fish after chronic releases into rivers. One uses a bioaccumulation factor approach which is applied to ecosystems in equilibrium, whereas the other is a dynamic model which considers the change of the concentrations in water and the metabolism in fish. The success of the models tested by three different scenarios depended upon whether mercury was in equilibrium in the environment. For the scenario where mercury concentrations reached equilibrium, the first model performed satisfactorily. For the scenario where equilibrium was not attained, the first model was not adequate but the second model could predict more accurately. The limitations of applications were suggested for the two models employed here. (author)

  12. Quantitative Modeling of Microbial Population Responses to Chronic Irradiation Combined with Other Stressors.

    Science.gov (United States)

    Shuryak, Igor; Dadachova, Ekaterina

    2016-01-01

    Microbial population responses to combined effects of chronic irradiation and other stressors (chemical contaminants, other sub-optimal conditions) are important for ecosystem functioning and bioremediation in radionuclide-contaminated areas. Quantitative mathematical modeling can improve our understanding of these phenomena. To identify general patterns of microbial responses to multiple stressors in radioactive environments, we analyzed three data sets on: (1) bacteria isolated from soil contaminated by nuclear waste at the Hanford site (USA); (2) fungi isolated from the Chernobyl nuclear-power plant (Ukraine) buildings after the accident; (3) yeast subjected to continuous γ-irradiation in the laboratory, where radiation dose rate and cell removal rate were independently varied. We applied generalized linear mixed-effects models to describe the first two data sets, whereas the third data set was amenable to mechanistic modeling using differential equations. Machine learning and information-theoretic approaches were used to select the best-supported formalism(s) among biologically-plausible alternatives. Our analysis suggests the following: (1) Both radionuclides and co-occurring chemical contaminants (e.g. NO2) are important for explaining microbial responses to radioactive contamination. (2) Radionuclides may produce non-monotonic dose responses: stimulation of microbial growth at low concentrations vs. inhibition at higher ones. (3) The extinction-defining critical radiation dose rate is dramatically lowered by additional stressors. (4) Reproduction suppression by radiation can be more important for determining the critical dose rate, than radiation-induced cell mortality. In conclusion, the modeling approaches used here on three diverse data sets provide insight into explaining and predicting multi-stressor effects on microbial communities: (1) the most severe effects (e.g. extinction) on microbial populations may occur when unfavorable environmental

  13. Quantitative Modeling of Microbial Population Responses to Chronic Irradiation Combined with Other Stressors.

    Directory of Open Access Journals (Sweden)

    Igor Shuryak

    Full Text Available Microbial population responses to combined effects of chronic irradiation and other stressors (chemical contaminants, other sub-optimal conditions are important for ecosystem functioning and bioremediation in radionuclide-contaminated areas. Quantitative mathematical modeling can improve our understanding of these phenomena. To identify general patterns of microbial responses to multiple stressors in radioactive environments, we analyzed three data sets on: (1 bacteria isolated from soil contaminated by nuclear waste at the Hanford site (USA; (2 fungi isolated from the Chernobyl nuclear-power plant (Ukraine buildings after the accident; (3 yeast subjected to continuous γ-irradiation in the laboratory, where radiation dose rate and cell removal rate were independently varied. We applied generalized linear mixed-effects models to describe the first two data sets, whereas the third data set was amenable to mechanistic modeling using differential equations. Machine learning and information-theoretic approaches were used to select the best-supported formalism(s among biologically-plausible alternatives. Our analysis suggests the following: (1 Both radionuclides and co-occurring chemical contaminants (e.g. NO2 are important for explaining microbial responses to radioactive contamination. (2 Radionuclides may produce non-monotonic dose responses: stimulation of microbial growth at low concentrations vs. inhibition at higher ones. (3 The extinction-defining critical radiation dose rate is dramatically lowered by additional stressors. (4 Reproduction suppression by radiation can be more important for determining the critical dose rate, than radiation-induced cell mortality. In conclusion, the modeling approaches used here on three diverse data sets provide insight into explaining and predicting multi-stressor effects on microbial communities: (1 the most severe effects (e.g. extinction on microbial populations may occur when unfavorable environmental

  14. Influence of Acupuncture on HPA Axis in a Rat Model of Chronic Stress-induced Depression

    Institute of Scientific and Technical Information of China (English)

    孙冬玮; 王珑; 孙忠人

    2007-01-01

    目的:讨抑郁症的神经生物学发病机制,揭示针刺治疗抑郁症的机理.方法:以Wistar大鼠为受试对象,采用给予孤养大鼠以长期不可预见的中等强度刺激的方法建立抑郁大鼠模型,检测应激后造成的抑郁模型大鼠行为学改变、下丘脑垂体肾上腺皮质轴(HPA)的变化,同时观察针刺干预效应及不同针法的疗效比较.结果:型组、生理盐水组血清CORT和ACTH含量明显高于正常对照组(P<0.05);手针治疗组、电针治疗组血清CORT和ACTH含量明显低于模型组(P<0.05);药物组血清CORT和ACTH含量明显低于生理盐水组(P<0.05);手针治疗组、电针治疗组、药物组比较差别无统计学意义.结论:刺百会、太冲具有较明显的抗抑郁效应,其机制可能与针刺对HPA轴的调整有关.%To investigate the neurobiological mechanism of depression pathogenesis and reveal the mechanism of acupuncture treatment of depression. Methods: Wistar rats were selected for subjects. A rat model of depression was made by individually housing with unpredicted chronic moderate stimuli. Changes in behavior and hypothalamus-pituitary-adrenocortical axis were examined in rat models of stress-induced depression. Meanwhile, the intervening effect of acupuncture was evaluated and the curative effects of different acupuncture methods compared. Results: CORT and ACTH contents of serum were significantly higher in the model and normal saline groups than in the control group (P<0.05), significantly lower in the hand acupuncture and electroacupuncture groups than in the model group (P<0.05) and significantly lower in the medication group than in the normal saline group (P<0.05). There were no significant differences between the hand acupuncture, electroacupuncture and medication groups. Conclusion: Acupuncture of Baihui(GV 20) and Taichong (LR 3) has a marked antidepressant effect. Its mechanism may be related to the regulation of HPA axis by acupuncture.

  15. Comparison of the capacity of two biotic ligand models to predict chronic copper toxicity to two Daphnia magna clones and formulation of a generalized bioavailability model.

    Science.gov (United States)

    Van Regenmortel, Tina; Janssen, Colin R; De Schamphelaere, Karel A C

    2015-07-01

    Although it is increasingly recognized that biotic ligand models (BLMs) are valuable in the risk assessment of metals in aquatic systems, the use of 2 differently structured and parameterized BLMs (1 in the United States and another in the European Union) to obtain bioavailability-based chronic water quality criteria for copper is worthy of further investigation. In the present study, the authors evaluated the predictive capacity of these 2 BLMs for a large dataset of chronic copper toxicity data with 2 Daphnia magna clones, termed K6 and ARO. One BLM performed best with clone K6 data, whereas the other performed best with clone ARO data. In addition, there was an important difference between the 2 BLMs in how they predicted the bioavailability of copper as a function of pH. These modeling results suggested that the effect of pH on chronic copper toxicity is different between the 2 clones considered, which was confirmed with additional chronic toxicity experiments. Finally, because fundamental differences in model structure between the 2 BLMs made it impossible to create an average BLM, a generalized bioavailability model (gBAM) was developed. Of the 3 gBAMs developed, the authors recommend the use of model gBAM-C(uni), which combines a log-linear relation between the 21-d median effective concentration (expressed as free Cu(2+) ion activity) and pH, with more conventional BLM-type competition constants for sodium, calcium, and magnesium. This model can be considered a first step in further improving the accuracy of chronic toxicity predictions of copper as a function of water chemistry (for a variety of Daphnia magna clones), even beyond the robustness of the current BLMs used in regulatory applications. PMID:25771778

  16. Elevation of neuron specific enolase and brain iron deposition on susceptibility-weighted imaging as diagnostic clues for beta-propeller protein-associated neurodegeneration in early childhood: Additional case report and review of the literature.

    Science.gov (United States)

    Takano, Kyoko; Shiba, Naoko; Wakui, Keiko; Yamaguchi, Tomomi; Aida, Noriko; Inaba, Yuji; Fukushima, Yoshimitsu; Kosho, Tomoki

    2016-02-01

    Beta-propeller protein-associated neurodegeneration (BPAN), also known as static encephalopathy of childhood with neurodegeneration in adulthood (SENDA), is a subtype of neurodegeneration with brain iron accumulation (NBIA). BPAN is caused by mutations in an X-linked gene WDR45 that is involved in autophagy. BPAN is characterized by developmental delay or intellectual disability until adolescence or early adulthood, followed by severe dystonia, parkinsonism, and progressive dementia. Brain magnetic resonance imaging (MRI) shows iron deposition in the bilateral globus pallidus (GP) and substantia nigra (SN). Clinical manifestations and laboratory findings in early childhood are limited. We report a 3-year-old girl with BPAN who presented with severe developmental delay and characteristic facial features. In addition to chronic elevation of serum aspartate transaminase, lactate dehydrogenase, creatine kinase, and soluble interleukin-2 receptor, she had persistent elevation of neuron specific enolase (NSE) in serum and cerebrospinal fluid. MRI using susceptibility-weighted imaging (SWI) demonstrated iron accumulation in the GP and SN bilaterally. Targeted next-generation sequencing identified a de novo splice-site mutation, c.831-1G>C in WDR45, which resulted in aberrant splicing evidenced by reverse transcriptase-PCR. Persistent elevation of NSE and iron deposition on SWI may provide clues for diagnosis of BPAN in early childhood. PMID:26481852

  17. Synergistic stress exacerbation in hippocampal neurons: Evidence favoring the dual-hit hypothesis of neurodegeneration.

    Science.gov (United States)

    Heinemann, Scott D; Posimo, Jessica M; Mason, Daniel M; Hutchison, Daniel F; Leak, Rehana K

    2016-08-01

    The dual-hit hypothesis of neurodegeneration states that severe stress sensitizes vulnerable cells to subsequent challenges so that the two hits are synergistic in their toxic effects. Although the hippocampus is vulnerable to a number of neurodegenerative disorders, there are no models of synergistic cell death in hippocampal neurons in response to combined proteotoxic and oxidative stressors, the two major characteristics of these diseases. Therefore, a relatively high-throughput dual-hit model of stress synergy was developed in primary hippocampal neurons. In order to increase the rigor of the study and strengthen the interpretations, three independent, unbiased viability assays were employed at multiple timepoints. Stress synergy was elicited when hippocampal neurons were treated with the proteasome inhibitor MG132 followed by exposure to the oxidative toxicant paraquat, but only after 48 h. MG132 and paraquat only elicited additive effects 24 h after the final hit and even loss of heat shock protein 70 activity and glutathione did not promote stress synergy at this early timepoint. Dual hits of MG132 elicited modest glutathione loss and slightly synergistic toxic effects 48 h after the second hit, but only at some concentrations and only according to two viability assays (metabolic fitness and cytoskeletal integrity). The thiol N-acetyl cysteine protected hippocampal neurons against dual MG132/MG132 hits but not dual MG132/paraquat hits. These findings support the view that proteotoxic and oxidative stress propel and propagate each other in hippocampal neurons, leading to synergistically toxic effects, but not as the default response and only after a delay. The neuronal stress synergy observed here lies in contrast to astrocytic responses to dual hits, because astrocytes that survive severe proteotoxic stress resist additional cell loss following second hits. In conclusion, a new model of hippocampal vulnerability was developed for the testing of therapies

  18. Chronic Non-Communicable Cardiovascular and Pulmonary Disease in sub-Saharan Africa: An Academic Model for Countering the Epidemic

    Science.gov (United States)

    Bloomfield, Gerald S.; Kimaiyo, Sylvester; Carter, E. Jane; Binanay, Cynthia; Corey, G. Ralph; Einterz, Robert M.; Tierney, William M.; Velazquez, Eric J.

    2011-01-01

    Summary Non-communicable diseases are rapidly overtaking infectious, perinatal, nutritional and maternal diseases as the major causes of worldwide death and disability. It is estimated that within the next 10-15 years, the increasing burden of chronic diseases and the ageing of the population will expose the world to an unprecedented burden of chronic diseases. Preventing the potential ramifications of a worldwide epidemic of chronic non-communicable diseases in a sustainable manner requires coordinated, collaborative efforts. Herein we present our collaboration's strategic plan to understand, treat and prevent chronic cardiovascular and pulmonary disease in Western Kenya which builds on a two decade partnership between academic universities in North America and Kenya; the Academic Model Providing Access to Healthcare (AMPATH). We emphasize the importance of training Kenyan clinician-investigators who will ultimately lead efforts in cardiovascular and pulmonary disease care, education and research. This penultimate aim will be achieved by our five main goals. Our goals include creating an administrative core capable of managing operations, develop clinical and clinical research training curricula, enhancing existing technology infrastructure and implementing relevant research programs. Leveraging a strong international academic partnership with respective expertise in cardiovascular medicine, pulmonary medicine and medical informatics we have undertaken to understand and counter cardiovascular and pulmonary disease in Kenya by addressing patient care, teaching and clinical research. PMID:21570512

  19. Outcome of Prolonged Ventricular Fibrillation and CPR in a Rat Model of Chronic Ischemic Left Ventricular Dysfunction

    Directory of Open Access Journals (Sweden)

    Xiangshao Fang

    2013-01-01

    Full Text Available Patients with chronic left ventricular (LV dysfunction are assumed to have a lower chance of successful CPR and lower likelihood of ultimate survival. However, these assumptions have rarely been documented. Therefore, we investigated the outcome of prolonged ventricular fibrillation (VF and CPR in a rat model of chronic LV dysfunction. Sprague-Dawley rats were randomized to (1 chronic LV dysfunction: animals underwent left coronary artery ligation; and (2 sham control. Echocardiography was used to measure cardiac performance before surgery and 4 weeks after surgery. Four weeks after surgical intervention, 8 min of VF was induced and defibrillation was delivered after 8 min of CPR. LV dilation and low ejection fraction were observed 4 weeks after coronary ligation. With optimal chest compressions, coronary perfusion pressure values during CPR were well maintained and indistinguishable between groups. There were no differences in resuscitability and numbers of shock required for successful resuscitation between groups. Despite the significantly decreased cardiac index in LV dysfunction animals before induction of VF, no differences in cardiac index were observed between groups following resuscitation, which was associated with the insignificant difference in postresuscitation survival. In conclusion, the outcomes of CPR were not compromised by the preexisting chronic LV dysfunction.

