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Sample records for htlv-1-associated neuroinflammatory disease

  1. Human T-Lymphotropic Virus Type 1 (HTLV-1 and Regulatory T Cells in HTLV-1-Associated Neuroinflammatory Disease

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    Yoshihisa Yamano

    2011-08-01

    Full Text Available Human T-lymphotropic virus type 1 (HTLV-1 is a retrovirus that is the causative agent of adult T cell leukemia/lymphoma (ATL and associated with multiorgan inflammatory disorders, including HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP and uveitis. HTLV-1-infected T cells have been hypothesized to contribute to the development of these disorders, although the precise mechanisms are not well understood. HTLV-1 primarily infects CD4+ T helper (Th cells that play a central role in adaptive immune responses. Based on their functions, patterns of cytokine secretion, and expression of specific transcription factors and chemokine receptors, Th cells that are differentiated from naïve CD4+ T cells are classified into four major lineages: Th1, Th2, Th17, and T regulatory (Treg cells. The CD4+CD25+CCR4+ T cell population, which consists primarily of suppressive T cell subsets, such as the Treg and Th2 subsets in healthy individuals, is the predominant viral reservoir of HTLV-1 in both ATL and HAM/TSP patients. Interestingly, CD4+CD25+CCR4+ T cells become Th1-like cells in HAM/TSP patients, as evidenced by their overproduction of IFN-γ, suggesting that HTLV-1 may intracellularly induce T cell plasticity from Treg to IFN-γ+ T cells. This review examines the recent research into the association between HTLV-1 and Treg cells that has greatly enhanced understanding of the pathogenic mechanisms underlying immune dysregulation in HTLV-1-associated neuroinflammatory disease.

  2. Leukotrienes are upregulated and associated with human T-lymphotropic virus type 1 (HTLV-1-associated neuroinflammatory disease.

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    Bruno Caetano Trindade

    Full Text Available Leukotrienes (LTs are lipid mediators involved in several inflammatory disorders. We investigated the LT pathway in human T-lymphotropic virus type 1 (HTLV-1 infection by evaluating LT levels in HTLV-1-infected patients classified according to the clinical status as asymptomatic carriers (HACs and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP patients. Bioactive LTB(4 and CysLTs were both increased in the plasma and in the supernatant of peripheral blood mononuclear cell cultures of HTLV-1-infected when compared to non-infected. Interestingly, CysLT concentrations were increased in HAM/TSP patients. Also, the concentration of plasma LTB(4 and LTC(4 positively correlated with the HTLV-1 proviral load in HTLV-1-infected individuals. The gene expression levels of LT receptors were differentially modulated in CD4(+ and CD8(+ T cells of HTLV-1-infected patients. Analysis of the overall plasma signature of immune mediators demonstrated that LT and chemokine amounts were elevated during HTLV-1 infection. Importantly, in addition to CysLTs, IP-10 was also identified as a biomarker for HAM/TSP activity. These data suggest that LTs are likely to be associated with HTLV-1 infection and HAM/TSP development, suggesting their putative use for clinical monitoring.

  3. Systemic diseases in patients with HTLV-1-associated uveitis.

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    Nakao, Kumiko; Abematsu, Noriko; Sakamoto, Taiji

    2017-07-08

    Human T-lymphotropic virus type 1 (HTLV-1) carriers may develop severe systemic diseases, such as adult T cell leukaemia (ATL) or HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). This study aims to investigate systemic diseases of HTLV-1 carriers who had developed HTLV-1-associated uveitis (HAU). We investigated the occurrence of systemic diseases in 200 patients with HAU by performing a retrospective investigation of their medical records and examining the results of a postal survey. The mean age of HAU onset was 49 years, and the total person-years from HAU onset was 1627. There were two cases of ATL. Of these, one was diagnosed with smouldering ATL at the time of HAU onset and the other developed acute-type ATL 4 years after HAU onset. There were 26 cases of HAM/TSP; of these, HAM/TSP occurred first in 13 cases and HAU occurred first in 11 cases. The interval between the onset of HAM/TSP and HAU ranged from 6 months to 6 years, with no significant difference observed based on whether HAM/TSP or HAU occurred first. Hyperthyroidism was noted in 45 cases and preceded onset in all cases. HAU onset occurred after starting thiamazole treatment, and in two cases HAU recurred each time thiamazole treatment was restarted. HTLV-1 carriers with HAU may develop HAM/TSP more frequently than general carriers. HTLV-1 carriers undergoing treatment for hyperthyroidism may be prone to developing HAU. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

  4. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP): still an obscure disease.

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    Pillat, Micheli Mainardi; Bauer, Moisés Evandro; de Oliveira, Augusto Cesar Penalva; Ulrich, Henning; Casseb, Jorge

    2011-12-01

    Human T-cell leukemia virus type 1 (HTLV-1) is the ethiologic agent of the neurological disorder HTLV-1- associated myelopathy/tropical spastic paraparesis (HAM/TSP). Although the majority of HTLV-1-infected individuals remain asymptomatic during their lifetime, approximately one percent of this population develops a myelopathy consisting of a chronic inflammation of the white and gray matter of the spinal cord. Glucocorticoids are widely used for treatment because of their anti-inflammatory properties, improving symptoms mainly in those patients with only a few years from onset of the disease, when inflammation is more prominent. Interferon-alpha and vitamin C are other therapies presenting some benefits in clinical practice, probably due to their anti-viral and immunomodulatory activities observed ex vivo. Furthermore, inhibitors of histone deacetylase, which increase virus expression but result in a substantial decline in the proviral load, have also been proposed. This review is intended to bridge the gap between clinical and basic science by presenting recent findings on HAM/TSP disease, mechanisms of drug action, and benefits of these therapies in HAM/TSP patients.

  5. HTLV-1 Associated Neurological Disorders.

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    Khan, Muhammad Yasir; Khan, Ishaq Nasib; Farman, Muhammad; Al Karim, Saleh; Qadri, Ishtiaq; Kamal, Muhammad Amjad; Al Ghamdi, Khalid; Harakeh, Steve

    2017-01-01

    Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus which is endemic to certain regions of the world and infects around 10-20 million people. HTLV-1 is the etiologic agent of Adult T cell leukemia/lymphoma and HTLV-1 associated neurological disorders including mainly HTLV-1 associated myelopathy/Tropical spastic paraparesis. The involvement of the central nervous diseases occurs among: HTLV-1 infected patients from endemic areas, HIV positive individuals and drug users. The ability of HTLV-1 to cause associated neuropathies starts with the virus crossing the blood brain barrier (BBB), then entering and infecting the cells of the central nervous system. As a consequence, to the viral attack, HTLV-1 infected lymphocytes produce pro-inflammatory cytokines like tumor necrosis factor alpha, Interleukin 1 beta and interleukin 6 which further disrupts the BBB. Different serological tests have been used in the diagnosis of HTLV-1. These include: ELISA, Western Blotting (WB), Immunofluorescence, Particle Agglutination and Polymerase Chain Reaction which is used as a confirmatory test. Danazol, pentoxifylline, azathioprine and vitamin C have been used in the treatment of the HTLV-1 associated neurological disorders. Other antiviral drugs (lamivudine, zidovudine), monoclonal antibodies (Daclizumab) and therapeutic agents (valporic acid, interferons) have also been evaluated. No known drug, so far, has been shown to be efficacious. The aim of this review is to present the complexities of HTLV-1 associated neurological disorders and their current ongoing treatment. In addition to discussing future possible therapeutic strategies, by targeting HTVL-1 viral components and gene/s products, for the treatment of those neurological conditions. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  6. In vivo expression of the HBZ gene of HTLV-1 correlates with proviral load, inflammatory markers and disease severity in HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP

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    Saito Kousuke

    2009-02-01

    Full Text Available Abstract Background Recently, human T-cell leukemia virus type 1 (HTLV-1 basic leucine zipper factor (HBZ, encoded from a minus strand mRNA was discovered and was suggested to play an important role in adult T cell leukemia (ATL development. However, there have been no reports on the role of HBZ in patients with HTLV-1 associated inflammatory diseases. Results We quantified the HBZ and tax mRNA expression levels in peripheral blood from 56 HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP patients, 10 ATL patients, 38 healthy asymptomatic carriers (HCs and 20 normal uninfected controls, as well as human leukemic T-cell lines and HTLV-1-infected T-cell lines, and the data were correlated with clinical parameters. The spliced HBZ gene was transcribed in all HTLV-1-infected individuals examined, whereas tax mRNA was not transcribed in significant numbers of subjects in the same groups. Although the amount of HBZ mRNA expression was highest in ATL, medium in HAM/TSP, and lowest in HCs, with statistical significance, neither tax nor the HBZ mRNA expression per HTLV-1-infected cell differed significantly between each clinical group. The HTLV-1 HBZ, but not tax mRNA load, positively correlated with disease severity and with neopterin concentration in the cerebrospinal fluid of HAM/TSP patients. Furthermore, HBZ mRNA expression per HTLV-1-infected cell was decreased after successful immunomodulatory treatment for HAM/TSP. Conclusion These findings suggest that in vivo expression of HBZ plays a role in HAM/TSP pathogenesis.

  7. A Fashi Lymphoproliferative Phenotype Reveals Non-Apoptotic Fas Signaling in HTLV-1-Associated Neuroinflammation

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    Menezes, Soraya Maria; Leal, Fabio E.; Dierckx, Tim; Khouri, Ricardo; Decanine, Daniele; Silva-Santos, Gilvaneia; Schnitman, Saul V.; Kruschewsky, Ramon; López, Giovanni; Alvarez, Carolina; Talledo, Michael; Gotuzzo, Eduardo; Nixon, Douglas F.; Vercauteren, Jurgen; Brassat, David; Liblau, Roland; Vandamme, Anne Mieke; Galvão-Castro, Bernardo; Van Weyenbergh, Johan

    2017-01-01

    Human T-cell lymphotropic virus (HTLV)-1 was the first human retrovirus to be associated to cancer, namely adult T-cell leukemia (ATL), but its pathogenesis remains enigmatic, since only a minority of infected individuals develops either ATL or the neuroinflammatory disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A functional FAS -670 polymorphism in an interferon (IFN)-regulated STAT1-binding site has been associated to both ATL and HAM/TSP susceptibility. Fashi T stem cell memory (Tscm) cells have been identified as the hierarchical apex of ATL, but have not been investigated in HAM/TSP. In addition, both FAS and STAT1 have been identified in an IFN-inducible HAM/TSP gene signature, but its pathobiological significance remains unclear. We comprehensively explored Fas expression (protein/mRNA) and function in lymphocyte activation, apoptosis, proliferation, and transcriptome, in PBMC from a total of 47 HAM/TSP patients, 40 asymptomatic HTLV-1-infected individuals (AC), and 58 HTLV-1 -uninfected healthy controls. Fas surface expression followed a two-step increase from HC to AC and from AC to HAM/TSP. In HAM/TSP, Fas levels correlated positively to lymphocyte activation markers, but negatively to age of onset, linking Fashi cells to earlier, more aggressive disease. Surprisingly, increased lymphocyte Fas expression in HAM/TSP was linked to decreased apoptosis and increased lymphoproliferation upon in vitro culture, but not to proviral load. This Fashi phenotype is HAM/TSP-specific, since both ex vivo and in vitro Fas expression was increased as compared to multiple sclerosis (MS), another neuroinflammatory disorder. To elucidate the molecular mechanism underlying non-apoptotic Fas signaling in HAM/TSP, we combined transcriptome analysis with functional assays, i.e., blocking vs. triggering Fas receptor in vitro with antagonist and agonist-, anti-Fas mAb, respectively. Treatment with agonist anti-Fas mAb restored apoptosis, indicating

  8. HTLV-1-associated arthropathy treated with anti-TNF-alpha agent.

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    Frenzel, Laurent; Moura, Bertrand; Marcais, Ambroise; Chapdelaine, Hugo; Hermine, Olivier

    2014-07-01

    Human T cell leukemia virus type 1 or HTLV-1 infection is a public health problem in endemic regions like Japan, Central America or Africa. Although the majority of HTLV-1 carriers remain asymptomatic throughout their lives, some patients could develop neurological disorder, inflammatory arthropathy also called HTLV-1-associated arthropathy or T-cell malignancy, the adult T-cell leukemia/lymphoma or ATL with a very poor prognosis. Described to be very close to rheumatoid arthritis, HTLV-1-associated arthropathy patients have few or no response to the first line therapy with corticosteroids and disease modifying antirheumatic drugs or DMARDs. The use of anti-TNF-α agents in these patients is an interesting alternative but asks the question of risk of developing an adult T-Cell leukemia/lymphoma. We reported an exceptional case of a smoldering ATL patient with an HTLV-1-associated arthropathy, refractory to corticosteroid, DMARDs and rituximab therapy, treated successfully with etanercept, without progression to aggressive ATL after 5 years.

  9. CSF CXCL10, CXCL9, and neopterin as candidate prognostic biomarkers for HTLV-1-associated myelopathy/tropical spastic paraparesis.

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    Tomoo Sato

    Full Text Available BACKGROUND: Human T-lymphotropic virus type 1 (HTLV-1 -associated myelopathy/tropical spastic paraparesis (HAM/TSP is a rare chronic neuroinflammatory disease. Since the disease course of HAM/TSP varies among patients, there is a dire need for biomarkers capable of predicting the rate of disease progression. However, there have been no studies to date that have compared the prognostic values of multiple potential biomarkers for HAM/TSP. METHODOLOGY/PRINCIPAL FINDINGS: Peripheral blood and cerebrospinal fluid (CSF samples from HAM/TSP patients and HTLV-1-infected control subjects were obtained and tested retrospectively for several potential biomarkers, including chemokines and other cytokines, and nine optimal candidates were selected based on receiver operating characteristic (ROC analysis. Next, we evaluated the relationship between these candidates and the rate of disease progression in HAM/TSP patients, beginning with a first cohort of 30 patients (Training Set and proceeding to a second cohort of 23 patients (Test Set. We defined "deteriorating HAM/TSP" as distinctly worsening function (≥3 grades on Osame's Motor Disability Score (OMDS over four years and "stable HAM/TSP" as unchanged or only slightly worsened function (1 grade on OMDS over four years, and we compared the levels of the candidate biomarkers in patients divided into these two groups. The CSF levels of chemokine (C-X-C motif ligand 10 (CXCL10, CXCL9, and neopterin were well-correlated with disease progression, better even than HTLV-1 proviral load in PBMCs. Importantly, these results were validated using the Test Set. CONCLUSIONS/SIGNIFICANCE: As the CSF levels of CXCL10, CXCL9, and neopterin were the most strongly correlated with rate of disease progression, they represent the most viable candidates for HAM/TSP prognostic biomarkers. The identification of effective prognostic biomarkers could lead to earlier detection of high-risk patients, more patient-specific treatment

  10. A Fas(hi) Lymphoproliferative Phenotype Reveals Non-Apoptotic Fas Signaling in HTLV-1-Associated Neuroinflammation.

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    Menezes, Soraya Maria; Leal, Fabio E; Dierckx, Tim; Khouri, Ricardo; Decanine, Daniele; Silva-Santos, Gilvaneia; Schnitman, Saul V; Kruschewsky, Ramon; López, Giovanni; Alvarez, Carolina; Talledo, Michael; Gotuzzo, Eduardo; Nixon, Douglas F; Vercauteren, Jurgen; Brassat, David; Liblau, Roland; Vandamme, Anne Mieke; Galvão-Castro, Bernardo; Van Weyenbergh, Johan

    2017-01-01

    Human T-cell lymphotropic virus (HTLV)-1 was the first human retrovirus to be associated to cancer, namely adult T-cell leukemia (ATL), but its pathogenesis remains enigmatic, since only a minority of infected individuals develops either ATL or the neuroinflammatory disorder HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). A functional FAS -670 polymorphism in an interferon (IFN)-regulated STAT1-binding site has been associated to both ATL and HAM/TSP susceptibility. Fas(hi) T stem cell memory (Tscm) cells have been identified as the hierarchical apex of ATL, but have not been investigated in HAM/TSP. In addition, both FAS and STAT1 have been identified in an IFN-inducible HAM/TSP gene signature, but its pathobiological significance remains unclear. We comprehensively explored Fas expression (protein/mRNA) and function in lymphocyte activation, apoptosis, proliferation, and transcriptome, in PBMC from a total of 47 HAM/TSP patients, 40 asymptomatic HTLV-1-infected individuals (AC), and 58 HTLV-1 -uninfected healthy controls. Fas surface expression followed a two-step increase from HC to AC and from AC to HAM/TSP. In HAM/TSP, Fas levels correlated positively to lymphocyte activation markers, but negatively to age of onset, linking Fas(hi) cells to earlier, more aggressive disease. Surprisingly, increased lymphocyte Fas expression in HAM/TSP was linked to decreased apoptosis and increased lymphoproliferation upon in vitro culture, but not to proviral load. This Fas(hi) phenotype is HAM/TSP-specific, since both ex vivo and in vitro Fas expression was increased as compared to multiple sclerosis (MS), another neuroinflammatory disorder. To elucidate the molecular mechanism underlying non-apoptotic Fas signaling in HAM/TSP, we combined transcriptome analysis with functional assays, i.e., blocking vs. triggering Fas receptor in vitro with antagonist and agonist-, anti-Fas mAb, respectively. Treatment with agonist anti-Fas mAb restored apoptosis

  11. Human T-lymphotropic virus 1 (HTLV-1)-associated lichenoid dermatitis induced by CD8+ T cells in HTLV-1 carrier, HTLV-1-associated myelopathy/tropical spastic paraparesis and adult T-cell leukemia/lymphoma.

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    Tokura, Yoshiki; Ito, Taisuke; Kawakami, Chika; Sugita, Kazunari; Kasuya, Akira; Tatsuno, Kazuki; Sawada, Yu; Nakamura, Motonobu; Shimauchi, Takatoshi

    2015-10-01

    Human T-lymphotropic virus type 1 (HTLV-1) induces adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and carrier. ATLL is a mature CD4+ CD25+ CCR4+ T-cell neoplasm, and approximately half of patients have direct skin involvement manifesting patch, plaque, tumor, multiple papules, erythroderma and purpura. However, there exist secondary eruptions without tumor cell infiltration in patients with ATLL or HAM/TSP and carriers of HTLV-1. To clarify the presence of reactive skin eruptions in HTLV-1-infected individuals, we reviewed our patients with HTLV-1-associated diseases. In 2002-2012, we saw 50 ATLL or HAM/TSP patients and HTLV-1 carriers presenting with skin lesions. We retrospectively selected cases that histologically showed lichenoid tissue reactions with predominant infiltration of CD8+ T cells, but not CD4+ tumor cells. The cases included erythroderma (HTLV-1 carrier), lichen planus (HTLV-1 carrier), alopecia areata (HAM/TSP), chronic actinic dermatitis (HTLV-1 carrier to acute ATLL conversion) and discoid lupus erythematosus (smoldering ATLL). They were graft-versus-host disease-like, major secondary lesions and seen in HTLV-1 carriers and patients with HAM/TSP and smoldering ATLL. We coin the term HTLV-1-associated lichenoid dermatitis (HALD) to encompass the conditions. HALD may occur in association with the elevated immunity toward HTLV-1-infected CD4+ T cells, thus sharing the pathogenetic role of cytotoxic T cells with HAM/TSP.

  12. Neuroinflammatory paradigms in lysosomal storage diseases

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    Megan Elizabeth Bosch

    2015-10-01

    Full Text Available Lysosomal storage diseases (LSDs include approximately 70 distinct disorders that collectively account for 14% of all inherited metabolic diseases. LSDs are caused by mutations in various enzymes/proteins that disrupt lysosomal function, which impairs macromolecule degradation following endosome-lysosome and phagosome-lysosome fusion and autophagy, ultimately disrupting cellular homeostasis. LSDs are pathologically typified by lysosomal inclusions composed of a heterogeneous mixture of various proteins and lipids that can be found throughout the body. However, in many cases the CNS is dramatically affected, which may result from heightened neuronal vulnerability based on their post-mitotic state. Besides intrinsic neuronal defects, another emerging factor common to many LSDs is neuroinflammation, which may negatively impact neuronal survival and contribute to neurodegeneration. Microglial and astrocyte activation is a hallmark of many LSDs that affect the CNS, which often precedes and predicts regions where eventual neuron loss will occur. However, the timing, intensity, and duration of neuroinflammation may ultimately dictate the impact on CNS homeostasis. For example, a transient inflammatory response following CNS insult/injury can be neuroprotective, as glial cells attempt to remove the insult and provide trophic support to neurons. However, chronic inflammation, as seen in several LSDs, can promote neurodegeneration by creating a neurotoxic environment due to elevated levels of cytokines, chemokines, and pro-apoptotic molecules. Although neuroinflammation has been reported in several LSDs, the cellular basis and mechanisms responsible for eliciting neuroinflammatory pathways are just beginning to be defined. This review highlights the role of neuroinflammation in select LSDs and its potential contribution to neuron loss.

  13. Plasma proteome analysis in HTLV-1-associated myelopathy/tropical spastic paraparesis

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    Stumpf Michael PH

    2011-10-01

    Full Text Available Abstract Background Human T lymphotropic virus Type 1 (HTLV-1 causes a chronic inflammatory disease of the central nervous system known as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM which resembles chronic spinal forms of multiple sclerosis (MS. The pathogenesis of HAM remains uncertain. To aid in the differential diagnosis of HAM and to identify pathogenetic mechanisms, we analysed the plasma proteome in asymptomatic HTLV-1 carriers (ACs, patients with HAM, uninfected controls, and patients with MS. We used surface-enhanced laser desorption-ionization (SELDI mass spectrometry to analyse the plasma proteome in 68 HTLV-1-infected individuals (in two non-overlapping sets, each comprising 17 patients with HAM and 17 ACs, 16 uninfected controls, and 11 patients with secondary progressive MS. Candidate biomarkers were identified by tandem Q-TOF mass spectrometry. Results The concentrations of three plasma proteins - high [β2-microglobulin], high [Calgranulin B], and low [apolipoprotein A2] - were specifically associated with HAM, independently of proviral load. The plasma [β2-microglobulin] was positively correlated with disease severity. Conclusions The results indicate that monocytes are activated by contact with activated endothelium in HAM. Using β2-microglobulin and Calgranulin B alone we derive a diagnostic algorithm that correctly classified the disease status (presence or absence of HAM in 81% of HTLV-1-infected subjects in the cohort.

  14. Ascorbic acid has superior ex vivo antiproliferative, cell death-inducing and immunomodulatory effects over IFN-α in HTLV-1-associated myelopathy.

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    Britta Moens

    Full Text Available BACKGROUND: Clear therapeutic guidelines for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP are missing due to the lack of randomized double-blind controlled clinical trials. Moderate yet similar clinical benefit has been demonstrated for IFN-α and high-dose ascorbic acid (AA monotherapy in a large open clinical trial. However, there is a lack of in vivo and in vitro studies exploring and comparing the effects of high-dose AA and IFN-α treatment in the context of HAM/TSP. Therefore, we performed the first comparative analysis of the ex vivo and in vitro molecular and cellular mechanisms of action of IFN-α and high-dose AA in HAM/TSP. PRINCIPAL FINDINGS: Through thymidine incorporation and quantification of Th1/Th2/Th17 cytokines, we demonstrate that high-dose AA displays differential and superior antiproliferative and immunomodulatory effects over IFN-α in HAM/TSP PBMCs ex vivo. In addition, high-dose AA, but not IFN-α, induced cell death in both HAM/TSP PBMCs and HTLV-1-infected T-cell lines MT-2 and MT-4. Microarray data combined with pathway analysis of MT-2 cells revealed AA-induced regulation of genes associated with cell death, including miR-155. Since miR-155 has recently been demonstrated to up-regulate IFN-γ, this microRNA might represent a novel therapeutic target in HAM/TSP, as recently demonstrated in multiple sclerosis, another neuroinflammatory disease. On the other hand, IFN-α selectively up-regulated antiviral and immune-related genes. CONCLUSIONS: In comparison to IFN-α, high-dose AA treatment has superior ex vivo and in vitro cell death-inducing, antiproliferative and immunomodulatory anti-HTLV-1 effects. Differential pathway activation by both drugs opens up avenues for targeted treatment in specific patient subsets.

  15. Magnetic resonance imaging for Human T-cell lymphotropic virus type 1 (HTLV1- associated myelopathy/tropical spastic paraparesis patients: a systematic review

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    Fariba Zemorshidi

    2015-06-01

    Full Text Available Introduction: Human T-cell lymphotropic virus type 1 (HTLV-1 associated myelopathy/tropical spastic paraparesis is a chronic progressive neurologic disease which might be associated by brain and spinal cord atrophy and lesions. Here we systematically reviewed the brain and spinal cord abnormalities reported by using magnetic resonance imaging modality on HTLV-1 associated myelopathy/tropical spastic paraparesis patients. Methods: PubMed was searched for all the relevant articles which used magnetic resonance imaging for patients with human HTLV-1 associated myelopathy/tropical spastic paraparesis disease. Included criteria were all the cohort and case series on with at least 10 patients. We had no time limitation for searched articles, but only English language articles were included in our systematic review. Exclusion criteria were none-English articles, case reports, articles with less than 10 patients, spastic paraparesis patients with unknown etiology, and patients with HTLVII. Results: Total of 14 relevant articles were extracted after studying title, abstracts, and full text of the irrelevant articles. Only 2/14 articles, reported brain atrophy incidence. 5/14 articles studied the brain lesions prevalence. Spinal cord atrophy and lesions, each were studied in 6/14 articles.Discussion: According to the extracted data, brain atrophy does not seem to happen frequently in patients with HTLV-1 associated myelopathy/tropical spastic paraparesis. None-specific brain lesions identified in articles are indicative of low specificity of magnetic resonance imaging technique despite its high sensitivity. Conclusion: Prevalence of spinal cord lesions and atrophy in these patients might be due to the degenerative processes associated with aging phenomenon. Further larger studies in endemic areas can more accurately reveal the specificity of magnetic resonance imaging for these patients.

  16. INTERFERON BETA-1A TREATMENT IN HTLV-1-ASSOCIATED MYELOPATHY/TROPICAL SPASTIC PARAPARESIS: A CASE REPORT

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    Graça Maria de Castro Viana

    2014-09-01

    Full Text Available Here a young patient (< 21 years of age with a history of infective dermatitis is described. The patient was diagnosed with myelopathy associated with HTLV-1/tropical spastic paraparesis and treated with interferon beta-1a. The disease was clinically established as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP, and laboratory tests confirmed the presence of antibodies to HTLV-1 in the cerebrospinal fluid (CSF. Mumps, cytomegalovirus, Epstein-Barr virus, schistosomiasis, herpes virus 1 and 2, rubella, measles, varicella-zoster toxoplasmosis, hepatitis, HIV, and syphilis were excluded by serology. The patient was diagnosed with neurogenic bladder and presented with nocturia, urinary urgency, paresthesia of the lower left limb, a marked reduction of muscle strength in the lower limbs, and a slight reduction in upper limb strength. During the fourth week of treatment with interferon beta-1a, urinary urgency and paresthesia disappeared and clinical motor skills improved.

  17. Turning a blind eye: HTLV-1-associated uveitis in Indigenous adults from Central Australia.

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    Chew, Rusheng; Henderson, Timothy; Aujla, Jaskirat; Whist, Eline; Einsiedel, Lloyd

    2017-07-28

    We describe the first two cases of HTLV-1 associated uveitis to be associated with HTLV-1c subtype infection. Case report. Uveitis was demonstrated in two Indigenous Australian men, both of whom had high HTLV-1c proviral loads in peripheral blood. Visual outcomes were poor in each case. Clinicians should be aware of HTLV-1c infection as a cause of uveitis in Australia, and HTLV-1 serology should be included in the basic uveitis work-up in HTLV-1-endemic areas.

  18. Treatment of rheumatoid arthritis with biologics may exacerbate HTLV-1-associated conditions

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    Terada, Yukiko; Kamoi, Koju; Ohno-Matsui, Kyoko; Miyata, Kazunori; Yamano, Chinami; Coler-Reilly, Ariella; Yamano, Yoshihisa

    2017-01-01

    Abstract Rationale: There are roughly 5 to 10 million persons infected with human T-lymphotropic virus type 1 (HTLV-1) worldwide, and the safety of treating this population with biologics remains poorly understood. Patient concerns and diagnosis: An HTLV-1-infected 66-year-old female with HTLV-1 uveitis (HU) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Her HU had been in remission and her HAM/TSP symptoms had been managed effectively with oral steroids for years. However, she developed severe rheumatoid arthritis (RA) after failing to respond well to conventional anti-rheumatic agents. Interventions: She was administered two intravenous 8mg/kg doses of the biologic tocilizumab. Outcomes: Subsequently, her RA symptoms resolved, but she suffered a recurrence of HU and exacerbation of HAM/TSP symptoms. When she was switched back to steroid-based treatment, HU and HAM symptoms both improved, but RA symptoms again worsened. Finally, an attempt to substitute the biologic abatacept and reduce the steroids failed when HAM/TSP symptoms again became aggravated. Lessons: To the best of our knowledge, this represents the first report worldwide of a biologic aggravating HTLV-1-associated conditions. This report suggests that caution is advised when using biologics to treat HTLV-1-infected patients, though further research is required to clarify the situation. PMID:28178142

  19. Treatment of rheumatoid arthritis with biologics may exacerbate HTLV-1-associated conditions: A case report.

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    Terada, Yukiko; Kamoi, Koju; Ohno-Matsui, Kyoko; Miyata, Kazunori; Yamano, Chinami; Coler-Reilly, Ariella; Yamano, Yoshihisa

    2017-02-01

    There are roughly 5 to 10 million persons infected with human T-lymphotropic virus type 1 (HTLV-1) worldwide, and the safety of treating this population with biologics remains poorly understood. An HTLV-1-infected 66-year-old female with HTLV-1 uveitis (HU) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Her HU had been in remission and her HAM/TSP symptoms had been managed effectively with oral steroids for years. However, she developed severe rheumatoid arthritis (RA) after failing to respond well to conventional anti-rheumatic agents. She was administered two intravenous 8mg/kg doses of the biologic tocilizumab. Subsequently, her RA symptoms resolved, but she suffered a recurrence of HU and exacerbation of HAM/TSP symptoms. When she was switched back to steroid-based treatment, HU and HAM symptoms both improved, but RA symptoms again worsened. Finally, an attempt to substitute the biologic abatacept and reduce the steroids failed when HAM/TSP symptoms again became aggravated. To the best of our knowledge, this represents the first report worldwide of a biologic aggravating HTLV-1-associated conditions. This report suggests that caution is advised when using biologics to treat HTLV-1-infected patients, though further research is required to clarify the situation.

  20. Immunogenetics and the Pathological Mechanisms of Human T-Cell Leukemia Virus Type 1- (HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP

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    Mineki Saito

    2010-01-01

    Full Text Available Human T-cell leukemia virus type 1 (HTLV-1 is a replication-competent human retrovirus associated with two distinct types of disease only in a minority of infected individuals: the malignancy known as adult T-cell leukemia (ATL and a chronic inflammatory central nervous system disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. Although the factors that cause these different manifestations of HTLV-1 infection are not fully understood, accumulating evidence suggests that complex virus-host interactions play an important role in determining the risk of HAM/TSP. This review focuses on the role of the immune response in controlling or limiting viral persistence in HAM/TSP patients, and the reason why some HTLV-1-infected people develop HAM/TSP whereas the majority remains asymptomatic carriers of the virus.

  1. Ciclosporin A proof of concept study in patients with active, progressive HTLV-1 associated myelopathy/tropical spastic paraparesis.

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    Fabiola Martin

    Full Text Available INTRODUCTION: Patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP become progressively impaired, with chronic pain, immobility and bladder, bowel and sexual dysfunction. Tested antiretroviral therapies have not been effective and most patients are offered a short course of corticosteroids or interferon-α, physiotherapy and symptomatic management. Pathogenesis studies implicate activated T-lymphocytes and cytokines in tissue damage. We therefore tested the hypothesis that inhibition of T-cell activation with ciclosporin A would be safe and clinically beneficial in patients with early and/or clinically progressing HAM/TSP. MATERIALS AND METHODS: Open label, proof of concept, pilot study of 48 weeks therapy with the calcineurin antagonist, ciclosporin A (CsA, in seven patients with 'early' (50% deterioration in timed walk during the preceding three months HAM/TSP. Primary outcomes were incidence of clinical failure at 48 weeks and time to clinical failure. RESULTS: All patients completed 72 weeks study participation and five showed objective evidence of clinical improvement after 3 months treatment with CsA. Two patients exhibited clinical failure over 6.4 person-years of follow-up to week 48. One patient had a >2 point deterioration in IPEC (Insituto de Pesquisa Clinica Evandro Chagas disability score at weeks 8 and 12, and then stopped treatment. The other stopped treatment at week 4 because of headache and tremor and deterioration in timed walk, which occurred at week 45. Overall pain, mobility, spasticity and bladder function improved by 48 weeks. Two patients recommenced CsA during follow-up due to relapse. CONCLUSIONS: These data provide initial evidence that treatment with CsA is safe and may partially reverse the clinical deterioration seen in patients with early/progressive HAM/TSP. This trial supports further investigation of this agent's safety and effectiveness in larger, randomised controlled studies in

  2. [Central nervous system leukemia mimicking rapidly progressive HTLV-1 associated myelopathy].

    Science.gov (United States)

    Haruki, Hiroyo; Tanaka, Shinichiro; Koga, Michiaki; Kawai, Motoharu; Negoro, Kiyoshi; Kanda, Takashi

    2009-03-01

    A 79-year-old woman was suffered from rapidly progressive paresthesia of lower limbs and gait disturbance. After one month, she showed flaccid paraplegia and hyperreflexia in the lower limbs with positive Babinski signs. Anti-HTLV-1 antibody titer was elevated in the serum, but negative in the cerebrospinal fluid (CSF). CSF examination showed mild pleocytosis, elevated protein, and normal glucose content. Adult T cell lymphoma (ATL)-like cells were seen in the CSF. MRI showed no abnormal intensity in the spinal cord and brain. Two months later, she showed rapid worsening of the paraplegia and she became unable to stand. A tentative diagnosis of rapidly progressive HTLV-1 associated myelopathy (HAM) was given, but intravenous methylprednisolone was ineffective. Six months later, she developed pneumonia, and abundant ATL cells were seen in the peripheral blood, suggesting a diagnosis of ATL. Direct infiltration of ATL cells to central nervous system was therefore suggested to have caused neurological abnormalities in this case. One may consider central nervous system leukemia when rapidly progressive HAM-like symptoms and signs are recognized, especially without positive anti-HTLV-1 antibody in the CSF.

  3. Cognitive event-related potentials and brain magnetic resonance imaging in HTLV-1 associated myelopathy (HAM).

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    Fukushima, T; Ikeda, T; Uyama, E; Uchino, M; Okabe, H; Ando, M

    1994-10-01

    Auditory and visual cognitive event-related potentials (ERPs) were investigated in 14 patients with HTLV-1 associated myelopathy (HAM) and in 36 normal controls. In the HAM patients, the latencies of P300 and N200 by the auditory tone method were significantly delayed, and N100 by the auditory click method was significantly delayed in latency. No abnormal ERP components were observed with visual methods. While these auditory abnormal ERPs were present in the HAM patients, there was no evidence of visual abnormal ERPs. Abnormal lesions on the white matter were evident at magnetic resonance imaging (MRI) in 6 (75%) of 8 patients. There was no correlation between MRI lesions and the abnormalities of ERPs, but there was a significant correlation between bifrontal index on MRI and P300 amplitudes at Cz and Pz sites by auditory tone method. In one patient, atrophy of bilateral parietal lobes was seen on MRI and P300 latencies delayed using various methods. Therefore, the possibility that electrophysiological cognitive impairment in patients with HAM is related to brain atrophy rather than to white matter lesions requires attention.

  4. Upregulation of hsa-miR-125b in HTLV-1 asymptomatic carriers and HTLV-1-associated myelopathy/tropical spastic paraparesis patients

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    Larissa Deadame de Figueiredo Nicolete

    2012-09-01

    Full Text Available The retrovirus human T lymphotropic virus type 1 (HTLV-1 promotes spastic paraparesis, adult T cell leukaemia and other diseases. Recently, some human microRNAs (miRNAs have been described as important factors in host-virus interactions. This study compared miRNA expression in control individuals, asymptomatic HTLV-1 carriers and HTLV-1 associated myelopathy (HAM/tropical spastic paraparesis patients. The proviral load and Tax protein expression were measured in order to characterize the patients. hsa-miR-125b expression was significantly higher in patients than in controls (p = 0.0285 or in the HAM group (p = 0.0312. Therefore, our findings suggest that miR-125b expression can be used to elucidate the mechanisms of viral replication and pathogenic processes.

  5. Evaluation of T Regulatory Lymphocytes Transcription Factors in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) Patients.

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    Ghezeldasht, Sanaz Ahmadi; Sadeghian, Hamed; Azarpazhooh, Mahmoud Reza; Shamsian, Seyyed Ali Akbar; Rafatpanah, Houshang; Mahmoodi, Mahmood; Rezaee, Seyyed Abdolrahim

    2017-08-01

    HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an aggressive neurological disease. The CD4(+)CD25(+) T cell population plays pivotal roles in the maintenance of immunological tolerance and prevention of such autoimmune diseases. In the current study, proviral load (PVL), factor forkhead box p3 (Foxp3), and glucocorticoid-induced tumor necrosis factor receptor-related protein (GITR) gene expression and regulatory T cells (Tregs) counts of 21 HAM/TSP patients and 16 HTLV-1 healthy carriers (ACs) were measured using real-time PCR, TaqMan method, and flow cytometry. The demographic, history of disease, and severity of myelopathy were assessed by a checklist and the Osame motor disability score (OMDS). The mean OMDS for HAM/TSP was 4.82 ± 2.37 which had no significant correlation with Treg count or the expression of Foxp3, GITR, and PVL. The CD4(+)CD25(+) cell counts had no significant differences between HAM/TSP and ACs. Findings revealed a higher PVL in HAM/TSPs (313.36 copies/10(4)) compared to ACs (144.93 copies/10(4), p = 0.035). The Foxp3 and GITR mRNA levels were lower in HAM/TSP patients (11.78 and 13.80, respectively) than those in healthy carriers (18.44 and 21.00, p = 0.041 and 0.03, respectively). There was a significant correlation between Treg frequency and Foxp3 gene expression (R = 0.67, p = 0.006) and GITR and Foxp3 (R = 0.84, p = 0.042) in HAM/TSP patients. Furthermore, the transcription factors have strong correlations with CD4(+)CD25(+) T cell frequencies. These findings suggest that HTLV-1 infection can modify the expression of main functional transcription factors, FOXP3 and GITR, which may lead to immune response deterioration of Tregs and consequently HAM/TSP manifestation.

  6. Aquaporin-4 antibodies are not related to HTLV-1 associated myelopathy.

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    Felipe von Glehn

    Full Text Available INTRODUCTION: The seroprevalence of human T-cell leukemia virus type 1 (HTLV-1 is very high among Brazilians (1:200. HTLV-1 associated myelopathy or tropical spastic paraparesis (HAM/TSP is the most common neurological complication of HTLV-1 infection. HAM/TSP can present with an acute/subacute form of longitudinally extensive myelitis, which can be confused with lesions seen in aquaporin-4 antibody (AQP4-Ab positive neuromyelitis optica spectrum disorders (NMOSD on MRI. Moreover, clinical attacks in patients with NMOSD have been shown to be preceded by viral infections in around 30% of cases. OBJECTIVE: To evaluate the frequency of AQP4-Ab in patients with HAM/TSP. To evaluate the frequency of HTLV-1 infection in patients with NMOSD. PATIENTS AND METHODS: 23 Brazilian patients with HAM/TSP, 20 asymptomatic HTLV-1+ serostatus patients, and 34 with NMOSD were tested for AQP4-Ab using a standardized recombinant cell based assay. In addition, all patients were tested for HTLV-1 by ELISA and Western blotting. RESULTS: 20/34 NMOSD patients were positive for AQP4-Ab but none of the HAM/TSP patients and none of the asymptomatic HTLV-1 infected individuals. Conversely, all AQP4-Ab-positive NMOSD patients were negative for HTLV-1 antibodies. One patient with HAM/TSP developed optic neuritis in addition to subacute LETM; this patient was AQP4-Ab negative as well. Patients were found to be predominantly female and of African descent both in the NMOSD and in the HAM/TSP group; Osame scale and expanded disability status scale scores did not differ significantly between the two groups. CONCLUSIONS: Our results argue both against a role of antibodies to AQP4 in the pathogenesis of HAM/TSP and against an association between HTLV-1 infection and the development of AQP4-Ab. Moreover, the absence of HTLV-1 in all patients with NMOSD suggests that HTLV-1 is not a common trigger of acute attacks in patients with AQP4-Ab positive NMOSD in populations with high HTLV-1

  7. Fyn Kinase Regulates Microglial Neuroinflammatory Responses in Cell Culture and Animal Models of Parkinson's Disease

    OpenAIRE

    2015-01-01

    Sustained neuroinflammation mediated by resident microglia is recognized as a key pathophysiological contributor to many neurodegenerative diseases, including Parkinson's disease (PD), but the key molecular signaling events regulating persistent microglial activation have yet to be clearly defined. In the present study, we examined the role of Fyn, a non-receptor tyrosine kinase, in microglial activation and neuroinflammatory mechanisms in cell culture and animal models of PD. The well-charac...

  8. Interferon Gamma: Influence on Neural Stem Cell Function in Neurodegenerative and Neuroinflammatory Disease

    OpenAIRE

    2016-01-01

    Interferon-gamma (IFNγ), a pleiotropic cytokine, is expressed in diverse neurodegenerative and neuroinflammatory conditions. Its protective mechanisms are well documented during viral infections in the brain, where IFNγ mediates non-cytolytic viral control in infected neurons. However, IFNγ also plays both protective and pathological roles in other central nervous system (CNS) diseases. Of the many neural cells that respond to IFNγ, neural stem/progenitor cells (NSPCs), the only pluripotent c...

  9. Fyn Kinase Regulates Microglial Neuroinflammatory Responses in Cell Culture and Animal Models of Parkinson's Disease.

    Science.gov (United States)

    Panicker, Nikhil; Saminathan, Hariharan; Jin, Huajun; Neal, Matthew; Harischandra, Dilshan S; Gordon, Richard; Kanthasamy, Kavin; Lawana, Vivek; Sarkar, Souvarish; Luo, Jie; Anantharam, Vellareddy; Kanthasamy, Anumantha G; Kanthasamy, Arthi

    2015-07-08

    Sustained neuroinflammation mediated by resident microglia is recognized as a key pathophysiological contributor to many neurodegenerative diseases, including Parkinson's disease (PD), but the key molecular signaling events regulating persistent microglial activation have yet to be clearly defined. In the present study, we examined the role of Fyn, a non-receptor tyrosine kinase, in microglial activation and neuroinflammatory mechanisms in cell culture and animal models of PD. The well-characterized inflammogens LPS and TNFα rapidly activated Fyn kinase in microglia. Immunocytochemical studies revealed that activated Fyn preferentially localized to the microglial plasma membrane periphery and the nucleus. Furthermore, activated Fyn phosphorylated PKCδ at tyrosine residue 311, contributing to an inflammogen-induced increase in its kinase activity. Notably, the Fyn-PKCδ signaling axis further activated the LPS- and TNFα-induced MAP kinase phosphorylation and activation of the NFκB pathway, implying that Fyn is a major upstream regulator of proinflammatory signaling. Functional studies in microglia isolated from wild-type (Fyn(+/+)) and Fyn knock-out (Fyn(-/-)) mice revealed that Fyn is required for proinflammatory responses, including cytokine release as well as iNOS activation. Interestingly, a prolonged inflammatory insult induced Fyn transcript and protein expression, indicating that Fyn is upregulated during chronic inflammatory conditions. Importantly, in vivo studies using MPTP, LPS, or 6-OHDA models revealed a greater attenuation of neuroinflammatory responses in Fyn(-/-) and PKCδ (-/-) mice compared with wild-type mice. Collectively, our data demonstrate that Fyn is a major upstream signaling mediator of microglial neuroinflammatory processes in PD. Parkinson's disease (PD) is a complex multifactorial disease characterized by the progressive loss of midbrain dopamine neurons. Sustained microglia-mediated neuroinflammation has been recognized as a major

  10. Role of Prostaglandins in Neuroinflammatory and Neurodegenerative Diseases

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    Lima, Isabel Vieira de Assis; Bastos, Leandro Francisco Silva; Limborço-Filho, Marcelo; Fiebich, Bernd L.; de Oliveira, Antonio Carlos Pinheiro

    2012-01-01

    Increasing data demonstrates that inflammation participates in the pathophysiology of neurodegenerative diseases. Among the different inflammatory mediators involved, prostaglandins play an important role. The effects induced by prostaglandins might be mediated by activation of their known receptors or by nonclassical mechanisms. In the present paper, we discuss the evidences that link prostaglandins, as well as the enzymes that produce them, to some neurological diseases. PMID:22778499

  11. Early Onset of HTLV-1 Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) and Adult T-cell Leukemia/Lymphoma (ATL): Systematic Search and Review.

    Science.gov (United States)

    Oliveira, Pedro D; Kachimarek, Amanda C; Bittencourt, Achiléa L

    2017-06-05

    Human T-cell lymphotropic virus type 1 (HTLV-1) is endemic in some regions and its vertical transmission occurs mainly through breastfeeding. About 10% of carriers develop associated diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP), adult T-cell leukemia/lymphoma (ATL) and infectious dermatitis associated with HTLV-1 (IDH). We searched for available case reports of early-onset HAM/TSP and ATL to evaluate demographic and disease aspects in infantile-juvenile patients. In the reviewed literature, 27 HAM/TSP and 31 ATL cases were found. In almost all of them, the most likely route of transmission was through breastfeeding. ATL is rarely reported, notwithstanding it may be underestimated because T-cell lymphomas are not investigated for HTLV-1 infection in this age group. IDH was frequently associated with HAM/TSP. The investigation of HTLV-1 infection in pregnant women is an important matter of public health and should be mandatory in endemic countries. © The Author [2017]. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  12. The use of botulinum toxin type A in the treatment of HTLV-1-associated overactive bladder refractory to conventional therapy

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    José Abraão Carneiro Neto

    2014-08-01

    Full Text Available Urinary symptoms occur in 19% of human T-cell lymphotropic virus type 1 (HTLV-1-infected patients who do not fulfill criteria for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP and in almost 100% of HAM/TSP patients. Few studies have evaluated therapies for overactive bladder (OAB caused by HTLV-1 infection. This case report describes the effect of onabotulinum toxin A on the urinary manifestations of three patients with HAM/TSP and OAB symptoms. The patients were intravesically administered 200 units of Botox®. Their incontinence episodes improved, and their OAB symptoms scores (OABSS reduced significantly. These data indicate that Botox® should be a treatment option for OAB associated with HTLV-1 infection.

  13. Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease.

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    Simon, Matthew J; Iliff, Jeffrey J

    2016-03-01

    Cerebrospinal fluid (CSF) circulation and turnover provides a sink for the elimination of solutes from the brain interstitium, serving an important homeostatic role for the function of the central nervous system. Disruption of normal CSF circulation and turnover is believed to contribute to the development of many diseases, including neurodegenerative conditions such as Alzheimer's disease, ischemic and traumatic brain injury, and neuroinflammatory conditions such as multiple sclerosis. Recent insights into CSF biology suggesting that CSF and interstitial fluid exchange along a brain-wide network of perivascular spaces termed the 'glymphatic' system suggest that CSF circulation may interact intimately with glial and vascular function to regulate basic aspects of brain function. Dysfunction within this glial vascular network, which is a feature of the aging and injured brain, is a potentially critical link between brain injury, neuroinflammation and the development of chronic neurodegeneration. Ongoing research within this field may provide a powerful new framework for understanding the common links between neurodegenerative, neurovascular and neuroinflammatory disease, in addition to providing potentially novel therapeutic targets for these conditions. This article is part of a Special Issue entitled: Neuro Inflammation edited by Helga E. de Vries and Markus Schwaninger.

  14. Interferon Gamma: Influence on Neural Stem Cell Function in Neurodegenerative and Neuroinflammatory Disease

    Science.gov (United States)

    Kulkarni, Apurva; Ganesan, Priya; O’Donnell, Lauren A.

    2016-01-01

    Interferon-gamma (IFNγ), a pleiotropic cytokine, is expressed in diverse neurodegenerative and neuroinflammatory conditions. Its protective mechanisms are well documented during viral infections in the brain, where IFNγ mediates non-cytolytic viral control in infected neurons. However, IFNγ also plays both protective and pathological roles in other central nervous system (CNS) diseases. Of the many neural cells that respond to IFNγ, neural stem/progenitor cells (NSPCs), the only pluripotent cells in the developing and adult brain, are often altered during CNS insults. Recent studies highlight the complex effects of IFNγ on NSPC activity in neurodegenerative diseases. However, the mechanisms that mediate these effects, and the eventual outcomes for the host, are still being explored. Here, we review the effects of IFNγ on NSPC activity during different pathological insults. An improved understanding of the role of IFNγ would provide insight into the impact of immune responses on the progression and resolution of neurodegenerative diseases.

  15. High HTLV-1 proviral load, a marker for HTLV-1 associated myelopathy/tropical spastic paraparesis, is also detected in patients with infective dermatitis associated with HTLV-1

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    J. Primo

    2009-08-01

    Full Text Available Salvador (BA, Brazil is an endemic area for human T-cell lymphotrophic virus type 1 (HTLV-1. The overall prevalence of HTLV-1 infection in the general population has been estimated to be 1.76%. HTLV-1 carriers may develop a variety of diseases such as adult T-cell leukemia/lymphoma, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP and infective dermatitis associated with HTLV-1 (IDH. IDH is a chronic and severe form of childhood exudative and infective dermatitis involving mainly the scalp, neck and ears. It has recently been observed that 30% of patients with IDH develop juvenile HAM/TSP. The replication of HTLV-1 has been reported to be greater in adult HAM/TSP patients than in asymptomatic HTLV-1 carriers. In the current study, the proviral load of 28 children and adolescents with IDH not associated with HAM/TSP was determined and the results were compared to those obtained in 28 HTLV-1 adult carriers and 28 adult patients with HAM/TSP. The proviral load in IDH patients was similar to that of patients with HAM/TSP and much higher than that found in HTLV-1 carriers. The high levels of proviral load in IDH patients were not associated with age, duration of illness, duration of breast-feeding, or activity status of the skin disease. Since proviral load is associated with neurological disability, these data support the view that IDH patients are at high risk of developing HAM/TSP.

  16. Mechanistic effects of IVIg in neuroinflammatory diseases: conclusions based on clinicopathologic correlations.

    Science.gov (United States)

    Dalakas, Marinos C

    2014-07-01

    The mechanisms of action of IVIg on immunoregulatory and neuroinflammatory network have been predominantly based on in vitro experiments and animal studies, rather than direct effects on human tissues. Based on clinicopathologic correlations and tissues obtained before and after IVIg therapy, the better documented and clinically-relevant in-vivo actions of IVIg include effects on: a) Antibodies. An extracted antigen-specific anti-immunoglobulin (idiotypic) fraction appears partially responsible for its effect in myasthenia gravis and GBS; b) Complement. Sera from Dermatomyositis (DM) patients responding to IVIg, inhibit complement consumption and intercept MAC formation leading to disappearance of MAC deposits in the repeated muscle biopsies and normalization of muscle tissue; c) Genes. In repeated muscle biopsies from DM patients who improved after IVIg, but not from Inclusion-Body-Myositis (IBM) who did not improve, there is a 2-fold alteration of 2206 tissue genes associated with inflammation, fibrosis, tissue remodeling and regeneration; and d) degenerative-proinflammatory molecules and β-amyloid, implicated in neurodegenerative CNS diseases and IBM. In repeated muscle biopsies of IBM patients who did not respond to IVIg, the mRNA or protein expression for chemokines, IFN-γ, TGF-ß, IL-10, Ubiquitin and aB-crystallin is reduced, but not for the key molecules ICOS, ICOSL, IL-6, IL1-β, perforin, APP, nitric oxide synthase and nitrotyrosine, in spite of good IVIg penetration in muscles. Collectively, the selective effectiveness of IVIg in human diseases seems to correlate in vivo with inhibition of causative inflammatory mediators. Study of accessible tissues before and after therapy and clinicopathologic correlations, may help explain the differential effect of IVIg in autoimmune or neuroinflammatory diseases.

  17. Cytoplasmic Localization of HTLV-1 HBZ Protein: A Biomarker of HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP)

    Science.gov (United States)

    Baratella, Marco; Forlani, Greta; Raval, Goutham U.; Tedeschi, Alessandra; Gout, Olivier; Gessain, Antoine; Accolla, Roberto S.

    2017-01-01

    HTLV-1 is the causative agent of a severe form of adult T cell leukemia/Lymphoma (ATL), and of a chronic progressive neuromyelopathy designated HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP). Two important HTLV-1-encoded proteins, Tax-1 and HBZ, play crucial roles in the generation and maintenance of the oncogenic process. Less information is instead available on the molecular and cellular mechanisms leading to HAM/TSP. More importantly, no single specific biomarker has been described that unambiguously define the status of HAM/TSP. Here we report for the first time the finding that HBZ, described until now as an exclusive nuclear protein both in chronically infected and in ATL cells, is instead exclusively localized in the cytoplasm of peripheral blood mononuclear cells (PBMC) from patients suffering of HAM/TSP. Interestingly, at the single cell level, HBZ and Tax-1 proteins are never found co-expressed in the same cell, suggesting the existence of mechanisms of expression uncoupling of these two important HTLV-1 viral products in HAM/TSP patients. Cells expressing cytoplasmic HBZ were almost exclusively found in the CD4+ T cell compartment that was not, at least in a representative HAM/TSP patient, expressing the CD25 marker. Less than 1 percent CD8+ T cells were fond positive for HBZ, while B cells and NK cells were found negative for HBZ in HAM/TSP patients. Our results identify the cytoplasmic localization of HBZ in HAM/TSP patient as a possible biomarker of this rather neglected tropical disease, and raise important hypotheses on the role of HBZ in the pathogenesis of the neuromyelopathy associated to HTLV-1 infection. PMID:28095504

  18. Role of IL-21 in HTLV-1 infections with emphasis on HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP).

    Science.gov (United States)

    Rajaei, Taraneh; Farajifard, Hamid; Rafatpanah, Houshang; Bustani, Reza; Valizadeh, Narges; Rajaei, Bahareh; Rezaee, Seyed Abdolrahim

    2017-06-01

    Interleukin-21 (IL-21) enhances the survival and cytotoxic properties of cytotoxic T cells (CTLs) and exhibits essential roles in controlling chronic viral infections. HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic progressive inflammatory disease of the nervous system. The main determinant of disease progression is efficiency of the CTL response to Human T lymphotropic virus types I (HTLV-1). In this study, the expression of host IL-21 and HTLV-I Tax and proviral load (PVL) was evaluated to understand the role and mechanism of IL-21 in HTLV-1 infections and the subsequent development of HAM/TSP. A cross-sectional study was carried out on 20 HAM/TSP patients, 20 asymptomatic HTLV-1 carriers (ACs) and 20 healthy controls (HCs) to evaluate the expression of IL-21 and Tax and PVL in non-activated and phorbol myristate acetate (PMA)-ionomycin-activated peripheral blood mononuclear cells (PBMCs). The mean mRNA expression of IL-21 in the non-activated and activated PBMCs was higher (by 5-13 times) in the HAM/TSP patients than in ACs and HCs (p < 0.05); however, there was no significant difference between ACs and HCs. In contrast to the IL-21 mRNA expression, the serum level of the IL-21 protein was significantly lower in the HAM/TSP patients than in ACs and HCs (p < 0.05). Furthermore, higher expression of Tax and PVL was observed in the HAM/TSP subjects than ACs (p < 0.05). In addition, Tax gene expression was positively correlated with PVL (R = 0.595, p = 0.000) and IL-21 gene expression (R = 0.395, p = 0.021) in the HTLV-1-infected subjects. In conclusion, the increase in IL-21 mRNA expression may reflect the attempt of infected T cells to induce an appropriate antiviral response, and the decrease in IL-21 protein expression may reflect the inhibition of IL-21 mRNA translation by viral factors in favour of virus evasion and dissemination.

  19. Early-life stress lastingly alters the neuroinflammatory response to amyloid pathology in an Alzheimer's disease mouse model.

    Science.gov (United States)

    Hoeijmakers, Lianne; Ruigrok, Silvie R; Amelianchik, Anna; Ivan, Daniela; van Dam, Anne-Marie; Lucassen, Paul J; Korosi, Aniko

    2017-07-01

    Exposure to stress during the sensitive period of early-life increases the risk to develop cognitive impairments and psychopathology later in life. In addition, early-life stress (ES) exposure, next to genetic causes, has been proposed to modulate the development and progression of Alzheimer's disease (AD), however evidence for this hypothesis is currently lacking. We here tested whether ES modulates progression of AD-related neuropathology and assessed the possible contribution of neuroinflammatory factors in this. We subjected wild-type (WT) and transgenic APP/PS1 mice, as a model for amyloid neuropathology, to chronic ES from postnatal day (P)2 to P9. We next studied how ES exposure affected; 1) amyloid β (Aβ) pathology at an early (4month old) and at a more advanced pathological (10month old) stage, 2) neuroinflammatory mediators immediately after ES exposure as well as in adult WT mice, and 3) the neuroinflammatory response in relation to Aβ neuropathology. ES exposure resulted in a reduction of cell-associated amyloid in 4month old APP/PS1 mice, but in an exacerbation of Aβ plaque load at 10months of age, demonstrating that ES affects Aβ load in the hippocampus in an age-dependent manner. Interestingly, ES modulated various neuroinflammatory mediators in the hippocampus of WT mice as well as in response to Aβ neuropathology. In WT mice, immediately following ES exposure (P9), Iba1-immunopositive microglia exhibited reduced complexity and hippocampal interleukin (IL)-1β expression was increased. In contrast, microglial Iba1 and CD68 were increased and hippocampal IL-6 expression was decreased at 4months, while these changes resolved by 10months of age. Finally, Aβ neuropathology triggered a neuroinflammatory response in APP/PS1 mice that was altered after ES exposure. APP/PS1 mice exhibited increased CD68 expression at 4months, which was further enhanced by ES, whereas the microglial response to Aβ neuropathology, as measured by Iba1 and CD11b, was

  20. Effects of host restriction factors and the HTLV-1 subtype on susceptibility to HTLV-1-associated myelopathy/tropical spastic paraparesis.

    Science.gov (United States)

    Nozuma, Satoshi; Matsuura, Eiji; Kodama, Daisuke; Tashiro, Yuichi; Matsuzaki, Toshio; Kubota, Ryuji; Izumo, Shuji; Takashima, Hiroshi

    2017-04-19

    Although human T-lymphotropic virus type 1 (HTLV-1) infection is a prerequisite for the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), specific provirus mutations in HAM/TSP have not yet been reported. In this study, we examined whether HAM/TSP patients had the disease-specific genomic variants of HTLV-1 by analyzing entire sequences of HTLV-1 proviruses in these patients, including familial cases. In addition, we investigated the genetic variants of host restriction factors conferring antiretroviral activity to determine which mutations may be related to resistance or susceptibility to HAM/TSP. The subjects included 30 patients with familial HAM/TSP (f-HAM/TSP), 92 patients with sporadic HAM/TSP (s-HAM/TSP), and 89 asymptomatic HTLV-1 carriers (ACs). In all 211 samples, 37 samples (18%) were classified into transcontinental subtype and 174 samples (82%) were classified as Japanese subtype. Among three groups, the percentage of transcontinental subtype in f-HAM/TSP, s-HAM/TSP and ACs was 33, 23 and 7%, respectively. The frequency of transcontinental subtype was significantly higher in both f-HAM/TSP (p < 0.001) and s-HAM/TSP (p < 0.001) than in ACs. Fifty mutations in HTLV-1 sequences were significantly more frequent in HAM/TSP patients than in ACs, however, they were common only in transcontinental subtype. Among these mutations, ten common mutations causing amino acid changes in the HTLV-1 sequences were specific to the transcontinental subtype. We examined host restriction factors, and detected a rare variant in TRIM5α in HAM/TSP patients. The patients with TRIM5α 136Q showed lower proviral loads (PVLs) than those with 136R (354 vs. 654 copies/10(4) PBMC, p = 0.003). The patients with the 304L variant of TRIM5α had significantly higher PVLs than those with 304H (1669 vs. 595 copies/10(4) PBMC, p = 0.025). We could not find any HAM/TSP-specific mutations of host restriction factors. Transcontinental subtype is

  1. Physalin F, a seco-steroid from Physalis angulata L., has immunosuppressive activity in peripheral blood mononuclear cells from patients with HTLV1-associated myelopathy.

