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Sample records for inflammatory demyelinating lesions

  1. Astrocytes as potential targets to suppress inflammatory demyelinating lesions in multiple sclerosis.

    PubMed

    De Keyser, Jacques; Laureys, Guy; Demol, Frauke; Wilczak, Nadine; Mostert, Jop; Clinckers, Ralph

    2010-11-01

    A hallmark of multiple sclerosis (MS) is the occurrence of focal inflammatory demyelinating lesions in the central nervous system. The prevailing view that activated anti-myelin T cells inherently mediate these lesions has been challenged after observations that these T cells, which are part of the normal immune repertoire, can also intermittently become activated in healthy people and subjects with other diseases. Astrocytes in the white matter of subjects with MS are deficient in beta(2) adrenergic receptors. Stimulation of beta(2) adrenergic receptors increases cAMP, leading to activation of protein kinase A (PKA). beta(2) adrenergic receptor deficiency will reduce the suppressive action of PKA on coactivator class II transactivator (CIITA), which is a key regulator of interferon gamma-induced major histocompatibility (MHC) class II molecule transcription. The expression of MHC class II may deviate astrocytes to function as facultative antigen presenting cells, which can then initiate the inflammatory cascade. In a proof of concept study in MS subjects it was shown that fluoxetine, which activates PKA in astrocytes, reduced the development of focal inflammatory lesions. If confirmed and extended by additional studies, suppressing the antigen presenting capacity of astrocytes could be a novel therapeutic option for the treatment of MS. PMID:20178822

  2. Demyelinative chiamal lesions.

    PubMed

    Spector, R H; Glaser, J S; Schatz, N J

    1980-12-01

    To clarify the clinical syndrome of demyelinative chiasmal involvement, six case histories were analyzed and the literature was reviewed. This entitity is characterized by especial predilection for women in the third to fifth decades; visual deficites of a chiasmal pattern that may be modest to marked, with a generallly good prognosis for functional recovery; and other signs and symptoms, not necessarily severe, of scattered lesions of the neuraxis. Neuroradiological studies, especially laminography of the sellar area and computerized tomography, must be employed to rule out a suprasellar mass lesion. The efficacy of systemic corticosteroid therapy is moot, but it seems reasonable to use such agents during acute stages, especially where vision is severely reduced on both sides. PMID:7447764

  3. Chronic Inflammatory Demyelinating Polyneuropathy

    PubMed Central

    Dimachkie, Mazen M.; Barohn, Richard J.

    2014-01-01

    Opinion statement Chronic Inflammatory polyneuropathies are an important group of neuromuscular disorders that present chronically and progress over more than 8 weeks, being referred to as chronic inflammatory demyelinating polyneuropathy (CIDP). Despite tremendous progress in elucidating disease pathogenesis, the exact triggering event remains unknown. Our knowledge regarding diagnosis and management of CIDP and its variants continues to expand, resulting in improved opportunities for identification and treatment. Most clinical neurologists will be involved in the management of patients with these disorders, and should be familiar with available therapies for CIDP. We review the distinctive clinical, laboratory, and electro-diagnostic features that aid in diagnosis. We emphasize the importance of clinical patterns that define treatment responsiveness and the most appropriate therapies in order to improve prognosis. PMID:23564314

  4. Tumefactive Demyelinating Lesions in Multiple Sclerosis and Associated Disorders.

    PubMed

    Frederick, Meredith C; Cameron, Michelle H

    2016-03-01

    Tumefactive demyelinating lesions are rare consequences of central nervous system (CNS) idiopathic inflammatory demyelinating diseases. Tumefactive demyelinating lesions pose a diagnostic challenge because they can mimic tumors and abscesses and because they can be caused by a heterogeneous range of disorders. This article reviews the recent literature on the clinical presentation; radiographic features; prognosis; and management of tumefactive demyelinating lesions in multiple sclerosis, acute demyelinating encephalomyelitis, neuromyelitis optica, and the rare variants of multiple sclerosis including Schilder's disease, Marburg acute multiple sclerosis, and Balo's concentric sclerosis. PMID:26847090

  5. Inflammatory demyelinating neuropathies.

    PubMed

    Muley, Suraj Ashok; Parry, Gareth J

    2009-05-01

    Early and effective treatment of chronic inflammatory demyelinating polyneuropathy (CIDP) is important to minimize axonal degeneration that occurs secondary to demyelination. The disease course is invariably chronic, so long-term treatment is often required, and adverse effects and costs are important considerations in devising a treatment plan. CIDP responds to prednisone, but long-term treatment can result in significant adverse effects. Azathioprine, mycophenolate mofetil, and cyclosporine can be used as steroid-sparing agents and may facilitate more rapid and successful tapering of prednisone. Intravenous immunoglobulin (IVIg) and plasma exchange are also effective in the treatment of CIDP and can be used in patients who are unresponsive to prednisone or develop steroid-related adverse effects. IVIg may also be used as a first-line treatment, but its cost can be a limiting factor. A few uncontrolled studies have suggested that pulsed weekly methylprednisolone is both effective and well tolerated in the long-term treatment of CIDP. Treatments based on rituximab or cyclophosphamide have also been used in resistant disease. Variants of CIDP have been described on the basis of their association with specific antibodies or immunoglobulins and their response to specific immunomodulatory treatments. Multifocal motor neuropathy with conduction block responds to IVIg in the majority of patients. However, weakness may slowly worsen over time, and some patients become unresponsive. Anecdotal reports suggest that rituximab may be useful in patients who develop progressive disease. Placebo-controlled trials in anti-myelin-associated glycoprotein neuropathy suggest that rituximab is effective and, with a combination of prednisone and cyclophosphamide, numbness and strength may improve. Other treatments that may be effective include plasma exchange and IVIg. Treatment is generally started with prednisone, IVIg, or plasma exchange. Rituximab and cyclophosphamide are used only

  6. Chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Mathey, Emily K; Pollard, John D

    2013-10-15

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is the commonest treatable neuropathy in the western world. Untreated it may result in severe disability but if diagnosed and treated early there is effective treatment for the majority of patients. Typical CIDP is readily recognised but the diagnosis of other subgroups can be more challenging. The pathology of polyradiculoneuropathies such as CIDP characteristically affects the most proximal regions of the peripheral nervous system, nerve roots and major plexuses. It is important to test these regions with electrodiagnostic studies since routine neurophysiology may not encounter regions of pathology. Although accepted as an autoimmune disorder with an underlying immunopathology involving T cell and B cell responses, there is no agreement on major target antigens; however recent studies have highlighted a role for molecules in non compact myelin which play an essential role in the formation and maintenance of the nodal structures and hence in the function of ion channels central to saltatory conduction. Controlled trials have proven the efficacy of corticosteroid, intravenous immunoglobulin and plasma exchange in the short term and intravenous immunoglobulin also in the long term. Immunosuppressive agents are widely used but their efficacy has not been proven in controlled trials. Recent trials have shown the importance of attempting treatment withdrawal in patients apparently in remission to conserve treatments that are very expensive and in short supply, since a significant proportion of patients may enter long lasting remission following short term therapy. For the relatively small group of patients who do not respond to these first line therapies new agents including monoclonal antibodies may have a role. PMID:23146613

  7. Review: the architecture of inflammatory demyelinating lesions: implications for studies on pathogenesis.

    PubMed

    Lassmann, H

    2011-12-01

    Recent technological advances provided the chance to analyse the molecular events involved in the pathogenesis of lesions in human disease. A major prerequisite for such studies is, however, that the pathological material used is exactly defined and characterized. In multiple sclerosis (MS), this is difficult, as several types of active lesions exist, depending upon the stage of the disease, the age and location of these lesions and the inter-individual differences between patients. In addition, within an active lesion, different closely adjacent zones are present reflecting initial tissue injury, debris removal or repair. Here evidence is reviewed, showing that distinct subareas of active MS lesions reflect different pathological hallmarks of lesion evolution. These data provide the basis for our understanding of the pathogenesis of tissue injury in MS and imply that studies on MS pathogenesis have to rely on a clear definition of the lesions analysed and have to focus on specific lesion areas, isolated by microdissection. In addition, these data also imply that molecules, identified in these studies, must be confirmed and validated in the correct context of lesion initiation and/or progression. PMID:21696413

  8. Atypical inflammatory demyelinating syndromes of the CNS.

    PubMed

    Hardy, Todd A; Reddel, Stephen W; Barnett, Michael H; Palace, Jacqueline; Lucchinetti, Claudia F; Weinshenker, Brian G

    2016-08-01

    Atypical inflammatory demyelinating syndromes are rare disorders that differ from multiple sclerosis owing to unusual clinical or MRI findings or poor response to treatments used for multiple sclerosis. These syndromes include neuromyelitis optica spectrum disorder, acute disseminated encephalomyelitis, tumefactive demyelination, Baló's concentric sclerosis, Schilder's disease, and Marburg's multiple sclerosis. The overlapping features of these syndromes with multiple sclerosis and with each other complicate diagnosis and their categorisation as distinct or related conditions. Recognition of these syndromes is crucial because they differ from multiple sclerosis and other demyelinating and non-demyelinating conditions in their prognosis and treatment. Advances in MRI, pathology, and immunobiology are needed to increase understanding of these syndromes, including the extent to which some of them represent distinct entities, and to assist with improvements in their diagnosis and management. PMID:27478954

  9. Inflammatory demyelination and neurodegeneration in early multiple sclerosis.

    PubMed

    Charil, Arnaud; Filippi, Massimo

    2007-08-15

    A number of recent magnetic resonance imaging studies have challenged the classical view of multiple sclerosis (MS) as a "two-stage" disease where an early inflammatory demyelinating phase with focal macroscopic lesions formed in the white matter (WM) of the central nervous system is followed by a late neurodegenerative phase, which is believed to be a mere consequence of repeated inflammatory insults and irreversible demyelination. These studies have consistently shown the presence of diffuse normal-appearing WM damage, marked gray matter involvement and significant cortical functional reorganization, as well as the occurrence of the neurodegenerative component of MS from the earliest clinical stages of the disease with only a partial relation to MRI markers of inflammatory demyelination. The present review argues that MS can no longer be viewed as a "two-stage" disease, which suggests that the two pathological components are dissociated in time, but rather as a "simultaneous two-component" disease, where the relative contributions of the various pathological processes of the disease to the development of "fixed" disability, their relationship and their evolution over time need to be clarified. This new view of MS should inform the development of future research protocols to define its actual physiopathology and prompt the institution of early treatment which should ideally target not only inflammatory demyelination, but also the neurodegenerative aspects of the disease, as well as promote neuroprotection and enhance reparative mechanisms and adaptive functional reorganization of the cortex. PMID:17397873

  10. MNGIE neuropathy: five cases mimicking chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Bedlack, Richard S; Vu, Tuan; Hammans, Simon; Sparr, Steven A; Myers, Bennett; Morgenlander, Joel; Hirano, Michio

    2004-03-01

    We report five patients with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) who had demyelinating peripheral neuropathy. The MNGIE neuropathy had clinical and electrodiagnostic features typical of acquired, rather than inherited, etiologies. In fact, three patients were actually treated for chronic inflammatory demyelinating polyneuropathy (CIDP). We discuss findings that may help distinguish patients with MNGIE from those with CIDP. PMID:14981734

  11. Progressive chronic inflammatory demyelinating polyneuropathy in a child with central nervous system involvement and myopathy.

    PubMed

    Barisić, Nina; Horvath, Rita; Grković, Lana; Mihelcić, Dina; Luetić, Tomislav

    2006-12-01

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is a chronic disorder, manifesting with monophasic or relapsing course. Progressive course is rare in children. The article presents a boy with progressive generalized muscle weakness and areflexia since the age of two, developed after viral infection. Electromyoneurography showed severe neurogenic lesion, with myopathic pattern in proximal muscles. Increased serum ganglioside antibody titers (anti-GM1 and anti-GD1b) were registered. Sural nerve biopsy revealed demyelination and onion bulbs. Inflammatory perivascular CD3 positive infiltrates were present in muscle and nerve biopsies. Brain magnetic resonance imaging showed cortical atrophy, hyperintensities of the white matter and gray matter hypointensities. Improvement occurred on intravenous immune globulins and methylprednisolone treatment. Demyelination might develop in central and peripheral nervous system associated with inflammatory myopathy in patients with progressive course of CIDP. PMID:17243577

  12. Chronic Inflammatory Demyelinating Polyradiculoneuropathy: From Bench to Bedside

    PubMed Central

    Peltier, Amanda C.; Donofrio, Peter D.

    2015-01-01

    Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) is the most common treatable chronic autoimmune neuropathy. Multiple diagnostic criteria have been established, with the primary goal of identifying neurophysiologic hallmarks of acquired demyelination. Treatment modalities have expanded to include numerous immuno-modulatory therapies, although the best evidence continues to be for corticosteroids, plasma exchange, and intravenous immunoglobulins (IVIg). This review describes the pathology, epidemiology, pathogenesis, diagnosis, and treatment of CIDP. PMID:23117943

  13. Cervical demyelinating lesion presenting with choreoathetoid movements and dystonia.

    PubMed

    de Pasqua, Silvia; Cevoli, Sabina; Calbucci, Fabio; Liguori, Rocco

    2016-09-15

    Pseudoathetosis and dystonia are rare manifestations of spinal cord disease that have been already reported in lesions involving the posterior columns at the cervical level. We report two patients with a cervical demyelinating lesion at C3-C4 level presenting with hand dystonia and pseudoathetoid movements. The movement disorder disappeared after steroid treatment. The cases we described highlight the importance of identifying secondary causes of movement disorders that can be reversible with appropriate therapy. PMID:27538633

  14. Structural brain lesions in inflammatory bowel disease

    PubMed Central

    Dolapcioglu, Can; Dolapcioglu, Hatice

    2015-01-01

    Central nervous system (CNS) complications or manifestations of inflammatory bowel disease deserve particular attention because symptomatic conditions can require early diagnosis and treatment, whereas unexplained manifestations might be linked with pathogenic mechanisms. This review focuses on both symptomatic and asymptomatic brain lesions detectable on imaging studies, as well as their frequency and potential mechanisms. A direct causal relationship between inflammatory bowel disease (IBD) and asymptomatic structural brain changes has not been demonstrated, but several possible explanations, including vasculitis, thromboembolism and malnutrition, have been proposed. IBD is associated with a tendency for thromboembolisms; therefore, cerebrovascular thromboembolism represents the most frequent and grave CNS complication. Vasculitis, demyelinating conditions and CNS infections are among the other CNS manifestations of the disease. Biological agents also represent a risk factor, particularly for demyelination. Identification of the nature and potential mechanisms of brain lesions detectable on imaging studies would shed further light on the disease process and could improve patient care through early diagnosis and treatment. PMID:26600970

  15. Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases.

    PubMed

    Bar-Or, Amit; Hintzen, Rogier Q; Dale, Russell C; Rostasy, Kevin; Brück, Wolfgang; Chitnis, Tanuja

    2016-08-30

    Elucidating pathophysiologic mechanisms underlying the spectrum of pediatric-onset CNS demyelinating diseases, particularly those that may distinguish multiple sclerosis (MS) from other entities, promises to both improve diagnostics and guide more-informed therapeutic decisions. Observations that pediatric- and adult-onset MS share the same genetic and environmental risk factors support the view that these conditions represent essentially the same illness manifesting at different ages. Nonetheless, special consideration must be given when CNS inflammation manifests in early life, at a time when multiple organs (including immune and nervous systems) are actively maturing. CSF analysis in pediatric-onset MS points to chronic CNS inflammation, supported by observations from limited pathologic material available for study. Emerging results implicate abnormalities in both effector and regulatory T cell subsets, and potentially immune senescence, in children with MS. Although CNS-directed antibodies (including antibodies recognizing myelin antigens; Kir4.1) can be documented in pediatric-onset MS, their pathophysiologic significance (as in adults) remains unclear. This is in contrast to the presence of serum and/or CSF antibodies recognizing aquaporin-4, which, when measured using validated cell-based assays, supports the diagnosis of a neuromyelitis optica spectrum disorder, distinct from MS. Presence of anti-myelin oligodendrocyte glycoprotein antibodies documented with similar cell-based assays may also be associated with pathophysiologically distinct disease phenotypes in children. The substantial impact of pediatric-onset MS on normal brain development and function underscores the importance of elucidating both the immunobiology and neurobiology of disease. Ongoing efforts are aimed at developing and validating biological measures that define pathophysiologically distinct monophasic and chronic forms of pediatric CNS demyelination. PMID:27572856

  16. Lesion Expansion in Experimental Demyelination Animal Models and Multiple Sclerosis Lesions.

    PubMed

    Große-Veldmann, René; Becker, Birte; Amor, Sandra; van der Valk, Paul; Beyer, Cordian; Kipp, Markus

    2016-09-01

    Gray matter pathology is an important aspect of multiple sclerosis (MS) pathogenesis and disease progression. In a recent study, we were able to demonstrate that the higher myelin content in the white matter parts of the brain is an important variable in the neuroinflammatory response during demyelinating events. Whether higher white matter myelination contributes to lesion development and progression is not known. Here, we compared lesion size of intra-cortical vs. white matter MS lesions. Furthermore, dynamics of lesion development was compared in the cuprizone and lysophosphatidylcholine models. We provide clear evidence that in the human brain, white matter lesions are significantly increased in size as compared to intra-cortical gray matter lesions. In addition, studies using the cuprizone mouse model revealed that the autonomous progression of white matter lesions is more severe compared to that in the gray matter. Focal demyelination revealed that the application of equal amounts of lysophosphatidylcholine results in more severe demyelination in the white compared to the gray matter. In summary, lesion progression is most intense in myelin-rich white matter regions, irrespective of the initial lesion trigger mechanism. A better understanding of myelin debris-triggered lesion expansion will pave the way for the development of new protective strategies in the future. PMID:26363796

  17. Multifocal inflammatory demyelination in a patient with rheumatoid arthritis and treatment complications.

    PubMed

    Lu, Jian-Qiang; Ringrose, Jennifer; Gross, Donald; Emery, Derek; Blevins, Gregg; Power, Christopher

    2016-08-15

    Rheumatoid arthritis (RA) and multiple sclerosis (MS) are both autoimmune diseases that share similar pathogenesis, but the development of MS in RA patients without the treatment of anti-tumor necrosis factor-alpha is rarely reported, which might be attributed to the use of other medications with potential immunosuppressive effects in the treatment of RA. Since MS can be clinically silent and autopsy examination of the central nervous system in RA patients is rarely described, the association of MS with RA may be possibly under-recognized. We report an autopsy case revealing multifocal inflammatory demyelination in a RA patient who had a prolonged use of methotrexate and hydroxychloroquine resulting in hydroxychloroquine-induced myopathies and heart failure. The neuropathological features of this case are consistent with MS, although there are some altered inflammatory demyelinating features such as relatively smaller lesions and less infiltration of inflammatory cells, particularly T-cells. Our present case, in combination with literature review, suggests that the RA treatment especially with hydroxychloroquine and methotrexate is likely to alter the characteristics of inflammatory demyelination and disease course. PMID:27423608

  18. Fibrillary glomerulonephritis combined with chronic inflammatory demyelinating polyneuropathy

    PubMed Central

    Sung, Woo Kyung; Jeong, Jin Uk; Bang, Ki Tae; Shin, Jong Ho; Yoo, Ji Hyung; Kim, Nak Min; Park, Jun Hyung; Kim, Joo Heon

    2015-01-01

    A 58-yr-old man presented with leg edema and subacute weakness of his bilateral lower extremities. Urinary and serum immunoelectrophoresis revealed the presence of lambda-type Bence Jones proteins. He was ultimately diagnosed with monoclonal gammopathy of undetermined significance (MGUS). A renal biopsy specimen showed fibrillary glomerulonephritis (FGN), which was randomly arranged as 12–20 m nonbranching fibrils in the basement membranes. Immunofluorescence studies were negative for immunoglobulin (Ig)G, IgM, IgA, C3, and kappa light chains in the capillary walls and mesangial areas. A Congo red stain for amyloid was negative. Electromyography and nerve conduction velocity examinations results were compatible with the presence of demyelinating polyneuropathy. This case showed a rare combination of FGN, without Ig deposition, and MGUS combined with chronic inflammatory demyelinating polyneuropathy (CIDP). PMID:26484033

  19. Fibrillary glomerulonephritis combined with chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Sung, Woo Kyung; Jeong, Jin Uk; Bang, Ki Tae; Shin, Jong Ho; Yoo, Ji Hyung; Kim, Nak Min; Park, Jun Hyung; Kim, Joo Heon

    2015-06-01

    A 58-yr-old man presented with leg edema and subacute weakness of his bilateral lower extremities. Urinary and serum immunoelectrophoresis revealed the presence of lambda-type Bence Jones proteins. He was ultimately diagnosed with monoclonal gammopathy of undetermined significance (MGUS). A renal biopsy specimen showed fibrillary glomerulonephritis (FGN), which was randomly arranged as 12-20 m nonbranching fibrils in the basement membranes. Immunofluorescence studies were negative for immunoglobulin (Ig)G, IgM, IgA, C3, and kappa light chains in the capillary walls and mesangial areas. A Congo red stain for amyloid was negative. Electromyography and nerve conduction velocity examinations results were compatible with the presence of demyelinating polyneuropathy. This case showed a rare combination of FGN, without Ig deposition, and MGUS combined with chronic inflammatory demyelinating polyneuropathy (CIDP). PMID:26484033

  20. Treatment of chronic inflammatory demyelinating polyradiculoneuropathy with methotrexate

    PubMed Central

    Fialho, D; Chan, Y‐C; Allen, D C; Reilly, M M; Hughes, R A C

    2006-01-01

    We discovered many reports of other immunosuppressive drugs being used in adults with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) but none of methotrexate. As weekly low dose oral methotrexate is safe, effective, and well tolerated in other diseases, we treated 10 patients with otherwise treatment resistant CIDP. Seven showed improvement in strength by at least two points on the MRC sum score and three worsened. Only two showed an improvement in disability and both were also receiving corticosteroids. We discuss the difficulty of detecting an improvement in treatment resistant CIDP and propose methotrexate as a suitable agent for testing in a randomised trial. PMID:16543541

  1. Autoantibodies against vinculin in patients with chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Beppu, Minako; Sawai, Setsu; Satoh, Mamoru; Mori, Masahiro; Kazami, Takahiro; Misawa, Sonoko; Shibuya, Kazumoto; Ishibashi, Masumi; Sogawa, Kazuyuki; Kado, Sayaka; Kodera, Yoshio; Nomura, Fumio; Kuwabara, Satoshi

    2015-10-15

    To identify the target molecules of chronic inflammatory demyelinating polyneuropathy (CIDP), we used proteomic-based approach in the extracted proteins from porcine cauda equina. Two of 31 CIDP patients had markedly elevated serum autoantibodies against vinculin, a cell adhesion protein. Both of the patients with anti-vinculin antibodies had similar clinical manifestation, which are compatible with those of "typical" CIDP. Immunocytochemistry showed that vinculin was stained at the myelin sheath of the sciatic nerves by serum samples. Our results suggest that vinculin is a possible immunological target molecule in a subpopulation of typical CIDP patients. PMID:26439954

  2. Progesterone and nestorone promote myelin regeneration in chronic demyelinating lesions of corpus callosum and cerebral cortex.