  20. Chronic noncommunicable cardiovascular and pulmonary disease in sub-Saharan Africa: an academic model for countering the epidemic.

    Science.gov (United States)

    Bloomfield, Gerald S; Kimaiyo, Sylvester; Carter, E Jane; Binanay, Cynthia; Corey, G Ralph; Einterz, Robert M; Tierney, William M; Velazquez, Eric J

    2011-05-01

    Noncommunicable diseases are rapidly overtaking infectious, perinatal, nutritional, and maternal diseases as the major causes of worldwide death and disability. It is estimated that, within the next 10 to 15 years, the increasing burden of chronic diseases and the aging of the population will expose the world to an unprecedented burden of chronic diseases. Preventing the potential ramifications of a worldwide epidemic of chronic noncommunicable diseases in a sustainable manner requires coordinated, collaborative efforts. Herein, we present our collaboration's strategic plan to understand, treat, and prevent chronic cardiovascular and pulmonary disease (CVPD) in western Kenya, which builds on a 2-decade partnership between academic universities in North America and Kenya, the Academic Model Providing Access to Healthcare. We emphasize the importance of training Kenyan clinician-investigators who will ultimately lead efforts in CVPD care, education, and research. This penultimate aim will be achieved by our 5 main goals. Our goals include creating an administrative core capable of managing operations, develop clinical and clinical research training curricula, enhancing existing technology infrastructure, and implementing relevant research programs. Leveraging a strong international academic partnership with respective expertise in cardiovascular medicine, pulmonary medicine, and medical informatics, we have undertaken to understand and counter CVPD in Kenya by addressing patient care, teaching, and clinical research. PMID:21570512

  1. Suppressive effect of compact bone-derived mesenchymal stem cells on chronic airway remodeling in murine model of asthma.

    Science.gov (United States)

    Ogulur, Ismail; Gurhan, Gulben; Aksoy, Ayca; Duruksu, Gokhan; Inci, Cigdem; Filinte, Deniz; Kombak, Faruk Erdem; Karaoz, Erdal; Akkoc, Tunc

    2014-05-01

    New therapeutic strategies are needed in the treatment of asthma besides vaccines and pharmacotherapies. For the development of novel therapies, the use of mesenchymal stem cells (MSCs) is a promising approach in regenerative medicine. Delivery of compact bone (CB) derived MSCs to the injured lungs is an alternative treatment strategy for chronic asthma. In this study, we aimed to isolate highly enriched population of MSCs from mouse CB with regenerative capacity, and to investigate the impact of these cells in airway remodeling and inflammation in experimental ovalbumin-induced mouse model of chronic asthma. mCB-MSCs were isolated, characterized, labeled with GFP and then transferred into mice with chronic asthma developed by ovalbumin (OVA) provocation. Histopathological changes including basement membrane, epithelium, subepithelial smooth thickness and goblet cell hyperplasia, and MSCs migration to lung tissues were evaluated. These histopathological alterations were increased in ovalbumin-treated mice compared to PBS group (Pasthma. The results reported here provided evidence that mCB-MSCs may be an alternative strategy for the treatment of remodeling and inflammation associated with chronic asthma. PMID:24613203

  2. A Study of the Protective Effect of Triticum aestivum L. in an Experimental Animal Model of Chronic Fatigue Syndrome

    OpenAIRE

    Mukundam Borah; Phulen Sarma; Swarnamoni Das

    2014-01-01

    Background: Oxidative stress plays a major role in the pathogenesis of chronic fatigue syndrome (CFS). Keeping in view the proven antioxidant activity of Triticum aestivum L., this study has been undertaken to explore the potential therapeutic benefit of this plant in the treatment of CFS. Objective: To study the protective effect of the ethanolic extract of the leaves of Triticum aestivum (EETA) in an experimental mice model of CFS. Materials and Methods: Five groups of albino mice (20-25 g)...

  3. YAP is up-regulated in the bronchial airway smooth muscle of the chronic asthma mouse model

    OpenAIRE

    Zhou, Jing; Xu, Fei; Yu, Jing Jing; Zhang, Wei

    2015-01-01

    Asthma is characterized by leukocytic infiltration and tissue remodeling with structural changes including subepithelial fibrosis and ASM cells proliferation. The Hippo pathway is a key regulatory point involved in cell proliferation, fibroblasts, and smooth muscle cell differentiation. In order to disclose the relation between asthma and the Hippo pathway, expression of the Yes-associated protein (YAP), a key gene in the Hippo pathway, in the bronchial smooth muscle of chronic asthma model (...

  4. The neuregulin, glial growth factor 2, diminishes autoimmune demyelination and enhances remyelination in a chronic relapsing model for multiple sclerosis

    OpenAIRE

    Cannella, Barbara; Hoban, Carolyn J; Gao, Yan-Ling; Garcia-Arenas, Renee; Lawson, Deborah; Marchionni, Mark; Gwynne, David; Raine, Cedric S.

    1998-01-01

    Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). The present study examined whether recombinant human GGF2 (rhGGF2) could effect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis. Mice with EAE were treated with ...

  5. Muscle-derived Stem Cell Sheets Support Pump Function and Prevent Cardiac Arrhythmias in a Model of Chronic Myocardial Infarction

    OpenAIRE

    Sekiya, Naosumi; Tobita, Kimimasa; Beckman, Sarah; Okada, Masaho; Gharaibeh, Burhan; Sawa, Yoshiki; Kormos, Robert L.; Huard, Johnny

    2013-01-01

    Direct intracardiac cell injection for heart repair is hindered by numerous limitations including: cell death, poor spreading of the injected cells, arrhythmia, needle injury, etc. Tissue-engineered cell sheet implantation has the potential to overcome some of these limitations. We evaluated whether the transplantation of a muscle-derived stem cell (MDSC) sheet could improve the regenerative capacity of MDSCs in a chronic model of myocardial infarction. MDSC sheet-implanted mice displayed a r...

  6. Effects of Electroacupuncture at Auricular Concha Region on the Depressive Status of Unpredictable Chronic Mild Stress Rat Models

    OpenAIRE

    Ru-Peng Liu; Ji-Liang Fang; Pei-Jing Rong; Yufeng Zhao; Hong Meng; Hui Ben; Liang Li; Zhan-Xia Huang; Xia Li; Ying-Ge Ma; Bing Zhu

    2013-01-01

    To explore new noninvasive treatment options for depression, this study investigated the effects of electroacupuncture (EA) at the auricular concha region (ACR) of depression rat models. Depression in rats was induced by unpredictable chronic mild stress (UCMS) combined with isolation for 21 days. Eighty male Wistar rats were randomly assigned into four groups: normal, UCMS alone, UCMS with EA-ACR treatment, and UCMS with EA-ear-tip treatment. Rats under inhaled anesthesia were treated once d...

  7. Chronic Cerebral Hypoperfusion Causes Decrease of O-GlcNAcylation, Hyperphosphorylation of Tau and Behavioral Deficits in Mice

    Directory of Open Access Journals (Sweden)

    Yang eZhao

    2014-02-01

    Full Text Available Chronic cerebral hypoperfusion (CCH is one of the causes of vascular dementia (VaD and is also an etiological factor for Alzheimer's disease (AD. However, how CCH causes cognitive impairment and contributes to Alzheimer’s pathology is poorly understood. Here we produced a mouse model of CCH by unilateral common carotid artery occlusion (UCCAO and studied the behavioral changes and brain abnormalities in mice 2.5 months after UCCAO. We found that CCH caused significant short-term memory deficits and mild long-term spatial memory impairment, as well as decreased level of protein O-GlcNAcylation, increased level of tau phosphorylation, dysregulated synaptic proteins and insulin signaling, and selective neurodegeneration in the brain. These findings provide mechanistic insight into the effects of CCH on memory and cognition and the likely link between AD and VaD.

  8. Uncertainty and sensitivity analysis of chronic exposure results with the MACCS reactor accident consequence model

    International Nuclear Information System (INIS)

    Uncertainty and sensitivity analysis techniques based on Latin hypercube sampling, partial correlation analysis and stepwise regression analysis are used in an investigation with the MACCS model of the chronic exposure pathways associated with a severe accident at a nuclear power station. The primary purpose of this study is to provide guidance on the variables to be considered in future review work to reduce the uncertainty in the important variables used in the calculation of reactor accident consequences. The effects of 75 imprecisely known input variables on the following reactor accident consequences are studied: crop growing season dose, crop long-term dose, water ingestion dose, milk growing season dose, long-term groundshine dose, long-term inhalation dose, total food pathways dose, total ingestion pathways dose, total long-term pathways dose, total latent cancer fatalities, area-dependent cost, crop disposal cost, milk disposal cost, population-dependent cost, total economic cost, condemnation area, condemnation population, crop disposal area and milk disposal area. When the predicted variables are considered collectively, the following input variables were found to be the dominant contributors to uncertainty: dry deposition velocity, transfer of cesium from animal feed to milk, transfer of cesium from animal feed to meat, ground concentration of Cs-134 at which the disposal of milk products will be initiated, transfer of Sr-90 from soil to legumes, maximum allowable ground concentration of Sr-90 for production of crops, fraction of cesium entering surface water that is consumed in drinking water, groundshine shielding factor, scale factor defining resuspension, dose reduction associated with decontamination, and ground concentration of 1-131 at which disposal of crops will be initiated due to accidents that occur during the growing season

  9. A plasminogen activator inhibitor-1 inhibitor reduces airway remodeling in a murine model of chronic asthma.

    Science.gov (United States)

    Lee, Sun H; Eren, Mesut; Vaughan, Douglas E; Schleimer, Robert P; Cho, Seong H

    2012-06-01

    We previously reported that plasminogen activator inhibitor (PAI)-1 deficiency prevents collagen deposition in the airways of ovalbumin (OVA)-challenged mice. In this study, we explored the therapeutic utility of blocking PAI-1 in preventing airway remodeling, using a specific PAI-1 inhibitor, tiplaxtinin. C57BL/6J mice were immunized with intraperitoneal injections of OVA on Days 0, 3, and 6. Starting on Day 11, mice were challenged with phosphate-buffered saline or OVA by nebulization three times per week for 4 weeks. Tiplaxtinin was mixed with chow and administered orally from 1 day before the phosphate-buffered saline or OVA challenge. Lung tissues were harvested after challenge and characterized histologically for infiltrating inflammatory cells, mucus-secreting goblet cells, and collagen deposition. Airway hyperresponsiveness was measured using whole-body plethysmography. Tiplaxtinin treatment significantly decreased levels of PAI-1 activity in bronchoalveolar lavage fluids, which indicates successful blockage of PAI-1 activity in the airways. The number of infiltrated inflammatory cells was reduced by tiplaxtinin treatment in the lungs of the OVA-challenged mice. Furthermore, oral administration of tiplaxtinin significantly attenuated the degree of goblet cell hyperplasia and collagen deposition in the airways of the OVA-challenged mice, and methacholine-induced airway hyperresponsiveness was effectively reduced by tiplaxtinin in these animals. This study supports our previous findings that PAI-1 promotes airway remodeling in a murine model of chronic asthma, and suggests that PAI-1 may be a novel target of treatment of airway remodeling in asthma. PMID:22323366

  10. Profiling of differentially expressed genes using suppression subtractive hybridization in an equine model of chronic asthma.