    Science.gov (United States)

    Pinto, Lorena A; Meira, Cássio S; Villarreal, Cristiane F; Vannier-Santos, Marcos A; de Souza, Claudia V C; Ribeiro, Ivone M; Tomassini, Therezinha C B; Galvão-Castro, Bernardo; Soares, Milena B P; Grassi, Maria F R

    2016-04-01

    Human T-lymphotropic virus type 1 (HTLV-1) induces a strong activation of the immune system, especially in individuals with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Physalin F is a secosteroid with potent anti-inflammatory and immunomodulatory activities. The present study aimed to investigate the effects of physalin F on peripheral blood mononuclear cells (PBMC) of HAM/TSP subjects. A concentration-dependent inhibition of spontaneous proliferation of PBMC from HAM/TSP subjects was observed in the presence of physalin F, as evaluated by (3)H-thymidine uptake. The IC50 for physalin F was 0.97 ± 0.11 μM. Flow cytometry analysis using Cytometric Bead Array (CBA) showed that physalin F (10 μM) significantly reduced the levels of IL-2, IL-6, IL-10, TNF-α and IFN-γ, but not IL-17A, in supernatants of PBMC cultures. Next, apoptosis induction was addressed by using flow cytometry to evaluate annexin V expression. Treatment with physalin F (10 μM) increased the apoptotic population of PBMC in HAM/TSP subjects. Transmission electron microscopy analysis of PBMC showed that physalin F induced ultrastructural changes, such as pyknotic nuclei, damaged mitochondria, enhanced autophagic vacuole formation, and the presence of myelin-like figures. In conclusion, physalin F induces apoptosis of PBMC, decreasing the spontaneous proliferation and cytokine production caused by HTLV-1 infection.

  2. HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis Is Not Associated with SNP rs12979860 of the IL-28B Gene

    Science.gov (United States)

    Vallinoto, Antonio C. R.; Santana, Bárbara Brasil; Sá, Keyla S. G.; Ferreira, Tuane C. S.; Sousa, Rita Catarina M.; Azevedo, Vânia N.; Feitosa, Rosimar N. M.; Machado, Luiz Fernando A.; Ishak, Marluísa O. G.; Ishak, Ricardo

    2015-01-01

    The present study investigated the association between the rs12979860 polymorphism in the IL-28B gene and HTLV-1 infection as well as the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1-infected patients (26 HAM/TSP symptomatic and 53 asymptomatic) and 300 seronegative healthy controls were investigated. Plasma levels of the cytokines TNF-α, TNF-β, IL-8, IL-10, IL-6, and IFN-γ from infected patients were measured using an indirect enzyme-linked immunosorbent assay. The HTLV proviral load was measured using a real-time PCR assay, and T-cell subset counts were determined by flow cytometry. Real-time PCR was used to genotype the rs12979860 SNP. The allelic and genotypic distributions displayed no significant differences among the investigated groups. No significant association between the serum cytokine levels and the presence of the rs12979860 SNP in symptomatic and asymptomatic subjects was observed. A positive correlation (p = 0.0015) between TNF-β and IFN-γ was observed in the asymptomatic group, but a positive correlation was only observed (p = 0.0180) between TNF-α and IL-6 in the HAM/TSP group. The proviral load was significantly higher in HAM/TSP patients than in asymptomatic subjects. The present results do not support a previous report indicating an association between the SNP rs12979860 and HAM/TSP outcome. PMID:26609200

  3. HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis Is Not Associated with SNP rs12979860 of the IL-28B Gene

    Directory of Open Access Journals (Sweden)

    Antonio C. R. Vallinoto

    2015-01-01

    Full Text Available The present study investigated the association between the rs12979860 polymorphism in the IL-28B gene and HTLV-1 infection as well as the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. HTLV-1-infected patients (26 HAM/TSP symptomatic and 53 asymptomatic and 300 seronegative healthy controls were investigated. Plasma levels of the cytokines TNF-α, TNF-β, IL-8, IL-10, IL-6, and IFN-γ from infected patients were measured using an indirect enzyme-linked immunosorbent assay. The HTLV proviral load was measured using a real-time PCR assay, and T-cell subset counts were determined by flow cytometry. Real-time PCR was used to genotype the rs12979860 SNP. The allelic and genotypic distributions displayed no significant differences among the investigated groups. No significant association between the serum cytokine levels and the presence of the rs12979860 SNP in symptomatic and asymptomatic subjects was observed. A positive correlation (p=0.0015 between TNF-β and IFN-γ was observed in the asymptomatic group, but a positive correlation was only observed (p=0.0180 between TNF-α and IL-6 in the HAM/TSP group. The proviral load was significantly higher in HAM/TSP patients than in asymptomatic subjects. The present results do not support a previous report indicating an association between the SNP rs12979860 and HAM/TSP outcome.

  4. Is nodding syndrome an Onchocerca volvulus-induced neuroinflammatory disorder? Uganda's story of research in understanding the disease

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    Richard Idro

    2016-04-01

    Full Text Available Nodding syndrome is a devastating neurological disorder, mostly affecting children in eastern Africa. An estimated 10 000 children are affected. Uganda, one of the most affected countries, set out to systematically investigate the disease and develop interventions for it. On December 21, 2015, the Ministry of Health held a meeting with community leaders from the affected areas to disseminate the results of the investigations made to date. This article summarizes the presentation and shares the story of studies into this peculiar disease. It also shares the results of preliminary studies on its pathogenesis and puts into perspective an upcoming treatment intervention. Clinical and electrophysiological studies have demonstrated nodding syndrome to be a complex epilepsy disorder. A definitive aetiological agent has not been established, but in agreement with other affected countries, a consistent epidemiological association has been demonstrated with infection by Onchocerca volvulus. Preliminary studies of its pathogenesis suggest that nodding syndrome may be a neuroinflammatory disorder, possibly induced by antibodies to O. volvulus cross-reacting with neuron proteins. Histological examination of post-mortem brains has shown some yet to be characterized polarizable material in the majority of specimens. Studies to confirm these observations and a clinical trial are planned for 2016.

  5. CNF1 increases brain energy level, counteracts neuroinflammatory markers and rescues cognitive deficits in a murine model of Alzheimer's disease.

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    Stefano Loizzo

    Full Text Available Overexpression of pro-inflammatory cytokines and cellular energy failure are associated with neuroinflammatory disorders, such as Alzheimer's disease. Transgenic mice homozygous for human ApoE4 gene, a well known AD and atherosclerosis animal model, show decreased levels of ATP, increased inflammatory cytokines level and accumulation of beta amyloid in the brain. All these findings are considered responsible for triggering cognitive decline. We have demonstrated that a single administration of the bacterial E. coli protein toxin CNF1 to aged apoE4 mice, beside inducing a strong amelioration of both spatial and emotional memory deficits, favored the cell energy restore through an increment of ATP content. This was accompanied by a modulation of cerebral Rho and Rac1 activity. Furthermore, CNF1 decreased the levels of beta amyloid accumulation and interleukin-1β expression in the hippocampus. Altogether, these data suggest that the pharmacological modulation of Rho GTPases by CNF1 can improve memory performances in an animal model of Alzheimer's disease via a control of neuroinflammation and a rescue of systemic energy homeostasis.

  6. Comorbidity between HTLV-1-associated adult T-cell lymphoma/leukemia and verrucous carcinoma: a case report.

    Science.gov (United States)

    Valencia, Miller; Moreno, Luis

    2017-03-30

    Adult T-cell Leukemia/Lymphoma (ATLL) is classified as a peripheral CD4+ T-cell neoplasm caused by the human T-cell lymphotropic virus type 1 (HTLV-1). Typical symptoms are associated with leukemic infiltration; however, atypical and exaggerated manifestations of verrucous carcinoma have also been described. We present here the case of a patient with multiple skin lesions, ischemic necrosis in the hallux and lymphadenopathies. Biopsies were taken, which showed verrucous epidermal carcinoma and cutaneous lymphoma. Splenomegaly and adenopathy in mesentery, retro peritoneum and lymph node chains in the limbs were observed. Bone marrow examination showed findings compatible with T-cell leukemia/lymphoma; and it was ELISA positive for HTLV-1/2. The patient had a good initial response to a CHOP scheme (cyclophosphamide, doxorubicin, vincristine and prednisone) with filgrastim. However, the patient had a relapse and died before the second cycle. Comorbidity could lead to the associated risk factors model. According to this model, secondary immunodeficiency caused by HTLV-1 may induce the development of verrucous carcinomas; alternatively, the disease could be due to a correlation between HTLV-1 and the human papillomavirus (HPV).

  7. Mediators Go Together: High Production of CXCL9, CXCL10, IFN-γ, and TNF-α in HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis.

    Science.gov (United States)

    Neco, Heytor Victor Pereira da Costa; Teixeira, Vanessa Gabryelle da Silva; da Trindade, Ana Carolina Lemos; Magalhães, Paula Machado Ribeiro; de Lorena, Virgínia Maria Barros; Castellano, Lúcio Roberto Cançado; de Souza, Joelma Rodrigues; Vasconcelos, Luydson Richardson; de Moura, Patrícia Muniz Mendes Freire; de Morais, Clarice Neuenschwander Lins

    2017-07-25

    HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a chronic demyelinating and disabling syndrome caused by human T lymphotropic virus 1 (HTLV-1). Although the pathogenic mechanisms that lead to HAM/TSP outcome have not been elucidated, genetic and immunological factors may be involved in the myelopathy occurrence. This study aimed to compare cytokines, chemokines, and nitric oxide (NO) levels in asymptomatic and HAM/TSP HTLV-1-infected patients. The study group consisted of 21 HAM/TSP and 48 asymptomatic HTLV-1 patients. Chemokines (CCL5, CCL2, CXCL8, CXCL9, and CXCL10) and cytokines [IL-2, interferon gamma (IFN-γ), tumor necrosis factor alpha (TNF-α), IL-4, IL-6, and IL-10] were measured using cytometric bead array, whereas NO production was measured after reaction of supernatants with nitrate reduction solution. CXCL9 and CXCL10 chemokines levels were found to be higher in the HAM/TSP group. CXCL9 was also strongly correlated with CXCL10 and both CXCL9 and CXCL10 were moderately correlated with CCL2 and CCL5 levels, in both HAM/TSP and asymptomatic groups. There was no significant difference related to NO, IL-4, IL-6, and IL-10 levels between the clinical groups but TNF-α and IFN-γ levels were increased in HAM/TSP patients. Thus, factors such as CXCL9, CXCL10, TNF-α, and IFN-γ could be good prognostic biomarker candidates, and further studies may help to clarify their association with HAM/TSP immunopathogenesis.

  8. CCR5 blockade for neuroinflammatory diseases--beyond control of HIV.

    Science.gov (United States)

    Martin-Blondel, Guillaume; Brassat, David; Bauer, Jan; Lassmann, Hans; Liblau, Roland S

    2016-02-01

    Chemokine receptors have been implicated in a wide range of CNS inflammatory diseases and have important roles in the recruitment and positioning of immune cells within tissues. Among them, the chemokine (C-C motif) receptor 5 (CCR5) can be targeted by maraviroc, a readily available and well-tolerated drug that was developed for the treatment of HIV. Correlative evidence implicates the CCR5-chemokine axis in multiple sclerosis, Rasmussen encephalitis, progressive multifocal leukoencephalopathy-associated immune reconstitution inflammatory syndrome, and infectious diseases, such as cerebral malaria and HIV-associated neurocognitive disorders. On the basis of this evidence, we postulate in this Review that CCR5 antagonists, such as maraviroc, offer neuroprotective benefits in settings in which CCR5 promotes deleterious neuroinflammation, particularly in diseases in which CD8(+) T cells seem to play a pivotal role.

  9. CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases.

    Science.gov (United States)

    Kerrn-Jespersen, B M; Lindelof, M; Illes, Zsolt; Blaabjerg, Morten; Lund, E L; Klausen, C; Christiansen, I; Sellebjerg, F; Kondziella, D

    2014-08-15

    Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast-enhancing perivascular lesions with a "salt-and-pepper" appearance on MRI, and 3) angiocentric, predominantly T-lymphocytic infiltration as revealed by brain biopsy. Inflammatory diseases including neuroinfections, CNS lymphoma and neurosarcoidosis must be excluded. Since CLIPPERS was described in 2010, many patients might have been misdiagnosed in the past. We therefore searched medical records from a large tertiary neurological center, the Department of Neurology at Rigshospitalet, Copenhagen University Hospital, for patients discharged between 1999 and 2013 with a diagnosis of "sarcoidosis with other localization", "other acute disseminating demyelination", "other demyelinating disease in the CNS" or "encephalitis, myelitis or encephalomyelitis". Of 206 identified patients, 24 had been examined by brain biopsy and were included for further evaluation. Following clinical, neuroradiological and neuropathological review, 3 patients (12.5%) were reclassified as having CLIPPERS. Median long-term follow-up was 75 months. The present results suggest that clinical re-evaluation of patients previously diagnosed with unspecified inflammatory demyelinating CNS disease or atypical neurosarcoidosis may increase the detection rate of CLIPPERS. Further, potentially severe neurological deficits and progressive parenchymal atrophy on MRI may suggest neurodegenerative features, which emphasizes the need for early immunomodulatory treatment.

  10. Mielopatia associada ao vírus linfotrópico humanode células T do tipo 1 (HTLV-1 Human T-cell lymphotropic virus type 1(HTLV-1 - associated myelopathy

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    João Gabriel Ramos Ribas

    2002-08-01

    Full Text Available A mielopatia associada ao HTLV-1 (HAM, também conhecida como paraparesia espástica tropical (TSP, é uma doença desmielinizante crônica progressiva que afeta a medula espinal e a substância branca do cérebro. Menos de 5% dos portadores crônicos do HTLV-1 desenvolverão essa complicação. As primeiras manifestações da doença ocorrem na quarta década da vida e observa-se relação mulher/homem de 2:1. Os distúrbios da marcha, a fraqueza e o enrijecimento dos membros inferiores constituem os principais sinais e sintomas de apresentação da mielopatia. As extremidades inferiores são afetadas com maior intensidade do que as extremidades superiores. A espasticidade pode variar de moderada a intensa e a dor lombar baixa revela-se comum. Com a progressão da doença há, com freqüência, disfunção vesical e intestinal. O envolvimento sensitivo mostra-se discreto e manifesta-se com graus variados de perdas sensitivas e sensação de disestesia. A ressonância nuclear magnética do sistema nervoso pode resultar normal ou revelar atrofia da medula espinal e alterações inespecíficas no cérebro. Há evidências de envolvimento imunológico na gênese da lesão medular. Não há tratamento eficaz para a mielopatia. Os corticoesteróides e o interferon-a produziram benefícios transitórios no tratamento da doença. Não houve melhora da marcha e da disfunção vesical em pacientes que usaram o danazol, um esteróide anabolizante. O valor da zidovudina (anti-retroviral no tratamento da mielopatia ainda não se encontra definido.HTLV-1-associated myelopathy (HAM, also known as tropical spastic paraparesis (TSP, is a chronic progressive demyelinating disease that affects the spinal cord and white matter of the central nervous system. The lifetime incidence of HAM in HTLV-1 carriers is estimated to be less than 5%. Typical time of onset is in the fourth decade of life, with a female-to-male rate of 2:1. Gait disturbance and weakness and

  11. Family Aggregation of Human T-Lymphotropic Virus 1-Associated Diseases: A Systematic Review

    Science.gov (United States)

    Alvarez, Carolina; Gotuzzo, Eduardo; Vandamme, Anne-Mieke; Verdonck, Kristien

    2016-01-01

    Human T-lymphotropic virus 1 (HTLV-1) is a retrovirus that produces a persistent infection. Two transmission routes (from mother to child and via sexual intercourse) favor familial clustering of HTLV-1. It is yet unknown why most HTLV-1 carriers remain asymptomatic while about 10% of them develop complications. HTLV-1 associated diseases were originally described as sporadic entities, but familial presentations have been reported. To explore what is known about family aggregation of HTLV-1-associated diseases we undertook a systematic review. We aimed at answering whether, when, and where family aggregation of HTLV-1-associated diseases was reported, which relatives were affected and which hypotheses were proposed to explain aggregation. We searched MEDLINE, abstract books of HTLV conferences and reference lists of selected papers. Search terms used referred to HTLV-1 infection, and HTLV-1-associated diseases, and family studies. HTLV-1-associated diseases considered are adult T-cell leukemia/lymphoma (ATLL), HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), HTLV-1-associated uveitis, and infective dermatitis. Seventy-four records reported HTLV-1-associated diseases in more than one member of the same family and were included. Most reports came from HTLV-1-endemic countries, mainly Japan (n = 30) and Brazil (n = 10). These reports described a total of 270 families in which more than one relative had HTLV-1-associated diseases. In most families, different family members suffered from the same disease (n = 223). The diseases most frequently reported were ATLL (115 families) and HAM/TSP (102 families). Most families (n = 144) included two to four affected individuals. The proportion of ATLL patients with family history of ATLL ranged from 2 to 26%. The proportion of HAM/TSP patients with family history of HAM/TSP ranged from 1 to 48%. The predominant cluster types for ATLL were clusters of siblings and parent-child pairs and for HAM/TSP, an affected

  12. Pentosan polysulfate treatment ameliorates motor function with increased serum soluble vascular cell adhesion molecule-1 in HTLV-1-associated neurologic disease.

    Science.gov (United States)

    Nakamura, Tatsufumi; Satoh, Katsuya; Fukuda, Taku; Kinoshita, Ikuo; Nishiura, Yoshihiro; Nagasato, Kunihiko; Yamauchi, Atsushi; Kataoka, Yasufumi; Nakamura, Tadahiro; Sasaki, Hitoshi; Kumagai, Kenji; Niwa, Masami; Noguchi, Mitsuru; Nakamura, Hideki; Nishida, Noriyuki; Kawakami, Atsushi

    2014-06-01

    The main therapeutic strategy against human T lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) characterized by lower extremity motor dysfunction is immunomodulatory treatment, with drugs such as corticosteroid hormone and interferon-α, at present. However, there are many issues in long-term treatment with these drugs, such as insufficient effects and various side effects. We now urgently need to develop other therapeutic strategies. The heparinoid, pentosan polysulfate sodium (PPS), has been safely used in Europe for the past 50 years as a thrombosis prophylaxis and for the treatment of phlebitis. We conducted a clinical trial to test the effect of subcutaneous administration of PPS in 12 patients with HAM/TSP in an open-labeled design. There was a marked improvement in lower extremity motor function, based on reduced spasticity, such as a reduced time required for walking 10 m and descending a flight of stairs. There were no significant changes in HTLV-I proviral copy numbers in peripheral blood contrary to the inhibitory effect of PPS in vitro for intercellular spread of HTLV-I. However, serum soluble vascular cell adhesion molecule (sVCAM)-1 was significantly increased without significant changes of serum level of chemokines (CXCL10 and CCL2). There was a positive correlation between increased sVCAM-1and reduced time required for walking 10 m. PPS might induce neurological improvement by inhibition of chronic inflammation in the spinal cord, through blocking the adhesion cascade by increasing serum sVCAM-1, in addition to rheological improvement of the microcirculation. PPS has the potential to be a new therapeutic tool for HAM/TSP.

  13. Triple Therapy with Prednisolone, Pegylated Interferon and Sodium Valproate Improves Clinical Outcome and Reduces Human T-Cell Leukemia Virus Type 1 (HTLV-1) Proviral Load, Tax and HBZ mRNA Expression in Patients with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis

    National Research Council Canada - National Science Library

    Boostani, Reza; Vakili, Rosita; Hosseiny, Samane Sadat; Shoeibi, Ali; Fazeli, Bahare; Etemadi, Mohammad Mehdi; Sabet, Faeze; Valizade, Narges; Rezaee, Seyed Abdolrahim

    2015-01-01

    .... HTLV-1 proviral load (PVL), and HBZ and Tax mRNA expression levels were measured in peripheral blood mononuclear cells of 13 patients with HTLV-1-associated myelopathy/tropical spastic paraparesis before and after treatment with 180 μ...

  14. Neuroinflammatory modulators of oligodendrogenesis

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    Ana Armada-Moreira

    2015-01-01

    Full Text Available Oligodendrocytes are key neural cells that are responsible for producing myelin sheaths that wrap around neuronal axons in the central nervous system. Myelin is essential to insulate neurons and maintain a fast and saltatory propagation of action potentials along the axon. However, oligodendrocytes are very susceptible to damage, and thus demyelination may arise from a brain lesion or a neurodegenerative disorder. Consequently, demyelination produces a loss of axonal insulation leading to sensory or motor neuron failure. During adulthood, there are two main sources of oligodendrocytes: parenchymal oligodendrocyte precursor cells (OPCs and subventricular zone derived OPCs. In this review, we will discuss oligodendrogenesis derived from these two sources, and also highlight their main extrinsic and intrinsic modulators. In addition, the neuroinflammatory mediators of oligodendrogenesis will also be assessed.

  15. Modelling neuroinflammatory phenotypes in vivo

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    Wyss-Coray Tony

    2004-07-01

    Full Text Available Abstract Inflammation of the central nervous system is an important but poorly understood part of neurological disease. After acute brain injury or infection there is a complex inflammatory response that involves activation of microglia and astrocytes and increased production of cytokines, chemokines, acute phase proteins, and complement factors. Antibodies and T lymphocytes may be involved in the response as well. In neurodegenerative disease, where injury is more subtle but consistent, the inflammatory response is continuous. The purpose of this prolonged response is unclear, but it is likely that some of its components are beneficial and others are harmful. Animal models of neurological disease can be used to dissect the specific role of individual mediators of the inflammatory response and assess their potential benefit. To illustrate this approach, we discuss how mutant mice expressing different levels of the cytokine transforming growth factor β-1 (TGF-β1, a major modulator of inflammation, produce important neuroinflammatory phenotypes. We then demonstrate how crosses of TGF-β1 mutant mice with mouse models of Alzheimer's disease (AD produced important new information on the role of inflammation in AD and on the expression of different neuropathological phenotypes that characterize this disease.

  16. The frequency of CD127low expressing CD4+CD25high T regulatory cells is inversely correlated with human T lymphotrophic virus type-1 (HTLV-1 proviral load in HTLV-1-infection and HTLV-1-associated myelopathy/tropical spastic paraparesis

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    Chieia Marco

    2008-07-01

    Full Text Available Abstract Background CD4+CD25high regulatory T (TReg cells modulate antigen-specific T cell responses, and can suppress anti-viral immunity. In HTLV-1 infection, a selective decrease in the function of TReg cell mediated HTLV-1-tax inhibition of FOXP3 expression has been described. The purpose of this study was to assess the frequency and phenotype of TReg cells in HTLV-1 asymptomatic carriers and in HTLV-1-associated neurological disease (HAM/TSP patients, and to correlate with measures of T cell activation. Results We were able to confirm that HTLV-I drives activation, spontaneous IFNγ production, and proliferation of CD4+ T cells. We also observed a significantly lower proportion of CTLA-4+ TReg cells (CD4+CD25high T cells in subjects with HAM/TSP patients compared to healthy controls. Ki-67 expression was negatively correlated to the frequency of CTLA-4+ TReg cells in HAM/TSP only, although Ki-67 expression was inversely correlated with the percentage of CD127low TReg cells in healthy control subjects. Finally, the proportion of CD127low TReg cells correlated inversely with HTLV-1 proviral load. Conclusion Taken together, the results suggest that TReg cells may be subverted in HAM/TSP patients, which could explain the marked cellular activation, spontaneous cytokine production, and proliferation of CD4+ T cells, in particular those expressing the CD25highCD127low phenotype. TReg cells represent a potential target for therapeutic intervention for patients with HTLV-1-related neurological diseases.

  17. Therapeutic versus neuroinflammatory effects of passive immunization is dependent on Aβ/amyloid burden in a transgenic mouse model of Alzheimer's disease

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    Bosetti Francesca

    2010-09-01

    Full Text Available Abstract Background Passive immunization with antibodies directed to Aβ decreases brain Aβ/amyloid burden and preserves memory in transgenic mouse models of Alzheimer's disease (AD. This therapeutic strategy is under intense scrutiny in clinical studies, but its application is limited by neuroinflammatory side effects (autoimmune encephalitis and vasogenic edema. Methods We intravenously administered the monoclonal Aβ protofibril antibody PFA1 to aged (22 month male and female 3 × tg AD mice with intermediate or advanced AD-like neuropathologies, respectively, and measured brain and serum Aβ and CNS cytokine levels. We also examined 17 month old 3 × tg AD female mice with intermediate pathology to determine the effect of amyloid burden on responses to passive immunization. Results The 22 month old male mice immunized with PFA1 had decreased brain Aβ, increased serum Aβ, and no change in CNS cytokine levels. In contrast, 22 month old immunized female mice revealed no change in brain Aβ, decreased serum Aβ, and increased CNS cytokine levels. Identical experiments in younger (17 month old female 3 × tg AD mice with intermediate AD-like neuropathologies revealed a trend towards decreased brain Aβ and increased serum Aβ accompanied by a decrease in CNS MCP-1. Conclusions These data suggest that passive immunization with PFA1 in 3 × tg AD mice with intermediate disease burden, regardless of sex, is effective in mediating potentially therapeutic effects such as lowering brain Aβ. In contrast, passive immunization of mice with a more advanced amyloid burden may result in potentially adverse effects (encephalitis and vasogenic edema mediated by certain proinflammatory cytokines.

  18. IL28B gene polymorphism SNP rs8099917 genotype GG is associated with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP in HTLV-1 carriers.

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    Tatiane Assone

    2014-09-01

    Full Text Available The polymorphisms of IL28B have been described as important in the pathogenesis of infections caused by some viruses. The aim of this research was to evaluate whether IL28B gene polymorphisms (SNP rs8099917 and SNP rs12979860 are associated with HAM/TSP.The study included 229 subjects, classified according to their neurological status in two groups: Group I (136 asymptomatic HTLV-1 carriers and Group II (93 HAM/TSP patients. The proviral loads were quantified, and the rs8099917 and rs12979860 SNPs in the region of IL28B-gene were analyzed by StepOnePlus Real-time PCR System.A multivariate model analysis, including gender, age, and HTLV-1 DNA proviral load, showed that IL28B polymorphisms were independently associated with HAM/TSP outcome in rs12979860 genotype CT (OR = 2.03; IC95% = 0.96-4.27 and in rs8099917 genotype GG (OR = 7.61; IC95%  = 1.82-31.72.Subjects with SNP rs8099917 genotype GG and rs12979618 genotype CT may present a distinct immune response against HTLV-1 infection. So, it seems reasonable to suggest that a search for IL28B polymorphisms should be performed for all HTLV-1-infected subjects in order to monitor their risk for disease development; however, since this is the first description of such finding in the literature, we should first replicate this study with more HTLV-1-infected persons to strengthen the evidence already provided by our results.

  19. IL28B Gene Polymorphism SNP rs8099917 Genotype GG Is Associated with HTLV-1-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) in HTLV-1 Carriers

    Science.gov (United States)

    Luiz, Olinda do Carmo; Malta, Fernanda; Pinho, João Renato Rebello; Gonçalves, Fernanda de Toledo; Duarte, Alberto Jose da Silva; de Oliveira, Augusto Cesar Penalva

    2014-01-01

    Background The polymorphisms of IL28B have been described as important in the pathogenesis of infections caused by some viruses. The aim of this research was to evaluate whether IL28B gene polymorphisms (SNP rs8099917 and SNP rs12979860) are associated with HAM/TSP. Methods The study included 229 subjects, classified according to their neurological status in two groups: Group I (136 asymptomatic HTLV-1 carriers) and Group II (93 HAM/TSP patients). The proviral loads were quantified, and the rs8099917 and rs12979860 SNPs in the region of IL28B-gene were analyzed by StepOnePlus Real-time PCR System. Results A multivariate model analysis, including gender, age, and HTLV-1 DNA proviral load, showed that IL28B polymorphisms were independently associated with HAM/TSP outcome in rs12979860 genotype CT (OR = 2.03; IC95% = 0.96–4.27) and in rs8099917 genotype GG (OR = 7.61; IC95% = 1.82–31.72). Conclusion Subjects with SNP rs8099917 genotype GG and rs12979618 genotype CT may present a distinct immune response against HTLV-1 infection. So, it seems reasonable to suggest that a search for IL28B polymorphisms should be performed for all HTLV-1-infected subjects in order to monitor their risk for disease development; however, since this is the first description of such finding in the literature, we should first replicate this study with more HTLV-1-infected persons to strengthen the evidence already provided by our results. PMID:25233462

  20. Injury-stimulated Sonic hedgehog expression in microglia contributes to neuroinflammatory response in the MPTP model of Parkinson's disease.

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    Lee, Jeong Hwi; Chung, Young Cheul; Bok, Eugene; Lee, Hankyu; Huh, Sue Hee; Lee, Ji Eun; Jin, Byung Kwan; Ko, Hyuk Wan

    2017-01-22

    Parkinson's disease (PD) is a progressive neurodegenerative disorder in which dopamine (DA) neurons in the substantia nigra pars compacta (SNpc) region are selectively destroyed. Sonic hedgehog (Shh) has been well known to play a key role in a variety of processes such as embryogenesis, cell proliferation and protection, and tissue repair during inflammation. However, the evidences for the innate role of Shh in adult brain injury are presently lacking and studies have been needed to unveil the importance of Shh in the process of neurodegeneration. Here, we investigated the role of Shh in the pathologic progress of Parkinson's disease in MPTP-induced animal model system. Interestingly, we observed that Shh expression was gradually increased in MPTP affected SNpc region. Activated microglia exclusively expressed SHH in vivo and we could recapitulate Shh induction in activated cultured primary microglia cells. Using the SHH responsive Cre-loxP binary genetic reporter transgenic mouse system, we also found that most of the cell types except for oligodendrocyte in the SNpc region reacted to the SHH by MPTP injection. Taken together, activated microglia induced Shh expression and most neural cells except oligodendrocyte responded to microglia-derived SHH in MPTP-treated SN. These results suggest that SHH in activated microglia by MPTP-injection might be involved in the innate processes of recovery from neurotoxin induced injury in the PD animal model system. Copyright © 2016 Elsevier Inc. All rights reserved.

  1. Age-related neuroinflammatory changes negatively impact on neuronal function

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    Marina A Lynch

    2010-01-01

    Full Text Available Neuroinflammatory changes, characterized by an increase in microglial activation and often accompanied by upregulation of inflammatory cytokines like interleukin-1β (IL-1β, are common to many, if not all, neurodegenerative diseases. Similar, though less dramatic neuroinflammatory changes are also known to occur with age. Among the consequences of these changes is an impairment in synaptic function and the evidence suggests that inflammatory cytokines may be the primary contributory factor responsible for the deficits in synaptic plasticity which have been identified in aged rodents. Specifically a decrease in the ability of aged rats to sustain long-term potentiation (LTP in perforant path-granule cells of the hippocampus is associated with increased microglial activation. This review considers the evidence which suggests a causal relationship between these changes and the factors which contribute to the age-related microglial activation, and reflects on data which demonstrate that agents which inhibit microglial activation also improve ability of rats to sustain LTP.

  2. Anti-Neuroinflammatory effects of the extract of Achillea fragrantissima

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    Rindner Miriam

    2011-10-01

    Full Text Available Abstract Background The neuroinflammatory process plays a central role in the initiation and progression of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases, and involves the activation of brain microglial cells. During the neuroinflammatory process, microglial cells release proinflammatory mediators such as cytokines, matrix metalloproteinases (MMP, Reactive oxygen species (ROS and nitric oxide (NO. In the present study, extracts from 66 different desert plants were tested for their effect on lipopolysaccharide (LPS - induced production of NO by primary microglial cells. The extract of Achillea fragrantissima (Af, which is a desert plant that has been used for many years in traditional medicine for the treatment of various diseases, was the most efficient extract, and was further studied for additional anti-neuroinflammatory effects in these cells. Methods In the present study, the ethanolic extract prepared from Af was tested for its anti-inflammatory effects on lipopolysaccharide (LPS-activated primary cultures of brain microglial cells. The levels of the proinflammatory cytokines interleukin1β (IL-1β and tumor necrosis factor-α (TNFα secreted by the cells were determined by reverse transcriptase-PCR and Enzyme-linked immunosorbent assay (ELISA, respectively. NO levels secreted by the activate cells were measured using Griess reagent, ROS levels were measured by 2'7'-dichlorofluorescein diacetate (DCF-DA, MMP-9 activity was measured using gel zymography, and the protein levels of the proinflammatory enzymes cyclooxygenase-2 (COX-2 and induced nitric oxide synthase (iNOS were measured by Western blot analysis. Cell viability was assessed using Lactate dehydrogenase (LDH activity in the media conditioned by the cells or by the crystal violet cell staining. Results We have found that out of the 66 desert plants tested, the extract of Af was the most efficient extract and inhibited ~70% of the NO produced by the LPS

  3. Microbiota Dysbiosis Controls the Neuroinflammatory Response after Stroke.

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    Singh, Vikramjeet; Roth, Stefan; Llovera, Gemma; Sadler, Rebecca; Garzetti, Debora; Stecher, Bärbel; Dichgans, Martin; Liesz, Arthur

    2016-07-13

    Acute brain ischemia induces a local neuroinflammatory reaction and alters peripheral immune homeostasis at the same time. Recent evidence has suggested a key role of the gut microbiota in autoimmune diseases by modulating immune homeostasis. Therefore, we investigated the mechanistic link among acute brain ischemia, microbiota alterations, and the immune response after brain injury. Using two distinct models of acute middle cerebral artery occlusion, we show by next-generation sequencing that large stroke lesions cause gut microbiota dysbiosis, which in turn affects stroke outcome via immune-mediated mechanisms. Reduced species diversity and bacterial overgrowth of bacteroidetes were identified as hallmarks of poststroke dysbiosis, which was associated with intestinal barrier dysfunction and reduced intestinal motility as determined by in vivo intestinal bolus tracking. Recolonizing germ-free mice with dysbiotic poststroke microbiota exacerbates lesion volume and functional deficits after experimental stroke compared with the recolonization with a normal control microbiota. In addition, recolonization of mice with a dysbiotic microbiome induces a proinflammatory T-cell polarization in the intestinal immune compartment and in the ischemic brain. Using in vivo cell-tracking studies, we demonstrate the migration of intestinal lymphocytes to the ischemic brain. Therapeutic transplantation of fecal microbiota normalizes brain lesion-induced dysbiosis and improves stroke outcome. These results support a novel mechanism in which the gut microbiome is a target of stroke-induced systemic alterations and an effector with substantial impact on stroke outcome. We have identified a bidirectional communication along the brain-gut microbiota-immune axis and show that the gut microbiota is a central regulator of immune homeostasis. Acute brain lesions induced dysbiosis of the microbiome and, in turn, changes in the gut microbiota affected neuroinflammatory and functional outcome

  4. Neuroinflammatory Mechanisms Linking Pain and Depression.

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    Burke, Nikita N; Finn, David P; Roche, Michelle

    2015-01-01

    Depression and chronic pain have been estimated to co-occur in up to 80% of patients suffering from these disorders, with this co-morbidity being more disabling and more expensive to both patients and society than either disorder alone. A number of neural substrates have been proposed to underlie this association; however, there has been increased interest and support for a role of neuroimmune and neuroinflammatory mechanisms as key players in this dyad. This chapter will provide an overview of the clinical and preclinical data supporting a role for neuroimmune alterations in depression-pain co-morbidity. We propose that such changes may impact on the functioning of key brain regions modulating emotional and nociceptive processing, thus resulting in the behavioural, psychological and physical symptoms observed in patients exhibiting depression and co-morbid pain.

  5. Anti-neuroinflammatory constituents from Asparagus cochinchinensis.

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    Jian, Rui; Zeng, Ke-Wu; Li, Jun; Li, Ning; Jiang, Yong; Tu, Pengfei

    2013-01-01

    Three new pregnane glycosides, aspacochinosides N (1), O (2), and P (3) were isolated from the roots of Asparagus cochinchinensis, together with four known furostanol glycosides. Their structures were determined by chemical methods and NMR spectral analysis, including extensive 1D and 2D NMR experiments. Compounds 1-7 were evaluated for their anti-neuroinflammatory activity in LPS-induced BV-2 microglial cells. Compounds 2, 3, and 4 showed significant inhibition on NO production in LPS-induced BV-2 microglial cells with IC(50) values of 13.51, 4.72, and 63.57μM, respectively. Copyright © 2012 Elsevier B.V. All rights reserved.

  6. T CD4+ cells count among patients co-infected with human immunodeficiency virus type 1 (HIV-1 and human T-cell leukemia virus type 1 (HTLV-1: high prevalence of tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM Contagens de células T CD4+ na co-infecção HIV-1 e HTLV-1: alta prevalência da paraparesia espástica tropical/mielopatia associada ao HTLV-1

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    Jorge Casseb

    2007-08-01

    Full Text Available INTRODUCTION: HIV positive patients co-infected with HTLV-1 may have an increase in their T CD4+ cell counts, thus rendering this parameter useless as an AIDS-defining event. OBJECTIVE: To study the effects induced by the co-infection of HIV-1 and HTLV-1 upon CD4+ cells. MATERIAL AND METHODS: Since 1997, our group has been following a cohort of HTLV-1-infected patients, in order to study the interaction of HTLV-1 with HIV and/or with hepatitis C virus (HCV, as well as HTLV-1-only infected asymptomatic carriers and those with tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM. One hundred and fifty HTLV-1-infected subjects have been referred to our clinic at the Institute of Infectious Diseases "Emílio Ribas", São Paulo. Twenty-seven of them were also infected with HIV-1 and HTLV-1-infection using two ELISAs and confirmed and typed by Western Blot (WB or polymerase chain reaction (PCR. All subjects were evaluated by two neurologists, blinded to the patient's HTLV status, and the TSP/HAM diagnostic was based on the World Health Organization (WHO classification. AIDS-defining events were in accordance with the Centers for Disease Control (CDC classification of 1988. The first T CD4+ cells count available before starting anti-retroviral therapy are shown compared to the HIV-1-infected subjects at the moment of AIDS defining event. RESULTS: A total of 27 HIV-1/HTLV-1 co-infected subjects were identified in this cohort; 15 already had AIDS and 12 remained free of AIDS. The median of T CD4+ cell counts was 189 (98-688 cells/mm³ and 89 (53-196 cells/mm³ for co-infected subjects who had an AIDS-defining event, and HIV-only infected individuals, respectively (p = 0.036. Eight of 27 co-infected subjects (30% were diagnosed as having a TSP/HAM simile diagnosis, and three of them had opportunistic infections but high T CD4+ cell counts at the time of their AIDS- defining event. DISCUSSION: Our results indicate that higher T CD4+ cells

  7. Rodent Models of Depression: Neurotrophic and Neuroinflammatory Biomarkers

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    Mikhail Stepanichev

    2014-01-01

    Full Text Available Rodent models are an indispensable tool for studying etiology and progress of depression. Since interrelated systems of neurotrophic factors and cytokines comprise major regulatory mechanisms controlling normal brain plasticity, impairments of these systems form the basis for development of cerebral pathologies, including mental diseases. The present review focuses on the numerous experimental rodent models of depression induced by different stress factors (exteroceptive and interoceptive during early life (including prenatal period or adulthood, giving emphasis to the data on the changes of neurotrophic factors and neuroinflammatory indices in the brain. These parameters are closely related to behavioral depression-like symptoms and impairments of neuronal plasticity and are both gender- and genotype-dependent. Stress-related changes in expression of neurotrophins and cytokines in rodent brain are region-specific. Some contradictory data reported by different groups may be a consequence of differences of stress paradigms or their realization in different laboratories. Like all experimental models, stress-induced depression-like conditions are experimental simplification of clinical depression states; however, they are suitable for understanding the involvement of neurotrophic factors and cytokines in the pathogenesis of the disease—a goal unachievable in the clinical reality. These major regulatory systems may be important targets for therapeutic measures as well as for development of drugs for treatment of depression states.

  8. A novel anti-neuroinflammatory pyridylimidazole compound KR-31360.

    Science.gov (United States)

    Ock, Jiyeon; Kim, Sangseop; Yi, Kyu-Yang; Kim, Nak-Jung; Han, Hyung Soo; Cho, Je-Yoel; Suk, Kyoungho

    2010-02-15

    Excessive microglial activation with overexpression of proinflammatory cytokines and oxidative stress products is linked to the progression of several neurodegenerative diseases; therefore, suppression of microglial activation is a potential therapeutic approach against these diseases. Since nitric oxide (NO) is one of the major inflammatory mediators that are produced by activated microglia, inhibitory effects of novel synthetic compounds on microglial NO production were investigated. From the mouse microglia cell-based assays, an imidazo [4,5-b] pyridine compound KR-31360 was identified as an inhibitor of microglial NO production with an IC(50) value of 2 microM. Structure-activity relationship study indicated that 5-position of imidazo [4,5-b] pyridine ring is critical for the activity. KR-31360 also inhibited lipopolysaccharide (LPS)-induced secretion of tumor necrosis factor alpha (TNF-alpha) and transcription of TNF-alpha, interleukin-1 beta, and inducible nitric oxide synthase as well as activation of nuclear factor kappa B and mitogen-activated protein kinases. KR-31360 was neuroprotective by suppressing microglial neurotoxicity in a microglia-neuron coculture. The neuroprotective activity of the compound was most effective when microglia were pretreated with the compound prior to LPS challenge. The inhibitory effect of KR-31360 on microglial activation was further demonstrated in a mouse neuroinflammation model in vivo: compared to vehicle-injected animals, KR-31360 injection attenuated LPS-induced microglial activation as evidenced by isolectin B4 staining and proinflammatory gene expression of brain sections. DNA microarray analysis supported that KR-31360 targeted Toll-like receptor 4 pathways. In addition to being a new drug candidate against neuroinflammatory diseases, the compound may be a powerful tool for the better understanding of microglia biology and neuroinflammation.

  9. Peripheral and Central Neuroinflammatory Changes and Pain Behaviors in an Animal Model of Multiple Sclerosis.

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    Duffy, Samuel S; Perera, Chamini J; Makker, Preet G S; Lees, Justin G; Carrive, Pascal; Moalem-Taylor, Gila

    2016-01-01

    Pain is a widespread and debilitating symptom of multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system. Although central neuroinflammation and demyelination have been implicated in MS-related pain, the contribution of peripheral and central mechanisms during different phases of the disease remains unclear. In this study, we used the animal model experimental autoimmune encephalomyelitis (EAE) to examine both stimulus-evoked and spontaneous pain behaviors, and neuroinflammatory changes, over the course of chronic disease. We found that mechanical allodynia of the hind paw preceded the onset of clinical EAE but was unmeasurable at clinical peak. This mechanical hypersensitivity coincided with increased microglial activation confined to the dorsal horn of the spinal cord. The development of facial mechanical allodynia also emerged in preclinical EAE, persisted at the clinical peak, and corresponded with pathology of the peripheral trigeminal afferent pathway. This included T cell infiltration, which arose prior to overt central lesion formation and specific damage to myelinated neurons during the clinical peak. Measurement of spontaneous pain using the mouse grimace scale, a facial expression-based coding system, showed increased facial grimacing in mice with EAE during clinical disease. This was associated with multiple peripheral and central neuroinflammatory changes including a decrease in myelinating oligodendrocytes, increased T cell infiltration, and macrophage/microglia and astrocyte activation. Overall, these findings suggest that different pathological mechanisms may underlie stimulus-evoked and spontaneous pain in EAE, and that these behaviors predominate in unique stages of the disease.

  10. Peripheral and central neuroinflammatory changes and pain behaviours in an animal model of multiple sclerosis

    Directory of Open Access Journals (Sweden)

    Samuel Shaw Duffy

    2016-09-01

    Full Text Available Pain is a widespread and debilitating symptom of multiple sclerosis (MS, a chronic inflammatory demyelinating disease of the central nervous system. Although central neuroinflammation and demyelination have been implicated in MS-related pain, the contribution of peripheral and central mechanisms during different phases of the disease remains unclear. In this study, we used the animal model experimental autoimmune encephalomyelitis (EAE to examine both stimulus-evoked and spontaneous pain behaviours, and neuroinflammatory changes, over the course of chronic disease. We found that mechanical allodynia of the hind paw preceded the onset of clinical EAE, but was unmeasurable at clinical peak. This mechanical hypersensitivity coincided with increased microglial activation confined to the dorsal horn of the spinal cord. The development of facial mechanical allodynia also emerged in pre-clinical EAE, persisted at the clinical peak, and corresponded with pathology of the peripheral trigeminal afferent pathway. This included T cell infiltration, which arose prior to overt central lesion formation, and specific damage to myelinated neurons during the clinical peak. Measurement of spontaneous pain using the mouse grimace scale, a facial expression-based coding system, showed increased facial grimacing in mice with EAE during clinical disease. This was associated with multiple peripheral and central neuroinflammatory changes including a decrease in myelinating oligodendrocytes, increased T cell infiltration and macrophage/microglia and astrocyte activation. Overall, these findings suggest that different pathological mechanisms may underlie stimulus-evoked and spontaneous pain in EAE, and that these behaviours predominate in unique stages of the disease.

  11. Anti-Neuroinflammatory ent-Kaurane Diterpenoids from Pteris multifida Roots

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    Jung Wha Kim

    2016-12-01

    Full Text Available Activated microglia are known to be a major source of cellular neuroinflammation which causes various neurodegenerative diseases, including Alzheimer’s disease. In our continuing efforts to search for new bioactive phytochemicals against neuroinflammatory diseases, the 80% methanolic extract of Pteris multifida (Pteridaceae roots was found to exhibit significant NO inhibitory activity in lipopolysaccharide (LPS-activated BV-2 microglia cells. Three new ent-kaurane diterpenoids, pterokaurane M1 2-O-β-d-glucopyranoside (4, 2β,16α-dihydroxy-ent-kaurane 2,16-di-O-β-d-glucopyranoside (10, and 2β,16α,17-trihydroxy-ent-kaurane 2-O-β-d-glucopyranoside (12, were isolated along with nine other known compounds from P. multifida roots. The chemical structures of the new compounds were determined by 1D- and 2D-NMR, HR-ESI-MS, and CD spectroscopic data analysis. Among the isolates, compounds 1 and 7 significantly inhibited NO production in LPS-stimulated BV-2 cells reducing the expression of the cyclooxygenase-2 (COX-2 protein and the level of pro-inflammatory mediators such as prostaglandin E2 (PGE2, tumor necrosis factor (TNF-α, interleukin (IL-1β, and IL-6. These results suggest that ent-kaurane diterpenes from P. multifida could be potential lead compounds that act as anti-neuroinflammatory agents.

  12. Divergent Neuroinflammatory Regulation of Microglial TREM Expression and Involvement of NF-κB

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    Owens, Rosie; Grabert, Kathleen; Davies, Claire L.; Alfieri, Alessio; Antel, Jack P.; Healy, Luke M.; McColl, Barry W.

    2017-01-01

    The triggering receptor expressed on myeloid cells (TREM) family of proteins are cell surface receptors with important roles in regulation of myeloid cell inflammatory activity. In the central nervous system, TREM2 is implicated in further roles in microglial homeostasis, neuroinflammation and neurodegeneration. Different TREM receptors appear to have contrasting roles in controlling myeloid immune activity therefore the relative and co-ordinated regulation of their expression is important to understand but is currently poorly understood. We sought to determine how microglial TREM expression is affected under neuroinflammatory conditions in vitro and in vivo. Our data show that microglial Trem1 and Trem2 gene expression are regulated in an opposing manner by lipopolysaccharide (LPS) in vitro in both adult murine and human microglia. LPS caused a significant induction of Trem1 and a contrasting suppression of Trem2 expression. We also observed similar divergent Trem1 and Trem2 responses in vivo in response to acute brain inflammation and acute cerebral ischaemia. Our data show that inhibition of NF-κB activation prevents the LPS-induced alterations in both Trem1 and Trem2 expression in vitro indicating NF-κB as a common signaling intermediate controlling these divergent responses. Distinct patterns of microglial Trem1 induction and Trem2 suppression to different Toll-like receptor (TLR) ligands were also evident, notably with Trem1 induction restricted to those ligands activating TLRs signaling via TRIF. Our data show co-ordinated but divergent regulation of microglial TREM receptor expression with a central role for NF-κB. Neuroinflammatory conditions that alter the balance in TREM expression could therefore be an important influence on microglial inflammatory and homeostatic activity with implications for neuroinflammatory and neurodegenerative disease. PMID:28303091

  13. Evaluating the Anti-Neuroinflammatory Capacity of Raw and Steamed Garlic as Well as Five Organosulfur Compounds

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    Su-Chen Ho

    2014-10-01

    Full Text Available The anti-neuroinflammatory capacities of raw and steamed garlic extracts as well as five organosulfur compounds (OSCs were examined in lipopolysaccharide (LPS-stimulated BV2 microglia. According to those results, steaming pretreatment blocked the formation of alliinase-catalyzed OSCs such as allicin and diallyl trisulfide (DATS in crushed garlic. Raw garlic, but not steamed garlic, dose-dependently attenuated the production of LPS-induced nitric oxide (NO, interleukin-1β (IL-1β, tumor necrosis factor (TNF-α, and monocyte chemoattractant protein-1 (MCP-1. DATS and diallyl disulfide at 200 and 400 μM, respectively, displayed significant anti-neuroinflammatory activity. Meanwhile, even at 1 mM, diallyl sulfide, S-allyl cysteine and alliin did not display such activity. Inhibition of nuclear factor-κB activation was the mechanism underlying this protective effect of raw garlic and DATS. Analysis results indicated that the anti-neuroinflammatory capacity of raw garlic is due to the alliin-derived OSCs. Importantly, DATS is a highly promising therapeutic candidate for treating inflammation-related neurodegenerative diseases.

  14. Evaluating the anti-neuroinflammatory capacity of raw and steamed garlic as well as five organosulfur compounds.

    Science.gov (United States)

    Ho, Su-Chen; Su, Min-Sheng

    2014-10-31

    The anti-neuroinflammatory capacities of raw and steamed garlic extracts as well as five organosulfur compounds (OSCs) were examined in lipopolysaccharide (LPS)-stimulated BV2 microglia. According to those results, steaming pretreatment blocked the formation of alliinase-catalyzed OSCs such as allicin and diallyl trisulfide (DATS) in crushed garlic. Raw garlic, but not steamed garlic, dose-dependently attenuated the production of LPS-induced nitric oxide (NO), interleukin-1β (IL-1β), tumor necrosis factor (TNF)-α, and monocyte chemoattractant protein-1 (MCP-1). DATS and diallyl disulfide at 200 and 400 μM, respectively, displayed significant anti-neuroinflammatory activity. Meanwhile, even at 1 mM, diallyl sulfide, S-allyl cysteine and alliin did not display such activity. Inhibition of nuclear factor-κB activation was the mechanism underlying this protective effect of raw garlic and DATS. Analysis results indicated that the anti-neuroinflammatory capacity of raw garlic is due to the alliin-derived OSCs. Importantly, DATS is a highly promising therapeutic candidate for treating inflammation-related neurodegenerative diseases.

  15. Psychological effects of calisthenic exercises on neuroinflammatory and rheumatic diseases.

    Science.gov (United States)

    Taspinar, O; Aydın, T; Celebi, A; Keskin, Y; Yavuz, S; Guneser, M; Camli, A; Tosun, M; Canbaz, N; Gok, M

    2015-10-01

    The aim of this study was to evaluate the effects of calisthenic exercises on psychological status in patients with ankylosing spondylitis (AS) and multiple sclerosis (MS). This study comprised 40 patients diagnosed with AS randomized into two exercise groups (group 1 = hospital-based, group 2 = home-based) and 40 patients diagnosed with MS randomized into two exercise groups (group 1 = hospital-based, group 2 = home-based). The exercise programme was completed by 73 participants (hospital-based = 34, home-based = 39). Mean age was 33.75 ± 5.77 years. After the 8-week exercise programme in the AS group, the home-based exercise group showed significant improvements in erythrocyte sedimentation rates (ESR). The hospital-based exercise group showed significant improvements in terms of the Bath AS Metrology Index (BASMI) and Hospital Anxiety and Depression Scale-Anxiety (HADS-A) scores. After the 8-week exercise programme in the MS group, the home-based and hospital-based exercise groups showed significant improvements in terms of the 10-m walking test, Berg Balance Scale (BBS), HADS-A, and MS international Quality of Life (MusiQoL) scores. There was a significant improvement in the hospital-based and a significant deterioration in the home-based MS patients according to HADS-Depression (HADS-D) score. The positive effects of exercises on neurologic and rheumatic chronic inflammatory processes associated with disability should not be underestimated.

  16. UNDERSTANDING THE NEUROINFLAMMATORY RESPONSE FOLLOWING CONCUSSION TO DEVELOP TREATMENT STRATEGIES

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    Zachary Robert Patterson

    2012-12-01

    Full Text Available Mild traumatic brain injuries (mTBI have been associated with long-term cognitive deficits relating to trauma-induced neurodegeneration. These long-term deficits include impaired memory and attention, changes in executive function, emotional instability and sensorimotor deficits. Furthermore, individuals with concussions show a high co-morbidity with a host of psychiatric illnesses (e.g. depression, anxiety, addiction and dementia. The neurological damage seen in mTBI patients is the result of the direct impact and mechanical injury, followed by a delayed neuroimmune response that can last hours, days and even months after the injury. As part of the neuroimmune response, a cascade of pro- and anti-inflammatory cytokines are released and can be detected at the site of injury as well as subcortical, and often contralateral, regions. It has been suggested that the delayed neuroinflammatory response to concussions is more damaging then the initial impact itself. However, evidence exists for favourable consequences of cytokine production following traumatic brain injuries as well. In some cases, treatments that reduce the inflammatory response will also hinder the brain's intrinsic repair mechanisms. At present, there is no evidence-based pharmacological treatment for concussions in humans. The ability to treat concussions with drug therapy requires an in-depth understanding of the pathophysiological and neuroinflammatory changes that accompany concussive injuries. The use of neurotrophic factors (e.g. nerve growth factor and anti-inflammatory agents as an adjunct for the management of post-concussion symptomology will be explored in this review.

  17. Understanding the neuroinflammatory response following concussion to develop treatment strategies.

    Science.gov (United States)

    Patterson, Zachary R; Holahan, Matthew R

    2012-01-01

    Mild traumatic brain injuries (mTBI) have been associated with long-term cognitive deficits relating to trauma-induced neurodegeneration. These long-term deficits include impaired memory and attention, changes in executive function, emotional instability, and sensorimotor deficits. Furthermore, individuals with concussions show a high co-morbidity with a host of psychiatric illnesses (e.g., depression, anxiety, addiction) and dementia. The neurological damage seen in mTBI patients is the result of the impact forces and mechanical injury, followed by a delayed neuroimmune response that can last hours, days, and even months after the injury. As part of the neuroimmune response, a cascade of pro- and anti-inflammatory cytokines are released and can be detected at the site of injury as well as subcortical, and often contralateral, regions. It has been suggested that the delayed neuroinflammatory response to concussions is more damaging then the initial impact itself. However, evidence exists for favorable consequences of cytokine production following traumatic brain injuries as well. In some cases, treatments that reduce the inflammatory response will also hinder the brain's intrinsic repair mechanisms. At present, there is no evidence-based pharmacological treatment for concussions in humans. The ability to treat concussions with drug therapy requires an in-depth understanding of the pathophysiological and neuroinflammatory changes that accompany concussive injuries. The use of neurotrophic factors [e.g., nerve growth factor (NGF)] and anti-inflammatory agents as an adjunct for the management of post-concussion symptomology will be explored in this review.

  18. Neuroinflammatory processes in cognitive disorders: Is there a role for flavonoids and n-3 polyunsaturated fatty acids in counteracting their detrimental effects?

    Science.gov (United States)

    Vauzour, David; Martinsen, Anneloes; Layé, Sophie

    2015-10-01

    Neuroinflammatory processes are known to contribute to the cascade of events culminating in the neuronal damage that underpins neurodegenerative disorders such as Parkinson's and Alzheimer's disease. With the ageing population and increased cases of neurodegenerative diseases, there is a crucial need for the development of new strategies capable to prevent, delay the onset or treat brain dysfunction and associated cognitive decline. Growing evidence sheds light on the use of dietary polyphenols and n-3 long chain polyunsaturated fatty acids to improve cognitive performance and reduce the neuroinflammatory and oxidative stress responses occurring with age and neurodegenerative pathologies. This review will summarise the most recent information related to the impact and mechanisms underlying the neuroinflammatory processes in neurodegenerative disorders. We will also detail the current evidence indicating that flavonoids and n-3 polyunsaturated fatty acids are strong candidates in preventing neuroinflammation and modulating age-related memory decline, and we will describe the potential mechanisms of action underlying their neuroprotective effects. As such, these dietary bioactives represent important precursor molecules in the quest to develop a new generation of drugs capable of counteracting neuroinflammation and neurodegenerative diseases.

  19. Mielopatia associada ao HTLV-1: análise clínico-epidemiológica em uma série de casos de 10 anos HTLV-1 associated myelopathy: clinical and epidemiological profile in a 10-year case series study

    Directory of Open Access Journals (Sweden)

    Ana Paula Silva Champs

    2010-12-01

    Full Text Available INTRODUÇÃO: A mielopatia associada ao retrovírus HTLV-1 (HAM/TSP é uma doença progressiva e incapacitante. O objetivo deste trabalho é determinar características clínico-epidemiológicas de pacientes com HAM/TSP. MÉTODOS: Série de casos admitidos de 01/1998 a 12/ 2007, em hospital de reabilitação utilizando os critérios diagnósticos de HAM/TSP. RESULTADOS: Participaram 206 pacientes, dos quais, 67% eram mulheres, com 53 anos de média de idade, nove anos de média de duração de doença. Os sintomas mais frequentes foram a diminuição da força em membros inferiores, espasticidade, dor, presença de bexiga neurogênica e a constipação intestinal. Os sinais neurológicos foram hiperreflexia, Babinsky, Hoffmann e neuropatia periférica. A presença de dor, de espasticidade muscular e de atrofia medular à ressonância nuclear magnética de medula espinhal foram associadas à duração da doença (pINTRODUCTION: Human T cell lymphotropic virus type 1 (HTLV-I myelopathy (HAM/TSP is a progressive disabling disorder. This work aimed to analyze clinical features and epidemiology in a sample of HAM/TSP. METHODS: All HTLV-1 infected patients with diagnostic criteria for HAM/TSP, consecutively admitted to the Sarah Hospital from 1998 to 2007, were included in the study. RESULTS: 206 patients (67% females; mean age: 53.8 years-old were diagnosed with HAM/TSP. The mean time of evolution was 9.0 years. The most common neurological symptoms were chronic progressive spastic paraparesis, spasticity, pain, neurogenic bladder and neurogenic bowel. The neurological findings were hyperreflexia, Babinsky, Hoffman and peripheral neuropathy. Pain, spasticity and spinal cord atrophy, observed in MRI, were associated with time of disease (p<0.05. CONCLUSIONS: HAM/TSP is a very disabling disorder, in which pain is reported early, while spasticity and thoracic spinal cord atrophy appear in a later phase of the disease. Cases of HAM/TSP exist with a

  20. Estrogens regulate neuroinflammatory genes via estrogen receptors α and β in the frontal cortex of middle-aged female rats

    Directory of Open Access Journals (Sweden)

    Mahó Sándor

    2011-07-01

    regulatory functions of glial cells in the E2-deprived female brain and in various neuroinflammatory diseases.

  1. CSF cytokines/chemokines as biomarkers in neuroinflammatory CNS disorders: A systematic review.

    Science.gov (United States)

    Kothur, Kavitha; Wienholt, Louise; Brilot, Fabienne; Dale, Russell C

    2016-01-01

    Despite improved understanding of the pathogenesis of neuroinflammatory disorders of the brain and development of new diagnostic markers, our biomarker repertoire to demonstrate and monitor inflammation remains limited. Using PubMed database, we reviewed 83 studies on CSF cytokines and chemokines and describe the pattern of elevation and possible role of cytokines/chemokines as biomarkers in viral and autoimmune inflammatory neurological disorders of the CNS. Despite inconsistencies and overlap of cytokines and chemokines in different neuroinflammation syndromes, there are some trends regarding the pattern of cytokines/chemokine elevation. Namely B cell markers, such as CXCL13 and BAFF are predominantly investigated and found to be elevated in autoantibody-associated disorders, whereas interferon gamma (IFN-γ) is elevated mainly in viral encephalitis. Th2 and Th17 cytokines are frequently elevated in acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica (NMO), whereas Th1 and Th17 cytokines are more commonly elevated in multiple sclerosis (MS). Cytokine/chemokine profiling might provide new insights into disease pathogenesis, and improve our ability to monitor inflammation and response to treatment.

  2. Anti-neuroinflammatory efficacy of the aldose reductase inhibitor FMHM via phospholipase C/protein kinase C-dependent NF-κB and MAPK pathways

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Ke-Wu [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Li, Jun [Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029 (China); Dong, Xin; Wang, Ying-Hong; Ma, Zhi-Zhong; Jiang, Yong; Jin, Hong-Wei [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Tu, Peng-Fei, E-mail: pengfeitu@vip.163.com [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Modern Research Center for Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing 100029 (China)

    2013-11-15

    Aldose reductase (AR) has a key role in several inflammatory diseases: diabetes, cancer and cardiovascular diseases. Therefore, AR inhibition seems to be a useful strategy for anti-inflammation therapy. In the central nervous system (CNS), microglial over-activation is considered to be a central event in neuroinflammation. However, the effects of AR inhibition in CNS inflammation and its underlying mechanism of action remain unknown. In the present study, we found that FMHM (a naturally derived AR inhibitor from the roots of Polygala tricornis Gagnep.) showed potent anti-neuroinflammatory effects in vivo and in vitro by inhibiting microglial activation and expression of inflammatory mediators. Mechanistic studies showed that FMHM suppressed the activity of AR-dependent phospholipase C/protein kinase C signaling, which further resulted in downstream inactivation of the IκB kinase/IκB/nuclear factor-kappa B (NF-κB) inflammatory pathway. Therefore, AR inhibition-dependent NF-κB inactivation negatively regulated the transcription and expression of various inflammatory genes. AR inhibition by FMHM exerted neuroprotective effects in lipopolysaccharide-induced neuron–microglia co-cultures. These findings suggested that AR is a potential target for neuroinflammation inhibition and that FMHM could be an effective agent for treating or preventing neuroinflammatory diseases. - Highlights: • FMHM is a natural-derived aldose reductase (AR) inhibitor. • FMHM inhibits various neuroinflammatory mediator productions in vitro and in vivo. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent NF-κB pathway. • FMHM inhibits neuroinflammation via aldose reductase/PLC/PKC-dependent MAPK pathway. • FMHM protects neurons against inflammatory injury in microglia-neuron co-cultures.