    PubMed

    El-Etr, Martine; Rame, Marion; Boucher, Celine; Ghoumari, Abdel M; Kumar, Narender; Liere, Philippe; Pianos, Antoine; Schumacher, Michael; Sitruk-Ware, Regine

    2015-01-01

    Multiple Sclerosis affects mainly women and consists in intermittent or chronic damages to the myelin sheaths, focal inflammation, and axonal degeneration. Current therapies are limited to immunomodulators and antiinflammatory drugs, but there is no efficient treatment for stimulating the endogenous capacity of myelin repair. Progesterone and synthetic progestins have been shown in animal models of demyelination to attenuate myelin loss, reduce clinical symptoms severity, modulate inflammatory responses and partially reverse the age-dependent decline in remyelination. Moreover, progesterone has been demonstrated to promote myelin formation in organotypic cultures of cerebellar slices. In the present study, we show that progesterone and the synthetic 19-nor-progesterone derivative Nestorone® promote the repair of severe chronic demyelinating lesions induced by feeding cuprizone to female mice for up to 12 weeks. Progesterone and Nestorone increase the density of NG2(+) oligodendrocyte progenitor cells and CA II(+) mature oligodendrocytes and enhance the formation of myelin basic protein (MBP)- and proteolipid protein (PLP)-immunoreactive myelin. However, while demyelination in response to cuprizone was less marked in corpus callosum than in cerebral cortex, remyelination appeared earlier in the former. The remyelinating effect of progesterone was progesterone receptor (PR)-dependent, as it was absent in PR-knockout mice. Progesterone and Nestorone also decreased (but did not suppress) neuroinflammatory responses, specifically astrocyte and microglial cell activation. Therefore, some progestogens are promising therapeutic candidates for promoting the regeneration of myelin. PMID:25092805

  3. Chronic inflammatory demyelinating polyradiculoneuropathy: from pathology to phenotype

    PubMed Central

    Mathey, Emily K; Park, Susanna B; Hughes, Richard A C; Pollard, John D; Armati, Patricia J; Barnett, Michael H; Taylor, Bruce V; Dyck, P James B; Kiernan, Matthew C; Lin, Cindy S-Y

    2015-01-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an inflammatory neuropathy, classically characterised by a slowly progressive onset and symmetrical, sensorimotor involvement. However, there are many phenotypic variants, suggesting that CIDP may not be a discrete disease entity but rather a spectrum of related conditions. While the abiding theory of CIDP pathogenesis is that cell-mediated and humoral mechanisms act together in an aberrant immune response to cause damage to peripheral nerves, the relative contributions of T cell and autoantibody responses remain largely undefined. In animal models of spontaneous inflammatory neuropathy, T cell responses to defined myelin antigens are responsible. In other human inflammatory neuropathies, there is evidence of antibody responses to Schwann cell, compact myelin or nodal antigens. In this review, the roles of the cellular and humoral immune systems in the pathogenesis of CIDP will be discussed. In time, it is anticipated that delineation of clinical phenotypes and the underlying disease mechanisms might help guide diagnostic and individualised treatment strategies for CIDP. PMID:25677463

  4. [Methylprednisolone pulse in treatment of childhood chronic inflammatory demyelinating polyneuropathy].

    PubMed

    Rafai, M A; Boulaajaj, F Z; Sekkat, Z; El Moutawakkil, B; Slassi, I

    2010-09-01

    Chronic inflammatory demyelinating polyneuropathy (CIDP) in children is rare and treatment is based primarily on intravenous immunoglobulins or oral corticosteroids. Boluses of methylprednisolone (MP) are a possible alternative. We report 3 cases of CIDP in children with good outcome after MP pulse therapy. One male (7 years of age) and 2 females (4 and 5 years of age) presented with recurring episodes of functional impotence of both lower limbs and walking impairment, partially reversible without treatment. Clinical and electrophysiological data and the analysis of the cerebrospinal fluid were compatible with CIDP. MP pulses were administered: the total number of pulses varied from 5 to 8, very satisfactory progression on the clinical and electrophysiological pattern was noted, without recurrence in the 3 cases. Childhood CIDP presents clinical, electrophysiological outcome, and prognostic particularities, recurring readily, and the outcome is good. Boluses of MP are an alternative for treatment of these neuropathies in childhood. PMID:20709511

  5. Chronic inflammatory demyelinating polyneuropathy associated with diabetes mellitus

    PubMed Central

    Fatehi, Farzad; Nafissi, Shahriar; Basiri, Keivan; Amiri, Mostafa; Soltanzadeh, Akbar

    2013-01-01

    Various forms of neuropathy are seen diabetic patients; chronic inflammatory demyelinating polyneuropathy (CIDP) seems not to be infrequent neuropathy in patients suffering from diabetes and it seems to be more common than in the general population; on the contrary, some authorities do not support pathogenetic association between diabetes mellitus (DM) and CIDP. Also, there are some controversies on the subject of CIDP treatment in diabetic patients. Some studies showed that patients with CIDP-DM considerably had recovered following treatment with immunotherapeutic modalities like (Intravenous immunoglobulin) IVIG and conversely, some else have argued against the prescription of IVIG in this group and recommend treatment with corticosteroids and provided that resistant, rituximab may be beneficial. The main limitation in most studies is the inadequate number of cases and as a result, problematic decision making in treatment. This article represents an inclusive review of diabetic CIDP presentation and treatment. PMID:24174953

  6. Novel immunotherapeutic strategies in chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Mathis, Stéphane; Vallat, Jean-Michel; Magy, Laurent

    2016-02-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a chronic immune-mediated neuropathy: it is clinically heterogeneous (relapsing-remitting form, chronic progressive form, monophasic form or CIDP having a Guillain-Barré syndrome-like onset), but potentially treatable. Although its pathophysiology remains largely unknown, CIDP is considered an immune-mediated neuropathy. Therefore, many immunotherapies have been proposed in this peripheral nervous system disorder, the most known efficient treatments being intravenous immunoglobulin, corticosteroids and plasma exchange. However, these therapies remain unsatisfactory for many patients, so numerous other immunotherapeutic strategies have been evaluated, based on their immunosuppressant or immunomodulatory potency. We have performed a large review of the literature about treatment in CIDP, with a special emphasis on novel and alternative immunotherapeutic strategies. PMID:26809024

  7. Improving the management of chronic inflammatory demyelinating polyradiculoneuropathy.

    PubMed

    Allen, Jeffrey A; Bril, Vera

    2016-06-01

    This article considers several issues of current interest relating to the management of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), including diagnostic pitfalls, differences between CIDP patients with and without concurrent diabetes mellitus and how to best measure treatment response in daily practice. Despite the availability of diagnostic criteria, many patients diagnosed with CIDP do not meet these criteria; reasons for misdiagnosis are discussed. There are no definitive predictors of treatment response in CIDP; however, certain clinical and electrophysiological characteristics may be helpful. Patients with CIDP and concurrent diabetes present an additional diagnostic challenge; the differences between these groups, including possible differences in response predictors are discussed. Finally, the most appropriate outcome measures for use in daily practice are considered. PMID:27230584

  8. [Subcutaneous immunoglobulin. Treatment in chronic inflammatory demyelinating polyradiculo-neuropathy].

    PubMed

    Nogués, Martín A; Varela, Francisco J; Seminario, Gisela; Insúa, María C; Bezrodnik, Liliana

    2016-01-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired disease that may affect nerve roots and peripheral nerves. Despite its low incidence, diagnosis is particularly important because there are different effective treatments. Human immunoglobulin is one of the mainstays of the treatment. Although there are few studies up to date, subcutaneous immunoglobulin (IgSC) has been proposed as an alternative to intravenous administration with similar efficacy. We present three cases with definite CIDP, classified according to the European Federation of Neurological Societies / Peripheral Nerve, Society (EFNS /PNS) criteria in which was used SCIgG as a treatment after success with the intravenous route. The Overall Neuropathy Limitations Scale (ONLS) was used to estimate the changes in the muscular strength before and after treatment. PMID:26826992

  9. Pathophysiology and biomarkers in chronic inflammatory demyelinating polyradiculoneuropathies.

    PubMed

    Svahn, J; Antoine, J-C; Camdessanché, J-P

    2014-12-01

    Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an acquired dysimmune disorder characterized by strong heterogeneity in terms of clinical manifestations, prognostic and response to treatment. To date, its pathophysiology and potential target antigens are not totally identified despite substantial progress in the understanding of the involved molecular mechanisms. Recent researches in the field have underlined the importance of cell-mediated immunity (lymphocytesT CD4+, CD8+ and macrophages), the breakdown of blood-nerve barrier, a failure of T-cell regulation, and the disruption of nodal and paranodal organization at the node of Ranvier. This last point is possibly mediated by autoantibodies towards axoglial adhesion molecules which may disrupt sodium and potassium voltage-gated channels clustering leading to a failure of saltatory conduction and the apparition of conduction blocks. The purpose of this article is to overview the main pathophysiologic mechanisms and biomarkers identified in CIDP. PMID:25459126

  10. Cause and prevention of demyelination in a model multiple sclerosis lesion

    PubMed Central

    Davies, Andrew L.; Tachrount, Mohamed; Kasti, Marianne; Laulund, Frida; Golay, Xavier; Smith, Kenneth J.

    2016-01-01

    Objective Demyelination is a cardinal feature of multiple sclerosis, but it remains unclear why new lesions form, and whether they can be prevented. Neuropathological evidence suggests that demyelination can occur in the relative absence of lymphocytes, and with distinctive characteristics suggestive of a tissue energy deficit. The objective was to examine an experimental model of the early multiple sclerosis lesion and identify pathogenic mechanisms and opportunities for therapy. Methods Demyelinating lesions were induced in the rat spinal dorsal column by microinjection of lipopolysaccharide, and examined immunohistochemically at different stages of development. The efficacy of treatment with inspired oxygen for 2 days following lesion induction was evaluated. Results Demyelinating lesions were not centered on the injection site, but rather formed 1 week later at the white–gray matter border, preferentially including the ventral dorsal column watershed. Lesion formation was preceded by a transient early period of hypoxia and increased production of superoxide and nitric oxide. Oligodendrocyte numbers decreased at the site shortly afterward, prior to demyelination. Lesions formed at a site of inherent susceptibility to hypoxia, as revealed by exposure of naive animals to a hypoxic environment. Notably, raising the inspired oxygen (80%, normobaric) during the hypoxic period significantly reduced or prevented the demyelination. Interpretation Demyelination characteristic of at least some early multiple sclerosis lesions can arise at a vascular watershed following activation of innate immune mechanisms that provoke hypoxia, and superoxide and nitric oxide formation, all of which can compromise cellular energy sufficiency. Demyelination can be reduced or eliminated by increasing inspired oxygen to alleviate the transient hypoxia. Ann Neurol 2016;79:591–604 PMID:26814844

  11. Calreticulin and other components of endoplasmic reticulum stress in rat and human inflammatory demyelination

    PubMed Central

    2013-01-01

    Background Calreticulin (CRT) is a chaperone protein, which aids correct folding of glycosylated proteins in the endoplasmic reticulum (ER). Under conditions of ER stress, CRT is upregulated and may be displayed on the surface of cells or be secreted. This ‘ecto-CRT’ may activate the innate immune response or it may aid clearance of apoptotic cells. Our and other studies have demonstrated upregulation of ER stress markers CHOP, BiP, ATF4, XBP1 and phosphorylated e-IF2 alpha (p-eIF2 alpha) in biopsy and post-mortem human multiple sclerosis (MS) samples. We extend this work by analysing changes in expression of CRT, BiP, CHOP, XBP1 and p-eIF2 alpha in a rat model of inflammatory demyelination. Demyelination was induced in the spinal cord by intradermal injection of recombinant mouse MOG mixed with incomplete Freund’s adjuvant (IFA) at the base of the tail. Tissue samples were analysed by semi-quantitative scoring of immunohistochemically stained frozen tissue sections. Data generated following sampling of tissue from animals with spinal cord lesions, was compared to that obtained using tissue derived from IFA- or saline-injected controls. CRT present in rat serum and in a cohort of human serum derived from 14 multiple sclerosis patients and 11 healthy controls was measured by ELISA. Results Stained tissue scores revealed significantly (p<0.05) increased amounts of CRT, CHOP and p-eIF2 alpha in the lesion, lesion edge and normal-appearing white matter when compared to controls. CHOP and p-eIF2 alpha were also significantly raised in regions of grey matter and the central canal (p<0.05). Immunofluorescent dual-label staining confirmed expression of these markers in astrocytes, microglia or neurons. Dual staining of rat and human spinal cord lesions with Oil Red O and CRT antibody showed co-localisation of CRT with the rim of myelin fragments. ELISA testing of sera from control and EAE rats demonstrated significant down-regulation (p<0.05) of CRT in the serum of

  12. Electrophysiological features of POEMS syndrome and chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Guo, Xiuming; Qin, Xinyue; Zhang, Yuping; Huang, Cheng; Yu, Gang

    2014-04-01

    Polyneuropathy is often an initial manifestation of polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes (POEMS) syndrome and therefore this disorder is frequently misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). We reviewed electrophysiological data in 20 patients with POEMS syndrome and 36 matched patients with CIDP to compare the electrophysiological features of POEMS syndrome and CIDP. Compared with CIDP controls, POEMS patients demonstrated (1) less prolonged distal motor latency and less reduced motor nerve and sensory nerve conduction velocities, (2) greater reduction of amplitudes of compound motor action potentials (CMAP) in distal stimulation, and similar reduction of amplitudes of CMAP in proximal stimulation, (3) similar reduction of amplitudes of sensory nerve action potentials (SNAP) in median and ulnar nerves, and a greater reduction of amplitudes of SNAP in tibial and peroneal nerves, (4) less temporal dispersion, (5) less frequent conduction block, (6) more frequent neurogenic injury in the muscles of the upper and lower limbs, and more frequent neurogenic injury in the muscles of the lower than upper limbs, (7) similar F wave and H reflex abnormalities, and (8) less frequent skin sympathetic response abnormalities. We concluded that before development of typical clinical manifestations, POEMS neuropathy can be distinguished from CIDP by neural electrophysiological examination. These electrophysiological features can be used for early diagnosis and initiating correct treatment of POEMS syndrome. PMID:24268501

  13. Stance Postural Strategies in Patients with Chronic Inflammatory Demyelinating Polyradiculoneuropathy

    PubMed Central

    Missori, Paolo; Trompetto, Carlo; Fattapposta, Francesco

    2016-01-01

    Introduction Polyneuropathy leads to postural instability and an increased risk of falling. We investigated how impaired motor impairment and proprioceptive input due to neuropathy influences postural strategies. Methods Platformless bisegmental posturography data were recorded in healthy subjects and patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Each subject stood on the floor, wore a head and a hip electromagnetic tracker. Sway amplitude and velocity were recorded and the mean direction difference (MDD) in the velocity vector between trackers was calculated as a flexibility index. Results Head and hip postural sway increased more in patients with CIDP than in healthy controls. MDD values reflecting hip strategies also increased more in patients than in controls. In the eyes closed condition MDD values in healthy subjects decreased but in patients remained unchanged. Discussion Sensori-motor impairment changes the balance between postural strategies that patients adopt to maintain upright quiet stance. Motor impairment leads to hip postural strategy overweight (eyes open), and prevents strategy re-balancing when the sensory context predominantly relies on proprioceptive input (eyes closed). PMID:26977594

  14. Morphogenesis of the demyelinating lesions in Baló's concentric sclerosis.

    PubMed

    Barz, Helmut; Barz, Ulrich; Schreiber, Almut

    2016-06-01

    In tissues with elastic properties, an edema causes a raised tissue pressure and therefore a diminished blood flow. The authors assume that an increased tissue pressure due to local and/or relapsing edema may be the cause for incomplete necrosis (e.g. demyelinated lesions) or seldom complete necrosis in the brain. Newly forming demyelinating lesions seldom show small tissue bands with normal appearing myelin sheaths in the immediate vicinity of precursor lesions (Baló type of MS). The small myelinated bands are the result of a "protected zone" on the edge of previous demyelinated lesions. The authors explain this protected zone with two arguments. Firstly, the resorptive granulation tissue of more or less older lesions is relatively rich in capillaries. These capillaries may act as an energy reservoir that can nourish not only the plaque, but also a narrow adjacent myelinated tissue band by diffusion, even if the capillary blood flow in this tissue band is limited due to the greater tissue pressure of a new developing lesion in the neighborhood. Secondly, another protective mechanism may act simultaneously: older or more sclerosed lesions and small adherent bands of myelinated tissue with them may swell less in cases of an edema than in normal tissue. The hardening of the older lesions is caused by proliferated fiber-forming astrocytes in the sense of scarring. In an area with an increased tissue pressure, the capillaries are less compressed in a sclerosed lesion than in regions of normal grey and white matter. In addition, the adherent myelinated tissue band closest to the edge of a hardened plaque is better protected against swelling and compression than the further away tissue. Theoretically, this protection zone is comparable with protected blood vessels in the Haversian canals or the medullary spaces of bones. Both theses of protecting mechanisms at the edges of demyelinated lesions support the assumption of a hypoxic causation principle of demyelinating

  15. Acute inflammatory demyelinating polyradiculoneuropathy in a patient receiving oxaliplatin-based chemotherapy.

    PubMed

    Yoon, Ju Young; Nam, Tai Seung; Kim, Myeong Kyu; Hwang, Jun Eul; Shim, Hyun-Jeong; Cho, Sang Hee; Chung, Ik Joo; Bae, Woo Kyun