    Directory of Open Access Journals (Sweden)

    Jean-Pierre Lavoie

    Full Text Available BACKGROUND: Gene expression analyses are used to investigate signaling pathways involved in diseases. In asthma, they have been primarily derived from the analysis of bronchial biopsies harvested from mild to moderate asthmatic subjects and controls. Due to ethical considerations, there is currently limited information on the transcriptome profile of the peripheral lung tissues in asthma. OBJECTIVE: To identify genes contributing to chronic inflammation and remodeling in the peripheral lung tissue of horses with heaves, a naturally occurring asthma-like condition. METHODS: Eleven adult horses (6 heaves-affected and 5 controls were studied while horses with heaves were in clinical remission (Pasture, and during disease exacerbation induced by a 30-day natural antigen challenge during stabling (Challenge. Large peripheral lung biopsies were obtained by thoracoscopy at both time points. Using suppression subtractive hybridization (SSH, lung cDNAs of controls (Pasture and Challenge and asymptomatic heaves-affected horses (Pasture were subtracted from cDNAs of horses with heaves in clinical exacerbation (Challenge. The differential expression of selected genes of interest was confirmed using quantitative PCR assay. RESULTS: Horses with heaves, but not controls, developed airway obstruction when challenged. Nine hundred and fifty cDNA clones isolated from the subtracted library were screened by dot blot array and 224 of those showing the most marked expression differences were sequenced. The gene expression pattern was confirmed by quantitative PCR in 15 of 22 selected genes. Novel genes and genes with an already defined function in asthma were identified in the subtracted cDNA library. Genes of particular interest associated with asthmatic airway inflammation and remodeling included those related to PPP3CB/NFAT, RhoA, and LTB4/GPR44 signaling pathways. CONCLUSIONS: Pathways representing new possible targets for anti-inflammatory and anti

  11. Uncertainty and sensitivity analysis of chronic exposure results with the MACCS reactor accident consequence model

    International Nuclear Information System (INIS)

    Uncertainty and sensitivity analysis techniques based on Latin hypercube sampling, partial correlation analysis and stepwise regression analysis are used in an investigation with the MACCS model of the chronic exposure pathways associated with a severe accident at a nuclear power station. The primary purpose of this study is to provide guidance on the variables to be considered in future review work to reduce the uncertainty in the important variables used in the calculation of reactor accident consequences. The effects of 75 imprecisely known input variables on the following reactor accident consequences are studied: crop growing-season dose, crop long-term dose, water ingestion dose, milk growing-season dose, long-term groundshine dose, long-term inhalation dose, total food pathways dose, total ingestion pathways dose, total long-term pathways dose, total latent cancer fatalities, area-dependent cost, crop disposal cost, milk disposal cost, population-dependent cost, total economic cost, condemnation area, condemnation population, crop disposal area and milk disposal area. When the predicted variables are considered collectively, the following input variables were found to be the dominant contributors to uncertainty: dry deposition velocity, transfer of cesium from animal feed to milk, transfer of cesium from animal feed to meet, ground concentration of Cs-134 at which the disposal of milk products will be initiated, transfer of Sr-90 from soil to legumes, maximum allowable ground concentration of Sr-90 for production of crops, fraction of cesium entering surface water that is consumed in drinking water, groundshine shielding factor, scale factor defining resuspension, dose reduction associated with decontamination, and ground concentration of I-131 at which disposal of crops will be initiated due to accidents that occur during the growing season. Reducing the uncertainty in the preceding variables was found to substantially reduce the uncertainty in the

  12. Uncertainty and sensitivity analysis of chronic exposure results with the MACCS reactor accident consequence model

    Energy Technology Data Exchange (ETDEWEB)

    Helton, J.C. [Arizona State Univ., Tempe, AZ (United States); Johnson, J.D.; Rollstin, J.A. [Gram, Inc., Albuquerque, NM (United States); Shiver, A.W.; Sprung, J.L. [Sandia National Labs., Albuquerque, NM (United States)

    1995-01-01

    Uncertainty and sensitivity analysis techniques based on Latin hypercube sampling, partial correlation analysis and stepwise regression analysis are used in an investigation with the MACCS model of the chronic exposure pathways associated with a severe accident at a nuclear power station. The primary purpose of this study is to provide guidance on the variables to be considered in future review work to reduce the uncertainty in the important variables used in the calculation of reactor accident consequences. The effects of 75 imprecisely known input variables on the following reactor accident consequences are studied: crop growing season dose, crop long-term dose, water ingestion dose, milk growing season dose, long-term groundshine dose, long-term inhalation dose, total food pathways dose, total ingestion pathways dose, total long-term pathways dose, total latent cancer fatalities, area-dependent cost, crop disposal cost, milk disposal cost, population-dependent cost, total economic cost, condemnation area, condemnation population, crop disposal area and milk disposal area. When the predicted variables are considered collectively, the following input variables were found to be the dominant contributors to uncertainty: dry deposition velocity, transfer of cesium from animal feed to milk, transfer of cesium from animal feed to meat, ground concentration of Cs-134 at which the disposal of milk products will be initiated, transfer of Sr-90 from soil to legumes, maximum allowable ground concentration of Sr-90 for production of crops, fraction of cesium entering surface water that is consumed in drinking water, groundshine shielding factor, scale factor defining resuspension, dose reduction associated with decontamination, and ground concentration of 1-131 at which disposal of crops will be initiated due to accidents that occur during the growing season.

  13. Longitudinal study of a mouse model of chronic pulmonary inflammation using breath hold gated micro-CT

    International Nuclear Information System (INIS)

    To evaluate the feasibility of using automatic quantitative analysis of breath hold gated micro-CT images to detect and monitor disease in a mouse model of chronic pulmonary inflammation, and to compare image-based measurements with pulmonary function tests and histomorphometry. Forty-nine A/J mice were used, divided into control and inflammation groups. Chronic inflammation was induced by silica aspiration. Fourteen animals were imaged at baseline, and 4, 14, and 34 weeks after silica aspiration, using micro-CT synchronized with ventilator-induced breath holds. Lung input impedance was measured as well using forced oscillation techniques. Five additional animals from each group were killed after micro-CT for comparison with histomorphometry. At all time points, micro-CT measurements show statistically significant differences between the two groups, while first differences in functional test parameters appear at 14 weeks. Micro-CT measurements correlate well with histomorphometry and discriminate diseased and healthy groups better than functional tests. Longitudinal studies using breath hold gated micro-CT are feasible on the silica-induced model of chronic pulmonary inflammation, and automatic measurements from micro-CT images correlate well with histomorphometry, being more sensitive than functional tests to detect lung damage in this model. (orig.)

  14. Different susceptibility to neurodegeneration of dorsal and ventral hippocampal dentate gyrus: a study with transgenic mice overexpressing GSK3β.

    Directory of Open Access Journals (Sweden)

    Almudena Fuster-Matanzo

    Full Text Available Dorsal hippocampal regions are involved in memory and learning processes, while ventral areas are related to emotional and anxiety processes. Hippocampal dependent memory and behaviour alterations do not always come out in neurodegenerative diseases at the same time. In this study we have tested the hypothesis that dorsal and ventral dentate gyrus (DG regions respond in a different manner to increased glycogen synthase kinase-3β (GSK3β levels in GSK3β transgenic mice, a genetic model of neurodegeneration. Reactive astrocytosis indicate tissue stress in dorsal DG, while ventral area does not show that marker. These changes occurred with a significant reduction of total cell number and with a significantly higher level of cell death in dorsal area than in ventral one as measured by fractin-positive cells. Biochemistry analysis showed higher levels of phosphorylated GSK3β in those residues that inactivate the enzyme in hippocampal ventral areas compared with dorsal area suggesting that the observed susceptibility is in part due to different GSK3 regulation. Previous studies carried out with this animal model had demonstrated impairment in Morris Water Maze and Object recognition tests point out to dorsal hippocampal atrophy. Here, we show that two tests used to evaluate emotional status, the light-dark box and the novelty suppressed feeding test, suggest that GSK3β mice do not show any anxiety-related disorder. Thus, our results demonstrate that in vivo overexpression of GSK3β results in dorsal but not ventral hippocampal DG neurodegeneration and suggest that both areas do not behave in a similar manner in neurodegenerative processes.

  15. Model for end-stage liver disease-sodium predicts prognosis in patients with chronic severe hepatitis B

    Institute of Scientific and Technical Information of China (English)

    CAI Chang-jie; CHEN Huan; LU Min-qiang; CHEN Gui-hua

    2008-01-01

    Background Serum sodium predicts prognosis in chronic severe hepatitis B and may improve the prognostic accuracy of the model for end-stage liver disease (MELD) score, but the available information is limited. The present study was undertaken to study the clinical use of the serum sodium incorporated MELD (MELD-Na) and assess its validity by the concordance (c)-statistics in predicting the prognosis of the patient with chronic severe hepatitis B. Methods A total of 426 adult patients with a diagnosis of chronic severe hepatitis B between January 1, 2007, and December 31, 2007 at a single center were studied. The scores of serum sodium, MELD, MELD-Na, and △MELD-Na (△MELD-Na=MELD-Na at 14 days after medical treatment -MELD-Na score on admission) of the patients with chronic severe hepatitis B were calculated. The 3-month mortality in the patients was measured, and the validity of the models was determined by means of the concordance (c) statistics.Results The average MELD, MELD-Na scores of survival group were 25.70±5.08 and 26.60±6.90.and those of dead group were 35.60±6.78 and 42.80±9.57 on admission.There was a significant difference in MELD and MELD-Na between the survivaI and dead groups(P40 were 2.O%,5.4%,35.4%,53.8%and 86.9%,respectively.There was a significant difference in the 3-ionth mortality between the five groups(P0 group Was 65.9%.and that of the △MELD-Na≤0 group Was 15.8%;there Was a significant difference in the 3-month mortality between the twogroups(P<0.05).Conclusions MELD-Na score is a valid model to predict the 3-month mortality in paUents with chronic severe hepatitis B.△MELD-Na is a clinically useful parameter for predicting the therapeutic effect of chronic severe hepatitisB.

  16. Multivariate profiling of neurodegeneration-associated changes in a subcellular compartment of neurons via image processing

    Directory of Open Access Journals (Sweden)

    Kumarasamy Saravana K

    2008-11-01

    differentiates all three bchs phenotypes (loss of function as well as overexpression from the wild type. Conclusion Our model demonstrates that neurodegeneration-associated endolysosomal defects can be detected, analyzed, and classified rapidly and accurately as a diagnostic imaging-based screening tool.

  17. Re-evaluation of metal bioaccumulation and chronic toxicity in Hyalella azteca using saturation curves and the biotic ligand model

    Energy Technology Data Exchange (ETDEWEB)

    Borgmann, U.; Norwood, W.P.; Dixon, D.G

    2004-10-01

    Bioaccumulation by Hyalella of all metals studied so far in our laboratory was re-evaluated to determine if the data could be explained satisfactorily using saturation models. Saturation kinetics are predicted by the biotic ligand model (BLM), now widely used in modelling acute toxicity, and are a pre-requisite if the BLM is to be applied to chronic toxicity. Saturation models provided a good fit to all the data. Since these are mechanistically based, they provide additional insights into metal accumulation mechanisms not immediately apparent when using allometric models. For example, maximum Cd accumulation is dependent on the hardness of the water to which Hyalella are acclimated. The BLM may need to be modified when applied to chronic toxicity. Use of saturation models for bioaccumulation, however, also necessitates the need for using saturation models for dose-response relationships in order to produce unambiguous estimates of LC50 values based on water and body concentrations. This affects predictions of toxicity at very low metal concentrations and results in lower predicted toxicity of mixtures when many metals are present at low concentrations.

  18. Memory and brain-derived neurotrophic factor after subchronic or chronic amphetamine treatment in an animal model of mania.

    Science.gov (United States)

    Fries, Gabriel R; Valvassori, Samira S; Bock, Hugo; Stertz, Laura; Magalhães, Pedro Vieira da Silva; Mariot, Edimilson; Varela, Roger B; Kauer-Sant'Anna, Marcia; Quevedo, João; Kapczinski, Flávio; Saraiva-Pereira, Maria Luiza

    2015-09-01

    Progression of bipolar disorder (BD) has been associated with cognitive impairment and changes in neuroplasticity, including a decrease in serum brain-derived neurotrophic factor (BDNF). However, no study could examine BDNF levels directly in different brain regions after repeated mood episodes to date. The proposed animal model was designed to mimic several manic episodes and evaluate whether the performance in memory tasks and BDNF levels in hippocampus, prefrontal cortex, and amygdala would change after repeated amphetamine (AMPH) exposure. Adult male Wistar rats were divided into subchronic (AMPH for 7 days) and chronic groups (35 days), mimicking manic episodes at early and late stages of BD, respectively. After open field habituation or inhibitory avoidance test, rats were killed, brain regions were isolated, and BDNF mRNA and protein levels were measured by quantitative real-time PCR and ELISA, respectively. AMPH impaired habituation memory in both subchronic and chronic groups, and the impairment was worse in the chronic group. This was accompanied by increased Bdnf mRNA levels in the prefrontal cortex and amygdala region, as well as reduced BDNF protein in the hippocampus. In the inhibitory avoidance, AMPH significantly decreased the change from training to test when compared to saline. No difference was observed between subchronic and chronic groups, although chronically AMPH-treated rats presented increased Bdnf mRNA levels and decreased protein levels in hippocampus when compared to the subchronic group. Our results suggest that the cognitive impairment related to BD neuroprogression may be associated with BDNF alterations in hippocampus, prefrontal cortex, and amygdala. PMID:26026487

  19. Chronic treatment with the GLP1 analogue liraglutide increases cell proliferation and differentiation into neurons in an AD mouse model.