  3. Prior exposure to glucocorticoids sensitizes the neuroinflammatory and peripheral inflammatory responses to E. coli lipopolysaccharide.

    Science.gov (United States)

    Frank, Matthew G; Miguel, Zurine D; Watkins, Linda R; Maier, Steven F

    2010-01-01

    Acute and chronic stress has been found to sensitize or prime the neuroinflammatory response to both peripheral and central immunologic challenges. Several studies suggest that stress-induced sensitization of neuroinflammatory processes may be mediated by the glucocorticoid (GC) response to stress. GCs, under some conditions, exhibit pro-inflammatory properties, however whether GCs are sufficient to prime neuroinflammatory responses has not been systematically investigated. In the present investigation, we tested whether acute administration of exogenous GCs would be sufficient to reproduce the stress-induced sensitization of neuroinflammatory responses under a number of different timing relationships between GC administration and immune challenge (lipopolysaccharide; LPS). We demonstrate here that GCs potentiate both the peripheral (liver) and central (hippocampus) pro-inflammatory response (e.g. TNFalpha, IL-1beta, IL-6) to a peripheral immune challenge (LPS) if GCs are administered prior (2 and 24h) to challenge. Prior exposure (24h) to GCs also potentiated the pro-inflammatory response of hippocampal microglia to LPS ex vivo. In contrast, when GCs are administered after (1h) a peripheral immune challenge, GCs suppress the pro-inflammatory response to LPS in both liver and hippocampus. GCs also up-regulated microglial activation markers including Toll-like Receptor 2. The present data suggest that the temporal relationship between GC treatment and immune challenge may be an important factor determining whether GCs exhibit pro- or anti-inflammatory properties.

  4. Early upregulation of matrix metalloproteinases following reperfusion triggers neuroinflammatory mediators in brain ischemia in rat.

    Science.gov (United States)

    Amantea, Diana; Russo, Rossella; Gliozzi, Micaela; Fratto, Vincenza; Berliocchi, Laura; Bagetta, G; Bernardi, G; Corasaniti, M Tiziana

    2007-01-01

    Abnormal expression of matrix metalloproteinases (MMPs) has been implicated in the pathophysiology of neuroinflammatory processes that accompany most central nervous system disease. In particular, early upregulation of the gelatinases MMP-2 and MMP-9 has been shown to contribute to disruption of the blood-brain barrier and to death of neurons in ischemic stroke. In situ zymography reveals a significant increase in gelatinolytic MMPs activity in the ischemic brain hemisphere after 2-h middle cerebral artery occlusion (MCAo) followed by 2-h reperfusion in rat. Accordingly, gel zymography demonstrates that expression and activity of MMP-2 and MMP-9 are enhanced in cortex and striatum ipsilateral to the ischemic insult. The latter effect appears to be instrumental for development of delayed brain damage since administration of a broad spectrum, highly specific MMPs inhibitor, GM6001, but not by its negative control, results in a significant (50%) reduction in ischemic brain volume. Increased gelatinase activity in the ischemic cortex coincides with elevation (166% vs sham) of mature interleukin-1beta (IL-1beta) after 2-h reperfusion and this does not appear to implicate a caspase-1-dependent processing of pro(31kDa)-IL-1beta to yield mature (17kDa) IL-1beta. More importantly, when administered at a neuroprotective dose GM6001 abolishes the early IL-1beta increase in the ischemic cortex and reduces the cleavage of the cytokine proform supporting the deduction that MMPs may initiate IL-1beta processing. In conclusion, development of tissue damage that follows transient ischemia implicates a crucial interplay between MMPs and mediators of neuroinflammation (e.g., IL-1beta), and this further underscores the therapeutic potential of MMPs inhibitors in the treatment of stroke.

  5. Anti-neuroinflammatory capacity of fresh ginger is attributed mainly to 10-gingerol.

    Science.gov (United States)

    Ho, Su-Chen; Chang, Ku-Shang; Lin, Chih-Cheng

    2013-12-01

    Despite the anti-neuroinflammatory capacity of ginger, the corresponding active constituents are unclear. This study analyzed the composition of fresh ginger ethanolic extract by using LC-MS. Inhibitory activities of fresh ginger extract and seven gingerol-related compounds on the neuro-inflammation were also evaluated by using a lipopolysaccharide (LPS)-activated BV2 microglia culture model. Except for zingerone and 6-gingerol, other gingerols and shogaols at a concentration of 20 μM inhibited the production of nitric oxide, IL-1β, IL-6 and TNF-α as well as their mRNA levels in LPS-activated BV2 microglia. Blocking NF-κB activation was the underlying mechanism responsible for inhibiting the proinflammatory gene expression. Increasing the alkyl chain length enhanced the anti-neuroinflammatory capacity of gingerols yet, conversely, attenuated those of shogaols. 6-Gingerol was the most abundant compound in the fresh ginger extract, followed by 10-gingerol. Furthermore, fresh ginger extract exhibited a significant anti-neuroinflammatory capacity, which was largely owing to 10-gingerol, but not 6-gingerol.

  6. HIV-1, Methamphetamine and Astrocytes at Neuroinflammatory crossroads

    Directory of Open Access Journals (Sweden)

    Kathleen eBorgmann

    2015-10-01

    Full Text Available As a popular psychostimulant, methamphetamine (METH use leads to long-lasting, strong euphoric effects. While METH abuse is common in the general population, between 10-15% of human immunodeficiency virus-1 (HIV-1 patients report having abused METH. METH exacerbates the severity and onset of HIV-1-associated neurocognitive disorders (HAND through direct and indirect mechanisms. Repetitive METH use decreases adherence to antiretroviral drug regimens, increasing the likelihood of HIV-1 disease progression towards AIDS. METH exposure also directly affects both innate and adaptive immunity, altering lymphocyte number and activity, cytokine signaling, phagocytic function, and CNS infiltration through the blood brain barrier. Further, METH triggers the neuronal dopamine reward pathway and leads to altered neuronal activity and direct toxicity. Concurrently, METH and HIV-1 alter the neuroimmune balance and induce neuroinflammation. Neuroinflammation modulates a wide range of brain functions including neuronal signaling and activity, glial activation, viral infection, oxidative stress and excitotoxicity. Pathologically, glial activation is a hallmark of both HIV-1 and METH-associated neuroinflammation. Significant commonality exists in the neurotoxic mechanisms for both METH and HAND; however, the pathways dysregulated in astroglia during METH exposure are less clear. Thus alterations in astrocyte intracellular signaling pathways, gene expression and function during METH and HIV-1 comorbidity, neuroinflammation and HAND are carefully reviewed. Interventions targeting astrocytes in HAND and METH are presented as potential novel therapeutic approaches.

  7. Neuroinflammatory targets and treatments for epilepsy validated in experimental models.

    Science.gov (United States)

    Aronica, Eleonora; Bauer, Sebastian; Bozzi, Yuri; Caleo, Matteo; Dingledine, Raymond; Gorter, Jan A; Henshall, David C; Kaufer, Daniela; Koh, Sookyong; Löscher, Wolfgang; Louboutin, Jean-Pierre; Mishto, Michele; Norwood, Braxton A; Palma, Eleonora; Poulter, Michael O; Terrone, Gaetano; Vezzani, Annamaria; Kaminski, Rafal M

    2017-07-01

    A large body of evidence that has accumulated over the past decade strongly supports the role of inflammation in the pathophysiology of human epilepsy. Specific inflammatory molecules and pathways have been identified that influence various pathologic outcomes in different experimental models of epilepsy. Most importantly, the same inflammatory pathways have also been found in surgically resected brain tissue from patients with treatment-resistant epilepsy. New antiseizure therapies may be derived from these novel potential targets. An essential and crucial question is whether targeting these molecules and pathways may result in anti-ictogenesis, antiepileptogenesis, and/or disease-modification effects. Therefore, preclinical testing in models mimicking relevant aspects of epileptogenesis is needed to guide integrated experimental and clinical trial designs. We discuss the most recent preclinical proof-of-concept studies validating a number of therapeutic approaches against inflammatory mechanisms in animal models that could represent novel avenues for drug development in epilepsy. Finally, we suggest future directions to accelerate preclinical to clinical translation of these recent discoveries. Wiley Periodicals, Inc. © 2017 International League Against Epilepsy.

  8. Effects of alpha-7 nicotinic acetylcholine receptor positive allosteric modulator on lipopolysaccharide-induced neuroinflammatory pain in mice.

    Science.gov (United States)

    Abbas, Muzaffar; Rahman, Shafiqur

    2016-07-15

    Evidence indicates that microglial activation contributes to the pathophysiology and maintenance of neuroinflammatory pain involving central nervous system alpha-7 nicotinic acetylcholine receptors. The objective of the present study was to determine the effects of 3a,4,5,9b-Tetrahydro-4-(1-naphthalenyl)-3H-cyclopentan[c]quinoline-8-sulfonamide (TQS), an alpha-7 nicotinic acetylcholine receptor positive allosteric modulator (PAM), on tactile allodynia and thermal hyperalgesia following lipopolysaccharide (LPS)-induced microglial activation in hippocampus, a neuroinflammatory pain model in mice. In addition, we examined the effects of TQS on microglial activation marker, an ionized calcium-binding adapter molecule 1 (Iba-1), in the hippocampus may be associated with neuroinflammatory pain. Pretreatment of TQS (4mg/kg) significantly reduced LPS (1mg/kg)-induced tactile allodynia and thermal hyperalgesia. Moreover, pretreatment of methyllycaconitine (3mg/kg) significantly reversed TQS-induced antiallodynic and antihyperalgesic responses indicating the involvement of alpha-7 nicotinic acetylcholine receptor. Pretreatment of TQS significantly decreased LPS-induced increased in hippocampal Iba-1 expression. Overall, these results suggest that TQS reduces LPS-induced neuroinflammatory pain like symptoms via modulating microglial activation likely in the hippocampus and/or other brain region by targeting alpha-7 nicotinic acetylcholine receptor. Therefore, alpha-7 nicotinic acetylcholine receptor PAM such as TQS could be a potential drug candidate for the treatment of neuroinflammatory pain.

  9. P2Y12 Receptor on the Verge of a Neuroinflammatory Breakdown

    Directory of Open Access Journals (Sweden)

    Susanna Amadio

    2014-01-01

    Full Text Available In the CNS, neuroinflammation occurring during pathologies as amyotrophic lateral sclerosis (ALS and multiple sclerosis (MS is the consequence of an intricate interplay orchestrated by various cell phenotypes. Among the molecular cues having a role in this process, extracellular nucleotides are responsible for intercellular communication and propagation of inflammatory stimuli. This occurs by binding to several receptor subtypes, defined P2X/P2Y, which are widespread in different tissues and simultaneously localized on multiple cells. For instance, the metabotropic P2Y12 subtype is found in the CNS on microglia, affecting activation and chemotaxis, on oligodendrocytes, possessing a hypothesized role in myelination, and on astrocytes. By comparative analysis, we have established here that P2Y12 receptor immunolabelled by antibodies against C-terminus or second intracellular loop, is, respectively, distributed and modulated under neuroinflammatory conditions on ramified microglia or myelinated fibers, in primary organotypic cerebellar cultures, tissue slices from rat striatum and cerebellum, spinal cord sections from symptomatic/end stage SOD1-G93A ALS mice, and finally autoptic cortical tissue from progressive MS donors. We suggest that modulation of P2Y12 expression might play a dual role as analytic marker of branched/surveillant microglia and demyelinating lesions, thus potentially acquiring a predictive value under neuroinflammatory conditions as those found in ALS and MS.

  10. Rapid neuroinflammatory response localized to injured neurons after diffuse traumatic brain injury in swine.

    Science.gov (United States)

    Wofford, Kathryn L; Harris, James P; Browne, Kevin D; Brown, Daniel P; Grovola, Michael R; Mietus, Constance J; Wolf, John A; Duda, John E; Putt, Mary E; Spiller, Kara L; Cullen, D Kacy

    2017-04-01

    Despite increasing appreciation of the critical role that neuroinflammatory pathways play in brain injury and neurodegeneration, little is known about acute microglial reactivity following diffuse traumatic brain injury (TBI) - the most common clinical presentation that includes all concussions. Therefore, we investigated acute microglial reactivity using a porcine model of closed-head rotational velocity/acceleration-induced TBI that closely mimics the biomechanical etiology of inertial TBI in humans. We observed rapid microglial reactivity within 15min of both mild and severe TBI. Strikingly, microglial activation was restrained to regions proximal to individual injured neurons - as denoted by trauma-induced plasma membrane disruption - which served as epicenters of acute reactivity. Single-cell quantitative analysis showed that in areas free of traumatically permeabilized neurons, microglial density and morphology were similar between sham or following mild or severe TBI. However, microglia density increased and morphology shifted to become more reactive in proximity to injured neurons. Microglial reactivity around injured neurons was exacerbated following repetitive TBI, suggesting further amplification of acute neuroinflammatory responses. These results indicate that neuronal trauma rapidly activates microglia in a highly localized manner, and suggest that activated microglia may rapidly influence neuronal stability and/or pathophysiology after diffuse TBI. Copyright © 2017 Elsevier Inc. All rights reserved.

  11. Effectiveness of Combined Therapy with Pirfenidone and Erythromycin for Unclassifiable Interstitial Pneumonia Induced by HTLV-1-associated Bronchioloalveolar Disorder (HABA)

    Science.gov (United States)

    Yokohori, Naoko; Sato, Akitoshi; Hasegawa, Mizue; Katsura, Hideki; Hiroshima, Kenzo; Takemura, Tamiko

    2017-01-01

    Human T-cell lymphotropic virus type 1 (HTLV-1) is a retrovirus involved in the pathogenesis of adult T-cell leukemia (ATL) and HTVL-1-associated bronchioloalveolar disorder (HABA). The clinical and pathological findings of HABA have been characterized as either a diffuse panbronchiolitis (DPB) pattern or idiopathic interstitial pneumonia (IIP) pattern. Treatments for HABA include corticosteroids for the IIP pattern and erythromycin for the DPB pattern. We herein report a case of HABA-associated unclassifiable interstitial pneumonia that improved with combined therapy with pirfenidone and erythromycin. This is the first report on the effectiveness of combined therapy with pirfenidone and erythromycin for HABA. PMID:28050003

  12. Strongyloides hyperinfection following hematopoietic stem cell transplant in a patient with HTLV-1-associated T-cell leukemia.

    Science.gov (United States)

    Alpern, Jonathan D; Arbefeville, Sophie S; Vercellotti, Gregory; Ferrieri, Patricia; Green, Jaime S

    2017-02-01

    Strongyloides stercoralis has the potential to cause accelerated autoinfection in immunocompromised hosts. Screening tests for strongyloidiasis may be falsely negative in the setting of immunosuppression. We report a case of Strongyloides hyperinfection syndrome in a patient with human T-lymphotropic virus type 1-associated T-cell leukemia early after hematopoietic stem cell transplant. The diagnosis was made by stool ova and parasite examination, despite a negative screening enzyme-linked immunosorbent assay. Because of anticipated prolonged neutropenia, an extended course of treatment was utilized. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  13. Propentofylline Prevents Sickness Behavior and Depressive-Like Behavior Induced by Lipopolysaccharide in Rats via Neuroinflammatory Pathway

    Science.gov (United States)

    Cabral, Danilo; Coelho, Cideli P.; Queiroz-Hazarbassanov, Nicolle; Martins, Maria F. M.; Bondan, Eduardo F.; Bernardi, Maria M.; Kirsten, Thiago Berti

    2017-01-01

    Recent studies have demonstrated the intimate relationship between depression and immune disturbances. Aware of the efficacy limits of existing antidepressant drugs and the potential anti-inflammatory properties of propentofylline, we sought to evaluate the use of propentofylline as a depression treatment. We used a rat model of depression induced by repetitive lipopolysaccharide (LPS) administrations. We have studied sickness behavior, by assessing daily body weight, open field behavior, and TNF-α plasmatic levels. Anxiety-like behavior (light-dark test), depressive-like behavior (forced swim test), plasmatic levels of the brain-derived neurotrophic factor (BDNF, depression biomarker), and central glial fibrillary acidic protein (GFAP) expression (an astrocyte biomarker) were also evaluated. LPS induced body weight loss, open field behavior impairments (decreased locomotion and rearing, and increased immobility), and increased TNF-α levels in rats, compared with control group. Thus, LPS induced sickness behavior. LPS also increased the immobility and reduced climbing in the forced swim test, when compared with the control group, i.e., LPS induced depressive-like behavior in rats. Propentofylline prevented sickness behavior after four days of consecutive treatment, as well as prevented the depressive-like behavior after five days of consecutive treatments. Propentofylline also prevented the increase in GFAP expression induced by LPS. Neither LPS nor propentofylline has influenced the anxiety and BDNF levels of rats. In conclusion, repetitive LPS administrations induced sickness behavior and depressive-like behavior in rats. Propentofylline prevented both sickness behavior and depressive-like behavior via neuroinflammatory pathway. The present findings may contribute to a better understanding and treatment of depression and associated diseases. PMID:28056040

  14. Stab injury and device implantation within the brain results in inversely multiphasic neuroinflammatory and neurodegenerative responses

    Science.gov (United States)

    Potter, Kelsey A.; Buck, Amy C.; Self, Wade K.; Capadona, Jeffrey R.

    2012-08-01

    An estimated 25 million people in the US alone rely on implanted medical devices, ˜2.5 million implanted within the nervous system. Even though many devices perform adequately for years, the host response to medical devices often severely limits tissue integration and long-term performance. This host response is believed to be particularly limiting in the case of intracortical microelectrodes, where it has been shown that glial cell encapsulation and localized neuronal cell loss accompany intracortical microelectrode implantation. Since neuronal ensembles must be within ˜50 µm of the electrode to obtain neuronal spikes and local field potentials, developing a better understanding of the molecular and cellular environment at the device-tissue interface has been the subject of significant research. Unfortunately, immunohistochemical studies of scar maturation in correlation to device function have been inconclusive. Therefore, here we present a detailed quantitative study of the cellular events and the stability of the blood-brain barrier (BBB) following intracortical microelectrode implantation and cortical stab injury in a chronic survival model. We found two distinctly inverse multiphasic profiles for neuronal survival in device-implanted tissue compared to stab-injured animals. For chronically implanted animals, we observed a biphasic paradigm between blood-derived/trauma-induced and CNS-derived inflammatory markers driving neurodegeneration at the interface. In contrast, stab injured animals demonstrated a CNS-mediated neurodegenerative environment. Collectively these data provide valuable insight to the possibility of multiple roles of chronic neuroinflammatory events on BBB disruption and localized neurodegeneration, while also suggesting the importance to consider multiphasic neuroinflammatory kinetics in the design of therapeutic strategies for stabilizing neural interfaces.

  15. Methamphetamine sensitization attenuates the febrile and neuroinflammatory response to a subsequent peripheral immune stimulus

    Science.gov (United States)

    Buchanan, J.B.; Sparkman, N.L.; Johnson, R.W.

    2010-01-01

    Methamphetamine (MA) use is associated with activation of microglia and, at high doses, can induce neurotoxicity. Given the changes in the neuroinflammatory environment associated with MA, we investigated whether MA sensitization, a model of stimulant psychosis and an indicator of drug addiction, would interfere with the thermoregulatory and neuroinflammatory response to a subsequent peripheral immune stimulus. C57BL6/J mice were given either 1mg/kg MA or saline i.p. once a day for 5 days to produce behavioral sensitization. Seventy-two hours following the last MA injection, 100μg/kg LPS or saline was co-administered with 1mg/kg MA or saline and blood and brains were collected. Here we report that while co-administration of LPS and MA did not affect the LPS-induced increase in central cytokine mRNA, mice sensitized to MA showed an attenuated central response to LPS. Interestingly, the peripheral response to LPS was not affected by MA sensitization. Plasma cytokines increased similarly in all groups after LPS. Further, c-Fos expression in the nucleus of the solitary tract did not differ between groups, suggesting that the periphery-to-brain immune signal is intact in MA-sensitized mice and that the deficit lies in the central cytokine compartment. We also show that MA sensitization decreased LPS- or acute MA-induced microglial Iba1 expression compared to non-sensitized mice. Taken together, these data show that MA sensitization interferes with the normal central immune response, preventing the CNS from efficiently responding to signals from the peripheral immune system. PMID:20035859

  16. CLIPPERS among patients diagnosed with non-specific CNS neuroinflammatory diseases

    DEFF Research Database (Denmark)

    Kerrn-Jespersen, B M; Lindelof, Mette; Illes, Zsolt

    2014-01-01

    Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) is an inflammatory CNS disorder characterized by 1) subacute onset of cerebellar and brainstem symptoms, 2) peripontine contrast-enhancing perivascular lesions with a "salt-and-pepper" appeara...... neurological deficits and progressive parenchymal atrophy on MRI may suggest neurodegenerative features, which emphasizes the need for early immunomodulatory treatment....

  17. Potassium 2-(l-hydroxypentyl-benzoate attenuates neuroinflammatory responses and upregulates heme oxygenase-1 in systemic lipopolysaccharide-induced inflammation in mice

    Directory of Open Access Journals (Sweden)

    Chunyang Zhao

    2017-07-01

    Full Text Available A neuroinflammatory response is commonly involved in the progression of many neurodegenerative diseases. Potassium 2-(1-hydroxypentyl-benzoate (PHPB, a novel neuroprotective compound, has shown promising effects in the treatment of ischemic stroke and Alzheimer׳s disease (AD. In the present study, the anti-inflammatory effects of PHPB were investigated in the plasma and brain of C57BL/6 mice administered a single intraperitoneal (i.p. injection of lipopolysaccharide (LPS. Levels of iNOS and the cytokines TNFα, IL-1β and IL-10 were elevated in plasma, cerebral cortex and hippocampus after LPS injection and the number of microglia and astrocytes in cortex and hippocampus were increased. LPS also upregulated the expression of heme oxygenase-1 (HO-1 in the cortex and hippocampus. PHPB reduced the levels of iNOS and cytokines in the plasma and brain, decreased the number of microglia and astrocytes and further enhanced the upregulation of HO-1. In addition, PHPB inhibited the LPS-induced phosphorylation of ERK, P38 and JNK. These results suggest that PHPB is a potential candidate in the treatment of neurodegenerative diseases through inhibiting neuroinflammation.

  18. Imipramine attenuates neuroinflammatory signaling and reverses stress-induced social avoidance.

    Science.gov (United States)

    Ramirez, Karol; Shea, Daniel T; McKim, Daniel B; Reader, Brenda F; Sheridan, John F

    2015-05-01

    Psychosocial stress is associated with altered immunity, anxiety and depression. Previously we showed that repeated social defeat (RSD) promoted microglia activation and social avoidance behavior that persisted for 24days after cessation of RSD. The aim of the present study was to determine if imipramine (a tricyclic antidepressant) would reverse RSD-inducedsocial avoidance and ameliorate neuroinflammatory responses. To test this, C57BL/6 mice were divided into treatment groups. One group from RSD and controls received daily injections of imipramine for 24days, following 6 cycles of RSD. Two other groups were treated with saline. RSD mice spent significantly less time in the interaction zone when an aggressor was present in the cage. Administration of imipramine reversed social avoidance behavior, significantly increasing the interaction time, so that it was similar to that of control mice. Moreover, 24days of imipramine treatment in RSD mice significantly decreased stress-induced mRNA levels for IL-6 in brain microglia. Following ex vivo LPS stimulation, microglia from mice exposed to RSD, had higher mRNA expression of IL-6, TNF-α, and IL-1β, and this was reversed by imipramine treatment. In a second experiment, imipramine was added to drinking water confirming the reversal of social avoidant behavior and decrease in mRNA expression of IL-6 in microglia. These data suggest that the antidepressant imipramine may exert its effect, in part, by down-regulating microglial activation.

  19. CNS-targeted production of IL-17A induces glial activation, microvascular pathology and enhances the neuroinflammatory response to systemic endotoxemia.

    Directory of Open Access Journals (Sweden)

    Julian Zimmermann

    Full Text Available Interleukin-17A (IL-17A is a key cytokine modulating the course of inflammatory diseases. Whereas effector functions of IL-17A like induction of antimicrobial peptides and leukocyte infiltration could clearly be demonstrated for peripheral organs, CNS specific effects are not well defined and appear controversial. To further clarify the functional significance of IL-17A in the CNS, we generated a transgenic mouse line with astrocyte-restricted expression of the IL-17A gene. GFAP/IL-17A transgenic mice develop normally and do not show any signs of neurological dysfunction. However, histological characterization revealed astrocytosis and activation of microglia. Demyelination, neurodegeneration or prominent tissue damage was not observed but a vascular pathology mimicking microangiopathic features was evident. Histological and flow cytometric analysis demonstrated the absence of parenchymal infiltration of immune cells into the CNS of GFAP/IL-17A transgenic mice. In GFAP/IL-17A mice, LPS-induced endotoxemia led to a more pronounced microglial activation with expansion of a distinct CD45(high/CD11b(+ population and increased induction of proinflammatory cytokines compared with controls. Our data argues against a direct role of IL-17A in mediating tissue damage during neuroinflammation. More likely IL-17A acts as a modulating factor in the network of induced cytokines. This novel mouse model will be a very useful tool to further characterize the role of IL-17A in neuroinflammatory disease models.

  20. CNS-targeted production of IL-17A induces glial activation, microvascular pathology and enhances the neuroinflammatory response to systemic endotoxemia.

    Science.gov (United States)

    Zimmermann, Julian; Krauthausen, Marius; Hofer, Markus J; Heneka, Michael T; Campbell, Iain L; Müller, Marcus

    2013-01-01

    Interleukin-17A (IL-17A) is a key cytokine modulating the course of inflammatory diseases. Whereas effector functions of IL-17A like induction of antimicrobial peptides and leukocyte infiltration could clearly be demonstrated for peripheral organs, CNS specific effects are not well defined and appear controversial. To further clarify the functional significance of IL-17A in the CNS, we generated a transgenic mouse line with astrocyte-restricted expression of the IL-17A gene. GFAP/IL-17A transgenic mice develop normally and do not show any signs of neurological dysfunction. However, histological characterization revealed astrocytosis and activation of microglia. Demyelination, neurodegeneration or prominent tissue damage was not observed but a vascular pathology mimicking microangiopathic features was evident. Histological and flow cytometric analysis demonstrated the absence of parenchymal infiltration of immune cells into the CNS of GFAP/IL-17A transgenic mice. In GFAP/IL-17A mice, LPS-induced endotoxemia led to a more pronounced microglial activation with expansion of a distinct CD45(high)/CD11b(+) population and increased induction of proinflammatory cytokines compared with controls. Our data argues against a direct role of IL-17A in mediating tissue damage during neuroinflammation. More likely IL-17A acts as a modulating factor in the network of induced cytokines. This novel mouse model will be a very useful tool to further characterize the role of IL-17A in neuroinflammatory disease models.

  1. The Effect of Residual Endotoxin Contamination on the Neuroinflammatory Response to Sterilized Intracortical Microelectrodes.

    Science.gov (United States)

    Ravikumar, Madhumitha; Hageman, Daniel J; Tomaszewski, William H; Chandra, Gabriella M; Skousen, John L; Capadona, Jeffrey R

    2014-05-01

    A major limitation to the use of microelectrode technologies in both research and clinical applications is our inability to consistently record high quality neural signals. There is increasing evidence that recording instability is linked, in part, to neuroinflammation. A number of factors including extravasated blood products and macrophage released soluble factors are believed to mediate neuroinflammation and the resulting recording instability. However, the roles of other inflammatory stimuli, such as residual endotoxin contamination, are poorly understood. Therefore, to determine the effect of endotoxin contamination we examined the brain tissue response of C57/BL6 mice to non-functional microelectrodes with a range of endotoxin levels. Endotoxin contamination on the sterilized microelectrodes was measured using a limulus amebocyte lysate test following FDA guidelines. Microelectrodes sterilized by autoclave, dry heat, or ethylene oxide gas, resulted in variable levels of residual endotoxins of 0.55 EU/mL, 0.22 EU/mL, and 0.11 EU/mL, respectively. Histological evaluation at two weeks showed a direct correlation between microglia/macrophage activation and endotoxin levels. Interestingly, astrogliosis, neuronal loss, and blood brain barrier dysfunction demonstrated a threshold-dependent response to bacterial endotoxins. However, at sixteen weeks, no histological differences were detected, regardless of initial endotoxin levels. Therefore, our results demonstrate that endotoxin contamination, within the range examined, contributes to initial but not chronic microelectrode associated neuroinflammation. Our results suggest that minimizing residual endotoxins may impact early recording quality. To this end, endotoxins should be considered as a potent stimulant to the neuroinflammatory response to implanted intracortical microelectrodes.

  2. Esculetin attenuates lipopolysaccharide (LPS)-induced neuroinflammatory processes and depressive-like behavior in mice.

    Science.gov (United States)

    Zhu, Lingpeng; Nang, Chen; Luo, Fen; Pan, Hong; Zhang, Kai; Liu, Jingyan; Zhou, Rui; Gao, Jin; Chang, Xiayun; He, He; Qiu, Yue; Wang, Jinglei; Long, Hongyan; Liu, Yu; Yan, Tianhua

    2016-09-01

    Esculetin is one of the major bioactive compounds of Cichorium intybus L. The main purpose of the present study was to investigate the effects and possible underlying mechanism of esculetin (Esc) on lipopolysaccharide (LPS)-induced neuroinflammatory processes and depressive-like behavior in mice. Mice were pretreatment with esculetin (Esc, 20, 40mg/kg, intragastric administration) and a positive control drug fluoxetine (Flu, 20mg/kg, intragastric administration) once daily for 7 consecutive days. At the 7th day, LPS (0.83mg/kg) was intraperitoneal injection 30min after drug administration. Higher dose (40mg/kg) of esculetin and fluoxetine significantly decreased immobility time in TST and FST. There was no significant effect on locomotor activity in mice by the drugs. Esculetin significantly reduced LPS-induced elevated levels of pro-inflammatory cytokines including interleukin-6 (IL-6), interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) in serum and hippocampus. Esculetin attenuated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) protein expression by inhibiting nuclear factor-κB (NF-κB) pathway in hippocampus. In addition, neuroprotection of esculetin was attributed to the upregulations of Brain derived neurotrophic factor (BDNF) and phosphorylated tyrosine kinase B (p-TrkB) protein expression in hippocampus. The obtained results demonstrated that esculetin exhibited antidepressant-like effects which might be related to the inhibition of NF-κB pathway and the activation of BDNF/TrkB signaling.

  3. Taurine Chloramine Suppresses LPS-Induced Neuroinflammatory Responses through Nrf2-Mediated Heme Oxygenase-1 Expression in Mouse BV2 Microglial Cells.

    Science.gov (United States)

    Lee, Dong-Sung; Kwon, Ki Han; Cheong, Sun Hee

    2017-01-01

    The brain is sensitive to the inflammation and oxidative stress that can cause the aging or neurodegenerative diseases. We investigated the anti-neuroinflammatory activities of taurine chloramine (TauCl) on lipopolysaccharide (LPS)-treated mouse BV2 microglia mediated through heme oxygenase (HO)-1 expression. TauCl inhibited the protein expressions of prostaglandin E2 (PGE2), cyclooxygenase (COX)-2, nitric oxide (NO), and inducible nitric oxide synthase (iNOS) in LPS-treated BV2 microglia. TauCl markedly inhibited interleukin-6 (IL-6), interleukin-1 (IL-1) and tumor necrosis factor- (TNF-) production. These effects were related to the suppression of the degradation and phosphorylation of inhibition of nuclear factor kappa B- (IB-), translocation of nuclear factor kappa B (NF-B) as well as DNA binding activity. In addition, TauCl induced the HO-1 expression by increasing the nuclear factor E2-related factor 2 (Nrf2) translocation to the nucleus in mouse BV2 microglia. These findings suggest that TauCl has protective effects of neurodegenerative disorders caused by neuroinflammation.

  4. Increased proviral load in HTLV-1-infected patients with rheumatoid arthritis or connective tissue disease

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    Olindo Stéphane

    2005-02-01

    Full Text Available Abstract Background Human T-lymphotropic virus type 1 (HTLV-1 proviral load is related to the development of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP and has also been shown to be elevated in the peripheral blood in HTLV-1-infected patients with uveitis or alveolitis. Increased proliferation of HTLV-1-infected cells in, or migration of such cells into, the central nervous system is also seen in HAM/TSP. In the present study, we evaluated the proviral load in a cohort of HTLV-1-infected patients with arthritic conditions. Results HTLV-1 proviral load in the peripheral blood from 12 patients with RA and 6 patients with connective tissue disease was significantly higher than that in matched asymptomatic HTLV-1 carriers, but similar to that in matched HAM/TSP controls. HAM/TSP was seen in one-third of the HTLV-1-infected patients with RA or connective tissue disease, but did not account for the higher proviral load compared to the asymptomatic carrier group. The proviral load was increased in the synovial fluid and tissue from an HTLV-1-infected patient with RA, the values suggesting that the majority of infiltrated cells were HTLV-1-infected. In the peripheral blood from HTLV-1-infected patients with RA or connective tissue disease, HTLV-1 proviral load correlated with the percentages of memory CD4+ T cells and activated T cells, and these percentages were shown to be markedly higher in the synovial fluid than in the peripheral blood in an HTLV-1-infected patient with RA. Conclusions These biological findings are consistent with a role of the retrovirus in the development of arthritis in HTLV-1-infected patients. A high level of HTLV-1-infected lymphocytes in the peripheral blood and their accumulation in situ might play a central role in the pathogenesis of HTLV-1-associated inflammatory disorders. Alternatively, the autoimmune arthritis, its etiological factors or treatments might secondarily enhance HTLV-1 proviral load.

  5. Lignans from the shed trunk barks of the critically endangered plant Abies beshanzuensis and their anti-neuroinflammatory activities.

    Science.gov (United States)

    Hu, Chang-Ling; Xiong, Juan; Xu, Peng; Cheng, Ke-Jun; Yang, Guo-Xun; Hu, Jin-Feng

    2017-06-01

    During a further and comprehensive phytochemical investigation on the shed trunk barks of the critically endangered plant Abies beshanzuensis, one new (1) and ten known (2-11) lignans with diverse structures were isolated. On the basis of spectroscopic methods, the new structure was established to be (7S,8R,8'R)-4'-methoxyl-α-conidendrin (1). Among the isolated lignans, (-)-matairesinol (5) and (-)-arctigenin (6) showed significant anti-neuroinflammatory activities by inhibiting the overproduction of nitric oxide in lipopolysaccharide-stimulated murine BV-2 microglial cells, with IC50 values of 11.5 and 19.0 μM, respectively.

  6. Betulinic acid regulates generation of neuroinflammatory mediators responsible for tissue destruction in multiple sclerosis in vitro

    Institute of Scientific and Technical Information of China (English)

    Jana BLA(Z)EVSKI; Filip PETKOVI(C); Miljana MOM(C)ILOVI(C); Reinhard PASCHKE; Goran N KALUDEROVI(C); Marija MOSTARICA STOJKOVI(C); Djordje MILJKOVI(C)

    2013-01-01

    Aim:To investigate the influences of betulinic acid (BA),a triterpenoid isolated from birch bark,on neuroinflammatory mediators involved in the pathogenesis of multiple sclerosis and experimental autoimmune encephalomyelitis in vitro.Methods:Encephalitogenic T cells were prepared from draining lymph nodes and spinal cords of Dark Agouti rats 8 to 10 d after immunization with myelin basic protein (MBP) and complete Freund's adjuvant.Macrophages were isolated from the peritoneal cavity of adult untreated rats.Astrocytes were isolated from neonatal rat brains.The cells were cultured and then treated with different agents.IFN-y,IL-17,iNOS and CXCL12 mRNA levels in the cells were analyzed with RT-PCR.iNOS and CXCL12 protein levels were detected using immunoblot.NO and ROS generation was measured using Griess reaction and flow cytometry,respectively.Results:In encephalitogenic T cells stimulated with MBP (10 μg/mL),addition of BA inhibited IL-17 and IFN-γ production in a dosedependent manner.The estimated IC50 values for IL-17 and IFN y were 11.2 and 63.8 μmol/L,respectively.When the macrophages were stimulated with LPS (10 ng/mL),addition of BA (50 μmol/L) significantly increased ROS generation,and suppressed NO generation.The astrocytes were stimulated with ConASn containing numerous inflammatory mediators,which mimicked the inflammatory milieu within CNS; addition of BA (50 μmol/L) significantly increased ROS generation,and blocked ConASn-induced increases in iNOS and CXCL12 mRNA levels,but did not affect iNOS and CXCL12 protein levels.Importantly,in both the macrophages and astrocytes,addition of BA (50 μmol/L) inhibited lipid peroxidation.Conclusion:Besides inhibiting encephalitogenic T cell cytokines and reducing NO generation,BA induces tissue-damaging ROS generation within CNS.

  7. A neurotoxic regimen of methamphetamine exacerbates the febrile and neuroinflammatory response to a subsequent peripheral immune stimulus

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    Johnson Rodney W

    2010-11-01

    Full Text Available Abstract Methamphetamine (MA use is associated with activation of microglia and, at high doses, can induce neurotoxicity. Given the changes in the neuroinflammatory environment associated with MA, we investigated whether MA administration would interfere with the thermoregulatory and neuroinflammatory response to a subsequent peripheral immune stimulus. C57BL6/J mice were given four i.p. injections of either 5 mg/kg MA or saline at two hour intervals. Twenty-four hours following the first MA injection, mice were given 100 μg/kg LPS or saline i.p. and blood and brains were collected. Here we report that mice exposed to MA developed higher fevers in response to LPS than did those given LPS alone. MA also exacerbated the LPS-induced increase in central cytokine mRNA. MA alone increased microglial Iba1 expression and expression was further increased when mice were exposed to both MA and LPS, suggesting that MA not only activated microglia but also influenced their response to a peripheral immune stimulus. Taken together, these data show that MA administration exacerbates the normal central immune response, most likely by altering microglia.

  8. Cytokines, Chaperones and Neuroinflammatory Responses in Heroin-Related Death: What Can We Learn from Different Patterns of Cellular Expression?

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    Vittorio Fineschi

    2013-09-01

    Full Text Available Heroin (3,6-diacetylmorphine has various effects on the central nervous system with several neuropathological alterations including hypoxic-ischemic brain damage from respiratory depressing effects and neuroinflammatory response. Both of these mechanisms induce the release of cytokines, chemokines and other inflammatory mediators by the activation of many cell types such as leucocytes and endothelial and glial cells, especially microglia, the predominant immunocompetent cell type within the central nervous system. The aim of this study is to clarify the correlation between intravenous heroin administration in heroin related death and the neuroinflammatory response. We selected 45 cases among autopsies executed for heroin-related death (358 total cases; immunohistochemical studies and Western blotting analyses were used to investigate the expression of brain markers such as tumor necrosis factor-α, oxygen-regulated protein 150, (interleukins IL-1β, IL-6, IL-8, IL-10, IL-15, cyclooxygenase-2, heat shock protein 70, and CD68 (MAC387. Findings demonstrated that morphine induces inflammatory response and cytokine release. In particular, oxygen-regulated protein 150, cyclooxygenase-2, heat shock protein 70, IL-6 and IL-15 cytokines were over-expressed with different patterns of cellular expression.

  9. HTLV 1 associated adult T cell lymphoma/leukemia a clinicopathologic, immunophenotypic tale of three cases from non-endemic region of south India

    Directory of Open Access Journals (Sweden)

    Faiq Ahmed

    2012-01-01

    Full Text Available Adult T cell lymphoma/leukemia is a peripheral T-cell neoplasm caused by human T-cell lymphotrophic virus-1, affects mostly adults with systemic involvement and poor prognosis. Diagnosis of adult T-Cell leukemia/Lymphoma is challenging. The clinico-pathologic and immuno-phenotypic features of the three cases will be presented.

  10. The roles of blood-derived macrophages and resident microglia in the neuroinflammatory response to implanted Intracortical microelectrodes

    Science.gov (United States)

    Ravikumar, Madhumitha; Sunil, Smrithi; Black, James; Barkauskas, Deborah S.; Haung, Alex Y.; Miller, Robert H.; Selkirk, Stephen M.; Capadona, Jeffrey R.

    2014-01-01

    Resident microglia and blood-borne macrophages have both been implicated to play a dominant role in mediating the neuroinflammatory response affecting implanted intracortical microelectrodes. However, the distinction between each cell type has not been demonstrated due to a lack of discriminating cellular markers. Understanding the subtle differences of each cell population in mediating neuroinflammation can aid in determining the appropriate therapeutic approaches to improve microelectrode performance. Therefore, the goal of this study is to characterize the role of infiltrating blood-derived cells, specifically macrophages, in mediating neuroinflammation following intracortical microelectrode implantation. Interestingly, we found no correlation between microglia and neuron populations at the microelectrode-tissue interface. On the other hand, blood-borne macrophages consistently dominated the infiltrating cell population following microelectrode implantation. Most importantly, we found a correlation between increased populations of blood-derived cells (including the total macrophage population) and neuron loss at the microelectrode-tissue interface. Specifically, the total macrophage population was greatest at two and sixteen weeks post implantation, at the same time points when we observed the lowest densities of neuronal survival in closest proximity to the implant. Together, our results suggest a dominant role of infiltrating macrophages, and not resident microglia, in mediating neurodegeneration following microelectrode implantation. PMID:24973296

  11. Oxidative Stress Is Related to the Deleterious Effects of Heme Oxygenase-1 in an In Vivo Neuroinflammatory Rat Model

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    Claire Tronel

    2013-01-01

    Full Text Available Heme oxygenase-1 (HO-1 induction is associated with beneficial or deleterious effects depending on the experimental conditions adopted and the neurodegenerative rodent models used. The present study aimed first to evaluate the effects of cerebral HO-1 induction in an in vivo rat model of neuroinflammation by intrastriatal injection of quinolinic acid (QA and secondly to explore the role played by reactive oxygen species (ROS and free iron (Fe2+ derived from heme catabolism promoted by HO-1. Chronic I.P. treatment with the HO-1 inductor and substrate hemin was responsible for a significant dose-related increase of cerebral HO-1 production. Brain tissue loss, microglial activation, and neuronal death were significantly higher in rats receiving QA plus hemin (H-QA versus QA and controls. Significant increase of ROS production in H-QA rat brain was inhibited by the specific HO-1 inhibitor ZnPP which supports the idea that ROS level augmentation in hemin-treated animals is a direct consequence of HO-1 induction. The cerebral tissue loss and ROS level in hemin-treated rats receiving the iron chelator deferoxamine were significantly decreased, demonstrating the involvement of Fe2+in brain ROS production. Therefore, the deleterious effects of HO-1 expression in this in vivo neuroinflammatory model were linked to a hyperproduction of ROS, itself promoted by free iron liberation.

  12. TLR2 is a primary receptor for Alzheimer's amyloid beta peptide to trigger neuroinflammatory activation.

    NARCIS (Netherlands)

    Liu, S.; Liu, Y.; Hao, W.; Wolf, L.; Kiliaan, A.J.; Penke, B.; Rube, C.E.; Walter, J.; Heneka, M.T.; Hartmann, T.; Menger, M.D.; Fassbender, K.

    2012-01-01

    Microglia activated by extracellularly deposited amyloid beta peptide (Abeta) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering an

  13. TLR2 is a primary receptor for Alzheimer's amyloid beta peptide to trigger neuroinflammatory activation.

    NARCIS (Netherlands)

    Liu, S.; Liu, Y.; Hao, W.; Wolf, L.; Kiliaan, A.J.; Penke, B.; Rube, C.E.; Walter, J.; Heneka, M.T.; Hartmann, T.; Menger, M.D.; Fassbender, K.

    2012-01-01

    Microglia activated by extracellularly deposited amyloid beta peptide (Abeta) act as a two-edged sword in Alzheimer's disease pathogenesis: on the one hand, they damage neurons by releasing neurotoxic proinflammatory mediators (M1 activation); on the other hand, they protect neurons by triggering

  14. Schisandrin B exerts anti-neuroinflammatory activity by inhibiting the Toll-like receptor 4-dependent MyD88/IKK/NF-κB signaling pathway in lipopolysaccharide-induced microglia.

    Science.gov (United States)

    Zeng, Ke-Wu; Zhang, Tai; Fu, Hong; Liu, Geng-Xin; Wang, Xue-Mei

    2012-10-05

    Microglial-mediated neuroinflammation is now considered to be central to the pathogenesis of various neurodegenerative processes, including Alzheimer's disease and Parkinson's disease. Therefore, rational modulation of microglia function to obtain neuroprotective effects is important for the development of safe and effective anti-inflammatory and neuroprotective agents. Here, we investigated the anti-inflammatory and neuroprotective effects, and potential molecular mechanism of action of Schisandrin B (Sch B); which is isolated from the Schizandra fruit (Schisandra chinesnesis). Sch B exerted significant neuroprotective effects against microglial-mediated inflammatory injury in microglia-neuron co-cultures. In addition, Sch B significantly downregulated pro-inflammatory cytokines, including nitrite oxide (NO), tumor necrosis factor (TNF)-α, prostaglandin E(2) (PGE(2)), interleukin (IL)-1β and IL-6. Additionally, Sch B inhibited the interaction of Toll-like receptor 4 with the Toll adapter proteins MyD88, IRAK-1 and TRAF-6 resulting in an inhibition of the IKK/nuclear transcription factor (NF)-κB inflammatory signaling pathway. Furthermore, Sch B inhibited the production of reactive oxygen species (ROS) and NADPH oxidase activity in microglia. In summary, Sch B may exert neuroprotective activity by attenuating the microglial-mediated neuroinflammatory response by inhibiting the TLR4-dependent MyD88/IKK/NF-κB signaling pathway.

  15. Proximate Mediators of Microvascular Dysfunction at the Blood-Brain Barrier: Neuroinflammatory Pathways to Neurodegeneration

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    Barry W. Festoff

    2017-01-01

    Full Text Available Current projections are that by 2050 the numbers of people aged 65 and older with Alzheimer’s disease (AD in the US may increase threefold while dementia is projected to double every 20 years reaching ~115 million by 2050. AD is clinically characterized by progressive dementia and neuropathologically by neuronal and synapse loss, accumulation of amyloid plaques, and neurofibrillary tangles (NFTs in specific brain regions. The preclinical or presymptomatic stage of AD-related brain changes may begin over 20 years before symptoms occur, making development of noninvasive biomarkers essential. Distinct from neuroimaging and cerebrospinal fluid biomarkers, plasma or serum biomarkers can be analyzed to assess (i the presence/absence of AD, (ii the risk of developing AD, (iii the progression of AD, or (iv AD response to treatment. No unifying theory fully explains the neurodegenerative brain lesions but neuroinflammation (a lethal stressor for healthy neurons is universally present. Current consensus is that the earlier the diagnosis, the better the chance to develop treatments that influence disease progression. In this article we provide a detailed review and analysis of the role of the blood-brain barrier (BBB and damage-associated molecular patterns (DAMPs as well as coagulation molecules in the onset and progression of these neurodegenerative disorders.

  16. Neuroinflammatory contributions to pain after SCI: roles for central glial mechanisms and nociceptor-mediated host defense.

    Science.gov (United States)

    Walters, Edgar T

    2014-08-01

    Neuropathic pain after spinal cord injury (SCI) is common, often intractable, and can be severely debilitating. A number of mechanisms have been proposed for this pain, which are discussed briefly, along with methods for revealing SCI pain in animal models, such as the recently applied conditioned place preference test. During the last decade, studies of animal models have shown that both central neuroinflammation and behavioral hypersensitivity (indirect reflex measures of pain) persist chronically after SCI. Interventions that reduce neuroinflammation have been found to ameliorate pain-related behavior, such as treatment with agents that inhibit the activation states of microglia and/or astroglia (including IL-10, minocycline, etanercept, propentofylline, ibudilast, licofelone, SP600125, carbenoxolone). Reversal of pain-related behavior has also been shown with disruption by an inhibitor (CR8) and/or genetic deletion of cell cycle-related proteins, deletion of a truncated receptor (trkB.T1) for brain-derived neurotrophic factor (BDNF), or reduction by antisense knockdown or an inhibitor (AMG9810) of the activity of channels (TRPV1 or Nav1.8) important for electrical activity in primary nociceptors. Nociceptor activity is known to drive central neuroinflammation in peripheral injury models, and nociceptors appear to be an integral component of host defense. Thus, emerging results suggest that spinal and systemic effects of SCI can activate nociceptor-mediated host defense responses that interact via neuroinflammatory signaling with complex central consequences of SCI to drive chronic pain. This broader view of SCI-induced neuroinflammation suggests new targets, and additional complications, for efforts to develop effective treatments for neuropathic SCI pain.

  17. New Perspectives in Nuclear Neurology for the Evaluation of Parkinson's Disease

    NARCIS (Netherlands)

    Benadiba, Marcel; Luurtsema, Gert; Tumas, Vitor; Buchpigel, Carlos Alberto; Busatto, Geraldo F.

    2013-01-01

    The pathophysiology of Parkinson's disease (PD) has not yet been completely elucidated. However, during the past few years, significant progress has been made in understanding the intra- and extracellular mechanisms by which proteins such as alpha-synuclein and neuroinflammatory molecules may displa

  18. PPARγ, neuroinflammation, and disease

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    Mrak Robert E

    2004-05-01

    Full Text Available Abstract Background Peroxisome proliferator-activated receptors (PPARs are a class of nuclear transcription factors that are activated by fatty acids and their derivatives. One of these, PPARγ, regulates responsiveness to insulin in adipose cells, and PPARγ-activating drugs such as pioglitazone are used in the treatment of type 2 diabetes. PPARγ acts in myeloid-lineage cells, including T-cells and macrophages, to suppress their activation and their elaboration of inflammatory molecules. PPARγ activation also suppresses the activated phenotype in microglia, suggesting that PPARγ-activating drugs may be of benefit in chronic neuroinflammatory diseases. Some, but not all, nonsteroidal anti-inflammatory agents (indomethacin and ibuprofen in particular also have activating effects on PPARγ. Discussion and conclusions These observations suggest on the one hand a role for PPARγ-activating drugs in the treatment of chronic neuroinflammatory diseases-as shown for a patient with secondary progressive multiple sclerosis by Pershadsingh et al. in this issue of the Journal of Neuroinflammation-and suggest on the other hand a possible explanation for confusing and contradictory results in trials of nonsteroidal anti-inflammatory agents in Alzheimer's disease.

  19. Opiate addiction therapies and HIV-1 Tat: interactive effects on glial [Ca²⁺]i, oxyradical and neuroinflammatory chemokine production and correlative neurotoxicity.

    Science.gov (United States)

    Fitting, Sylvia; Zou, Shiping; El-Hage, Nazira; Suzuki, Masami; Paris, Jason J; Schier, Christina J; Rodríguez, José W; Rodriguez, Myosotys; Knapp, Pamela E; Hauser, Kurt F

    2014-01-01

    Few preclinical studies have compared the relative therapeutic efficacy of medications used to treat opiate addiction in relation to neuroAIDS. Here we compare the ability of methadone and buprenorphine, and the prototypic opiate morphine, to potentiate the neurotoxic and proinflammatory ([Ca²⁺]i, ROS, H₂O₂, chemokines) effects of HIV-1 Tat in neuronal and/or mixed-glial co-cultures. Repeated observations of neurons during 48 h exposure to combinations of Tat, equimolar concentrations (500 nM) of morphine, methadone, or buprenorphine exacerbated neurotoxicity significantly above levels seen with Tat alone. Buprenorphine alone displayed marked neurotoxicity at 500 nM, prompting additional studies of its neurotoxic effects at 5 nM and 50 nM concentrations ± Tat. In combination with Tat, buprenorphine displayed paradoxical, concentration-dependent, neurotoxic and neuroprotective actions. Buprenorphine neurotoxicity coincided with marked elevations in [Ca²⁺]i, but not increases in glial ROS or chemokine release. Tat by itself elevated the production of CCL5/RANTES, CCL4/MIP-1β, and CCL2/MCP-1. Methadone and buprenorphine alone had no effect, but methadone interacted with Tat to further increase production of CCL5/RANTES. In combination with Tat, all drugs significantly increased glial [Ca²⁺]i, but ROS was only significantly increased by co-exposure with morphine. Taken together, the increases in glial [Ca²⁺]i, ROS, and neuroinflammatory chemokines were not especially accurate predictors of neurotoxicity. Despite similarities, opiates displayed differences in their neurotoxic and neuroinflammatory interactions with Tat. Buprenorphine, in particular, was partially neuroprotective at a low concentration, which may result from its unique pharmacological profile at multiple opioid receptors. Overall, the results reveal differences among addiction medications that may impact neuroAIDS.

  20. Glucocorticoids Mediate Short-Term High-Fat Diet Induction of Neuroinflammatory Priming, the NLRP3 Inflammasome, and the Danger Signal HMGB1.

    Science.gov (United States)

    Sobesky, Julia L; D'Angelo, Heather M; Weber, Michael D; Anderson, Nathan D; Frank, Matthew G; Watkins, Linda R; Maier, Steven F; Barrientos, Ruth M

    2016-01-01

    The impact of the foods we eat on metabolism and cardiac physiology has been studied for decades, yet less is known about the effects of foods on the CNS, or the behavioral manifestations that may result from these effects. Previous studies have shown that long-term consumption of high-fat foods leading to diet-induced obesity sensitizes the inflammatory response of the brain to subsequent challenging stimuli, causing deficits in the formation of long-term memories. The new findings reported here demonstrate that short-term consumption of a high-fat diet (HFD) produces the same outcomes, thus allowing the examination of mechanisms involved in this process long before obesity and associated comorbidities occur. Rats fed an HFD for 3 d exhibited increases in corticosterone, the inflammasome-associated protein NLRP3 (nod-like receptor protein 3), and the endogenous danger signal HMGB1 (high-mobility group box 1) in the hippocampus. A low-dose (10 μg/kg) lipopolysaccharide (LPS) immune challenge potentiated the neuroinflammatory response in the hippocampus of rats fed the HFD, and caused a deficit in the formation of long-term memory, effects not observed in rats fed regular chow. The blockade of corticosterone action with the glucocorticoid receptor antagonist mifepristone prevented the NLRP3 and HMGB1 increases in unchallenged animals, normalized the proinflammatory response to LPS, and prevented the memory impairment. These data suggest that short-term HFD consumption increases vulnerability to memory disruptions caused by an immune challenge by upregulating important neuroinflammatory priming and danger signals in the hippocampus, and that these effects are mediated by increases in hippocampal corticosterone.

  1. Glucocorticoids Mediate Short-Term High-Fat Diet Induction of Neuroinflammatory Priming, the NLRP3 Inflammasome, and the Danger Signal HMGB1

    Science.gov (United States)

    Sobesky, Julia L.; D’Angelo, Heather M.; Anderson, Nathan D.; Watkins, Linda R.; Maier, Steven F.

    2016-01-01

    Abstract The impact of the foods we eat on metabolism and cardiac physiology has been studied for decades, yet less is known about the effects of foods on the CNS, or the behavioral manifestations that may result from these effects. Previous studies have shown that long-term consumption of high-fat foods leading to diet-induced obesity sensitizes the inflammatory response of the brain to subsequent challenging stimuli, causing deficits in the formation of long-term memories. The new findings reported here demonstrate that short-term consumption of a high-fat diet (HFD) produces the same outcomes, thus allowing the examination of mechanisms involved in this process long before obesity and associated comorbidities occur. Rats fed an HFD for 3 d exhibited increases in corticosterone, the inflammasome-associated protein NLRP3 (nod-like receptor protein 3), and the endogenous danger signal HMGB1 (high-mobility group box 1) in the hippocampus. A low-dose (10 μg/kg) lipopolysaccharide (LPS) immune challenge potentiated the neuroinflammatory response in the hippocampus of rats fed the HFD, and caused a deficit in the formation of long-term memory, effects not observed in rats fed regular chow. The blockade of corticosterone action with the glucocorticoid receptor antagonist mifepristone prevented the NLRP3 and HMGB1 increases in unchallenged animals, normalized the proinflammatory response to LPS, and prevented the memory impairment. These data suggest that short-term HFD consumption increases vulnerability to memory disruptions caused by an immune challenge by upregulating important neuroinflammatory priming and danger signals in the hippocampus, and that these effects are mediated by increases in hippocampal corticosterone. PMID:27595136

  2. Sub-chronic exposure to the insecticide dimethoate induces a proinflammatory status and enhances the neuroinflammatory response to bacterial lypopolysaccharide in the hippocampus and striatum of male mice

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    Astiz, Mariana, E-mail: marianaastiz@gmail.com; Diz-Chaves, Yolanda, E-mail: ydiz@cajal.csic.es; Garcia-Segura, Luis M., E-mail: lmgs@cajal.csic.es

    2013-10-15

    Dimethoate is an organophosphorus insecticide extensively used in horticulture. Previous studies have shown that the administration of dimethoate to male rats, at a very low dose and during a sub-chronic period, increases the oxidation of lipids and proteins, reduces the levels of antioxidants and impairs mitochondrial function in various brain regions. In this study, we have assessed in C57Bl/6 adult male mice, whether sub-chronic (5 weeks) intoxication with a low dose of dimethoate (1.4 mg/kg) affects the expression of inflammatory molecules and the reactivity of microglia in the hippocampus and striatum under basal conditions and after an immune challenge caused by the systemic administration of lipopolysaccharide. Dimethoate increased mRNA levels of tumor necrosis factor α (TNFα) and interleukin (IL) 6 in the hippocampus, and increased the proportion of Iba1 immunoreactive cells with reactive phenotype in dentate gyrus and striatum. Lipopolysaccharide caused a significant increase in the mRNA levels of IL1β, TNFα, IL6 and interferon-γ-inducible protein 10, and a significant increase in the proportion of microglia with reactive phenotype in the hippocampus and the striatum. Some of the effects of lipopolysaccharide (proportion of Iba1 immunoreactive cells with reactive phenotype and IL6 mRNA levels) were amplified in the animals treated with dimethoate, but only in the striatum. These findings indicate that a sub-chronic period of administration of a low dose of dimethoate, comparable to the levels of the pesticide present as residues in food, causes a proinflammatory status in the brain and enhances the neuroinflammatory response to the lipopolysaccharide challenge with regional specificity. - Highlights: • The dose of pesticide used was comparable to the levels of residues found in food. • Dimethoate administration increased cytokine expression and microglia reactivity. • Hippocampus and striatum were differentially affected by the treatment.

  3. Proteomic analysis of the effects of aged garlic extract and its FruArg component on lipopolysaccharide-induced neuroinflammatory response in microglial cells.

    Directory of Open Access Journals (Sweden)

    Hui Zhou

    Full Text Available Aged garlic extract (AGE is widely used as a dietary supplement, and is claimed to promote human health through anti-oxidant/anti-inflammatory activities with hypolipidemic, antiplatelet and neuroprotective effects. Prior studies of AGE have mainly focused on its organosulfur compounds, with little attention paid to its carbohydrate derivatives, such as N-α-(1-deoxy-D-fructos-1-yl-L-arginine (FruArg. The goal of this study is to investigate actions of AGE and FruArg on antioxidative and neuroinflammatory responses in lipopolysaccharide (LPS-activated murine BV-2 microglial cells using a proteomic approach. Our data show that both AGE and FruArg can significantly inhibit LPS-induced nitric oxide (NO production in BV-2 cells. Quantitative proteomic analysis by combining two dimensional differential in-gel electrophoresis (2D-DIGE with mass spectrometry revealed that expressions of 26 proteins were significantly altered upon LPS exposure, while levels of 20 and 21 proteins exhibited significant changes in response to AGE and FruArg treatments, respectively, in LPS-stimulated BV-2 cells. Notably, approximate 78% of the proteins responding to AGE and FruArg treatments are in common, suggesting that FruArg is a major active component of AGE. MULTICOM-PDCN and Ingenuity Pathway Analyses indicate that the proteins differentially affected by treatment with AGE and FruArg are involved in inflammatory responses and the Nrf2-mediated oxidative stress response. Collectively, these results suggest that AGE and FruArg attenuate neuroinflammatory responses and promote resilience in LPS-activated BV-2 cells by suppressing NO production and by regulating expression of multiple protein targets associated with oxidative stress.

  4. Association of Tuberculosis Status with Neurologic Disease and Immune Response in HTLV-1 Infection.

    Science.gov (United States)

    Souza, Anselmo; Carvalho, Natália; Neves, Yuri; Braga Santos, Silvane; Bastos, Maria de Lourdes; Arruda, Sérgio; Netto, Eduardo Martins; Glesby, Marshall J; Carvalho, Edgar

    2017-06-26

    The human T cell lymphotropic virus type 1 (HTLV-1) is the etiologic agent of HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). HTLV-1 infected individuals have increased susceptibility to Mycobacterium tuberculosis infection but the influence of tuberculosis (TB) on the course of HTLV-1 infection is unknown. The aim of this study was to evaluate the influence of TB on immunological, virologic, and neurologic features of HTLV-1 infection. This is a retrospective analysis of individuals enrolled in a cohort study from an HTLV-1 clinic who were evaluated for past or latent tuberculosis (LTB) and classified clinically as HTLV-1 carriers, probable HAM/TSP and definite HAM/TSP. Spontaneous cytokine production (interferon-gamma [IFN-γ], tumor necrosis factor [TNF], and interleukin[IL]-10), serum chemokines (CXCL9 and CXCL10) and HTLV-1 proviral load were evaluated. Of 172 participants, 64 did not have histories of TB (TB- group), 81 had LTB and 27 had TB in the past (TB+ group). In the TB+ group, there was a higher frequency of HAM/TSP patients (35%) than in HTLV-1 carriers (10%) (OR = 3.8, p = .0001). HAM/TSP patients with histories of TB had higher IFN-γ/IL-10 and TNF/IL-10 ratios when compared with HAM/TSP patients without histories of TB. There were no differences in serum chemokine production and proviral load across TB groups stratified on HTLV-1 clinical status. In conclusion, TB may influence the development of HAM/TSP, and patients with these two diseases have an impairment in the modulation of immune response.