    2012-06-01

    We report a case of acute inflammatory demyelinating polyradiculoneuropathy (AIDP) that developed in a patient with cholangiocarcinoma after receiving oxaliplatin-based chemotherapy. A 62-year-old man had multiple hypodense lesions with delayed enhancement in the both lobes of the liver on abdominal computed tomography. He was treated with 5-fluorouracil, leucovorin and oxaliplatin (100 mg/m(2)). After eight cycles of treatment and a cumulative oxaliplatin dose of 780 mg/m(2), he developed an unsteady gait, dysphagia, weakness of both the upper and lower limbs and impairment of all sensory modalities. Nerve conduction studies confirmed the diagnosis of AIDP. Immunoglobulin G i.v. was administered for 5 days but the neurological deficits of both his upper and lower limbs did not improve. This case highlights unusual peripheral nervous system manifestations in a patient who received chemotherapy with oxaliplatin. PMID:22524580

  16. Clinical and Pharmacological Aspects of Inflammatory Demyelinating Diseases in Childhood: An Update

    PubMed Central

    Spalice, Alberto; Parisi, Pasquale; Papetti, Laura; Nicita, Francesco; Ursitti, Fabiana; Del Balzo, Francesca; Properzi, Enrico; Verrotti, Alberto; Ruggieri, Martino; Iannetti, Paola

    2010-01-01

    Inflammatory demyelinating diseases comprise a spectrum of disorders affecting the myelin of the central and peripheral nervous system. These diseases can usually be differentiated on the basis of clinical, radiological, laboratory and pathological findings. Recent studies have contributed to current awareness that inflammatory demyelinating diseases are not restricted to the adult age group, but are more common in pediatric age than previously believed. Some of pediatric inflammatory demyelinating diseases carry an unfavorable long-term prognosis but appropriate treatments can improve the outcome. The possibility of physical and cognitive disability resulting from these diseases, highlights the urgent need for therapeutic strategies for neurorehabilitation, neuroregeneration, and neurorepair. This review discusses characteristics of primary demyelinating diseases more frequently observed in childhood, focusing on epidemiology, clinical aspects and treatments. PMID:21119885

  17. Clinical and pharmacological aspects of inflammatory demyelinating diseases in childhood: an update.

    PubMed

    Spalice, Alberto; Parisi, Pasquale; Papetti, Laura; Nicita, Francesco; Ursitti, Fabiana; Del Balzo, Francesca; Properzi, Enrico; Verrotti, Alberto; Ruggieri, Martino; Iannetti, Paola

    2010-06-01

    Inflammatory demyelinating diseases comprise a spectrum of disorders affecting the myelin of the central and peripheral nervous system. These diseases can usually be differentiated on the basis of clinical, radiological, laboratory and pathological findings. Recent studies have contributed to current awareness that inflammatory demyelinating diseases are not restricted to the adult age group, but are more common in pediatric age than previously believed. Some of pediatric inflammatory demyelinating diseases carry an unfavorable long-term prognosis but appropriate treatments can improve the outcome. The possibility of physical and cognitive disability resulting from these diseases, highlights the urgent need for therapeutic strategies for neurorehabilitation, neuroregeneration, and neurorepair. This review discusses characteristics of primary demyelinating diseases more frequently observed in childhood, focusing on epidemiology, clinical aspects and treatments. PMID:21119885

  18. Isolated tumefactive demyelinating lesions: diagnosis and long-term evolution of 16 patients in a multicentric study.

    PubMed

    Siri, A; Carra-Dalliere, Clarisse; Ayrignac, X; Pelletier, J; Audoin, B; Pittion-Vouyovitch, S; Debouverie, M; Lionnet, C; Viala, F; Sablot, D; Brassat, D; Ouallet, J-C; Ruet, A; Brochet, B; Taillandier, L; Bauchet, L; Derache, N; Defer, G; Cabre, P; de Seze, J; Lebrun Frenay, C; Cohen, M; Labauge, P

    2015-07-01

    Isolated tumefactive demyelinating lesion (TDL) is a rare disease and a challenging entity especially for the differential diagnosis, biopsy indications, and therapeutic decisions. Long-term evolution is not well known. The objective of the study is to describe clinical and MRI characteristics and long-term follow-up of patients with isolated TDL. We performed a retrospective study including patients (1) with one TDL radiologically defined by a ≥20 mm FLAIR hyperintensity involving the white matter associated with T1 hypointensity that enhanced after gadolinium injection and (2) without any other MS lesion on the first MRI. Tumor, abscess, or other inflammatory diseases (ADEM, Baló's concentric sclerosis, systemic disease) were excluded. Sixteen patients (11 females/5 males) were included. The mean age of onset was 35.7 years (range 20-65). MRI disclosed supratentorial lesions with a mean size of 39.4 mm and usually mild edema/mass effect. Peripheral (mainly open-ring pattern) and central (mainly heterogeneous) enhancement were respectively seen in 9/16 and 11/16 patients. CSF study (n = 15) found oligoclonal bands (OCB) in seven. A cerebral biopsy was performed in 11 cases showing acute inflammatory demyelination. Thirteen patients were treated by pulse steroids with marked improvement in ten. At last clinical follow-up (mean 65.8 months, range 6-181), diagnosis was MS in 5 (31 %), isolated TDL in 10 (63 %) and one patient had a second TDL (6 %). Isolated tumefactive demyelinating lesions are a rare diagnostic entity. After a mean follow-up of 5 years, almost one-third became MS whereas most of the patients had no further event. PMID:25929666

  19. Human Endogenous Retrovirus and Neuroinflammation in Chronic Inflammatory Demyelinating Polyradiculoneuropathy

    PubMed Central

    Faucard, Raphaël; Madeira, Alexandra; Gehin, Nadège; Authier, François-Jérôme; Panaite, Petrica-Adrian; Lesage, Catherine; Burgelin, Ingrid; Bertel, Mélanie; Bernard, Corinne; Curtin, François; Lang, Aloïs B.; Steck, Andreas J.; Perron, Hervé; Kuntzer, Thierry; Créange, Alain

    2016-01-01

    Background Human endogenous retroviruses HERV-W encode a pro-inflammatory protein, named MSRV-Env from its original identification in Multiple Sclerosis. Though not detected in various neurological controls, MSRV-Env was found in patients with chronic inflammatory demyelinating polyradiculoneuropathies (CIDPs). This study investigated the expression of MSRV in CIDP and evaluated relevant MSRV-Env pathogenic effects. Methods 50 CIDP patients, 19 other neurological controls (ONDs) and 65 healthy blood donors (HBDs) were recruited from two different countries. MSRV-env and -pol transcripts, IL6 and CXCL10 levels were quantified from blood samples. MSRV-Env immunohistology was performed in distal sensory nerves from CIDP and neurological controls biopsies. MSRV-Env pathogenic effects and mode of action were assayed in cultured primary human Schwann cells (HSCs). Findings In both cohorts, MSRV-env and -pol transcripts, IL6 positivity prevalence and CXCL10 levels were significantly elevated in CIDP patients when compared to HBDs and ONDs (statistically significant in all comparisons). MSRV-Env protein was detected in Schwann cells in 5/7 CIDP biopsies. HSC exposed to or transfected with MSRV-env presented a strong increase of IL6 and CXCL10 transcripts and protein secretion. These pathogenic effects on HSC were inhibited by GNbAC1, a highly specific and neutralizing humanized monoclonal antibody targeting MSRV-Env. Interpretation The present study showed that MSRV-Env may trigger the release of critical immune mediators proposed as instrumental factors involved in the pathophysiology of CIDP. Significant MSRV-Env expression was detected in a significant proportion of patients with CIDP, in which it may play a role according to its presently observed effects on Schwann cells along with previously known effects on immune cells. Experimental results also suggest that a biomarker-driven therapeutic strategy targeting this protein with a neutralizing antibody such as GNbAC1

  20. Imaging in Pediatric Demyelinating and Inflammatory Diseases of Brain- Part 2.

    PubMed

    Sudhakar, Sniya Valsa; Muthusamy, Karthik; Mani, Sunithi; Gibikote, Sridhar; Shroff, Manohar

    2016-09-01

    Imaging plays an important role in diagnosis, management, prognostication and follow up of pediatric demyelinating and inflammatory diseases of brain and forms an integral part of the diagnostic criteria. This article reviews the spectrum of aquaporinopathies with an in-depth discussion on present criteria and differentiation from other demyelinating diseases with clinical vignettes for illustration; the latter part of article deals with the spectrum of CNS vasculitis. PMID:27130513

  1. Contactin 1 IgG4 associates to chronic inflammatory demyelinating polyneuropathy with sensory ataxia

    PubMed Central

    Miura, Yumako; Devaux, Jérôme J.; Fukami, Yuki; Manso, Constance; Belghazi, Maya; Wong, Anna Hiu Yi

    2015-01-01

    A Spanish group recently reported that four patients with chronic inflammatory demyelinating polyneuropathy carrying IgG4 autoantibodies against contactin 1 showed aggressive symptom onset and poor response to intravenous immunoglobulin. We aimed to describe the clinical and serological features of Japanese chronic inflammatory demyelinating polyneuropathy patients displaying the anti-contactin 1 antibodies. Thirteen of 533 (2.4%) patients with chronic inflammatory demyelinating polyneuropathy had anti-contactin 1 IgG4 whereas neither patients from disease or normal control subjects did (P = 0.02). Three of 13 (23%) patients showed subacute symptom onset, but all of the patients presented with sensory ataxia. Six of 10 (60%) anti-contactin 1 antibody-positive patients had poor response to intravenous immunoglobulin, whereas 8 of 11 (73%) antibody-positive patients had good response to corticosteroids. Anti-contactin 1 IgG4 antibodies are a possible biomarker to guide treatment option. PMID:25808373

  2. Imaging in Pediatric Demyelinating and Inflammatory Diseases of the Brain- Part 1.

    PubMed

    Sudhakar, Sniya Valsa; Muthusamy, Karthik; Mani, Sunithi; Gibikote, Sridhar; Shroff, Manohar

    2016-09-01

    Imaging plays an important role in the diagnosis, management, prognostication and follow up of pediatric demyelinating and inflammatory diseases of the brain and forms an integral part of the diagnostic criteria. Conventional and advanced MR imaging is the first and only reliable imaging modality. This article reviews the typical and atypical imaging features of common and some uncommon demyelinating and inflammatory diseases with emphasis on the criteria for categorization. Imaging protocols and the role of advanced imaging techniques are also covered appropriately. PMID:26634264

  3. Olig2-expressing progenitor cells preferentially differentiate into oligodendrocytes in cuprizone-induced demyelinated lesions.

    PubMed

    Islam, Mohammad Shyful; Tatsumi, Kouko; Okuda, Hiroaki; Shiosaka, Sadao; Wanaka, Akio

    2009-01-01

    Many oligodendrocyte progenitor cells (OPCs) are found in acute or chronic demyelinated area, but not all of them differentiate efficiently into mature oligodendrocytes in the demyelinated central nervous system (CNS). Recent studies have shown that the basic helix-loop-helix transcription factor Olig2, which stimulates OPCs to differentiate into oligodendrocyte, is strongly up-regulated in many pathological conditions including acute or chronic demyelinating lesions in the adult CNS. Despite their potential role in the treatment of demyelinating diseases, the long-term fate of these up-regulated Olig2 cells has not been identified due to the lack of stable labeling methods. To trace their fate we have used double-transgenic mice, in which we were able to label Olig2-positive cells conditionally with green fluorescent protein (GFP). Demyelination was induced in these mice by feeding cuprizone, a copper chelator. After 6 weeks of cuprizone exposure, GFP-positive (GFP(+)) cells were processed for a second labeling with antibodies to major neural cell markers APC (mature oligodendrocyte marker), GFAP (astrocyte marker), NeuN (neuron marker), Iba1 (microglia marker) and NG2 proteoglycan (oligodendrocyte progenitor marker). More than half of the GFP(+) cells in the external capsule showed co-localization with NG2 proteoglycan. While the percentages of NG2-positive (NG2(+)) and APC-positive (APC(+)) oligodendrocyte lineage cells in cuprizone-treated mice were significantly higher than those in the normal diet group, no significant difference was observed for GFAP-positive (GFAP(+)) astrocytic lineage cells. Our data therefore provide direct evidence that proliferation and differentiation of local and/or recruited Olig2 progenitors contribute to remyelination in demyelinated lesions. PMID:19070638

  4. Occurrence and long-term outcome of tumefactive demyelinating lesions in multiple sclerosis.

    PubMed

    Totaro, Rocco; Di Carmine, C; Splendiani, A; Torlone, S; Patriarca, L; Carrocci, C; Sciamanna, S; Marini, C; Carolei, A

    2016-07-01

    Although tumefactive multiple sclerosis is a well recognized variant of multiple sclerosis, prognostic uncertainty still exists about long term prognosis. The aim of this study was to estimate the occurrence and long term outcome of tumefactive demyelinating lesions (TDLs) in a cohort of multiple sclerosis patients. We reviewed brain MRI of 443 patients referred to our MS clinic. All patients meeting the McDonald criteria for multiple sclerosis and showing at least one TDL were included. Kaplan-Meier estimates of disease-free survival in patient cohort were compared with control group without TDLs using a log-rank test. Seven cases with TDLs were identified (occurrence 1.58 %). Tumefactive demyelinating lesion recurrence was 16.6 %. Cumulative proportion of patients free from clinical relapse and from new T2 lesions was lower in the control group although not reaching statistical significance (30 vs 50 %; P = 0.666 and 21.7 vs 33.3 %; P = 0.761, respectively). Disability progression analysis showed a not significant trend towards lower probability of remaining progression free for TDL patients (50 vs 61 %; P = 0.295). Occurrence of tumefactive demyelinating lesions in our cohort was higher than those reported in other studies. Overall, TDLs were not predictive of poor outcome in terms of disability progression. PMID:27083895

  5. Antibodies to MOG in adults with inflammatory demyelinating disease of the CNS

    PubMed Central

    Woodhall, Mark R.; Kim, Ji-Sun; Kim, Seong-Joon; Park, Kyung Seok; Vincent, Angela; Lee, Kwang-Woo

    2015-01-01

    Objective: To evaluate the clinical relevance of myelin oligodendrocyte glycoprotein antibody (MOG-Ab) in a cohort of adults with inflammatory demyelinating disease (IDD) of the CNS. Methods: Live cell-based assays for MOG-Ab (IgG1 subset) and antibody to aquaporin-4 (AQP4-Ab) were performed in a cohort of 270 adult patients with IDD and 72 controls. Patients were first grouped by positive antibody result as MOG-Ab or AQP4-Ab, and the remainder were grouped by published diagnostic criteria. Results: Seventeen patients with IDD (6.3%) had MOG-Abs and 49 patients (18.1%) had AQP4-Abs; none had both antibodies. The MOG-Ab patients predominantly manifested with isolated symptoms of optic neuritis (83%). One-third of these patients experienced relapses, which involved only the optic nerve, and all relapsed within 1 year of disease onset. At onset, MRI in the MOG-Ab group uniquely demonstrated perineural enhancement, extending to the soft tissues around the optic nerves (33%). Although about 30% of MOG-Ab patients had brain MRI lesions, they had fewer periventricular lesions than the 26 patients with relapsing-remitting multiple sclerosis (MS); none of these lesions were ovoid or perpendicular to the ventricle. Moreover, MOG-Ab patients did not meet the diagnostic criteria for definite neuromyelitis optica (NMO) and had less spinal cord involvement than the AQP4-Ab group. Four patients (23.5%) had poor visual outcomes (<0.2) or paraplegia. Conclusions: MOG-Abs may be a disease-specific biomarker in adult patients with IDD who have a disease distinct from NMO or MS. The radiologic as well as clinical manifestations of MOG-Ab patients can be useful in their differential diagnosis. PMID:26516628

  6. Fampridine-PR (prolonged released 4-aminopyridine) is not effective in patients with inflammatory demyelination of the peripheral nervous system.

    PubMed

    Leussink, Verena-Isabell; Stettner, Mark; Warnke, Clemens; Hartung, Hans-Peter

    2016-06-01

    Fampridine-PR is a voltage-gated potassium channel inhibitor potentially improving nerve conduction in demyelinated axons. Based on its established clinical efficacy in patients with demyelination in the central nervous system, we assessed if fampridine-PR is also effective in patients with inflammatory demyelination of the peripheral nerve. In this small open-label study, 10 patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) were treated with fampridine-PR 10 mg BID for 28 days and assessed clinically as well as by nerve conduction studies. In this study, Fampridine-PR failed to improve CIDP based on clinical measures and nerve conduction studies. Our findings suggest that Fampridine-PR appears to be ineffective in demyelinating polyneuropathies. These observations may indicate a more complex mode of action beyond improving action potential conduction in demyelinated axons. PMID:26968589

  7. Serum cytokine and chemokine profiles in patients with chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Beppu, Minako; Sawai, Setsu; Misawa, Sonoko; Sogawa, Kazuyuki; Mori, Masahiro; Ishige, Takayuki; Satoh, Mamoru; Nomura, Fumio; Kuwabara, Satoshi

    2015-02-15

    To identify serum cytokine networks specific to chronic inflammatory demyelinating polyneuropathy (CIDP), serum samples of two subgroups (18 patients with typical CIDP and 12 patients with multifocal acquired demyelinating sensory and motor neuropathy [MADSAM]) were analyzed with multiplex magnetic bead-based cytokine assay. TNF-α, HGF, MIP-1β and IL-1β levels were significantly higher in total CIDP patients than in normal controls. Of these, HGF levels were elevated in typical CIDP patients, but not in MADSAM patients. Patients with high HGF levels showed good responses to steroid treatment. Different cytokine profiles among the CIDP subtypes presumably reflect differences in pathophysiology. PMID:25669993

  8. Chronic Inflammatory Demyelinating Polyneuropathy Following Anti-TNF-α Therapy With Infliximab for Crohn's Disease.

    PubMed

    Kamel, Amir Y; Concepcion, Orestes; Schlachterman, Alexander; Glover, Sarah; Forsmark, Christopher Y

    2016-04-01

    We present a 29-year-old male with Crohn's disease who developed chronic inflammatory demyelinating polyneuropathy (CIDP) related to infliximab therapy. He developed lower extremity weakness and dysesthesia 3 weeks after a fourth infliximab dose. Laboratory examination revealed an elevated cerebrospinal fluid protein without pleocytosis. The patient initially responded to plasmapheresis therapy with marked symptomatic improvement, but relapsed and was refractory to subsequent treatments with plasmaphereisis, intravenous immunoglobulin, and glucocorticoids. While a causal relationship between infliximab and CIDP cannot be proven, clinicians should monitor Crohn's disease patients who are receiving TNF-α antagonists for neurologic symptoms suggestive of demyelinating disease. PMID:27144200

  9. Chronic Inflammatory Demyelinating Polyneuropathy Following Anti-TNF-α Therapy With Infliximab for Crohn's Disease

    PubMed Central

    Concepcion, Orestes; Schlachterman, Alexander; Glover, Sarah; Forsmark, Christopher Y.