    Directory of Open Access Journals (Sweden)

    Vadivel Parthsarathy

    Full Text Available Neurogenesis is a life long process, but the rate of cell proliferation and differentiation decreases with age. In Alzheimer's patients, along with age, the presence of Aβ in the brain inhibits this process by reducing stem cell proliferation and cell differentiation. GLP-1 is a growth factor that has neuroprotective properties. GLP1 receptors are present on neuronal progenitor cells, and the GLP-1 analogue liraglutide has been shown to increase cell proliferation in an Alzheimer's disease (AD mouse model. Here we investigated acute and chronic effects of liraglutide on progenitor cell proliferation, neuroblast differentiation and their subsequent differentiation into neurons in wild type and APP/PS-1 mice at different ages. APP/PS1 and their littermate controls, aged 3, 6, 12, 15 months were injected acutely or chronically with 25 nmol/kg liraglutide. Acute treatment with liraglutide showed an increase in cell proliferation in APP/PS1 mice, but not in controls whereas chronic treatment increased cell proliferation at all ages (BrdU and Ki67 markers. Moreover, numbers of immature neurons (DCX were increased in both acute and chronic treated animals at all ages. Most newly generated cells differentiated into mature neurons (NeuN marker. A significant increase was observed with chronically treated 6, 12, 15 month APP/PS1 and WT groups. These results demonstrate that liraglutide, which is currently on the market as a treatment for type 2 diabetes (Victoza(TM, increases neurogenesis, which may have beneficial effects in neurodegenerative disorders like AD.

  20. A proposed predictive model for advanced fibrosis in patients with chronic hepatitis B and its validation

    Science.gov (United States)

    Nishikawa, Hiroki; Hasegawa, Kunihiro; Ishii, Akio; Takata, Ryo; Enomoto, Hirayuki; Yoh, Kazunori; Kishino, Kyohei; Shimono, Yoshihiro; Iwata, Yoshinori; Nakano, Chikage; Nishimura, Takashi; Aizawa, Nobuhiro; Sakai, Yoshiyuki; Ikeda, Naoto; Takashima, Tomoyuki; Iijima, Hiroko; Nishiguchi, Shuhei

    2016-01-01

    Abstract We created a predictive model using serum-based biomarkers for advanced fibrosis (F3 or more) in patients with chronic hepatitis B (CHB) and to confirm the accuracy in an independent cohort. A total of 249 CHB patients were analyzed. To achieve our study aim, a training group (n = 125) and a validation group (n = 124) were formed. In the training group, parameters related to the presence of advanced fibrosis in univariate and multivariate analyses were examined, and a formula for advanced fibrosis was created. Next, we verified the applicability of the predictive model in the validation group. Multivariate analysis identified that gamma-glutamyl transpeptidase (GGT, P = 0.0343) and platelet count (P = 0.0034) were significant predictors of the presence of advanced fibrosis, while Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP, P = 0.0741) and hyaluronic acid (P = 0.0916) tended to be significant factors. Using these 4 parameters, we created the following formula: GMPH score = −0.755 − (0.015 × GGT) − (0.268 × WFA+-M2BP) + (0.167 × platelet count) + (0.003 × hyaluronic acid). In 8 analyzed variables (WFA+-M2BP, aspartate aminotransferase-to-platelet ratio index, FIB-4 index, prothrombin time, platelet count, hyaluronic acid, Forns index, and GMPH score), GMPH score had the highest area under the receiver operating characteristic (AUROC) curve for advanced fibrosis with a value of 0.8064 in the training group and in the validation group, GMPH score also had the highest AUROC (0.7782). In all subgroup analyses of the hepatitis B virus (HBV) status (HB surface antigen quantification, HBV-DNA quantification, and HBe antigen seropositivity), GMPH score in F3 or F4 was significantly lower than that in F0 to F2. In the above mentioned 8 variables, differences between the liver fibrosis stages (F0 to F1 vs F2, F2 vs F3, F3 vs F4, F0 to F1 vs F3, F0 to F1 vs F4, and F2 vs

  1. Clinical Heterogeneity of Atypical Pantothenate Kinase-Associated Neurodegeneration in Koreans

    Directory of Open Access Journals (Sweden)

    Jae-Hyeok Lee

    2016-01-01

    Full Text Available Objective Neurodegeneration with brain iron accumulation (NBIA represents a group of inherited movement disorders characterized by iron accumulation in the basal ganglia. Recent advances have included the identification of new causative genes and highlighted the wide phenotypic variation between and within the specific NBIA subtypes. This study aimed to investigate the current status of NBIA in Korea. Methods We collected genetically confirmed NBIA patients from twelve nationwide referral hospitals and from a review of the literature. We conducted a study to describe the phenotypic and genotypic characteristics of Korean adults with atypical pantothenate kinase-associated neurodegeneration (PKAN. Results Four subtypes of NBIA including PKAN (n = 30, PLA2G6-related neurodegeneration (n = 2, beta-propeller protein-associated neurodegeneration (n = 1, and aceruloplasminemia (n = 1 have been identified in the Korean population. The clinical features of fifteen adults with atypical PKAN included early focal limb dystonia, parkinsonism-predominant feature, oromandibular dystonia, and isolated freezing of gait (FOG. Patients with a higher age of onset tended to present with parkinsonism and FOG. The p.R440P and p.D378G mutations are two major mutations that represent approximately 50% of the mutated alleles. Although there were no specific genotype-phenotype correlations, most patients carrying the p.D378G mutation had a late-onset, atypical form of PKAN. Conclusions We found considerable phenotypic heterogeneity in Korean adults with atypical PKAN. The age of onset may influence the presentation of extrapyramidal symptoms.

  2. Cognitive Functioning in Children with Pantothenate-Kinase-Associated Neurodegeneration Undergoing Deep Brain Stimulation

    Science.gov (United States)

    Mahoney, Rachel; Selway, Richard; Lin, Jean-Pierre

    2011-01-01

    Aim: To examine the cognitive functioning of young people with pantothenate-kinase-associated neurodegeneration (PKAN) after pallidal deep brain stimulation (DBS). PKAN is characterized by progressive generalized dystonia and has historically been associated with cognitive decline. With growing evidence that DBS can improve motor function in…

  3. Total Flavone of Hawthorn Leaf inhibits neuronal apoptosis in brain tissue of rat models of chronic cerebral ischemia

    Institute of Scientific and Technical Information of China (English)

    Tan Rong-fang; Xia Ai-hua; Wu Xiao-guang; Cao Na-na; Li Meng-meng; Zhang Tian-ge; Wang Yi-ru; Yue Zhi-ling

    2014-01-01

    BACKGROUND: Cerebrovascular disease often causes dysfunction of the brain nerve, and nerve cel apoptosis is the important factor of cerebral nerve dysfunction. The excessive expression of c-fos can block the transduction of intracelular signal so that producing some apoptosis-promoting factors, which involve in nerve cel apoptosis process after ischemia injury of brain. Bcl-2 is an inhibited factor. It might to be the key to treat ischemic cerebrovascular disease by inhibiting or reducing the apoptosis of nerve cels after ischemia injury. OBJECTIVE: To investigate the therapeutic effect and mechanism of the Total Flavone of Hawthorn Leaf on chronic cerebral ischemia rats. METHODS: A total of 72 healthy male Sprague-Dawley rats were randomly divided into sham surgery group, model group, Total Flavone of Hawthorn Leaf group and ginkgo leaf group. Permanent bilateral carotid artery ligation was used to prepare chronic cerebral ischemia model in the model group, Total Flavone of Hawthorn Leaf group and ginkgo leaf group. Total Flavone of Hawthorn Leaf group and ginkgo leaf group respectively received 140 mg/kg Total Flavone of Hawthorn Leaf and 12.3 mg/kg ginkgo leaf intragastricaly for 36 days from 36 days after model induction. Model group and sham surgery group received 3.5 mL/kg physiological saline intragastricaly. RESULTS AND CONCLUSION: Compared with the model group, the expression of c-fos protein significantly deceased in the Total Flavone of Hawthorn Leaf group (P 0.05). These data indicated that the protective effect of Total Flavone of Hawthorn Leaf on chronic cerebral ischemia was associated with its inhibition of neuronal apoptosis. Its mechanism of anti-apoptosis might be associated with up-regulating expression of Bcl-2, down-regulating expression of c-fos and decreasing Ca2+ content in brain.

  4. Allogeneic amniotic membrane-derived mesenchymal stromal cell transplantation in a porcine model of chronic myocardial ischemia

    Directory of Open Access Journals (Sweden)

    Kimura M

    2012-01-01

    Full Text Available Introduction. Amniotic membrane contains a multipotential stem cell population and is expected to possess the machinery to regulate immunological reactions. We investigated the safety and efficacy of allogeneic amniotic membrane-derived mesenchymal stromal cell (AMSC transplantation in a porcine model of chronic myocardial ischemia as a preclinical trial. Methods. Porcine AMSCs were isolated from amniotic membranes obtained by cesarean section just before delivery and were cultured to increase their numbers before transplantation. Chronic myocardial ischemia was induced by implantation of an ameroid constrictor around the left circumflex coronary artery. Four weeks after ischemia induction, nine swine were assigned to undergo either allogeneic AMSC transplantation or normal saline injection. Functional analysis was performed by echocardiography, and histological examinations were carried out by immunohistochemistry 4 weeks after AMSC transplantation. Results. Echocardiography demonstrated that left ventricular ejection fraction was significantly improved and left ventricular dilatation was well attenuated 4 weeks after AMSC transplantation. Histological assessment showed a significant reduction in percentage of fibrosis in the AMSC transplantation group. Injected allogeneic green fluorescent protein (GFP-expressing AMSCs were identified in the immunocompetent host heart without the use of any immunosuppressants 4 weeks after transplantation. Immunohistochemistry revealed that GFP colocalized with cardiac troponin T and cardiac troponin I. Conclusions. We have demonstrated that allogeneic AMSC transplantation produced histological and functional improvement in the impaired myocardium in a porcine model of chronic myocardial ischemia. The transplanted allogeneic AMSCs survived without the use of any immunosuppressants and gained cardiac phenotype through either their transdifferentiation or cell fusion.

  5. Histological and In Vivo Microscopic Analysis of the Bone Marrow Microenvironment in a Murine Model of Chronic Myelogenous Leukemia.

    Science.gov (United States)

    Weissenberger, Eva S; Krause, Daniela S

    2016-01-01

    Imaging of the leukemic bone marrow microenvironment, also called the leukemic bone marrow niche, is an essential method to determine and to evaluate the progression of chronic myelogenous leukemia (CML) and other leukemias in murine models. In this chapter we introduce the murine model of CML primarily used in our laboratory by describing blood and bone marrow analysis as well as the method of histological sectioning and immunohistochemistry in combination with various stainings that can help to understand the complex interaction between leukemic cells, their normal hematopoietic counterparts, and the bone marrow microenvironment. We conclude with describing how to image the bone marrow niche using in vivo microscopy. PMID:27581139

  6. Staging of liver fibrosis in chronic hepatitis B patients with a composite predictive model:A comparative study

    Institute of Scientific and Technical Information of China (English)

    2010-01-01

    AIM:To evaluate the efficacy of 6 noninvasive liver fibrosis models and to identify the most valuable model for the prediction of liver fibrosis stage in chronic hepatitis B(CHB) patients.METHODS:Seventy-eight CHB patients were consecutively enrolled in this study.Liver biopsy was performed and blood serum was obtained at admission.Histological diagnosis was made according to the METAVIR system.Significant fibrosis was defined as stage score ≥ 2,severe fibrosis as stage score ≥ 3.The diagnostic accuracy of ...

  7. Etanercept decreases HMGB1 expression in dorsal root ganglion neuron cells in a rat chronic constriction injury model

    OpenAIRE

    WANG, RUI-KE; Zhang, Qin-Qin; PAN, YUN-DAN; Guo, Qu-Lian

    2012-01-01

    In the present study, we examined the effect of etanercept on high mobility group box 1 (HMGB1) expression in dorsal root ganglion (DRG) neuron cells in a rat model of chronic constriction injury (CCI) of the sciatic nerve, with the aim of exploring the molecular mechanism underlying the therapeutic effect of etanercept on sciatica-related nociception and the potential interaction between tumor necrosis factor-α (TNF-α) and HMGB1 in DRG neuron cells. A rat CCI model was employed and the anima...