  5. [Human retrovirus HTLV-1: descriptive and molecular epidemiology, origin, evolution, diagnosis and associated diseases].

    Science.gov (United States)

    Gessain, A

    2011-08-01

    Human T-cell leukemia/lymphoma virus type 1 (HTLV-1) was the first oncogenic human retrovirus discovered in 1980. It is estimated that around 10-20 million people are infected with HTLV-1 worldwide. However, HTLV-1 is not a ubiquitous virus. Indeed, HTLV-1 is present throughout the world with clusters of high endemicity including mainly southern Japan, the Caribbean region, parts of South America and intertropical Africa, with foci in the Middle East and Australia. The origin of this puzzling geographical repartition is probably linked to a founder effect in certain human groups. In the high endemic areas, 0.5 to 50% of the people have antibodies against HTLV-1 antigens. HTLV-1 seroprevalence increases with age, especially in women. HTLV-1 has 3 modes of transmission: mother to child, mainly through prolonged breastfeeding (> 6 months); sexual, mainly but not exclusively occurring from male to female; and by blood products contaminated by infected lymphocytes. HTLV-1 is mainly the etiological agent of two very severe diseases: a malignant T CD4+ cell lymphoproliferation of very poor prognosis, named adult T-cell leukemia/lymphoma (ATLL), and a chronic neuro-myelopathy named tropical spastic paraparesis/HTLV-1-associated myelopathy (TSP/HAM). HTLV-1 is also associated with rare anterior uveitis, infective dermatitis and myositis in some high HTLV-1 endemic areas. The repartition of the different molecular subtypes or genotypes is mainly linked to the geographical origin of the infected persons but not to the associated pathology. HTLV-1 possesses a remarkable genetic stability probably linked to viral amplification via clonal expansion of infected cells rather than by reverse transcription. This stability can be used as a molecular tool to gain better insights into the origin, evolution and modes of dissemination of HTLV-1 and infected populations. HTLV-1 originated in humans through interspecies transmission from STLV-1, a very closely related retrovirus, highly

  6. Neutrophil Gelatinase-Associated Lipocalin and its Receptors in Alzheimer's Disease (AD) Brain Regions: Differential Findings in AD with and without Depression

    NARCIS (Netherlands)

    Dekens, D.W.; Naude, P.J.; Engelborghs, S.; Vermeiren, Y.; Dam, D. Van; Oude Voshaar, R.C.; Eisel, U.L.; De Deyn, P.P.

    2016-01-01

    Co-existing depression worsens Alzheimer's disease (AD) pathology. Neutrophil gelatinase-associated lipocalin (NGAL) is a newly identified (neuro)inflammatory mediator in the pathophysiologies of both AD and depression. This study aimed to compare NGAL levels in healthy controls, AD without depressi

  7. Treadmill Exercise Prevents Increase of Neuroinflammation Markers Involved in the Dopaminergic Damage of the 6-OHDA Parkinson's Disease Model.

    Science.gov (United States)

    Real, Caroline Cristiano; Garcia, Priscila Crespo; Britto, Luiz R G

    2017-08-11

    Parkinson's disease (PD) involves loss of dopaminergic neurons in the substantia nigra (SN), which can be correlated to neuroinflammatory changes with the aging of the nervous system. On the other hand, exercise can reduce the deleterious effects promoted by age, but the mechanism involved is still unclear. This study investigated the preventive exercise-induced changes on neuroinflammatory processes in a rat model of PD induced by unilateral striatal injections of 6-hydroxydopamine (6-OHDA). Adult male Wistar rats were divided into two groups: (1) sedentary (SED) or (2) exercised (EX), animals that did treadmill exercise three times per week, every other day, for 4 weeks prior to 6-OHDA or saline injection. The rats were then divided into four sub-groups: (1) sedentary saline (SED), (2) sedentary 6-OHDA (SED + 6-OHDA), (3) exercised saline (EX), and (4) exercised 6-OHDA (EX + 6-OHDA). Seven and 30 days after surgery, brains were collected for immunohistochemistry and immunoblotting for dopaminergic and neuroinflammatory markers into SN and striatum. The SED + 6-OHDA animals presented an increase in the astrocyte, microglial, and oxidative species activation. On the other hand, EX + 6-OHDA animals did not present neuroinflammatory responses and performed better apormorphine test. Our data suggest that treadmill exercise throughout life can markedly reduce the chances of dopamine decrease, reinforcing studies that showed a lower incidence of Parkinson's disease in patients who were active during life.

  8. Microglial activation in Parkinson’s disease using [18F]-FEPPA

    OpenAIRE

    Ghadery, Christine; Koshimori, Yuko; Coakeley, Sarah; Harris, Madeleine; Rusjan, Pablo; Kim, Jinhee; Houle, Sylvain; Antonio P. Strafella

    2017-01-01

    Background Neuroinflammatory processes including activated microglia have been reported to play an important role in Parkinson’s disease (PD). Increased expression of translocator protein (TSPO) has been observed after brain injury and inflammation in neurodegenerative diseases. Positron emission tomography (PET) radioligand targeting TSPO allows for the quantification of neuroinflammation in vivo. Methods Based on the genotype of the rs6791 polymorphism in the TSPO gene, we included 25 mixed...

  9. Dose-dependent changes in neuroinflammatory and arachidonic acid cascade markers with synaptic marker loss in rat lipopolysaccharide infusion model of neuroinflammation

    Directory of Open Access Journals (Sweden)

    Kellom Matthew

    2012-05-01

    Full Text Available Abstract Background Neuroinflammation, caused by six days of intracerebroventricular infusion of bacterial lipopolysaccharide (LPS, stimulates rat brain arachidonic acid (AA metabolism. The molecular changes associated with increased AA metabolism are not clear. We examined effects of a six-day infusion of a low-dose (0.5 ng/h and a high-dose (250 ng/h of LPS on neuroinflammatory, AA cascade, and pre- and post-synaptic markers in rat brain. We used artificial cerebrospinal fluid-infused brains as controls. Results Infusion of low- or high-dose LPS increased brain protein levels of TNFα, and iNOS, without significantly changing GFAP. High-dose LPS infusion upregulated brain protein and mRNA levels of AA cascade markers (cytosolic cPLA2-IVA, secretory sPLA2-V, cyclooxygenase-2 and 5-lipoxygenase, and of transcription factor NF-κB p50 DNA binding activity. Both LPS doses increased cPLA2 and p38 mitogen-activated protein kinase levels, while reducing protein levels of the pre-synaptic marker, synaptophysin. Post-synaptic markers drebrin and PSD95 protein levels were decreased with high- but not low-dose LPS. Conclusions Chronic LPS infusion has differential effects, depending on dose, on inflammatory, AA and synaptic markers in rat brain. Neuroinflammation associated with upregulated brain AA metabolism can lead to synaptic dysfunction.

  10. Neuroinflammatory and oxidative stress phenomena in MPS IIIA mouse model: the positive effect of long-term aspirin treatment.

    Science.gov (United States)

    Arfi, Audrey; Richard, Magali; Gandolphe, Christelle; Bonnefont-Rousselot, Dominique; Thérond, Patrice; Scherman, Daniel

    2011-05-01

    Sanfilippo disease (MPS IIIA) is an autosomal recessive lysosomal storage disorder resulting from sulfamidase deficiency, which is characterized by severe neurological impairment. Various tissues of MPS IIIA mice accumulate undegraded glycosaminoglycans and mimic the human neurodegenerative disorder, and are an excellent tool to both delineate disease pathogenesis and test potential therapies. The relationship between abnormal glycosaminoglycan storage and neurodysfunction remains ill defined. Pathways such as inflammation or oxidative stress have been highlighted in many neurodegenerative disorders, including lysosomal storage diseases, as major components of the neuropathology. By using quantitative polymerase chain reaction, we have compared the expression of selected genes in normal and MPS IIIA mouse cerebral tissues, focusing on inflammation, apoptosis and oxidative stress-related genes. We have identified several genes strongly over-expressed in the central nervous system of a MPS IIIA mouse, reflecting a neurological deterioration state. We have used these genes as markers to follow-up a long-term aspirin treatment. Aspirin treatment led to the normalization of inflammation- and oxidative stress-related mRNA levels in treated MPS IIIA mouse brains. A biochemical correction of an oxidative stress phenomenon both in the brain and peripheral organs of treated MPS IIIA mice was also obtained. These results suggest that anti-inflammatory intervention may be of potential benefit in MPS IIIA disease. Copyright © 2011 Elsevier Inc. All rights reserved.

  11. Long-term follow-up of HTLV-1 proviral load in asymptomatic carriers and in incident cases of HAM/TSP: what is its relevance as a prognostic marker for neurologic disease?

    Science.gov (United States)

    Martins, Marina Lobato; Guimarães, Jacqueline Cronemberger; Ribas, João Gabriel; Romanelli, Luiz Cláudio Ferreira; de Freitas Carneiro-Proietti, Anna Bárbara

    2017-02-01

    HTLV-1 proviral load (pvl) is an important risk marker for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), but its value as prognostic marker is not well defined. Long-term prospective cohort studies are necessary to clarify this question. Here, we analyzed HTLV-1 pvl in the peripheral blood of 82 asymptomatic carriers (AC; 351 samples), 12 HAM/TSP patients (HAM; 46 samples), and six incident cases of HAM/TSP (iHAM), with serial samples collected before (n = 10) and after (n = 20) the disease onset. The mean interval of follow-up was 10 years in the AC group and 8 years in HAM and iHAM groups. pvl was not significantly different between the first and last measurements in the three groups, but there was a trend to decrease over time. Coefficient of variation of pvl was significantly lower in the AC group than in HAM (p = 0.015) and iHAM (p = 0.022) patients. AC and HAM individuals showed a significant and strong positive correlation between the first and last measurements of pvl, but not iHAM subjects. All individuals who developed HAM/TSP during the follow-up had high pvl level (>1 %) before the onset of disease, but a typical increase in pvl was not observed in that period. The data suggest that there is a trend to reach an equilibrium plateau of pvl over time, characteristic of each individual. A significant rate of AC keeps high pvl levels for a long time without developing clinical symptoms associated to HTLV-1 infection. Thus, serial quantification of pvl in the peripheral blood does not seem to be a good prognostic marker for HAM/TSP.

  12. Increased bilateral expression of α1-adrenoceptors on peripheral nerves, blood vessels and keratinocytes does not account for pain or neuroinflammatory changes after distal tibia fracture in rats.

    Science.gov (United States)

    Drummond, E S; Dawson, L F; Finch, P M; Li, W; Guo, T-Z; Kingery, W S; Drummond, P D

    2014-12-05

    In certain forms of nerve injury and inflammation, noradrenaline augments pain via actions on up-regulated α1-adrenoceptors (α1-ARs). The aim of this study was to use immunohistochemistry to examine α1-AR expression on peripheral neurons, cutaneous blood vessels and keratinocytes after distal tibia fracture and cast immobilization, a model of complex regional pain syndrome type 1. We hypothesized that there would be increased α1-AR expression on neurons and keratinocytes in the injured limb in comparison to the contralateral unaffected limb after distal tibia fracture, in association with inflammatory changes and pain. α1-AR expression was increased on plantar keratinocytes, dermal blood vessels and peripheral nerve fibers at 16weeks after injury both in the fractured and contralateral uninjured limb. Similar changes were seen in controls whose limb had been immobilized in a cast for 4weeks but not fractured. Neurofilament 200 (NF200), a marker of myelinated neurons, and calcitonin gene-related peptide (CGRP), a neuropeptide involved in neuro-inflammatory signaling, decreased 4weeks after fracture and casting but then increased at the 16-week time point. As some of these changes were also detected in the contralateral hind limb, they probably were triggered by a systemic response to fracture and casting. Soon after the cast was removed, intraplantar injections of the α1-AR antagonist prazosin released local vasoconstrictor tone but had no effect on pain behaviors. However, systemic injection of prazosin inhibited behavioral signs of pain, suggesting that fracture and/or casting triggered an up-regulation of α1-ARs in central nociceptive pathways that augmented pain. Together, these findings indicate that α1-AR expression increases in the hind limbs after distal tibia fracture and cast immobilization. However, these peripheral increases do not contribute directly to residual pain.

  13. Sub-chronic exposure to the insecticide dimethoate induces a proinflammatory status and enhances the neuroinflammatory response to bacterial lypopolysaccharide in the hippocampus and striatum of male mice.

    Science.gov (United States)

    Astiz, Mariana; Diz-Chaves, Yolanda; Garcia-Segura, Luis M

    2013-10-15

    Dimethoate is an organophosphorus insecticide extensively used in horticulture. Previous studies have shown that the administration of dimethoate to male rats, at a very low dose and during a sub-chronic period, increases the oxidation of lipids and proteins, reduces the levels of antioxidants and impairs mitochondrial function in various brain regions. In this study, we have assessed in C57Bl/6 adult male mice, whether sub-chronic (5weeks) intoxication with a low dose of dimethoate (1.4mg/kg) affects the expression of inflammatory molecules and the reactivity of microglia in the hippocampus and striatum under basal conditions and after an immune challenge caused by the systemic administration of lipopolysaccharide. Dimethoate increased mRNA levels of tumor necrosis factor α (TNFα) and interleukin (IL) 6 in the hippocampus, and increased the proportion of Iba1 immunoreactive cells with reactive phenotype in dentate gyrus and striatum. Lipopolysaccharide caused a significant increase in the mRNA levels of IL1β, TNFα, IL6 and interferon-γ-inducible protein 10, and a significant increase in the proportion of microglia with reactive phenotype in the hippocampus and the striatum. Some of the effects of lipopolysaccharide (proportion of Iba1 immunoreactive cells with reactive phenotype and IL6 mRNA levels) were amplified in the animals treated with dimethoate, but only in the striatum. These findings indicate that a sub-chronic period of administration of a low dose of dimethoate, comparable to the levels of the pesticide present as residues in food, causes a proinflammatory status in the brain and enhances the neuroinflammatory response to the lipopolysaccharide challenge with regional specificity.

  14. Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice.

    Directory of Open Access Journals (Sweden)

    Virginie F Labrousse

    Full Text Available Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA and eicosapentaenoic acid (EPA are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this purpose, mice were exposed to a control diet throughout life and were further submitted to a diet enriched in EPA and DHA during 2 additional months. Cytokine expression together with a thorough analysis of astrocytes morphology assessed by a 3D reconstruction was measured in the hippocampus of young (3-month-old and aged (22-month-old mice. In addition, the effects of EPA and DHA on spatial memory and associated Fos activation in the hippocampus were assessed. We showed that a 2-month EPA/DHA treatment increased these long-chain ω3 PUFAs in the brain, prevented cytokines expression and astrocytes morphology changes in the hippocampus and restored spatial memory deficits and Fos-associated activation in the hippocampus of aged mice. Collectively, these data indicated that diet-induced accumulation of EPA and DHA in the brain protects against neuroinflammation and cognitive impairment linked to aging, further reinforcing the idea that increased EPA and DHA intake may provide protection to the brain of aged subjects.

  15. Low-dose ribavirin treatments attenuate neuroinflammatory activation of BV-2 Cells by interfering with inducible nitric oxide synthase.

    Science.gov (United States)

    Bozic, Iva; Savic, Danijela; Jovanovic, Marija; Bjelobaba, Ivana; Laketa, Danijela; Nedeljkovic, Nadezda; Stojiljkovic, Mirjana; Pekovic, Sanja; Lavrnja, Irena

    2015-01-01

    Microglia play a key role in defending central nervous system from various internal and external threats. However, their excessive and/or chronic activation is associated with deleterious effects in a variety of neurodegenerative diseases. Previously, we have shown that ribavirin when applied in clinically relevant dosage (10 μM) modulates activated microglia in complex fashion inducing both anti- and proinflammatory effects, simultaneously causing cytotoxicity. Here, we examined potential of low-dose ribavirin (0.1 and 1 μM) to modulate activated BV-2 microglia. Morphological and functional activation of BV-2 cells was achieved with lipopolysaccharide (LPS) stimulation. Our results demonstrated that low-dose ribavirin did not induce cell death, while 10 μM ribavirin promoted LPS induced apoptosis. We determined that 1 μM ribavirin was equally efficient in deactivation of LPS induced morphological changes as 10 μM ribavirin treatment. Ribavirin showed halfway success in reducing markers of functional activation of microglia. Namely, none of the doses had effect on LPS triggered production of proinflammatory cytokine tumor necrosis factor alpha. On the other hand, low-dose ribavirin proved its effectiveness in reduction of another inflammatory mediator, nitric oxide, by inhibiting inducible form of nitric oxide synthase. Our results imply that low-dose ribavirin may alleviate nitrosative stress during neuroinflammation.

  16. Low-Dose Ribavirin Treatments Attenuate Neuroinflammatory Activation of BV-2 Cells by Interfering with Inducible Nitric Oxide Synthase

    Directory of Open Access Journals (Sweden)

    Iva Bozic

    2015-01-01

    Full Text Available Microglia play a key role in defending central nervous system from various internal and external threats. However, their excessive and/or chronic activation is associated with deleterious effects in a variety of neurodegenerative diseases. Previously, we have shown that ribavirin when applied in clinically relevant dosage (10 μM modulates activated microglia in complex fashion inducing both anti- and proinflammatory effects, simultaneously causing cytotoxicity. Here, we examined potential of low-dose ribavirin (0.1 and 1 μM to modulate activated BV-2 microglia. Morphological and functional activation of BV-2 cells was achieved with lipopolysaccharide (LPS stimulation. Our results demonstrated that low-dose ribavirin did not induce cell death, while 10 μM ribavirin promoted LPS induced apoptosis. We determined that 1 μM ribavirin was equally efficient in deactivation of LPS induced morphological changes as 10 μM ribavirin treatment. Ribavirin showed halfway success in reducing markers of functional activation of microglia. Namely, none of the doses had effect on LPS triggered production of proinflammatory cytokine tumor necrosis factor alpha. On the other hand, low-dose ribavirin proved its effectiveness in reduction of another inflammatory mediator, nitric oxide, by inhibiting inducible form of nitric oxide synthase. Our results imply that low-dose ribavirin may alleviate nitrosative stress during neuroinflammation.

  17. Short-term long chain omega3 diet protects from neuroinflammatory processes and memory impairment in aged mice.

    Science.gov (United States)

    Labrousse, Virginie F; Nadjar, Agnès; Joffre, Corinne; Costes, Laurence; Aubert, Agnès; Grégoire, Stéphane; Bretillon, Lionel; Layé, Sophie

    2012-01-01

    Regular consumption of food enriched in omega3 polyunsaturated fatty acids (ω3 PUFAs) has been shown to reduce risk of cognitive decline in elderly, and possibly development of Alzheimer's disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are the most likely active components of ω3-rich PUFAs diets in the brain. We therefore hypothesized that exposing mice to a DHA and EPA enriched diet may reduce neuroinflammation and protect against memory impairment in aged mice. For this purpose, mice were exposed to a control diet throughout life and were further submitted to a diet enriched in EPA and DHA during 2 additional months. Cytokine expression together with a thorough analysis of astrocytes morphology assessed by a 3D reconstruction was measured in the hippocampus of young (3-month-old) and aged (22-month-old) mice. In addition, the effects of EPA and DHA on spatial memory and associated Fos activation in the hippocampus were assessed. We showed that a 2-month EPA/DHA treatment increased these long-chain ω3 PUFAs in the brain, prevented cytokines expression and astrocytes morphology changes in the hippocampus and restored spatial memory deficits and Fos-associated activation in the hippocampus of aged mice. Collectively, these data indicated that diet-induced accumulation of EPA and DHA in the brain protects against neuroinflammation and cognitive impairment linked to aging, further reinforcing the idea that increased EPA and DHA intake may provide protection to the brain of aged subjects.

  18. Coordinated gene expression of neuroinflammatory and cell signaling markers in dorsolateral prefrontal cortex during human brain development and aging.

    Directory of Open Access Journals (Sweden)

    Christopher T Primiani

    Full Text Available BACKGROUND: Age changes in expression of inflammatory, synaptic, and neurotrophic genes are not well characterized during human brain development and senescence. Knowing these changes may elucidate structural, metabolic, and functional brain processes over the lifespan, as well vulnerability to neurodevelopmental or neurodegenerative diseases. HYPOTHESIS: Expression levels of inflammatory, synaptic, and neurotrophic genes in the human brain are coordinated over the lifespan and underlie changes in phenotypic networks or cascades. METHODS: We used a large-scale microarray dataset from human prefrontal cortex, BrainCloud, to quantify age changes over the lifespan, divided into Development (0 to 21 years, 87 brains and Aging (22 to 78 years, 144 brains intervals, in transcription levels of 39 genes. RESULTS: Gene expression levels followed different trajectories over the lifespan. Many changes were intercorrelated within three similar groups or clusters of genes during both Development and Aging, despite different roles of the gene products in the two intervals. During Development, changes were related to reported neuronal loss, dendritic growth and pruning, and microglial events; TLR4, IL1R1, NFKB1, MOBP, PLA2G4A, and PTGS2 expression increased in the first years of life, while expression of synaptic genes GAP43 and DBN1 decreased, before reaching plateaus. During Aging, expression was upregulated for potentially pro-inflammatory genes such as NFKB1, TRAF6, TLR4, IL1R1, TSPO, and GFAP, but downregulated for neurotrophic and synaptic integrity genes such as BDNF, NGF, PDGFA, SYN, and DBN1. CONCLUSIONS: Coordinated changes in gene transcription cascades underlie changes in synaptic, neurotrophic, and inflammatory phenotypic networks during brain Development and Aging. Early postnatal expression changes relate to neuronal, glial, and myelin growth and synaptic pruning events, while late Aging is associated with pro-inflammatory and synaptic loss

  19. Sesquiterpene dimmer (DSF-27) inhibits the release of neuroinflammatory mediators from microglia by targeting spleen tyrosine kinase (Syk) and Janus kinase 2 (Jak2): Two major non-receptor tyrosine signaling proteins involved in inflammatory events

    Energy Technology Data Exchange (ETDEWEB)

    Zeng, Ke-Wu [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Wang, Shu [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Department of Medicinal Chemistry and Pharmaceutical Analysis, Logistics College of Chinese People' s Armed Police Forces, Tianjin 300162 (China); Dong, Xin; Jiang, Yong; Jin, Hong-Wei [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China); Tu, Peng-Fei, E-mail: pengfeitu@vip.163.com [State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191 (China)

    2014-03-15

    Non-receptor protein tyrosine kinases (NRPTKs)-dependent inflammatory signal transduction cascades play key roles in immunoregulation. However, drug intervention through NRPTKs-involved immunoregulation mechanism in microglia (the major immune cells of the central nervous system) has not been widely investigated. A main aim of the present study is to elucidate the contribution of two major NRPTKs (Syk and Jak2) in neuroinflammation suppression by a bioactive sesquiterpene dimmer (DSF-27). We found that LPS-stimulated BV-2 cells activated Syk and further initiated Akt/NF-κB inflammatory pathway. This Syk-dependent Akt/NF-κB inflammatory pathway can be effectively ameliorated by DSF-27. Moreover, Jak2 was activated by LPS, which was followed by transcriptional factor Stat3 activation. The Jak2/Stat3 signal was suppressed by DSF-27 through inhibition of Jak2 and Stat3 phosphorylation, promotion of Jak/Stat3 inhibitory factors PIAS3 expression, and down-regulation of ERK and p38 MAPK phosphorylation. Furthermore, DSF-27 protected cortical and mesencephalic dopaminergic neurons against neuroinflammatory injury. Taken together, our findings indicate NRPTK signaling pathways including Syk/NF-κB and Jak2/Stat3 cascades are potential anti-neuroinflammatory targets in microglia, and may also set the basis for the use of sesquiterpene dimmer as a therapeutic approach for neuroinflammation via interruption of these pathways. - Highlights: • Sesquiterpene dimmer DSF-27 inhibits inflammatory mediators' production in microglia. • Syk-dependent Akt/NF-κB pathway is important for DSF-27's anti-inflammation activity. • Jak2/Stat3 pathway is important for DSF-27's anti-inflammation activity. • Jak2/Stat3 signaling pathway is partly regulated by ERK and p38 MAPKs and PIAS3. • DSF-27 protects neurons against microglia-mediated neuroinflammatory injury.

  20. Freqüência de doenças reumáticas em indivíduos infectados pelo HTLV-1 Frequency of rheumatic diseases in individuals infected with HTLV-1

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    Mônica Martinelli Nunes de Carvalho

    2006-10-01

    .INTRODUCTION: the HTLV-1 is a human retrovirus associated with adult T-cell leukaemia (ATL and with HTLV-1- associated myelopathy or tropical spastic paraparesis, which has also been implicated in the development of autoimmunity. OBJECTIVE: the aim of this study was to determine the frequency of autoimmune rheumatic diseases in patients infected with HTLV-1. PATIENTS AND METHODS: it was included 137 individuals infected with HTLV-1 from the Multidisciplinary Ambulatory of Immunology Service, HUPES-UFBA, Salvador (BA, from January 2003 to May 2004. All participants answered to a general questionnaire regarding rheumathological manifestations and specific questionnaires to confirm the diagnose criteria of rheumatoid arthritis (RA, systemic lupus erythematosus (SLE, Sjögren’s syndrome (SS and polymyositis. Additionally, they were submitted to specific clinical exams, besides complementary evaluations. RESULTS: 24 patients had diagnose of probable Sjögren’s syndrome (17.5%, 18 patients (13.1% had RA, one patient had diagnose of SLE (0.7% and another of mixed connective tissue disease (0.7%, respectively. HTLV-1-associated arthropathy (HAAP was suspected in 22 individuals (16.1%. Sjögren’s syndrome and RA were more frequent in patients with myelopathy (33.3 and 25.9%, respectively than in asymptomatic carriers (13.6 and 10%, respectively. The frequency of HTLV-1-associated arthropathy was the same in both groups. CONCLUSION: in this study it was observed a high frequency of Sjögren’s syndrome and RA in individuals infected with HTLV-1, mainly in those with myelopathy. Therefore, with this results that support data in the literature, we should call attention to the occurrence of autoimmune rheumatic diseases in these kind of patients.

  1. Pro-inflammatory cytokines derived from West Nile virus (WNV-infected SK-N-SH cells mediate neuroinflammatory markers and neuronal death

    Directory of Open Access Journals (Sweden)

    Nerurkar Vivek R

    2010-10-01

    Full Text Available Abstract Background WNV-associated encephalitis (WNVE is characterized by increased production of pro-inflammatory mediators, glial cells activation and eventual loss of neurons. WNV infection of neurons is rapidly progressive and destructive whereas infection of non-neuronal brain cells is limited. However, the role of neurons and pathological consequences of pro-inflammatory cytokines released as a result of WNV infection is unclear. Therefore, the objective of this study was to examine the role of key cytokines secreted by WNV-infected neurons in mediating neuroinflammatory markers and neuronal death. Methods A transformed human neuroblastoma cell line, SK-N-SH, was infected with WNV at multiplicity of infection (MOI-1 and -5, and WNV replication kinetics and expression profile of key pro-inflammatory cytokines were analyzed by plaque assay, qRT-PCR, and ELISA. Cell death was measured in SK-N-SH cell line in the presence and absence of neutralizing antibodies against key pro-inflammatory cytokines using cell viability assay, TUNEL and flow cytometry. Further, naïve primary astrocytes were treated with UV-inactivated supernatant from mock- and WNV-infected SK-N-SH cell line and the activation of astrocytes was measured using flow cytometry and ELISA. Results WNV-infected SK-N-SH cells induced the expression of IL-1β, -6, -8, and TNF-α in a dose- and time-dependent manner, which coincided with increase in virus-induced cell death. Treatment of cells with anti-IL-1β or -TNF-α resulted in significant reduction of the neurotoxic effects of WNV. Furthermore treatment of naïve astrocytes with UV-inactivated supernatant from WNV-infected SK-N-SH cell line increased expression of glial fibrillary acidic protein and key inflammatory cytokines. Conclusion Our results for the first time suggest that neurons are one of the potential sources of pro-inflammatory cytokines in WNV-infected brain and these neuron-derived cytokines contribute to WNV

  2. The research prowess of neuroinflammatory mechanisms of postoperative delirium%术后谵妄神经炎症机制的研究进展

    Institute of Scientific and Technical Information of China (English)

    武姗姗; 张宗旺

    2016-01-01

    Background Postoperative delirium (POD),a common complication of elderly patients,frequently occurs 24-72 h after surgery.Though the pathophysiology of delirium is complex and not well known,studies have shown that inflammatory responses in the central nervous system may play an important role.Ulinastatin,a kind of glycoprotein,separated and purified from the urine of healthy men,could inhibite a variety of protease,sugar and lipid hydrolase enzyme,prevent the cell and organ function from damaging by surgical stimulation,inhibit inflammatory reaction after operation,make the cell membrane stability,protect the structure and function of the blood brain barrier and reduce neurological impairment.Objective To explore the neuroinflammatory mechanisms of POD,and provide a theoretical basis for its prevention.Content In this paper,we discussed how the peripheral inflammation leads to neuroinflammation and how the inflammatory cytokines TNF-α,IL-1β,IL-6 and S100β protein play a clinical effect,and the cerebral protective effect of ulinastatin and so on.Trend Providing a new idea for the prevention of POD and clinical application of ulinastatin.%背景 术后谵妄(postoperative delirium,POD)常发生于手术后24~72 h,是老年人术后常见并发症.谵妄的病理生理机制很复杂,目前尚不完全清楚,但已有研究表明中枢神经系统炎症反应可能在其中发挥重要作用.乌司他丁是从健康男性尿液中分离纯化得到的糖蛋白,对多种蛋白酶、糖和脂水解酶均有抑制作用,能够防治由手术刺激造成的细胞和器官功能的损伤,抑制手术后炎症反应,稳定细胞膜,保护血脑屏障的结构和功能,起到减少神经系统的功能损害作用. 目的 探讨POD的神经炎症机制,为其抗炎防治提供理论依据. 内容 就外周炎症反应如何导致中枢神经系统炎症,炎性细胞因子(如TNF-α、IL-1β、IL-6)和S100β蛋白的临床效应及乌司他丁的脑保

  3. Muscular weakness represents the main limiting factor of walk, functional independence and quality of life of myelopathy patients associated to HTLV-1

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    Renata Costa Caiafa

    2016-04-01

    Full Text Available ABSTRACT HTLV-1-associated myelopathy is a progressive disabling disease associated with gait abnormalities. Objective To identify and quantify the main muscles affected by weakness and spasticity, their impact on gait, functional capacity and on quality of life of HTLV-1-associated myelopathy patients. Method We evaluated lower limbs muscular strength according to the Medical Research Council scale, spasticity according to the modified Ashworth scale, daily activities according to the Barthel Index and quality of life according to the Short-Form Health Survey-36 of 26 HTLV-1-associated myelopathy patients. Results The muscles most affected by weakness included the dorsal flexors and knee flexors. Spasticity predominated in the hip adductor muscles and in plantar flexors. Assistance for locomotion, minimal dependence in daily activities, limitations in functional capacity and physical aspects were the most common findings. Conclusion The impairment of gait, functional dependence and quality of life were predominantly a consequence of intense muscle weakness in HTLV-1-associated myelopathy patients.

  4. Early molecular and behavioral response to lipopolysaccharide in the WAG/Rij rat model of absence epilepsy and depressive-like behavior, involves interplay between AMPK, AKT/mTOR pathways and neuroinflammatory cytokine release.

    Science.gov (United States)

    Russo, Emilio; Andreozzi, Francesco; Iuliano, Rodolfo; Dattilo, Vincenzo; Procopio, Teresa; Fiume, Giuseppe; Mimmi, Selena; Perrotti, Nicola; Citraro, Rita; Sesti, Giorgio; Constanti, Andrew; De Sarro, Giovambattista

    2014-11-01

    The mammalian target of rapamycin (mTOR) pathway has been recently indicated as a suitable drug target for the prevention of epileptogenesis. The mTOR pathway is known for its involvement in the control of the immune system. Since neuroinflammation is recognized as a major contributor to epileptogenesis, we wished to examine whether the neuroprotective effects of mTOR modulation could involve a suppression of the neuroinflammatory process in epileptic brain. We have investigated the early molecular mechanisms involved in the effects of intracerebral administration of the lipopolysaccharide (LPS) in the WAG/Rij rat model of absence epilepsy, in relation to seizure generation and depressive-like behavior; we also tested whether the effects of LPS could be modulated by treatment with rapamycin (RAP), a specific mTOR inhibitor. We determined, in specific rat brain areas, levels of p-mTOR/p-p70S6K and also p-AKT/p-AMPK as downstream or upstream indicators of mTOR activity and tested the effects of LPS and RAP co-administration. Changes in the brain levels of pro-inflammatory cytokines IL-1β and TNF-α and their relative mRNA expression levels were measured, and the involvement of nuclear factor-κB (NF-κB) was also examined in vitro. We confirmed that RAP inhibits the aggravation of absence seizures and depressive-like/sickness behavior induced by LPS in the WAG/Rij rats through the activation of mTOR and show that this effect is correlated with the ability of RAP to dampen and delay LPS increases in neuroinflammatory cytokines IL-1β and TNF-α, most likely through inhibition of the activation of NF-κB. Our results suggest that such a mechanism could contribute to the antiseizure, antiepileptogenic and behavioral effects of RAP and further highlight the potential therapeutic usefulness of mTOR inhibition in the management of human epilepsy and other neurological disorders. Furthermore, we show that LPS-dependent neuroinflammatory effects are also mediated by a

  5. Neuroimmunological processes in Parkinson's disease and their relation to α-synuclein: microglia as the referee between neuronal processes and peripheral immunity

    OpenAIRE

    Vanesa Sanchez-Guajardo; Barnum, Christopher J.; Tansey, Malú G.; Marina Romero-Ramos

    2013-01-01

    The role of neuroinflammation and the adaptive immune system in PD (Parkinson's disease) has been the subject of intense investigation in recent years, both in animal models of parkinsonism and in post-mortem PD brains. However, how these processes relate to and modulate α-syn (α-synuclein) pathology and microglia activation is still poorly understood. Specifically, how the peripheral immune system interacts, regulates and/or is induced by neuroinflammatory processes taking place during PD is...

  6. Anti-neuroinflammatory Activity of Elephantopus scaber L. via Activation of Nrf2/HO-1 Signaling and Inhibition of p38 MAPK Pathway in LPS-Induced Microglia BV-2 Cells

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    Chim-Kei Chan

    2017-06-01

    Full Text Available Elephantopus scaber L. (family: Asteraceae has been traditionally utilized as a folkloric medicine and scientifically shown to exhibit anti-inflammatory activities in various in vivo inflammatory models. Given the lack of study on the effect of E. scaber in neuroinflammation, this study aimed to investigate the anti-neuroinflammatory effect and the underlying mechanisms of ethyl acetate fraction from the leaves of E. scaber (ESEAF on the release of pro-inflammatory mediators in lipopolysaccharide (LPS-induced microglia cells (BV-2. Present findings showed that ESEAF markedly attenuated the translocation of NF-κB to nucleus concomitantly with the significant mitigation on the LPS-induced production of NO, iNOS, COX-2, PGE2, IL-1β, and TNF-α. These inflammatory responses were reduced via the inhibition of p38. Besides, ESEAF was shown to possess antioxidant activities evident by the DPPH and SOD scavenging activities. The intracellular catalase enzyme activity was enhanced by ESEAF in the LPS-stimulated BV-2 cells. Furthermore, the formation of ROS induced by LPS in BV-2 cells was reduced upon the exposure to ESEAF. Intriguingly, the reduction of ROS was found in concerted with the activation of Nrf2 and HO-1. It is conceivable that the activation promotes the scavenging power of antioxidant enzymes as well as to ameliorate the inflammatory response in LPS-stimulated BV-2 cells. Finally, the safety profile analysis through oral administration of ESEAF at 2000 mg/kg did not result in any mortalities, adverse effects nor histopathologic abnormalities of organs in mice. Taken altogether, the cumulative findings suggested that ESEAF holds the potential to develop as nutraceutical for the intervention of neuroinflammatory disorders.

  7. The choreography of neuroinflammation in Huntington's disease.

    Science.gov (United States)

    Crotti, Andrea; Glass, Christopher K

    2015-06-01

    Currently, the concept of 'neuroinflammation' includes inflammation associated with neurodegenerative diseases, in which there is little or no infiltration of blood-derived immune cells into the brain. The roles of brain-resident and peripheral immune cells in these inflammatory settings are poorly understood, and it is unclear whether neuroinflammation results from immune reaction to neuronal dysfunction/degeneration, and/or represents cell-autonomous phenotypes of dysfunctional immune cells. Here, we review recent studies examining these questions in the context of Huntington's disease (HD), where mutant Huntingtin (HTT) is expressed in both neurons and glia. Insights into the cellular and molecular mechanisms underlying neuroinflammation in HD may provide a better understanding of inflammation in more complex neurodegenerative disorders, and of the contribution of the neuroinflammatory component to neurodegenerative disease pathogenesis.

  8. DISEASES

    DEFF Research Database (Denmark)

    Pletscher-Frankild, Sune; Pallejà, Albert; Tsafou, Kalliopi;

    2015-01-01

    Text mining is a flexible technology that can be applied to numerous different tasks in biology and medicine. We present a system for extracting disease-gene associations from biomedical abstracts. The system consists of a highly efficient dictionary-based tagger for named entity recognition...... of human genes and diseases, which we combine with a scoring scheme that takes into account co-occurrences both within and between sentences. We show that this approach is able to extract half of all manually curated associations with a false positive rate of only 0.16%. Nonetheless, text mining should...... not stand alone, but be combined with other types of evidence. For this reason, we have developed the DISEASES resource, which integrates the results from text mining with manually curated disease-gene associations, cancer mutation data, and genome-wide association studies from existing databases...

  9. Microglial activation and neuroinflammation in Alzheimer's disease: a critical examination of recent history

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    Wolfgang J Streit

    2010-06-01

    Full Text Available The neurofibrillary degeneration that occurs in Alzheimer’s disease (AD is thought to be the result of a chronic and damaging neuroinflammatory response mediated by neurotoxic substances produced by activated microglial cells. This neuroinflammation hypothesis of AD pathogenesis has led to numerous clinical trials with anti-inflammatory drugs, none of which have shown clear benefits for slowing or preventing disease onset and progression. In this paper, I make the point that AD is not an inflammatory condition, and reconstruct the sequence of events during the 1980s and 1990s that I believe led to the development of this faulty theory.

  10. Prion Strain Differences in Accumulation of PrPSc on Neurons and Glia Are Associated with Similar Expression Profiles of Neuroinflammatory Genes: Comparison of Three Prion Strains.

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    James A Carroll

    2016-04-01

    Full Text Available Misfolding and aggregation of host proteins are important features of the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, frontotemporal dementia and prion diseases. In all these diseases, the misfolded protein increases in amount by a mechanism involving seeded polymerization. In prion diseases, host prion protein is misfolded to form a pathogenic protease-resistant form, PrPSc, which accumulates in neurons, astroglia and microglia in the CNS. Here using dual-staining immunohistochemistry, we compared the cell specificity of PrPSc accumulation at early preclinical times post-infection using three mouse scrapie strains that differ in brain regional pathology. PrPSc from each strain had a different pattern of cell specificity. Strain 22L was mainly associated with astroglia, whereas strain ME7 was mainly associated with neurons and neuropil. In thalamus and cortex, strain RML was similar to 22L, but in substantia nigra, RML was similar to ME7. Expression of 90 genes involved in neuroinflammation was studied quantitatively using mRNA from thalamus at preclinical times. Surprisingly, despite the cellular differences in PrPSc accumulation, the pattern of upregulated genes was similar for all three strains, and the small differences observed correlated with variations in the early disease tempo. Gene upregulation correlated with activation of both astroglia and microglia detected in early disease prior to vacuolar pathology or clinical signs. Interestingly, the profile of upregulated genes in scrapie differed markedly from that seen in two acute viral CNS diseases (LaCrosse virus and BE polytropic Friend retrovirus that had reactive gliosis at levels similar to our prion-infected mice.

  11. T cell receptor signaling pathway is overexpressed in CD4 + T cells from HAM/TSP individuals

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    Mariana Tomazini Pinto

    Full Text Available ABSTRACT Human T-lymphotropic virus type 1 (HTLV-1 is a human retrovirus related to the chronic neuroinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. CD4+ T cells activation appears to play a key role on HTLV-1 infection. Here we investigated the expression of genes associated to T cell activation CD3e molecule, epsilon (CD3?, lymphocyte-specific protein tyrosine kinase (LCK, vav 1 guanine nucleotide exchange factor (VAV1, and zeta-chain (TCR associated protein kinase 70 kDa (ZAP70 on T lymphocytes of HTLV-1-infected individuals and compared to healthy uninfected individuals (CT. We observed that CD3?, LCK, ZAP70, and VAV1 gene expression were increased in CD4+ T cells from HAM/TSP group compared to HTLV-1 asymptomatic patients (HAC. Moreover, ZAP70 and VAV1 were also upregulated in HAM/TSP compared to CT group. We detected a positive correlation among all these genes. We also observed that CD3?, LCK, and VAV1 genes had a positive correlation with the proviral load (PVL and Tax expression. These results suggest that PVL and Tax protein could drive CD3?, LCK, and VAV1 gene expression in CD4+ T cells, and these genes function on a synchronized way on the CD4+ T cell activation. The elucidation of the mechanisms underlying T cell receptor signaling pathway is of considerable interest and might lead to new insights into the mechanism of HAM/TSP.

  12. The Neuro-Immune Pathophysiology of Central and Peripheral Fatigue in Systemic Immune-Inflammatory and Neuro-Immune Diseases.

    Science.gov (United States)

    Morris, Gerwyn; Berk, Michael; Galecki, Piotr; Walder, Ken; Maes, Michael

    2016-03-01

    Many patients with systemic immune-inflammatory and neuro-inflammatory disorders, including depression, rheumatoid arthritis, systemic lupus erythematosus, Sjögren's disease, cancer, cardiovascular disorder, Parkinson's disease, multiple sclerosis, stroke, and chronic fatigue syndrome/myalgic encephalomyelitis, endure pathological levels of fatigue. The aim of this narrative review is to delineate the wide array of pathways that may underpin the incapacitating fatigue occurring in systemic and neuro-inflammatory disorders. A wide array of immune, inflammatory, oxidative and nitrosative stress (O&NS), bioenergetic, and neurophysiological abnormalities are involved in the etiopathology of these disease states and may underpin the incapacitating fatigue that accompanies these disorders. This range of abnormalities comprises: increased levels of pro-inflammatory cytokines, e.g., interleukin-1 (IL-1), IL-6, tumor necrosis factor (TNF) α and interferon (IFN) α; O&NS-induced muscle fatigue; activation of the Toll-Like Receptor Cycle through pathogen-associated (PAMPs) and damage-associated (DAMPs) molecular patterns, including heat shock proteins; altered glutaminergic and dopaminergic neurotransmission; mitochondrial dysfunctions; and O&NS-induced defects in the sodium-potassium pump. Fatigue is also associated with altered activities in specific brain regions and muscle pathology, such as reductions in maximum voluntary muscle force, downregulation of the mitochondrial biogenesis master gene peroxisome proliferator-activated receptor gamma coactivator 1-alpha, a shift to glycolysis and buildup of toxic metabolites within myocytes. As such, both mental and physical fatigue, which frequently accompany immune-inflammatory and neuro-inflammatory disorders, are the consequence of interactions between multiple systemic and central pathways.

  13. Fingolimod: A Disease-Modifier Drug in a Mouse Model of Amyotrophic Lateral Sclerosis.

    Science.gov (United States)

    Potenza, Rosa Luisa; De Simone, Roberta; Armida, Monica; Mazziotti, Valentina; Pèzzola, Antonella; Popoli, Patrizia; Minghetti, Luisa

    2016-10-01

    Fingolimod phosphate (FTY720), the first approved oral therapy for multiple sclerosis, primarily acts as an immunomodulator. Its concomitant effects in the central nervous system, however, indicate a potentially broader spectrum of activity in neurodegenerative diseases. In the present study, we investigated the possible effects of fingolimod in a mouse model of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by a strong neuroinflammatory component. Fingolimod (0.1 and 1 mg/kg i.p.) was administered to mSOD1(G93A) mice, a well-characterized mouse model of ALS, starting from the onset of motor symptoms to the end stage of the disease. The drug was able to improve the neurological phenotype (p < 0.05) and to extend the survival (p < 0.01) of ALS mice. The beneficial effect of fingolimod administration was associated with a significant modulation of neuroinflammatory and protective genes (CD11b, Foxp3, iNOS, Il1β, Il10, Arg1, and Bdnf) in motor cortex and spinal cord of animals. Our data show, for the first time, that fingolimod is protective in ALS mice and that its beneficial effects are accompanied by a modulation of microglial activation and innate immunity. Considering that the treatment was started in already symptomatic mice, our data strongly support fingolimod as a potential new therapeutic approach to ALS.

  14. Natural therapeutic agents for neurodegenerative diseases from a traditional herbal medicine Pongamia pinnata (L.) Pierre.

    Science.gov (United States)

    Li, Jiayuan; Jiang, Zhe; Li, Xuezheng; Hou, Yue; Liu, Fen; Li, Ning; Liu, Xia; Yang, Lihua

    2015-01-01

    Neurodegenerative diseases are associated with neuroinflammation, manifested by over-production of nitric oxide (NO) by microglial cells. Now there still lack effective treatment and prevention for the neurodegenerative diseases. Concerning neuroinflammation mediated by microglia cell, bioactivity-guided phytochemical research of Pongamia pinnata (L.) Pierre was performed in this study. A new chlorinated flavonoid, 2′,6′-dichlore-3′, 5′-dimethoxy-[2′′,3′′:7,8]-furanoflavone (1) was identified together with 29 known compounds, including flavonoids (compounds 2-17), isoflavonoids (compounds 18-23), chalcones (compounds 24-25), flavonones (compounds 26-27), triterpenes (28-29) and alkaloid (30) from the effective dichloride methane extract of dry stem of P. pinnata (L.) Pierre. Their structures were elucidated by physicochemical and spectral methods. The anti-neuroinflammatory activities were assayed in BV-2 cells by assessing LPS-induced NO production. Then pongaglabol methyl ether (2), lonchocarpin (24) and glabrachromene II (25) were selected as potential therapeutic agents for neurodegenerative diseases because of their significant anti-neuroinflammatory activities. Furthermore, the characteristics of structure type existing in P. pinnata (L.) Pierre and brief SAR were summarized, respectively.

  15. Effect of quinolinic acid on human astrocytes morphology and functions: implications in Alzheimer's disease

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    Brew Bruce J

    2009-12-01

    Full Text Available Abstract The excitotoxin quinolinic acid (QUIN is synthesized through the kynurenine pathway (KP by activated monocyte lineage cells. QUIN is likely to play a role in the pathogenesis of several major neuroinflammatory diseases including Alzheimer's disease (AD. The presence of reactive astrocytes, astrogliosis, increased oxidative stress and inflammatory cytokines are important pathological hallmarks of AD. We assessed the stimulatory effects of QUIN at low physiological to high excitotoxic concentrations in comparison with the cytokines commonly associated with AD including IFN-γ and TNF-α on primary human astrocytes. We found that QUIN induces IL-1β expression, a key mediator in AD pathogenesis, in human astrocytes. We also explored the effect of QUIN on astrocyte morphology and functions. At low concentrations, QUIN treatment induced concomitantly a marked increase in glial fibrillary acid protein levels and reduction in vimentin levels compared to controls; features consistent with astrogliosis. At pathophysiological concentrations QUIN induced a switch between structural protein expressions in a dose dependent manner, increasing VIM and concomitantly decreasing GFAP expression. Glutamine synthetase (GS activity was used as a functional metabolic test for astrocytes. We found a significant dose-dependent reduction in GS activity following QUIN treatment. All together, this study showed that QUIN is an important factor for astroglial activation, dysregulation and cell death with potential relevance to AD and other neuroinflammatory diseases.

  16. Does neuroinflammation fan the flame in neurodegenerative diseases?

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    McAlpine Fiona E

    2009-11-01

    Full Text Available Abstract While peripheral immune access to the central nervous system (CNS is restricted and tightly controlled, the CNS is capable of dynamic immune and inflammatory responses to a variety of insults. Infections, trauma, stroke, toxins and other stimuli are capable of producing an immediate and short lived activation of the innate immune system within the CNS. This acute neuroinflammatory response includes activation of the resident immune cells (microglia resulting in a phagocytic phenotype and the release of inflammatory mediators such as cytokines and chemokines. While an acute insult may trigger oxidative and nitrosative stress, it is typically short-lived and unlikely to be detrimental to long-term neuronal survival. In contrast, chronic neuroinflammation is a long-standing and often self-perpetuating neuroinflammatory response that persists long after an initial injury or insult. Chronic neuroinflammation includes not only long-standing activation of microglia and subsequent sustained release of inflammatory mediators, but also the resulting increased oxidative and nitrosative stress. The sustained release of inflammatory mediators works to perpetuate the inflammatory cycle, activating additional microglia, promoting their proliferation, and resulting in further release of inflammatory factors. Neurodegenerative CNS disorders, including multiple sclerosis (MS, Alzheimer's disease (AD, Parkinson's disease (PD, Huntington's disease (HD, amyotrophic lateral sclerosis (ALS, tauopathies, and age-related macular degeneration (ARMD, are associated with chronic neuroinflammation and elevated levels of several cytokines. Here we review the hallmarks of acute and chronic inflammatory responses in the CNS, the reasons why microglial activation represents a convergence point for diverse stimuli that may promote or compromise neuronal survival, and the epidemiologic, pharmacologic and genetic evidence implicating neuroinflammation in the

  17. WHAT WE ARE LEARNING ON HTLV-1 PATHOGENESISFROM ANIMAL MODELS

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    Madeleine eDuc Dodon

    2012-08-01

    Full Text Available Isolated and identified more than 30 years ago, Human T-cell Leukemia Virus type 1 (HTLV-1 is the etiological agent of adult T-cell leukemia/lymphoma (ATL, an aggressive lymphoproliferative disease of activated CD4+ T cells, and other inflammatory disorders such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP. A variety of animal models have contributed to the fundamental knowledge of HTLV-1 transmission, pathogenesis and to the design of novel therapies to treat HTLV-1 associated diseases. Small animal models (rabbits, rats, mice as well as large animal models (monkeys have been utilized to significantly advance characterization of the viral proteins and of virus-infected cells in the early steps of infection, as well as in the development of leukemogenic and immunopathogenic processes. Over the past two decades, the creation of new immuno-compromised mouse strains that are robustly reconstituted with a functional human immune system (HIS after being transplanted with human tissues or progenitor cells has revolutionized the in vivo investigation of viral infection and pathogenesis. Recent observations obtained in HTLV-1-infected humanized HIS mice that develop lymphomas provide the opportunity to study the evolution of the proviral clonality in human T cells present in different lymphoid organs. Current progress in the improvement of those humanized models will favor the testing of drugs and the development of targeted therapies against HTLV-1-associated diseases.

  18. Therapeutic potential of mGluR5 targeting in Alzheimer's disease

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    Anil eKumar

    2015-06-01

    Full Text Available Decades of research dedicated towards Alzheimer's disease (AD has culminated in much of the current understanding of the neurodegeneration associated with disease. However, delineating the pathophysiology and finding a possible cure for the disease is still wanting. This is in part due to the lack of knowledge pertaining to the connecting link between neurodegenerative and neuroinflammatory pathways. Consequently, the inefficacy and ill-effects of the drugs currently available for AD encourage the need for alternative and safe therapeutic intervention. In this review we highlight the potential of mGluR5, a metabotropic glutamatergic receptor, in understanding the mechanism underlying the neuronal death and neuroinflammation in AD. We also discuss the role of mGlu5 receptor in mediating the neuron-glia interaction in the disease. Finally, we discuss the potential of mGluR5 as target for treating AD.

  19. Neuroinflammatory TNFα Impairs Memory via Astrocyte Signaling.

    Science.gov (United States)

    Habbas, Samia; Santello, Mirko; Becker, Denise; Stubbe, Hiltrud; Zappia, Giovanna; Liaudet, Nicolas; Klaus, Federica R; Kollias, George; Fontana, Adriano; Pryce, Christopher R; Suter, Tobias; Volterra, Andrea

    2015-12-17

    The occurrence of cognitive disturbances upon CNS inflammation or infection has been correlated with increased levels of the cytokine tumor necrosis factor-α (TNFα). To date, however, no specific mechanism via which this cytokine could alter cognitive circuits has been demonstrated. Here, we show that local increase of TNFα in the hippocampal dentate gyrus activates astrocyte TNF receptor type 1 (TNFR1), which in turn triggers an astrocyte-neuron signaling cascade that results in persistent functional modification of hippocampal excitatory synapses. Astrocytic TNFR1 signaling is necessary for the hippocampal synaptic alteration and contextual learning-memory impairment observed in experimental autoimmune encephalitis (EAE), an animal model of multiple sclerosis (MS). This process may contribute to the pathogenesis of cognitive disturbances in MS, as well as in other CNS conditions accompanied by inflammatory states or infections.

  20. Astrocyte loss and astrogliosis in neuroinflammatory disorders

    NARCIS (Netherlands)

    Hostenbach, Stephanie; Cambron, Melissa; D'haeseleer, Miguel; Kooijman, Ron; De Keyser, Jacques

    2014-01-01

    Neuroinflammation can lead to either damage of astrocytes or astrogliosis. Astrocyte loss may be caused by cytotoxic T cells as seen in Rasmussen encephalitis, auto-antibodies such as in neuromyelitis optica (aquaporin-4 antibodies), or cytokines such as TNF-alpha in major depressive disorder. Inter

  1. Metabolic Profiling of Central Nervous System Disease in Trypanosoma brucei rhodesiense infection.

    Science.gov (United States)

    Lamour, Sabrina D; Alibu, Vincent P; Holmes, Elaine; Sternberg, Jeremy M

    2017-09-12

    The progression of Human African Trypanosomiasis from the early hemolymphatic stage to the late meningoencephalitic stage is of critical diagnostic importance as it determines the choice of potentially toxic drug regimens. Current diagnostic criteria involving analysis of cerebrospinal fluid (CSF) for parasites and/or pleiocytosis are sensitive, but recent evidence suggests that specificity may be poor. We used an untargeted global metabolic profiling approach for the discovery of novel candidate stage diagnostic markers in CSF from Trypanosoma brucei rhodesiense patients using 1H nuclear magnetic resonance (NMR) spectroscopy. Metabolic markers did not resolve early and late stage cases but were associated with neuro-inflammatory responses and the presentation of neurological disturbances. In particular increased 3-hydroxybutyrate and alanine and reduced concentrations of mannose and urea were discriminatory for the presentation of daytime somnolence and gait ataxia. CSF metabolite concentrations provide markers for neuroinflammatory responses during CNS invasion by trypanosomes and are associated with the presentation of neurological disturbances independently of disease stage determined by current criteria. This suggests that applying a dichotomous stage diagnosis on the basis of CSF pleiocytosis does not accurately reflect the biological changes occurring as parasites invade the CNS and has implications for biomarker discovery strategies.

  2. Doenças reumáticas auto-imunes em indivíduos infectados pelo HTLV-1 Autoimmune rheumatic diseases in HTLV-1 infected individuals

    Directory of Open Access Journals (Sweden)

    Mônica Martinelli Nunes de Carvalho

    2006-10-01

    Full Text Available O HTLV-1 foi o primeiro retrovírus humano a ser associado às doenças malignas leucemia e linfoma de células T do adulto (LLTA. Ele está relacionado também a uma doença inflamatória crônica do sistema nervoso central (SNC conhecida como paraparesia espástica tropical/mielopatia associada ao HTLV-1 (PET/MAH. O HTLV-1 tem sido implicado na patogênese de várias doenças auto-imunes, tais como: diabetes, esclerose múltipla, dermatite infectiva, uveíte e artropatia. Ao longo dos anos, a infecção retroviral tem assumido um importante papel na patogênese das doenças reumáticas auto-imunes. Partículas semelhantes aos retrovírus têm sido identificadas em tecidos de pacientes com artrite reumatóide (AR, síndrome de Sjögren, lúpus eritematoso sistêmico (LES e polimiosite. A síndrome de Sjögren e a AR têm sido as doenças reumáticas mais encontradas nos pacientes infectados pelo HTLV-1, sendo a freqüência mais elevada nos pacientes com mielopatia. A alta prevalência de síndrome de Sjögren e de AR entre os indivíduos com mielopatia sugere que a carga viral e a resposta inflamatória exacerbada, que concorrem para o desenvolvimento da mielopatia, devem também influenciar no desenvolvimento das doenças reumáticas auto-imunes.The HTLV-1 was the first human retrovirus associated with adult T-cell leukemia/lymphoma (LLTA. The virus also causes a chronic inflammatory disease of the central nervous system named HTLV-1-associated myelopathy or tropical spastic paraparesis (HAM/TSP. HTLV-1 has been implicated in the pathogenesis of many autoimmune diseases, such as diabetes, multiple sclerosis, infective dermatitis, uveitis and arthropathy. It has long been suggested that retroviral infection may play a role in the pathogenesis of autoimmune rheumatic diseases. Particles resembling retroviruses have been reported in tissue from patients with rheumatoid arthritis (RA, Sjögren’s syndrome, systemic lupus erythematosus (SLE and

  3. Neuroinflammation in Alzheimer's disease wanes with age

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    Hoozemans Jeroen JM

    2011-12-01

    Full Text Available Abstract Background Inflammation is a prominent feature in Alzheimer's disease (AD. It has been proposed that aging has an effect on the function of inflammation in the brain, thereby contributing to the development of age-related diseases like AD. However, the age-dependent relationship between inflammation and clinical phenotype of AD has never been investigated. Methods In this study we have analysed features of the neuroinflammatory response in clinically and pathologically confirmed AD and control cases in relation to age (range 52-97 years. The mid-temporal cortex of 19 controls and 19 AD cases was assessed for the occurrence of microglia and astrocytes by immunohistochemistry using antibodies directed against CD68 (KP1, HLA class II (CR3/43 and glial fibrillary acidic protein (GFAP. Results By measuring the area density of immunoreactivity we found significantly more microglia and astrocytes in AD cases younger than 80 years compared to older AD patients. In addition, the presence of KP1, CR3/43 and GFAP decreases significantly with increasing age in AD. Conclusion Our data suggest that the association between neuroinflammation and AD is stronger in relatively young patients than in the oldest patients. This age-dependent relationship between inflammation and clinical phenotype of AD has implications for the interpretation of biomarkers and treatment of the disease.

  4. A Dysregulated Endocannabinoid-Eicosanoid Network Supports Pathogenesis in a Mouse Model of Alzheimer's Disease

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    Justin R. Piro

    2012-06-01

    Full Text Available Although inflammation in the brain is meant as a defense mechanism against neurotoxic stimuli, increasing evidence suggests that uncontrolled, chronic, and persistent inflammation contributes to neurodegeneration. Most neurodegenerative diseases have now been associated with chronic inflammation, including Alzheimer's disease (AD. Whether anti-inflammatory approaches can be used to treat AD, however, is a major unanswered question. We recently demonstrated that monoacylglycerol lipase (MAGL hydrolyzes endocannabinoids to generate the primary arachidonic acid pool for neuroinflammatory prostaglandins. In this study, we show that genetic inactivation of MAGL attenuates neuroinflammation and lowers amyloid β levels and plaques in an AD mouse model. We also find that pharmacological blockade of MAGL recapitulates the cytokine-lowering effects through reduced prostaglandin production, rather than enhanced endocannabinoid signaling. Our findings thus reveal a role of MAGL in modulating neuroinflammation and amyloidosis in AD etiology and put forth MAGL inhibitors as a potential next-generation strategy for combating AD.

  5. Having a Coffee Break: The Impact of Caffeine Consumption on Microglia-Mediated Inflammation in Neurodegenerative Diseases.

    Science.gov (United States)

    Madeira, Maria H; Boia, Raquel; Ambrósio, António F; Santiago, Ana R

    2017-01-01

    Caffeine is the major component of coffee and the most consumed psychostimulant in the world and at nontoxic doses acts as a nonselective adenosine receptor antagonist. Epidemiological evidence suggests that caffeine consumption reduces the risk of several neurological and neurodegenerative diseases. However, despite the beneficial effects of caffeine consumption in human health and behaviour, the mechanisms by which it impacts the pathophysiology of neurodegenerative diseases still remain to be clarified. A promising hypothesis is that caffeine controls microglia-mediated neuroinflammatory response associated with the majority of neurodegenerative conditions. Accordingly, it has been already described that the modulation of adenosine receptors, namely, the A2A receptor, affords neuroprotection through the control of microglia reactivity and neuroinflammation. In this review, we will summarize the main effects of caffeine in the modulation of neuroinflammation in neurodegenerative diseases.