    2016-01-01

    We present a 29-year-old male with Crohn's disease who developed chronic inflammatory demyelinating polyneuropathy (CIDP) related to infliximab therapy. He developed lower extremity weakness and dysesthesia 3 weeks after a fourth infliximab dose. Laboratory examination revealed an elevated cerebrospinal fluid protein without pleocytosis. The patient initially responded to plasmapheresis therapy with marked symptomatic improvement, but relapsed and was refractory to subsequent treatments with plasmaphereisis, intravenous immunoglobulin, and glucocorticoids. While a causal relationship between infliximab and CIDP cannot be proven, clinicians should monitor Crohn's disease patients who are receiving TNF-α antagonists for neurologic symptoms suggestive of demyelinating disease. PMID:27144200

  10. Accumulation of Extracellular Matrix in Advanced Lesions of Canine Distemper Demyelinating Encephalitis.

    PubMed

    Seehusen, Frauke; Al-Azreg, Seham A; Raddatz, Barbara B; Haist, Verena; Puff, Christina; Spitzbarth, Ingo; Ulrich, Reiner; Baumgärtner, Wolfgang

    2016-01-01

    In demyelinating diseases, changes in the quality and quantity of the extracellular matrix (ECM) may contribute to demyelination and failure of myelin repair and axonal sprouting, especially in chronic lesions. To characterize changes in the ECM in canine distemper demyelinating leukoencephalitis (DL), histochemical and immunohistochemical investigations of formalin-fixed paraffin-embedded cerebella using azan, picrosirius red and Gomori`s silver stain as well as antibodies directed against aggrecan, type I and IV collagen, fibronectin, laminin and phosphacan showed alterations of the ECM in CDV-infected dogs. A significantly increased amount of aggrecan was detected in early and late white matter lesions. In addition, the positive signal for collagens I and IV as well as fibronectin was significantly increased in late lesions. Conversely, the expression of phosphacan was significantly decreased in early and more pronounced in late lesions compared to controls. Furthermore, a set of genes involved in ECM was extracted from a publically available microarray data set and was analyzed for differential gene expression. Gene expression of ECM molecules, their biosynthesis pathways, and pro-fibrotic factors was mildly up-regulated whereas expression of matrix remodeling enzymes was up-regulated to a relatively higher extent. Summarized, the observed findings indicate that changes in the quality and content of ECM molecules represent important, mainly post-transcriptional features in advanced canine distemper lesions. Considering the insufficiency of morphological regeneration in chronic distemper lesions, the accumulated ECM seems to play a crucial role upon regenerative processes and may explain the relatively small regenerative potential in late stages of this disease. PMID:27441688

  11. Accumulation of Extracellular Matrix in Advanced Lesions of Canine Distemper Demyelinating Encephalitis

    PubMed Central

    Seehusen, Frauke; Al-Azreg, Seham A.; Raddatz, Barbara B.; Haist, Verena; Puff, Christina; Spitzbarth, Ingo; Ulrich, Reiner; Baumgärtner, Wolfgang

    2016-01-01

    In demyelinating diseases, changes in the quality and quantity of the extracellular matrix (ECM) may contribute to demyelination and failure of myelin repair and axonal sprouting, especially in chronic lesions. To characterize changes in the ECM in canine distemper demyelinating leukoencephalitis (DL), histochemical and immunohistochemical investigations of formalin-fixed paraffin-embedded cerebella using azan, picrosirius red and Gomori`s silver stain as well as antibodies directed against aggrecan, type I and IV collagen, fibronectin, laminin and phosphacan showed alterations of the ECM in CDV-infected dogs. A significantly increased amount of aggrecan was detected in early and late white matter lesions. In addition, the positive signal for collagens I and IV as well as fibronectin was significantly increased in late lesions. Conversely, the expression of phosphacan was significantly decreased in early and more pronounced in late lesions compared to controls. Furthermore, a set of genes involved in ECM was extracted from a publically available microarray data set and was analyzed for differential gene expression. Gene expression of ECM molecules, their biosynthesis pathways, and pro-fibrotic factors was mildly up-regulated whereas expression of matrix remodeling enzymes was up-regulated to a relatively higher extent. Summarized, the observed findings indicate that changes in the quality and content of ECM molecules represent important, mainly post-transcriptional features in advanced canine distemper lesions. Considering the insufficiency of morphological regeneration in chronic distemper lesions, the accumulated ECM seems to play a crucial role upon regenerative processes and may explain the relatively small regenerative potential in late stages of this disease. PMID:27441688

  12. Challenges in the treatment of chronic inflammatory demyelinating polyradiculoneuropathy.

    PubMed

    Guimarães-Costa, R; Iancu Ferfoglia, R; Viala, K; Léger, J-M

    2014-10-01

    Chronic idiopathic demyelinating polyradiculoneuropathy (CIDP) is a rare disease, the most frequent one within the spectrum of the so-called "chronic immune-mediated neuropathies". Challenges in the treatment of CIDP firstly concern its diagnosis, which may be difficult, mainly for the atypical forms. Secondly, challenges encompass the choice of the first-line treatment, such as corticosteroids, intravenous immunoglobulins (IVIg), and plasma exchanges (PE) that have been proven as efficacious by several randomized controlled trials (RCT). Recent reports have focused on both different regimens of corticosteroids, and the occurrence of relapses following treatment with either corticosteroids or IVIg. These data may be helpful for the choice of the first-line treatment and may result in changing the guidelines for treatment of CIDP in clinical practice. The third and more difficult challenge is to manage long-term treatment for CIDP, since no immunomodulatory treatment has to date been proven as efficacious in this situation. Lastly, challenges in the treatment concern the choice of the best outcome measure for CIDP in RCT and clinical practice. The aim of this article is to overview the results of the more recently reported published trials for CIDP, and to give some insights for the current and future management of CIDP. PMID:25200479

  13. Imaging inflammatory acne: lesion detection and tracking

    NASA Astrophysics Data System (ADS)

    Cula, Gabriela O.; Bargo, Paulo R.; Kollias, Nikiforos

    2010-02-01

    It is known that effectiveness of acne treatment increases when the lesions are detected earlier, before they could progress into mature wound-like lesions, which lead to scarring and discoloration. However, little is known about the evolution of acne from early signs until after the lesion heals. In this work we computationally characterize the evolution of inflammatory acne lesions, based on analyzing cross-polarized images that document acne-prone facial skin over time. Taking skin images over time, and being able to follow skin features in these images present serious challenges, due to change in the appearance of skin, difficulty in repositioning the subject, involuntary movement such as breathing. A computational technique for automatic detection of lesions by separating the background normal skin from the acne lesions, based on fitting Gaussian distributions to the intensity histograms, is presented. In order to track and quantify the evolution of lesions, in terms of the degree of progress or regress, we designed a study to capture facial skin images from an acne-prone young individual, followed over the course of 3 different time points. Based on the behavior of the lesions between two consecutive time points, the automatically detected lesions are classified in four categories: new lesions, resolved lesions (i.e. lesions that disappear completely), lesions that are progressing, and lesions that are regressing (i.e. lesions in the process of healing). The classification our methods achieve correlates well with visual inspection of a trained human grader.

  14. Non-infectious inflammatory genital lesions.

    PubMed

    Andreassi, Lucio; Bilenchi, Roberta

    2014-01-01

    The genitalia may be the site of non-infectious inflammatory lesions that are generally manifested as balanoposthitis and vulvovaginitis. In men, these forms constitute 50% of all balanoposthitis forms, and in women, vulvovaginitis frequency is even higher. They consist of genital locations of general skin diseases, such as psoriasis, lichen planus, lichen sclerosus, and other clinical entities with their own physiognomy, such as Zoon's balanitis-vulvitis. Diagnosis of genital non-infectious inflammatory lesions is usually made on clinical criteria. A biopsy is only necessary for the identification of clinical conditions that may simulate inflammatory form but are actually premalignant processes. PMID:24559568

  15. Overview of the pathogenesis and treatment of chronic inflammatory demyelinating polyneuropathy with intravenous immunoglobulins

    PubMed Central

    Mahdi-Rogers, Mohamed; Rajabally, Yusuf A

    2010-01-01

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is an acquired heterogeneous disorder of immune origin affecting the peripheral nerves, causing motor weakness and sensory symptoms and signs. The precise pathophysiology of CIDP remains uncertain although B and T cell mechanisms are believed to be implicated. Intravenous immunoglobulins (IVIg) have been shown in a number of trials to be an effective treatment for CIDP. IVIg is thought to exert its immunomodulatory effects by affecting several components of the immune system including B-cells, T-cells, macrophages and complement. This article provides an overview of the pathogenesis of CIDP and of its treatment with IVIg. PMID:20376173

  16. Diagnostic utility of aquaporin-4 in the analysis of active demyelinating lesions

    PubMed Central

    Popescu, Bogdan F.G.; Guo, Yong; Jentoft, Mark E.; Parisi, Joseph E.; Lennon, Vanda A.; Pittock, Sean J.; Weinshenker, Brian G.; Wingerchuk, Dean M.; Giannini, Caterina; Metz, Imke; Brück, Wolfgang; Shuster, Elizabeth A.; Carter, Jonathan; Boyd, Clara D.; Clardy, Stacey Lynn; Cohen, Bruce A.

    2015-01-01

    Objective: To assess, in a surgical biopsy cohort of active demyelinating lesions, the diagnostic utility of aquaporin-4 (AQP4) immunohistochemistry in identifying neuromyelitis optica (NMO) or NMO spectrum disorder (NMOSD) and describe pathologic features that should prompt AQP4 immunohistochemical analysis and AQP4–immunoglobulin G (IgG) serologic testing. Methods: This was a neuropathologic cohort study of 20 surgical biopsies (19 patients; 11 cord/9 brain), performed because of diagnostic uncertainty, interpreted as active demyelinating disease and containing 2 or more of the following additional features: tissue vacuolation, granulocytic infiltrates, or astrocyte injury. Results: AQP4 immunoreactivity was lost in 18 biopsies and increased in 2. Immunopathologic features of the AQP4 loss cohort were myelin vacuolation (18), dystrophic astrocytes and granulocytes (17), vascular hyalinization (16), macrophages containing glial fibrillary acid protein (GFAP)–positive debris (14), and Creutzfeldt-Peters cells (0). All 14 cases with available serum tested positive for AQP4-IgG after biopsy. Diagnosis at last follow-up was NMO/NMOSD (15) and longitudinally extensive transverse myelitis (1 each relapsing and single). Immunopathologic features of the AQP4 increased cohort were macrophages containing GFAP-positive debris and granulocytes (2), myelin vacuolation (1), dystrophic astrocytes (1), Creutzfeldt-Peters cells (1), and vascular hyalinization (1). Diagnosis at last follow-up was multiple sclerosis (MS) and both tested AQP4-IgG seronegative after biopsy. Conclusions: AQP4 immunohistochemistry with subsequent AQP4-IgG testing has diagnostic utility in identifying cases of NMO/NMOSD. This study highlights the importance of considering NMOSD in the differential diagnosis of tumefactive brain or spinal cord lesions. AQP4-IgG testing may avert biopsy and avoid ineffective therapies if these patients are erroneously treated for MS. PMID:25503621

  17. Systemic Lupus Erythematosus With Acute Inflammatory Demyelinating Polyneuropathy: A Case Report and Review of the Literature

    PubMed Central

    Li, Xiangling; Wang, Yanqiang

    2016-01-01

    We recently encountered a patient with acute inflammatory demyelinating polyneuropathy (AIDP) that was associated with systemic lupus erythematosus (SLE). A 34-year-old Chinese female with a 3-year history of SLE presented with acute bilateral leg weakness and paraparesis, and lost the ability to walk 1 day after noticing bilateral leg numbness and pain for 12 days. Physical examination revealed bilateral facial muscle paralysis, muscle strength in the legs with graded 1/5 proximally and 2/5 distally bilaterally and absence of deep tendon reflex in both knees and ankles. Paresthesia was observed in distal limbs with glove and stocking distribution. Cerebrospinal fluid analysis demonstrated albuminocytologic dissociation. Electrophysiologic survey also indicated sensory-motor demyelinating polyneuropathy. The diagnosis of SLE was established based on her initial symptoms including intermittent fevers, hair loss, oral ulcers, malar rash and arthritis affecting the elbow, wrist and hand joints; positive immunologic findings for antinuclear antibody (ANA), anti-DNA antibody, anti-Smith (anti-Sm) antibody, low serum complement levels, and the kidney biopsy specimen showed glomerular mesangial proliferation with focal endothelial cell proliferation (ISN/PPS 2004 classification lupus nephritis, class III). Treatment with intravenous immunoglobulin, methylprednisolone and cyclophosphamide resulted in clinical and electrophysiological improvement. PMID:27298667

  18. Systemic Lupus Erythematosus With Acute Inflammatory Demyelinating Polyneuropathy: A Case Report and Review of the Literature.

    PubMed

    Li, Xiangling; Wang, Yanqiang

    2016-07-01

    We recently encountered a patient with acute inflammatory demyelinating polyneuropathy (AIDP) that was associated with systemic lupus erythematosus (SLE). A 34-year-old Chinese female with a 3-year history of SLE presented with acute bilateral leg weakness and paraparesis, and lost the ability to walk 1 day after noticing bilateral leg numbness and pain for 12 days. Physical examination revealed bilateral facial muscle paralysis, muscle strength in the legs with graded 1/5 proximally and 2/5 distally bilaterally and absence of deep tendon reflex in both knees and ankles. Paresthesia was observed in distal limbs with glove and stocking distribution. Cerebrospinal fluid analysis demonstrated albuminocytologic dissociation. Electrophysiologic survey also indicated sensory-motor demyelinating polyneuropathy. The diagnosis of SLE was established based on her initial symptoms including intermittent fevers, hair loss, oral ulcers, malar rash and arthritis affecting the elbow, wrist and hand joints; positive immunologic findings for antinuclear antibody (ANA), anti-DNA antibody, anti-Smith (anti-Sm) antibody, low serum complement levels, and the kidney biopsy specimen showed glomerular mesangial proliferation with focal endothelial cell proliferation (ISN/PPS 2004 classification lupus nephritis, class III). Treatment with intravenous immunoglobulin, methylprednisolone and cyclophosphamide resulted in clinical and electrophysiological improvement. PMID:27298667

  19. Acute paretic syndrome in juvenile White Leghorn chickens resembles late stages of acute inflammatory demyelinating polyneuropathies in humans

    PubMed Central

    2010-01-01

    Background Sudden limb paresis is a common problem in White Leghorn flocks, affecting about 1% of the chicken population before achievement of sexual maturity. Previously, a similar clinical syndrome has been reported as being caused by inflammatory demyelination of peripheral nerve fibres. Here, we investigated in detail the immunopathology of this paretic syndrome and its possible resemblance to human neuropathies. Methods Neurologically affected chickens and control animals from one single flock underwent clinical and neuropathological examination. Peripheral nervous system (PNS) alterations were characterised using standard morphological techniques, including nerve fibre teasing and transmission electron microscopy. Infiltrating cells were phenotyped immunohistologically and quantified by flow cytometry. The cytokine expression pattern was assessed by quantitative real-time PCR (qRT-PCR). These investigations were accomplished by MHC genotyping and a PCR screen for Marek's disease virus (MDV). Results Spontaneous paresis of White Leghorns is caused by cell-mediated, inflammatory demyelination affecting multiple cranial and spinal nerves and nerve roots with a proximodistal tapering. Clinical manifestation coincides with the employment of humoral immune mechanisms, enrolling plasma cell recruitment, deposition of myelin-bound IgG and antibody-dependent macrophageal myelin-stripping. Disease development was significantly linked to a 539 bp microsatellite in MHC locus LEI0258. An aetiological role for MDV was excluded. Conclusions The paretic phase of avian inflammatory demyelinating polyradiculoneuritis immunobiologically resembles the late-acute disease stages of human acute inflammatory demyelinating polyneuropathy, and is characterised by a Th1-to-Th2 shift. PMID:20109187

  20. A case of inflammatory demyelinating polyradiculoneuropathy associated with T-cell lymphoma.

    PubMed

    Wada, M; Kurita, K; Tajima, K; Kawanami, T; Kato, T

    2003-01-01

    Malignant lymphoma may present prominent peripheral nervous system disorders with variable etiologies. We describe a patient who presented with chronic relapsing polyradiculoneuropathy accompanied by right facial nerve palsy. Gadolinium enhancement of the right facial nerve and cervical spinal roots was noted on magnetic resonance imaging (MRI). Sural nerve biopsy specimens showed mononuclear cell infiltration around the vessels in the epineurium. Histopathological and immunohistochemical investigations of sural nerve specimens revealed perivascular infiltration of lymphocytes with T-cell dominancy. No apparent direct invasion of lymphoma cells was seen. The results of nerve conduction studies, sural nerve biopsy and cerebrospinal fluid examination were suggestive of immune-mediated inflammatory demyelinating neuropathy. The chronic and relapsing fashion and unique radiological findings in our patient expand on the previously reported features of peripheral neuropathy associated with peripheral T-cell lymphoma. PMID:12542515

  1. Office immunotherapy in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy.

    PubMed

    Dyck, Peter J; Taylor, Bruce V; Davies, Jenny L; Mauermann, Michelle L; Litchy, William J; Klein, Christopher J; Dyck, P James B

    2015-10-01

    Intravenous immunoglobulin [IVIg], plasma exchange [PE], and corticosteroids are efficacious treatment in chronic inflammatory demyelinating polyneuropathy [CIDP]. IVIg is effective in multifocal motor neuropathy [MMN]. NIS, NIS-weakness, sum scores of raw amplitudes of motor fiber (CMAPs) amplitudes, and Dyck/Rankin score provided reliable measures to detect and scale abnormality and reflect change; they are therefore ideal for office management of response-based immunotherapy (R-IRx) of CIDP. Using efficacious R-IRx, a large early and late therapeutic response (≥ one-fourth were in remission or had recovered) was demonstrated in CIDP. In MMN only an early improvement with late non-significant worsening was observed. The difference in immunotherapy response supports a fundamental difference between CIDP (immune attack on Schwann cells and myelin) and MMN (attack on nodes of Ranvier and axons). PMID:25976871

  2. Treatment of Chronic Inflammatory Demyelinating Polyneuropathy: From Molecular Bases to Practical Considerations

    PubMed Central

    Ripellino, Paolo; Fleetwood, Thomas; Cantello, Roberto; Comi, Cristoforo

    2014-01-01

    Chronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease of the peripheral nervous system, in which both cellular and humoral immune responses are involved. The disease is clinically heterogeneous with some patients displaying pure motor form and others also showing a variable degree of sensory dysfunction; disease evolution may also differ from patient to patient, since monophasic, progressive, and relapsing forms are reported. Underlying such clinical variability there is probably a broad spectrum of molecular dysfunctions that are and will be the target of therapeutic strategies. In this review we first explore the biological bases of current treatments and subsequently we focus on the practical management that must also take into account pharmacoeconomic issues. PMID:24527207

  3. [Inflammatory odontogenic lesions of the jaws].

    PubMed

    Gallini, G; Merlini, C; Martelossi, L; Benetti, C

    1991-04-15

    The apical granuloma, the periapical abcess and the radicular cyst are the most frequent between the inflammatory odontogenic lesions of the jaws. These three lesions are caused by the necrosis of the pulp but are very different between each other from an histological point of view and they can correspond to different stages of the same pathological process considering the fact that from a granuloma can arise a periapical abcess or a radicular cyst and from a radicular cyst and abcess can originate. About these three pathological processes we discuss in this article the clinical, radiographical, ethiological, microscopical features, we suggest the treatment and the differential diagnosis. PMID:2070926

  4. Chronic inflammatory demyelinating polyneuropathy: decreased claudin-5 and relocated ZO-1

    PubMed Central

    Kanda, T; Numata, Y; Mizusawa, H

    2004-01-01

    Objectives: To clarify the dynamics of molecules composing the blood–nerve barrier (BNB) in inflammatory neuropathies. Methods: The expression of four tight junction (TJ) proteins—claudin-1, claudin-5, occludin, and ZO-1—was analysed immunohistochemically in sural nerve biopsy specimens obtained from patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). Results: Claudin-1 was detected only in perineurial cells, whereas claudin-5 was present in endothelial cells, irrespective of vessel location or size. Occludin and ZO-1 were found in perineurial cells, in addition to some epineurial and endoneurial endothelial cells. In CIDP, percentages of endoneurial small vessels immunoreactive for claudin-5 were significantly decreased, as were ZO-1 immunoreactive endoneurial small vessels, with staining localised to interfaces between cells. Claudin-1 and occludin immunoreactivity did not differ appreciably between the neuropathies examined. Conclusions: The downregulation of claudin-5 and altered localisation of ZO-1 seen in CIDP specimens may indicate that BNB derangement occurs in inflammatory neuropathies. Further investigation of TJ molecules may suggest new treatments based on properties of the BNB. PMID:15090575

  5. Accelerated repair of demyelinated CNS lesions in the absence of non-muscle myosin IIB.

    PubMed

    Rusielewicz, Tomasz; Nam, Jennifer; Damanakis, Evangelos; John, Gareth R; Raine, Cedric S; Melendez-Vasquez, Carmen V

    2014-04-01

    The oligodendrocyte (OL), the myelinating cell of the central nervous system, undergoes dramatic changes in the organization of its cytoskeleton as it differentiates from a precursor (oligodendrocyte precursor cells) to a myelin-forming cell. These changes include an increase in its branching cell processes, a phenomenon necessary for OL to myelinate multiple axon segments. We have previously shown that levels and activity of non-muscle myosin II (NMII), a regulator of cytoskeletal contractility, decrease as a function of differentiation and that inhibition of NMII increases branching and myelination of OL in coculture with neurons. We have also found that mixed glial cell cultures derived from NMIIB knockout mice display an increase in mature myelin basic protein-expressing OL compared with wild-type cultures. We have now extended our studies to investigate the role of NMIIB ablation on myelin repair following focal demyelination by lysolecithin. To this end, we generated an oligodendrocyte-specific inducible knockout model using a Plp-driven promoter in combination with a temporally activated CRE-ER fusion protein. Our data indicate that conditional ablation of NMII in adult mouse brain, expedites lesion resolution and remyelination by Plp+ oligodendrocyte-lineage cells when compared with that observed in control brains. Taken together, these data validate the function of NMII as that of a negative regulator of OL myelination in vivo and provide a novel target for promoting myelin repair in conditions such as multiple sclerosis. PMID:24470341

  6. A diagnosis challenge-L4 nerve root compression as the initial presentation of chronic inflammatory demyelinating polyneuropathy.