  8. Maternal epileptic seizure induced by Pentylenetetrazol: Apoptotic neurodegeneration and decreased GABAB1 receptor expression in prenatal rat brain

    Directory of Open Access Journals (Sweden)

    Naseer Muhammad

    2009-06-01

    Full Text Available Abstract Epilepsy is a prominent sign of neurological dysfunction in children with various fetal and maternal deficiencies. However, the detailed mechanism and influences underlying epileptic disorders are still unrevealed. The hippocampal neurons are vulnerable to epilepsy-induced pathologic changes and often manifests as neuronal death. The present study was designed to investigate the effect of maternal epileptic seizure on apoptotic neuronal death, modulation of GABAB1 receptor (R, and protein kinase A-α (PKA in prenatal rat hippocampal neurons at gestational days (GD 17.5. Seizure was induced in pregnant rat using intraperitoneal injection of pentylenetetrazol (PTZ (40 mg/kg for 15 days. To confirm the seizure electroencephalography (EEG data was obtained by the Laxtha EEG-monitoring device in the EEG recording room and EEG were monitored 5 min and 15 min after PTZ injection. The RT-PCR and Western blot results showed significant increased expression of cytochrome-c and caspases-3, while decreased levels of GABAB1R, and PKA protein expression upon ethanol, PTZ and ethanol plus PTZ exposure in primary neuronal cells cultured from PTZ-induced seizure model as compare to non-PTZ treated maternal group. Apoptotic neurodegeneration was further confirmed with Fluoro-Jade B and propidium iodide staining, where neurons were scattered and shrunken, with markedly condensed nuclei in PTZ treated group compared with control. This study for the first time indicate that PTZ-induced seizures triggered activation of caspases-3 to induce widespread apoptotic neuronal death and decreased GABAB1R expression in hippocampal neurons, providing a possible mechanistic link between maternal epilepsy induced neurodegeneration alteration of GABAB1R and PKA expression level during prenatal brain development. This revealed new aspects of PTZ and ethanol's modulation on GABAB1R, learning and memory. Further, explain the possibility that children delivered by epileptic

  9. Improving Population Health by Incorporating Chronic Disease and Injury Prevention Into Value-Based Care Models.

    Science.gov (United States)

    Petersen, Ruth; Rushing, Jill; Nelson, Sharon; Rhyne, Sharon

    2016-01-01

    Today's health system transformation provides a prime opportunity to leverage the capacity of public health to reduce the burden of chronic disease and injury, improve population health, and contain health care costs. Health care settings and organizations should support public health capacity as a key investment in population health. PMID:27422946

  10. A Model of Self-Regulation for Control of Chronic Disease

    Science.gov (United States)

    Clark, Noreen M.; Gong, Molly; Kaciroti, Niko

    2014-01-01

    Chronic disease poses increasing threat to individual and community health. The day-to-day manager of disease is the patient who undertakes actions with the guidance of a clinician. The ability of the patient to control the illness through an effective therapeutic plan is significantly influenced by social and behavioral factors. This article…

  11. The ideal epidemiological intervention study model on chronic non-infectious diseases - the way forward?

    DEFF Research Database (Denmark)

    Jensen, Olaf Chresten

    Introduction Intervention studies in public- and occupational health on chronic non-infectious diseases have been increasingly used. Also in the maritime health area, intervention studies have been done and some are on the way. The intervention methods are most often counselling or education...

  12. Chronic Spinal Compression Model in Minipigs: A Systematic Behavioral, Qualitative, and Quantitative Neuropathological Study

    Czech Academy of Sciences Publication Activity Database

    Navarro, R.; Juhás, Štefan; Keshavarzi, S.; Juhásová, Jana; Motlík, Jan; Johe, K.; Marsala, S.; Scadeng, M.; Lazar, P.; Tomori, Z.; Schulteis, G.; Beattie, M.; Ciacci, J. D.; Marsala, M.

    2012-01-01

    Roč. 29, č. 3 (2012), s. 499-513. ISSN 0897-7151 R&D Projects: GA MŠk 1M0538; GA TA ČR TA01011466 Institutional research plan: CEZ:AV0Z50450515 Keywords : axonal loss * chronic spinal injury * minipig Subject RIV: FH - Neurology Impact factor: 4.295, year: 2012

  13. Differential Effects of Treatments for Chronic Depression: A Latent Growth Model Reanalysis

    Science.gov (United States)

    Stulz, Niklaus; Thase, Michael E.; Klein, Daniel N.; Manber, Rachel; Crits-Christoph, Paul

    2010-01-01

    Objective: Psychotherapy-pharmacotherapy combinations are frequently recommended for the treatment of chronic depressive disorders. Our aim in this novel reanalysis of archival data was to identify patient subgroups on the basis of symptom trajectories and examine the clinical significance of the resultant classification on basis of differential…

  14. Low maternal care exacerbates adult stress susceptibility in the chronic mild stress rat model of depression

    DEFF Research Database (Denmark)

    Henningsen, Kim; Dyrvig, Mads; Bouzinova, Elena V;

    2012-01-01

    In the present study we report the finding that the quality of maternal care, in early life, increased the susceptibility to stress exposure in adulthood, when rats were exposed to the chronic mild stress paradigm. Our results indicate that high, as opposed to low maternal care, predisposed rats ...

  15. Fasting reduces liver fibrosis in a mouse model for chronic cholangiopathies

    NARCIS (Netherlands)

    Sokolovic, Aleksandar; van Roomen, Cindy P. A. A.; Ottenhoff, Roelof; Scheij, Saskia; Hiralall, Johan K.; Claessen, Nike; Aten, Jan; Elferink, Ronald P. J. Oude; Groen, Albert K.; Sokolovic, Milka

    2013-01-01

    Chronic cholangiopathies often lead to fibrosis, as a result of a perpetuated wound healing response, characterized by increased inflammation and excessive deposition of proteins of the extracellular matrix. Our previous studies have shown that food deprivation suppresses the immune response, which

  16. Chronic Unpredictable Stress (CUS)-Induced Anxiety and Related Mood Disorders in a Zebrafish Model: Altered Brain Proteome Profile Implicates Mitochondrial Dysfunction

    OpenAIRE

    Sumana Chakravarty; Bommana R Reddy; Sudhakar, Sreesha R.; Sandeep Saxena; Tapatee Das; Vuppalapaty Meghah; Cherukuvada V Brahmendra Swamy; Arvind Kumar; Idris, Mohammed M.

    2013-01-01

    Anxiety and depression are major chronic mood disorders, and the etiopathology for each appears to be repeated exposure to diverse unpredictable stress factors. Most of the studies on anxiety and related mood disorders are performed in rodents, and a good model is chronic unpredictable stress (CUS). In this study, we have attempted to understand the molecular basis of the neuroglial and behavioral changes underlying CUS-induced mood disorders in the simplest vertebrate model, the zebrafish, D...

  17. Progression of Behavioral and CNS Deficits in a Viable Murine Model of Chronic Neuronopathic Gaucher Disease.

    Science.gov (United States)

    Dai, Mei; Liou, Benjamin; Swope, Brittany; Wang, Xiaohong; Zhang, Wujuan; Inskeep, Venette; Grabowski, Gregory A; Sun, Ying; Pan, Dao

    2016-01-01

    To study the neuronal deficits in neuronopathic Gaucher Disease (nGD), the chronological behavioral profiles and the age of onset of brain abnormalities were characterized in a chronic nGD mouse model (9V/null). Progressive accumulation of glucosylceramide (GC) and glucosylsphingosine (GS) in the brain of 9V/null mice were observed at as early as 6 and 3 months of age for GC and GS, respectively. Abnormal accumulation of α-synuclein was present in the 9V/null brain as detected by immunofluorescence and Western blot analysis. In a repeated open-field test, the 9V/null mice (9 months and older) displayed significantly less environmental habituation and spent more time exploring the open-field than age-matched WT group, indicating the onset of short-term spatial memory deficits. In the marble burying test, the 9V/null group had a shorter latency to initiate burying activity at 3 months of age, whereas the latency increased significantly at ≥12 months of age; 9V/null females buried significantly more marbles to completion than the WT group, suggesting an abnormal response to the instinctive behavior and an abnormal activity in non-associative anxiety-like behavior. In the conditional fear test, only the 9V/null males exhibited a significant decrease in response to contextual fear, but both genders showed less response to auditory-cued fear compared to age- and gender-matched WT at 12 months of age. These results indicate hippocampus-related emotional memory defects. Abnormal gait emerged in 9V/null mice with wider front-paw and hind-paw widths, as well as longer stride in a gender-dependent manner with different ages of onset. Significantly higher liver- and spleen-to-body weight ratios were detected in 9V/null mice with different ages of onsets. These data provide temporal evaluation of neurobehavioral dysfunctions and brain pathology in 9V/null mice that can be used for experimental designs to evaluate novel therapies for nGD. PMID:27598339

  18. Protective effects of quercetine on the neuronal injury in frontal cortex after chronic toluene exposure.

    Science.gov (United States)

    Kanter, Mehmet

    2013-08-01

    The aim of this study was designed to evaluate the possible protective effects of quercetine (QE) on the neuronal injury in the frontal cortex after chronic toluene exposure in rats. The rats were randomly allotted into one of the three experimental groups, namely, groups A (control), B (toluene treated) and C (toluene-treated with QE), where each group contains 10 animals. Control group received 1 ml of normal saline solution, and toluene treatment was performed by the inhalation of 3000 ppm toluene in an 8-h/day and 6-day/week order for 12 weeks. The rats in QE-treated group was given QE (15 mg/kg body weight) once a day intraperitoneally for 12 weeks, starting just after toluene exposure. Tissue samples were obtained for histopathological investigation. To date, no histopathological changes of neurodegeneration in the frontal cortex after chronic toluene exposure in rats by QE treatment have been reported. In this study, the morphology of neurons in the QE treatment group was well protected. Chronic toluene exposure caused severe degenerative changes, shrunken cytoplasm and extensively dark picnotic nuclei in neurons of the frontal cortex. We conclude that QE therapy causes morphologic improvement in neurodegeneration of frontal cortex after chronic toluene exposure in rats. We believe that further preclinical research into the utility of QE may indicate its usefulness as a potential treatment on neurodegeneration after chronic toluene exposure in rats. PMID:22252859

  19. Describing and analysing primary health care system support for chronic illness care in Indigenous communities in Australia's Northern Territory – use of the Chronic Care Model

    OpenAIRE

    Stewart Allison; Dowden Michelle; Robinson Gary; Cunningham Joan; Bailie Ross; Si Damin; Connors Christine; Weeramanthri Tarun

    2008-01-01

    Abstract Background Indigenous Australians experience disproportionately high prevalence of, and morbidity and mortality from chronic illness such as diabetes, renal disease and cardiovascular disease. Improving the understanding of how Indigenous primary care systems are organised to deliver chronic illness care will inform efforts to improve the quality of care for Indigenous people. Methods This cross-sectional study was conducted in 12 Indigenous communities in Australia's Northern Territ...

  20. Effect of nuclear factor antisense oligonucleotide on cardiac muscle myosin isoenzymes and cytokines in rat models of chronic heart failure

    International Nuclear Information System (INIS)

    Objective: To investigate the effect of nuclear factor kappa B (NF-κB) antisense oligonucleotide (AS-ON) on cardiac muscle myosin isoenzymes (MI) and serum cytokines (TNF-α, IL-1β, Fas) expressions in rat models of chronic heart failure. Methods: Wistar rat models of chronic heart failure were prepared with abdominal aorta constriction. Half of the models were treated with intrapericardial injection of 0.5ml AS-ON at the time of model preparation. Control rats were given intrapericardial injection of normal saline. Non-invasive echocardiographic study or invasive hemodynamic studies with sacrifice of the animal and procurement of left ventricular cardiac muscle for examination of myosin isoenzymes with SDS-PAGE were performed on 10 models each eveny two weeks until six months after establishment of the models. Inner canthus blood aspiration for determination of serum cytokines (TNF -α and IL-1β with RIA and Fas with ELISA) were done at the same time. Results: In the models without AS-ON treatment, cardiac function was deterioated somewhat at 3 months and frank cardiac failure was apparent at 6 months. In the AS-OD treated models, carbiac function parameters were much better, with lower TNF-α, IL-1β and Fas levels as well as less V1→V3 shift in myosin isoenzymes. Conclusion: Intrapericardial injection of AS-ON was of great benefit in prevention of development of cardiac failure in the rat models with abdominal aorta constriction, probably throngh maintainence of normal cytokines network as well as inbibition of V1 →V3 shift of myosin isoenzymes. (authors)

  1. A Development of Domestic Food Chain Model Data for Chronic Effect Estimation of Off-site Consequence Analysis

    International Nuclear Information System (INIS)

    The FCM includes complex transport phenomena of radiation materials on a biokinetic system of contaminated environments. An estimation of chronic health effects is a key part of the level 3 PSA (Probabilistic Safety Assessment), which depends on the FCM estimation from contaminated foods ingestion. A cultural ingestion habit of a local region and agricultural productions are different to the general features over worldwide scale or case by case. This is a reason to develop a domestic FCM data for the level 3 PSA. However, a generation of the specific FCM data is a complex process and under a large degree of uncertainty due to inherent biokinetic models. As a preliminary study, the present study focuses on an infrastructure development to generation of a specific FCM data. During this process, the features of FCM data to generate a domestic FCM data were investigated. Based on the insights obtained from this process, a specific domestic FCM data was developed. The present study was developed a domestic FCM data to estimate the chronic health effects of off-site consequence analysis. From this study, an insight was obtained, that a domestic FCM data is roughly 20 times higher than the MACCS2 defaults data. Based on this observation, it is clear that the specific chronic health effects of a domestic plant site should be considered in the off-site consequence analysis

  2. An experimental model for chronic compression of dorsal root ganglion produced by intervertebral foramen stenosis in the rat.