  6. Having a Coffee Break: The Impact of Caffeine Consumption on Microglia-Mediated Inflammation in Neurodegenerative Diseases

    Directory of Open Access Journals (Sweden)

    Maria H. Madeira

    2017-01-01

    Full Text Available Caffeine is the major component of coffee and the most consumed psychostimulant in the world and at nontoxic doses acts as a nonselective adenosine receptor antagonist. Epidemiological evidence suggests that caffeine consumption reduces the risk of several neurological and neurodegenerative diseases. However, despite the beneficial effects of caffeine consumption in human health and behaviour, the mechanisms by which it impacts the pathophysiology of neurodegenerative diseases still remain to be clarified. A promising hypothesis is that caffeine controls microglia-mediated neuroinflammatory response associated with the majority of neurodegenerative conditions. Accordingly, it has been already described that the modulation of adenosine receptors, namely, the A2A receptor, affords neuroprotection through the control of microglia reactivity and neuroinflammation. In this review, we will summarize the main effects of caffeine in the modulation of neuroinflammation in neurodegenerative diseases.

  7. Strongyloidiasis and infective dermatitis alter human T lymphotropic virus-1 clonality in vivo.

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    Nicolas A Gillet

    Full Text Available Human T-lymphotropic Virus-1 (HTLV-1 is a retrovirus that persists lifelong by driving clonal proliferation of infected T-cells. HTLV-1 causes a neuroinflammatory disease and adult T-cell leukemia/lymphoma. Strongyloidiasis, a gastrointestinal infection by the helminth Strongyloides stercoralis, and Infective Dermatitis associated with HTLV-1 (IDH, appear to be risk factors for the development of HTLV-1 related diseases. We used high-throughput sequencing to map and quantify the insertion sites of the provirus in order to monitor the clonality of the HTLV-1-infected T-cell population (i.e. the number of distinct clones and abundance of each clone. A newly developed biodiversity estimator called "DivE" was used to estimate the total number of clones in the blood. We found that the major determinant of proviral load in all subjects without leukemia/lymphoma was the total number of HTLV-1-infected clones. Nevertheless, the significantly higher proviral load in patients with strongyloidiasis or IDH was due to an increase in the mean clone abundance, not to an increase in the number of infected clones. These patients appear to be less capable of restricting clone abundance than those with HTLV-1 alone. In patients co-infected with Strongyloides there was an increased degree of oligoclonal expansion and a higher rate of turnover (i.e. appearance and disappearance of HTLV-1-infected clones. In Strongyloides co-infected patients and those with IDH, proliferation of the most abundant HTLV-1⁺ T-cell clones is independent of the genomic environment of the provirus, in sharp contrast to patients with HTLV-1 infection alone. This implies that new selection forces are driving oligoclonal proliferation in Strongyloides co-infection and IDH. We conclude that strongyloidiasis and IDH increase the risk of development of HTLV-1-associated diseases by increasing the rate of infection of new clones and the abundance of existing HTLV-1⁺ clones.

  8. Targeting neuroinflammation in Alzheimer’s disease

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    Bronzuoli, Maria Rosanna; Iacomino, Aniello; Steardo, Luca; Scuderi, Caterina

    2016-01-01

    Almost 47 million people suffer from dementia worldwide, with an estimated new case diagnosed every 3.2 seconds. Alzheimer’s disease (AD) accounts for approximately 60%–80% of all dementia cases. Given this evidence, it is clear dementia represents one of the greatest global public health challenges. Currently used drugs alleviate the symptoms of AD but do not treat the underlying causes of dementia. Hence, a worldwide quest is under way to find new treatments to stop, slow, or even prevent AD. Besides the classic targets of the oldest therapies, represented by cholinergic and glutamatergic systems, β-amyloid (Aβ) plaques, and tau tangles, new therapeutic approaches have other targets. One of the newest and most promising strategies is the control of reactive gliosis, a multicellular response to brain injury. This phenomenon occurs as a consequence of a persistent glial activation, which leads to cellular dysfunctions and neuroinflammation. Reactive gliosis is now considered a key abnormality in the AD brain. It has been demonstrated that reactive astrocytes surround both Aβ plaques and tau tangles. In this condition, glial cells lose some of their homeostatic functions and acquire a proinflammatory phenotype amplifying neuronal damage. So, molecules that are able to restore their physiological functions and control the neuroinflammatory process offer new therapeutic opportunities for this devastating disease. In this review, we describe the role of neuroinflammation in the AD pathogenesis and progression and then provide an overview of the recent research with the aim of developing new therapies to treat this disorder. PMID:27843334

  9. Wnt/TLR Dialog in Neuroinflammation, Relevance in Alzheimer's Disease.

    Science.gov (United States)

    Zolezzi, Juan M; Inestrosa, Nibaldo C

    2017-01-01

    The innate immune system (IIS) represents the first line of defense against exogenous and endogenous harmful stimuli. Different types of pathogens and diverse molecules can activate the IIS via a ligand-receptor mechanism. Cytokine release, recruitment of immunocompetent cells, and inflammation constitute the initial steps in an IIS-mediated response. While balanced IIS activity can resolve a harmful event, an altered response, such as deficient or persistent IIS activity, will have a critical effect on organism homeostasis. In this regard, chronic IIS activation has been associated with a wide range of diseases, including chronic inflammatory disorders (inflammatory bowel disease, arthritis, chronic obstructive pulmonary disease, among others), cancer and, more recently, neurodegenerative disorders. The relevance of the immune response, particularly inflammation, in the context of neurodegeneration has motivated rigorous research focused on unveiling the mechanisms underlying this response. Knowledge regarding the molecular hallmarks of the innate immune response and understanding signaling pathway cross talk are critical for developing new therapeutic strategies aimed at modulating the neuroinflammatory response within the brain. In the present review, we discuss the IIS in the central nervous system, particularly the cross talk between the toll-like receptor-signaling cascade and the wingless-related MMTV integration site (Wnt) signaling pathway and its relevance in neurodegenerative disorders such as Alzheimer's disease.

  10. Human T-Cell Lymphotropic Virus Type I (HTLV-1: implications for autoimmune diseases Vírus linfotrópico de células T humano tipo 1 (HTLV-1: implicações em doenças autoimunes

    Directory of Open Access Journals (Sweden)

    Dênis Augusto Santana Reis

    2012-06-01

    Full Text Available Autoimmunity is characterized by tissue destruction that implicates functional damages caused by self-reactive cells that escape self-tolerance mechanisms. Autoimmune diseases can be initiated by viral infections and the study of the association between these viruses and autoimmunity has advanced the understanding of the molecular mechanisms involved in autoimmune diseases. The Human T-Cell Lymphotropic Virus Type I (HTLV-1 is a deltavirus that infects preferentially lymphocytes. Retrovirus particles like has been identified in patients with autoimmune diseases. Therefore this review had by objective approach the main aspects involving HTLV-1 with systemic lupus erythematosus and rheumatoid arthritis. Studies show that retroviruses can integrate their genetic material in host DNA, changing the expression gene profile related with apoptosis and immunologic system molecules. It’s known that HTLV-1 can cause different clinical manifestations in their careers and the mechanisms that triggers the HTLV-1 associated autoimmune diseases are not well known. Besides the perpetuation and marked production of pro-inflammatory cytokines, studies have demonstrated that both Th17 cells and T regulatory cells (Tregs are involved in autoimmune diseases pathogenesis. Therefore the HTLV-1 viral particles recognized could be used as a risk marker in the development of autoimmune diseases.A autoimunidade é caracterizada pela destruição tecidual, que acarreta danos funcionais, causados por células autoreativas que escapam dos mecanismos de autotolerância. Doenças autoimunes podem ser iniciadas por infecções virais e o estudo da associação entre essas viroses e a autoimunidade tem possibilitado melhor conhecimento dos mecanismos moleculares envolvidos nas doenças autoimunes. O vírus linfotrópico de células T humano tipo 1 (HTLV-1 é um delta vírus que infecta preferencialmente linfócitos. Partículas semelhantes aos retrovírus foram identificadas em

  11. Closed head injury--an inflammatory disease?

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    Schmidt, Oliver I; Heyde, Christoph E; Ertel, Wolfgang; Stahel, Philip F

    2005-04-01

    Closed head injury (CHI) remains the leading cause of death and persisting neurological impairment in young individuals in industrialized nations. Research efforts in the past years have brought evidence that the intracranial inflammatory response in the injured brain contributes to the neuropathological sequelae which are, in large part, responsible for the adverse outcome after head injury. The presence of hypoxia and hypotension in the early resuscitative period of brain-injured patients further aggravates the inflammatory response in the brain due to ischemia/reperfusion-mediated injuries. The profound endogenous neuroinflammatory response after CHI, which is phylogenetically aimed at defending the intrathecal compartment from invading pathogens and repairing lesioned brain tissue, contributes to the development of cerebral edema, breakdown of the blood-brain barrier, and ultimately to delayed neuronal cell death. However, aside from these deleterious effects, neuroinflammation has been recently shown to mediate neuroreparative mechanisms after brain injury as well. This "dual effect" of neuroinflammation was the focus of extensive experimental and clinical research in the past years and has lead to an expanded basic knowledge on the cellular and molecular mechanisms which regulate the intracranial inflammatory response after CHI. Thus, head injury has recently evolved as an inflammatory and immunological disease much more than a pure traumatological, neurological, or neurosurgical entity. The present review will summarize the so far known mechanisms of posttraumatic neuroinflammation after CHI, based on data from clinical and experimental studies, with a special focus on the role of pro-inflammatory cytokines, chemokines, and the complement system.

  12. NETosis in Alzheimer’s Disease

    Science.gov (United States)

    Pietronigro, Enrica Caterina; Della Bianca, Vittorina; Zenaro, Elena; Constantin, Gabriela

    2017-01-01

    Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the progressive deterioration of cognitive functions. Its neuropathological features include amyloid-β (Aβ) accumulation, the formation of neurofibrillary tangles, and the loss of neurons and synapses. Neuroinflammation is a well-established feature of AD pathogenesis, and a better understanding of its mechanisms could facilitate the development of new therapeutic approaches. Recent studies in transgenic mouse models of AD have shown that neutrophils adhere to blood vessels and migrate inside the parenchyma. Moreover, studies in human AD subjects have also shown that neutrophils adhere and spread inside brain vessels and invade the parenchyma, suggesting these cells play a role in AD pathogenesis. Indeed, neutrophil depletion and the therapeutic inhibition of neutrophil trafficking, achieved by blocking LFA-1 integrin in AD mouse models, significantly reduced memory loss and the neuropathological features of AD. We observed that neutrophils release neutrophil extracellular traps (NETs) inside blood vessels and in the parenchyma of AD mice, potentially harming the blood–brain barrier and neural cells. Furthermore, confocal microscopy confirmed the presence of NETs inside the cortical vessels and parenchyma of subjects with AD, providing more evidence that neutrophils and NETs play a role in AD-related tissue destruction. The discovery of NETs inside the AD brain suggests that these formations may exacerbate neuro-inflammatory processes, promoting vascular and parenchymal damage during AD. The inhibition of NET formation has achieved therapeutic benefits in several models of chronic inflammatory diseases, including autoimmune diseases affecting the brain. Therefore, the targeting of NETs may delay AD pathogenesis and offer a novel approach for the treatment of this increasingly prevalent disease. PMID:28303140

  13. Blood platelets in the progression of Alzheimer's disease.

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    Nina S Gowert

    Full Text Available Alzheimer's disease (AD is characterized by neurotoxic amyloid-ß plaque formation in brain parenchyma and cerebral blood vessels known as cerebral amyloid angiopathy (CAA. Besides CAA, AD is strongly related to vascular diseases such as stroke and atherosclerosis. Cerebrovascular dysfunction occurs in AD patients leading to alterations in blood flow that might play an important role in AD pathology with neuronal loss and memory deficits. Platelets are the major players in hemostasis and thrombosis, but are also involved in neuroinflammatory diseases like AD. For many years, platelets were accepted as peripheral model to study the pathophysiology of AD because platelets display the enzymatic activities to generate amyloid-ß (Aß peptides. In addition, platelets are considered to be a biomarker for early diagnosis of AD. Effects of Aß peptides on platelets and the impact of platelets in the progression of AD remained, however, ill-defined. The present study explored the cellular mechanisms triggered by Aß in platelets. Treatment of platelets with Aß led to platelet activation and enhanced generation of reactive oxygen species (ROS and membrane scrambling, suggesting enhanced platelet apoptosis. More important, platelets modulate soluble Aß into fibrillar structures that were absorbed by apoptotic but not vital platelets. This together with enhanced platelet adhesion under flow ex vivo and in vivo and platelet accumulation at amyloid deposits of cerebral vessels of AD transgenic mice suggested that platelets are major contributors of CAA inducing platelet thrombus formation at vascular amyloid plaques leading to vessel occlusion critical for cerebrovascular events like stroke.

  14. ELR chemokine signaling in host defense and disease in a viral model of central nervous system disease

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    Martin P Hosking

    2014-06-01

    Full Text Available Intracranial infection of the neurotropic JHM strain of mouse hepatitis virus (JHMV into the central nervous system (CNS of susceptible strains of mice results in an acute encephalomyelitis, accompanied by viral replication in glial cells and robust infiltration of virus-specific T cells that contribute to host defense through cytokine secretion and cytolytic activity. Mice that survive the acute stage of disease develop an immune-mediated demyelinating diseases characterized by viral persistence in white matter tracts and a chronic neuroinflammatory response dominated by T cells and macrophages. Early following JHMV infection, there is a dynamic expression of chemokines and chemokine receptors that contribute to neuroinflammation by regulating innate and adaptive immune responses as well influencing glial biology. In response to JHMV infection, we have shown that signaling through the chemokine receptor CXCR2 contributes to host defense through recruitment of polymorphonuclear cells (PMNs to the CNS that enhance permeability of the blood-brain-barrier (BBB and facilitating entry of virus-specific T cells into the parenchyma. Further, CXCR2 promotes the protection of oligodendroglia from cytokine-induced apoptosis and restricts the severity of demyelination. This review covers aspects related to the role of CXCR2 in host defense and disease in response to JHMV infection.

  15. Isolation Housing Exacerbates Alzheimer's Disease-Like Pathophysiology in Aged APP/PS1 Mice.

    Science.gov (United States)

    Huang, Huang; Wang, Linmei; Cao, Min; Marshall, Charles; Gao, Junying; Xiao, Na; Hu, Gang; Xiao, Ming

    2015-01-07

    Alzheimer's disease is a neurodegenerative disease characterized by gradual declines in social, cognitive, and emotional functions, leading to a loss of expected social behavior. Social isolation has been shown to have adverse effects on individual development and growth as well as health and aging. Previous experiments have shown that social isolation causes an early onset of Alzheimer's disease-like phenotypes in young APP695/PS1-dE9 transgenic mice. However, the interactions between social isolation and Alzheimer's disease still remain unknown. Seventeen-month-old male APP695/PS1-dE9 transgenic mice were either singly housed or continued group housing for 3 months. Then, Alzheimer's disease-like pathophysiological changes were evaluated by using behavioral, biochemical, and pathological analyses. Isolation housing further promoted cognitive dysfunction and Aβ plaque accumulation in the hippocampus of aged APP695/PS1-dE9 transgenic mice, associated with increased γ-secretase and decreased neprilysin expression. Furthermore, exacerbated hippocampal atrophy, synapse and myelin associated protein loss, and glial neuroinflammatory reactions were observed in the hippocampus of isolated aged APP695/PS1-dE9 transgenic mice. The results demonstrate that social isolation exacerbates Alzheimer's disease-like pathophysiology in aged APP695/PS1-dE9 transgenic mice, highlighting the potential role of group life for delaying or counteracting the Alzheimer's disease process. © The Author 2015. Published by Oxford University Press on behalf of CINP.

  16. Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer's disease mice.

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    Alves, Sandro; Churlaud, Guillaume; Audrain, Mickael; Michaelsen-Preusse, Kristin; Fol, Romain; Souchet, Benoit; Braudeau, Jérôme; Korte, Martin; Klatzmann, David; Cartier, Nathalie

    2016-12-20

    Interleukin-2 (IL-2)-deficient mice have cytoarchitectural hippocampal modifications and impaired learning and memory ability reminiscent of Alzheimer's disease. IL-2 stimulates regulatory T cells whose role is to control inflammation. As neuroinflammation contributes to neurodegeneration, we investigated IL-2 in Alzheimer's disease. Therefore, we investigated IL-2 levels in hippocampal biopsies of patients with Alzheimer's disease relative to age-matched control individuals. We then treated APP/PS1ΔE9 mice having established Alzheimer's disease with IL-2 for 5 months using single administration of an AAV-IL-2 vector. We first found decreased IL-2 levels in hippocampal biopsies of patients with Alzheimer's disease. In mice, IL-2-induced systemic and brain regulatory T cells expansion and activation. In the hippocampus, IL-2 induced astrocytic activation and recruitment of astrocytes around amyloid plaques, decreased amyloid-β42/40 ratio and amyloid plaque load, improved synaptic plasticity and significantly rescued spine density. Of note, this tissue remodelling was associated with recovery of memory deficits, as assessed in the Morris water maze task. Altogether, our data strongly suggest that IL-2 can alleviate Alzheimer's disease hallmarks in APP/PS1ΔE9 mice with established pathology. Therefore, this should prompt the investigation of low-dose IL-2 in Alzheimer's disease and other neuroinflammatory/neurodegenerative disorders.

  17. Linking multiple pathogenic pathways in Alzheimer’s disease

    Science.gov (United States)

    Bou Khalil, Rami; Khoury, Elie; Koussa, Salam

    2016-01-01

    Alzheimer’s disease (AD) is a chronic neurodegenerative disorder presenting as progressive cognitive decline with dementia that does not, to this day, benefit from any disease-modifying drug. Multiple etiologic pathways have been explored and demonstrate promising solutions. For example, iron ion chelators, such as deferoxamine, are a potential therapeutic solution around which future studies are being directed. Another promising domain is related to thrombin inhibitors. In this minireview, a common pathophysiological pathway is suggested for the pathogenesis of AD to prove that all these mechanisms converge onto the same cascade of neuroinflammatory events. This common pathway is initiated by the presence of vascular risk factors that induce brain tissue hypoxia, which leads to endothelial cell activation. However, the ensuing hypoxia stimulates the production and release of reactive oxygen species and pro-inflammatory proteins. Furthermore, the endothelial activation may become excessive and dysfunctional in predisposed individuals, leading to thrombin activation and iron ion decompartmentalization. The oxidative stress that results from these modifications in the neurovascular unit will eventually lead to neuronal and glial cell death, ultimately leading to the development of AD. Hence, future research in this field should focus on conducting trials with combinations of potentially efficient treatments, such as the combination of intranasal deferoxamine and direct thrombin inhibitors. PMID:27354962

  18. Sleep and hippocampal neurogenesis: Implications for Alzheimer's disease.

    Science.gov (United States)

    Kent, Brianne A; Mistlberger, Ralph E

    2017-02-27

    Alzheimer's disease (AD) is the most common cause of dementia and currently there are no effective disease-modifying treatments available. Hallmark symptoms of AD include impaired hippocampus-dependent episodic memory and disrupted sleep and circadian rhythms. The pathways connecting these symptoms are of particular interest because it is well established that sleep and circadian disruption can impair hippocampus-dependent learning and memory. In rodents, these procedures also markedly suppress adult hippocampal neurogenesis, a form of brain plasticity that is believed to play an important role in pattern separation, and thus episodic memory. A causal role for sleep disruptions in AD pathophysiology is suggested by evidence for sleep-dependent glymphatic clearance of metabolic waste products from the brain. This review explores a complementary hypothesis that sleep and circadian disruptions in AD contribute to cognitive decline by activating neuroendocrine and neuroinflammatory signaling pathways that suppress hippocampal neurogenesis. Evidence for this hypothesis underscores the promise of sleep, circadian rhythms, and neurogenesis as therapeutic targets for remediation of memory impairment in AD.

  19. Neuroinflammation as a Common Mechanism Associated with the Modifiable Risk Factors for Alzheimer's and Parkinson`s Diseases.

    Science.gov (United States)

    McKenzie, Jordan Alexander; Spielman, Lindsay J; Pointer, Caitlin B; Lowry, Jessica R; Bajwa, Ekta; Lee, Carolyn W; Klegeris, Andis

    2017-03-15

    Alzheimer's disease (AD) and Parkinson's disease (PD) are among the most common causes of dementia, which increasingly contribute to morbidity and mortality worldwide. A common hallmark in the pathogenesis of these two diseases is neuroinflammation, which is initially triggered by the presence of pathological structures associated with these disorders. Chronic neuroinflammation is sustained by persistent and aberrant microglial activation in the brain, which results in damage and death of neighboring cells, including neurons and glial cells. Two types of risk factors contribute to the development of AD and PD: non-modifiable risk factors and modifiable risk factors. Non-modifiable risk factors include genetic susceptibility that increases an individual's risk of developing the disease, whereas modifiable risk factors include a wide variety of health- and lifestyle-related factors that may be altered by changing individual behaviors. Exposure to environmental toxins could be viewed as a partially modifiable risk factor. This review focuses on four modifiable risk factors including physical inactivity, vascular disease-related conditions, obesity and type two diabetes mellitus, all of which have been identified as risk factors for the development of AD and PD. We highlight that control of the modifiable risk factors is a valid approach for managing the increased incidence of AD and PD. We describe neuroinflammatory mechanisms, which are common to AD and PD, that may link both these neurodegenerative diseases with the four common modifiable risk factors. Understanding these mechanisms could help identify novel therapeutic targets for combating these neurodegenerative diseases.

  20. Mucopolysaccharidosis IIIB, a lysosomal storage disease, triggers a pathogenic CNS autoimmune response

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    Popovich Phillip G

    2010-07-01

    Full Text Available Abstract Background Recently, using a mouse model of mucopolysaccharidosis (MPS IIIB, a lysosomal storage disease with severe neurological deterioration, we showed that MPS IIIB neuropathology is accompanied by a robust neuroinflammatory response of unknown consequence. This study was to assess whether MPS IIIB lymphocytes are pathogenic. Methods Lymphocytes from MPS IIIB mice were adoptively transferred to naïve wild-type mice. The recipient animals were then evaluated for signs of disease and inflammation in the central nervous system. Results Our results show for the first time, that lymphocytes isolated from MPS IIIB mice caused a mild paralytic disease when they were injected systemically into naïve wild-type mice. This disease is characterized by mild tail and lower trunk weakness with delayed weight gain. The MPS IIIB lymphocytes also trigger neuroinflammation within the CNS of recipient mice characterized by an increase in transcripts of IL2, IL4, IL5, IL17, TNFα, IFNα and Ifi30, and intraparenchymal lymphocyte infiltration. Conclusions Our data suggest that an autoimmune response directed at CNS components contributes to MPS IIIB neuropathology independent of lysosomal storage pathology. Adoptive transfer of purified T-cells will be needed in future studies to identify specific effector T-cells in MPS IIIB neuroimmune pathogenesis.

  1. DNA Methylation Profiles of Selected Pro-Inflammatory Cytokines in Alzheimer Disease.

    Science.gov (United States)

    Nicolia, Vincenzina; Cavallaro, Rosaria A; López-González, Irene; Maccarrone, Mauro; Scarpa, Sigfrido; Ferrer, Isidre; Fuso, Andrea

    2017-01-01

    By means of functional genomics analysis, we recently described the mRNA expression profiles of various genes involved in the neuroinflammatory response in the brains of subjects with late-onset Alzheimer Disease (LOAD). Some of these genes, namely interleukin (IL)-1β and IL-6, showed distinct expression profiles with peak expression during the first stages of the disease and control-like levels at later stages. IL-1β and IL-6 genes are modulated by DNA methylation in different chronic and degenerative diseases; it is also well known that LOAD may have an epigenetic basis. Indeed, we and others have previously reported gene-specific DNA methylation alterations in LOAD and in related animal models. Based on these data, we studied the DNA methylation profiles, at single cytosine resolution, of IL-1β and IL-6 5'-flanking region by bisulphite modification in the cortex of healthy controls and LOAD patients at 2 different disease stages: Braak I-II/A and Braak V-VI/C. Our analysis provides evidence that neuroinflammation in LOAD is associated with (and possibly mediated by) epigenetic modifications. © 2017 American Association of Neuropathologists, Inc. All rights reserved.

  2. Wnt/TLR Dialog in Neuroinflammation, Relevance in Alzheimer’s Disease

    Science.gov (United States)

    Zolezzi, Juan M.; Inestrosa, Nibaldo C.

    2017-01-01

    The innate immune system (IIS) represents the first line of defense against exogenous and endogenous harmful stimuli. Different types of pathogens and diverse molecules can activate the IIS via a ligand–receptor mechanism. Cytokine release, recruitment of immunocompetent cells, and inflammation constitute the initial steps in an IIS-mediated response. While balanced IIS activity can resolve a harmful event, an altered response, such as deficient or persistent IIS activity, will have a critical effect on organism homeostasis. In this regard, chronic IIS activation has been associated with a wide range of diseases, including chronic inflammatory disorders (inflammatory bowel disease, arthritis, chronic obstructive pulmonary disease, among others), cancer and, more recently, neurodegenerative disorders. The relevance of the immune response, particularly inflammation, in the context of neurodegeneration has motivated rigorous research focused on unveiling the mechanisms underlying this response. Knowledge regarding the molecular hallmarks of the innate immune response and understanding signaling pathway cross talk are critical for developing new therapeutic strategies aimed at modulating the neuroinflammatory response within the brain. In the present review, we discuss the IIS in the central nervous system, particularly the cross talk between the toll-like receptor-signaling cascade and the wingless-related MMTV integration site (Wnt) signaling pathway and its relevance in neurodegenerative disorders such as Alzheimer’s disease. PMID:28286503

  3. Who fans the flames of Alzheimer's disease brains? Misfolded tau on the crossroad of neurodegenerative and inflammatory pathways

    Directory of Open Access Journals (Sweden)

    Zilka Norbert

    2012-03-01

    Full Text Available Abstract Neurodegeneration, induced by misfolded tau protein, and neuroinflammation, driven by glial cells, represent the salient features of Alzheimer's disease (AD and related human tauopathies. While tau neurodegeneration significantly correlates with disease progression, brain inflammation seems to be an important factor in regulating the resistance or susceptibility to AD neurodegeneration. Previously, it has been shown that there is a reciprocal relationship between the local inflammatory response and neurofibrillary lesions. Numerous independent studies have reported that inflammatory responses may contribute to the development of tau pathology and thus accelerate the course of disease. It has been shown that various cytokines can significantly affect the functional and structural properties of intracellular tau. Notwithstanding, anti-inflammatory approaches have not unequivocally demonstrated that inhibition of the brain immune response can lead to reduction of neurofibrillary lesions. On the other hand, our recent data show that misfolded tau could represent a trigger for microglial activation, suggesting the dual role of misfolded tau in the Alzheimer's disease inflammatory cascade. On the basis of current knowledge, we can conclude that misfolded tau is located at the crossroad of the neurodegenerative and neuroinflammatory pathways. Thus disease-modified tau represents an important target for potential therapeutic strategies for patients with Alzheimer's disease.

  4. The pathogenic role of the inflammasome in neurodegenerative diseases.

    Science.gov (United States)

    Freeman, Leslie C; Ting, Jenny P-Y

    2016-01-01

    The inflammasome is a large macromolecular complex that contains multiple copies of a receptor or sensor of pathogen-derived or damage-derived molecular patterns, pro-caspase-1, and an adaptor called ASC (apoptotic speck containing protein with a CARD), which results in caspase-1 maturation. Caspase-1 then mediates the release of pro-inflammatory cytokines such as IL-1β and IL-18. These cytokines play critical roles in mediating immune responses during inflammation and innate immunity. Broader studies of the inflammasome over the years have implicated their roles in the pathogenesis of a variety of inflammatory diseases. Recently, studies have shown that the inflammasome modulates neuroinflammatory cells and the initial stages of neuroinflammation. A secondary cascade of events associated with neuroinflammation (such as oxidative stress) has been shown to activate the inflammasome, making the inflammasome a promising therapeutic target in the modulation of neurodegenerative diseases. This review will focus on the pathogenic role that inflammasomes play in neurologic diseases such as Alzheimer's disease, traumatic brain injury, and multiple sclerosis. We here review the role of the inflammasome in the pathogenesis of traumatic brain injury (TBI). TBI is initiated by physical force exerted to head, resulting in neuronal injury and death. Primary insult is followed by a secondary cascade of events following neuroinflammation such as mitochondrial dysfunction, production of reactive oxygen species, potassium effluxes, and release of circulating DNA. These events can potentially trigger the activation of NLRP3, NLRP1, and AIM2 during TBI but have yet to be confirmed (dashed lines). NLRP3, NLRP1, and AIM2 associate with the adaptor protein ASC, which initiates the cleavage of pro-caspase-1 to the mature form of caspase-1 which cleaves pro-IL-1β and pro-IL-18 into their mature forms of IL-1β and IL-18.

  5. In vivo Evidence for Therapeutic Properties of Cannabidiol (CBD) for Alzheimer's Disease

    Science.gov (United States)

    Watt, Georgia; Karl, Tim

    2017-01-01

    Alzheimer's disease (AD) is a debilitating neurodegenerative disease that is affecting an increasing number of people. It is characterized by the accumulation of amyloid-β and tau hyperphosphorylation as well as neuroinflammation and oxidative stress. Current AD treatments do not stop or reverse the disease progression, highlighting the need for new, more effective therapeutics. Cannabidiol (CBD) is a non-psychoactive phytocannabinoid that has demonstrated neuroprotective, anti-inflammatory and antioxidant properties in vitro. Thus, it is investigated as a potential multifunctional treatment option for AD. Here, we summarize the current status quo of in vivo effects of CBD in established pharmacological and transgenic animal models for AD. The studies demonstrate the ability of CBD to reduce reactive gliosis and the neuroinflammatory response as well as to promote neurogenesis. Importantly, CBD also reverses and prevents the development of cognitive deficits in AD rodent models. Interestingly, combination therapies of CBD and Δ9-tetrahydrocannabinol (THC), the main active ingredient of cannabis sativa, show that CBD can antagonize the psychoactive effects associated with THC and possibly mediate greater therapeutic benefits than either phytocannabinoid alone. The studies provide “proof of principle” that CBD and possibly CBD-THC combinations are valid candidates for novel AD therapies. Further investigations should address the long-term potential of CBD and evaluate mechanisms involved in the therapeutic effects described. PMID:28217094

  6. Heart Disease

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    ... type of heart disease you have. Symptoms of heart disease in your blood vessels (atherosclerotic disease) Cardiovascular disease ... can sometimes be found early with regular evaluations. Heart disease symptoms caused by abnormal heartbeats (heart arrhythmias) A ...

  7. Neuroinflammatory response to experimental stroke is inhibited by boldine.

    Science.gov (United States)

    de Lima, Neila Maria R; Ferreira, Emerson de O; Fernandes, Mara Yone S D; Lima, Francisco Arnaldo V; Neves, Kelly Rose T; do Carmo, Marta Regina S; de Andrade, Geanne M

    2017-04-01

    Inflammation plays a pivotal role in the development of ischemic brain damage. Astrocyte activation promotes the production of several proinflammatory mediators, such as TNF-α and iNOS. Eventually, neuronal death occurs, leading to the development of motor and memory deficits in patients. Boldine is the main alkaloid in the leaves and bark of the Peumus boldus Molina, and has anti-inflammatory and antioxidant properties. The aim of this work was to investigate the neuroprotective effect of boldine on neuroinflammation and memory deficits induced by permanent middle cerebral artery occlusion (pMCAO) in mice. Thirty minutes before pMCAO and during the next 5 days, animals received vehicle (0.025 µmol/l HCl) or boldine (8, 16 and 25 mg/kg, intraperitoneally). The extension of the infarct area, neurological scores, and myeloperoxidase activity were evaluated 24 h after pMCAO. Locomotor activity, working, and aversive memory were evaluated 72 h after pMCAO, object recognition memory was tested 96 h after pMCAO, and spatial memory was tested 120 h after pMCAO. Cresyl violet, Fluoro-Jade C staining, and immunohistochemical for GFAP, TNF-α, and iNOS were also carried out. The treatment with boldine significantly decreased the infarct area, improved the neurological scores, and increased cell viability. The vertical exploratory activity and aversive, spatial, object recognition, and working memory deficits induced by pMCAO were prevented by boldine. Moreover, myeloperoxidase activity and GFAP, TNF-α, and iNOS immunoreactivity were decreased significantly by boldine. Although various mechanisms such as its antioxidant activity should be considered, these results suggest that the neuroprotective effect of boldine might be related in part to its anti-inflammatory properties.

  8. Salicornia bigelovii Torr Attenuates Neuro-Inflammatory Responses ...

    African Journals Online (AJOL)

    BV- microglial cells were stimulated with LPS to study the protein expression and .... complete culture medium and treated with the. SBE extract .... and pathological processes leading to increased inflammatory .... Nutritional characterization of.

  9. Evaluation of Antioxidant and Anti-neuroinflammatory Activities of ...

    African Journals Online (AJOL)

    fusiforme contains a number of compounds possessing ... in activated microglial cells has not been studied. ... initiating inflammatory responses in the brain through ... equal volume of sterile water was added to all .... LPS strongly induced BV-2 cells to produce an .... reactive nitrogen oxides mediate neuronal cell death.

  10. Neuroinflammatory Cytokines-The Common Thread in Alzheimer's Pathogenesis.

    Science.gov (United States)

    Griffin, W Sue T; Barger, Steven W

    2010-01-01

    This article discusses the potential role of the cytokine cycle and its corollary as drivers of the relentless progression of Alzheimer's neuropathologies, whether they are the result of gene mutations, gene polymorphisms, and/or environmental and comorbid conditions. Based on the discovery of cytokine overexpression as an accompaniment to the dementia-related glial activation, the cytokine hypothesis was proposed. This states that in response to the negative impact on neurons of known and unknown risk factors-which include genetic inheritance, comorbid and environmental factors-microglia and astrocytes become activated and produce excess amounts of the immune-modulating cytokine interleukin-1 (IL-1) and the neuritogenic cytokine S100B, respectively. Finding that these glial events occur in fetuses and neonates with Down syndrome provided the first evidence that productive immune responses by activated glia precede rather than follow overt AD-related pathology. This finding can be added to the demonstration of IL-1 induction of amyloid β (Aβ) precursor protein and astrocyte activation with excess production of neuritogenic factor S100B. This combination suggests that IL-1 and S100B overexpression would favor the Aβ production and dystrophic neurite growth necessary for laying down neuritic Aβ plaques. This, together with demonstration of IL-1 induction of excessive production of the precursors of other features common in AD prompted a corollary to the cytokine hypothesis. The corollary states that regardless of the primary cause of the neuronal insult, the result will be chronic glial activation, which in turn will result in further neuronal injury, still more glial activation with excess cytokine expression and so on. This article discusses known causes, genetic and environmental risk factors, and comorbid conditions, and the potential contribution of glial activation with excessive cytokine expression to each.

  11. Glia proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative diseases: function-based and target-based discovery approaches.

    Science.gov (United States)

    Van Eldik, Linda J; Thompson, Wendy L; Ralay Ranaivo, Hantamalala; Behanna, Heather A; Martin Watterson, D

    2007-01-01

    Inflammation is the body's defense mechanism against threats such as bacterial infection, undesirable substances, injury, or illness. The process is complex and involves a variety of specialized cells that mobilize to neutralize and dispose of the injurious material so that the body can heal. In the brain, a similar inflammation process occurs when glia, especially astrocytes and microglia, undergo activation in response to stimuli such as injury, illness, or infection. Like peripheral immune cells, glia in the central nervous system also increase production of inflammatory cytokines and neutralize the threat to the brain. This brain inflammation, or neuroinflammation, is generally beneficial and allows the brain to respond to changes in its environment and dispose of damaged tissue or undesirable substances. Unfortunately, this beneficial process sometimes gets out of balance and the neuroinflammatory process persists, even when the inflammation-provoking stimulus is eliminated. Uncontrolled chronic neuroinflammation is now known to play a key role in the progression of damage in a number of neurodegenerative diseases. Thus, overproduction of proinflammatory cytokines offers a pathophysiology progression mechanism that can be targeted in new therapeutic development for multiple neurodegenerative diseases. We summarize in this chapter the evidence supporting proinflammatory cytokine upregulation as a therapeutic target for neurodegenerative disorders, with a focus on Alzheimer's disease. In addition, we discuss the drug discovery process and two approaches, function-driven and target-based, that show promise for development of neuroinflammation-targeted, disease-modifying therapeutics for multiple neurodegenerative disorders.

  12. A Common Variant of IL-6R is Associated with Elevated IL-6 Pathway Activity in Alzheimer's Disease Brains.

    Science.gov (United States)

    Haddick, Patrick C G; Larson, Jessica L; Rathore, Nisha; Bhangale, Tushar R; Phung, Qui T; Srinivasan, Karpagam; Hansen, David V; Lill, Jennie R; Pericak-Vance, Margaret A; Haines, Jonathan; Farrer, Lindsay A; Kauwe, John S; Schellenberg, Gerard D; Cruchaga, Carlos; Goate, Alison M; Behrens, Timothy W; Watts, Ryan J; Graham, Robert R; Kaminker, Joshua S; van der Brug, Marcel

    2017-01-01

    The common p.D358A variant (rs2228145) in IL-6R is associated with risk for multiple diseases and with increased levels of soluble IL-6R in the periphery and central nervous system (CNS). Here, we show that the p.D358A allele leads to increased proteolysis of membrane bound IL-6R and demonstrate that IL-6R peptides with A358 are more susceptible to cleavage by ADAM10 and ADAM17. IL-6 responsive genes were identified in primary astrocytes and microglia and an IL-6 gene signature was increased in the CNS of late onset Alzheimer's disease subjects in an IL6R allele dependent manner. We conducted a screen to identify variants associated with the age of onset of Alzheimer's disease in APOE ɛ4 carriers. Across five datasets, p.D358A had a meta P = 3 ×10-4 and an odds ratio = 1.3, 95% confidence interval 1.12 -1.48. Our study suggests that a common coding region variant of the IL-6 receptor results in neuroinflammatory changes that may influence the age of onset of Alzheimer's disease in APOE ɛ4 carriers.

  13. Frontiers in therapeutic development of allopregnanolone for Alzheimer's disease and other neurological disorders

    Directory of Open Access Journals (Sweden)

    Ronald W. Irwin

    2014-07-01

    Full Text Available Allopregnanolone (Allo, a neurosteroid, has emerged as a promising promoter of endogenous regeneration in brain. In a mouse model of Alzheimer’s disease, Allo induced neurogenesis, oligodendrogenesis, white matter generation and cholesterol homeostasis while simultaneously reducing β-amyloid and neuroinflammatory burden. Allo activates signaling pathways and gene expression required for regeneration of neural stem cells and their differentiation into neurons. In parallel, Allo activates systems to sustain cholesterol homeostasis and reduce β-amyloid generation. To advance Allo into studies for chronic human neurological conditions, we examined translational and clinical parameters: dose, regimen, route, formulation, outcome measures, and safety regulations. A treatment regimen of once per week at sub-sedative doses of Allo was optimal for regeneration and reduction in Alzheimer’s pathology. This regimen had a high safety profile following chronic exposure in aged normal and Alzheimer’s mice. Formulation of Allo for multiple routes of administration has been developed for both preclinical and clinical testing. Preclinical evidence for therapeutic efficacy of Allo spans multiple neurological diseases including Alzheimer’s, Parkinson’s, multiple sclerosis, Niemann-Pick, diabetic neuropathy, status epilepticus, and traumatic brain injury. To successfully translate Allo as a therapeutic for multiple neurological disorders, it will be necessary to tailor dose and regimen to the targeted therapeutic mechanisms and disease etiology. Treatment paradigms conducted in accelerated disease models in young animals have a low probability of successful translation to chronic diseases in adult and aged humans. Gender, genetic risks, stage and burden of disease are critical determinants of efficacy. This review focuses on recent advances in development of Allo for Alzheimer’s disease that have the potential to accelerate therapeutic translation for

  14. The role of melatonin in multiple sclerosis, Huntington's disease and cerebral ischemia.

    Science.gov (United States)

    Escribano, Begoña M; Colín-González, Ana L; Santamaría, Abel; Túnez, Isaac

    2014-01-01

    Melatonin is produced and released by the pineal gland in a circadian rhythm. This neurohormone has proven to be an antioxidant and anti-inflammatory molecule able to reduce or mitigate cell damage associated with oxidative stress and inflammation, and this phenomenon underlies neurodegenerative disorders. These facts have drawn attention to this indole, triggering interest in evaluating its changes and in its relationship to the processes indicated, and analyzing its role in the mechanisms involved at the onset and development of neurodegenerative diseases, as well as its therapeutic potential. Multiple sclerosis, the most common cause of non-traumatic disability in young adults, is a chronic neuroinflammatory disease, characterized by demyelination, inflammation, and neuronal and oxidative damage. In its early diagnosis, it often requires a differential screening with other neurodegenerative diseases with similar symptoms, such as Huntington's disease, an autosomal dominant disorder. The onset of both diseases occurs in the second or third decade of life. On the other hand, cerebral ischemia is a major cause of human disability all over the world. Although a cerebral stroke can occur as the result of different damaging insults, severe ischemia produces the death of neuronal cells within minutes. Changes in melatonin levels have been observed in these processes (Huntington's disease, multiple sclerosis and cerebral ischemia) as part of their pathogenic features. This review aims to update and discuss the role played by melatonin during neurodegenerative processes, specifically in multiple sclerosis, Huntington's disease, and cerebral ischemia, and its possible therapeutic use. We also provide readers with an update on the many neuroprotective mechanisms exerted by this neurohormone in the Central Nervous System.

  15. ALS patients’ regulatory T lymphocytes are dysfunctional, and correlate with disease progression rate and severity

    Science.gov (United States)

    Beers, David R.; Zhao, Weihua; Wang, Jinghong; Zhang, Xiujun; Wen, Shixiang; Neal, Dan; Thonhoff, Jason R.; Alsuliman, Abdullah S.; Shpall, Elizabeth J.; Rezvani, Katy

    2017-01-01

    Neuroinflammation is a pathological hallmark of ALS in both transgenic rodent models and patients, and is characterized by proinflammatory T lymphocytes and activated macrophages/microglia. In ALS mouse models, decreased regulatory T lymphocytes (Tregs) exacerbate the neuroinflammatory process, leading to accelerated motoneuron death and shortened survival; passive transfer of Tregs suppresses the neuroinflammation and prolongs survival. Treg numbers and FOXP3 expression are also decreased in rapidly progressing ALS patients. A key question is whether the marked neuroinflammation in ALS can be attributed to the impaired suppressive function of ALS Tregs in addition to their decreased numbers. To address this question, T lymphocyte proliferation assays were performed. Compared with control Tregs, ALS Tregs were less effective in suppressing responder T lymphocyte proliferation. Although both slowly and rapidly progressing ALS patients had dysfunctional Tregs, the greater the clinically assessed disease burden or the more rapidly progressing the patient, the greater the Treg dysfunction. Epigenetically, the percentage methylation of the Treg-specific demethylated region was greater in ALS Tregs. After in vitro expansion, ALS Tregs regained suppressive abilities to the levels of control Tregs, suggesting that autologous passive transfer of expanded Tregs might offer a novel cellular therapy to slow disease progression. PMID:28289705

  16. Subtype and regional-specific neuroinflammation in sporadic creutzfeldt-jakob disease.

    Science.gov (United States)

    Llorens, Franc; López-González, Irene; Thüne, Katrin; Carmona, Margarita; Zafar, Saima; Andréoletti, Olivier; Zerr, Inga; Ferrer, Isidre

    2014-01-01

    The present study identifies deregulated cytokines and mediators of the immune response in the frontal cortex and cerebellum of sporadic Creutzfeldt-Jakob disease (sCJD) MM1 and VV2 subtypes compared to age-matched controls. Deregulated genes include pro- and anti-inflammatory cytokines, toll-like receptors, colony stimulating factors, cathepsins, members of the complement system, and members of the integrin and CTL/CTLD family with particular regional and sCJD subtype patterns. Analysis of cytokines and mediators at protein level shows expression of selected molecules and receptors in neurons, in astrocytes, and/or in microglia, thus suggesting interactions between neurons and glial cells, mainly microglia, in the neuroinflammatory response in sCJD. Similar inflammatory responses have been shown in the tg340 sCJD MM1 mice, revealing a progressive deregulation of inflammatory mediators with disease progression. Yet, inflammatory molecules involved are subjected to species differences in humans and mice. Moreover, inflammatory-related cell signaling pathways NFκB/IKK and JAK/STAT are activated in sCJD and sCJD MM1 mice. Together, the present observations show a self-sustained complex inflammatory and inflammatory-related responses occurring already at early clinical stages in animal model and dramatically progressing at advanced stages of sCJD. Considering this scenario, measures tailored to modulate (activate or inhibit) specific molecules could be therapeutic options in CJD.

  17. HTLV-1 viral RNA is detected rarely in plasma of HTLV-1 infected subjects.

    Science.gov (United States)

    Demontis, Maria Antonietta; Sadiq, Maaz Tahir; Golz, Simon; Taylor, Graham P

    2015-12-01

    Plasma of patients infected with HTLV-1 is considered non-infectious but detection of HTLV-1 genomic RNA in plasma has been recently reported. The aim of this project was to detect and quantify HTLV-1 RNA in plasma and assess its potential value in diagnosis and prognosis. RNA from 1 ml of plasma from 65 subjects infected with HTLV-1 (27 asymptomatic carriers [AC]), 17 patients with HTLV-1-associated myelopathy (HAM/TSP), 14 with adult T-cell leukemia/lymphoma (ATLL), two co-infected with HIV, and five with other HTLV-1-associated disease, was extracted and reverse transcribed. HTLV-1 specific nested PCR was performed using primers to amplify the conserved Tax region. All samples were run in quadruplicate, nested PCR products were detected by gel electrophoresis. HTLV-1 RNA was detected in plasma from 18 (28%) patients, always at a very low copy number (3-13 copies viral cDNA per milliliter of plasma). Mean values of HTLV-1 proviral load did not differ between patients in whom HTLV-1 RNA was detected and patients in whom it was not possible to detect HTLV-1 RNA in plasma. HTLV-1 genomic RNA can be detected in the plasma of a minority of patients but not at a level or frequency to be useful clinically or diagnostically. Lack of transmission of HTLV-1 by plasma is due to the rare presence of HTLV-1 virions, regardless of any other factor.

  18. Dynamic acquisition of HTLV-1 tax protein by mononuclear phagocytes: Role in neurologic disease.

    Science.gov (United States)

    Matsuura, Eiji; Enose-Akahata, Yoshimi; Yao, Karen; Oh, Unsong; Tanaka, Yuetsu; Takashima, Hiroshi; Jacobson, Steven

    2017-03-15

    Pathology of HTLV-1 associated myelopathy/Tropical spastic paraparesis (HAM/TSP) is believed to be the result of "bystander damage" involving effector CD8 (+) T lymphocytes (CTLs) killing of virus infected cells. But the specific cellular events leading up to tissue injury are still unclear. Here, we developed the Microscopy Imaging of Cytotoxic T lymphocyte assay with Fluorescence emission (MI-CaFé), an optimized visualization analysis to explore the interactions between CTLs and virus infected or viral antigen presenting target cells. Various cell-to-cell formations can be observed and our results demonstrate elevated frequencies of CTL-target cell conjugates in HAM/TSP patient PBMCs compared to control PBMCs. Furthermore, HTLV-1 Tax protein expression can be localized at the cell-cell junctions and also tracked moving from an infected cell to a CD14 (+) mononuclear phagocyte (MP). Activation of CD14 (+) MPs in HAM/TSP patient PBMCs and antigenic presentation of HTLV-1 Tax by MPs can be inferred by their spontaneous cytotoxicity after 18h of in vitro culture. Given that CD4 (+) T lymphocytes are the primary reservoirs of HTLV-1 and MPs are scavenger cells responsible for pathogen clearance, spontaneous cytotoxicity against MPs in HAM/TSP PBMCs suggests a mechanism of chronic inflammation, secondary to low level of persistent virus infection within the central nervous system. Published by Elsevier B.V.

  19. Lung disease

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000066.htm Lung disease To use the sharing features on this page, ... fibrosis and sarcoidosis are examples of lung tissue disease. Lung circulation diseases -- These diseases affect the blood vessels ...

  20. Gaucher disease

    OpenAIRE

    POSPÍŠILOVÁ, Iva

    2012-01-01

    This thesis is about the disease called Gaucher disease, or Morbus Gaucher. There is described the history of the disease, various forms of disease, effect of bones, visceral organs, hematological changes, changes in metabolism etc.; differential diagnosis, diagnosis and therapy.

  1. Review of Amyotrophic Lateral Sclerosis, Parkinson's and Alzheimer's diseases helps further define pathology of the novel paradigm for Alzheimer's with heavy metals as primary disease cause.

    Science.gov (United States)

    Cavaleri, Franco

    2015-12-01

    Pathologies of neurological diseases are increasingly recognized to have common structural and molecular events that can fit, sometimes loosely, into a central pathological theme. A better understanding of the genetic, proteomic and metabolic similarities between three common neurodegenerative diseases - Amyotrophic Lateral Sclerosis (ALS), Parkinson's disease (PD) and Alzheimer's disease (AD) - and how these similarities relate to their unique pathological features may shed more light on the underlying pathology of each. These are complex multigenic neuroinflammatory diseases caused by a combined action by multiple genetic mutations, lifestyle factors and environmental elements including a proposed contribution by transition metals. This comprehensive dynamic makes disease decoding and treatment difficult. One case of ALS, for example, can manifest from a very different pool of genetic mutations than another. In the case of ALS multiple genes in addition to SOD1 are implicated in the pathogenesis of both sporadic and familial variants of the disease. These genes play different roles in the processing and trafficking of signalling, metabolic and structural proteins. However, many of these genetic mutations or the cellular machinery they regulate can play a role in one form or another in PD and AD as well. In addition, the more recent understanding of how TREM-2 mutations factor into inflammatory response has shed new light on how chronic inflammatory activity can escalate to uncontrolled systemic levels in a variety of inflammatory diseases from neurodegenerative, auto-inflammatory and autoimmune diseases. TREM-2 mutations represent yet another complicating element in these multigenic disease pathologies. This review takes us one step back to discuss basic pathological features of these neurodegenerative diseases known to us for some time. However, the objective is to discuss the possibility of related or linked mechanisms that may exist through these basic disease

  2. Hashimoto's Disease

    Science.gov (United States)

    ... is Hashimoto’s disease? Hashimoto’s disease, also called chronic lymphocytic thyroiditis or autoimmune thyroiditis, is an autoimmune disease. An ... Points to Remember • Hashimoto’s disease, also called chronic lymphocytic thyroiditis or autoimmune thyroiditis, is an autoimmune disease. • Hashimoto’s ...

  3. Long-term immunomodulatory effect of amniotic stem cells in an Alzheimer's disease model.

    Science.gov (United States)

    Kim, Kyung-Sul; Kim, Hyun Sook; Park, Ji-Min; Kim, Han Wool; Park, Mi-Kyung; Lee, Hyun-Seob; Lim, Dae Seog; Lee, Tae Hee; Chopp, Michael; Moon, Jisook

    2013-10-01

    Amyloid beta (Aβ) plays a major role in Alzheimer's disease (AD), and neuroinflammatory processes mediated by Aβ plaque-induced microglial cells and astrocytes contribute to AD pathogenesis. The present study examined human placenta amniotic membrane-derived mesenchymal stem cells (AMSCs), which have potent immunomodulatory and paracrine effects in a Tg2576 (APPswe) transgenic mouse model of AD. AMSCs secreted high levels of transforming growth factor-β under in vitro inflammatory environment conditions. Six weeks after the intravenous injection of AMSCs, APPswe mice showed evidence of improved spatial learning, which significantly correlated with the observation of fewer Aβ plaques in brain. The number of ED1-positive phagocytic microglial cells associated with Aβ plaques was higher in AMSC-injected mice than in phosphate-buffered saline-injected mice, and the level of Aβ-degrading enzymes (matrix metallopeptidase-9 and insulin-degrading enzyme) was also significantly higher. Furthermore, the level of proinflammatory cytokines, interleukin-1 and tumor necrosis factor-α, was lower and that of anti-inflammatory cytokines, interleukin-10 and transforming growth factor-β, was higher in AMSC-injected mice than phosphate-buffered saline-injected mice. These effects lasted until 12 weeks after AMSC injection. Taken together, these results collectively suggest that injection of AMSCs might show significant long-lasting improvement in AD pathology and memory function via immunomodulatory and paracrine mechanisms. Copyright © 2013 Elsevier Inc. All rights reserved.

  4. Neuroinflammation - an early event in both the history and pathogenesis of Alzheimer's disease.

    Science.gov (United States)

    Eikelenboom, Piet; van Exel, Erik; Hoozemans, Jeroen J M; Veerhuis, Rob; Rozemuller, Annemieke J M; van Gool, Willem A

    2010-01-01

    About hundred years ago, Oskar Fischer proposed that the senile plaques are the consequence of the deposition of a foreign substance that could induce an inflammatory response leading to an abnormal neuritic response of the surrounding neurons. To show that the interest in inflammation in Alzheimer's disease (AD) is not only an early event in the history of AD but that inflammation is also an early event in the pathogenesis of AD. Evaluation of the neuropathological, epidemiological and genetic evidence for a role of inflammation early in the pathogenesis of AD. Neuropathological studies show presence of activated microglia and inflammation-related mediators in the cerebral neocortex of autopsied patients with a low Braak stage for AD pathology. Prospective population-based cohort studies indicate that higher serum levels of acute phase proteins predict dementia. On a genetic level, it was found that the production capacity of proinflammatory cytokines after stimulation with lipopolysaccharide (a process that is under strong genetic control) is higher in offspring with a parental history of late-onset AD. Neuropathological studies show that a neuroinflammatory response in the cerebral neocortex parallels the early stages of AD pathology and precedes the late stage, tau-related pathology. Epidemiological and genetic studies indicate that systemic markers of the innate immunity are risk factors for late-onset AD. Copyright 2010 S. Karger AG, Basel.

  5. Subtype and regional-specific neuroinflammation in sporadic Creutzfeldt-Jakob disease

    Directory of Open Access Journals (Sweden)

    Franc eLlorens

    2014-08-01

    Full Text Available The present study identifies deregulated cytokines and mediators of the immune response in the frontal cortex and cerebellum of sCJD MM1 and VV2 subtypes compared to age-matched controls. Deregulated genes include pro- and anti-inflammatory cytokines, toll-like receptors, colony stimulating factors, cathepsins, members of the complement system, and members of the integrin and CTL/CTLD family with particular regional and sCJD subtype patterns. Analysis of cytokines and mediators at protein level shows expression of selected molecules and receptors in neurons and/or in astrocytes and/or in microglia thus suggesting interactions between neurons and glial cells, mainly microglia, in the neuroinflammatory response in sCJD. Similar inflammatory responses have been shown in the tg340 sCJD MM1 mice, revealing a progressive deregulation of inflammatory mediators with disease progression. Yet inflammatory molecules involved are subjected to species differences in humans and mice. Moreover, inflammatory-related cell signalling pathways NFκB/IKK and JAK/STAT are activated in sCJD and sCJD MM1 mice. Together, the present observations show a self-sustained complex inflammatory and inflammatory-related responses occurring already at early clinical stages in animal model and dramatically progressing at advanced stages of sCJD. Considering this scenario, measures tailored to modulate (activate or inhibit specific molecules could be therapeutic options in CJD.

  6. Targeting Microglial KATP Channels to Treat Neurodegenerative Diseases: A Mitochondrial Issue

    Directory of Open Access Journals (Sweden)

    Manuel J. Rodríguez

    2013-01-01

    Full Text Available Neurodegeneration is a complex process involving different cell types and neurotransmitters. A common characteristic of neurodegenerative disorders is the occurrence of a neuroinflammatory reaction in which cellular processes involving glial cells, mainly microglia and astrocytes, are activated in response to neuronal death. Microglia do not constitute a unique cell population but rather present a range of phenotypes closely related to the evolution of neurodegeneration. In a dynamic equilibrium with the lesion microenvironment, microglia phenotypes cover from a proinflammatory activation state to a neurotrophic one directly involved in cell repair and extracellular matrix remodeling. At each moment, the microglial phenotype is likely to depend on the diversity of signals from the environment and of its response capacity. As a consequence, microglia present a high energy demand, for which the mitochondria activity determines the microglia participation in the neurodegenerative process. As such, modulation of microglia activity by controlling microglia mitochondrial activity constitutes an innovative approach to interfere in the neurodegenerative process. In this review, we discuss the mitochondrial KATP channel as a new target to control microglia activity, avoid its toxic phenotype, and facilitate a positive disease outcome.

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

    Directory of Open Access Journals (Sweden)

    Ghosh Anamitra

    2012-10-01

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

  8. Kawasaki Disease

    Science.gov (United States)

    Kawasaki disease is a rare childhood disease. It makes the walls of the blood vessels in the ... veins, and capillaries. No one knows what causes Kawasaki disease. Symptoms include High fever that lasts longer ...

  9. Alzheimer Disease

    Science.gov (United States)

    ... CPR: A Real Lifesaver Kids Talk About: Coaches Alzheimer Disease KidsHealth > For Kids > Alzheimer Disease Print A A ... slow it down. When Someone You Love Has Alzheimer Disease You might feel sad or angry — or both — ...

  10. Crohn's Disease

    Science.gov (United States)

    Crohn's disease causes inflammation of the digestive system. It is one of a group of diseases called inflammatory ... small intestine called the ileum. The cause of Crohn's disease is unknown. It may be due to an ...

  11. Crohn disease

    Science.gov (United States)

    ... from doing your everyday activities. You have side effects from medicines you are taking for your condition. Alternative Names Crohn's disease; Inflammatory bowel disease - Crohn's disease; Regional enteritis; Ileitis; ...

  12. Meniere's Disease

    Science.gov (United States)

    ... Meniere's disease can affect your social life, your productivity and the overall quality of your life. Learn ... www.mayoclinic.org/diseases-conditions/menieres-disease/basics/definition/CON-20028251 . Mayo Clinic Footer Legal Conditions and ...

  13. Kawasaki disease

    Science.gov (United States)

    ... lymph node syndrome; Infantile polyarteritis Images Kawasaki's disease - edema of the hand Kawasaki's disease, peeling of the fingertips References Dominguez SR, Anderson MS. Advances in the treatment of Kawasaki disease. Curr Opin Pediatr . 2013;25( ...

  14. Gaucher's Disease

    Science.gov (United States)

    ... of developing the most common variety of Gaucher's disease. Gaucher's disease may increase the risk of: Growth delays ... illness can be difficult, but having a rare disease like Gaucher's may be even harder. Few people know about ...

  15. Huntington's Disease

    Science.gov (United States)

    Huntington's disease (HD) is an inherited disease that causes certain nerve cells in the brain to waste ... express emotions. If one of your parents has Huntington's disease, you have a 50 percent chance of ...

  16. Sever's Disease

    Science.gov (United States)

    ... take place on hard surfaces, such as track, basketball, soccer, and gymnastics. Sever's disease also can result ... diagnosing Sever's disease, some doctors order them to rule out other problems, such as fractures. Sever's disease ...

  17. Celiac Disease

    Science.gov (United States)

    ... digestive problems called inflammatory bowel disease (IBD) or lactose intolerance . And in some cases, a kid won't ... for Kids With Celiac Disease Inflammatory Bowel Disease Lactose Intolerance Are Your Bowels Moving? Indigestion Nut and Peanut ...

  18. Krüppel-like factor 4 regulates amyloid-β (Aβ)-induced neuroinflammation in Alzheimer's disease.

    Science.gov (United States)

    Li, Liuhong; Zi, Xiaohong; Hou, Deren; Tu, Qiuyun

    2017-03-16

    Alzheimer's disease (AD), one of the most common neurodegenerative diseases, is characterized by extracellular deposition of amyloid-β (Aβ) peptide, and neuro-inflammatory processes mediated by microglial activation are known to play a pivotal role in AD. However, the expression pattern and function of Krüppel-like factor (KLF) 4 in AD remain unknown. In this study, KLF4 was found to be increased at both the gene and protein levels in response to incubation with oligomeric Aβ42 in a dose-dependent manner in BV2 microglial cells. An in vivo study also displayed that expression of KLF4 in the brains of J20 transgenic AD model mice was increased due to accumulation of Aβ. Mechanistically, activation of p53 resulting from an increase in phosphorylation at ser15 was verified as the mediator of the oligomeric Aβ42-induced expression of KLF4. Subsequent experiments have demonstrated that KLF4 silencing in BV2 cells attenuates oligomeric Aβ42-induced neuroinflammation by ameliorating the release of proinflammatory cytokines, such as tumor necrosis factor-a (TNF-α), interleukin (IL)-1β, IL-6, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2). In addition, overexpression of KLF4 promoted oligomeric Aβ42-induced neuroinflammation by exacerbating the release of pro-inflammatory factors. These results suggest a KLF4 plays a potential role in oligomeric Aβ42-induced neurotoxicity and the pathogenesis of AD.

  19. Ribbing disease

    Directory of Open Access Journals (Sweden)

    Mukkada Philson

    2010-01-01

    Full Text Available Ribbing disease is a rare sclerosing dysplasia that involves long tubular bones, especially the tibia and femur. It occurs after puberty and is reported to be more common in women. In this article we describe how Ribbing disease can be differentiated from diseases like Engelmann-Camurati disease, van Buchem disease, Erdheim-Chester disease, osteoid osteoma, chronic osteomyelitis, stress fracture, etc.