    PubMed

    Cojocaru, Inimioara Mihaela; Alexianu, Marilena; Bastian, Alexandra; Sapira, Violeta; Herţea, Cristina; Cojocaru, M

    2012-01-01

    The authors present the case of a 65-year-old woman who was admitted for paraparesis and paresthesias in the inferior limbs. The neurological examination revealed the difficulty in extension of the right foot and of the right toe, accompanied by paresthesias located in the anterolateral area of the right leg, dorsum and plantar area of the foot, the reduction of the right knee jerk, and of the ankle tendon jerk both sides. The vertebro-spinal MRI showed lumbar canal stenosis with L4 intraforaminal compression on the right, and L2-L3 on the left. CSF examination revealed mild increase in protein concentration. The morphological picture of the sural nerve biopsy was compatible with a chronic inflammatory neuropathy and severe muscular lesions of neurogenic origin were observed on right gastrocnemius muscle biopsy. The diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) was established. Solu-medrol (0.5 g/d)-5 days, then medrol (prednisolone) was done, followed by improving of the symptomatology. For the relapse of the disease intravenous immunoglobulins (IVIG)-0.4 g/kg/d-5 days was the elective treatment. Six months later she presented a new relapse. IVIG were administered with the remission of the sensitive symptoms. A chronic treatment with medrol was recommended. The diagnosis of L4 disc herniation was obvious in the studied case, but the electroneurographic examination brought extra data for the associated diagnosis of CIDP whose onset was asymmetrical and initially paucisymptomatic. Neither the electroneurographic examination nor the CSF examination were total relevant for CIDP, imposing the sural nerve biopsy. The diagnosis of CIDP involves a team-work composed of neurologist, electroneurophysiologist and neuropathologist. PMID:23610977

  7. [Diagnosis of pediatric multiple sclerosis initially presenting with tumefactive demyelinating lesion using ¹H-magnetic resonance spectroscopy].

    PubMed

    Kageyama, Takashi; Gotoh, Yoko; Sano, Fumie; Katoh, Takeo; Nambu, Mituhiko; Okada, Tsutomu; Suenaga, Toshihiko

    2011-09-01

    We report a case of tumefactive demyelinating lesion (TDL) diagnosed using (1)H-magnetic resonance spectroscopy (¹H-MRS) and conventional magnetic resonance imaging (MRI). A 7-year-old girl was admitted to our hospital with complaints of sleepiness and clumsiness of the right limbs. Neurological examination showed somnolence, right-sided apraxia, and hemiparesis with enhanced tendon reflexes and Babinski sign. Conventional brain MRI revealed extensive hyperintensity in the subcortical white matter of the left frontal lobe in both T₂ weighted and fluid attenuated inversion recovery images. Gadolinium-enhanced T₁ weighted images showed a tumor-like lesion in this area with interrupted rim enhancement, termed open ring sign, and a periventricular lesion along the inferior horn of the right lateral ventricle and a juxtacortical lesion under the right motor cortex. In ¹H-MRS, both single voxel spectroscopy (SVS) and chemical shift imaging showed elevation of choline and reduction of N-acetylaspartate in the left frontal lobe lesion. Furthermore, SVS with a short echo time revealed elevated peaks for glutamate/glutamine complex in this lesion. These results suggested the demyelinating nature of this tumor-like lesion, in accordance with the concept of TDL. Based on this diagnosis, we treated the patient with three sets of methylprednisolone pulse therapy, which resulted in the reduction of TDL and neurological improvement. A follow-up study using MRI also demonstrated two more lesions in the corona radiata and internal capsule of the left hemisphere, supporting a diagnosis of multiple sclerosis based on the revised McDonald's criteria (2010). We concluded that ¹H-MRS may be beneficial in the differential diagnosis of TDL. PMID:21946426

  8. Peripheral Nerve Ultrasonography in Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Multifocal Motor Neuropathy: Correlations with Clinical and Neurophysiological Data.

    PubMed

    Merola, Aristide; Rosso, Michela; Romagnolo, Alberto; Peci, Erdita; Cocito, Dario

    2016-01-01

    Objective. This cross-sectional study analyzes the pattern of ultrasound peripheral nerve alterations in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) at different stages of functional disability. Material and Methods. 22 CIDP and 10 MMN patients and a group of 70 healthy controls were evaluated with an ultrasound scan of the median, ulnar, peroneal, tibial, and sural nerves. Results were correlated with clinical disability scales and nerve conduction studies. Results. Patients with intermediate functional impairment showed relatively larger cross-sectional areas than subjects with either a milder (p < 0.05) or more severe impairment (p < 0.05), both in CIDP and in MMN. In addition, MMN was associated with greater side-to-side intranerve variability (p < 0.05), while higher cross-sectional areas were observed in CIDP (p < 0.05) and in nerve segments with predominantly demyelinating features (p < 0.05). Higher CSA values were observed in nerves with demyelinating features versus axonal damage (p < 0.05 for CIDP; p < 0.05 for MMN). Discussion and Conclusions. Greater extent of quantitative and qualitative US alterations was observed in patients at intermediate versus higher functional disability and in nerves with demyelinating versus axonal damage. CIDP and MMN showed differential US aspects, with greater side-to-side intranerve variability in MMN and higher cross-sectional areas in CIDP. PMID:27313890

  9. Peripheral Nerve Ultrasonography in Chronic Inflammatory Demyelinating Polyradiculoneuropathy and Multifocal Motor Neuropathy: Correlations with Clinical and Neurophysiological Data

    PubMed Central

    Merola, Aristide; Rosso, Michela; Romagnolo, Alberto; Peci, Erdita; Cocito, Dario

    2016-01-01

    Objective. This cross-sectional study analyzes the pattern of ultrasound peripheral nerve alterations in patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy (MMN) at different stages of functional disability. Material and Methods. 22 CIDP and 10 MMN patients and a group of 70 healthy controls were evaluated with an ultrasound scan of the median, ulnar, peroneal, tibial, and sural nerves. Results were correlated with clinical disability scales and nerve conduction studies. Results. Patients with intermediate functional impairment showed relatively larger cross-sectional areas than subjects with either a milder (p < 0.05) or more severe impairment (p < 0.05), both in CIDP and in MMN. In addition, MMN was associated with greater side-to-side intranerve variability (p < 0.05), while higher cross-sectional areas were observed in CIDP (p < 0.05) and in nerve segments with predominantly demyelinating features (p < 0.05). Higher CSA values were observed in nerves with demyelinating features versus axonal damage (p < 0.05 for CIDP; p < 0.05 for MMN). Discussion and Conclusions. Greater extent of quantitative and qualitative US alterations was observed in patients at intermediate versus higher functional disability and in nerves with demyelinating versus axonal damage. CIDP and MMN showed differential US aspects, with greater side-to-side intranerve variability in MMN and higher cross-sectional areas in CIDP. PMID:27313890

  10. Unusual basal ganglia lesions in a diabetic uraemic patient proven to be demyelination: first pathological observation

    PubMed Central

    Tajima, Yasutaka; Mito, Yasunori; Yanai, Mituru; Fukazawa, Yu-ichiro

    2012-01-01

    A 64-year-old man suffering from diabetes mellitus and chronic renal failure was admitted to our hospital because of consciousness disturbance and parkinsonism. Cranial MRI showed very characteristic features involving the bilateral basal ganglia. Subsequent postmortem examinations demonstrated demyelination in the affected areas. These myelin destruction patterns were quite similar to those of central pontine myelinolysis. However, rapid correction of hyponatraemia was ruled out in this patient. Therefore, a new demyelinating brain disease associated with diabetes mellitus and chronic renal failure was suggested. PMID:22948993

  11. Combination therapy of Lovastatin and Rolipram Provides Neuroprotection and Promotes Neurorepair in Inflammatory Demyelination Model of Multiple Sclerosis

    PubMed Central

    Paintlia, Ajaib S; Paintlia, Manjeet K; Singh, Inderjit; Skoff, Robert B; Singh, Avtar K

    2009-01-01

    Drug combination therapies for central nervous system (CNS) demyelination diseases including multiple sclerosis (MS) are gaining momentum over monotherapy. Over the past decade, both in vitro and in vivo studies established that statins (HMG-CoA reductase inhibitors) and rolipram (phosphodiesterase-4 inhibitor; blocks the degradation of intracellular cyclic AMP) can prevent the progression of MS in affected individuals via different mechanisms of action. In the present study, we evaluated the effectiveness of lovastatin and rolipram in combination therapy to promote neurorepair in an inflammatory CNS demyelination model of MS, experimental autoimmune encephalomyelitis (EAE). Combination treatment with suboptimal doses of these drugs in an established case of EAE (clinical disease score ≥2.0) significantly attenuated the infiltration of inflammatory cells and protected myelin sheath and axonal integrity in the CNS. It was accompanied with elevated level of cyclic AMP and activation of its associated protein kinase A. Interestingly, combination treatment with these drugs impeded neurodegeneration and promoted neurorepair in established EAE animals (clinical disease score ≥3.5) as verified by quantitative real-time polymerase chain reaction, immunohistochemistry, and electron microscopic analyses. These effects of combination therapy were minimal and/or absent with either drug alone in these settings. Together, these data suggest that combination therapy with lovastatin and rolipram has the potential to provide neuroprotection and promote neurorepair in MS, and may have uses in other related CNS demyelinating diseases. PMID:18720408

  12. Steroids for chronic inflammatory demyelinating polyradiculoneuropathy: evidence base and clinical practice.

    PubMed

    Press, R; Hiew, F L; Rajabally, Y A

    2016-04-01

    Evidence-based therapies for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) consist of corticosteroids, intravenous immunglobulins (IVIg), and plasma exchange. Steroids represent the oldest treatment used historically. In countries where readily available and affordable, IVIg tends to be favored as first-line treatment. The reason for this preference, despite substantially higher costs, is the perception that IVIg is more efficacious and safer than corticosteroids. However, the unselected use of IVIg as a first-line treatment option in all cases of CIDP raises issues of cost-effectiveness in the long-term. Furthermore, serious although rare, particularly thromboembolic side effects may result from their use. Recent data from randomized trials suggest pulsed corticosteroids to have a higher potential in achieving therapy-free remission or longer remission-free periods compared with IVIg, as well as relatively low rates of serious side effects when given as pulsed intravenous infusions during short periods of time. These specific advantages suggest that pulsed steroids could in many cases be used, as the first, rather than second choice of treatment when initiating immunomodulation in CIDP, primarily in hopes of achieving a remission after the short-term use. This article reviews the evidence base for the use of corticosteroids in its various forms in CIDP and factors that may influence clinicians' choice between IVIg and pulsed steroid treatment. The issue of efficacy, relapse rate and time, and side effect profile are analyzed, and some aspects from the authors' experience are discussed in relation to the possibility of using the steroid option as first-line therapy in a large proportion of patients with CIDP. PMID:26437234

  13. The Subventricular Zone Is Able to Respond to a Demyelinating Lesion After Localized Radiation

    PubMed Central

    Capilla-Gonzalez, Vivian; Guerrero-Cazares, Hugo; Bonsu, Janice M.; Gonzalez-Perez, Oscar; Achanta, Pragathi; Wong, John; Garcia-Verdugo, Jose Manuel; Quiñones-Hinojosa, Alfredo

    2016-01-01

    Radiation is a common tool in the treatment of brain tumors that induces neurological deficits as a side effect. Some of these deficits appear to be related to the impact of radiation on the neurogenic niches, producing a drastic decrease in the proliferative capacity of these regions. In the adult mammalian brain, the subventricular zone (SVZ) of the lateral ventricles is the main neurogenic niche. Neural stem/precursor cells (NSCs) within the SVZ play an important role in brain repair following injuries. However, the irradiated NSCs' ability to respond to damage has not been previously elucidated. In this study, we evaluated the effects of localized radiation on the SVZ ability to respond to a lysolecithin-induced demyelination of the striatum. We demonstrated that the proliferation rate of the irradiated SVZ was increased after brain damage and that residual NSCs were reactivated. The irradiated SVZ had an expansion of doublecortin positive cells that appeared to migrate from the lateral ventricles toward the demyelinated striatum, where newly generated oligodendrocytes were found. In addition, in the absence of demyelinating damage, remaining cells in the irradiated SVZ appeared to repopulate the neurogenic niche a year post-radiation. These findings support the hypothesis that NSCs are radioresistant and can respond to a brain injury, recovering the neurogenic niche. A more complete understanding of the effects that localized radiation has on the SVZ may lead to improvement of the current protocols used in the radiotherapy of cancer. PMID:24038623

  14. Tamoxifen accelerates the repair of demyelinated lesions in the central nervous system

    PubMed Central

    Gonzalez, Ginez A.; Hofer, Matthias P.; Syed, Yasir A.; Amaral, Ana I.; Rundle, Jon; Rahman, Saifur; Zhao, Chao; Kotter, Mark R. N.

    2016-01-01

    Enhancing central nervous system (CNS) myelin regeneration is recognized as an important strategy to ameliorate the devastating consequences of demyelinating diseases such as multiple sclerosis. Previous findings have indicated that myelin proteins, which accumulate following demyelination, inhibit remyelination by blocking the differentiation of rat oligodendrocyte progenitor cells (OPCs) via modulation of PKCα. We therefore screened drugs for their potential to overcome this differentiation block. From our screening, tamoxifen emerges as a potent inducer of OPC differentiation in vitro. We show that the effects of tamoxifen rely on modulation of the estrogen receptors ERα, ERβ, and GPR30. Furthermore, we demonstrate that administration of tamoxifen to demyelinated rats in vivo accelerates remyelination. Tamoxifen is a well-established drug and is thus a promising candidate for a drug to regenerate myelin, as it will not require extensive safety testing. In addition, Tamoxifen plays an important role in biomedical research as an activator of inducible genetic models. Our results highlight the importance of appropriate controls when using such models. PMID:27554391

  15. Sildenafil (Viagra) Protective Effects on Neuroinflammation: The Role of iNOS/NO System in an Inflammatory Demyelination Model

    PubMed Central

    Raposo, Catarina; Nunes, Ana Karolina de Santana; Luna, Rayana Leal de Almeida; Araújo, Shyrlene Meiry da Rocha; da Cruz-Höfling, Maria Alice; Peixoto, Christina Alves

    2013-01-01

    We recently demonstrated that sildenafil reduces the expression of cytokines, COX-2, and GFAP in a demyelinating model induced in wild-type (WT) mice. Herein, the understandings of the neuroprotective effect of sildenafil and the mediation of iNOS/NO system on inflammatory demyelination induced by cuprizone were investigated. The cerebella of iNOS−/− mice were examined after four weeks of treatment with cuprizone alone or combined with sildenafil. Cuprizone increased GFAP, Iba-1, TNF-α, COX-2, IL-1β, and IFN-γ expression, decreased expression of glutathione S-transferase pi (GSTpi), and damaged myelin in iNOS−/− mice. Sildenafil reduced Iba-1, IFN-γ, and IL-1β levels but had no effect on the expression of GFAP, TNF-α, and COX-2 compared to the cuprizone group. Sildenafil elevated GSTpi levels and improved the myelin structure/ultrastructure. iNOS−/− mice suffered from severe inflammation following treatment with cuprizone, while WT mice had milder inflammation, as found in the previous study. It is possible that inflammatory regulation through iNOS-feedback is absent in iNOS−/− mice, making them more susceptible to inflammation. Sildenafil has at least a partial anti-inflammatory effect through iNOS inhibition, as its effect on iNOS−/− mice was limited. Further studies are required to explain the underlying mechanism of the sildenafil effects. PMID:23970812

  16. Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination.

    PubMed

    Haines, Jeffery D; Herbin, Olivier; de la Hera, Belén; Vidaurre, Oscar G; Moy, Gregory A; Sun, Qingxiang; Fung, Ho Yee Joyce; Albrecht, Stefanie; Alexandropoulos, Konstantina; McCauley, Dilara; Chook, Yuh Min; Kuhlmann, Tanja; Kidd, Grahame J; Shacham, Sharon; Casaccia, Patrizia

    2015-04-01

    Axonal damage has been associated with aberrant protein trafficking. We examined a newly characterized class of compounds that target nucleo-cytoplasmic shuttling by binding to the catalytic groove of the nuclear export protein XPO1 (also known as CRM1, chromosome region maintenance protein 1). Oral administration of reversible CRM1 inhibitors in preclinical murine models of demyelination significantly attenuated disease progression, even when started after the onset of paralysis. Clinical efficacy was associated with decreased proliferation of immune cells, characterized by nuclear accumulation of cell cycle inhibitors, and preservation of cytoskeletal integrity even in demyelinated axons. Neuroprotection was not limited to models of demyelination, but was also observed in another mouse model of axonal damage (that is, kainic acid injection) and detected in cultured neurons after knockdown of Xpo1, the gene encoding CRM1. A proteomic screen for target molecules revealed that CRM1 inhibitors in neurons prevented nuclear export of molecules associated with axonal damage while retaining transcription factors modulating neuroprotection. PMID:25706475

  17. Tumefactive fibro-inflammatory lesions of the head and neck.

    PubMed

    Wold, L E; Weiland, L H

    1983-07-01

    Seven patients had tumefactive inflammatory fibrous lesions of the head similar in histologic appearance to Riedel's thyroiditis, sclerosing mediastinitis, and retroperitoneal fibrosis. Five patients were females, and the mean age at presentation was 48 years. Four patients presented clinically with a mass. Histologically, these lesions were characterized by an admixture of mature fibrous tissue and an inflammatory infiltrate of lymphocytes and scattered polymorphonuclear leukocytes. Initially, all patients had been treated surgically. Two patients received radiation therapy when recurrent disease could not be controlled surgically. Five of the six patients on whom follow-up information was available were alive at follow-up that ranged from 14 to 49 months (mean 29). These lesions are distinct histologically from desmoid tumors, fibromatoses, and nodular fasciitis. The spectrum of fibrosclerosing lesions (Riedel's thyroiditis, idiopathic mediastinal fibrosis, retroperitoneal fibrosis, and sclerosing cholangitis) probably includes this group of tumefactive inflammatory fibrous lesions of the head. PMID:6614311

  18. Transplanted microvascular endothelial cells promote oligodendrocyte precursor cell survival in ischemic demyelinating lesions.