    Science.gov (United States)

    Hu, S J; Xing, J L

    1998-07-01

    Under anesthesia and sterile surgery, a small stainless steel rod (4 mm in length and 0.5-0.8 mm in diameter) was inserted into the L5 intervertebral foramen in the rat, developing intervertebral foramen stenosis and hence producing a chronic steady compression of the dorsal root ganglion (DRG). The hind paw on the injured side exhibited a significant reduction in the latency of foot withdrawal to noxious heat and manifested a persistent heat hyperalgesia 5-35 days after surgery. Injection of 1% carrageenan into the intervertebral foramen, presumably causing inflammation of the DRG, also produced hyperalgesia to heat on the hind paw of the injured side 5-21 days after surgery. Extracellular electrophysiological recordings from myelinated dorsal root fibers were performed in vivo. Spontaneous activity was present in 21.5% of the fibers recorded from DRG neurons injured with chronic compression in contrast to 1.98% from uninjured DRG neurons. The pattern of spontaneous activity was periodic and bursting in 75.3% of the spontaneously active fibers. These neurons had a greatly enhanced sensitivity to mechanical stimulation of the injured DRG and a prolonged after discharge. In response to TEA, topically applied to the DRG, excitatory responses were evoked in the injured, but not the uninjured, DRG neurons. Application of this experimental model may further our understanding of the neural mechanisms by which chronic compression of DRG induces low back pain and sciatica. PMID:9755014

  3. Mesenchymal stem cells and serelaxin synergistically abrogate established airway fibrosis in an experimental model of chronic allergic airways disease.

    Science.gov (United States)

    Royce, Simon G; Shen, Matthew; Patel, Krupesh P; Huuskes, Brooke M; Ricardo, Sharon D; Samuel, Chrishan S

    2015-11-01

    This study determined if the anti-fibrotic drug, serelaxin (RLN), could augment human bone marrow-derived mesenchymal stem cell (MSC)-mediated reversal of airway remodeling and airway hyperresponsiveness (AHR) associated with chronic allergic airways disease (AAD/asthma). Female Balb/c mice subjected to the 9-week model of ovalbumin (OVA)-induced chronic AAD were either untreated or treated with MSCs alone, RLN alone or both combined from weeks 9-11. Changes in airway inflammation (AI), epithelial thickness, goblet cell metaplasia, transforming growth factor (TGF)-β1 expression, myofibroblast differentiation, subepithelial and total lung collagen deposition, matrix metalloproteinase (MMP) expression, and AHR were then assessed. MSCs alone modestly reversed OVA-induced subepithelial and total collagen deposition, and increased MMP-9 levels above that induced by OVA alone (all p<0.05 vs OVA group). RLN alone more broadly reversed OVA-induced epithelial thickening, TGF-β1 expression, myofibroblast differentiation, airway fibrosis and AHR (all p<0.05 vs OVA group). Combination treatment further reversed OVA-induced AI and airway/lung fibrosis compared to either treatment alone (all p<0.05 vs either treatment alone), and further increased MMP-9 levels. RLN appeared to enhance the therapeutic effects of MSCs in a chronic disease setting; most likely a consequence of the ability of RLN to limit TGF-β1-induced matrix synthesis complemented by the MMP-promoting effects of MSCs. PMID:26426509

  4. A Development of Domestic Food Chain Model Data for Chronic Effect Estimation of Off-site Consequence Analysis

    Energy Technology Data Exchange (ETDEWEB)

    Han, Seok-Jung; KEUM, Dong-Kwon; Jang, Seung-Cheol [KAERI, Daejeon (Korea, Republic of)

    2015-05-15

    The FCM includes complex transport phenomena of radiation materials on a biokinetic system of contaminated environments. An estimation of chronic health effects is a key part of the level 3 PSA (Probabilistic Safety Assessment), which depends on the FCM estimation from contaminated foods ingestion. A cultural ingestion habit of a local region and agricultural productions are different to the general features over worldwide scale or case by case. This is a reason to develop a domestic FCM data for the level 3 PSA. However, a generation of the specific FCM data is a complex process and under a large degree of uncertainty due to inherent biokinetic models. As a preliminary study, the present study focuses on an infrastructure development to generation of a specific FCM data. During this process, the features of FCM data to generate a domestic FCM data were investigated. Based on the insights obtained from this process, a specific domestic FCM data was developed. The present study was developed a domestic FCM data to estimate the chronic health effects of off-site consequence analysis. From this study, an insight was obtained, that a domestic FCM data is roughly 20 times higher than the MACCS2 defaults data. Based on this observation, it is clear that the specific chronic health effects of a domestic plant site should be considered in the off-site consequence analysis.

  5. A Novel Closed-Chest Porcine Model of Chronic Ischemic Heart Failure Suitable for Experimental Research in Cardiovascular Disease

    Directory of Open Access Journals (Sweden)

    Giuseppe Biondi-Zoccai

    2013-01-01

    Full Text Available Cardiac pathologies are among the leading causes of mortality and morbidity in industrialized countries, with myocardial infarction (MI representing one of the major conditions leading to heart failure (HF. Hitherto, the development of consistent, stable, and reproducible models of closed-chest MI in large animals, meeting the clinical realism of a patient with HF subsequent to chronic ischemic necrosis, has not been successful. We hereby report the design and ensuing application of a novel porcine experimental model of closed-chest chronic ischemia suitable for biomedical research, mimicking post-MI HF. We also emphasize the key procedural steps involved in replicating this unprecedented model, from femoral artery and vein catheterization to MI induction by permanent occlusion of the left anterior descending coronary artery through superselective deployment of platinum-nylon coils, as well as endomyocardial biopsy sampling for histologic analysis and cell harvesting. Our model could indeed represent a valuable contribution and tool for translational research, providing precious insights to understand and overcome the many hurdles concerning, and currently quenching, the preclinical steps mandatory for the clinical translation of new cardiovascular technologies for personalized HF treatments.

  6. Applications of mathematical modeling in managing the spread of chronic wasting disease (CWD) in wild deer under alternative harvesting scenarios.

    Science.gov (United States)

    Al-Arydah, M; Croteau, M C; Oraby, T; Smith, R J; Krewski, D

    2016-01-01

    The application of a recently developed mathematical model for predicting the spread of chronic wasting disease (CWD) in wild deer was assessed under different scenarios where harvesting is employed in disease management. A process-based mathematical model for CWD transmission in wild deer populations was recently developed and parameterized by Al-arydah et al. (2011) to provide a scientific basis for understanding the factors that affect spread of CWD and evaluate concomitant disease-control strategies. The impact of gender on CWD transmission was shown to have a significant influence on the spread of the disease in the wild. Our model demonstrates a range of harvesting rates in which CWD is controlled and deer populations survive. However, if harvesting rates are too low, the disease remains endemic for decades. Conversely, the Canadian deer population is eradicated if harvesting rates are excessive. Future investigation includes building the model to assess the spread of CWD under different disease-management scenarios. PMID:27556563

  7. Ascending central canal dilation and progressive ependymal disruption in a contusion model of rodent chronic spinal cord injury

    Directory of Open Access Journals (Sweden)

    Keirstead Hans S

    2007-09-01

    Full Text Available Abstract Background Chronic spinal cord injury (SCI can lead to an insidious decline in motor and sensory function in individuals even years after the initial injury and is accompanied by a slow and progressive cytoarchitectural destruction. At present, no pathological mechanisms satisfactorily explain the ongoing degeneration. Methods Adult female Sprague-Dawley rats were anesthetized laminectomized at T10 and received spinal cord contusion injuries with a force of 250 kilodynes using an Infinite Horizon Impactor. Animals were randomly distributed into 5 groups and killed 1 (n = 4, 28 (n = 4, 120 (n = 4, 450 (n = 5, or 540 (n = 5 days after injury. Morphometric and immunohistochemical studies were then performed on 1 mm block sections, 6 mm cranial and 6 mm caudal to the lesion epicenter. The SPSS 11.5 t test was used to determine differences between quantitative measures. Results Here, we document the first report of an ascending central canal dilation and progressive ependymal disruption cranial to the epicenter of injury in a contusion model of chronic SCI, which was characterized by extensive dural fibrosis and intraparenchymal cystic cavitation. Expansion of the central canal lumen beyond a critical diameter corresponded with ependymal cell ciliary loss, an empirically predictable thinning of the ependymal region, and a decrease in cell proliferation in the ependymal region. Large, aneurysmal dilations of the central canal were accompanied by disruptions in the ependymal layer, periependymal edema and gliosis, and destruction of the adjacent neuropil. Conclusion Cells of the ependymal region play an important role in CSF homeostasis, cellular signaling and wound repair in the spinal cord. The possible effects of this ascending pathology on ependymal function are discussed. Our studies suggest central canal dilation and ependymal region disruption as steps in the pathogenesis of chronic SCI, identify central canal dilation as a marker of

  8. Combinational chelation therapy abrogates lead-induced neurodegeneration in rats

    International Nuclear Information System (INIS)

    Lead, a ubiquitous and potent neurotoxicant causes oxidative stress which leads to numerous neurobehavioral and physiological alterations. The ability of lead to bind sulfhydryl groups or compete with calcium could be one of the reasons for its debilitating effects. In the present study, we addressed: i) if chelation therapy could circumvent the altered oxidative stress and prevent neuronal apoptosis in chronic lead-intoxicated rats, ii) whether chelation therapy could reverse biochemical and behavioral changes, and iii) if mono or combinational therapy with captopril (an antioxidant) and thiol chelating agents (DMSA/MiADMSA) is more effective than individual thiol chelator in lead-exposed rats. Results indicated that lead caused a significant increase in reactive oxygen species, nitric oxide, and intracellular free calcium levels along with altered behavioral abnormalities in locomotor activity, exploratory behavior, learning, and memory that were supported by changes in neurotransmitter levels. A fall in membrane potential, release of cytochrome c, and DNA damage indicated mitochondrial-dependent apoptosis. Most of these alterations showed significant recovery following combined therapy with captopril with MiADMSA and to a smaller extend with captopril + DMSA over monotherapy with these chelators. It could be concluded from our present results that co-administration of a potent antioxidant (like captopril) might be a better treatment protocol than monotherapy to counter lead-induced oxidative stress. The major highlight of the work is an interesting experimental evidence of the efficacy of combinational therapy using an antioxidant with a thiol chelator in reversing neurological dystrophy caused due to chronic lead exposure in rats.

  9. Developing an active implementation model for a chronic disease management program

    OpenAIRE

    Smidth, Margrethe; Christensen, Morten Bondo; Olesen, Frede; Vedsted, Peter

    2013-01-01

    Background Introduction and diffusion of new disease management programs in healthcare is usually slow, but active theory-driven implementation seems to outperform other implementation strategies. However, we have only scarce evidence on the feasibility and real effect of such strategies in complex primary care settings where municipalities, general practitioners and hospitals should work together. The Central Denmark Region recently implemented a disease management program for chronic obstru...

  10. Characterization of a Dexamethasone-Immunosuppressed C57BL/6N Mouse Model for Chronic Cryptosporidiosis

    OpenAIRE

    Martin, Edward G.

    1993-01-01

    Cryptosporidium parvum is a coccidian protozoan that colonizes epithelial cells lining respiratory and digestive tracts of animals and humans. Cryptosporidiosis is a well-recognized zoonotic disease infecting primarily neonates and immunocompromised hosts, including human immunodeficiency virus-infected patients. Clinical disease is manifested as a chronic diarrheal illness that is self-limiting in immunocompetent hosts and prolonged and often life-threatening in hosts with compromised immune...

  11. Bidirectional Relationship between Chronic Kidney Disease and Periodontal Disease: Structural Equation Modeling

    OpenAIRE

    Fisher, Monica A; Taylor, George W.; West, Brady T.; McCarthy, Ellen T.

    2010-01-01

    Periodontal disease is associated with diabetes, heart disease, and chronic kidney disease (CKD), an effect postulated to be due in part to endovascular inflammation. While a bidirectional relationship between CKD and periodontal disease is plausible, it has not been previously reported in the literature. Over 11 200 adults 18 years or older were identified in the Third National Health and Nutrition Examination Survey. Analyses were conducted in two stages. First, multivariable logistic regre...

  12. Profiling of Differentially Expressed Genes Using Suppression Subtractive Hybridization in an Equine Model of Chronic Asthma

    OpenAIRE

    Lavoie, Jean-Pierre; Lefebvre-Lavoie, Josiane; Leclere, Mathilde; Lavoie-Lamoureux, Anouk; Chamberland, Annie; Laprise, Catherine; Lussier, Jacques

    2012-01-01

    Background Gene expression analyses are used to investigate signaling pathways involved in diseases. In asthma, they have been primarily derived from the analysis of bronchial biopsies harvested from mild to moderate asthmatic subjects and controls. Due to ethical considerations, there is currently limited information on the transcriptome profile of the peripheral lung tissues in asthma. Objective To identify genes contributing to chronic inflammation and remodeling in the peripheral lung tis...

  13. Scalable Modeling of Multivariate Longitudinal Data for Prediction of Chronic Kidney Disease Progression

    OpenAIRE

    Futoma, Joseph; Sendak, Mark; Cameron, C. Blake; Heller, Katherine

    2016-01-01

    Prediction of the future trajectory of a disease is an important challenge for personalized medicine and population health management. However, many complex chronic diseases exhibit large degrees of heterogeneity, and furthermore there is not always a single readily available biomarker to quantify disease severity. Even when such a clinical variable exists, there are often additional related biomarkers routinely measured for patients that may better inform the predictions of their future dise...

  14. Actions of the FAAH inhibitor URB597 in neuropathic and inflammatory chronic pain models

    OpenAIRE

    Jayamanne, Angelo; Greenwood, Ruth; Mitchell, Vanessa A; Aslan, Sevda; Piomelli, Daniele; Vaughan, Christopher W

    2005-01-01

    While cannabinoid receptor agonists have analgesic activity in chronic pain states, they produce a spectrum of central CB1 receptor-mediated motor and psychotropic side effects. The actions of endocannabinoids, such as anandamide are terminated by removal from the extracellular space, then subsequent enzymatic degradation by fatty-acid amide hydrolase (FAAH). In the present study, we compared the effect of a selective FAAH inhibitor, URB597, to that of a pan-cannabinoid receptor agonist HU210...