  20. Bladder Diseases

    Science.gov (United States)

    ... frequent, urgent urination Bladder cancer Doctors diagnose bladder diseases using different tests. These include urine tests, x- ... National Institute of Diabetes and Digestive and Kidney Diseases

  1. SIRT1 Suppresses Human T-Cell Leukemia Virus Type 1 Transcription

    Science.gov (United States)

    Tang, Hei-Man Vincent; Gao, Wei-Wei; Chan, Chi-Ping; Cheng, Yun; Deng, Jian-Jun; Yuen, Kit-San; Iha, Hidekatsu

    2015-01-01

    ABSTRACT Human T-cell leukemia virus type 1 (HTLV-1)-associated diseases are poorly treatable, and HTLV-1 vaccines are not available. High proviral load is one major risk factor for disease development. HTLV-1 encodes Tax oncoprotein, which activates transcription from viral long terminal repeats (LTR) and various types of cellular promoters. Counteracting Tax function might have prophylactic and therapeutic benefits. In this work, we report on the suppression of Tax activation of HTLV-1 LTR by SIRT1 deacetylase. The transcriptional activity of Tax on the LTR was largely ablated when SIRT1 was overexpressed, but Tax activation of NF-κB was unaffected. On the contrary, the activation of the LTR by Tax was boosted when SIRT1 was depleted. Treatment of cells with resveratrol shunted Tax activity in a SIRT1-dependent manner. The activation of SIRT1 in HTLV-1-transformed T cells by resveratrol potently inhibited HTLV-1 proviral transcription and Tax expression, whereas compromising SIRT1 by specific inhibitors augmented HTLV-1 mRNA expression. The administration of resveratrol also decreased the production of cell-free HTLV-1 virions from MT2 cells and the transmission of HTLV-1 from MT2 cells to uninfected Jurkat cells in coculture. SIRT1 associated with Tax in HTLV-1-transformed T cells. Treatment with resveratrol prevented the interaction of Tax with CREB and the recruitment of CREB, CRTC1, and p300 to Tax-responsive elements in the LTR. Our work demonstrates the negative regulatory function of SIRT1 in Tax activation of HTLV-1 transcription. Small-molecule activators of SIRT1 such as resveratrol might be considered new prophylactic and therapeutic agents in HTLV-1-associated diseases. IMPORTANCE Human T-cell leukemia virus type 1 (HTLV-1) causes a highly lethal blood cancer or a chronic debilitating disease of the spinal cord. Treatments are unsatisfactory, and vaccines are not available. Disease progression is associated with robust expression of HTLV-1 genes

  2. Fifth Disease

    Science.gov (United States)

    ... roseola. Fifth disease is sometimes called “slapped cheek disease.” The illness’s bright red rash on the face looks like ... disease Most children and adults who get fifth disease experience only mild illness. They recover completely and have no complications. But ...

  3. Heart Diseases

    Science.gov (United States)

    ... you're like most people, you think that heart disease is a problem for others. But heart disease is the number one killer in the U.S. ... of disability. There are many different forms of heart disease. The most common cause of heart disease is ...

  4. Whipple's Disease

    Science.gov (United States)

    ... more common conditions with similar symptoms, including inflammatory rheumatic disease—characterized by inflammation and loss of function in ... Management Liver Disease Urologic Diseases Endocrine Diseases Diet & Nutrition Blood Diseases Diagnostic Tests La información de la salud en ...

  5. Major Alterations of Phosphatidylcholine and Lysophosphotidylcholine Lipids in the Substantia Nigra Using an Early Stage Model of Parkinson’s Disease

    Directory of Open Access Journals (Sweden)

    Kyle Farmer

    2015-08-01

    Full Text Available Parkinson’s disease (PD is a progressive neurodegenerative disease affecting the nigrostriatal pathway, where patients do not manifest motor symptoms until >50% of neurons are lost. Thus, it is of great importance to determine early neuronal changes that may contribute to disease progression. Recent attention has focused on lipids and their role in pro- and anti-apoptotic processes. However, information regarding the lipid alterations in animal models of PD is lacking. In this study, we utilized high performance liquid chromatography electrospray ionization tandem mass spectrometry (HPLC-ESI-MS/MS and novel HPLC solvent methodology to profile phosphatidylcholines and sphingolipids within the substantia nigra. The ipsilateral substantia nigra pars compacta was collected from rats 21 days after an infusion of 6-hydroxydopamine (6-OHDA, or vehicle into the anterior dorsal striatum. We identified 115 lipid species from their mass/charge ratio using the LMAPS Lipid MS Predict Database. Of these, 19 lipid species (from phosphatidylcholine and lysophosphotidylcholine lipid classes were significantly altered by 6-OHDA, with most being down-regulated. The two lipid species that were up-regulated were LPC (16:0 and LPC (18:1, which are important for neuroinflammatory signalling. These findings provide a first step in the characterization of lipid changes in early stages of PD-like pathology and could provide novel targets for early interventions in PD.

  6. VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington’s disease

    Science.gov (United States)

    Díaz-Alonso, Javier; Paraíso-Luna, Juan; Navarrete, Carmen; del Río, Carmen; Cantarero, Irene; Palomares, Belén; Aguareles, José; Fernández-Ruiz, Javier; Bellido, María Luz; Pollastro, Federica; Appendino, Giovanni; Calzado, Marco A.; Galve-Roperh, Ismael; Muñoz, Eduardo

    2016-01-01

    Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid receptors and PPARγ. We previously showed that VCE-003, a cannabigerol (CBG) quinone derivative, is a novel neuroprotective and anti-inflammatory cannabinoid acting through PPARγ. We have now generated a non-thiophilic VCE-003 derivative named VCE-003.2 that preserves the ability to activate PPARγ and analyzed its neuroprotective activity. This compound exerted a prosurvival action in progenitor cells during neuronal differentiation, which was prevented by a PPARγ antagonist, without affecting neural progenitor cell proliferation. In addition, VCE-003.2 attenuated quinolinic acid (QA)-induced cell death and caspase-3 activation and also reduced mutant huntingtin aggregates in striatal cells. The neuroprotective profile of VCE-003.2 was analyzed using in vivo models of striatal neurodegeneration induced by QA and 3-nitropropionic acid (3NP) administration. VCE-003.2 prevented medium spiny DARPP32+ neuronal loss in these Huntington’s-like disease mice models improving motor deficits, reactive astrogliosis and microglial activation. In the 3NP model VCE-003.2 inhibited the upregulation of proinflammatory markers and improved antioxidant defenses in the brain. These data lead us to consider VCE-003.2 to have high potential for the treatment of Huntington’s disease (HD) and other neurodegenerative diseases with neuroinflammatory traits. PMID:27430371

  7. VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington's disease.

    Science.gov (United States)

    Díaz-Alonso, Javier; Paraíso-Luna, Juan; Navarrete, Carmen; Del Río, Carmen; Cantarero, Irene; Palomares, Belén; Aguareles, José; Fernández-Ruiz, Javier; Bellido, María Luz; Pollastro, Federica; Appendino, Giovanni; Calzado, Marco A; Galve-Roperh, Ismael; Muñoz, Eduardo

    2016-07-19

    Cannabinoids have shown to exert neuroprotective actions in animal models by acting at different targets including canonical cannabinoid receptors and PPARγ. We previously showed that VCE-003, a cannabigerol (CBG) quinone derivative, is a novel neuroprotective and anti-inflammatory cannabinoid acting through PPARγ. We have now generated a non-thiophilic VCE-003 derivative named VCE-003.2 that preserves the ability to activate PPARγ and analyzed its neuroprotective activity. This compound exerted a prosurvival action in progenitor cells during neuronal differentiation, which was prevented by a PPARγ antagonist, without affecting neural progenitor cell proliferation. In addition, VCE-003.2 attenuated quinolinic acid (QA)-induced cell death and caspase-3 activation and also reduced mutant huntingtin aggregates in striatal cells. The neuroprotective profile of VCE-003.2 was analyzed using in vivo models of striatal neurodegeneration induced by QA and 3-nitropropionic acid (3NP) administration. VCE-003.2 prevented medium spiny DARPP32(+) neuronal loss in these Huntington's-like disease mice models improving motor deficits, reactive astrogliosis and microglial activation. In the 3NP model VCE-003.2 inhibited the upregulation of proinflammatory markers and improved antioxidant defenses in the brain. These data lead us to consider VCE-003.2 to have high potential for the treatment of Huntington's disease (HD) and other neurodegenerative diseases with neuroinflammatory traits.

  8. Novel tactics for neuroprotection in Parkinson's disease: Role of antibiotics, polyphenols and neuropeptides.

    Science.gov (United States)

    Reglodi, Dora; Renaud, Justine; Tamas, Andrea; Tizabi, Yousef; Socías, Sergio B; Del-Bel, Elaine; Raisman-Vozari, Rita

    2015-11-02

    Parkinson's disease is a progressive neurodegenerative disorder characterized by the degeneration of midbrain nigral dopaminergic neurons. Although its etiology remains unknown, the pathological role of several factors has been highlighted, namely oxidative stress, neuroinflammation, protein misfolding, and mitochondrial dysfunction, in addition to genetic predispositions. The current therapy is mainly symptomatic with l-DOPA aiming to replace dopamine. Novel therapeutic approaches are being investigated with the intention of influencing pathways leading to neuronal death and dysfunction. The present review summarizes three novel approaches, the use of which is promising in pre-clinical studies. Polyphenols have been shown to possess neuroprotective properties on account of their well-established antioxidative and anti-inflammatory actions but also due to their influence on protein misfolding and mitochondrial homeostasis. Within the amazing ancillary effects of antibiotics, their neuroprotective properties against neurodegenerative and neuroinflammatory processes are of great interest for the development of effective therapies against Parkinson's disease. Experimental evidence supports the potential of antibiotics as neuroprotective agents, being useful not only to prevent the formation of toxic α-synuclein oligomers but also to ameliorate mitochondrial dysfunction and neuroinflammation. Neuropeptides offer another approach with their diverse effects in the nervous system. Among them, pituitary adenylate cyclase-activating polypeptide, a member of the secretin/glucagon superfamily, has several advantageous effects in models of neurodegeneration, namely anti-apoptotic, anti-inflammatory and antioxidant actions, the combination of which offers a potent protective effect in dopaminergic neurons. Owing to their pleiotropic modes of action, these novel therapeutic candidates have potential in tackling the multidimensional features of Parkinson's disease.

  9. Blood-based biomarkers of Alzheimer's disease: diagnostic algorithms and new technologies.

    Science.gov (United States)

    Carmona, Pedro; Molina, Marina; Toledano, Adolfo

    2016-01-01

    New concepts about Alzheimer's disease (AD), considered as a clinical-biological entity, make essential the definition of biomarkers that could be used for the in vivo diagnosis of the disorder before dementia develops. Different types of genetic, biochemical and neuroimaging markers have been described, highlighting some of the changes that occur in the brain during the course of the disease, yet there is little proof of their pathognomonic and diagnostic value. Furthermore, many of the assays used are difficult to perform, the equipment/reagents are expensive or potentially hazardous (e.g.; use of radioactive compounds, CSF extraction). Thus, there is a need to define more suitable and convenient approaches, such as the determination of blood parameters that are easy to obtain and that can be repeated as necessary without contraindications. These data can be used by algorithms that combine specific and non-specific changes to classify patients at different stages of AD and/or distinguish AD from other related diseases with a greater specificity and reliability (> 80%). The blood parameters considered in this review are varied, including: β-amyloid, tau, apolipoproteins and proteins, as well as the metabolic behavior of blood cells, etc. Among the proteins, cytokines/chemokines and other cell factors related to both neuro-inflammatory and peripheral-inflammatory processes in AD are of prime importance. New technologies to detect and quantify these substances, reasonably priced such as the vibrational spectroscopy, panels of parameters and algorithms to assess the results, would be fundamental for the early AD diagnosis and to define new potential therapies.

  10. Are lipid disorders involved in the predominance of human T-lymphotropic virus-1 infections in women?

    Directory of Open Access Journals (Sweden)

    Luciana Debortoli de Carvalho

    2015-12-01

    Full Text Available Abstract INTRODUCTION : The human T-lymphotropic virus-1 (HTLV-1 is associated with chronic inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP, a chronic inflammatory disease. Disturbances in lipid metabolism are involved in inflammatory and demyelinating diseases. METHODS : Plasma levels of triglycerides, total cholesterol, and fractions of HTLV-1-infected individuals of both sexes with different clinical progressions were determined. RESULTS : Elevated levels of triglyceride and very low-density lipoproteins (VLDL were exclusively detected in HTLV-1-infected women from asymptomatic and HAM/TSP groups compared with uninfected individuals (p = 0.02. CONCLUSIONS : Elevated triglyceride and VLDL levels in HTLV-1-infected women may be related to the predominance of HAM/TSP in women.

  11. Addison disease

    Science.gov (United States)

    ... amounts of some or all of its hormones ( hypopituitarism ) Autoimmune disorder that affects the nerves and the ... disease) Dermatitis herpetiformis Diabetes Graves disease Hyperthyroidism Hypoparathyroidism Hypopituitarism Immune response Myasthenia gravis Ovarian hypofunction Pernicious anemia ...

  12. Fifth disease

    Science.gov (United States)

    Parvovirus B19; Erythema infectiosum; Slapped cheek rash ... Fifth disease is caused by human parvovirus B19. It often affects preschoolers or school-age children during the spring. The disease spreads through the fluids in the nose and ...

  13. Rh Disease

    Science.gov (United States)

    ... Loss > Birth defects & other health conditions > Rh disease Rh disease E-mail to a friend Please fill ... Rh-negative with a blood test. What is Rh factor? Rh factor is a protein that’s found ...

  14. Binswanger's Disease

    Science.gov (United States)

    ... Craniosynostosis Information Page Creutzfeldt-Jakob Disease Information Page Cushing's Syndrome Information Page Dandy-Walker Syndrome Information Page Deep Brain Stimulation for Parkinson's Disease Information Page Dementia Information ...

  15. Batten Disease

    Science.gov (United States)

    ... Craniosynostosis Information Page Creutzfeldt-Jakob Disease Information Page Cushing's Syndrome Information Page Dandy-Walker Syndrome Information Page Deep Brain Stimulation for Parkinson's Disease Information Page Dementia Information ...

  16. Behcet's Disease

    Science.gov (United States)

    ... Craniosynostosis Information Page Creutzfeldt-Jakob Disease Information Page Cushing's Syndrome Information Page Dandy-Walker Syndrome Information Page Deep Brain Stimulation for Parkinson's Disease Information Page Dementia Information ...

  17. Krabbe Disease

    Science.gov (United States)

    ... Craniosynostosis Information Page Creutzfeldt-Jakob Disease Information Page Cushing's Syndrome Information Page Dandy-Walker Syndrome Information Page Deep Brain Stimulation for Parkinson's Disease Information Page Dementia Information ...

  18. Crohn's Disease

    Science.gov (United States)

    ... prognosis of Crohn's disease in adults. http://www.uptodate.com/home. Accessed June 2, 2014. Smoking and ... cancer surveillance in inflammatory bowel disease. http://www.uptodate.com/home. Accessed June 9, 2014. Inflammatory bowel ...

  19. Addison Disease

    Science.gov (United States)

    ... your blood pressure and water and salt balance. Addison disease happens if the adrenal glands don't make ... A problem with your immune system usually causes Addison disease. The immune system mistakenly attacks your own tissues, ...

  20. Liver Diseases

    Science.gov (United States)

    Your liver is the largest organ inside your body. It helps your body digest food, store energy, and remove poisons. There are many kinds of liver diseases: Diseases caused by viruses, such as hepatitis ...

  1. Valve Disease

    Science.gov (United States)

    ... heart valves, valve insufficiency, valve regurgitation, valve stenosis, valvular heart disease Every time your heart beats, blood flows into, ... removed from the market after being linked to heart valve disease. An infection in the lining of the heart's ...

  2. Wilson Disease

    Science.gov (United States)

    Wilson disease is a rare inherited disorder that prevents your body from getting rid of extra copper. You ... extra copper into bile, a digestive fluid. With Wilson disease, the copper builds up in your liver, and ...

  3. Gaucher disease

    Science.gov (United States)

    ... doesn't have the disease is called a silent carrier. The lack of the glucocerebrosidase enzyme causes ... liver Fatigue Heart valve problems Lung disease (rare) Seizures Severe swelling at birth Skin changes

  4. Legionnaire disease

    Science.gov (United States)

    ... features on this page, please enable JavaScript. Legionnaire disease is an infection of the lungs and airways. It is caused by Legionella bacteria. Causes The bacteria that cause Legionnaire disease have ...

  5. Parkinson's Disease

    Science.gov (United States)

    ... messages it needs to move normally. continue What Causes Parkinson's Disease? Experts agree that low dopamine levels in ... or other chemicals. No one knows the exact cause of Parkinson's disease, but we do know that it has ...

  6. Fabry Disease

    Science.gov (United States)

    ... Foundation National Organization for Rare Disorders (NORD) National Tay-Sachs and Allied Diseases Association See all related ... Foundation National Organization for Rare Disorders (NORD) National Tay-Sachs and Allied Diseases Association See all related ...

  7. Canavan Disease

    Science.gov (United States)

    ... Foundation, Inc. Canavan Research Foundation Genetic Alliance National Tay-Sachs and Allied Diseases Association See all related ... Foundation, Inc. Canavan Research Foundation Genetic Alliance National Tay-Sachs and Allied Diseases Association See all related ...

  8. Digestive Diseases

    Science.gov (United States)

    ... Celiac Disease Bowel Control Problems (Fecal Incontinence) Gas Lactose Intolerance Diarrhea Diverticulosis & Diverticulitis Acid Reflux (GER & GERD) More Digestive Disease Topics Children and Teens Acid Reflux (GER & GERD) in Infants Acid Reflux (GER & GERD) in Children & Teens Chronic ...

  9. Gaucher Disease

    Science.gov (United States)

    Gaucher disease is a rare, inherited disorder. It is a type of lipid metabolism disorder. If you have ... affected. It usually starts in childhood or adolescence. Gaucher disease has no cure. Treatment options for types 1 ...

  10. Liver disease

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/000205.htm Liver disease To use the sharing features on this page, please enable JavaScript. The term "liver disease" applies to many conditions that stop the ...

  11. Wilson Disease

    Science.gov (United States)

    ... in copper, such as –shellfish –liver –mushrooms –nuts –chocolate • A person cannot prevent Wilson disease; however, people with a family history of Wilson disease, especially those with an affected ...

  12. Chagas Disease

    Science.gov (United States)

    Chagas disease is caused by a parasite. It is common in Latin America but not in the United ... There are no vaccines or medicines to prevent Chagas disease. If you travel to areas where it occurs, ...

  13. Legionnaires' Disease

    Science.gov (United States)

    ... Disease Sources Investigation Protocol Outbreak Response What is Legionella? Exposure and Transmission Disease Symptoms Incidence and Risk ... form of pneumonia. More than 43 species of Legionella have been identified and more than 20 linked ...

  14. Heart Disease

    Science.gov (United States)

    ... daily aspirin to prevent heart attack? Does taking birth control pills increase my risk for heart disease? Does using ... tells you to. Return to top Does taking birth control pills increase my risk for heart disease? Taking birth ...

  15. Liver Disease

    Science.gov (United States)

    ... stay still. Liver disease has many causes. Infection Parasites and viruses can infect the liver, causing inflammation ... beyond. National Institute of Diabetes and Digestive and Kidney Diseases. http://digestive.niddk.nih.gov/ddiseases/pubs/ ...

  16. Kidney Diseases

    Science.gov (United States)

    ... until you go to the bathroom. Most kidney diseases attack the nephrons. This damage may leave kidneys ... medicines. You have a higher risk of kidney disease if you have diabetes, high blood pressure, or ...

  17. Eye Diseases

    Science.gov (United States)

    ... the back of the eye Macular degeneration - a disease that destroys sharp, central vision Diabetic eye problems ... defense is to have regular checkups, because eye diseases do not always have symptoms. Early detection and ...

  18. Parasitic Diseases

    Science.gov (United States)

    ... water, a bug bite, or sexual contact. Some parasitic diseases are easily treated and some are not. Parasites ... can be seen with the naked eye. Some parasitic diseases occur in the United States. Contaminated water supplies ...

  19. Activated iron-containing microglia in the human hippocampus identified by magnetic resonance imaging in Alzheimer disease.

    Science.gov (United States)

    Zeineh, Michael M; Chen, Yuanxin; Kitzler, Hagen H; Hammond, Robert; Vogel, Hannes; Rutt, Brian K

    2015-09-01

    Although amyloid plaques and neurofibrillary pathology play important roles in Alzheimer disease (AD), our understanding of AD is incomplete, and the contribution of microglia and iron to neurodegeneration is unknown. High-field magnetic resonance imaging (MRI) is exquisitely sensitive to microscopic iron. To explore iron-associated neuroinflammatory AD pathology, we studied AD and control human brain specimens by (1) performing ultra-high resolution ex vivo 7 Tesla MRI, (2) coregistering the MRI with successive histologic staining for iron, microglia, amyloid beta, and tau, and (3) quantifying the relationship between magnetic resonance signal intensity and histological staining. In AD, we identified numerous small MR hypointensities primarily within the subiculum that were best explained by the combination of microscopic iron and activated microglia (p = 0.025), in contradistinction to the relatively lesser contribution of tau or amyloid. Neuropathologically, this suggests that microglial-mediated neurodegeneration may occur in the hippocampal formation in AD and is detectable by ultra-high resolution MRI.

  20. Synergistical neuroprotection of rofecoxib and statins against malonic acid induced Huntington's disease like symptoms and related cognitive dysfunction in rats.

    Science.gov (United States)

    Kumar, Anil; Sharma, Neha; Mishra, Jitendriya; Kalonia, Harikesh

    2013-06-05

    Malonic acid (MA) is a reversible inhibitor of succinate dehydrogenase (SDH) which induces mitochondrial dysfunction followed by secondary excitotoxicity and apoptosis due to generation of reactive oxygen species. Therapeutic potential of rofecoxib and statins have been well documented in several experimental models of neurodegenerative disorders, however, its exact mechanism of action is not known properly. Therefore, the present study is an attempt to investigate the effect of rofecoxib along with the statins against MA induced behavioural and biochemical alterations in rats. Single intrastriatal MA (6 µmol) significantly caused motor incordination, memory dysfunction and alteration in the antioxidant enzyme levels, mitochondrial enzyme complex (I, II, IV) activities, mitochondrial redox ratio and pro-inflammatory cytokine [tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6)] levels in the striatum as compared to the naive group. Fourteen days treatment with rofecoxib, atorvastatin, simvastatin significantly attenuated these behavioural, biochemical, and cellular alterations as compared to control (MA treated group). However, the treatment of rofecoxib along with atorvastatin or simvastatin significantly attenuated these behavioural, biochemical, and cellular alterations as compared to their individual effects. The results of the present study demonstrated that rofecoxib modulates the protective effects of statins against MA-induced neurobehavioral and related biochemical and cellular alterations in rats. This further provides evidence toward the involvement of neuroinflammatory cascade in the pathogenesis of Huntington's disease.

  1. Correlations of (18)F-THK5351 PET with post-mortem burden of tau and astrogliosis in Alzheimer's disease.

    Science.gov (United States)

    Harada, Ryuichi; Ishiki, Aiko; Kai, Hideaki; Sato, Naomi; Furukawa, Katsutoshi; Furumoto, Shozo; Tago, Tetsuro; Tomita, Naoki; Watanuki, Shoichi; Hiraoka, Kotaro; Ishikawa, Yoichi; Funaki, Yoshihito; Nakamura, Tadaho; Yoshikawa, Takeo; Iwata, Ren; Tashiro, Manabu; Sasano, Hironobu; Kitamoto, Tetsuyuki; Yanai, Kazuhiko; Arai, Hiroyuki; Kudo, Yukitsuka; Okamura, Nobuyuki

    2017-09-01

    Clinical PET studies using (18)F-THK5351 have demonstrated significant tracer retention in sites susceptible to tau burden in Alzheimer's disease (AD). However, the in vivo PET signal to reflect tau aggregates remains controversial. Methods: We examined the spatial pattern of tracer binding, amyloid-β, tau and gliosis in an autopsy-confirmed AD case who underwent (18)F-THK5351 and (11)C-PiB PET before death. Results: Regional in vivo (18)F-THK5351 retention was significantly correlated with the density of tau aggregates in the neocortex and monoamine oxidase-B (MAO-B) in the whole brain, but not correlated with that of insoluble amyloid-β. Furthermore, significant association was observed between the density of tau aggregates, MAO-B and glial fibrillary acidic protein, suggesting that neocortical tau would strongly influence the formation of reactive astrocytes. Conclusion:(18)F-THK5351 PET may have limited utility as a biomarker of tau pathology in AD, however could be used to monitor the neuroinflammatory processes in the living brain. Copyright © 2017 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  2. Kawasaki Disease

    Science.gov (United States)

    ... Life7. Questions8. Resources What is Kawasaki disease? Kawasaki disease is a rare illness. It can occur in infants and children younger ... may have diarrhea, vomiting, and stomach pain. Kawasaki disease might make your child irritable. The illness can last for a few weeks. What causes ...

  3. Lyme Disease.

    Science.gov (United States)

    Taylor, George C.

    1991-01-01

    This overview of the public health significance of Lyme disease includes the microbiological specifics of the infectious spirochete, the entomology and ecology of the ticks which are the primary disease carrier, the clinical aspects and treatment stages, the known epidemiological patterns, and strategies for disease control and for expanded public…

  4. [Gaucher Disease].

    Science.gov (United States)

    Okuyama, Torayuki

    2015-09-01

    Gaucher disease is an autosomal recessive disorder caused by congenital deficiency of lysosomal glucocerebrosidase. Gaucher disease is classified into three types. In addition to enzyme replacement therapy, substrate reduction therapy, chemical chaperon therapy, and hematopoietic stem cell transplantation therapy are considered for the effective treatment of Gaucher disease.

  5. Menetrier's Disease

    Science.gov (United States)

    ... producing cells in the stomach, which decreases stomach acid. Ménétrier’s disease is also called Ménétrier disease or hypoproteinemic hypertrophic ... Alternate Versions PDF Version (102 KB) Additional Links Peptic Ulcer Disease Upper GI Endoscopy This content is provided as ...

  6. Glomerular Diseases

    Science.gov (United States)

    ... Disease Mineral & Bone Disorder Diabetes Inspidus Glomerular Diseases Goodpasture Syndrome Henoch-Schönlein Purpura IgA Nephropathy Kidney Disease in ... effective as cyclophosphamide and has milder side effects. Goodpasture's Syndrome involves an autoantibody that specifically targets the kidneys ...

  7. A multimodal RAGE-specific inhibitor reduces amyloid β–mediated brain disorder in a mouse model of Alzheimer disease

    Science.gov (United States)

    Deane, Rashid; Singh, Itender; Sagare, Abhay P.; Bell, Robert D.; Ross, Nathan T.; LaRue, Barbra; Love, Rachal; Perry, Sheldon; Paquette, Nicole; Deane, Richard J.; Thiyagarajan, Meenakshisundaram; Zarcone, Troy; Fritz, Gunter; Friedman, Alan E.; Miller, Benjamin L.; Zlokovic, Berislav V.

    2012-01-01

    In Alzheimer disease (AD), amyloid β peptide (Aβ) accumulates in plaques in the brain. Receptor for advanced glycation end products (RAGE) mediates Aβ-induced perturbations in cerebral vessels, neurons, and microglia in AD. Here, we identified a high-affinity RAGE-specific inhibitor (FPS-ZM1) that blocked Aβ binding to the V domain of RAGE and inhibited Aβ40- and Aβ42-induced cellular stress in RAGE-expressing cells in vitro and in the mouse brain in vivo. FPS-ZM1 was nontoxic to mice and readily crossed the blood-brain barrier (BBB). In aged APPsw/0 mice overexpressing human Aβ-precursor protein, a transgenic mouse model of AD with established Aβ pathology, FPS-ZM1 inhibited RAGE-mediated influx of circulating Aβ40 and Aβ42 into the brain. In brain, FPS-ZM1 bound exclusively to RAGE, which inhibited β-secretase activity and Aβ production and suppressed microglia activation and the neuroinflammatory response. Blockade of RAGE actions at the BBB and in the brain reduced Aβ40 and Aβ42 levels in brain markedly and normalized cognitive performance and cerebral blood flow responses in aged APPsw/0 mice. Our data suggest that FPS-ZM1 is a potent multimodal RAGE blocker that effectively controls progression of Aβ-mediated brain disorder and that it may have the potential to be a disease-modifying agent for AD. PMID:22406537

  8. Pro-inflammatory S100A9 Protein as a Robust Biomarker Differentiating Early Stages of Cognitive Impairment in Alzheimer's Disease.

    Science.gov (United States)

    Horvath, Istvan; Jia, Xueen; Johansson, Per; Wang, Chao; Moskalenko, Roman; Steinau, Andreas; Forsgren, Lars; Wågberg, Thomas; Svensson, Johan; Zetterberg, Henrik; Morozova-Roche, Ludmilla A

    2016-01-20

    Pro-inflammatory protein S100A9 was established as a biomarker of dementia progression and compared with others such as Aβ(1-42) and tau-proteins. CSF samples from 104 stringently diagnosed individuals divided into five subgroups were analyzed, including nondemented controls, stable mild cognitive impairment (SMCI), mild cognitive impairment due to Alzheimer's disease (MCI-AD), Alzheimer's disease (AD), and vascular dementia (VaD) patients. ELISA, dot-blotting, and electrochemical impedance spectroscopy were used as research methods. The S100A9 and Aβ(1-42) levels correlated with each other: their CSF content decreased already at the SMCI stage and declined further under MCI-AD, AD, and VaD conditions. Immunohistochemical analysis also revealed involvement of both Aβ(1-42) and S100A9 in the amyloid-neuroinflammatory cascade already during SMCI. Tau proteins were not yet altered in SMCI; however their contents increased during MCI-AD and AD, diagnosing later dementia stages. Thus, four biomarkers together, reflecting different underlying pathological causes, can accurately differentiate dementia progression and also distinguish AD from VaD.

  9. Autotransplantation of bone marrow-derived stem cells as a therapy for neurodegenerative diseases.

    Science.gov (United States)

    Kan, I; Melamed, E; Offen, D

    2007-01-01

    Neurodegenerative diseases are characterized by a progressive degeneration of selective neural populations. This selective hallmark pathology and the lack of effective treatment modalities make these diseases appropriate candidates for cell therapy. Bone marrow-derived mesenchymal stem cells (MSCs) are self-renewing precursors that reside in the bone marrow and may further be exploited for autologous transplantation. Autologous transplantation of MSCs entirely circumvents the problem of immune rejection, does not cause the formation of teratomas, and raises very few ethical or political concerns. More than a few studies showed that transplantation of MSCs resulted in clinical improvement. However, the exact mechanisms responsible for the beneficial outcome have yet to be defined. Possible rationalizations include cell replacement, trophic factors delivery, and immunomodulation. Cell replacement theory is based on the idea that replacement of degenerated neural cells with alternative functioning cells induces long-lasting clinical improvement. It is reasoned that the transplanted cells survive, integrate into the endogenous neural network, and lead to functional improvement. Trophic factor delivery presents a more practical short-term approach. According to this approach, MSC effectiveness may be credited to the production of neurotrophic factors that support neuronal cell survival, induce endogenous cell proliferation, and promote nerve fiber regeneration at sites of injury. The third potential mechanism of action is supported by the recent reports claiming that neuroinflammatory mechanisms play an important role in the pathogenesis of neurodegenerative disorders. Thus, inhibiting chronic inflammatory stress might explain the beneficial effects induced by MSC transplantation. Here, we assemble evidence that supports each theory and review the latest studies that have placed MSC transplantation into the spotlight of biomedical research.

  10. Morgellons Disease

    OpenAIRE

    Ohn, Jungyoon; Park, Seon Yong; Moon, Jungyoon; Choe, Yun Seon; Kim, Kyu Han

    2017-01-01

    Morgellons disease is a rare disease with unknown etiology. Herein, we report the first case of Morgellons disease in Korea. A 30-year-old woman presented with a 2-month history of pruritic erythematous patches and erosions on the arms, hands, and chin. She insisted that she had fiber-like materials under her skin, which she had observed through a magnifying device. We performed skin biopsy, and observed a fiber extruding from the dermal side of the specimen. Histopathological examination sho...

  11. Celiac Disease

    Directory of Open Access Journals (Sweden)

    Hero Brokalaki

    2008-07-01

    Full Text Available Celiac disease is a small intestine disease caused by the immunological response to gluten, a component of wheat, rye and barley. The worldwide prevalence of celiac disease ranges between 0.2% and 2.2 %. The clinical features of celiac disease includes diarrhea, steatorrhea, flatulence, abdominal pain and weight loss. The asymptomatic type of celiac disease is characterized by soft or normally shaped stool, weakness, lassitude and moderate weight loss. In children, celiac disease usually arises between the first and the third year of age, with diarrhea, flatulence and low weight. The malabsorption in small intestine causes many extaintestinal manifestations, such us anemia, bone abnormalities, hemorrhage and neuropathy. Celiac disease is diagnosed by histological examination of tissue samples taken by duodenum due gastroscopy and by the detection of certain antibodies in blood (anti-GL-IgG, anti-GL-IgA, ΕΜΑ-IgA και anti-tTg-IgA. The only therapeutic approach to celiac disease is a gluten-free diet and, if it is necessary, the administration of iron, folic acid, calcium and vitamins (K, B12. The prognosis of celiac disease is excellent, if there is an early diagnosis and the patient keeps for life a gluten free diet.

  12. Celiac disease

    Directory of Open Access Journals (Sweden)

    Holtmeier Wolfgang

    2006-03-01

    Full Text Available Abstract Celiac disease is a chronic intestinal disease caused by intolerance to gluten. It is characterized by immune-mediated enteropathy, associated with maldigestion and malabsorption of most nutrients and vitamins. In predisposed individuals, the ingestion of gluten-containing food such as wheat and rye induces a flat jejunal mucosa with infiltration of lymphocytes. The main symptoms are: stomach pain, gas, and bloating, diarrhea, weight loss, anemia, edema, bone or joint pain. Prevalence for clinically overt celiac disease varies from 1:270 in Finland to 1:5000 in North America. Since celiac disease can be asymptomatic, most subjects are not diagnosed or they can present with atypical symptoms. Furthermore, severe inflammation of the small bowel can be present without any gastrointestinal symptoms. The diagnosis should be made early since celiac disease causes growth retardation in untreated children and atypical symptoms like infertility or neurological symptoms. Diagnosis requires endoscopy with jejunal biopsy. In addition, tissue-transglutaminase antibodies are important to confirm the diagnosis since there are other diseases which can mimic celiac disease. The exact cause of celiac disease is unknown but is thought to be primarily immune mediated (tissue-transglutaminase autoantigen; often the disease is inherited. Management consists in life long withdrawal of dietary gluten, which leads to significant clinical and histological improvement. However, complete normalization of histology can take years.

  13. Leigh's Disease

    Science.gov (United States)

    ... Related Dementias Bioengineering Epilepsy Health Disparities Neural Interfaces Parkinson's Disease Spinal Cord Injury Stem Cells Traumatic Brain Injury Trans-Agency Activities Interagency Research ...

  14. Celiac disease

    Directory of Open Access Journals (Sweden)

    Radlović Nedeljko

    2013-01-01

    Full Text Available Celiac disease is a multysystemic autoimmune disease induced by gluten in wheat, barley and rye. It is characterized by polygenic predisposition, high prevalence (1%, widely heterogeneous expression and frequent association with other autoimmune diseases, selective deficit of IgA and Down, Turner and Williams syndrome. The basis of the disease and the key finding in its diagnostics is symptomatic or asymptomatic inflammation of the small intestinal mucosa which resolves by gluten-free diet. Therefore, the basis of the treatment involves elimination diet, so that the disorder, if timely recognized and adequately treated, also characterizes excellent prognosis.

  15. The Role of Microglia in Retinal Neurodegeneration: Alzheimer's Disease, Parkinson, and Glaucoma.

    Science.gov (United States)

    Ramirez, Ana I; de Hoz, Rosa; Salobrar-Garcia, Elena; Salazar, Juan J; Rojas, Blanca; Ajoy, Daniel; López-Cuenca, Inés; Rojas, Pilar; Triviño, Alberto; Ramírez, José M

    2017-01-01

    Microglia, the immunocompetent cells of the central nervous system (CNS), act as neuropathology sensors and are neuroprotective under physiological conditions. Microglia react to injury and degeneration with immune-phenotypic and morphological changes, proliferation, migration, and inflammatory cytokine production. An uncontrolled microglial response secondary to sustained CNS damage can put neuronal survival at risk due to excessive inflammation. A neuroinflammatory response is considered among the etiological factors of the major aged-related neurodegenerative diseases of the CNS, and microglial cells are key players in these neurodegenerative lesions. The retina is an extension of the brain and therefore the inflammatory response in the brain can occur in the retina. The brain and retina are affected in several neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and glaucoma. AD is an age-related neurodegeneration of the CNS characterized by neuronal and synaptic loss in the cerebral cortex, resulting in cognitive deficit and dementia. The extracellular deposits of beta-amyloid (Aβ) and intraneuronal accumulations of hyperphosphorylated tau protein (pTau) are the hallmarks of this disease. These deposits are also found in the retina and optic nerve. PD is a neurodegenerative locomotor disorder with the progressive loss of dopaminergic neurons in the substantia nigra. This is accompanied by Lewy body inclusion composed of α-synuclein (α-syn) aggregates. PD also involves retinal dopaminergic cell degeneration. Glaucoma is a multifactorial neurodegenerative disease of the optic nerve, characterized by retinal ganglion cell loss. In this pathology, deposition of Aβ, synuclein, and pTau has also been detected in retina. These neurodegenerative diseases share a common pathogenic mechanism, the neuroinflammation, in which microglia play an important role. Microglial activation has been reported in AD, PD, and glaucoma in

  16. Is "Parkinson's disease" one disease?

    OpenAIRE

    Calne, D B

    1989-01-01

    Consideration is given to how and why categories of ill health are divided into diseases. Aetiology is a fundamental criterion for the delineation of individual diseases. The same clinical and pathological picture may have many different causes; for example meningococcal meningitis and pneumococcal meningitis are distinct diseases that may display the same symptoms and signs. On the other hand, a single aetiology may lead to quite separate clinical and pathological phenomena; for example, neu...

  17. Endocrine Diseases

    Science.gov (United States)

    ... high or too low, you may have an endocrine disease or disorder. Endocrine diseases and disorders also occur if your body does not respond to hormones the way it is supposed to. Featured Topics Adrenal Insufficiency ... Topics Research Discoveries & News Children with Cushing ...

  18. Batten Disease

    Science.gov (United States)

    ... children with Batten disease who were treated with vitamins C and E and with diets low in vitamin A. However, these treatments did not prevent the ... Complications of AIDS Information Page Neurological Complications of Lyme Disease ... Page Neuromyelitis Optica Information Page Neuronal Migration ...

  19. Myocardial disease

    Institute of Scientific and Technical Information of China (English)

    1997-01-01

    970309 Myocardial injury of Keshan disease andapoptosis. ZHONG Xuekuan(钟学宽), et al. KeshanDis Instit, Harbin Med Univ, Harbin, 150086. Chin JEndemiol 1997, 16(2): 81-82. Objective: To discuss the relationship between my-ocardial injury Of Keshan disease and apoptosis. Meth-

  20. Wilson Disease

    Science.gov (United States)

    ... individuals with WD is liver disease, appearing in late childhood or early adolescence as acute hepatitis, liver failure, or progressive chronic ... individuals with WD is liver disease, appearing in late childhood or early adolescence as acute hepatitis, liver failure, or progressive chronic ...

  1. Kidney Disease

    Science.gov (United States)

    ... version of this page please turn Javascript on. Kidney Disease What is Kidney Disease? What the Kidneys Do Click for more information You have two ... damaged, wastes can build up in the body. Kidney Function and Aging Kidney function may be reduced ...

  2. Hartnup disease

    Directory of Open Access Journals (Sweden)

    Jerajani Hemangi

    1994-01-01

    Full Text Available A rare case of Hartnup disease is presented - the patient being an 11 year old school girl suffering from a typically pellagroid rash in the absence of any other signs of malnutrition. No accompanying neurological or psychiatric features are seen, but electro-encephalography revealed abnormal baseline activity. Investigations and management are detailed and the literature on Hartnup disease reviewed.

  3. Disease Lab

    OpenAIRE

    Powell, Jim; Lewis, Matt

    2016-01-01

    Students use transparencies and dry erase markers to simulate the spread of a zombie virus among a fixed population. Students are then challenged to create their own "disease" and develop an ODE model for the resulting data. From this exercise students gain greater understanding of population and SIR models, disease dynamics, parameter estimation and compartment modeling.

  4. Alzheimer's Disease

    Science.gov (United States)

    ... to note that Alzheimer's disease is not a normal part of aging. What Is Alzheimer's Disease? Video length: 2 min 29 sec Click to watch this video The course of Alzheimer’s disease—which symptoms appear and how quickly changes occur—varies from person to person. The time ...

  5. Facioscapulohumeral disease

    NARCIS (Netherlands)

    Padberg, George Waltherus Adrianus Maria

    1982-01-01

    The purpose of this study is to discuss several aspects of facioscapulohumeral disease, also called "autosomal dominant facioscapulohumeral muscular dystrophy" or "Landouzy-Dejerine type of muscular dystrophy" or "Landouzy-Dejerine' s disease" . We consider this disorder well defined and

  6. Whipple Disease

    Science.gov (United States)

    ... more common conditions with similar symptoms, including • inflammatory rheumatic disease— characterized by inflammation and loss of function in ... way to prevent Whipple disease. Eating, Diet, and Nutrition A person with Whipple disease and malabsorption may need • a diet high in ...

  7. Krabbe Disease

    Science.gov (United States)

    ... books/NBK1238/. Accessed Feb. 28, 2014. Krabbe disease. Genetics Home Reference. http://ghr.nlm.nih.gov/condition/krabbe-disease. Accessed Feb, 28. 2014. Ropper AH, et al. Adams & Victor's Principles of Neurology. 9th ed. New York, N.Y.: ...

  8. Periodontal Disease and Systemic Health

    Science.gov (United States)

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

  9. Vascular Disease Foundation

    Science.gov (United States)

    ... Contact Us Vascular Disease What is Vascular Disease? Education and Awareness Vascular Diseases Abdominal Aortic Aneurysm Aortic Dissection Arteriovenous Malformation Atherosclerosis Buerger's Disease Carotid Artery Disease ...

  10. What Is Vascular Disease?

    Science.gov (United States)

    ... Contact Us Vascular Disease What is Vascular Disease? Education and Awareness Vascular Diseases Abdominal Aortic Aneurysm Aortic Dissection Arteriovenous Malformation Atherosclerosis Buerger's Disease Carotid Artery Disease ...

  11. Celiac Disease

    Directory of Open Access Journals (Sweden)

    Manoochehr Karjoo

    2014-08-01

    Full Text Available Celiac disease also known as gluten-sensitive enteropathy is characterized by intestinal mucosal damage and malabsorption from dietary intake of wheat, rye or barley. Symptoms may appear with introduction of cereal in the first 3 years of life. A second peak in symptoms occurs in adults during the third or forth decade and even as late as eight decade of life. The prevalence of this disease is approximately 1 in 250 adults. The disease is more prevalent in Ireland as high as 1 in 120 adults. The disorder occurs in Arab, Hispanics, Israeli Jews, Iranian and European but is rare in Chinese and African American. To have celiac disease the patient should have the celiac disease genetic markers as HLA DQ 2 and HLA DQ 8. Patient with celiac disease may have 95 per cent for DQ 2 and the rest is by DQ 8. Someone may have the genetic marker and never develops the disease. In general 50 percent with markers may develop celiac disease. To develop the disease the gene needs to become activated. This may happen with a viral or bacterial infection, a surgery, delivery, accident, or psychological stress. After activation of gene cause the tight junction to opens with the release of Zonulin This results in passage of gluten through the tight junction and formation of multiple antibodies and autoimmune disease. This also allows entrance of other proteins and development of multiple food allergies. As a result is shortening, flattening of intestinal villi resulting in food, vitamins and minerals malabsorption.

  12. Role of the HTLV-1 viral factors in the induction of apoptosis.

    Science.gov (United States)

    Karimi, Mohammad; Mohammadi, Hamed; Hemmatzadeh, Maryam; Mohammadi, Asadollah; Rafatpanah, Houshang; Baradaran, Behzad

    2017-01-01

    Adult T-cell leukemia (ATL) and HTLV-1-associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP) are the two main diseases that are caused by the HTLV-1 virus. One of the features of HTLV-1 infection is its resistance against programmed cell death, which maintains the survival of cells to oncogenic transformation and underlies the viruses' therapeutic resistance. Two main genes by which the virus develops cancer are Tax and HBZ; playing an essential role in angiogenesis in regulating viral transcription and modulating multiple host factors as well as apoptosis pathways. Here we have reviewed by prior research how the apoptosis pathways are suppressed by the Tax and HBZ and new drugs which have been designed to deal with this suppression.

  13. Pompe's disease.

    Science.gov (United States)

    van der Ploeg, Ans T; Reuser, Arnold J J

    2008-10-11

    Pompe's disease, glycogen-storage disease type II, and acid maltase deficiency are alternative names for the same metabolic disorder. It is a pan-ethnic autosomal recessive trait characterised by acid alpha-glucosidase deficiency leading to lysosomal glycogen storage. Pompe's disease is also regarded as a muscular disorder, but the generalised storage of glycogen causes more than mobility and respiratory problems. The clinical spectrum is continuous and broad. First symptoms can present in infants, children, and adults. Cardiac hypertrophy is a key feature of classic infantile Pompe's disease. For a long time, there was no means to stop disease progression, but the approval of enzyme replacement therapy has substantially changed the prospects for patients. With this new development, the disease is now among the small but increasing number of lysosomal storage disorders, for which treatment has become a reality. This review is meant to raise general awareness, to present and discuss the latest insights in disease pathophysiology, and to draw attention to new developments about diagnosis and care. We also discuss the developments that led to the approval of enzyme replacement therapy with recombinant human alpha-glucosidase from Chinese hamster ovary cells (alglucosidase alfa) by the US Food and Drug Administration and European Medicines Agency in 2006, and review clinical practice.

  14. Refractory disease in autoimmune diseases

    NARCIS (Netherlands)

    Vasconcelos, Carlos; Kallenberg, Cees; Shoenfeld, Yehuda

    2011-01-01

    Refractory disease (RD) definition has different meanings but it is dynamic, according to knowledge and the availability of new drugs. It should be differentiated from severe disease and damage definitions and it must take into account duration of adequate therapy and compliance of the patient. It c

  15. Kummell disease.

    Science.gov (United States)

    Nickell, Larry T; Schucany, William G; Opatowsky, Michael J

    2013-07-01

    Kummell disease, or avascular necrosis of a vertebral body, presents as vertebral osteonecrosis typically affecting a thoracic vertebra with compression deformity, intravertebral vacuum cleft, and exaggerated kyphosis weeks to months after a minor traumatic injury. This rare disease is increasing in prevalence secondary to an aging population and the associated rise in osteoporosis. Treatment with vertebroplasty or surgical decompression and fusion is often required. We present a classic case of Kummell disease to illustrate the salient features of the condition, with associated imaging findings on computed tomography and magnetic resonance imaging.

  16. Crohn's disease.

    LENUS (Irish Health Repository)

    Shanahan, Fergus

    2012-02-03

    Crohn\\'s disease is a disorder mediated by T lymphocytes which arises in genetically susceptible individuals as a result of a breakdown in the regulatory constraints on mucosal immune responses to enteric bacteria. Regulation of immune reactivity to enteric antigens has improved understanding of the pathophysiological mechanisms of Crohn\\'s disease, and has expanded therapeutic options for patients with this disorder. Disease heterogeneity is probable, with various underlying defects associated with a similar pathophysiological outcome. Although most conventional drug treatments are directed at modification of host response, therapeutic manipulation of the enteric flora is becoming a realistic option.

  17. Fahr's Disease

    Directory of Open Access Journals (Sweden)

    Tezcan Caliskan

    2013-06-01

    Full Text Available Fahr's disease refers to sporadic or familial idiopathic basal ganglia, cerebral and cerebellar calcification. Patients may remain symptom-free but approximately two-thirds of the patients are symptomatic. Typical presentation starts in the 4th to 5th decades of life. Patients present with pyramidal, extrapyramidal, cerebellar, psychiatric and cognitive manifestations. Various diagnostic studies can be used to detect Fahr's disease and associated abnormalities. There is no specific treatment other than symptomatic support. In this review, clinical features and different types of presentations of Fahr's disease are discussed under the light of current literature. [J Contemp Med 2013; 3(2.000: 133-135

  18. [Fabry disease].

    Science.gov (United States)

    Boggio, Paula; Luna, Paula Carolina; Abad, María Eugenia; Larralde, Margarita

    2009-01-01

    Fabry disease is an uncommon, X-linked lysosomal storage disorder, caused by partial or complete deficiency of the enzyme a-galactosidase A. The defect leads to accumulation of uncleaved globotriaosylceramide on the vascular endothelium and visceral tissues, being the skin, heart, kidneys and central nervous system the most affected organs. We performed review of the literature related to the disease and emphasized that early recognition of angiokeratomas and hypohidrosis are key diagnostic signs of this serious disease. We also addressed the need of multidisciplinary assessment of these patients.

  19. Morgellons Disease.

    Science.gov (United States)

    Ohn, Jungyoon; Park, Seon Yong; Moon, Jungyoon; Choe, Yun Seon; Kim, Kyu Han

    2017-04-01

    Morgellons disease is a rare disease with unknown etiology. Herein, we report the first case of Morgellons disease in Korea. A 30-year-old woman presented with a 2-month history of pruritic erythematous patches and erosions on the arms, hands, and chin. She insisted that she had fiber-like materials under her skin, which she had observed through a magnifying device. We performed skin biopsy, and observed a fiber extruding from the dermal side of the specimen. Histopathological examination showed only mild lymphocytic infiltration, and failed to reveal evidence of any microorganism. The polymerase chain reaction for Borrelia burgdorferi was negative in her serum.

  20. Stargardt Disease

    Science.gov (United States)

    ... Resources Low Vision Specialists Retinal Physicians My Retina Tracker Registry Genetic Testing Clinical Trials Join the Fight ... of lipofuscin, a fatty byproduct of normal cell activity. In Stargardt disease, lipofuscin accumulates abnormally. The Foundation ...

  1. Pick disease

    Science.gov (United States)

    ... in behavior Failure to show emotional warmth, concern, empathy, sympathy Inappropriate mood Not caring about events or ... and steadily becomes worse. The person becomes totally disabled early in the course of the disease. Pick ...

  2. Vaginal Diseases

    Science.gov (United States)

    Vaginal problems are some of the most common reasons women go to the doctor. They may have ... that affect the vagina include sexually transmitted diseases, vaginal cancer, and vulvar cancer. Treatment of vaginal problems ...

  3. Legionnaires' Disease

    Science.gov (United States)

    Legionnaires' disease is a type of pneumonia caused by bacteria. You usually get it by breathing in mist from water that contains the bacteria. The mist may come from hot tubs, showers, or air-conditioning units for ...

  4. Infectious Diseases

    Science.gov (United States)

    ... people worldwide than any other single cause. Infectious diseases are caused by germs. Germs are tiny living things that are found everywhere - in air, soil and water. You can get infected by touching, eating, drinking ...

  5. Parkinson's Disease

    Science.gov (United States)

    ... sleep behavior disorder, which involves acting out your dreams. Medications may help your sleep problems. Bladder problems. ... will diagnose Parkinson's disease based on your medical history, a review of your signs and symptoms, and ...

  6. Gaucher Disease

    Science.gov (United States)

    ... Translational Research Research at NINDS Focus on Research Alzheimer's & Related Dementias Bioengineering Epilepsy Health Disparities Neural Interfaces Parkinson's Disease Spinal Cord Injury Stem Cells Traumatic Brain Injury Trans-Agency Activities Interagency Research ...

  7. Alexander Disease

    Science.gov (United States)

    ... Translational Research Research at NINDS Focus on Research Alzheimer's & Related Dementias Bioengineering Epilepsy Health Disparities Neural Interfaces Parkinson's Disease Spinal Cord Injury Stem Cells Traumatic Brain Injury Trans-Agency Activities Interagency Research ...

  8. Menkes Disease

    Science.gov (United States)

    ... Translational Research Research at NINDS Focus on Research Alzheimer's & Related Dementias Bioengineering Epilepsy Health Disparities Neural Interfaces Parkinson's Disease Spinal Cord Injury Stem Cells Traumatic Brain Injury Trans-Agency Activities Interagency Research ...

  9. Tickborne Diseases

    Science.gov (United States)

    ... of Award Clinical Terms of Award Restriction for China Clinical Terms Guidance Compliance Sample Letter Inclusion Codes ... Division of AIDS Division of Allergy, Immunology, and Transplantation Division of Microbiology and Infectious Diseases Division of ...

  10. Prion Diseases

    Science.gov (United States)

    ... of Award Clinical Terms of Award Restriction for China Clinical Terms Guidance Compliance Sample Letter Inclusion Codes ... Division of AIDS Division of Allergy, Immunology, and Transplantation Division of Microbiology and Infectious Diseases Division of ...

  11. [Prion diseases].

    Science.gov (United States)

    Zarranz, J J

    2006-10-01

    Prion diseases are one of the paradigms of modern neurological nosology founded on molecular grounds. Their incidence is low, however the public health challenges derived from their transmissibility, especially due to the appearance of a variant of Creutzfeldt-Jakob disease (vCJD) confers them a preferential place among health care authority concerns. The evolution of data from the European surveillance systems suggests a generalized underdiagnosis of prion diseases and casts doubts about their ability to detect a possible second wave of atypical vCJD, especially if their clinical-pathological characteristics change. Recent data also challenge the feasibility of a subclassification of prion diseases according to their genetic-molecular features

  12. Celiac Disease

    Science.gov (United States)

    ... gluten and to certain other proteins in the intestinal lining — a sign that the person could have celiac disease — then the doctor may order a biopsy of the small intestine to confirm the diagnosis. In the case of ...

  13. Autoinflammatory Diseases

    Science.gov (United States)

    ... disease. Colchicine – a medication also approved to treat gout (a form of arthritis) – has been used successfully as a treatment for FMF. Colchicine reduces inflammation throughout the body. ...

  14. Behcet's disease.

    Science.gov (United States)

    Nair, Jagdish R; Moots, Robert J

    2017-02-01

    Behçet's disease (BD) is a chronic relapsing and remitting vasculitis of unknown aetiology. It has the capacity to affect almost all organ systems because of its potential to involve both arteries and veins of all sizes, resulting in significant organ-threatening morbidity and mortality. Traditionally known as the 'silk road' disease, it has a worldwide occurrence. The aetiopathological mechanisms of disease development in BD remain poorly understood, but genome wide studies show human leukocyte antigen and non-human leukocyte antigen associations. Environmental influences and genetic factors may have a role in the aetiopathogenetic mechanisms that lead to development of the disease, indicating the autoimmune and auto-inflammatory nature of BD. The evidence base for treatment is limited but new knowledge is emerging and current treatment options range from symptomatic treatment, through to non-biological and biological immunosuppressive drugs, to cover the spectrum of clinical manifestations.

  15. Parkinson disease

    Science.gov (United States)

    ... control movement. Surgery to destroy brain tissue that causes Parkinson symptoms. Stem cell transplant and other procedures are ... in brain function and early death. Possible Complications Parkinson disease may cause problems such as: Difficulty performing daily activities Difficulty ...

  16. Heart Disease

    Science.gov (United States)

    ... Atherosclerosis is also the most common cause of cardiovascular disease. It can be caused by correctable problems, such as an unhealthy diet, lack of exercise, being overweight and smoking. Causes of heart arrhythmia ...

  17. Lyme Disease

    Science.gov (United States)

    ... can also spread to the nervous system, causing facial paralysis ( Bell_s_palsy ), or meningitis. The last stage of ... symptoms, joint pain or a swollen joint, or facial paralysis. Can I Prevent Lyme Disease? There's no surefire ...

  18. Endocrine Diseases

    Science.gov (United States)

    Your endocrine system includes eight major glands throughout your body. These glands make hormones. Hormones are chemical messengers. They ... levels. In the United States, the most common endocrine disease is diabetes. There are many others. They ...

  19. Hashimoto's Disease

    Science.gov (United States)

    ... use a combination of x rays and computer technology to create images. For a CT scan, a ... than men. Although the disease often occurs in adolescent or young women, it more commonly appears between ...

  20. Gum Disease

    Science.gov (United States)

    ... away from the teeth. This is known as periodontitis (pronounced: pair-ee-oh-don-TY-tus), a more advanced form of gum disease. With periodontitis, gums become weakened and form pockets around the ...

  1. Planning Diseases.

    Science.gov (United States)

    Gabel, Medard

    1984-01-01

    To solve societal problems, both local and global, a global approach is needed. Serious diseases that are crippling present-day problem solving and planning are discussed, and the characteristics of a healthy, effective planning approach are described. (RM)

  2. [Lyme disease].

    Science.gov (United States)

    Portillo, Aránzazu; Santibáñez, Sonia; Oteo, José A

    2014-02-01

    Lyme disease (LD) is a worldwide-distributed multisystemic process caused by Borrelia burgdorferi sensu lato (s.l.) and transmitted by hard ticks. In fact, it is the most common tick-borne infectious disease in the northern hemisphere. In Spain it is transmitted by Ixodes ricinus ticks and Borrelia garinii is the genoespecies of B. burgdorferi s.l. mostly involved in our area. LD is known as "the last great imitator" due to the broad clinical spectrum that may cause. Except in the case of erythema migrans (pathognomonic feature of the disease), the remaining clinical manifestations should be confirmed using microbiological tests. This review is intended to provide readers a current vision of the etiology, epidemiology, clinical manifestations, laboratory diagnosis and treatment of Lyme disease in our environment. Controversial aspects arising from the use of non-validated microbiological tests that are being used without scientific rigor are highlighted.

  3. The PPAR-γ Agonist 15-Deoxy-Δ12,14-Prostaglandin J2 Attenuates Microglial Production of IL-12 Family Cytokines: Potential Relevance to Alzheimer's Disease

    Directory of Open Access Journals (Sweden)

    Jihong Xu

    2008-01-01

    Full Text Available Accumulation of amyloid-β peptide (Aβ appears to contribute to the pathogenesis of Alzheimer's disease (AD. Therapeutic hope for the prevention or removal of Aβ deposits has been placed in strategies involving immunization against the Aβ peptide. Initial Aβ immunization studies in animal models of AD showed great promise. However, when this strategy was attempted in human subjects with AD, an unacceptable degree of meningoencephalitis occurred. It is generally believed that this adverse outcome resulted from a T-cell response to Aβ. Specifically, CD4+ Th1 and Th17 cells may contribute to severe CNS inflammation and limit the utility of Aβ immunization in the treatment of AD. Interleukin (IL-12 and IL-23 play critical roles in the development of Th1 and Th17 cells, respectively. In the present study, Aβ1−42 synergistically elevated the expression of IL-12 and IL-23 triggered by inflammatory activation of microglia, and the peroxisome proliferator-activated receptor (PPAR-γ agonist 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2 effectively blocked the elevation of these proinflammatory cytokines. Furthermore, 15d-PGJ2 suppressed the Aβ-related synergistic induction of CD14, MyD88, and Toll-like receptor 2, molecules that play critical roles in neuroinflammatory conditions. Collectively, these studies suggest that PPAR-γ agonists may be effective in modulating the development of AD.

  4. Neuroimmunological processes in Parkinson's disease and their relation to α-synuclein: microglia as the referee between neuronal processes and peripheral immunity

    Directory of Open Access Journals (Sweden)

    Marina Romero‑Ramos

    2013-04-01

    Full Text Available The role of neuroinflammation and the adaptive immune system in PD (Parkinson's disease has been the subject of intense investigation in recent years, both in animal models of parkinsonism and in post-mortem PD brains. However, how these processes relate to and modulate α-syn (α-synuclein pathology and microglia activation is still poorly understood. Specifically, how the peripheral immune system interacts, regulates and/or is induced by neuroinflammatory processes taking place during PD is still undetermined. We present herein a comprehensive review of the features and impact that neuroinflamation has on neurodegeneration in different animal models of nigral cell death, how this neuroinflammation relates to microglia activation and the way microglia respond to α-syn in vivo. We also discuss a possible role for the peripheral immune system in animal models of parkinsonism, how these findings relate to the state of microglia activation observed in these animal models and how these findings compare with what has been observed in humans with PD. Together, the available data points to the need for development of dual therapeutic strategies that modulate microglia activation to change not only the way microglia interact with the peripheral immune system, but also to modulate the manner in which microglia respond to encounters with α-syn. Lastly, we discuss the immune-modulatory strategies currently under investigation in animal models of parkinsonism and the degree to which one might expect their outcomes to translate faithfully to a clinical setting.

  5. Neuroimmunological Processes in Parkinson's Disease and their Relation to α-Synuclein: Microglia as the Referee between Neuronal Processes and Peripheral Immunity

    Directory of Open Access Journals (Sweden)

    Vanesa Sanchez-Guajardo

    2013-03-01

    Full Text Available The role of neuroinflammation and the adaptive immune system in PD (Parkinson's disease has been the subject of intense investigation in recent years, both in animal models of parkinsonism and in post-mortem PD brains. However, how these processes relate to and modulate α-syn (α-synuclein pathology and microglia activation is still poorly understood. Specifically, how the peripheral immune system interacts, regulates and/or is induced by neuroinflammatory processes taking place during PD is still undetermined. We present herein a comprehensive review of the features and impact that neuroinflamation has on neurodegeneration in different animal models of nigral cell death, how this neuroinflammation relates to microglia activation and the way microglia respond to α-syn in vivo. We also discuss a possible role for the peripheral immune system in animal models of parkinsonism, how these findings relate to the state of microglia activation observed in these animal models and how these findings compare with what has been observed in humans with PD. Together, the available data points to the need for development of dual therapeutic strategies that modulate microglia activation to change not only the way microglia interact with the peripheral immune system, but also to modulate the manner in which microglia respond to encounters with α-syn. Lastly, we discuss the immune-modulatory strategies currently under investigation in animal models of parkinsonism and the degree to which one might expect their outcomes to translate faithfully to a clinical setting.