    PubMed

    Iijima, Keiya; Kurachi, Masashi; Shibasaki, Koji; Naruse, Masae; Puentes, Sandra; Imai, Hideaki; Yoshimoto, Yuhei; Mikuni, Masahiko; Ishizaki, Yasuki

    2015-11-01

    We previously showed that transplantation of brain microvascular endothelial cells (MVECs) greatly stimulated remyelination in the white matter infarct of the internal capsule (IC) induced by endothelin-1 injection and improved the behavioral outcome. In the present study, we examined the effect of MVEC transplantation on the infarct volume using intermittent magnetic resonance image and on the behavior of oligodendrocyte lineage cells histochemically. Our results in vivo show that MVEC transplantation reduced the infarct volume in IC and apoptotic death of oligodendrocyte precursor cells (OPCs). These results indicate that MVECs have a survival effect on OPCs, and this effect might contribute to the recovery of the white matter infarct. The conditioned-medium from cultured MVECs reduced apoptosis of cultured OPCs, while the conditioned medium from cultured fibroblasts did not show such effect. These results suggest a possibility that transplanted MVECs increased the number of OPCs through the release of humoral factors that prevent their apoptotic death. Identification of such humoral factors may lead to the new therapeutic strategy against ischemic demyelinating diseases. PMID:26212499

  19. Performance of Apparent Diffusion Coefficient Values and Conventional MRI Features in Differentiating Tumefactive Demyelinating Lesions From Primary Brain Neoplasms

    PubMed Central

    Mabray, Marc C.; Cohen, Benjamin A.; Villanueva-Meyer, Javier E.; Valles, Francisco E.; Barajas, Ramon F.; Rubenstein, James L.; Cha, Soonmee

    2015-01-01

    OBJECTIVE Tumefactive demyelinating lesions (TDLs) remain one of the most common brain lesions to mimic a brain tumor, particularly primary CNS lymphoma (PCNSL) and high-grade gliomas. The purpose of our study was to evaluate the ability of apparent diffusion coefficient (ADC) values and conventional MRI features to differentiate TDLs from PCNSLs and high-grade gliomas. MATERIALS AND METHODS Seventy-five patients (24 patients with TDLs, 28 with PCNSLs, and 23 with high-grade gliomas) with 168 brain lesions (70 TDLs, 68 PCNSLs, and 30 high-grade gliomas) who underwent DWI before surgery or therapy were included in the study. Minimum ADC (ADCmin) and average ADC (ADCavg) values were calculated for each lesion. ANOVA and ROC analyses were performed. ROC analyses were also performed for the presence of incomplete rim enhancement and for the number of lesions. Multiple-variable logistic regression with ROC analysis was then performed to evaluate performance in multiple-variable models. RESULTS ADCmin was statistically significantly higher (p < 0.01) in TDLs (mean, 0.886; 95% CI, 0.802–0.931) than in PCNSLs (0.547; 95% CI, 0.496–0.598) and high-grade gliomas (0.470; 95% CI, 0.385–0.555). (All ADC values in this article are reported in units of × 10−3 mm2/s.) ADCavg was statistically significantly higher (p < 0.01) in TDLs (mean, 1.362; 95% CI, 1.268–1.456) than in PCNSLs (0.990; 95% CI, 0.919–1.061) but not in high-grade gliomas (1.216; 95% CI, 1.074–1.356). Multiple-variable models showed statistically significant individual effects and superior diagnostic performance on ROC analysis. CONCLUSION TDLs can be diagnosed on preoperative MRI with a high degree of specificity; MRI features of incomplete rim enhancement, high ADC values, and a large number of lesions individually increase the probability and diagnostic confidence that a lesion is a TDL. PMID:26496556

  20. Pericarditis and chronic inflammatory demyelinating polyneuropathy during therapy with pegylated interferon alfa-2a for chronic hepatitis C.

    PubMed

    Nishio, Kazuaki; Konndo, Takeshi; Okada, Shunichi; Enchi, Machiko

    2010-09-27

    We report a case of pericarditis and chronic inflammatory demyelinating polyneuropathy with biological signs of a lupus-like syndrome due to pegylated interferon alfa-2a therapy during treatment for chronic hepatitis C. The patient developed moderate weakness in the lower limbs and dyspnea. He was hospitalized for congestive heart failure. An electrocardiogram showed gradual ST-segment elevation in leads V(1) through V(6) without coronary artery disease. A transthoracic cardiac ultrasonographic study revealed moderate pericardial effusion with normal left ventricular function. Anti-DNA antibody and antids DNA IgM were positive. Neurological examination revealed a symmetrical predominantly sensory polyneuropathy with impairment of light touch and pin prick in globe and stoking-like distribution. Treatment with prednisolone improved the pericarditis and motor nerve disturbance and the treatment with intravenous immunoglobulin improved the sensory nerve disturbance. PMID:21161021

  1. Pericarditis and chronic inflammatory demyelinating polyneuropathy during therapy with pegylated interferon alfa-2a for chronic hepatitis C

    PubMed Central

    Nishio, Kazuaki; Konndo, Takeshi; Okada, Shunichi; Enchi, Machiko

    2010-01-01

    We report a case of pericarditis and chronic inflammatory demyelinating polyneuropathy with biological signs of a lupus-like syndrome due to pegylated interferon alfa-2a therapy during treatment for chronic hepatitis C. The patient developed moderate weakness in the lower limbs and dyspnea. He was hospitalized for congestive heart failure. An electrocardiogram showed gradual ST-segment elevation in leads V1 through V6 without coronary artery disease. A transthoracic cardiac ultrasonographic study revealed moderate pericardial effusion with normal left ventricular function. Anti-DNA antibody and antids DNA IgM were positive. Neurological examination revealed a symmetrical predominantly sensory polyneuropathy with impairment of light touch and pin prick in globe and stoking-like distribution. Treatment with prednisolone improved the pericarditis and motor nerve disturbance and the treatment with intravenous immunoglobulin improved the sensory nerve disturbance. PMID:21161021

  2. Variant of multiple sclerosis with dementia and tumefactive demyelinating brain lesions

    PubMed Central

    Hamed, Sherifa A

    2015-01-01

    We describe an unusual clinical and diagnostic feature of a patient with multiple sclerosis (MS). A 25-year-old woman was admitted to the Neurology department (December 2009) with one month history of rapid cognitive deterioration. She had poor cognition, dysphasia, reduction in visual acuity and temporal pallor of the optic discs. She had prolonged latencies of P100 component of visual evoked potentials (VEPs). Magnetic resonance imaging (MRI)-brain showed multifocal large (≥ 3 cm) white-matter hypointense lesions in T1W and hyperintense in T2W and fluid-attenuated inversion recovery images and patchy enhancement. A diagnosis of tumefactive MS was given. She received two consecutive 5-d courses of 1 g daily intravenous methylprednisolone for 2 mo and oral prednisolone in dose of 80 mg twice/daily in between. At the 3rd month, Mini Mental State Examination and VEPs returned to normal but not the MRI. Patient continued oral steroids after hospital discharge (March 2010) for 9 mo with significant MRI improvement after which tapering of steroids started for a year. The patient refused immunomodulation therapy due to her low socioeconomic status. Neither clinical relapse nor new MRI lesions were observed throughout the next 4 years. In spite of the aggressive course of tumefactive MS variant, good prognosis may be seen in some patients. PMID:26090374

  3. Contribution of plexus MRI in the diagnosis of atypical chronic inflammatory demyelinating polyneuropathies.

    PubMed

    Lozeron, Pierre; Lacour, Marie-Christine; Vandendries, Christophe; Théaudin, Marie; Cauquil, Cécile; Denier, Christian; Lacroix, Catherine; Adams, David

    2016-01-15

    Nerve enlargement has early been recognized in CIDP and plexus MRI hypertrophy has been reported in typical CIDP cases. Our aim is to determine plexus MRI value in the diagnosis of CIDP with an initial atypical presentation, which, up to now, has not been demonstrated. Retrospective study of 33 consecutive patients suspected of CIDP. Plexus MRI was performed on the most affected territory (brachial or lumbar). Were assessed: plexus trophicity, T2-STIR signal intensity and gadolinium enhancement. Final CIDP diagnosis was made after comprehensive workup. A histo-radiological correlation was performed. Final CIDP diagnosis was made in 25 (76%) including 21 with initial atypical clinical presentation. Eleven CIDP patients (52%) with initial atypical clinical presentation had abnormal plexus MRI including 9 suggestive of CIDP (43%) and none of the patients with an alternative diagnosis. Hypertrophy of the proximal plexus and/or extraforaminal roots was found in 8 cases and Gadolinium enhancement in 2 cases. Abnormalities were more frequent on brachial (86%) than lumbosacral MRIs (29%) and asymmetrical (72%) and most often associated with histological signs of demyelination. The nerve biopsy was suggestive of CIDP in 9/13 patients with normal MRI. Plexus MRI seems useful in the diagnostic strategy of patients with suspicion of CIDP with atypical presentation. Nerve biopsy remains important when other investigations are inconclusive. PMID:26723995

  4. Cortical grey matter demyelination can be induced by elevated pro-inflammatory cytokines in the subarachnoid space of MOG-immunized rats.

    PubMed

    Gardner, Christopher; Magliozzi, Roberta; Durrenberger, Pascal F; Howell, Owain W; Rundle, Jon; Reynolds, Richard

    2013-12-01

    A substantial proportion of cases with secondary progressive multiple sclerosis have extensive inflammation in the leptomeninges that is associated with increased subpial demyelination, neuronal loss and an exacerbated disease course. However, the mechanisms underlying this extensive subpial pathology are poorly understood. We hypothesize that pro-inflammatory cytokine production within the meninges may be a key to this process. Post-mortem cerebrospinal fluid and dissected cerebral leptomeningeal tissue from patients with multiple sclerosis were used to study the presence of tumour necrosis factor and interferon gamma protein and messenger RNA levels. A novel model of subpial cortical grey matter demyelination was set up in Dark Agouti rats and analysed using quantitative immunohistochemistry. Increased expression of the pro-inflammatory cytokines tumour necrosis factor and interferon gamma was found in the meninges of cases with secondary progressive multiple sclerosis exhibiting tertiary lymphoid-like structures. Injection of tumour necrosis factor and interferon gamma into the subarachnoid space of female Dark Agouti rats pre-immunized with a subclinical dose of myelin oligodendrocyte glycoprotein mimicked the pathology seen in multiple sclerosis, including infiltration of lymphocytes (CD4+ and CD8+ T cells and CD79+ B cells) into the meninges and extensive subpial demyelination. Extensive microglial/macrophage activation was present in a gradient from the pial surface to deeper cortical layers. Demyelination did not occur in control animals immunized with incomplete Freund's adjuvant and injected with cytokines. These results support the hypothesis that pro-inflammatory molecules produced in the meninges play a major role in cortical demyelination in multiple sclerosis, but also emphasize the involvement of an anti-myelin immune response. PMID:24176976

  5. The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain.

    PubMed

    Haider, Lukas; Zrzavy, Tobias; Hametner, Simon; Höftberger, Romana; Bagnato, Francesca; Grabner, Günther; Trattnig, Siegfried; Pfeifenbring, Sabine; Brück, Wolfgang; Lassmann, Hans

    2016-03-01

    Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies. PMID:26912645

  6. The topograpy of demyelination and neurodegeneration in the multiple sclerosis brain

    PubMed Central

    Haider, Lukas; Hametner, Simon; Höftberger, Romana; Bagnato, Francesca; Grabner, Günther; Trattnig, Siegfried; Pfeifenbring, Sabine; Brück, Wolfgang

    2016-01-01

    Multiple sclerosis is a chronic inflammatory disease with primary demyelination and neurodegeneration in the central nervous system. In our study we analysed demyelination and neurodegeneration in a large series of multiple sclerosis brains and provide a map that displays the frequency of different brain areas to be affected by these processes. Demyelination in the cerebral cortex was related to inflammatory infiltrates in the meninges, which was pronounced in invaginations of the brain surface (sulci) and possibly promoted by low flow of the cerebrospinal fluid in these areas. Focal demyelinated lesions in the white matter occurred at sites with high venous density and additionally accumulated in watershed areas of low arterial blood supply. Two different patterns of neurodegeneration in the cortex were identified: oxidative injury of cortical neurons and retrograde neurodegeneration due to axonal injury in the white matter. While oxidative injury was related to the inflammatory process in the meninges and pronounced in actively demyelinating cortical lesions, retrograde degeneration was mainly related to demyelinated lesions and axonal loss in the white matter. Our data show that accumulation of lesions and neurodegeneration in the multiple sclerosis brain does not affect all brain regions equally and provides the pathological basis for the selection of brain areas for monitoring regional injury and atrophy development in future magnetic resonance imaging studies. PMID:26912645

  7. Abnormal sodium channel distribution in optic nerve axons in a model of inflammatory demyelination.

    PubMed

    Craner, Matthew J; Lo, Albert C; Black, Joel A; Waxman, Stephen G

    2003-07-01

    Myelinated fibres are characterized by the aggregation of Nav1.6 sodium channels within the axon membrane at nodes of Ranvier, where their presence supports saltatory conduction. In this study, we used immunocytochemical methods to study the organization of sodium channels along axons in experimental allergic encephalomyelitis (EAE), a model of multiple sclerosis. We studied axons within the optic nerve, a CNS tract commonly affected in multiple sclerosis, and their cell bodies of origin (retinal ganglion cells), using subtype-specific antibodies generated against sodium channel subtypes Nav1.1, Nav1.2, Nav1.3 and Nav1.6, which previously have been shown to be expressed by retinal ganglion cells. We demonstrate a significant switch from Nav1.6 to Nav1.2 expression in the optic nerve in EAE; there was a reduction in frequency of Nav1.6-positive nodes (84.5% Nav1.6-immunopositive nodes in control versus 32.9% in EAE) and increased frequency of Nav1.2-positive nodes (11.8% Nav1.2 immunopositive nodes in control versus 74.9% in EAE). Moreover, we observed a significant increase in the number of linear (presumably demyelinated) axonal profiles demonstrating extended diffuse immunostaining for Nav1.2 in EAE versus control optic nerves. These changes within the optic nerve are paralleled by decreased levels of Nav1.6 and increased Nav1.2 protein, together with increased levels of Nav1.2 mRNA, within retinal ganglion cells in EAE. Our findings of a loss of Nav1.6 and increased expression of Nav1.2 suggest that electrogenesis in EAE may revert to a stage similar to that observed in immature retinal ganglion cells in which Nav1.2 channels support conduction of action potentials along axons. PMID:12805113

  8. Diagnostic value of aquaporin 4 antibody in assessing idiopathic inflammatory demyelinating central nervous system diseases in Egyptian patients.

    PubMed

    Kishk, Nirmeen A; Abokrysha, Noha T; Rashed, Laila; Ahmed, Nagwa

    2015-04-01

    Neuromyelitis optica immunoglobulin G (NMO-IgG) binds selectively to aquaporin 4 (AQP4). We aimed to evaluate the frequency of AQP4 antibody in Egyptian patients. We retrospectively evaluated 39 consecutive Egyptian patients with suspected idiopathic inflammatory demyelinating central nervous system disease (IIDCD) who visited the multiple sclerosis clinic at Kaser Al-Aini Hospital. The patients were diagnosed with NMO, other NMO spectrum disorders, or multiple sclerosis using the respective current diagnostic criteria. For the anti-AQP4 antibody assays, serum samples from all patients and 16 healthy matched controls were evaluated. The coded sera were tested for AQP4 antibody using an enzyme-linked immunosorbent assay kit. The relations between the clinical diagnosis and the AQP4 antibody serologic status were studied. Among the 39 patients, 21 (53.85%) were AQP4 antibody-positive. NMO spectrum disorders patients had a significantly higher level of AQP4 antibody compared with MS patients and controls (p<0.001). Only eight patients (36.36%) met the Wingerchuk 2006 criteria for NMO diagnosis excluding AQP4 antibody-seropositive status. AQP4 antibody was highly prevalent (almost 54%) in Egyptian IIDCD patients. Our research revealed that we must maintain a high index of suspicion for NMO spectrum disorders. PMID:25677878

  9. Aquaporin-4 Immuneglobulin G Testing in 36 Consecutive Jamaican Patients with Inflammatory Central Nervous System Demyelinating Disease

    PubMed Central

    Sandy, Sherri; Seemungal, Terence A.R.; Ali, Amza

    2014-01-01

    Epidemiological studies of neuromyelitis optica (NMO) in Jamaica are lacking. Here we reviewed the clinical records of 700 patients undergoing neurological evaluation at the Kingston Public Hospital, the largest tertiary institution in Jamaica over a 4 month period. We investigated the diagnostic utility of Aquaporin-4 ImmuneglobulinG (AQP4-IgG) testing in 36 consecutive patients with a diagnosis of an inflammatory demyelinating disorder (IDD) of the central nervous system (CNS). Patients were classified into 3 categories: i) NMO, n=10; ii) multiple sclerosis (MS), n=14 and iii) unclassified IDD (n=12). All sera were tested for AQP-IgG status by cell binding assay (Euroimmun). No MS cases were positive. Ninety per cent of NMO cases were positive. Four of 12 patients with unclassified IDD tested positive for AQP4-IgG. AQP4-IgG seropositivity was associated with a lower socioeconomic status, higher EDSS (P=0.04) and lower pulmonary function than the seronegative cases (P=0.007). Aquaporin-4 autoimmunity may account for a significant proportion of Jamaican CNS IDDs. PMID:25309712

  10. Defining and Regulating Acute Inflammatory Lesion Formation during the Pathogenesis of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis.

    PubMed

    Bolton, Christopher; Smith, Paul

    2015-01-01

    The primary pathology of the human central nervous system disease multiple sclerosis (MS) and the animal counterpart experimental autoimmune encephalomyelitis (EAE) includes immunological and inflammatory events. Immune system involvement in MS has been widely debated but the role of inflammation has received less attention. Classic acute inflammation features vasculitis, resident tissue macrophage and mast cell participation plus the involvement of circulatory-derived neutrophils and platelets. Pre-lesion development in MS incorporates cerebral vasculitis, activated resident microglia in normal appearing white matter together with infiltrating cell types and factors indicative of an acute inflammatory reaction. Similarly, the formation of perivascular lesions during early EAE includes characteristic neurovasculitis, the participation of central nervous system microglial phenotypes plus haemopoietic cells and mediators, signifying an ongoing acute inflammatory response. EAE has been extensively used as a screen to select drugs for MS treatment but has been criticised as unrepresentative of the human condition due to fundamental differences in disease induction and pathogenesis. The review provides compelling evidence for a distinct acute inflammatory phase in MS lesion formation that is convincingly reproduced in early EAE pathology. Moreover, consideration of drug efficacy studies undertaken during initial EAE validates the occurrence of an acute inflammatory phase in disease pathogenesis. Critical appraisal, recognition and acceptance of the mutual acute inflammatory components inherent in the primary pathology of MS and EAE reveals new targets and encourages confident and reliable employment of the animal model in the assessment of novel compounds for the control of key primary pathological events in human demyelinating disease. PMID:26177741

  11. Inflammatory myofibroblastic tumor, inflammatory fibrosarcoma, and related lesions: an historical review with differential diagnostic considerations.

    PubMed

    Coffin, C M; Dehner, L P; Meis-Kindblom, J M

    1998-05-01

    The concept of the inflammatory myofibroblastic tumor (IMT) has evolved from an already perplexing pathological process, the inflammatory pseudotumor, which was initially recognized in the lung and regarded as a pseudoneoplasm, although its histological features resembled a spindle cell sarcoma. Despite the pathological findings and their apparent prognostic implications, most affected individuals regardless of the primary site have had favorable clinical outcomes. The designation of inflammatory pseudotumor came to be widely accepted, although these lesions were clearly tumors or masses that may or may not have been pseudoneoplasms. An aberrant or exaggerated response to tissue injury without an established cause has generally been favored as the pathogenesis of the inflammatory pseudotumor or IMT. Once the myofibroblast was identified and its function in tissue repair was established, this cell type was found in a variety of soft tissue lesions from nodular fasciitis to malignant fibrous histiocytoma. The myofibroblast was eventually recognized as the principal cell type in the inflammatory pseudotumor, which provided the opportunity to redesignate this tumor as IMT. Some of the clinical and pathological aspects of the IMT began to suggest the possibility that these lesions are more similar to neoplasms than a postinflammatory process. Another step in the evolution of the inflammatory pseudotumor and IMT occurred with the report of a mesenteric or retroperitoneal tumor with similar pathological features to the latter tumors but with more aggressive behavior to warrant an interpretation of malignancy as an inflammatory fibrosarcoma. The IMT and inflammatory fibrosarcoma appear to have many overlapping clinical and pathological features. These tumors are histogenetically related, and if they are separate entities, they are differentiated more by degrees than absolutes. The therapeutic approach to these tumors should relay primarily on surgical resection. Studies in

  12. Conducting processes in simulated chronic inflammatory demyelinating polyneuropathy at 20°C-42°C.

    PubMed

    Stephanova, D I; Daskalova, M; Mladenov, M

    2015-03-01

    Decreased conducting processes leading usually to conduction block and increased weakness of limbs during cold (cold paresis) or warmth (heat paresis) have been reported in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). To explore the mechanisms of these symptoms, the effects of temperature (from 20°C to 42°C) on nodal action potentials and their current kinetics in previously simulated case of 70% CIDP are investigated, using our temperature dependent multi-layered model of the myelinated human motor nerve fiber. The results show that potential amplitudes have a bifid form at 20°C. As in the normal case, for the CIDP case, the nodal action potentials are determined mainly by the nodal sodium currents (I Na ) for the temperature range of 20-39°C, as the contribution of nodal fast and slow potassium currents (I Kf and I Ks ) to the total ionic current (Ii) is negligible. Also, the contribution of I Kf and I Ks to the membrane repolarization is enhanced at temperatures higher than 39°C. However, in the temperature range of 20-42°C, all potential parameters in the CIDP case, except for the conduction block during hyperthermia (≥ 40°C) which is again at 45°C, worsen: (i) conduction velocities and potential amplitudes are decreased; (ii) afterpotentials and threshold stimulus currents for the potential generation are increased; (iii) the current kinetics of action potentials is slowed and (iv) the conduction block during hypothermia (≤ 25°C) is at temperatures lower than 20°C. These potential parameters are more altered during hyperthermia and are most altered during hypothermia. The present results suggest that the conducting processes in patients with CIDP are in higher risk during hypothermia than hyperthermia. PMID:25597276

  13. [Aortic inflammatory lesions in Behçet's disease].