  15. Altered colonic function and microbiota profile in a mouse model of chronic depression

    OpenAIRE

    Park, A J; Collins, J.; BLENNERHASSETT, P. A.; Ghia, J E; Verdu, E. F.; Bercik, P; COLLINS, S. M.

    2013-01-01

    Background Depression often coexists with the irritable bowel syndrome (IBS) which is characterized by alterations in gut function. There is emerging evidence that the microbial composition (microbiota) of the gut is altered in IBS, but the basis for this is poorly understood. The aim of this study was to determine whether the induction of chronic depression results in changes in the colonic function and in its microbial community, and to explore underlying mechanisms. Methods Bilateral olfac...

  16. Peripheral and central alterations in a chronic model of food restriction : role of ghrelin

    OpenAIRE

    Méquinion, Mathieu

    2014-01-01

    Chronic food restriction is one of the major features observed in anorexia nervosa (AN), especially in the restrictive type. This major eating disorder affects mainly teenager girls and young women. Additionally to the restriction behavior, important physical activity is observed in a large number of patients (40-80% of cases). This disease induces various physiological alterations that concern neuroendocrine, metabolic and bone (osteopenia, osteoporosis) pathways, which have dramatic consequ...

  17. Oral lichen planus is a unique disease model for studying chronic inflammation and oral cancer

    OpenAIRE

    Liu, Yi; Messadi, Diana; Wu, Hongkun; Hu, Shen

    2010-01-01

    Oral lichen planus (OLP) is a chronic inflammatory disease, which has been defined by the World Health Organization as a potential precancerous condition, representing a generalized state associated with a significantly increased risk of oral cancer. We would like to put forward a hypothesis that inflammatory mediators such as cytokines and chemokines released from infiltrating T lymphocytes induce fundamental changes of proteins in oral epithelial cells, leading to the progression of OLP to ...

  18. Neural Stem Cell Grafting in an Animal Model of Chronic Temporal Lobe Epilepsy

    OpenAIRE

    Hattiangady, Bharathi; Shetty, Ashok K.

    2011-01-01

    Neural stem cell (NSC) transplantation into the hippocampus could offer an alternative therapy to hippocampal resection in patients with drug-resistant chronic epilepsy, which afflicts ~30% of mesial temporal lobe epilepsy (TLE) cases. Multipotent, self-renewing NSCs could be expanded from multiple regions of the developing and adult brain, human embryonic stem cells (hESCs), induced pluripotent stem cells (iPSCs). However, to provide a comprehensive methodology involved in testing the effica...

  19. Chronic Treatment with Clenbuterol Modulates Endothelial Progenitor Cells and Circulating Factors in a Murine Model of Cardiomyopathy

    OpenAIRE

    Rider, James E.; Polster, Sean P.; Lee, Sangjin; Charles, Nathan J.; Adhikari, Neeta; Mariash, Ami; Tadros, George; Stangland, Jenna; Smolenski, Ryszard T.; Terracciano, Cesare M.; Barton, Paul J R.; Birks, Emma J.; Yacoub, Magdi H; Miller, Leslie W.; Hall, Jennifer L.

    2009-01-01

    The purpose of this study was to determine the effects of chronic treatment with the beta 2 adrenergic receptor agonist clenbuterol on endothelial progenitor cells (EPC) in a well-characterized model of heart failure, the muscle LIM protein knockout (MLP−/−) mouse. MLP−/−mice were treated daily with clenbuterol (2 mg/kg) or saline subcutaneously for 6 weeks. Clenbuterol led to a 30% increase in CD31+ cells in the bone marrow of MLP−/− heart failure mice (p

  20. Stress in Adolescents with a Chronically Ill Parent: Inspiration from Rolland’s Family Systems-Illness Model

    OpenAIRE

    Sieh, D. S.; Dikkers, A. L. C.; Visser-Meily, J. M. A.; Meijer, A.M.

    2012-01-01

    This article was inspired by Rolland’s Family Systems-Illness (FSI) model, aiming to predict adolescent stress as a function of parental illness type. Ninety-nine parents with a chronic medical condition, 82 partners, and 158 adolescent children (51 % girls; mean age = 15.1 years) participated in this Dutch study. The Dutch Stress Questionnaire for Children was used to measure child report of stress. Ill parents completed the Beck Depression Inventory. Children filled in a scale of the Invent...

  1. Impairment of cognitive function and reduced hippocampal cholinergic activity in a rat model of chronic intermittent hypoxia

    Institute of Scientific and Technical Information of China (English)

    Chunling Zhao; Yan Chen; Chunlai Zhang; Linya Lü; Qian Xu

    2011-01-01

    The present study established a rat model of chronic intermittent hypoxia (CIH) to simulate obstructive sleep apnea syndrome. CIH rats were evaluated for cognitive function using the Morris water maze, and neuronal pathology in the hippocampus was observed using hematoxylin-eosin staining. In addition, hippocampal choline acetyl transferase (ChAT) and nicotinic acetylcholine receptor (nAChR) expression was determined by immunohistochemistry. Our results revealed necrotic hippocampal neurons, decreased ChAT and nAChR expression, as well as cognitive impairment in CIH rats. These results suggest that hippocampal neuronal necrosis and decreased cholinergic activity may be involved in CIH-induced cognitive impairment in rats.

  2. Synergistic Effects of Celecoxib and Bupropion in a Model of Chronic Inflammation-Related Depression in Mice

    OpenAIRE

    Maciel, Izaque S; Silva, Rodrigo B. M.; Morrone, Fernanda B; João B Calixto; Campos, Maria M

    2013-01-01

    This study was aimed to characterize the depression-like behaviour in the classical model of chronic inflammation induced by Complete Freund's Adjuvant (CFA). Male Swiss mice received an intraplantar (i.pl.) injection of CFA (50 µl/paw) or vehicle. Behavioural and inflammatory responses were measured at different time-points (1 to 4 weeks), and different pharmacological tools were tested. The brain levels of IL-1β and BDNF, or COX-2 expression were also determined. CFA elicited a time-depende...

  3. Total Lignans of Schisandra chinensis Ameliorates Aβ1-42-Induced Neurodegeneration with Cognitive Impairment in Mice and Primary Mouse Neuronal Cells.

    Science.gov (United States)

    Zhao, Xu; Liu, Chunmei; Xu, Mengjie; Li, Xiaolong; Bi, Kaishun; Jia, Ying

    2016-01-01

    Lignan compounds extracted from Schisandra chinensis (Turcz.) Baill. have been reported to possess various biological activities, and have potential in the treatment of Alzheimer's disease. This study was designed to investigate the effects of total lignans of Schisandra chinensis (TLS) on cognitive function and neurodegeneration in the model of AD induced by Aβ1-42 in vivo and in vitro. It was found that intragastric infusion with TLS (50 and 200 mg/kg) to Aβ1-42-induced mice significantly increased the number of avoidances in the shuttle-box test and swimming time in the target quadrant in the Morris water maze test. TLS at dose of 200 mg/kg significantly restored the activities of total antioxidant capacity (T-AOC), as well as the level of malondialdehyde (MDA) both in the hippocampus and cerebral cortex in mice. Results of histopathological examination indicated that TLS noticeably ameliorated the neurodegeneration in the hippocampus in mice. On the other hand, TLS (100 μM) could protect the Aβ1-42-induced primary mouse neuronal cells by blocking the decrease of mitochondrial membrane potential (MMP), change the expressions of Bcl-2 (important regulator in the mitochondria apoptosis pathway). Moreover, TLS also decreased the activity of β-secretase 1 (BACE1), crucial protease contributes to the hydrolysis of amyloid precursor protein (APP), and inhibited the expression of JKN/p38, which involved in the MAPKs signaling pathways in both mice and primary mouse neuronal cells. In summary, TLS might protect against cognitive deficits and neurodegeneration by releasing the damage of oxidative stress, inhibiting the expression of BACE1 and the MAPKs inflammatory signaling pathways. PMID:27035824

  4. Total Lignans of Schisandra chinensis Ameliorates Aβ1-42-Induced Neurodegeneration with Cognitive Impairment in Mice and Primary Mouse Neuronal Cells.

    Directory of Open Access Journals (Sweden)

    Xu Zhao

    Full Text Available Lignan compounds extracted from Schisandra chinensis (Turcz. Baill. have been reported to possess various biological activities, and have potential in the treatment of Alzheimer's disease. This study was designed to investigate the effects of total lignans of Schisandra chinensis (TLS on cognitive function and neurodegeneration in the model of AD induced by Aβ1-42 in vivo and in vitro. It was found that intragastric infusion with TLS (50 and 200 mg/kg to Aβ1-42-induced mice significantly increased the number of avoidances in the shuttle-box test and swimming time in the target quadrant in the Morris water maze test. TLS at dose of 200 mg/kg significantly restored the activities of total antioxidant capacity (T-AOC, as well as the level of malondialdehyde (MDA both in the hippocampus and cerebral cortex in mice. Results of histopathological examination indicated that TLS noticeably ameliorated the neurodegeneration in the hippocampus in mice. On the other hand, TLS (100 μM could protect the Aβ1-42-induced primary mouse neuronal cells by blocking the decrease of mitochondrial membrane potential (MMP, change the expressions of Bcl-2 (important regulator in the mitochondria apoptosis pathway. Moreover, TLS also decreased the activity of β-secretase 1 (BACE1, crucial protease contributes to the hydrolysis of amyloid precursor protein (APP, and inhibited the expression of JKN/p38, which involved in the MAPKs signaling pathways in both mice and primary mouse neuronal cells. In summary, TLS might protect against cognitive deficits and neurodegeneration by releasing the damage of oxidative stress, inhibiting the expression of BACE1 and the MAPKs inflammatory signaling pathways.

  5. Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann-Pick type C disease in a mouse model.

    Science.gov (United States)

    Alam, Md Suhail; Getz, Michelle; Haldar, Kasturi

    2016-02-17

    Histone deacetylase inhibitors (HDACi) are approved for treating rare cancers and are of interest as potential therapies for neurodegenerative disorders. We evaluated a triple combination formulation (TCF) comprising the pan-HDACi vorinostat, the caging agent 2-hydroxypropyl-β-cyclodextrin (HPBCD), and polyethylene glycol (PEG) for treating a mouse model (the Npc1(nmf164) mouse) of Niemann-Pick type C (NPC) disease, a difficult-to-treat cerebellar disorder. Vorinostat alone showed activity in cultured primary cells derived from Npc1(nmf164) mice but did not improve animal survival. However, low-dose, once-weekly intraperitoneal injections of the TCF containing vorinostat increased histone acetylation in the mouse brain, preserved neurites and Purkinje cells, delayed symptoms of neurodegeneration, and extended mouse life span from 4 to almost 9 months. We demonstrate that the TCF boosted the ability of HDACi to cross the blood-brain barrier and was not toxic even when used long term. Further, the TCF enabled dose reduction, which has been a major challenge in HDACi therapy. TCF simultaneously treats neurodegenerative and systemic symptoms of Niemann-Pick type C disease in a mouse model. PMID:26888431

  6. Role of Ca+2 and other second messengers in excitatory amino acid receptor mediated neurodegeneration: clinical perspectives

    DEFF Research Database (Denmark)

    Schousboe, A; Belhage, B; Frandsen, A

    1997-01-01

    Neurodegeneration associated with neurological disorders such as epilepsy, Huntington's Chorea, Alzheimer's disease, and olivoponto cerebellar atrophy or with energy failure such as ischemia, hypoxia, and hypoglycemia proceeds subsequent to overexposure of neurons to excitatory amino acids of which...

  7. Intrahepatic Transcriptional Signature Associated with Response to Interferon-α Treatment in the Woodchuck Model of Chronic Hepatitis B.

    Directory of Open Access Journals (Sweden)

    Simon P Fletcher

    2015-09-01

    Full Text Available Recombinant interferon-alpha (IFN-α is an approved therapy for chronic hepatitis B (CHB, but the molecular basis of treatment response remains to be determined. The woodchuck model of chronic hepatitis B virus (HBV infection displays many characteristics of human disease and has been extensively used to evaluate antiviral therapeutics. In this study, woodchucks with chronic woodchuck hepatitis virus (WHV infection were treated with recombinant woodchuck IFN-α (wIFN-α or placebo (n = 12/group for 15 weeks. Treatment with wIFN-α strongly reduced viral markers in the serum and liver in a subset of animals, with viral rebound typically being observed following cessation of treatment. To define the intrahepatic cellular and molecular characteristics of the antiviral response to wIFN-α, we characterized the transcriptional profiles of liver biopsies taken from animals (n = 8-12/group at various times during the study. Unexpectedly, this revealed that the antiviral response to treatment did not correlate with intrahepatic induction of the majority of IFN-stimulated genes (ISGs by wIFN-α. Instead, treatment response was associated with the induction of an NK/T cell signature in the liver, as well as an intrahepatic IFN-γ transcriptional response and elevation of liver injury biomarkers. Collectively, these data suggest that NK/T cell cytolytic and non-cytolytic mechanisms mediate the antiviral response to wIFN-α treatment. In summary, by studying recombinant IFN-α in a fully immunocompetent animal model of CHB, we determined that the immunomodulatory effects, but not the direct antiviral activity, of this pleiotropic cytokine are most closely correlated with treatment response. This has important implications for the rational design of new therapeutics for the treatment of CHB.