  6. Neuroimmunological processes in Parkinson's disease and their relation to α-synuclein: microglia as the referee between neuronal processes and peripheral immunity.

    Science.gov (United States)

    Sanchez-Guajardo, Vanesa; Barnum, Christopher J; Tansey, Malú G; Romero-Ramos, Marina

    2013-04-30

    The role of neuroinflammation and the adaptive immune system in PD (Parkinson's disease) has been the subject of intense investigation in recent years, both in animal models of parkinsonism and in post-mortem PD brains. However, how these processes relate to and modulate α-syn (α-synuclein) pathology and microglia activation is still poorly understood. Specifically, how the peripheral immune system interacts, regulates and/or is induced by neuroinflammatory processes taking place during PD is still undetermined. We present herein a comprehensive review of the features and impact that neuroinflamation has on neurodegeneration in different animal models of nigral cell death, how this neuroinflammation relates to microglia activation and the way microglia respond to α-syn in vivo. We also discuss a possible role for the peripheral immune system in animal models of parkinsonism, how these findings relate to the state of microglia activation observed in these animal models and how these findings compare with what has been observed in humans with PD. Together, the available data points to the need for development of dual therapeutic strategies that modulate microglia activation to change not only the way microglia interact with the peripheral immune system, but also to modulate the manner in which microglia respond to encounters with α-syn. Lastly, we discuss the immune-modulatory strategies currently under investigation in animal models of parkinsonism and the degree to which one might expect their outcomes to translate faithfully to a clinical setting.

  7. Extrapyramidal disease

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008119 Therapeutic effect of neuropeptide PACAP27 on Parkinson′s disease in mice. WANG Gang(王刚), et al.Dept Neurol & Neurol Instit, Ruijin Hosp, Shanghai Jiaotong Univ, Med Sch, Shanghai 200025. Chin J Neurol 2007;40(12):837-841. Objective To investigate the effects of different doses of pituitary adenylate cyclase-activating polypeptide (PACAP) on the functional and morphological outcome in a mice model of Parkinson′s disease (PD) re

  8. Muscular disease

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    930186 The diagnostic value of MRI on neuro-muscular disease.CHEN Qingtang(陈清棠),etal.Dept Neurol,1st Hosp,Beijing Med Univ,100034.Chin J Neurol & Psychiat 1992;25(5):267-269.The article concentrated on the study ofskeletal muscles of four extremities in 12 casesof different kinds of neuromuscular diseases and4 volunteers with MRI.The results revealed:MRI could clearly display individual muscle,muscle groups or abnormal muscles morphologi-

  9. [Ledderhose's disease].

    Science.gov (United States)

    Bardelli, M; D'Arienzo, M; Veneziani, C

    1991-01-01

    The authors describe the clinical appearance of Ledderhose disease and emphasize the association with Dupuytren disease. They report on a series of patients treated at the 2nd Orthopedic Unit of University of Florence and describe the operating technique used. They believe that the procedure of removal of nodules must always be performed in association with careful exeresis of normal tissue, employing total aponeurectomy only in revision surgery.

  10. Bowel disease

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008069 The application of Montreal classification in inflammatory bowel disease. YANG Chuanhua(杨川华), et al. Renji Hosp, Shanghai Instit, Shanghai Jiaotong Univ Med Coll, Shanghai 200001. Chin J Intern Med 2008;47(1):7-10. Objective To investigate the clinical features of Crohn′s disease (CD) and ulcerative colitis (UC) according to the Montreal classification. Methods The clinical data of 110 cases of CD or UC were reviewed. The age at

  11. Extrapyramidal disease

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    2008486 Neuropsychiatric problems in patients with Parkinson’s disease. ZHOU Mingzhu(周明珠), et al. Dept Neurol, Xinhua Hosp Shanghai Jiaotong Univ, Sch Med, Shanghai 200092.Natl Med J China 2008;88(21):1442-1445. Objective To survey the prevalence and distribution of neuropsychiatric problems in patients with Parkinson’s disease (PD), and to investigate their effects on life quality and the interactions among different neuropsychiatric problems.

  12. Huntington's disease

    OpenAIRE

    Bates, G P; Dorsey, R.; Gusella, J F; Hayden, M. R.; Kay, C; Leavitt, B. R.; Nance, M; Ross, C A; Scahill, R. I.; Wetzel, R.; Wild, E. J.; Tabrizi, S.J.

    2015-01-01

    Huntington’s disease is devastating to patients and their families — with autosomal dominant inheritance, onset typically in the prime of adult life, progressive course and combination of motor, cognitive and behavioural features. The disease is caused by an expanded CAG trinucleotide repeat (of variable length) in HTT, the gene which encodes the protein huntingtin. In mutation carriers, huntingtin is produced with abnormally long polyglutamine sequences that confers toxic gains of function a...

  13. [Kawasaki's disease].

    Science.gov (United States)

    Cortes, J; Martínez, B; Montini, C; Barraza, P; Reyes, A

    1989-08-01

    We described a case of Kawasaki's disease in a chilean girl, one year and 5 months old of age, who presented the oral characteristics, cutaneous and systemic manifestation of the condition, that is not very common for the dentist but that it is necessary to know due to the heart complications and the mortality associated with the disease, and it is necessary that the dentist recognize early this condition.

  14. HIRAYAMA DISEASE

    Directory of Open Access Journals (Sweden)

    Shaik Sulaiman

    2016-05-01

    Full Text Available Hirayama’s disease, also known as Monomelic Amyotrophy (MMA, juvenile non-progressive amyotrophy, Sobue disease. It is rare and benign condition. It is a focal, lower motor neuron type of disorder, which occurs mainly in young males. Age of onset, it is first seen most commonly in people in their second and third decades. Geographically, it is seen most commonly in Asian countries like India and Japan. Cause of this disease is unknown in most cases. MRI of cervical spine in flexion is the investigation of choice, which will reveal the cardinal features of Hirayama disease. CASE REPORT 20 years old male came with the complaints of tremors of both hands more of right hand and weakness and wasting of right hand, which is slowly progressive for past 6 months. Lower limbs had no abnormality with normal deep tendon reflexes. On examination, there was wasting and weakness of hypothenar and interosseous muscles of right hand. MRI showed thinning of cord from C5 to C7 level. Proximal epidural fat and tiny flow voids with anterior migration of the posterior dural layer at C5-7 level on flexion MRI. Based on these features a diagnosis of focal amyotrophy was made. A cervical collar was prescribed and patient is under regular follow-up. CONCLUSION Hirayama disease is a rare self-limiting disease. Early diagnosis is necessary as the use of a simple cervical collar which will prevent neck flexion, has been shown to stop the progression.

  15. LTR point mutations in the Tax-responsive elements of HTLV-1 isolates from HIV/HTLV-1-coinfected patients

    Directory of Open Access Journals (Sweden)

    Magri Mariana

    2012-09-01

    Full Text Available Abstract Background In Virology Journal 2011, 8:535, Neto et al. described point mutations into Tax-responsive elements (TRE of the LTR region of HTLV-1 isolates from asymptomatic carriers from Sao Paulo, Brazil, and hypothesized that the presence of the G232A mutation in the TRE-1 increase viral proliferation and consequently the proviral load (PvL, while the A184G mutation in the TRE-2 do not have such effect. Findings We performed the real-time PCR assay (pol and sequenced LTR region of HTLV-1 isolates from 24 HIV/HTLV-1-coinfected patients without HTLV-1-associated diseases from the same geographic area. These sequences were classified as belonging to the transcontinental subgroup A of the Cosmopolitan subtype a. The frequency of G232A mutation (16/24, 66.7% was high as much as 61.8% reported by Neto’s in HTLV-1 asymptomatic carriers with high PvL. High frequency (13/24, 54.2% of double mutations G232A and A184G was also detected in HIV/HTLV-1-coinfected patients. We did not quantify PvL, but comparative analyses of the cycle threshold (Ct median values of the group of isolates presenting the mutated-types sequences (Ct 33.5, n = 16 versus the group of isolates with the wild-type sequences (Ct 32, n = 8 showed no statistical difference (p = 0.4220. Conclusion The frequencies of mutated-type sequences in the TRE-1 and TRE-2 motifs were high in HIV/HTLV-1-coinfected patients from Sao Paulo, Brazil. If these LTR point mutations have predictive value for the development of HTLV-1-associated diseases or they correspond to the subtype of virus that circulate in this geographic area has to be determined.

  16. Altered Neuroinflammation and Behavior after Traumatic Brain Injury in a Mouse Model of Alzheimer's Disease.

    Science.gov (United States)

    Kokiko-Cochran, Olga; Ransohoff, Lena; Veenstra, Mike; Lee, Sungho; Saber, Maha; Sikora, Matt; Teknipp, Ryan; Xu, Guixiang; Bemiller, Shane; Wilson, Gina; Crish, Samuel; Bhaskar, Kiran; Lee, Yu-Shang; Ransohoff, Richard M; Lamb, Bruce T

    2016-04-01

    Traumatic brain injury (TBI) has acute and chronic sequelae, including an increased risk for the development of Alzheimer's disease (AD). TBI-associated neuroinflammation is characterized by activation of brain-resident microglia and infiltration of monocytes; however, recent studies have implicated beta-amyloid as a major manipulator of the inflammatory response. To examine neuroinflammation after TBI and development of AD-like features, these studies examined the effects of TBI in the presence and absence of beta-amyloid. The R1.40 mouse model of cerebral amyloidosis was used, with a focus on time points well before robust AD pathologies. Unexpectedly, in R1.40 mice, the acute neuroinflammatory response to TBI was strikingly muted, with reduced numbers of CNS myeloid cells acquiring a macrophage phenotype and decreased expression of inflammatory cytokines. At chronic time points, macrophage activation substantially declined in non-Tg TBI mice; however, it was relatively unchanged in R1.40 TBI mice. The persistent inflammatory response coincided with significant tissue loss between 3 and 120 days post-injury in R1.40 TBI mice, which was not observed in non-Tg TBI mice. Surprisingly, inflammatory cytokine expression was enhanced in R1.40 mice compared with non-Tg mice, regardless of injury group. Although R1.40 TBI mice demonstrated task-specific deficits in cognition, overall functional recovery was similar to non-Tg TBI mice. These findings suggest that accumulating beta-amyloid leads to an altered post-injury macrophage response at acute and chronic time points. Together, these studies emphasize the role of post-injury neuroinflammation in regulating long-term sequelae after TBI and also support recent studies implicating beta-amyloid as an immunomodulator.

  17. Possible therapeutic uses of Salvia triloba and Piper nigrum in Alzheimer's disease-induced rats.

    Science.gov (United States)

    Ahmed, Hanaa H; Salem, Ahmed M; Sabry, Gilane M; Husein, Ahmed A; Kotob, Soheir E

    2013-05-01

    This study aimed to investigate the role of Salvia triloba L. and Piper nigrum extracts in ameliorating neuroinflammatory insults characteristic of Alzheimer's disease (AD) in an experimentally induced rat model. Adult male Sprague-Dawley rats were classified into Group 1 (n=10): normal healthy animals serving as the negative control group; Group 2 (n=60): the AD-induced group. After AD induction, animals in the AD-induced group were divided randomly and equally into 6 subgroups. The first subgroup served as AD control; the second one, which served as positive control, was treated orally with the conventional therapy for AD (rivastigmine) at a dose of 0.3 mg/kg body weight (b.w.) daily for 3 months. The third and fourth subgroups were, respectively, treated orally with the S. triloba extract at a dose of 750 and 375 mg/kg b.w. daily for 3 months. The fifth and sixth subgroups were, respectively, treated orally with the P. nigrum extract at a dose of 187.5 and 93.75 mg/kg b.w. daily for 3 months. Levels of brain acetylcholine (Ach), serum and brain acetylcholinesterase (AchE) activity, C-reactive protein (CRP), total nuclear factor kappa-B (NF-κB), and monocyte chemoattractant protein-1 (MCP-1) were estimated. The results showed that administration of AlCl3 resulted in a significant elevation in the levels of AchE activity, CRP, NF-κB, and MCP-1 accompanied with a significant depletion in the Ach level. Treatment of AD rats with each of the selected medicinal plant extracts caused marked improvement in the measured biochemical parameters. In conclusion, S. triloba and P. nigrum methanolic extracts have potent anti-inflammatory effects against neuroinflammation characterizing AD.

  18. Deciphering the molecular profile of plaques, memory decline and neuron loss in two mouse models for Alzheimer's disease by deep sequencing.

    Science.gov (United States)

    Bouter, Yvonne; Kacprowski, Tim; Weissmann, Robert; Dietrich, Katharina; Borgers, Henning; Brauß, Andreas; Sperling, Christian; Wirths, Oliver; Albrecht, Mario; Jensen, Lars R; Kuss, Andreas W; Bayer, Thomas A

    2014-01-01

    One of the central research questions on the etiology of Alzheimer's disease (AD) is the elucidation of the molecular signatures triggered by the amyloid cascade of pathological events. Next-generation sequencing allows the identification of genes involved in disease processes in an unbiased manner. We have combined this technique with the analysis of two AD mouse models: (1) The 5XFAD model develops early plaque formation, intraneuronal Aβ aggregation, neuron loss, and behavioral deficits. (2) The Tg4-42 model expresses N-truncated Aβ4-42 and develops neuron loss and behavioral deficits albeit without plaque formation. Our results show that learning and memory deficits in the Morris water maze and fear conditioning tasks in Tg4-42 mice at 12 months of age are similar to the deficits in 5XFAD animals. This suggested that comparative gene expression analysis between the models would allow the dissection of plaque-related and -unrelated disease relevant factors. Using deep sequencing differentially expressed genes (DEGs) were identified and subsequently verified by quantitative PCR. Nineteen DEGs were identified in pre-symptomatic young 5XFAD mice, and none in young Tg4-42 mice. In the aged cohort, 131 DEGs were found in 5XFAD and 56 DEGs in Tg4-42 mice. Many of the DEGs specific to the 5XFAD model belong to neuroinflammatory processes typically associated with plaques. Interestingly, 36 DEGs were identified in both mouse models indicating common disease pathways associated with behavioral deficits and neuron loss.

  19. Learning about Crohn's Disease

    Science.gov (United States)

    ... genetic terms used on this page. Learning About Crohn's Disease What is Crohn's disease? What are the symptoms ... disease Additional Resources for Crohn's Disease What is Crohn's disease? Crohn's disease, an idiopathic (of unknown cause), chronic ...

  20. HIV and Rheumatic Disease

    Science.gov (United States)

    ... A Patient / Caregiver Diseases & Conditions HIV & Rheumatic Diseases HIV and Rheumatic Disease Fast Facts Rheumatic diseases related ... knows he or she has HIV. What are HIV-associated rheumatic diseases? Some diseases of the joints ...

  1. HIV and Rheumatic Disease

    Science.gov (United States)

    ... A Patient / Caregiver Diseases & Conditions HIV & Rheumatic Diseases HIV and Rheumatic Disease Fast Facts Rheumatic diseases related ... knows he or she has HIV. What are HIV-associated rheumatic diseases? Some diseases of the joints ...

  2. Niemann-Pick Disease

    Science.gov (United States)

    ... Disease] National Niemann-Pick Disease Foundation, Inc. National Tay-Sachs and Allied Diseases Association See all related ... Disease] National Niemann-Pick Disease Foundation, Inc. National Tay-Sachs and Allied Diseases Association See all related ...

  3. Interleukin-1beta and TNF-alpha: reliable targets for protective therapies in Parkinson´s Disease?

    Directory of Open Access Journals (Sweden)

    María Celeste Leal

    2013-04-01

    Full Text Available Neuroinflammation has received increased attention as a target for putative neuroprotective therapies in Parkinson´s Disease (PD. Two prototypic pro-inflammatory cytokines Interleukin-1beta (IL-1 and Tumor necrosis factor-alpha (TNF have been implicated as main effectors of the functional consequences of neuroinflammation on neurodegeneration in PD models. In this review, we describe that the functional interaction between these cytokines in the brain differs from the periphery (e.g. their expression is not induced by each other and present data showing predominantly a toxic effect of these cytokines when expressed at high doses and for a sustained period of time in the substantia nigra pars compacta (SN. In addition, we highlight opposite evidence showing protective effects of these two main cytokines when conditions of duration, amount of expression or state of activation of the target or neighboring cells are changed. Furthermore, we discuss these results in the frame of previous disappointing results from anti-TNF clinical trials against Multiple Sclerosis, another neurodegenerative disease with a clear neuroinflammatory component. In conclusion, we hypothesize that the available evidence suggests that the duration and dose of IL-1 or TNF expression is crucial to predict their functional effect on the SN. Since these parameters are not amenable for measurement in the SN of PD patients, we call for an in-depth analysis to identify downstream mediators that could be common to the toxic (and not the protective effects of these cytokines in the SN. This strategy could spare the possible neuroprotective effect of these cytokines operative in the patient at the time of treatment, increasing the probability of efficacy in a clinical setting. Alternatively, receptor-specific agonists or antagonists could also provide a way to circumvent undesired effects of general anti-inflammatory or specific anti IL-1 or TNF therapies against PD.

  4. Pentraxin-3 is upregulated in the central nervous system during MS and EAE, but does not modulate experimental neurological disease.

    Science.gov (United States)

    Ummenthum, Kimberley; Peferoen, Laura A N; Finardi, Annamaria; Baker, David; Pryce, Gareth; Mantovani, Alberto; Bsibsi, Malika; Bottazzi, Barbara; Peferoen-Baert, Regina; van der Valk, Paul; Garlanda, Cecilia; Kipp, Markus; Furlan, Roberto; van Noort, Johannes M; Amor, Sandra

    2016-03-01

    Pentraxin-3 (PTX3), an acute-phase protein released during inflammation, aids phagocytic clearance of pathogens and apoptotic cells, and plays diverse immunoregulatory roles in tissue injury. In neuroinflammatory diseases, like MS, resident microglia could become activated by endogenous agonists for Toll like receptors (TLRs). Previously we showed a strong TLR2-mediated induction of PTX3 in cultured human microglia and macrophages by HspB5, which accumulates in glia during MS. Given the anti-inflammatory effects of HspB5, we examined the contribution of PTX3 to these effects in MS and its animal model EAE. Our data indicate that TLR engagement effectively induces PTX3 expression in human microglia, and that such expression is readily detectable in MS lesions. Enhanced PTX3 expression is prominently expressed in microglia in preactive MS lesions, and in microglia/macrophages engaged in myelin phagocytosis in actively demyelinating lesions. Yet, we did not detect PTX3 in cerebrospinal fluid of MS patients. PTX3 expression is also elevated in spinal cords during chronic relapsing EAE in Biozzi ABH mice, but the EAE severity and time course in PTX3-deficient mice did not differ from WT mice. Moreover, systemic PTX3 administration did not alter the disease onset or severity. Our findings reveal local functions of PTX3 during neuroinflammation in facilitating myelin phagocytosis, but do not point to a role for PTX3 in controlling the development of autoimmune neuroinflammation. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. [Dupuytren disease].

    Science.gov (United States)

    Wagner, Pablo; Román, Javier A; Vergara, Jorge

    2012-09-01

    Dupuytren disease (DD) is a connective tissue disorder that consists in fibromatosis of the palmar and digital fascia (in form of nodules or flanges) that leads to the development of flexion contractures of the palm and fingers. The little and ring finger are particularly affected. The disease can limit hand function, reducing the quality of life. The disease can have a traumatic origin and is also associated with conditions such as diabetes mellitus, alcoholism, dyslipidemia, epilepsy and AIDS, among others. However, none of these conditions can fully explain the genesis of DD. A hereditary component is described in 40% of patients and is attributed to an autosomal dominant gene of variable penetrance, probably related to collagen synthesis. However there are also spontaneous and recessive inheritance cases. The diagnosis is clinical and based on physical examination. Treatment ranges from observation or use of injectable collagenase to the surgical option in cases with significant functional limitations.

  6. Celiac disease

    DEFF Research Database (Denmark)

    Hvas, Christian Lodberg; Jensen, Michael Dam; Reimer, Maria Christina;

    2015-01-01

    , which are found in wheat, rye, and barley. The disease prevalence is 0.5-1.0%, but CD remains under-diagnosed. The diagnosis relies on the demonstration of lymphocyte infiltration, crypt hyperplasia, and villous atrophy in duodenal biopsies. Serology, malabsorption, biochemical markers......This national clinical guideline approved by the Danish Society for Gastroenterology and Hepatology describes the diagnosis and treatment of celiac disease (CD) in adults. CD is a chronic immunemediated enteropathy of the small intestine triggered by the ingestion of gluten-containing proteins...... the small intestinal mucosa and absorption. Adherence to a GFD usually requires dietary advice from a clinical dietician. The monitoring of antibody levels and malabsorption markers is crucial during follow-up and allows for early treatment of disease complications. Important complications include...

  7. Myocardial disease

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    930497 Ectopic expression and the significanceof HLA—class II antigens in the myocardium ofpatients with dilated cardiomyopathy.LI Yunyou(李运友),et al.lst Affili Hosp,Nanjing MedCoil,Nanjing,210029.Chin J Cardiol 1993;21(1):15—16.Expression of HLA—class II antigens(DQ,DP)in the myocardium of patients with differentheart diseases and normal controls was studiedwith indirect immunofluorescence(IIF).Thepositive rates in different groups were observedas follows:dilated cardiomyopathy(DCM,12/13,+++),rheumatic heart disease(2/4,++),congenital heart diseases(1/14,+),left a-trial myxoma(0/1)and normal controls(1/8,

  8. Celiac disease

    DEFF Research Database (Denmark)

    Hvas, Christian Lodberg; Jensen, Michael Dam; Reimer, Maria Christina

    2015-01-01

    This national clinical guideline approved by the Danish Society for Gastroenterology and Hepatology describes the diagnosis and treatment of celiac disease (CD) in adults. CD is a chronic immunemediated enteropathy of the small intestine triggered by the ingestion of gluten-containing proteins......, which are found in wheat, rye, and barley. The disease prevalence is 0.5-1.0%, but CD remains under-diagnosed. The diagnosis relies on the demonstration of lymphocyte infiltration, crypt hyperplasia, and villous atrophy in duodenal biopsies. Serology, malabsorption, biochemical markers...... the small intestinal mucosa and absorption. Adherence to a GFD usually requires dietary advice from a clinical dietician. The monitoring of antibody levels and malabsorption markers is crucial during follow-up and allows for early treatment of disease complications. Important complications include...

  9. Dent's disease

    Directory of Open Access Journals (Sweden)

    Thakker Rajesh V

    2010-10-01

    Full Text Available Abstract Dent's disease is a renal tubular disorder characterized by manifestations of proximal tubule dysfunction, including low-molecular-weight proteinuria, hypercalciuria, nephrolithiasis, nephrocalcinosis, and progressive renal failure. These features are generally found in males only, and may be present in early childhood, whereas female carriers may show a milder phenotype. Prevalence is unknown; the disorder has been reported in around 250 families to date. Complications such as rickets or osteomalacia may occur. The disease is caused by mutations in either the CLCN5 (Dent disease 1 or OCRL1 (Dent disease 2 genes that are located on chromosome Xp11.22 and Xq25, respectively. CLCN5 encodes the electrogenic Cl-/H+ exchanger ClC-5, which belongs to the CLC family of Cl- channels/transporters. OCRL1 encodes a phosphatidylinositol bisphosphate (PIP2 5-phosphatase and mutations are also associated with Lowe Syndrome. The phenotype of Dent's disease is explained by the predominant expression of ClC-5 in the proximal tubule segments of the kidney. No genotype-phenotype correlation has been described thus far, and there is considerable intra-familial variability in disease severity. A few patients with Dent's disease do not harbour mutations in CLCN5 and OCRL1, pointing to the involvement of other genes. Diagnosis is based on the presence of all three of the following criteria: low-molecular-weight proteinuria, hypercalciuria and at least one of the following: nephrocalcinosis, kidney stones, hematuria, hypophosphatemia or renal insufficiency. Molecular genetic testing confirms the diagnosis. The differential diagnosis includes other causes of generalized dysfunction of the proximal tubules (renal Fanconi syndrome, hereditary, acquired, or caused by exogenous substances. Antenatal diagnosis and pre-implantation genetic testing is not advised. The care of patients with Dent's disease is supportive, focusing on the treatment of hypercalciuria and

  10. Celiac disease

    DEFF Research Database (Denmark)

    Hvas, Christian Lodberg; Jensen, Michael Dam; Reimer, Maria Christina;

    2015-01-01

    the small intestinal mucosa and absorption. Adherence to a GFD usually requires dietary advice from a clinical dietician. The monitoring of antibody levels and malabsorption markers is crucial during follow-up and allows for early treatment of disease complications. Important complications include......This national clinical guideline approved by the Danish Society for Gastroenterology and Hepatology describes the diagnosis and treatment of celiac disease (CD) in adults. CD is a chronic immunemediated enteropathy of the small intestine triggered by the ingestion of gluten-containing proteins...

  11. Hansen's disease: a vanishing disease?

    Directory of Open Access Journals (Sweden)

    Sinésio Talhari

    2012-12-01

    Full Text Available The introduction, implementation, successes and failures of multidrug therapy (MDT in all Hansen's disease endemic countries are discussed in this paper. The high efficacy of leprosy treatment with MDT and the global reduction of prevalence led the World Health Organization, in 1991, to establish the goal of elimination of Hansen's disease (less than 1 patient per 10,000 inhabitants to be accomplished by the year 2000. Brazil, Nepal and East Timor are among the few countries that didn't reach the elimination goal by the year 2000 or even 2005. The implications of these aspects are highlighted in this paper. Current data from endemic and previously endemic countries that carry a regular leprosy control programme show that the important fall in prevalence was not followed by the reduction of the incidence. This means that transmission of Mycobacterium leprae is still an issue. It is reasonable to conclude that we are still far from the most important goal of Hansen's disease control: the interruption of transmission and reduction of incidence. It is necessary to emphasize to health managers the need of keeping Hansen's disease control activities to better develop control programmes in the future. The recent international proposal to interrupt the transmission of leprosy by the year 2020 seems to unrealistic and it is discussed in this paper. The possibility of epidemiological impact related to the human immunodeficiency virus/Hansen's disease coinfection is also considered.

  12. Hansen's disease: a vanishing disease?

    Science.gov (United States)

    Talhari, Sinésio; Grossi, Maria Aparecida de Faria; Oliveira, Maria Leide W D R de; Gontijo, Bernardo; Talhari, Carolina; Penna, Gerson Oliveira

    2012-12-01

    The introduction, implementation, successes and failures of multidrug therapy (MDT) in all Hansen's disease endemic countries are discussed in this paper. The high efficacy of leprosy treatment with MDT and the global reduction of prevalence led the World Health Organization, in 1991, to establish the goal of elimination of Hansen's disease (less than 1 patient per 10,000 inhabitants) to be accomplished by the year 2000. Brazil, Nepal and East Timor are among the few countries that didn't reach the elimination goal by the year 2000 or even 2005. The implications of these aspects are highlighted in this paper. Current data from endemic and previously endemic countries that carry a regular leprosy control programme show that the important fall in prevalence was not followed by the reduction of the incidence. This means that transmission of Mycobacterium leprae is still an issue. It is reasonable to conclude that we are still far from the most important goal of Hansen's disease control: the interruption of transmission and reduction of incidence. It is necessary to emphasize to health managers the need of keeping Hansen's disease control activities to better develop control programmes in the future. The recent international proposal to interrupt the transmission of leprosy by the year 2020 seems to unrealistic and it is discussed in this paper. The possibility of epidemiological impact related to the human immunodeficiency virus/Hansen's disease coinfection is also considered.

  13. Myocardial disease

    Institute of Scientific and Technical Information of China (English)

    1992-01-01

    920666 Immunocytochemical study ofCuZn superoxide dismutase in the myocardi-um of normal subjects and patients ofrheumatic heart disease.ZHENG Yi(郑毅),et al. Dept Intern Med, Navy General Hosp,PLA, Beijing. 100037. Natl Med J China 1992;72(4): 225-227. By using the methods of immunocytochemistry

  14. Parkinson's disease

    DEFF Research Database (Denmark)

    Astradsson, Arnar; Aziz, Tipu Z

    2015-01-01

    -derived therapy in people with Parkinson's disease? We searched: Medline, Embase, The Cochrane Library and other important databases up to September 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from...

  15. Wilson Disease

    Science.gov (United States)

    ... prevent organ damage. Changes in Eating, Diet, and Nutrition People with Wilson disease should reduce their dietary copper intake by avoiding foods that are high in copper, such as shellfish liver mushrooms nuts chocolate People should not eat these foods during the ...

  16. Mitochondrial Diseases

    Science.gov (United States)

    ... fats) that come from your food. When the mitochondria are defective, the cells do not have enough energy. The unused oxygen ... disease can vary. It depends on how many mitochondria are defective, and where ... organ, tissue, or cell type is affected. But often the problem affects ...

  17. Behcet's Disease

    Science.gov (United States)

    ... to stop taking the medicine suddenly, because the medicine alters the body’s production of the natural corticosteroid hormones. Long-term use of these medications can have side effects such as osteoporosis (a disease that leads to bone fragility), weight gain, delayed ...

  18. Huntington's disease

    DEFF Research Database (Denmark)

    Hjermind, Lena Elisabeth; Law, Ian; Jønch, Aia

    2011-01-01

    In this open-label pilot study, the authors evaluated the effect of memantine on the distribution of brain glucose metabolism in four Huntington's disease (HD) patients as determined by serial 18-fluoro-deoxyglucose [F(18)]FDG-PET scans over a period of 3-4 months (90-129 days, with one patient...

  19. Parkinson disease

    Science.gov (United States)

    In Parkinson disease, dopamine production becomes irregular and inadequate and nerve cells cannot properly transmit messages. This results in the loss of muscle function. By providing an even, adequate supply of medication that the body converts into dopamine, neurons are able to transmit ...

  20. Meningococcal disease

    Directory of Open Access Journals (Sweden)

    Alex Koyfman

    2011-12-01

    Full Text Available The first cases of meningococcal meningitis were described in Geneva in 1805 and in New England in 1806, the causative agent finally being identified by Anton Weichselbaum in 1887. The first meningococcal epidemics occurred in sub-Saharan Africa in the early 1900s and periodic outbreaks continue to occur worldwide today. Neisseria meningitidis colonizes the naso-oropharyngeal mucosa in approximately 10–20% of healthy individuals. When it invades the bloodstream, meningococcus has the potential to cause devastating disease. It can affect people of any age, but primarily infects children and adolescents. Meningococcemia classically follows an upper respiratory illness consisting of myalgias, fever, headache, and nausea. It can present as an indolent infection with rapid recovery or progress within a few hours into a fulminant illness affecting multiple organ systems. As such, meningococcemia is one of the important causes of sepsis. Prior to antibiotic therapy, the disease carried a 70% mortality rate. Despite advances in early diagnosis and treatment, 10–15% of affected patients die from the disease and another 10–20% are left with severe morbidities (neurologic disability, hearing loss, loss of a limb. Meningococcal disease remains a significant global health threat.

  1. Lung Diseases

    Science.gov (United States)

    When you breathe, your lungs take in oxygen from the air and deliver it to the bloodstream. The cells in your body need oxygen to ... you breathe nearly 25,000 times. People with lung disease have difficulty breathing. Millions of people in ...

  2. INFECTIOUS DISEASE

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    2.1 Viral disease2003263 Isolation, identification and sequence analyses of dengue virus type 2 strain GD19/2001. REN Rui-wen(任瑞文), et al. Milit Med Instit Guangzhou Milit District, Guangzhou 510507. Chin J Epidemiol 2003; 24 (4):288-290. Objective:To identify the virus isolated from patients

  3. INFECTIOUS DISEASE

    Institute of Scientific and Technical Information of China (English)

    2004-01-01

    3.1 Viral disease2004310 One-step simultaneous detection of G-genotype of human group a rotaviruses by multiplex RT-PCR. TANG Shaowen (唐少文) , et al. Dept Epidemiol, Tongji Med Coll Huozhong Univ Sci & Technol, Wuhan 430030. Chin J Lab Med 2004; 27 (4):234-236

  4. INFECTIOUS DISEASE

    Institute of Scientific and Technical Information of China (English)

    2004-01-01

    4. 1 Viral disease2004174 Study on the seropositive prevalence of humanimmunodeficiency virus in a village residents living in rural region of central China. CHENG Hua (程华), et al. Public Health Sch, Fudan Univ, Shanghai 200032. Chin J Epidemiol 2004;25(4):317 -321.

  5. Huntington's Disease

    Science.gov (United States)

    ... seizures. More than 30,000 Americans have HD. Huntington’s disease is caused by a mutation in the gene for a protein called huntingtin. The defect causes the cytosine, adenine, and guanine (CAG) building blocks of DNA to repeat many more ...

  6. Huntington disease

    Science.gov (United States)

    ... President of the Florida Society of Neurology (FSN). Review provided by VeriMed Healthcare Network. Also reviewed by David Zieve, MD, MHA, Isla Ogilvie, PhD, and the A.D.A.M. Editorial team. Huntington's Disease Read more Latest Health News Read more Health ...

  7. Prionic diseases

    Directory of Open Access Journals (Sweden)

    Abelardo Q-C Araujo

    2013-09-01

    Full Text Available Prion diseases are neurodegenerative illnesses due to the accumulation of small infectious pathogens containing protein but apparently lacking nucleic acid, which have long incubation periods and progress inexorably once clinical symptoms appear. Prions are uniquely resistant to a number of normal decontaminating procedures. The prionopathies [Kuru, Creutzfeldt-Jakob disease (CJD and its variants, Gerstmann-Sträussler-Scheinker (GSS syndrome and fatal familial insomnia (FFI] result from accumulation of abnormal isoforms of the prion protein in the brains of normal animals on both neuronal and non-neuronal cells. The accumulation of this protein or fragments of it in neurons leads to apoptosis and cell death. There is a strong link between mutations in the gene encoding the normal prion protein in humans (PRNP - located on the short arm of chromosome 20 – and forms of prion disease with a familial predisposition (familial CJD, GSS, FFI. Clinically a prionopathy should be suspected in any case of a fast progressing dementia with ataxia, myoclonus, or in individuals with pathological insomnia associated with dysautonomia. Magnetic resonance imaging, identification of the 14-3-3 protein in the cerebrospinal fluid, tonsil biopsy and genetic studies have been used for in vivo diagnosis circumventing the need of brain biopsy. Histopathology, however, remains the only conclusive method to reach a confident diagnosis. Unfortunately, despite numerous treatment efforts, prionopathies remain short-lasting and fatal diseases.

  8. INFECTIOUS DISEASE

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    3.1 Viral disease2003162 The clinical and epidemiological analysis on 46 patients with epidemic hemorrhagic fever in Huainan areas. WANG Kexia(王克霞). Sch Med, An-hui Univ Sci & Tehnol, Huainan 232001. Chin J En-demiol 2003;22(1):48-50.

  9. Extraphyramidal disease

    Institute of Scientific and Technical Information of China (English)

    2009-01-01

    2009250 Effects of bilateral deep brain stimulation of the subthalamic nucleus on depression in patients with parkinson’s disease. WANG Xuelian(王学廉),et al.Dept Neurosurg,Tangdu Hosp,4th Milit Med Univ,Xi’an,710038.Chin J Nerv Ment Dis,2009;35(2):88-92.

  10. Chagas Disease

    Science.gov (United States)

    ... contact with an infected triatomine bug also called “kissing bug,”“benchuca,” “vinchuca,”“chinche,”or “barbeiro” Who can ... get Chagas disease? ■ Usually from contact with a kissing bug ■ After the kissing bug bites, it poops. ...

  11. Neurodegenerative disorders: Parkinson's disease and Huntington's disease

    Science.gov (United States)

    Hague, S; Klaffke, S; Bandmann, O

    2005-01-01

    Parkinson's disease and Huntington's disease are both model diseases. Parkinson's disease is the most common of several akinetic-rigid syndromes and Huntington's disease is only one of an ever growing number of trinucleotide repeat disorders. Molecular genetic studies and subsequent molecular biological studies have provided fascinating new insights into the pathogenesis of both disorders and there is now real hope for disease modifying treatment in the not too distant future for patients with Parkinson's disease or Huntington's disease. PMID:16024878

  12. Neurodegenerative disorders: Parkinson's disease and Huntington's disease.

    Science.gov (United States)

    Hague, S M; Klaffke, S; Bandmann, O

    2005-08-01

    Parkinson's disease and Huntington's disease are both model diseases. Parkinson's disease is the most common of several akinetic-rigid syndromes and Huntington's disease is only one of an ever growing number of trinucleotide repeat disorders. Molecular genetic studies and subsequent molecular biological studies have provided fascinating new insights into the pathogenesis of both disorders and there is now real hope for disease modifying treatment in the not too distant future for patients with Parkinson's disease or Huntington's disease.

  13. Infectious Disease

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    3.1 Viral disease2007149 Study on platelet β3 integrin expression levels and their relationships with disease severity in patients with hemorrhagic fever with renal syndrome.GAO Maicang(高麦仓), et al. Dept Infect Dis, 1st Affili Hosp, Sch Med, Xi′an Jiaotong Univ , Xi′an 710061. Chin J Infect Dis 2007;25(3):152-153. Objective To investigate the relationship between the expression level of platelet membrane glycoprotein 133(GP Ⅲa, CD61) and the severity of disease in patients with hemorrhagic fever with renal syndrome(HFRS). Methods One hundred and four patients with HFRS and 30 healthy individuals were recruited. The percentage of CD61 positive platelets and the mean fluorescence intensities (MFI) of platelet membrane glycoprotein β3 were determined by flow cytometry (FCM). The 104 patients studied were divided into three groups based on their expression levels of platelet membrane glycoprotein β3 at oliguric phase. Clinical data and laboratory parameters in different groups were compared and analyzed. Results The expression levels of CD61 in patients with HFRS were significantly higher than those in control group, although no significant difference in the percentage of CD61 positive platelets between patients with HFRS and controls was detected. The MFI of CD61 expression in patients with HFRS at fever phase, oliguric phase and polyuric phase was 19. 75±2.57, 17.46±1.48 and 15. 55±0.60, respectively, which was significantly higher than that in control group (3. 20±0.12). The expression level of CD61 in patients with HFRS at oliguric phase was negatively correlated with platelet count and serum albumin(r=-0.637 and -0. 695. respectively) and positively correlated with white blood cell count, blood urea nitrogen, serum creatinine and alanine aminotransferase(r= 0.945, 0. 904, 0.956 and 0. 891, respectively). When the patients were compared according to the expression levels of CD61, it was indicated that the higher the expression level of CD61, the

  14. Celiac disease

    Institute of Scientific and Technical Information of China (English)

    Luis Rodrigo

    2006-01-01

    Celiac disease (CD) is a common autoimmune disorder,induced by the intake of gluten proteins present in wheat, barley and rye. Contrary to common belief,this disorder is a protean systemic disease, rather than merely a pure digestive alteration. CD is closely associated with genes that code HLA-Ⅱ antigens, mainly of DQ2 and DQ8 classes. Previously, it was considered to be a rare childhood disorder, but is actually considered a frequent condition, present at any age, which may have multiple complications. Tissue transglutaminase-2(tTG), appears to be an important component of this disease, both, in its pathogenesis and diagnosis. Active CD is characterized by intestinal and/or extra-intestinal symptoms, villous atrophy and crypt hyperplasia, and strongly positive tTG auto-antibodies. The duodenal biopsy is considered to be the "gold standard" for diagnosis, but its practice has significant limitations in its interpretation, especially in adults. Occasionally, it results in a false-negative because of patchy mucosal changes and the presence of mucosal villous atrophy is often more severe in the proximal jejunum, usually not reached by endoscopic biopsies. CD is associated with increased rates of several diseases, such as iron deficiency anemia, osteoporosis, dermatitis herpetiformis,several neurologic and endocrine diseases, persistent chronic hypertransami-nasemia of unknown origin,various types of cancer and other autoimmune disorders.Treatment of CD dictates a strict, life-long gluten-free diet, which results in remission for most individuals,although its effect on some associated extraintestinal manifestations remains to be established.

  15. Bacterial disease

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    930445 A report on investigation of an outbreakof legionnaires’disease in a hotel in Beijing.DENG Changying(邓长英),et al.Beijing ArmedForce General Hosp,Beijing,100027.Chin J Epi-demiol 1993;14(2):78—79.During the period from February to March,1992,an outbreak of upper respiratory infection(influenza—like syndrome)took place in a hotelin Beijing.An epidemiological investigation andbacteriological examination were carried out inthis hotel.The results showed that it was anoutbreak of Legionnaires’disease caused by Le-gionella pneumophila serogroup 10(Lpl0).Theincidence was 13.51%(5/37).This is the firstreport on Lp10 infection in China.

  16. Parkinson's disease

    DEFF Research Database (Denmark)

    Astradsson, Arnar; Aziz, Tipu Z

    2015-01-01

    INTRODUCTION: The mean age of onset of Parkinson's disease is about 65 years, with a median time of 9 years between diagnosis and death. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of fetal cell or stem cell......-derived therapy in people with Parkinson's disease? We searched: Medline, Embase, The Cochrane Library and other important databases up to September 2014 (Clinical Evidence reviews are updated periodically; please check our website for the most up-to-date version of this review). We included harms alerts from...... relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found two studies that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS...

  17. Menkes disease.

    Science.gov (United States)

    Tümer, Zeynep; Møller, Lisbeth B

    2010-05-01

    Menkes disease (MD) is a lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration and connective tissue disturbances, together with the peculiar 'kinky' hair are the main manifestations. MD is inherited as an X-linked recessive trait, and as expected the vast majority of patients are males. MD occurs due to mutations in the ATP7A gene and the vast majority of ATP7A mutations are intragenic mutations or partial gene deletions. ATP7A is an energy dependent transmembrane protein, which is involved in the delivery of copper to the secreted copper enzymes and in the export of surplus copper from cells. Severely affected MD patients die usually before the third year of life. A cure for the disease does not exist, but very early copper-histidine treatment may correct some of the neurological symptoms.

  18. Morgellons disease?

    Science.gov (United States)

    Accordino, Robert E; Engler, Danielle; Ginsburg, Iona H; Koo, John

    2008-01-01

    Morgellons disease, a pattern of dermatologic symptoms very similar, if not identical, to those of delusions of parasitosis, was first described many centuries ago, but has recently been given much attention on the internet and in the mass media. The present authors present a history of Morgellons disease, in addition to which they discuss the potential benefit of using this diagnostic term as a means of building trust and rapport with patients to maximize treatment benefit. The present authors also suggest "meeting the patient halfway" and creating a therapeutic alliance when providing dermatologic treatment by taking their cutaneous symptoms seriously enough to provide both topical ointments as well as antipsychotic medications, which can be therapeutic in these patients.

  19. CSF markers of Alzheimer’s pathology and microglial activation are associated with altered white matter microstructure in asymptomatic adults at risk for Alzheimer’s disease

    Science.gov (United States)

    Melah, Kelsey E; Lu, Sharon Yuan-Fu; Hoscheidt, Siobhan M; Alexander, Andrew L; Adluru, Nagesh; Destiche, Daniel J; Carlsson, Cynthia M; Zetterberg, Henrik; Blennow, Kaj; Okonkwo, Ozioma C; Gleason, Carey E; Dowling, N Maritza; Bratzke, Lisa C; Rowley, Howard A; Sager, Mark A; Asthana, Sanjay; Johnson, Sterling C; Bendlin, Barbara B

    2015-01-01

    Background The immune response in Alzheimer’s disease (AD) involves activation of microglia which may remove β-amyloid. However, overproduction of inflammatory compounds may exacerbate neural damage in Alzheimer’s disease. AD pathology accumulates years before diagnosis, yet the extent to which neuroinflammation is involved in the earliest disease stages is unknown. Objective To determine whether neuroinflammation exacerbates neural damage in preclinical AD. Methods We utilized cerebrospinal fluid (CSF) and magnetic resonance imaging collected in 192 asymptomatic late-middle-aged adults (mean age=60.98 years). Neuroinflammatory markers chitinase-3-like protein 1 (YKL-40) and monocyte chemoattractant protein-1 (MCP-1) in CSF were utilized as markers of neuroinflammation. Neural cell damage was assessed using CSF neurofilament light chain protein (NFL), CSF total tau (T-Tau), and neural microstructure assessed with diffusion tensor imaging (DTI). With regard to AD pathology, CSF Aβ42 and tau phosphorylated at threonine 181 (P-Tau181) were used as markers of amyloid and tau pathology, respectively. We hypothesized that higher YKL-40 and MCP-1 in the presence of AD pathology would be associated with higher NFL, T-Tau, and altered microstructure on DTI. Results Neuroinflammation was associated with markers of neural damage. Higher CSF YKL-40 was associated with both higher CSF NFL and T-Tau. Inflammation interacted with AD pathology, such that greater MCP-1 and lower Aβ42 was associated with altered microstructure in bilateral frontal and right temporal lobe and that greater MCP-1 and greater P-Tau181 was associated with altered microstructure in precuneus. Conclusion Inflammation may play a role in neural damage in preclinical AD. PMID:26836182

  20. Lyme Disease.

    Science.gov (United States)

    Hu, Linden T

    2016-05-03

    This issue provides a clinical overview of Lyme disease, focusing on prevention, diagnosis, treatment, and practice improvement. The content of In the Clinic is drawn from the clinical information and education resources of the American College of Physicians (ACP), including MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinic in collaboration with the ACP's Medical Education and Publishing divisions and with the assistance of additional science writers and physician writers.

  1. Ledderhose Disease

    Science.gov (United States)

    Fausto de Souza, Dominique; Micaelo, Lilian; Cuzzi, Tullia

    2010-01-01

    Plantar fibromatosis, or Ledderhose disease, is a rare hyperproliferative disorder of the plantar aponeurosis. It may occur at any age with the greatest prevalence at middle age and beyond. This disorder is more common in men than woman and it is sometimes associated with other forms of fibromatosis. A 28-year-old Brazilian woman with a six-year history of painless bilateral plantar nodules is described in this article. PMID:20877526

  2. INFECTIOUS DISEASE

    Institute of Scientific and Technical Information of China (English)

    2003-01-01

    4.1 Viral disease2003021 Analysis on the epidemiologic features of Dengue fever in Guangdong province, 1990 - 2000. LUO Huiming(罗会明), et al. Dis Contr & Prev Center Guangdong Prov, Guangzhou 510300. Chin J Epi-demiol 2002;23(6):427-430.Objective: To determine the epidemiological characteristics and risk factors of Dengue fever in Guangdong province in 1990 - 2000, and to develop the strategy for

  3. Fungal disease

    Institute of Scientific and Technical Information of China (English)

    1993-01-01

    930031 Experimental studies on lung lesionsof rabbits caused by streptomyces thermohy-groscopicus.LIU Fang(刘仿),et al.Dept Mi-crobiol,Hubei Med Coll,Xianning Branch,437100.Chin J Tuberc & Respir Dis 1992;15(4):207—208.Imitating the natural way of infection ofFarmer’s lung disease,we succeeded in inducingChina Medical Abstracts(Internal Medicine)

  4. Wilson's disease.

    Science.gov (United States)

    Loudianos, G; Gitlin, J D

    2000-01-01

    Wilson's disease is an autosomal recessive disorder of copper metabolism resulting from the absence or dysfunction of a copper transporting P-type ATPase encoded on chromosome 13. This ATPase is expressed in hepatocytes where it is localized to the trans-Golgi network and transports copper into the secretory pathway for incorporation into ceruloplasmin and excretion into the bile. Under physiologic circumstances, biliary excretion represents the sole mechanism for copper excretion, and thus affected individuals have progressive copper accumulation in the liver. When the capacity for hepatic storage is exceeded, cell death ensues with copper release into the plasma, hemolysis, and tissue deposition. Presentation in childhood may include chronic hepatitis, asymptomatic cirrhosis, or acute liver failure. In young adults, neuropsychiatric symptoms predominate and include dystonia, tremor, personality changes, and cognitive impairments secondary to copper accumulation in the central nervous system. The laboratory diagnosis of Wilson's disease is confirmed by decreased serum ceruloplasmin, increased urinary copper content, and elevated hepatic copper concentration. Molecular genetic analysis is complex as more than 100 unique mutations have been identified and most individuals are compound heterozygotes. Copper chelation with penicillamine is an effective therapy in most patients and hepatic transplantation is curative in individuals presenting with irreversible liver failure. Elucidation of the molecular genetic basis of Wilson's disease has permitted new insights into the mechanisms of cellular copper homeostasis.

  5. Polycystic Kidney Disease

    Science.gov (United States)

    ... Kidney Disease Polycystic Kidney Disease (PKD) Related Topics Section Navigation Kidney Disease Acquired Cystic Kidney Disease Amyloidosis & ... for a Child with Kidney Disease Ectopic Kidney Medullary Sponge Kidney Kidney Dysplasia Kidney Failure Choosing a ...

  6. Coronary heart disease

    Science.gov (United States)

    Heart disease, Coronary heart disease, Coronary artery disease; Arteriosclerotic heart disease; CHD; CAD ... slow down or stop. A risk factor for heart disease is something that increases your chance of getting ...

  7. Parkinson's Disease Dementia

    Science.gov (United States)

    ... Find your local chapter Join our online community Parkinson's Disease Dementia Parkinson's disease dementia is an impairment in ... disease. About Symptoms Diagnosis Causes & risks Treatments About Parkinson's disease dementia The brain changes caused by Parkinson's disease ...

  8. [Goodpasture disease].

    Science.gov (United States)

    Fomegné, G; Dratwa, M; Wens, R; Mesquita, M; Van der Straaten, M; Vanden Haute, K; Fosso, C

    2006-01-01

    We report one case of acute renal failure with oliguria, microscopic haematuria and normocytic anemia in a 86-year old Swedish woman. A full investigation led to the diagnosis of Goodpasture disease, an isolated form of Goodpasture syndrome. Goodpasture disease is and autoimmune disorder characterized by the development of autoantibodies to the NC1 domain of the alpha3 chain of type IV collagen, found mainly in glomerular basement membranes (GBM). When the disease affects both the lung and the kidney, it is called Goodpasture syndrome but the pulmonary or renal involvement can be isolated or separated in years. Its pathogenesis is not well known. It occurs essentially in Caucasian subjects, preferentially from Nordic and Anglo-Saxon countries (higher prevalence of HLA DR B1-15 and B1-4 group). Are also mentioned, the exposure to hydrocarbons, rustproof, insecticides and greasy solvents. The annual incidence of Goodpasture syndrome is rare and has been estimated in Europe to be about 0.5 to 1 case per million inhabitants. The isolated renal form represents about 1/3 of the cases. The clinical presentation is characterized by rapidly progressive renal failure with oliguria or anuria and in case of lung involvement, pulmonary hemorrhage responsible of hemoptysis, sometimes massive. Renal biopsy and immunofluorescence analysis play a key role in the diagnosis. The presence of both linear deposits of IgG along the glomerular basement membrane (GBM) and circulating anti-GBM antibodies is of paramount importance. The treatment, which depends on the degree of renal involvement, is based on the association of corticosteroids, cyclophosphamide and plasma exchanges.

  9. Celiac disease

    DEFF Research Database (Denmark)

    Hvas, Christian Lodberg; Jensen, Michael Dam; Reimer, Maria Christina

    2015-01-01

    This national clinical guideline approved by the Danish Society for Gastroenterology and Hepatology describes the diagnosis and treatment of celiac disease (CD) in adults. CD is a chronic immunemediated enteropathy of the small intestine triggered by the ingestion of gluten-containing proteins......, and identification of specific HLA haplotypes may contribute to CD diagnosis. Classical CD presents with diarrhoea and weight loss, but non-classical CD with vague or extraintestinal symptoms is common. The treatment for CD is a lifelong gluten-free diet (GFD), which, in the majority of patients, normalises...

  10. Menkes disease

    DEFF Research Database (Denmark)

    Tümer, Zeynep; Møller, Lisbeth B

    2010-01-01

    of patients are males. MD occurs due to mutations in the ATP7A gene and the vast majority of ATP7A mutations are intragenic mutations or partial gene deletions. ATP7A is an energy dependent transmembrane protein, which is involved in the delivery of copper to the secreted copper enzymes and in the export......Menkes disease (MD) is a lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration and connective tissue disturbances, together with the peculiar 'kinky' hair are the main manifestations. MD is inherited as an X-linked recessive trait, and as expected the vast majority...

  11. Menkes disease

    OpenAIRE

    Tümer, Zeynep; Møller, Lisbeth B

    2009-01-01

    Menkes disease (MD) is a lethal multisystemic disorder of copper metabolism. Progressive neurodegeneration and connective tissue disturbances, together with the peculiar ‘kinky' hair are the main manifestations. MD is inherited as an X-linked recessive trait, and as expected the vast majority of patients are males. MD occurs due to mutations in the ATP7A gene and the vast majority of ATP7A mutations are intragenic mutations or partial gene deletions. ATP7A is an energy dependent transmembrane...

  12. Celiac disease.

    Science.gov (United States)

    Polanco, Isabel

    2008-08-01

    Celiac disease is an immunologically mediated enteropathy of the small intestine, characterized by lifelong intolerance to the gliadin and related prolamines from wheat and other cereals, that occurs in genetically predisposed individuals. Symptoms result from structural damage to the mucosa of the small intestine, which may cause malabsorption with positive autoantibodies in the sera. Normal mucosal architecture is restored after the use of a gluten-free diet and the normalization of the autoantibodies. Villous atrophy and high levels of autoantibodies reappear when gluten is reintroduced into the diet (gluten challenge).

  13. Infectious Disease

    Institute of Scientific and Technical Information of China (English)

    2006-01-01

    2.1 Viral disease 2006009 Correlation analysis of type A influenza virus genetic variation characteristic with survival selective pressure ZHOU xiao -ming(周晓明 ) ,et al. Sch Pub Health,Fudan Univ. Shanghai 200032. China J Infect Dis 2005;23(4) :221 -224 Objective:To study the relationship betweer. type A influenza virus genetic variation with survival selective pressure to find possible vaccine conserved antigen target. Methods:Seven strains of same HA (Hemagglutinin) serotype, regional and isolation time closely related type A influenza virus were selected with full HA gene coding sequence , Blast2 program was used to calculate the param-

  14. Neuroprotective and anti-inflammatory properties of a coffee component in the MPTP model of Parkinson's disease.

    Science.gov (United States)

    Lee, Kang-Woo; Im, Joo-Young; Woo, Jong-Min; Grosso, Hilary; Kim, Yoon-Seong; Cristovao, Ana Clara; Sonsalla, Patricia K; Schuster, David S; Jalbut, Marla M; Fernandez, Jose R; Voronkov, Michael; Junn, Eunsung; Braithwaite, Steven P; Stock, Jeffry B; Mouradian, M Maral

    2013-01-01

    Consumption of coffee is associated with reduced risk of Parkinson's disease (PD), an effect that has largely been attributed to caffeine. However, coffee contains numerous components that may also be neuroprotective. One of these compounds is eicosanoyl-5-hydroxytryptamide (EHT), which ameliorates the phenotype of α-synuclein transgenic mice associated with decreased protein aggregation and phosphorylation, improved neuronal integrity and reduced neuroinflammation. Here, we sought to investigate if EHT has an effect in the MPTP model of PD. Mice fed a diet containing EHT for four weeks exhibited dose-dependent preservation of nigral dopaminergic neurons following MPTP challenge compared to animals given control feed. Reductions in striatal dopamine and tyrosine hydroxylase content were also less pronounced with EHT treatment. The neuroinflammatory response to MPTP was markedly attenuated, and indices of oxidative stress and JNK activation were significantly prevented with EHT. In cultured primary microglia and astrocytes, EHT had a direct anti-inflammatory effect demonstrated by repression of lipopolysaccharide-induced NFκB activation, iNOS induction, and nitric oxide production. EHT also exhibited a robust anti-oxidant activity in vitro. Additionally, in SH-SY5Y cells, MPP(+)-induced demethylation of phosphoprotein phosphatase 2A (PP2A), the master regulator of the cellular phosphoregulatory network, and cytotoxicity were ameliorated by EHT. These findings indicate that the neuroprotective effect of EHT against MPTP is through several mechanisms including its anti-inflammatory and antioxidant activities as well as its ability to modulate the methylation and hence activity of PP2A. Our data, therefore, reveal a strong beneficial effect of a novel component of coffee in multiple endpoints relevant to PD.

  15. Cyanotoxins at low doses induce apoptosis and inflammatory effects in murine brain cells: Potential implications for neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Larissa Takser

    2016-01-01

    Full Text Available Cyanotoxins have been shown to be highly toxic for mammalian cells, including brain cells. However, little is known about their effect on inflammatory pathways. This study investigated whether mammalian brain and immune cells can be a target of certain cyanotoxins, at doses approximating those in the guideline levels for drinking water, either alone or in mixtures. We examined the effects on cellular viability, apoptosis and inflammation signalling of several toxins on murine macrophage-like RAW264.7, microglial BV-2 and neuroblastoma N2a cell lines. We tested cylindrospermopsin (CYN, microcystin-LR (MC-LR, and anatoxin-a (ATX-a, individually as well as their mixture. In addition, we studied the neurotoxins β-N-methylamino-l-alanine (BMAA and its isomer 2,4-diaminobutyric acid (DAB, as well as the mixture of both. Cellular viability was determined by the MTT assay. Apoptosis induction was assessed by measuring the activation of caspases 3/7. Cell death and inflammation are the hallmarks of neurodegenerative diseases. Thus, our final step was to quantify the expression of a major proinflammatory cytokine TNF-α by ELISA. Our results show that CYN, MC-LR and ATX-a, but not BMAA and DAB, at low doses, especially when present in a mixture at threefold less concentrations than individual compounds are 3–15 times more potent at inducing apoptosis and inflammation. Our results suggest that common cyanotoxins at low doses have a potential to induce inflammation and apoptosis in immune and brain cells. Further research of the neuroinflammatory effects of these compounds in vivo is needed to improve safety limit levels for cyanotoxins in drinking water and food.

  16. Women's Heart Disease: Heart Disease Risk Factors

    Science.gov (United States)

    ... this page please turn JavaScript on. Feature: Women's Heart Disease Heart Disease Risk Factors Past Issues / Winter 2014 Table of ... or habits may raise your risk for coronary heart disease (CHD). These conditions are known as risk factors. ...

  17. Crohn disease - children - discharge

    Science.gov (United States)

    Inflammatory bowel disease in children - Crohn disease; IBD in children - Crohn disease; Regional enteritis - children; Ileitis - children; Granulomatous ileocolitis - children; Colitis in children; CD - children

  18. Infectious diseases and arthropods

    National Research Council Canada - National Science Library

    Goddard, Jerome

    2000-01-01

    .... His book covers mosquito-, tick-, and flea-borne diseases, and a variety of other miscellaneous vector-borne diseases, including Chagas' disease, African sleeping sickness, onchocerciasis, scrub...

  19. Parkinson's Disease Videos

    Medline Plus

    Full Text Available ... of Parkinson's Disease OHSU - Parkinson's Disease: Managing Depression, Anxiety & Psychosis OHSU - Parkinson's Disease: Pharmacological Management of Depression, Anxiety & Psychosis OHSU - Therapeutic ...

  20. Hirayama disease

    Directory of Open Access Journals (Sweden)

    Atul T Tayade

    2010-01-01

    Full Text Available A 17-year-old male, who gave up his favorite sport cricket and started playing football, presented with one-year history of slowly progressive atrophic weakness of forearms and hands. Neurological examination showed weak and wasted arms, forearms and hand but no evidence of pyramidal tract, spinothalmic tract and posterior column lesions. Plain cervical spine radiographs showed no abnormal findings. Cervical magnetic resonance imaging (MRI showed asymmetric cord atrophy; images obtained with neck flexed showed the anterior shifting of the posterior wall of the lower cervical dural sac resulting in cord compression. These findings suggest Hirayama disease, a kind of cervical myelopathy related to the flexion movements of the neck.

  1. [Bone disease in Gaucher's disease].

    Science.gov (United States)

    Roca Espiau, Mercedes

    2011-09-01

    The exposition aims, is to review the pathophysiological mechanisms of bone marrow involvement and the patterns of marrow infiltration by Gaucher cells. We have reviewed the different methods of assessment of bone marrow infiltration and its temporal development. Qualitative methods include simple radiography, magnetic resonance imaging (MRI), computed tomography (CT) and radioisotope. The simple radiography is the basic element, but its sensitivity is limited and only allows for assessing changes and trabecular bone remodeling MRI allows us to appreciate the bone marrow infiltration, detection of complications and response to therapy. Radioisotopes can contribute to the differential diagnosis of osteomyelitis and bone crises. Among the quantitative methods are the QCSI (quantitative chemical shift imaging) and the dual-energy X-ray absorptiometry (DEXA), as well as new quantitative techniques of CT, MRI and ultrasound densitometry. The QCSI performed an assessment of fat content of bone marrow in the spine. DEXA quantifies bone density by measuring the attenuation coefficient. The semiquantitative methods have various "scores" to establish criteria for generalized bone disease endpoints of disease progression and response to therapy.

  2. A new humanized ataxin-3 knock-in mouse model combines the genetic features, pathogenesis of neurons and glia and late disease onset of SCA3/MJD.