    PubMed

    Desbois, A-C; Wechsler, B; Cacoub, P; Saadoun, D

    2016-04-01

    The arterial lesions affect about 10% of patients with Behçet's disease (BD). Aortic inflammatory involvement includes predominantly aortic aneurysmal lesions affecting most often the abdominal aorta. They account for the severity of the disease and are a leading cause of death when they hit the aorta or pulmonary arteries. Within the arterial lesions of BD, aortic involvement is, with femoral lesions, the most common site involved (18-28% of patients with vascular disease). Unlike other large vessels vasculitis (i.e. giant cell arteritis and Takayasu's arteritis) diffuse aortitis is observed in less than 5% of patients with BD. Aortic lesions of BD may be asymptomatic (systematic imaging or occasionally associated with other vascular event) or be revealed by the occurrence of abdominal, thoracic or lumbar pain, or an aortic valve insufficiency. Fever is frequently associated. Increase in acute phase reactants is common in these patients. Histological analysis may show infiltration by lymphocytes, neutrophils and plasma cells in the media and adventitia and a proliferation of the vasa vasorum in the media as well as a fibroblastic proliferation. In the later phase, a fibrous thickening of the media and adventitia is observed as well as a proliferation and thickening of the vasa vasorum. The therapeutic management should always include a medical treatment for the control of inflammation (corticosteroids, immunosuppressive drugs and/or biotherapy) and often an endovascular or surgical treatment if the aneurysm is threatening. The choice between endovascular or surgical treatment is considered case by case, depending on the experience of the team, anatomical conditions and of the clinical presentation. In this review, we provide a detailed and updated review of the literature to describe the aortic inflammatory damage associated with Behçet's disease. PMID:26611428

  14. Ultrasonography and computed tomography of inflammatory abdominal wall lesions

    SciTech Connect

    Yeh, H.C.; Rabinowitz, J.G.

    1982-09-01

    Twenty-four patients with inflammatory lesions of the abdominal wall were examined by ultrasonography. Nine of these patients underwent computed tomographic (CT) scanning as well. Both ultrasonography and CT clearly delineated the exact location and extent of abdominal wall abscesses. Abscesses were easily differentiated from cellulitis or phlegmon with ultrasound. The peritoneal line was more clearly delineated on ultrasonograms than on CT scans; abscesses were also more distinct on the ultrasonograms because of their low echogenicity compared with the surrounding structures. Gas bubbles, fat density with specific low attenuation values, and underlying inflamed bowel loops in obese patients with Crohn's disease were better delineated by CT.

  15. Movement disorders in multiple sclerosis and other demyelinating diseases.

    PubMed

    Mehanna, Raja; Jankovic, Joseph

    2013-05-15

    Multiple sclerosis is an autoimmune inflammatory demyelinating disease of the central nervous system characterized by dissemination of the lesions in time and space. While tremor is frequently seen in patients with multiple sclerosis, other movement disorders such as parkinsonism, dystonia, chorea, ballism, paroxysmal dystonia, paroxysmal chorea, myoclonus, tourettism, restless leg syndrome and hemifacial spasm are less frequently reported. In this systematic review of the literature, we describe the different movement disorders reported in patients with multiple sclerosis and attempt to characterize their relation with the underlying demyelinating process. We also summarize the reports of movement disorders described in other demyelinating diseases such as neuromyelitis optica, acute disseminated encephalomyelitis and central pontine myelinolysis. PMID:23522528

  16. Organ-Specific Protective Role of NKT Cells in Virus-Induced Inflammatory Demyelination and Myocarditis Depends on Mouse Strain

    PubMed Central

    Kawai, Eiichiro; Sato, Fumitaka; Omura, Seiichi; Martinez, Nicholas E.; Reddy, Pratap C.; Taniguchi, Masaru; Tsunoda, Ikuo

    2014-01-01

    Theiler’s murine encephalomyelitis virus (TMEV) can induce demyelination or myocarditis in susceptible mouse strains. A deficiency of NKT cells exacerbated TMEV-induced demyelinating disease (TMEV-IDD) in SJL/J and BALB/c mice. In C57BL/6 background, however, NKT-cell-deficient Jαt 18 KO mice remained as resistant to TMEV-IDD as wild-type mice. Echocardiography and histology showed that Jα18 KO mice developed more severe myocarditis (greater T cell infiltration and fibrosis) than wild-type mice, suggesting a protective role of NKT cells in myocarditis in C57BL/6 mice. Jα18 KO mice had higher cardiac viral RNA and anti-viral antibody titers, but had lower lymphoproliferation and IL-4 and IL-10 production. PMID:25434008

  17. Central Nervous System Idiopathic Inflammatory Demyelinating Disorders in South Americans: A Descriptive, Multicenter, Cross-Sectional Study

    PubMed Central

    Papais-Alvarenga, Regina Maria; Vasconcelos, Claudia Cristina Ferreira; Carra, Adriana; de Castillo, Ibis Soto; Florentin, Sara; Diaz de Bedoya, Fernando Hamuy; Mandler, Raul; de Siervi, Luiza Campanella; Pimentel, Maria Lúcia Vellutini; Alvarenga, Marina Papais; Papais Alvarenga, Marcos; Grzesiuk, Anderson Kuntz; Gama Pereira, Ana Beatriz Calmon; Gomes Neto, Antonio Pereira; Velasquez, Carolina; Soublette, Carlos; Fleitas, Cynthia Veronica; Diniz, Denise Sisteroli; Armas, Elizabeth; Batista, Elizabeth; Hernandez, Freda; Pereira, Fernanda Ferreira Chaves da Costa; Siqueira, Heloise Helena; Cabeça, Hideraldo; Sanchez, Jose; Brooks, Joseph Bruno Bidin; Gonçalves, Marcus Vinicius; Barroso, Maria Cristina Del Negro; Ravelo, Maria Elena; Castillo, Maria Carlota; Ferreira, Maria Lúcia Brito; Rocha, Maria Sheila Guimarães; Parolin, Monica Koncke Fiuza; Molina, Omaira; Marinho, Patricia Beatriz Christino; Christo, Paulo Pereira; Brant de Souza, Renata; Pessanha Neto, Silvio; Camargo, Solange Maria das Graças; Machado, Suzana Costa; Neri, Vanderson Carvalho; Fragoso, Yara Dadalti; Alvarenga, Helcio; Thuler, Luiz Claudio Santos

    2015-01-01

    The idiopathic inflammatory demyelinating disease (IIDD) spectrum has been investigated among different populations, and the results have indicated a low relative frequency of neuromyelitis optica (NMO) among multiple sclerosis (MS) cases in whites (1.2%-1.5%), increasing in Mestizos (8%) and Africans (15.4%-27.5%) living in areas of low MS prevalence. South America (SA) was colonized by Europeans from the Iberian Peninsula, and their miscegenation with natives and Africans slaves resulted in significant racial mixing. The current study analyzed the IIDD spectrum in SA after accounting for the ethnic heterogeneity of its population. A cross-sectional multicenter study was performed. Only individuals followed in 2011 with a confirmed diagnosis of IIDD using new diagnostic criteria were considered eligible. Patients’ demographic, clinical and laboratory data were collected. In all, 1,917 individuals from 22 MS centers were included (73.7% female, 63.0% white, 28.0% African, 7.0% Mestizo, and 0.2% Asian). The main disease categories and their associated frequencies were MS (76.9%), NMO (11.8%), other NMO syndromes (6.5%), CIS (3.5%), ADEM (1.0%), and acute encephalopathy (0.4%). Females predominated in all main categories. The white ethnicity also predominated, except in NMO. Except in ADEM, the disease onset occurred between 20 and 39 years old, early onset in 8.2% of all cases, and late onset occurred in 8.9%. The long-term morbidity after a mean disease time of 9.28±7.7 years was characterized by mild disability in all categories except in NMO, which was scored as moderate. Disease time among those with MS was positively correlated with the expanded disability status scale (EDSS) score (r=0.374; p=<0.001). This correlation was not observed in people with NMO or those with other NMO spectrum disorders (NMOSDs). Among patients with NMO, 83.2% showed a relapsing-remitting course, and 16.8% showed a monophasic course. The NMO-IgG antibody tested using indirect

  18. Central Nervous System Idiopathic Inflammatory Demyelinating Disorders in South Americans: A Descriptive, Multicenter, Cross-Sectional Study.

    PubMed

    Papais-Alvarenga, Regina Maria; Vasconcelos, Claudia Cristina Ferreira; Carra, Adriana; de Castillo, Ibis Soto; Florentin, Sara; Diaz de Bedoya, Fernando Hamuy; Mandler, Raul; de Siervi, Luiza Campanella; Pimentel, Maria Lúcia Vellutini; Alvarenga, Marina Papais; Alvarenga, Marcos Papais; Grzesiuk, Anderson Kuntz; Gama Pereira, Ana Beatriz Calmon; Gomes Neto, Antonio Pereira; Velasquez, Carolina; Soublette, Carlos; Fleitas, Cynthia Veronica; Diniz, Denise Sisteroli; Armas, Elizabeth; Batista, Elizabeth; Hernandez, Freda; Pereira, Fernanda Ferreira Chaves da Costa; Siqueira, Heloise Helena; Cabeça, Hideraldo; Sanchez, Jose; Brooks, Joseph Bruno Bidin; Gonçalves, Marcus Vinicius; Barroso, Maria Cristina Del Negro; Ravelo, Maria Elena; Castillo, Maria Carlota; Ferreira, Maria Lúcia Brito; Rocha, Maria Sheila Guimarães; Parolin, Monica Koncke Fiuza; Molina, Omaira; Marinho, Patricia Beatriz Christino; Christo, Paulo Pereira; Brant de Souza, Renata; Pessanha Neto, Silvio; Camargo, Solange Maria das Graças; Machado, Suzana Costa; Neri, Vanderson Carvalho; Fragoso, Yara Dadalti; Alvarenga, Helcio; Thuler, Luiz Claudio Santos

    2015-01-01

    The idiopathic inflammatory demyelinating disease (IIDD) spectrum has been investigated among different populations, and the results have indicated a low relative frequency of neuromyelitis optica (NMO) among multiple sclerosis (MS) cases in whites (1.2%-1.5%), increasing in Mestizos (8%) and Africans (15.4%-27.5%) living in areas of low MS prevalence. South America (SA) was colonized by Europeans from the Iberian Peninsula, and their miscegenation with natives and Africans slaves resulted in significant racial mixing. The current study analyzed the IIDD spectrum in SA after accounting for the ethnic heterogeneity of its population. A cross-sectional multicenter study was performed. Only individuals followed in 2011 with a confirmed diagnosis of IIDD using new diagnostic criteria were considered eligible. Patients' demographic, clinical and laboratory data were collected. In all, 1,917 individuals from 22 MS centers were included (73.7% female, 63.0% white, 28.0% African, 7.0% Mestizo, and 0.2% Asian). The main disease categories and their associated frequencies were MS (76.9%), NMO (11.8%), other NMO syndromes (6.5%), CIS (3.5%), ADEM (1.0%), and acute encephalopathy (0.4%). Females predominated in all main categories. The white ethnicity also predominated, except in NMO. Except in ADEM, the disease onset occurred between 20 and 39 years old, early onset in 8.2% of all cases, and late onset occurred in 8.9%. The long-term morbidity after a mean disease time of 9.28±7.7 years was characterized by mild disability in all categories except in NMO, which was scored as moderate. Disease time among those with MS was positively correlated with the expanded disability status scale (EDSS) score (r=0.374; p=<0.001). This correlation was not observed in people with NMO or those with other NMO spectrum disorders (NMOSDs). Among patients with NMO, 83.2% showed a relapsing-remitting course, and 16.8% showed a monophasic course. The NMO-IgG antibody tested using indirect

  19. Neuroradiological evaluation of demyelinating disease

    PubMed Central

    Tillema, Jan-Mendelt

    2013-01-01

    Central nervous system inflammatory demyelinating disease can affect patients across the life span. Consensus definitions and criteria of all of the different acquired demyelinating diseases that fall on this spectrum have magnetic resonance imaging criteria. The advances of both neuroimaging techniques and important discoveries in immunology have produced an improved understanding of these conditions and classification. Neuroimaging plays a central role in the accurate diagnosis, prognosis, disease monitoring and research efforts that are being undertaken in this disease. This review focuses on the imaging spectrum of acquired demyelinating disease. PMID:23858328

  20. Association Between the Single Nucleotide Polymorphism and the Level of Aquaporin-4 Protein Expression in Han and Minority Chinese with Inflammatory Demyelinating Diseases of the Central Nervous System.

    PubMed

    Chu, Lan; Dai, Qingqing; Xu, Zhu; He, Dian; Wang, Hao; Wang, Qingsong; Zhang, Yifan; Zhu, Yingwu; Li, Yuan; Cai, Gang; Slavica, Krantic; Allan, Kermode

    2016-07-01

    The purpose of this study was to determine whether or not aquaporin-4 (AQP4) gene mutations are related to the pathogenesis of inflammatory demyelinating diseases in the central nervous system. Polymorphisms of AQP4 exons 1-5 were determined by sequencing DNA from 67 patients with central nervous system inflammatory demyelinating diseases, including neuromyelitis optica (NMO), multiple sclerosis, recurrent or simultaneous bilateral optic neuritis, and longitudinally extensive transverse myelitis. A plasmid with the identified new missense mutation was constructed, and human embryonic kidney cells (HEK293A) were transfected with either the pEGFP-N1-AQP4-M23 vector (bearing the identified mutated cDNA sequence) or with the plasmid bearing the wild-type AQP4 gene sequence. AQP4 protein expression was analyzed in both experimental groups using Western Blot analysis following protein extraction from transfected cells. A synonymous mutation (rs1839318) was detected on exon 3, and an additional synonymous mutation was detected on the exon 2-2 (rs72557968). Most importantly, a new missense mutation was detected on exon 2-1. According to Western blot analysis, the mutated cDNA sequence yielded increased AQP4 protein expression in comparison with the wild-type cDNA sequence (P < 0.05). AQP4 gene mutations are uncommon, occurring in only 3 out of 67 patients. Although it is possible that the mutations contributed to an increased risk of inflammatory central nervous system disease in these individuals, it is unlikely that mutations are a significant contributor to most patients with NMO spectrum disorders in China. PMID:25895050

  1. Neurotropin attenuates local inflammatory response and inhibits demyelination induced by chronic constriction injury of the mouse sciatic nerve.

    PubMed

    Nishimoto, Shunsuke; Okada, Kiyoshi; Tanaka, Hiroyuki; Okamoto, Michio; Fujisawa, Hiroki; Okada, Tomoyuki; Naiki, Mitsuru; Murase, Tsuyoshi; Yoshikawa, Hideki

    2016-07-01

    Neuropathic pain caused by nerve damage in the central and/or peripheral nervous systems is a refractory disorder and the management of such chronic pain has become a major issue. Neurotropin is a drug widely used in Japan and China to treat chronic pain. Although Neurotropin has been demonstrated to suppress chronic pain through the descending pain inhibitory system, the mechanism of analgesic action in the peripheral nervous system remains to be elucidated. In this study, we investigated the local effects of Neurotropin on peripheral nerve damage in a chronic constriction injury (CCI) model. Neurotropin reduced mRNA expressions of IL-1β, IL-6, and TNF-α in the sciatic nerve 1 day after the injury. Activation of Erk was also inhibited locally in the Neurotropin treatment group. Since Erk activation results in demyelination along with dedifferentiation of Schwann cells, we investigated the expression level of myelin basic protein. Five days after the injury, Neurotropin attenuated the downregulation of myelin basic protein in the sciatic nerve in the CCI model. Local effects of Neurotropin around the injury site may result in discovery of new treatments for not only neuropathic pain but also demyelinating diseases and peripheral nervous system injury. PMID:27233579

  2. Theiler's Virus Infection: Pathophysiology of Demyelination and Neurodegeneration

    PubMed Central

    Sato, Fumitaka; Tanaka, Hiroki; Hasanovic, Faris; Tsunoda, Ikuo

    2010-01-01

    Multiple sclerosis (MS) has been suggested to be an autoimmune demyelinating disease of the central nervous system (CNS), whose primary target is either myelin itself, or myelin-forming cells, the oligodendrocytes. Although axonal damage occurs in MS, it is regarded as a secondary event to the myelin damage. Here, the lesion develops from the myelin (outside) to the axons (inside) “Outside-In model”. The Outside-In model has been supported by an autoimmune model for MS, experimental autoimmune (allergic) encephalomyelitis (EAE). However, recently, 1) EAE-like disease has also been shown to be induced by immune responses against axons, and 2) immune responses against axons and neurons as well as neurodegeneration independent of inflammatory demyelination have been reported in MS, which can not be explained by the Outside-In model. Theiler's murine encephalomyelitis virus (TMEV)-induced demyelinating disease (TMEV-IDD) is a viral model for MS. In TMEV infection, axonal injury precedes demyelination, where the lesion develops from the axons (inside) to the myelin (outside) “Inside-Out model”. The initial axonal damage could result in the release of neuroantigens, inducing autoimmune responses against myelin antigens, which potentially attack the myelin from outside the nerve fiber. Thus, the Inside-Out and Outside-In models can make a “vicious” immunological cycle or initiate an immune cascade. PMID:20537875

  3. Fulminant Demyelinating Diseases

    PubMed Central

    Rahmlow, Megan R.; Kantarci, Orhun

    2013-01-01

    Fulminant demyelinating disease is a heading that covers acute disseminated encephalomyelitis and its variant acute hemorrhagic leukoencephalitis (Hurst disease), severe relapses of multiple sclerosis (MS), variants of MS (tumefactive MS, Marburg variant, Balo concentric sclerosis, myelinoclastic diffuse sclerosis), and neuromyelitis optica-spectrum disorders associated with aquaporin autoimmunity. These categories of inflammatory demyelinating disease often prompt hospital admission and many necessitate intensive care monitoring due to the aggressive nature of the illness and associated neurologic morbidity. In this review, we highlight the discriminating clinical, radiographic, and pathologic features of these disorders. Acute management is often accomplished with use of high-dose intravenous steroids and plasma exchange. Aggressive disease may respond to immunosuppression. Prognosis for recovery varies among the disorders but most patients improve. Factors influencing outcome are also discussed. PMID:23983890

  4. Pathologic Heterogeneity Persists in Early Active Multiple Sclerosis Lesions

    PubMed Central

    Metz, Imke; Weigand, Stephen D; Popescu, Bogdan F G; Frischer, Josa M; Parisi, Joseph E; Guo, Yong; Lassmann, Hans; Brück, Wolfgang; Lucchinetti, Claudia F.