  8. Determinants of success of coronary angioplasty in patients with a chronic total occlusion: a multiple logistic regression model to improve selection of patients.

    OpenAIRE

    Tan, K H; Sulke, N.; Taub, N A; Watts, E.; Karani, S.; Sowton, E

    1993-01-01

    OBJECTIVE--To study the determinants of success of coronary angioplasty in patients with chronic total occlusions, and to formulate a multiple logistic regression model to improve selection of patients. DESIGN--A retrospective analysis of clinical and angiographic data on a consecutive series of patients. PATIENTS--312 patients (mean age 55, range 31 to 79 years, 86% men) who underwent coronary angioplasty procedure for a chronic total occlusion between 1981 and 1992. RESULTS--Procedural succ...

  9. Comments on Brazilian workshop model for training investigators in chronic graft-versus-host disease according to the 2005-2006 National Institutes of Health recommendations

    OpenAIRE

    Rita de Cássia Barbosa da Silva Tavares; Márcia de Matos Silva; Luis Fernando da Silva Bouzas; Maria Cláudia Rodrigues; Afonso Celso Vigorito; Vaneusa Funke; Marcos Mauad; Maria Elvira Pizzigatti Correa; Clarissa Vasconcellos de Souza; Elenaide Nunes; Alessandra Ferrari; Ariana Paixão; Talita Martins; Érika Pallottino; Mary Evelyn Dantas Flowers

    2011-01-01

    BACKGROUND: The lack of standardization of clinical diagnostic criteria, classification and severity scores of chronic graft-versus-host disease led the National Institutes of Health to propose consensus criteria for the purpose of clinical trials. METHODS: Here we describe a one-day workshop model conducted by the Chronic Graft-versus-Host Disease Brazil-Seattle Consortium Study Group to train investigators interested in participating in multicenter clinical trials in Brazil. Workshop partic...

  10. A comprehensive model of adjustment to pain in the co-occurrence of PTSD and chronic musculoskeletal pain: vulnerability and protective pathways

    OpenAIRE

    Ruíz-Párraga, Gema Teresa; López-Martínez, Alicia; Esteve, Rosa; Ramírez-Maestre, Carmen; Serrano, Elena

    2015-01-01

    There are a significant comorbidity between PTSD and chronic pain. Thus, studies clarifying the vulnerability and protective variables and mechanisms associated with PTSD and chronic pain are needed. The aim of this study was to examine the association between trauma, resilience, PTSD symptoms, and the variables included in the fear-avoidance models (anxiety sensitivity, catastrophizing, fear-avoidance beliefs, fear of pain, pain hypervigilance) as well as pain acceptance and experiential avo...

  11. A unified mathematical model to quantify performance impairment for both chronic sleep restriction and total sleep deprivation.

    Science.gov (United States)

    Rajdev, Pooja; Thorsley, David; Rajaraman, Srinivasan; Rupp, Tracy L; Wesensten, Nancy J; Balkin, Thomas J; Reifman, Jaques

    2013-08-21

    Performance prediction models based on the classical two-process model of sleep regulation are reasonably effective at predicting alertness and neurocognitive performance during total sleep deprivation (TSD). However, during sleep restriction (partial sleep loss) performance predictions based on such models have been found to be less accurate. Because most modern operational environments are predominantly characterized by chronic sleep restriction (CSR) rather than by episodic TSD, the practical utility of this class of models has been limited. To better quantify performance during both CSR and TSD, we developed a unified mathematical model that incorporates extant sleep debt as a function of a known sleep/wake history, with recent history exerting greater influence. This incorporation of sleep/wake history into the classical two-process model captures an individual's capacity to recover during sleep as a function of sleep debt and naturally bridges the continuum from CSR to TSD by reducing to the classical two-process model in the case of TSD. We validated the proposed unified model using psychomotor vigilance task data from three prior studies involving TSD, CSR, and sleep extension. We compared and contrasted the fits, within-study predictions, and across-study predictions from the unified model against predictions generated by two previously published models, and found that the unified model more accurately represented multiple experimental studies and consistently predicted sleep restriction scenarios better than the existing models. In addition, we found that the model parameters obtained by fitting TSD data could be used to predict performance in other sleep restriction scenarios for the same study populations, and vice versa. Furthermore, this model better accounted for the relatively slow recovery process that is known to characterize CSR, as well as the enhanced performance that has been shown to result from sleep banking. PMID:23623949

  12. Antidepressant-Like Effects of Cordycepin in a Mice Model of Chronic Unpredictable Mild Stress

    Directory of Open Access Journals (Sweden)

    Zhang Tianzhu

    2014-01-01

    Full Text Available Cordycepin (3′-deoxyadenosine, a major bioactive component isolated from Cordyceps militaris, has multiple pharmacological activities. This study is attempted to investigate whether cordycepin (COR possesses beneficial effects on chronic unpredictable mild stress- (CUMS- induced behavioral deficits (depression-like behaviors and explore the possible mechanisms. ICR mice were subjected to chronic unpredictable mild stress for 42 consecutive days. Then, COR and fluoxetine (FLU, positive control drug were administered for 21 consecutive days at the last three weeks of CUMS procedure. The classical behavioral tests, open field test (OFT, sucrose preference test (SPT, tail suspension test (TST, and forced swimming test (FST, were applied to evaluate the antidepressant effects of COR. Then the serotonin (5-HT and noradrenaline (NE concentrations in hippocampal were evaluated by HPLC; tumor necrosis factor-α (TNF-α and interleukin-6 (IL-6 in hippocampal were evaluated, and the proteins of TNF-α, IL-6, NF-κBP65 5-HT receptor (5-HTR, and brain-derived neurotrophic factor (BDNF in hippocampal were evaluated by Western blot. Our results indicated that 6 weeks of CUMS exposure induced significant depression-like behavior, with low 5-HT and NE levels, high TNF-α and IL-6 in brain and high hippocampal TNF-α, IL-6, P-NF-κBP65, and 5-HTR levels, and low BDNF expression levels. Whereas, chronic COR (20, 40 mg/kg treatments reversed the behavioral deficiency induced by CUMS exposure, treatment with COR normalized the change of TNF-α, IL-6, 5-HT, and NE levels, which demonstrated that COR could partially restore CUMS-induced 5-HT receptor impairments and inflammation. Besides, hippocampal BDNF expressions were also upregulated after COR treatments. In conclusion, COR remarkably improved depression-like behavior in CUMS mice and its antidepressant activity is mediated, at least in part, by the upregulating BDNF and downregulating 5-HTR levels and

  13. Diaphragm Muscle Remodeling in a Rat Model of Chronic Intermittent Hypoxia

    OpenAIRE

    Shortt, Christine M.; Fredsted, Anne; Bradford, Aidan; O’Halloran, Ken D.

    2013-01-01

    Respiratory muscle remodeling occurs in human sleep apnea—a common respiratory disorder characterized by chronic intermittent hypoxia (CIH) due to recurrent apnea during sleep. We sought to determine if CIH causes remodeling in rat sternohyoid (upper airway dilator) and diaphragm muscles. Adult male Wistar rats were exposed to CIH (n=8), consisting of 90 sec of hypoxia (5% at the nadir; SaO2 ~80%)/90 sec of normoxia, 8 hr per day, for 7 consecutive days. Sham animals (n=8) were exposed to alt...

  14. Clinical challenges of chronic wounds: searching for an optimal animal model to recapitulate their complexity

    OpenAIRE

    Robert Nunan; HARDING, KEITH G.; Paul Martin

    2014-01-01

    The efficient healing of a skin wound is something that most of us take for granted but is essential for surviving day-to-day knocks and cuts, and is absolutely relied on clinically whenever a patient receives surgical intervention. However, the management of a chronic wound – defined as a barrier defect that has not healed in 3 months – has become a major therapeutic challenge throughout the Western world, and it is a problem that will only escalate with the increasing incidence of condition...

  15. Recent developments on models and inclusion criteria for chronic ankle instability

    Institute of Scientific and Technical Information of China (English)

    Songning; Zhang

    2012-01-01

    <正>In the most recent report of injury data on 15 sports from the U.S.National Collegiate Athletic Association(NCAA) Injury Surveillance System over a span of 16 years (1988-2004),ankle ligament sprains were the most common injury.Residual symptoms such as recurrent sprains,pain, instability,and giving way are common after an initial,acute ligament sprain.Chronic ankle instability(CAI) is one of these common problems,and has enjoyed increased interest in the recent literature.However,CAI remains a poorly-defined and understood condition.

  16. Chronic neutropenia. A new canine model induced by human granulocyte colony-stimulating factor.

    OpenAIRE

    Hammond, W. P.; Csiba, E; Canin, A; Hockman, H; Souza, L M; Layton, J E; Dale, D C

    1991-01-01

    Normal dogs were treated with recombinant human granulocyte colony-stimulating factor (rhG-CSF) at 10 micrograms/kg/day for 30 d, which caused an initial neutrophilia, followed by a prolonged period of chronic neutropenia. A control dog treated with recombinant canine G-CSF (rcG-CSF) showed persistent neutrophilia over 3 mo. Serum from dogs during neutropenia contained an antibody to rhG-CSF, which neutralized the stimulatory effects of both rhG-CSF and rcG-CSF on dog marrow neutrophilic prog...

  17. Metallothionein prevents neurodegeneration and central nervous system cell death after treatment with gliotoxin 6-aminonicotinamide

    DEFF Research Database (Denmark)

    Penkowa, Milena; Quintana, Albert; Carrasco, Javier;

    2004-01-01

    Transgenic expression of interleukin-6 (IL-6) in the CNS under the control of the glial fibrillary acidic protein (GFAP) gene promoter (GFAP-IL6 mice) induces significant inflammation and neurodegeneration but also affords neuroprotection against acute traumatic brain injury. This neuroprotection......-IL6 mice crossed with TgMT mice (GFAP-IL6 x TgMT). 6-AN caused acute damage of brainstem gray matter areas identified by necrosis of astrocytes, followed by inflammatory responses. After 6-AN-induced toxicity, secondary damage was observed, consisting of oxidative stress, neurodegeneration, and...... apoptotic cell death. We hereby show that the primary injury caused by 6-AN was comparable in wild-type and GFAP-IL6 mice, but MT-I overexpression could significantly protect the brain tissue. As expected, GFAP-IL6 mice showed increased CNS inflammation with more gliosis, macrophages, and lymphocytes...

  18. Optic Atrophy in a Patient With Atypical Pantothenate Kinase-Associated Neurodegeneration.

    Science.gov (United States)

    Han, Jinu; Kim, Do Wook; Lee, Chul-Ho; Han, Sueng-Han

    2016-06-01

    Pantothenate kinase-associated neurodegeneration (PKAN) is an autosomal recessive neurodegeneration with brain iron accumulation and characterized by extrapyramidal signs, vision loss, and intellectual decline. PKAN is caused by mutations in the PANK2 gene, which codes for a mitochondrial enzyme that phosphorylates vitamin B5 in the first reaction of the coenzyme A biosynthetic pathway. Visual failure in this disorder is typically due to pigmentary retinopathy. Yet our patient, a 13-year-old girl with PKAN, developed bilateral optic atrophy and the appearance of the retina and electroretinography were normal. Optic atrophy is a rare finding in patients with PKAN. It is important for the clinician to consider PKAN in the differential diagnosis of patients presenting with signs of extrapyramidal dysfunction, cognitive decline, and vision loss because of optic atrophy. PMID:26828840

  19. Human embryonic stem cell-derived neurons as a tool for studying neuroprotection and neurodegeneration

    OpenAIRE

    Hardingham, G. E.; Patani, R; Baxter, P.; Wyllie, David; Chandran, S

    2010-01-01

    The capacity to generate myriad differentiated cell types, including neurons, from human embryonic stem (hES) cell lines offers great potential for developing cell-based therapies and also for increasing our understanding of human developmental mechanisms. In addition, the emerging development of this technology as an experimental tool represents a potential opportunity for neuroscientists interested in mechanisms of neuroprotection and neurodegeneration. Potentially unlimited generation of w...

  20. Microglial AGE-Albumin Is Critical in Promoting Alcohol-Induced Neurodegeneration in Rats and Humans

    OpenAIRE

    Byun, Kyunghee; Bayarsaikhan, Delger; Bayarsaikhan, Enkhjargal; Son, Myeongjoo; Oh, Seyeon; Lee, Jaesuk; Son, Hye-in; Won, Moo-Ho; Seung U. Kim; Song, Byoung-Joon; Lee, Bonghee

    2014-01-01

    Alcohol is a neurotoxic agent, since long-term heavy ingestion of alcohol can cause various neural diseases including fetal alcohol syndrome, cerebellar degeneracy and alcoholic dementia. However, the molecular mechanisms of alcohol-induced neurotoxicity are still poorly understood despite numerous studies. Thus, we hypothesized that activated microglial cells with elevated AGE-albumin levels play an important role in promoting alcohol-induced neurodegeneration. Our results revealed that micr...