    Science.gov (United States)

    Switonski, Pawel M; Szlachcic, Wojciech J; Krzyzosiak, Wlodzimierz J; Figiel, Maciej

    2015-01-01

    Spinocerebellar ataxia type 3 (SCA3/MJD) is a neurodegenerative disease triggered by the expansion of CAG repeats in the ATXN3 gene. Here, we report the generation of the first humanized ataxin-3 knock-in mouse model (Ki91), which provides insights into the neuronal and glial pathology of SCA3/MJD. First, mutant ataxin-3 accumulated in cell nuclei across the Ki91 brain, showing diffused immunostaining and forming intranuclear inclusions. The humanized allele revealed expansion and contraction of CAG repeats in intergenerational transmissions. CAG mutation also exhibited age-dependent tissue-specific expansion, which was most prominent in the cerebellum, pons and testes of Ki91 animals. Moreover, Ki91 mice displayed neuroinflammatory processes, showing astrogliosis in the cerebellar white matter and the substantia nigra that paralleled the transcriptional deregulation of Serpina3n, a molecular sign of neurodegeneration and brain damage. Simultaneously, the cerebellar Purkinje cells in Ki91 mice showed neurodegeneration, a pronounced decrease in Calbindin D-28k immunoreactivity and a mild decrease in cell number, thereby modeling the degeneration of the cerebellum observed in SCA3. Moreover, these molecular and cellular neuropathologies were accompanied by late behavioral deficits in motor coordination observed in rotarod and static rod tests in heterozygous Ki91 animals. In summary, we created an ataxin-3 knock-in mouse model that combines the molecular and behavioral disease phenotypes with the genetic features of SCA3. This model will be very useful for studying the pathogenesis and responses to therapy of SCA3/MJD and other polyQ disorders.

  3. Undifferentiated Connective Tissue Disease

    Science.gov (United States)

    ... Home Conditions Undifferentiated Connective Tissue Disease (UCTD) Undifferentiated Connective Tissue Disease (UCTD) Make an Appointment Find a Doctor ... L. Goldstein, MD, MMSc (February 01, 2016) Undifferentiated connective tissue disease (UCTD) is a systemic autoimmune disease. This ...

  4. Associated Autoimmune Diseases

    Science.gov (United States)

    ... gland in the neck, thick and coarse hair. Addison’s Disease Arare disease involving the adrenal gland. The prevalence of celiac disease in people with addison’s disease is significant. Symptoms of Addison’s may include weight ...

  5. Genetics and Rheumatic Disease

    Science.gov (United States)

    ... Well with Rheumatic Disease Genetics and Rheumatic Disease Genetics and Rheumatic Disease Fast Facts Studying twins has ... 70%, and for non-identical pairs, even lower. Genetics and ankylosing spondylitis Each rheumatic disease has its ...

  6. Chronic Beryllium Disease

    Science.gov (United States)

    ... Science Education & Training Home Conditions Chronic Beryllium Disease Chronic Beryllium Disease Make an Appointment Find a Doctor ... MD, MSPH, FCCP (February 01, 2016) What is chronic beryllium disease (CBD)? Chronic beryllium disease (CBD) is ...

  7. Heart disease - risk factors

    Science.gov (United States)

    Heart disease - prevention; CVD - risk factors; Cardiovascular disease - risk factors; Coronary artery disease - risk factors; CAD - risk ... a certain health condition. Some risk factors for heart disease you cannot change, but some you can. ...

  8. Inflammation and Heart Disease

    Science.gov (United States)

    ... Disease Venous Thromboembolism Aortic Aneurysm More Inflammation and Heart Disease Updated:Oct 12,2016 Understand the risks of ... inflammation causes cardiovascular disease, inflammation is common for heart disease and stroke patients and is thought to be ...

  9. Lipid Storage Diseases

    Science.gov (United States)

    ... age 2, usually from lung disease. Children with Tay-Sachs and Sandhoff diseases often die at an ... age 2, usually from lung disease. Children with Tay-Sachs and Sandhoff diseases often die at an ...

  10. Heart disease and women

    Science.gov (United States)

    ... this page: //medlineplus.gov/ency/article/007188.htm Heart disease and women To use the sharing features on ... please enable JavaScript. People often DO NOT consider heart disease a woman's disease. Yet cardiovascular disease is the ...

  11. Men and Heart Disease

    Science.gov (United States)

    ... Pressure Salt Cholesterol Million Hearts® WISEWOMAN Men and Heart Disease Fact Sheet Recommend on Facebook Tweet Share Compartir Source: Interactive Atlas of Heart Disease and Stroke Heart Disease Facts in Men Heart disease is the leading ...

  12. American Lyme Disease Foundation

    Science.gov (United States)

    ... Infectious Diseases, 35: 451-464, 2002) What is Lyme Disease? Lyme disease (LD) is an infection caused by ... mission with your own tax-deductible contribution. American Lyme Disease Foundation, Inc. PO Box 466 Lyme, CT 06371 ...

  13. Thyroid Disease (for Parents)

    Science.gov (United States)

    ... Teaching Kids to Be Smart About Social Media Thyroid Disease KidsHealth > For Parents > Thyroid Disease Print A ... many other parts of the body. What Is Thyroid Disease? Thyroid disease is when the thyroid gland ...

  14. Thyroid Disease and Teens

    Science.gov (United States)

    ... Surgery? Choosing the Right Sport for You Shyness Thyroid Disease KidsHealth > For Teens > Thyroid Disease Print A ... other parts of your body. continue What Is Thyroid Disease? Thyroid disease occurs when the thyroid gland ...

  15. Genetics and Rheumatic Disease

    Science.gov (United States)

    ... Well with Rheumatic Disease Genetics and Rheumatic Disease Genetics and Rheumatic Disease Fast Facts Studying twins has ... 70%, and for non-identical pairs, even lower. Genetics and ankylosing spondylitis Each rheumatic disease has its ...

  16. Pelvic Inflammatory Disease (PID)

    Science.gov (United States)

    ... Management Education & Events Advocacy For Patients About ACOG Pelvic Inflammatory Disease (PID) Home For Patients Search FAQs Pelvic Inflammatory ... Inflammatory Disease (PID) FAQ077, September 2015 PDF Format Pelvic Inflammatory Disease (PID) Gynecologic Problems What is pelvic inflammatory disease ( ...

  17. Thyroid Disease (for Parents)

    Science.gov (United States)

    ... Old Feeding Your 1- to 2-Year-Old Thyroid Disease KidsHealth > For Parents > Thyroid Disease A A ... many other parts of the body. What Is Thyroid Disease? Thyroid disease is when the thyroid gland ...

  18. Thyroid Disease and Teens

    Science.gov (United States)

    ... Loss Surgery? A Week of Healthy Breakfasts Shyness Thyroid Disease KidsHealth > For Teens > Thyroid Disease A A ... other parts of your body. continue What Is Thyroid Disease? Thyroid disease occurs when the thyroid gland ...

  19. Sickle Cell Disease

    Science.gov (United States)

    ... sickle cell disease?Sickle cell disease, also called sickle cell anemia, is a hereditary condition (which means it runs ... disease, hemoglobin SS disease, hemoglobin synthesis, hemoglobinopathies, ... cell anemia, sickle cell crisis, vaso-occlusive crisis Family Health, ...

  20. Gaucher Disease in Pregnancy

    Science.gov (United States)

    ... from your health care provider. What is Gaucher disease? Gaucher disease is a genetic disorder. People with Gaucher ... severe and depend on the type of Gaucher disease. Gaucher disease occurs in approximately 1 in 60,000 ...

  1. Aortic Valve Disease

    Science.gov (United States)

    ... Tricuspid Valve Disease Cardiac Rhythm Disturbances Thoracic Aortic Aneurysm Pediatric and Congenital Heart Disease Heart abnormalities that are ... Transplantation End-stage Lung Disease Adult Lung Transplantation Pediatric Lung ... Aortic Aneurysm Aortic Valve Disease Overview The human heart has ...

  2. What Is Vascular Disease?

    Science.gov (United States)

    ... Donors Corporate Sponsors Donor Privacy Policy What Is Vascular Disease? What Is Vascular Disease? Vascular disease is any abnormal condition of ... steps to prevent vascular disease here. Understanding the Vascular System Your vascular system – the highways of the ...

  3. Parkinson's disease.

    Science.gov (United States)

    Benninger, David H

    2013-01-01

    In advanced Parkinson's disease (PD), the emergence of symptoms refractory to conventional therapy poses therapeutic challenges. The success of deep brain stimulation (DBS) and advances in the understanding of the pathophysiology of PD have raised interest in noninvasive brain stimulation as an alternative therapeutic tool. The rationale for its use draws from the concept that reversing abnormalities in brain activity and physiology thought to cause the clinical deficits may restore normal functioning. Currently the best evidence in support of this concept comes from DBS, which improves motor deficits, and modulates brain activity and motor cortex physiology, although whether a causal interaction exists remains largely undetermined. Most trials of noninvasive brain stimulation in PD have applied repetitive transcranial magnetic stimulation (rTMS), targeting the motor cortex. Current studies suggest a possible therapeutic potential for rTMS and transcranial direct current stimulation (tDCS), but clinical effects so far have been small and negligible with regard to functional independence and quality of life. Approaches to potentiate the efficacy of rTMS include increasing stimulation intensity and novel stimulation parameters that derive their rationale from studies on brain physiology. These novel parameters are intended to simulate normal firing patterns or to act on the hypothesized role of oscillatory activity in the motor cortex and basal ganglia with regard to motor control and its contribution to the pathogenesis of motor disorders. Noninvasive brain stimulation studies will enhance our understanding of PD pathophysiology and might provide further evidence for potential therapeutic applications.

  4. [Castleman disease].

    Science.gov (United States)

    Belletti, Gerardo A; Savio, Verónica; Minoldo, Daniel; Caminos, Susana; Yorio, Marcelo A

    2004-01-01

    A 66 years female, who was since last year under astenia, arthralgias, pimply lesions in spread plates and tests showing eritrosedimentation over 100 mm, anemi, leucocitosis with neutrofilia, policlonal hypergammaglobulinemia, slight proteinuria and IgE on 900. This patient was sporadically treated with corticoids. When made the medical consult had lost 34lb., was under anorexy, as well as dyspepsia. Hemoglobyn 6.9 gr/dl, leucocytes 20000/mm3, neutrofils at 90%, proteinogram the same as former, with hypoalbuminemia. She was taking prednisona, 16 mg/day. When examined showed depress of conscience, astenia, and dermic lesions already quoted. 4 cm nonpainful right axillary adenopaty adhered to deep planes. Medulogram with increased iron, hyperegenerative. Ganglionar biopsia: linfoid hyperplasic process linked to inmune response. Toracoabdominal tomography with adenomegalia in torax and retroperitoneo. Skin biopsia: neutrofilic vasculitis. The patient suspends the 16 mg of prednisona and fever as well as generalized adenopatias come up. After laying aside other ethiologies, and understanding as Castleman Multicentric disease, it is started to supply prednisona 1 mg/kg of weight with a clinical and biochemical fast and outstanding response. After 7 months it was progressively suspended the esteroids and 60 days later, the process fall back; for that, corticoids are restarted, with a good evolution. The illness of Castleman although it is not very frequent, it should be considered as differential diagnosis in those clinical cases that are accompanied with important general commitment, linphadenopaties and respons to steroid therapy.

  5. Blood and Lymph Diseases

    Science.gov (United States)

    ... and Disease [Internet]. Bethesda (MD): National Center for Biotechnology Information (US); 1998-. Blood and Lymph Diseases. PDF version of this page ( ... On Blood and Lymph Diseases - Genes and Disease Blood and Lymph Diseases - Genes and Disease Your browsing ... Biotechnology Information , U.S. National Library of Medicine 8600 Rockville ...

  6. Air pollution & the brain: Subchronic diesel exhaust exposure causes neuroinflammation and elevates early markers of neurodegenerative disease

    Directory of Open Access Journals (Sweden)

    McDonald Jacob

    2011-08-01

    Full Text Available Abstract Background Increasing evidence links diverse forms of air pollution to neuroinflammation and neuropathology in both human and animal models, but the effects of long-term exposures are poorly understood. Objective We explored the central nervous system consequences of subchronic exposure to diesel exhaust (DE and addressed the minimum levels necessary to elicit neuroinflammation and markers of early neuropathology. Methods Male Fischer 344 rats were exposed to DE (992, 311, 100, 35 and 0 μg PM/m3 by inhalation over 6 months. Results DE exposure resulted in elevated levels of TNFα at high concentrations in all regions tested, with the exception of the cerebellum. The midbrain region was the most sensitive, where exposures as low as 100 μg PM/m3 significantly increased brain TNFα levels. However, this sensitivity to DE was not conferred to all markers of neuroinflammation, as the midbrain showed no increase in IL-6 expression at any concentration tested, an increase in IL-1β at only high concentrations, and a decrease in MIP-1α expression, supporting that compensatory mechanisms may occur with subchronic exposure. Aβ42 levels were the highest in the frontal lobe of mice exposed to 992 μg PM/m3 and tau [pS199] levels were elevated at the higher DE concentrations (992 and 311 μg PM/m3 in both the temporal lobe and frontal lobe, indicating that proteins linked to preclinical Alzheimer's disease were affected. α Synuclein levels were elevated in the midbrain in response to the 992 μg PM/m3 exposure, supporting that air pollution may be associated with early Parkinson's disease-like pathology. Conclusions Together, the data support that the midbrain may be more sensitive to the neuroinflammatory effects of subchronic air pollution exposure. However, the DE-induced elevation of proteins associated with neurodegenerative diseases was limited to only the higher exposures, suggesting that air pollution-induced neuroinflammation may

  7. Muscle disease.

    Science.gov (United States)

    Tsao, Chang-Yong

    2014-02-01

    On the basis of strong research evidence, Duchenne muscular dystrophy (DMD), the most common severe childhood form of muscular dystrophy, is an X-linked recessive disorder caused by out-of-frame mutations of the dystrophin gene. Thus, it is classified asa dystrophinopathy. The disease onset is before age 5 years. Patients with DMD present with progressive symmetrical limb-girdle muscle weakness and become wheelchair dependent after age 12 years. (2)(3). On the basis of some research evidence,cardiomyopathy and congestive heart failure are usually seen in the late teens in patients with DMD. Progressive scoliosis and respiratory in sufficiency often develop once wheelchair dependency occurs. Respiratory failure and cardiomyopathy are common causes of death, and few survive beyond the third decade of life. (2)(3)(4)(5)(6)(7). On the basis of some research evidence, prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) or deflazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone (not available in the United States), as a single morning dose is recommended for DMD patients older than 5 years, which may prolong independent walking from a few months to 2 years. (2)(3)(16)(17). Based on some research evidence, treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be beneficial in DMD patients with cardiac abnormalities. (2)(3)(5)(18). Based on expert opinion, children with muscle weakness and increased serum creatine kinase levels may be associated with either genetic or acquired muscle disorders (Tables 1 and 3). (14)(15)

  8. Alzheimer disease: An interactome of many diseases

    Directory of Open Access Journals (Sweden)

    Balaji S Rao

    2014-01-01

    Full Text Available Alzheimer Disease (AD is an outcome as well as source of many diseases. Alzheimer is linked with many other diseases like Diabetes type 2, cholesterolemia, hypertension and many more. But how each of these diseases affecting other is still unknown to scientific community. Signaling Pathways of one disease is interlinked with other disease. But to what extent healthy brain is affected when any signaling in human body is disturbed is the question that matters. There is a need of Pathway analysis, Protein-Protein interaction (PPI and the conserved interactome study in AD and linked diseases. It will be helpful in finding the potent drug or vaccine target in conscious manner. In the present research the Protein-Protein interaction of all the proteins involved in Alzheimer Disease is analyzed using ViSANT and osprey tools and pathway analysis further reveals the significant genes/proteins linking AD with other diseases.

  9. Association between periodontal diseases and systemic diseases.

    Science.gov (United States)

    Weidlich, Patrícia; Cimões, Renata; Pannuti, Claudio Mendes; Oppermann, Rui Vicente

    2008-01-01

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

  10. Inflammatory bowel disease and airway diseases

    Science.gov (United States)

    Vutcovici, Maria; Brassard, Paul; Bitton, Alain

    2016-01-01

    Airway diseases are the most commonly described lung manifestations of inflammatory bowel disease (IBD). However, the similarities in disease pathogenesis and the sharing of important environmental risk factors and genetic susceptibility suggest that there is a complex interplay between IBD and airway diseases. Recent evidence of IBD occurrence among patients with airway diseases and the higher than estimated prevalence of subclinical airway injuries among IBD patients support the hypothesis of a two-way association. Future research efforts should be directed toward further exploration of this association, as airway diseases are highly prevalent conditions with a substantial public health impact. PMID:27678355

  11. Association between periodontal diseases and systemic diseases

    Directory of Open Access Journals (Sweden)

    Patrícia Weidlich

    2008-08-01

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

  12. 2-cyclohexylamino-5,8-dimethoxy-1,4-naphthoquinone inhibits LPS-induced BV2 microglial activation through MAPK/NF-kB signaling pathways

    Directory of Open Access Journals (Sweden)

    Hu-Nan Sun

    2016-07-01

    Significance: Our findings demonstrate that our newly synthesized compound derived from DMNQ, 2-cyclohexylamino-5,8-dimethoxy-1,4-naphthoquinone (R6, might be a therapeutic agent for the treatment of glia-mediated neuroinflammatory diseases.

  13. Toxicological aspects of injectable gold-hyaluronan combination as a treatment for neuroinflammation

    DEFF Research Database (Denmark)

    Pedersen, Dan Sonne; Locht, Linda Jansons; Tran, Thao Phuong

    2014-01-01

    Secondary inflammatory reactions to stroke or trauma contribute to irreplaceable loss of brain tissue of the affected patients. Likewise, neuroinflammatory processes are the main pathophysiological feature in Multiple Sclerosis (MS), a common neurodegenerative disease among young adults. In the s...

  14. Nuclear imaging of neuroinflammation : a comprehensive review of [C-11]PK11195 challengers

    NARCIS (Netherlands)

    Chauveau, Fabien; Boutin, Herve; Van Camp, Nadja; Dolle, Frederic; Tavitian, Bertrand

    2008-01-01

    Neurodegenerative, inflammatory and neoplastic brain disorders involve neuroinflammatory reactions, and a biomarker of neuroinflammation would be useful for diagnostic, drug development and therapy control of these frequent diseases. In vivo imaging can document the expression of the peripheral benz

  15. Skin Diseases: Skin Health and Skin Diseases

    Science.gov (United States)

    Skip Navigation Bar Home Current Issue Past Issues Skin Diseases Skin Health and Skin Diseases Past Issues / Fall 2008 Table of Contents ... acne to wrinkles Did you know that your skin is the largest organ of your body? It ...

  16. Acquired Cystic Kidney Disease

    Science.gov (United States)

    ... Kidney Disease (CKD) What Is Chronic Kidney Disease? Causes of CKD Tests & Diagnosis Managing CKD Eating Right Preventing CKD ... as polycystic kidney disease (PKD), another disease that causes the kidneys to ... chronic kidney disease (CKD)—a condition that develops over many years ...

  17. Lyme Disease (For Parents)

    Science.gov (United States)

    ... Teaching Kids to Be Smart About Social Media Lyme Disease KidsHealth > For Parents > Lyme Disease Print A A ... en español La enfermedad de Lyme What Is Lyme Disease? Lyme disease is the leading tick-borne disease ...

  18. Virus diseases of fish

    Science.gov (United States)

    Watson, Stanley W.

    1954-01-01

    Viruses are probably the cause of a wide spectrum of fish diseases. Although relatively few virus diseases of fish are known today, some of the diseases of unknown etiology, as well as some diseases presently accepted as due to bacteria, protozoa, fungi or nutritional deficiencies, possibly will be recognized eventually as virus diseases.

  19. Characterisation of Immune and Neuroinflammatory Changes Associated with Chemotherapy-Induced Peripheral Neuropathy.

    Science.gov (United States)

    Makker, Preet G S; Duffy, Samuel S; Lees, Justin G; Perera, Chamini J; Tonkin, Ryan S; Butovsky, Oleg; Park, Susanna B; Goldstein, David; Moalem-Taylor, Gila

    2017-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) and associated neuropathic pain is a debilitating adverse effect of cancer treatment. Current understanding of the mechanisms underpinning CIPN is limited and there are no effective treatment strategies. In this study, we treated male C57BL/6J mice with 4 cycles of either Paclitaxel (PTX) or Oxaliplatin (OXA) over a week and tested pain hypersensitivity and changes in peripheral immune responses and neuroinflammation on days 7 and 13 post 1st injection. We found that both PTX and OXA caused significant mechanical allodynia. In the periphery, PTX and OXA significantly increased circulating CD4+ and CD8+ T-cell populations. OXA caused a significant increase in the percentage of interleukin-4+ lymphocytes in the spleen and significant down-regulation of regulatory T (T-reg) cells in the inguinal lymph nodes. However, conditional depletion of T-reg cells in OXA-treated transgenic DEREG mice had no additional effect on pain sensitivity. Furthermore, there was no leukocyte infiltration into the nervous system of OXA- or PTX-treated mice. In the peripheral nervous system, PTX induced expression of the neuronal injury marker activating transcription factor-3 in IB4+ and NF200+ sensory neurons as well as an increase in the chemokines CCL2 and CCL3 in the lumbar dorsal root ganglion. In the central nervous system, PTX induced significant astrocyte activation in the spinal cord dorsal horn, and both PTX and OXA caused reduction of P2ry12+ homeostatic microglia, with no measurable changes in IBA-1+ microglia/macrophages in the dorsal and ventral horns. We also found that PTX induced up-regulation of several inflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL11, CCL4, CCL3, IL-12p70 and GM-CSF) in the spinal cord. Overall, these findings suggest that PTX and OXA cause distinct pathological changes in the periphery and nervous system, which may contribute to chemotherapy-induced neuropathic pain.

  20. Treatment with dexamethasone and vitamin D3 attenuates neuroinflammatory age-related changes in rat hippocampus.

    Science.gov (United States)

    Moore, Michelle; Piazza, Alessia; Nolan, Yvonne; Lynch, Marina A

    2007-10-01

    Among the changes which occur in the brain with age is an increase in hippocampal concentration of proinflammatory cytokines like interleukin-1beta (IL-1beta) and an increase in IL-1beta-induced signaling. Here we demonstrate that the increase in IL-1beta concentration is accompanied by an increase in expression of IL-1 type I receptor (IL-1RI) and an age-related increase in microglial activation, as shown by increased expression of the cell surface marker, major histocompatibility complex II (MHCII) and increased MHCII staining. The evidence indicates that these age-related changes were abrogated in hippocampus of aged rats treated with dexamethasone and vitamin D3. Similarly, the age-related increases in activation of the stress-activated protein kinase, c-Jun N-terminal kinase (JNK), as well as caspase-3 and PARP were all attenuated in hippocampal tissue prepared from rats that received dexamethasone and vitamin D3. The data indicate that dexamethasone and vitamin D3 ameliorated the age-related increase in IFNgamma and suggest that IFNgamma may be the trigger leading to microglial activation, since it increases MHCII mRNA and IL-1beta release from cultured glia. In parallel with its ability to decrease microglial activation in vivo, we report that treatment of cultured glia with dexamethasone and vitamin D3 blocked the lipopolysaccharide increased MHCII mRNA and IL-1beta concentration, while the IL-1beta-induced increases in activation of JNK and caspase 3 in cultured neurons were also reversed by treatment with dexamethasone and vitamin D3. The data suggest that the antiinflammatory effect of dexamethasone and vitamin D3 derives from their ability to downreguate microglial activation.

  1. Neuroinflammatory Pathobiology in Gulf War Illness: Characterization with an Animal Model

    Science.gov (United States)

    2014-06-01

    treatment of GWI. Future studies will benefit from a better understanding of the molecular underpinnings of the immune “priming” in order to...physiological stressors, e.g., heat, exercise and war stress were encountered in theater during the 1991Gulf War and may have contributed to the...neuroinflammation, these GWI-relevant agents were not used in the neurophysiology studies. So the model consisted of CORT in the drinking water for 7 days

  2. Anti-oxidative and anti-neuroinflammatory effects of ethyl acetate ...

    African Journals Online (AJOL)

    Tropical Journal of Pharmaceutical Research June 2016; 15 (6): 1175-1181. ISSN: 1596-5996 ... induced increase in TNF-α level (p < 0.01at concentrations of 40 and 80 μg/mL) in BV-2 cells. .... MiniTM, Roche, Mannheim, Germany). The.

  3. Insulin-Associated Neuroinflammatory Pathways as Therapeutic Targets for Traumatic Brain Injury

    Science.gov (United States)

    Cerecedo-López, Christian D.; Kim-Lee, Jennifer H.; Hernandez, Diana; Acosta, Sandra A.; Borlongan, Cesar V.

    2014-01-01

    Traumatic brain injury (TBI) is characterized by an abrupt blow or exchange of force against the head and can be categorized as mild, moderate, and severe. The secondary cell death after TBI displays ischemic-like patterns including neuroinflammation. The scavenger receptor cluster of differentiation (CD) 36 is a lipid-associated protein capable of transducing intracellular signals to promote inflammatory mechanisms within different cell types. Expression and activation of CD36 is closely related to dyslipidemia secondary to diabetes. Diabetes mellitus (DM) has been documented as a co-morbidity factor in TBI, in that patients with a history of diabetes present with more severe brain damage and slower recovery from TBI than non-diabetic patients. Indeed, a strict regulation of blood serum glucose by the use of insulin promotes a better outcome for TBI patients. Based on these recent findings, we now advance the hypothesis that CD36 via DM insulin-associated pathways is closely involved in TBI chronic pathology. PMID:24332562

  4. CSF neurofilament light chain is elevated in OMS (decreasing with immunotherapy) and other pediatric neuroinflammatory disorders.

    Science.gov (United States)

    Pranzatelli, Michael R; Tate, Elizabeth D; McGee, Nathan R; Verhulst, Steven J

    2014-01-15

    Using a panel of seven brain cell-specific biomarkers in cerebrospinal fluid (CSF), pediatric opsoclonus-myoclonus syndrome (OMS) (n=234) was compared to pediatric non-inflammatory neurological controls (n=84) and other inflammatory neurological disorders (OIND) (n=44). Only CSF NFL was elevated in untreated OMS versus controls (+83%). It was 87% higher in OIND than in OMS. On combination treatment with front-loaded ACTH, IVIg, rituximab, median CSF NFL decreased by 60% to control levels. These biochemical data suggest neuronal/axonal injury in some children with OMS without indicators of astrogliosis, and reduction on sufficient immunotherapy.

  5. Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties

    DEFF Research Database (Denmark)

    Prajeeth, Chittappen K; Kronisch, Julius; Khorooshi, Reza M. H.

    2017-01-01

    , cytokines and chemokines using real-time PCR. Data obtained was analysed using Kruskal- Wallis test. Results: We observed in α4-deficient mice weak microglial activation but comparable astrogliosis to that of wild-type mice in the regions of the brain populated with Th17 infiltrates suggesting that Th17...

  6. Characterisation of Immune and Neuroinflammatory Changes Associated with Chemotherapy-Induced Peripheral Neuropathy

    Science.gov (United States)

    Makker, Preet G. S.; Duffy, Samuel S.; Lees, Justin G.; Perera, Chamini J.; Tonkin, Ryan S.; Butovsky, Oleg; Park, Susanna B.; Goldstein, David

    2017-01-01

    Chemotherapy-induced peripheral neuropathy (CIPN) and associated neuropathic pain is a debilitating adverse effect of cancer treatment. Current understanding of the mechanisms underpinning CIPN is limited and there are no effective treatment strategies. In this study, we treated male C57BL/6J mice with 4 cycles of either Paclitaxel (PTX) or Oxaliplatin (OXA) over a week and tested pain hypersensitivity and changes in peripheral immune responses and neuroinflammation on days 7 and 13 post 1st injection. We found that both PTX and OXA caused significant mechanical allodynia. In the periphery, PTX and OXA significantly increased circulating CD4+ and CD8+ T-cell populations. OXA caused a significant increase in the percentage of interleukin-4+ lymphocytes in the spleen and significant down-regulation of regulatory T (T-reg) cells in the inguinal lymph nodes. However, conditional depletion of T-reg cells in OXA-treated transgenic DEREG mice had no additional effect on pain sensitivity. Furthermore, there was no leukocyte infiltration into the nervous system of OXA- or PTX-treated mice. In the peripheral nervous system, PTX induced expression of the neuronal injury marker activating transcription factor-3 in IB4+ and NF200+ sensory neurons as well as an increase in the chemokines CCL2 and CCL3 in the lumbar dorsal root ganglion. In the central nervous system, PTX induced significant astrocyte activation in the spinal cord dorsal horn, and both PTX and OXA caused reduction of P2ry12+ homeostatic microglia, with no measurable changes in IBA-1+ microglia/macrophages in the dorsal and ventral horns. We also found that PTX induced up-regulation of several inflammatory cytokines and chemokines (TNF-α, IFN-γ, CCL11, CCL4, CCL3, IL-12p70 and GM-CSF) in the spinal cord. Overall, these findings suggest that PTX and OXA cause distinct pathological changes in the periphery and nervous system, which may contribute to chemotherapy-induced neuropathic pain. PMID:28125674

  7. Cognitive and neuroinflammatory consequences of mild repeated stress are exacerbated in aged mice

    Science.gov (United States)

    Buchanan, J.B.; Sparkman, N.L.; Chen, J.; Johnson, R.W.

    2008-01-01

    Summary Peripheral immune stimulation as well as certain types of psychological stress increases brain levels of inflammatory cytokines such as interleukin-1β (IL-1β), IL-6 and tumor necrosis factor α (TNFα). We have demonstrated that aged mice show greater increases in central inflammatory cytokines, as well as greater cognitive deficits, compared to adults in response to peripheral lipopolysaccharide (LPS) administration. Because aged mice are typically more sensitive to systemic stressors such as LPS, and certain psychological stressors induce physiological responses similar to those that follow LPS, we hypothesized that aged mice would be more sensitive to the physiological and cognitive effects of mild stress than adult mice. Here, adult (3–5 mo) and aged (22–23 mo) male BALB/c mice were trained in the Morris water maze for 5 days. Mice were then exposed to a mild restraint stress of 30 minutes before being tested in a working memory version of the water maze over a 3 day period. On day 4 mice were stressed and then killed for collection of blood and brain. In a separate group of animals, mice were killed immediately after one, two or three 30 min restraint sessions and blood for peripheral corticosterone and cytokine protein measurement, and brains were dissected for central cytokine mRNA measurement. Stress disrupted spatial working memory in both adult and aged mice but to a much greater extent in the aged mice. In addition, aged mice showed an increase in stress-induced expression of hippocampal IL-1β mRNA and MHC class II protein compared to non-stressed controls while expression in adult mice was unaffected by stress. These data show that aged mice are more sensitive to both the cognitive and inflammatory effects of mild stress than are adult mice and suggest a possible a role for IL-1β. PMID:18407425

  8. KEGG DISEASE / Acute encephalitis [KEGG DISEASE

    Lifescience Database Archive (English)

    Full Text Available DISEASE: H01417 Entry H01417Disease Name Acute encephalitis Description Acute encep...ns Infections caused by dsDNA viruses H01417Acute encephalitis Human diseases in ICD-10 classification [BR:b...of the central nervous system G04Encephalitis, myelitis and encephalomyelitis H01417Acute encephalitis Patho...elines for management. Journal Eur J Neurol 12:331-43 (2005) KEGG DISEASE / Acute encephalitis ...

  9. Coronary Artery Disease - Coronary Heart Disease

    Science.gov (United States)

    ... result of coronary artery disease, or CAD, said Edward A. Fisher, M.D., Ph.D., M.P. ... Problems and Disease • High Blood Pressure (HBP) • Metabolic Syndrome • Pericarditis • Peripheral Artery Disease (PAD) • Stroke • Vascular Health • ...

  10. KEGG DISEASE / Acute alcohol sensitivity [KEGG DISEASE

    Lifescience Database Archive (English)

    Full Text Available DISEASE: H01071 Entry H01071Disease Name Acute alcohol sensitivity Description Alde...bolism Congenital disorders of carbohydrate metabolism H01071Acute alcohol sensit...eases. Journal Cardiovasc Res 88:51-7 (2010) KEGG DISEASE / Acute alcohol sensitivity ...

  11. Lysosomal storage disease 2 - Pompe's disease

    NARCIS (Netherlands)

    van der Ploeg, Ans T.; Reuser, Arnold J. J.

    2008-01-01

    Pompe's disease, glycogen-storage disease type II, and acid maltase deficiency are alternative names for the same metabolic disorder. It is a pan-ethnic autosomal recessive trait characterised by acid alpha-glucosidase deficiency leading to lysosomal glycogen storage. Pompe's disease is also

  12. Protection of dopaminergic neurons in a mouse model of Parkinson's disease by a physically-modified saline containing charge-stabilized nanobubbles.

    Science.gov (United States)

    Khasnavis, Saurabh; Roy, Avik; Ghosh, Supurna; Watson, Richard; Pahan, Kalipada

    2014-03-01

    Neuroinflammation underlies the pathogenesis of various neurodegenerative disorders including Parkinson's disease (PD). Despite intense investigations, no effective therapy is available to stop its onset or halt its progression. RNS60 is a novel therapeutic containing charge-stabilized nanobubbles in saline, generated by subjecting normal saline to Taylor-Couette-Poiseuille flow under elevated oxygen pressure. Recently, we have delineated that RNS60 inhibits the expression of proinflammatory molecules in glial cells via type 1A phosphatidylinositol-3 kinase (PI3K)-mediated upregulation of IκBα. In this study, we demonstrate that RNS60 inhibited the expression of proinflammatory molecules in cultured microglial cells stimulated by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridium ion (MPP(+)) and in vivo in the nigra of MPTP-intoxicated mice. While investigating the underlying mechanisms, we found that MPTP intoxication rapidly stimulated the activation of type IB PI3K p110γ in the nigra, while suppressing the activation of type IA PI3K p110α/β. Interestingly, RNS60 treatment suppressed the activation of p110γ PI3K, while inducing the activation of p110α/β PI3K in the nigra of MPTP-intoxicated mice. Accordingly, RNS60 treatment increased the level of IκBα and inhibited the activation of NF-κB in the SNpc of MPTP-intoxicated mice. These findings paralleled dopaminergic neuronal protection, normalized striatal neurotransmitters, and improved motor functions in MPTP-intoxicated mice. These results strongly suggest a promising therapeutic role of this simple modified saline in PD and other neuroinflammatory disorders.

  13. Neuroprotective effect of physical exercise in a mouse model of Alzheimer's disease induced by β-amyloid₁₋₄₀ peptide.

    Science.gov (United States)

    Souza, Leandro C; Filho, Carlos B; Goes, André T R; Fabbro, Lucian Del; de Gomes, Marcelo G; Savegnago, Lucielli; Oliveira, Mauro Schneider; Jesse, Cristiano R

    2013-08-01

    This study was designed to investigate the potential neuroprotective effect of exercise in a mouse model of Alzheimer's disease (AD) induced by intracerebroventricular (i.c.v.) injection of beta-amyloid₁₋₄₀ (Aβ₁₋₄₀) peptide. For this aim, male Swiss Albino mice were submitted to swimming training (ST) with progressive increase in intensity and duration for 8 weeks before Aβ₁₋₄₀ administration (400 pmol/animal; 3 μl/site, i.c.v. route). The cognitive behavioral, oxidative stress, and neuroinflammatory markers in hippocampus and prefrontal cortex of mice were assessed 7 days after Aβ₁₋₄₀ administration. Our results demonstrated that ST was effective in preventing impairment in short- and long-term memories in the object recognition test. ST attenuated the increased levels of reactive species and decreased non-protein thiol levels in hippocampus and prefrontal cortex induced by Aβ₁₋₄₀. Also, Aβ₁₋₄₀ inhibited superoxide dismutase activity and increased glutathione peroxidase, glutathione reductase, and glutathione S-transferase activities in hippocampus and prefrontal cortex-alterations that were mitigated by ST. In addition, ST was effective against the increase of tumor necrosis factor-alpha and interleukin-1 beta levels and the decrease of interleukin-10 levels in hippocampus and prefrontal cortex. This study confirmed the hypothesis that exercise is able to protect against some mechanisms of Aβ₁₋₄₀-induced neurotoxicity. In conclusion, we suggest that exercise can prevent the cognitive decline, oxidative stress, and neuroinflammation induced by Aβ₁₋₄₀ in mice supporting the hypothesis that exercise can be used as a non-pharmacological tool to reduce the symptoms of AD.

  14. Different distribution patterns of lymphocytes and microglia in the hippocampus of patients with residual versus paranoid schizophrenia: further evidence for disease course-related immune alterations?

    Science.gov (United States)

    Busse, Stefan; Busse, Mandy; Schiltz, Kolja; Bielau, Hendrik; Gos, Tomasz; Brisch, Ralf; Mawrin, Christian; Schmitt, Andrea; Jordan, Wolfgang; Müller, Ulf J; Bernstein, Hans-Gert; Bogerts, Bernhard; Steiner, Johann

    2012-11-01

    Certain cytokines have been identified in the peripheral blood as trait markers of schizophrenia, while others are considered relapse-related state markers. Furthermore, data from peripheral blood, cerebrospinal fluid (CSF) and nuclear imaging studies suggest that (1) blood-brain barrier (BBB) dysfunction (e.g., immigration of lymphocytes into brain tissue and intrathecal antibody production) correlates with the development of negative symptoms, while (2) the brain's mononuclear phagocyte system (microglial cells) is activated during acute psychosis. Based on these neuroinflammatory hypotheses, we have quantified the numerical density of immunostained CD3+ T-lymphocytes, CD20+ B-lymphocytes, and HLA-DR+ microglial cells in the posterior hippocampus of 17 schizophrenia patients and 11 matched controls. Disease course-related immune alterations were considered by a separate analysis of residual (prevailing negative symptoms, n=7) and paranoid (prominent positive symptoms, n=10) schizophrenia cases. Higher densities of CD3+ and CD20+ lymphocytes were observed in residual versus paranoid schizophrenia (CD 3: left: P=0.047, right: P=0.038; CD20: left: P=0.020, right: P=0.010) and controls (CD3: left: P=0.057, right: P=0.069; CD20: left: P=0.008, right: P=0.006). In contrast, HLA-DR+ microglia were increased in paranoid schizophrenia versus residual schizophrenia (left: P=0.030, right: P=0.012). A similar trend emerged when this group was compared to controls (left: P=0.090, right: P=0.090). BBB impairment and infiltration of T cells and B cells may contribute to the pathophysiology of residual schizophrenia, while microglial activation seems to play a role in paranoid schizophrenia. The identification of diverse immune endophenotypes may facilitate the development of distinct anti-inflammatory schizophrenia therapies to normalize BBB function, (auto)antibody production or microglial activity.

  15. Anemia of chronic disease

    Science.gov (United States)

    ... disease Long-term infections, such as bacterial endocarditis, osteomyelitis (bone infection), HIV/AIDS , hepatitis B or hepatitis ... disease Crohn disease Erythropoietin test Juvenile idiopathic arthritis Osteomyelitis Rheumatic fever Ulcerative colitis Review Date 2/1/ ...

  16. Parkinson's Disease Videos

    Medline Plus

    Full Text Available ... Parkinson's Disease Cognition: A Mind Guide to Parkinson’s Disease Nutrition Matters Speech and Swallowing Psychosis: A Mind Guide to Parkinson's Disease Guide to Deep Brain Stimulation You Can Make ...

  17. Parkinson's Disease Videos

    Medline Plus

    Full Text Available ... and Social Network? How Does Parkinson's Disease Affect Memory? How Does Parkinson's Disease Affect the Urinary System? ... Parkinson's Disease Patients with a Depression Diagnosis? What Type of Exercise or Exercise Programs Are Recommended? What ...

  18. Newcastle Disease Virus (PDQ)

    Science.gov (United States)

    ... Professionals Questions to Ask about Your Treatment Research Newcastle Disease Virus (PDQ®)–Patient Version Overview Go to ... cancer (see Question 8 ). Questions and Answers About Newcastle Disease Virus What is Newcastle disease virus? Newcastle ...

  19. Learn About Neuromuscular Disease

    Science.gov (United States)

    ... Inherited and Endocrine Myopathies Metabolic Diseases of Muscle Mitochondrial Myopathies (MM) Myotonic Muscular Dystrophy (MMD) Spinal-Bulbar Muscular ... Deficient Congenital Muscular Dystrophy Metabolic Diseases of Muscle Mitochondrial Myopathy Miyoshi Distal Myopathy Motor Neurone Disease Muscle-Eye- ...

  20. Autoimmune liver disease panel

    Science.gov (United States)

    Liver disease test panel - autoimmune ... Autoimmune disorders are a possible cause of liver disease. The most common of these diseases are autoimmune hepatitis and primary biliary cholangitis (formerly called primary biliary cirrhosis). This group of tests ...

  1. Liver Disease and IBD

    Science.gov (United States)

    ... Home > Resources > Liver Disease and IBD Go Back Liver Disease and IBD Email Print + Share Several complications ... be necessary to make the definitive diagnosis. FATTY LIVER DISEASE (HEPATCI STEATOSIS) This is the most common ...

  2. Leprosy (Hansen's Disease)

    Science.gov (United States)

    ... with facebook share with twitter share with linkedin Leprosy (Hansen's Disease) Leprosy (Hansen's Disease) is a chronic ... as Mycobacterium leprae . Why Is the Study of Leprosy (Hansen's Disease) a Priority for NIAID? At the ...

  3. Reflux and Lung Disease

    Science.gov (United States)

    ... Healthy Eating Reflux and Lung Disease Reflux and Lung Disease Make an Appointment Ask a Question Find a Doctor Many people with chronic lung disease also suffer from gastroesophageal reflux (GERD). In this ...

  4. Tay-Sachs Disease

    Science.gov (United States)

    Tay-Sachs disease is a rare, inherited disease. It is a type of lipid metabolism disorder. It ... cells, causing mental and physical problems. . Infants with Tay-Sachs disease appear to develop normally for the ...

  5. Diabetic Heart Disease

    Science.gov (United States)

    ... be coronary heart disease (CHD), heart failure, and diabetic cardiomyopathy. Diabetes by itself puts you at risk for heart disease. Other risk factors include Family history of heart disease Carrying extra ...

  6. Heart Disease (For Kids)

    Science.gov (United States)

    ... CPR: A Real Lifesaver Kids Talk About: Coaches Heart Disease KidsHealth > For Kids > Heart Disease Print A A ... chest pain, heart attacks, and strokes . What Is Heart Disease? The heart is the center of the cardiovascular ...

  7. Heart Diseases and Disorders

    Science.gov (United States)

    ... Resources Heart Diseases & Disorders Back to Patient Resources Heart Diseases & Disorders Millions of people experience irregular heartbeats, called ... harmless and happen in healthy people free of heart disease. However, some abnormal heart rhythms can be serious ...

  8. Parkinson disease - discharge

    Science.gov (United States)

    Your doctor has told you that you have Parkinson disease . This disease affects the brain and leads to ... have you take different medicines to treat your Parkinson disease and many of the problems that may come ...

  9. What Is Parkinson's Disease?

    Science.gov (United States)

    ... resources & more. Order Free Materials Today What is Parkinson’s Disease? Parkinson's disease (PD) is a chronic and progressive movement disorder, ... million people in the US are living with Parkinson's disease. The cause is unknown, and although there is ...

  10. Cardiovascular Disease and Diabetes

    Science.gov (United States)

    ... Disease Venous Thromboembolism Aortic Aneurysm More Cardiovascular Disease & Diabetes Updated:Apr 14,2017 The following statistics speak ... disease. This content was last reviewed August 2015. Diabetes • Home • About Diabetes • Why Diabetes Matters Introduction Cardiovascular ...

  11. Heart Disease Risk Factors

    Science.gov (United States)

    ... Hearts® WISEWOMAN Program Other Chronic Disease Topics Diabetes Nutrition Obesity Physical Activity Stroke Heart Disease Risk Factors Recommend ... Hearts® WISEWOMAN Program Other Chronic Disease Topics Diabetes Nutrition Obesity Physical Activity Stroke File Formats Help: How do ...

  12. Lyme disease (image)

    Science.gov (United States)

    Lyme disease is an acute inflammatory disease characterized by skin changes, joint inflammation and symptoms similar to the ... that is caused by the bacterium Borrelia burgdorferi . Lyme disease is transmitted by the bite of a deer ...

  13. Kidney Disease (Nephropathy)

    Science.gov (United States)

    ... Text Size: A A A Listen En Español Kidney Disease (Nephropathy) Kidneys are remarkable organs. Inside them ... resulting in kidney disease. How Does Diabetes Cause Kidney Disease? When our bodies digest the protein we ...

  14. Learning about Dercum Disease

    Science.gov (United States)

    ... About Dercum Disease Specific Genetic Disorders Specific Genetic Disorders Learning About Prostate Cancer See Also: Talking Glossary of ... Definitions for genetic terms used on this page. Learning About Dercum Disease What is Dercum disease? What are the symptoms ...

  15. Learning about Parkinson's Disease

    Science.gov (United States)

    ... About Parkinson's Disease Specific Genetic Disorders Specific Genetic Disorders Learning About Prostate Cancer See Also: Talking Glossary of ... diseases Journal of Biological Chemistry , June 9, 2011 Learning About Parkinson's Disease What do we know about heredity and Parkinson's ...

  16. Pediatric Celiac Disease

    Science.gov (United States)

    ... of Pediatric Gastroenterology and Nutrition Nurses Print Share Celiac Disease Many kids have sensitivities to certain foods, and ... protein found in wheat, rye, and barley. Pediatric Celiac Disease If your child has celiac disease, consuming gluten ...

  17. Eye Disease Simulations

    Science.gov (United States)

    ... USAJobs Home > Eye Health Information > Eye Disease Simulations Eye Disease Simulations Age-Related Macular Degeneration Cataract Diabetic ... information page Back to top Diabetic Retinopathy Diabetic Eye Disease information page Back to top Glaucoma Glaucoma ...

  18. Diabetic Eye Disease

    Science.gov (United States)

    ... Other Dental Problems Diabetes & Sexual & Urologic Problems Diabetic Eye Disease What is diabetic eye disease? Diabetic eye disease is a group of ... loss can occur. How does diabetes affect my eyes? Diabetes affects your eyes when your blood glucose, ...

  19. Understanding cardiovascular disease

    Science.gov (United States)

    ... page: //medlineplus.gov/ency/patientinstructions/000759.htm Understanding cardiovascular disease To use the sharing features on this page, ... lead to heart attack or stroke. Types of Cardiovascular Disease Coronary heart disease (CHD) is the most common ...

  20. Menopause and Heart Disease

    Science.gov (United States)

    ... Peripheral Artery Disease Venous Thromboembolism Aortic Aneurysm More Menopause and Heart Disease Updated:Jun 23,2017 Heart ... can become more evident after the onset of menopause. Menopause does not cause cardiovascular diseases . However, certain ...

  1. Cholestatic liver disease masquerading as Wilson disease.

    Science.gov (United States)

    Sood, Vikrant; Rawat, Dinesh; Khanna, Rajeev; Alam, Seema

    2015-03-01

    Wilson disease and cholestatic liver diseases may present as a diagnostic dilemma if standard guidelines incorporating markers of copper overload are followed. We hereby present a series of four cases of sclerosing cholangitis masquerading as Wilson disease. True Wilson disease cases had significantly lower ceruloplasmin (6 vs. 16 mg/dL) and higher 24-hour urinary copper (322.3 vs. 74.5 μg/day) as compared to mimickers. Initial low serum ceruloplasmin levels normalized in mimickers on follow up, and this may used as a diagnostic indicator. Standard Wilson disease diagnostic criteria thus need further modification especially in developing countries to help avoid mismanagement.

  2. Disease cycle approach to plant disease prediction.

    Science.gov (United States)

    De Wolf, Erick D; Isard, Scott A

    2007-01-01

    Plant disease cycles represent pathogen biology as a series of interconnected stages of development including dormancy, reproduction, dispersal, and pathogenesis. The progression through these stages is determined by a continuous sequence of interactions among host, pathogen, and environment. The stages of the disease cycle form the basis of many plant disease prediction models. The relationship of temperature and moisture to disease development and pathogen reproduction serve as the basis for most contemporary plant disease prediction systems. Pathogen dormancy and inoculum dispersal are considered less frequently. We found extensive research efforts evaluating the performance of prediction models as part of operation disease management systems. These efforts appear to be greater than just a few decades ago, and include novel applications of Bayesian decision theory. Advances in information technology have stimulated innovations in model application. This trend must accelerate to provide the disease management strategies needed to maintain global food supplies.

  3. Rheumatoid lung disease

    Science.gov (United States)

    Lung disease - rheumatoid arthritis; Rheumatoid nodules; Rheumatoid lung ... They often cause no symptoms. The cause of lung disease associated with rheumatoid arthritis is unknown. Sometimes, the ...

  4. Liver in systemic disease

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    Potential causes of abnormal liver function tests include viral hepatitis, alcohol intake, nonalcoholic fatty liver disease, autoimmune liver diseases, hereditary diseases, hepatobiliary malignancies or infection, gallstones and drug-induced liver injury. Moreover, the liver may be involved in systemic diseases that mainly affect other organs. Therefore, in patients without etiology of liver injury by screening serology and diagnostic imaging, but who have systemic diseases, the abnormal liver function test results might be caused by the systemic disease. In most of these patients, the systemic disease should be treated primarily. However, some patients with systemic disease and severe liver injury or fulminant hepatic failure require intensive treatments of the liver.

  5. Biomarker for Glycogen Storage Diseases

    Science.gov (United States)

    2017-07-03

    Fructose Metabolism, Inborn Errors; Glycogen Storage Disease; Glycogen Storage Disease Type I; Glycogen Storage Disease Type II; Glycogen Storage Disease Type III; Glycogen Storage Disease Type IV; Glycogen Storage Disease Type V; Glycogen Storage Disease Type VI; Glycogen Storage Disease Type VII; Glycogen Storage Disease Type VIII

  6. Manifestações cutâneas da infecção e das doenças relacionadas ao vírus linfotrópico de células T humanas do tipo 1 Cutaneous manifestations in human T-cell lymphotropic virus type 1 infection

    Directory of Open Access Journals (Sweden)

    Marcelo Grossi Araújo

    2008-10-01

    Full Text Available O vírus linfotrópico de células T humanas tipo 1 (HTLV-1 é um retrovírus encontrado em todo o mundo e, no Brasil, tem distribuição heterogênea com várias regiões consideradas de alta prevalência. Está relacionado com doenças graves e/ou incapacitantes, como a leucemia/linfoma de células T do adulto, com a doença neurológica conhecida como mielopatia associada ao HTLV-1/paraparesia espástica tropical, com a uveíte associada ao HTLV-1 e com a dermatite infecciosa. O risco para o aparecimento dessas doenças depende, principalmente, de fatores genéticos, da forma como a infecção foi adquirida e da carga proviral. Estima-se que até 10% dos infectados possam desenvolver alguma doença relacionada ao vírus ao longo da vida. O comprometimento da pele tem sido descrito tanto nas doenças relacionadas ao HTLV-1 quanto nos indivíduos portadores assintomáticos. Vários mecanismos são propostos para explicar as lesões da pele, seja pela presença direta do vírus em células, pela imunossupressão ou por resposta inflamatória que a infecção pelo vírus poderia desencadear. Dentre as manifestações dermatológicas mais freqüentes destacam-se a xerose, as dermatofitoses e as infecções bacterianas recorrentes. Neste artigo são revistos os principais aspectos referentes à infecção e às doenças relacionadas ao HTLV- 1, com ênfase na discussão das manifestações dermatológicas observadas nesse contexto.Humam T lymphotropic virus type 1 (HTLV-1 has heteregenous distribution world-wide and, in Brazil, there are high prevalence areas. HTLV-1 has been associated to severe diseases, such as adult T cell leukaemia/ lymphoma, HTLV-1 associated myelopahthy/ tropical spastic parapesis, HTLV-1 associated uveitis and HTLV-1 associated infective dermatitis. Genetics, proviral load and infection route are related to disease risk along life. The lifetime risk to develop HTLV-1 related diseases may be close to 10%. Skin lesions are

  7. [Wilson's disease: clinical spectrum of liver disease].

    Science.gov (United States)

    Ochoa Palominos, Alejandra; Ibáñez Samaniego, Luis; Catalina Rodríguez, María-Vega; Pajares Díaz, José; Clemente Ricote, Gerardo

    2013-02-01

    Wilson's disease is a hereditary autosomal recessive disorder of copper metabolism,characterized by copper accumulation in the liver and brain. This rare entity, which has a broad clinical spectrum, is often difficult to diagnose and should therefore always be suspected in patients with liver disease of unclear cause. We describe two types of manifestation of liver disease in two patients; the first developed fulminant hepatic failure requiring urgent liver transplantation and the second showed advanced chronic liver disease and received standard medical treatment. The objective of this clinical observation is to analyze the diagnosis of Wilson's disease in two patients with distinct onset, illustrating the broad clinical spectrum of the disease, and its treatment.

  8. Interstitial Lung Diseases

    Science.gov (United States)

    Interstitial lung disease is the name for a large group of diseases that inflame or scar the lungs. The inflammation and scarring make it hard to ... air is responsible for some types of interstitial lung diseases. Specific types include Black lung disease among ...

  9. What Causes Heart Disease?

    Science.gov (United States)

    ... page from the NHLBI on Twitter. What Causes Heart Disease? Research suggests that coronary heart disease (CHD) begins with damage to the lining and ... causing coronary microvascular disease (MVD). Coronary MVD is heart disease that affects the heart's tiny arteries. The cause ...

  10. PERIANAL CROHNS-DISEASE

    NARCIS (Netherlands)

    HOEDEMAKER, HOT

    1994-01-01

    Perianal disease in Crohn's disease is a difficult matter to deal with. The indication for therapy is not always clear in this disease with a relatively mild natural course. More confusion is caused by the fact that not all disease in the perianal region in a patient with Crohn's has to be Crohn-rel

  11. Occupational skin diseases

    DEFF Research Database (Denmark)

    Mahler, Vera; Aalto-Korte, Kristiina; Alfonso, Jose Hernan

    2017-01-01

    BACKGROUND: Work-related skin diseases (WSD) are caused or worsened by a professional activity. Occupational skin diseases (OSD) need to fulfil additional legal criteria which differ from country to country. OSD range amongst the five most frequently notified occupational diseases (musculoskeletal...... diseases, neurologic diseases, lung diseases, diseases of the sensory organs, skin diseases) in Europe. OBJECTIVE: To retrieve information and compare the current state of national frameworks and pathways to manage patients with occupational skin disease with regard to prevention, diagnosis, treatment...... in Science and Technology (COST) Action TD 1206 (StanDerm) (www.standerm.eu). RESULTS: Besides a national health service or a statutory health insurance, most European member states implemented a second insurance scheme specifically geared at occupational diseases [insurance against occupational risks...

  12. [Periodontal disease in pediatric rheumatic diseases].

    Science.gov (United States)

    Fabri, Gisele M C; Savioli, Cynthia; Siqueira, José T; Campos, Lucia M; Bonfá, Eloisa; Silva, Clovis A

    2014-01-01

    Gingivitis and periodontitis are immunoinflammatory periodontal diseases characterized by chronic localized infections usually associated with insidious inflammation This narrative review discusses periodontal diseases and mechanisms influencing the immune response and autoimmunity in pediatric rheumatic diseases (PRD), particularly juvenile idiopathic arthritis (JIA), childhood-onset systemic lupus erythematosus (C-SLE) and juvenile dermatomyositis (JDM). Gingivitis was more frequently observed in these diseases compared to health controls, whereas periodontitis was a rare finding. In JIA patients, gingivitis and periodontitis were related to mechanical factors, chronic arthritis with functional disability, dysregulation of the immunoinflammatory response, diet and drugs, mainly corticosteroids and cyclosporine. In C-SLE, gingivitis was associated with longer disease period, high doses of corticosteroids, B-cell hyperactivation and immunoglobulin G elevation. There are scarce data on periodontal diseases in JDM population, and a unique gingival pattern, characterized by gingival erythema, capillary dilation and bush-loop formation, was observed in active patients. In conclusion, gingivitis was the most common periodontal disease in PRD. The observed association with disease activity reinforces the need for future studies to determine if resolution of this complication will influence disease course or severity.

  13. Huntington’s Disease

    Science.gov (United States)

    2012-05-01

    New advances in disease testing and diagnosis, such as genetic testing , now provide increased means for disease diagnosis but also possible therapeutic...treatments. Indeed, according to some experts, genetic testing and therapy may be key to future disease detection, therapy, and even prevention. In...associated with its long-term management. 15. SUBJECT TERMS Neurological disease , genetic testing , aeromedical concerns, Huntington’s disease 16

  14. Genetic diseases in adults.

    Science.gov (United States)

    Kolettis, Peter N

    2003-02-01

    Genetic diseases that do not primarily affect the genitourinary tract may have urologic manifestations. These urologic manifestations range from benign and malignant renal disease to infertility. Thus, the practicing urologist may be involved in the care of these patients and should have knowledge of these diseases. Continued improvements in the diagnosis and treatment of these genetic diseases will likely result in improved survival and will increase the number of patients who may develop urologic manifestations of these diseases.

  15. Pregnancy and periodontal disease

    OpenAIRE

    SAĞLAM, Ebru; SARUHAN, Nesrin; Çanakçı, Cenk Fatih

    2015-01-01

    Some maternal immunological changes due to pregnancy increases susceptibility to infections. Periodontal disease, the main cause is plaque, is a common disease which is seen multifactorial and varying severity. There are many clinical criteria for diagnosis of periodontal disease. Correlation between pregnancy and periodontal inflammation is known for many years. Periodontal disease affects pregnant’s systemic condition and also has negative effects on fetus. Periodontal disease increases the...

  16. Designer Self-Assemble Peptides Maximize the Therapeutic Benefits of Neural Stem Cell Transplantation for Alzheimer's Disease via Enhancing Neuron Differentiation and Paracrine Action.

    Science.gov (United States)

    Cui, Guo-hong; Shao, Shui-jin; Yang, Jia-jun; Liu, Jian-ren; Guo, Hai-dong

    2016-03-01

    maximize the therapeutic benefits of NSC transplantation for AD through improving the survival and differentiation of transplanted stem cells and promoting the effects of neuroprotection, anti-neuroinflammatory and paracrine action. Our results may have important clinical implications for the design of future NSC-based strategies using the biomaterials for various neurodegenerative diseases including AD.

  17. Dynamic changes in pro- and anti-inflammatory cytokines in microglia after PPAR-γ agonist neuroprotective treatment in the MPTPp mouse model of progressive Parkinson's disease.

    Science.gov (United States)

    Pisanu, Augusta; Lecca, Daniela; Mulas, Giovanna; Wardas, Jadwiga; Simbula, Gabriella; Spiga, Saturnino; Carta, Anna R

    2014-11-01

    Neuroinflammatory changes play a pivotal role in the progression of Parkinson's disease (PD) pathogenesis. Recent findings have suggested that activated microglia may polarize similarly to peripheral macrophages in the central nervous system (CNS), assuming a pro-inflammatory M1 phenotype or the alternative anti-inflammatory M2 phenotype via cytokine production. A skewed M1 activation over M2 has been related to disease progression in Alzheimer disease, and modulation of microglia polarization may be a therapeutic target for neuroprotection. By using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-probenecid (MPTPp) mouse model of progressive PD, we investigated dynamic changes in the production of pro-inflammatory cytokines, such as tumor necrosis factor (TNF)-α and interleukin (IL)-1β, and anti-inflammatory cytokines, such as transforming growth factor (TGF)-β and IL-10, within Iba-1-positive cells in the substantia nigra compacta (SNc). In addition, to further characterize changes in the M2 phenotype, we measured CD206 in microglia. Moreover, in order to target microglia polarization, we evaluated the effect of the peroxisome-proliferator-activated receptor (PPAR)-γ agonist rosiglitazone, which has been shown to exert neuroprotective effects on nigral dopaminergic neurons in PD models, and acts as a modulator of cytokine production and phenotype in peripheral macrophages. Chronic treatment with MPTPp induced a progressive degeneration of SNc neurons. The neurotoxin treatment was associated with a gradual increase in both TNF-α and IL-1β colocalization with Iba-1-positive cells, suggesting an increase in pro-inflammatory microglia. In contrast, TGF-β colocalization was reduced by the neurotoxin treatment, while IL-10 was mostly unchanged. Administration of rosiglitazone during the full duration of MPTPp treatment reverted both TNF-α and IL-1β colocalization with Iba-1 to control levels. Moreover, rosiglitazone induced an increase in TGF-β and IL-10

  18. The Relationship Between Fatty Liver Disease and Periodontal Disease

    Science.gov (United States)

    2017-03-22

    Periodontitis is a highly prevalent and destructive chronic disease. Numerous studies support an association between periodontal disease and other...systemic diseases ( diabetes , cardiovascular disease, chronic kidney disease, adverse pregnancy outcome, etc.). Non-alcoholic fatty liver disease is a...destruction seen in periodontal disease. The association between the two diseases has never been investigated. A reasonable mechanism in which periodontal

  19. Tay-Sachs Disease

    Science.gov (United States)

    ... Craniosynostosis Information Page Creutzfeldt-Jakob Disease Information Page Cushing's Syndrome Information Page Dandy-Walker Syndrome Information Page Deep Brain Stimulation for Parkinson's Disease Information Page Dementia Information ...

  20. Infantile Refsum Disease

    Science.gov (United States)

    ... Craniosynostosis Information Page Creutzfeldt-Jakob Disease Information Page Cushing's Syndrome Information Page Dandy-Walker Syndrome Information Page Deep Brain Stimulation for Parkinson's Disease Information Page Dementia Information ...