    2014-01-01

    Objective Multiple sclerosis (MS) lesions demonstrate immunopathological heterogeneity in patterns of demyelination. Previous cross-sectional studies reported immunopatterns of demyelination were identical among multiple active demyelinating lesions from the same individual, but differed between individuals, leading to the hypothesis of intraindividual pathological homogeneity and interindividual heterogeneity. Other groups suggested a time-dependent heterogeneity of lesions. The objective of our present study was to analyze tissue samples collected longitudinally to determine whether patterns of demyelination persist over time within a given patient. Methods Archival tissue samples derived from patients with pathologically confirmed CNS inflammatory demyelinating disease who had undergone either diagnostic serial biopsy or biopsy followed by autopsy, were analyzed immunohistochemically. Inclusion criteria was the presence of early active demyelinating lesions - required for immunopattern classification - obtained from the same patient at two or more time points. Results Among 1321 surgical biopsies consistent with MS, 22 cases met study inclusion criteria. Twenty-one patients (95%) showed a persistence of immunopathological patterns in tissue sampled from different time points. This persistence was demonstrated for all major patterns of demyelination. A single patient showed features suggestive of both pattern II and pattern III on biopsy, but only pattern II among all active lesions examined at autopsy. Interpretation These findings continue to support the concept of patient-dependent immunopathological heterogeneity in early MS and suggest that the mechanisms and targets of tissue injury may differ among patient subgroups. These observations have potentially significant implications for individualized therapeutic approaches. PMID:24771535

  5. Cost-utility of Intravenous Immunoglobulin (IVIG) compared with corticosteroids for the treatment of Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) in Canada

    PubMed Central

    2010-01-01

    Objectives Intravenous immunoglobulin (IVIG) has demonstrated improvement in chronic inflammatory demyelinating polyneuropathy (CIDP) patients in placebo controlled trials. However, IVIG is also much more expensive than alternative treatments such as corticosteroids. The objective of the paper is to evaluate, from a Canadian perspective, the cost-effectiveness of IVIG compared to corticosteroid treatment of CIDP. Methods A markov model was used to evaluate the costs and QALYs for IVIG and corticosteroids over 5 years of treatment for CIDP. Patients initially responding to IVIG could remain a responder or relapse every 12 week model cycle. Non-responding IVIG patients were assumed to be switched to corticosteroids. Patients on corticosteroids were at risk of a number of adverse events (fracture, diabetes, glaucoma, cataract, serious infection) in each cycle. Results Over the 5 year time horizon, the model estimated the incremental costs and QALYs of IVIG treatment compared to corticosteroid treatment to be $124,065 and 0.177 respectively. The incremental cost per QALY gained of IVIG was estimated to be $687,287. The cost per QALY of IVIG was sensitive to the assumptions regarding frequency and dosing of maintenance IVIG. Conclusions Based on common willingness to pay thresholds, IVIG would not be perceived as a cost effective treatment for CIDP. PMID:20565778

  6. Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) associated to hereditary neuropathy with liability to pressure palsies (HNPP) and revealed after influenza AH1N1 vaccination.

    PubMed

    Remiche, Gauthier; Abramowicz, Marc; Mavroudakis, Nicolas

    2013-12-01

    Neurological complications of AH1N1 vaccination such as Guillain-Barré syndrome were described in the previous years. Several reports suggest that hereditary neuropathies may be a predisposing factor for immune-mediated neuropathies. We report the case of a 54-year-old female who developed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) 5 weeks after AH1N1 vaccination. She had no previous neurological history, but neurophysiological features led us to suspect an underlying hereditary neuropathy. PMP22 gene analysis showed a typical deletion, confirming the diagnosis of hereditary neuropathy with liability to pressure palsies (HNPP). We observed a significant clinical and neurophysiological improvement of the neuropathy after intravenous immunoglobulin treatment. This is, to our knowledge, the first reported case of CIDP potentially triggered by AH1N1 vaccination. This and previous observations suggest that genetic-determined neuropathies could predispose to the occurrence of immune-mediated neuropathies. One must recall the possibility of a superimposed hereditary neuropathy like HNPP in patients with a clinical presentation of CIDP, especially when positive family history or unexpected neurophysiological features are present. PMID:24146347

  7. Nonsurgical management of a large periapical lesion associated with an immature tooth displaying external inflammatory resorption

    PubMed Central

    Fernandes, Marina; de Ataide, Ida

    2015-01-01

    Immature nonvital teeth can often be associated with periapical lesions. Presence of external inflammatory resorption can complicate the treatment plan. A 21-year-old female patient presented with a large periapical lesion in relation to teeth 11 and 12. Tooth 11 was an immature tooth undergoing external inflammatory resorption. Aspiration through the root canal was carried out to evacuate the purulent fluid in the periapical lesion. Triple antibiotic paste was then placed as an intracanal medicament for a period of 2 weeks, followed by calcium hydroxide therapy for a period of 2 months. Mineral trioxide aggregate was then placed as an apical barrier to a thickness of about 4 mm. Obturation of the remainder of the canal space was done after 48 h. Complete periapical healing was evident after 1 year and 6 months. Nonsurgical healing of a large periapical lesion associated with an immature tooth displaying external inflammatory resorption can be successfully achieved. PMID:26180425

  8. Role of glial cells in innate immunity and their role in CNS demyelination.

    PubMed

    Sriram, Subramaniam

    2011-10-28

    The adaptive and innate arms of the immune system are the two pillars of host defense against environmental pathogens. Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS which is considered to be autoimmune and is thought to result from breakdown in the usual checks and balances of the adaptive immune response. The major pathological outcome of the disease is "the MS plaque" a unique feature of CNS demyelination characterized by the destruction of oligodendrocytes with loss of myelin and underlying axons. The MS plaque is not seen in other inflammatory disorders of the CNS. The prevailing opinion suggests that MS is mediated by the activation of an adaptive immune response which targets neural antigens. Currently, the role of an innate immune in the development of the lesions in MS has remained unclear. We explore the potential cellular elements of the innate immune system and in particular glial cells, which are likely candidates in inducing the specific pathological picture that is evident in MS. Activated microglia and the release of molecules which are detrimental to oligodendrocyte have been suggested as mechanisms by which innate immunity causes demyelination in MS. However a microglia/macrophage centric model does not explain the specificity of lesion development in MS. We propose that activation pathways of receptors of the innate immune system present on oligodendrocytes and astrocytes rather than microglia are central to the pathogenesis of demyelination seen in MS. PMID:21907419

  9. Transcriptome Analysis of Peripheral Blood in Chronic Inflammatory Demyelinating Polyradiculoneuropathy Patients Identifies TNFR1 and TLR Pathways in the IVIg Response

    PubMed Central

    Richard, Alexandra; Corvol, Jean-Christophe; Debs, Rabab; Reach, Pauline; Tahiri, Khadija; Carpentier, Wassila; Gueguen, Justine; Guillemot, Vincent; Labeyrie, Céline; Adams, David; Viala, Karine; Cohen Aubart, Fleur

    2016-01-01

    Abstract We have studied the response to intravenous immunoglobulins (IVIg) by a transcriptomic approach in 11 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients (CIDP duration = 6 [0.83–6.5] years). RNA was extracted from cells in whole blood collected before and 3 weeks after IVIg treatment, and hybridized on Illumina chips. After RNA quality controls, gene expression was analyzed using statistical tests fitted for microarrays (R software, limma package), and a pathway analysis was performed using DAVID software. We identified 52 genes with expression that varied significantly after IVIg (fold change [FC] > 1.2, P < 0.001, false discovery rate [FDR] <0.05). Among these 52 genes, 7 were related to immunity, 3 were related to the tumor necrosis factor (TNF)-α receptor 1 (TNFR1) pathway (inhibitor of caspase-activated DNase (ICAD): FC = 1.8, P = 1.7E-7, FDR = 0.004; p21 protein-activated kinase 2 [PAK2]: FC = 1.66, P = 2.6E-5, FDR = 0.03; TNF-α-induced protein 8-like protein 1 [TNFAIP8L1]: P = 1.00E-05, FDR = 0.026), and 2 were related to Toll-like receptors (TLRs), especially TLRs 7 and 9, and were implicated in autoimmunity. These genes were UNC93B1 (FC = 1.6, P = 2E-5, FDR = 0.03), which transports TLRs 7 and 9 to the endolysosomes, and RNF216 (FC = 1.5, P = 1E-05, FDR = 0.03), which promotes TLR 9 degradation. Pathway analysis showed that the TNFR1 pathway was significantly lessened by IVIg (enrichment score = 24, Fischer exact test = 0.003). TNF-α gene expression was higher in responder patients than in nonresponders; however, it decreased after IVIg in responders (P = 0.04), but remained stable in nonresponders. Our data suggest the actions of IVIg on the TNFR1 pathway and an original mechanism involving innate immunity through TLRs in CIDP pathophysiology and the response to IVIg. We conclude that responder patients have stronger inflammatory activity

  10. Transcriptome Analysis of Peripheral Blood in Chronic Inflammatory Demyelinating Polyradiculoneuropathy Patients Identifies TNFR1 and TLR Pathways in the IVIg Response.

    PubMed

    Richard, Alexandra; Corvol, Jean-Christophe; Debs, Rabab; Reach, Pauline; Tahiri, Khadija; Carpentier, Wassila; Gueguen, Justine; Guillemot, Vincent; Labeyrie, Céline; Adams, David; Viala, Karine; Cohen Aubart, Fleur

    2016-05-01

    We have studied the response to intravenous immunoglobulins (IVIg) by a transcriptomic approach in 11 chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients (CIDP duration = 6 [0.83-6.5] years). RNA was extracted from cells in whole blood collected before and 3 weeks after IVIg treatment, and hybridized on Illumina chips. After RNA quality controls, gene expression was analyzed using statistical tests fitted for microarrays (R software, limma package), and a pathway analysis was performed using DAVID software. We identified 52 genes with expression that varied significantly after IVIg (fold change [FC] > 1.2, P < 0.001, false discovery rate [FDR] <0.05). Among these 52 genes, 7 were related to immunity, 3 were related to the tumor necrosis factor (TNF)-α receptor 1 (TNFR1) pathway (inhibitor of caspase-activated DNase (ICAD): FC = 1.8, P = 1.7E-7, FDR = 0.004; p21 protein-activated kinase 2 [PAK2]: FC = 1.66, P = 2.6E-5, FDR = 0.03; TNF-α-induced protein 8-like protein 1 [TNFAIP8L1]: P = 1.00E-05, FDR = 0.026), and 2 were related to Toll-like receptors (TLRs), especially TLRs 7 and 9, and were implicated in autoimmunity. These genes were UNC93B1 (FC = 1.6, P = 2E-5, FDR = 0.03), which transports TLRs 7 and 9 to the endolysosomes, and RNF216 (FC = 1.5, P = 1E-05, FDR = 0.03), which promotes TLR 9 degradation. Pathway analysis showed that the TNFR1 pathway was significantly lessened by IVIg (enrichment score = 24, Fischer exact test = 0.003). TNF-α gene expression was higher in responder patients than in nonresponders; however, it decreased after IVIg in responders (P = 0.04), but remained stable in nonresponders. Our data suggest the actions of IVIg on the TNFR1 pathway and an original mechanism involving innate immunity through TLRs in CIDP pathophysiology and the response to IVIg. We conclude that responder patients have stronger inflammatory activity that is

  11. T-Cell Apoptosis in Inflammatory Brain Lesions

    PubMed Central

    Bauer, Jan; Bradl, Monika; Hickey, William F.; Forss-Petter, Sonja; Breitschopf, Helene; Linington, Chris; Wekerle, Hartmut; Lassmann, Hans

    1998-01-01

    Elimination of inflammatory T cells by apoptosis appears to play an important role in the down-regulation of inflammation in the central nervous system. Here we report that apoptosis of T lymphocytes occurs to a similar extent in different models of autoimmune encephalomyelitis. Apoptosis is restricted to cells located in the neuroectodermal parenchyma, thereby leaving T cells present in the brain’s connective tissue compartments unharmed. Death of T cells in the parenchyma does not depend on antigen presentation by resident microglial cells or astrocytes. Adoptive transfer experiments with T lymphocytes carrying a specific genetic marker revealed that in the central nervous system these cells are destroyed regardless of their antigen specificity or state of activation. Although many of both antigen-dependent and -independent mechanisms in the induction of T-cell apoptosis may act simultaneously, our results suggest that the nervous system harbors a specific, currently undefined, mechanism that effectively eliminates infiltrating T lymphocytes. PMID:9736022

  12. Spatially Distinct Neutrophil Responses within the Inflammatory Lesions of Pneumonic Plague

    PubMed Central

    Stasulli, Nikolas M.; Eichelberger, Kara R.; Price, Paul A.; Pechous, Roger D.; Montgomery, Stephanie A.; Parker, Joel S.

    2015-01-01

    ABSTRACT During pneumonic plague, the bacterium Yersinia pestis elicits the development of inflammatory lung lesions that continue to expand throughout infection. This lesion development and persistence are poorly understood. Here, we examine spatially distinct regions of lung lesions using laser capture microdissection and transcriptome sequencing (RNA-seq) analysis to identify transcriptional differences between lesion microenvironments. We show that cellular pathways involved in leukocyte migration and apoptosis are downregulated in the center of lung lesions compared to the periphery. Probing for the bacterial factor(s) important for the alteration in neutrophil survival, we show both in vitro and in vivo that Y. pestis increases neutrophil survival in a manner that is dependent on the type III secretion system effector YopM. This research explores the complexity of spatially distinct host-microbe interactions and emphasizes the importance of cell relevance in assays in order to fully understand Y. pestis virulence. PMID:26463167

  13. Cytokine-Neuroantigen Fusion Proteins as a New Class of Tolerogenic, Therapeutic Vaccines for Treatment of Inflammatory Demyelinating Disease in Rodent Models of Multiple Sclerosis

    PubMed Central

    Mannie, Mark D.; Blanchfield, J. Lori; Islam, S. M. Touhidul; Abbott, Derek J.

    2012-01-01

    Myelin-specific induction of tolerance represents a promising means to modify the course of autoimmune inflammatory demyelinating diseases such as multiple sclerosis (MS). Our laboratory has focused on a novel preclinical strategy for the induction of tolerance to the major encephalitogenic epitopes of myelin that cause experimental autoimmune encephalomyelitis (EAE) in rats and mice. This novel approach is based on the use of cytokine-NAg (neuroantigen) fusion proteins comprised of the native cytokine fused either with or without a linker to a NAg domain. Several single-chain cytokine-NAg fusion proteins were tested including GMCSF-NAg, IFNbeta-NAg, NAgIL16, and IL2-NAg. These cytokine-NAg vaccines were tolerogenic, therapeutic vaccines that had tolerogenic activity when given as pre-treatments before encephalitogenic immunization and also were effective as therapeutic interventions during the effector phase of EAE. The rank order of inhibitory activity was as follows: GMCSF-NAg, IFNbeta-NAg > NAgIL16 > IL2-NAg > MCSF-NAg, IL4-NAg, IL-13-NAg, IL1RA-NAg, and NAg. Several cytokine-NAg fusion proteins exhibited antigen-targeting activity. High affinity binding of the cytokine domain to specific cytokine receptors on particular subsets of APC resulted in the concentrated uptake of the NAg domain by those APC which in turn facilitated the enhanced processing and presentation of the NAg domain on cell surface MHC class II glycoproteins. For most cytokine-NAg vaccines, the covalent linkage of the cytokine domain and NAg domain was required for inhibition of EAE, thereby indicating that antigenic targeting of the NAg domain to APC was also required in vivo for tolerogenic activity. Overall, these studies introduced a new concept of cytokine-NAg fusion proteins as a means to induce tolerance and to inhibit the effector phase of autoimmune disease. The approach has broad application for suppressive vaccination as a therapy for autoimmune diseases such as MS

  14. Chronic Inflammatory Demyelinating Polyneuropathy (CIDP)

    MedlinePlus

    ... and legs, loss of deep tendon reflexes (areflexia), fatigue, and abnormal sensations. CIDP is closely related to Guillain-Barre syndrome and it is considered the chronic counterpart of that acute disease. Is there any ...

  15. Apolipoprotein E Mimetic Promotes Functional and Histological Recovery in Lysolecithin-Induced Spinal Cord Demyelination in Mice

    PubMed Central

    Gu, Zhen; Li, Fengqiao; Zhang, Yi Ping; Shields, Lisa B.E.; Hu, Xiaoling; Zheng, Yiyan; Yu, Panpan; Zhang, Yongjie; Cai, Jun; Vitek, Michael P.; Shields, Christopher B.

    2014-01-01

    Objective Considering demyelination is the pathological hallmark of multiple sclerosis (MS), reducing demyelination and/or promoting remyelination is a practical therapeutic strategy to improve functional recovery for MS. An apolipoprotein E (apoE)-mimetic peptide COG112 has previously demonstrated therapeutic efficacy on functional and histological recovery in a mouse experimental autoimmune encephalomyelitis (EAE) model of human MS. In the current study, we further investigated whether COG112 promotes remyelination and improves functional recovery in lysolecithin induced focal demyelination in the white matter of spinal cord in mice. Methods A focal demyelination model was created by stereotaxically injecting lysolecithin into the bilateral ventrolateral funiculus (VLF) of T8 and T9 mouse spinal cords. Immediately after lysolecithin injection mice were treated with COG112, prefix peptide control or vehicle control for 21 days. The locomotor function of the mice was measured by the beam walking test and Basso Mouse Scale (BMS) assessment. The nerve transmission of the VLF of mice was assessed in vivo by transcranial magnetic motor evoked potentials (tcMMEPs). The histological changes were also examined by by eriochrome cyanine staining, immunohistochemistry staining and electron microscopy (EM) method. Results The area of demyelination in the spinal cord was significantly reduced in the COG112 group. EM examination showed that treatment with COG112 increased the thickness of myelin sheaths and the numbers of surviving axons in the lesion epicenter. Locomotor function was improved in COG112 treated animals when measured by the beam walking test and BMS assessment compared to controls. TcMMEPs also demonstrated the COG112-mediated enhancement of amplitude of evoked responses. Conclusion The apoE-mimetic COG112 demonstrates a favorable combination of activities in suppressing inflammatory response, mitigating demyelination and in promoting remyelination and

  16. CCL19 and CCL21 modulate the inflammatory milieu in atherosclerotic lesions

    PubMed Central

    Akhavanpoor, Mohammadreza; Gleissner, Christian A; Gorbatsch, Stephanie; Doesch, Andreas O; Akhavanpoor, Hamidreza; Wangler, Susanne; Jahn, Frederik; Lasitschka, Felix; Katus, Hugo A; Erbel, Christian

    2014-01-01

    Despite advances in the pharmacologic and interventional treatment of coronary artery disease, atherosclerosis remains the leading cause of death worldwide. Atherosclerosis is a chronic inflammatory disease, and elevated expression of CCL19 and CCL21 has been observed in ruptured lesions of coronary arteries of patients with myocardial infarction and carotid plaques of patients with ischemic symptoms, as well as in plasma of coronary artery disease patients. However, the exact role of CCL19 and CCL21 in atherosclerosis remains unknown. In order to identify CCL19 and CCL21 as a novel therapeutic target, we performed bone marrow transplantation as an immunomodulatory treatment concept. Bone marrow of plt/plt mice (lacking CCL19 and CCL21-Ser) was transplanted into atherogenic Ldlr−/− mice. The study demonstrated a significantly increased inflammatory cellular infiltration into the lesions of plt/plt/Ldlr−/− mice versus controls. Although the level of chemoattraction was increased, messenger ribonucleic acid and protein levels in thoracic aorta and serum of several proinflammatory cytokines (TNFα, IFNγ, IL-6, IL-12, and IL-17) were significantly reduced in plt/plt/Ldlr−/− versus control mice. Increased influx, accompanied by reduced activation of leukocytes in atherosclerotic lesion, was accompanied by increased plaque stability but unchanged lesion development. In conclusion, modulation of the chemokines CCL19 and CCL21 represents a potent immunoregulatory treatment approach, and thus represents a novel therapeutic target to stabilize atherosclerotic lesions. PMID:25473269

  17. CCL19 and CCL21 modulate the inflammatory milieu in atherosclerotic lesions.

    PubMed

    Akhavanpoor, Mohammadreza; Gleissner, Christian A; Gorbatsch, Stephanie; Doesch, Andreas O; Akhavanpoor, Hamidreza; Wangler, Susanne; Jahn, Frederik; Lasitschka, Felix; Katus, Hugo A; Erbel, Christian

    2014-01-01

    Despite advances in the pharmacologic and interventional treatment of coronary artery disease, atherosclerosis remains the leading cause of death worldwide. Atherosclerosis is a chronic inflammatory disease, and elevated expression of CCL19 and CCL21 has been observed in ruptured lesions of coronary arteries of patients with myocardial infarction and carotid plaques of patients with ischemic symptoms, as well as in plasma of coronary artery disease patients. However, the exact role of CCL19 and CCL21 in atherosclerosis remains unknown. In order to identify CCL19 and CCL21 as a novel therapeutic target, we performed bone marrow transplantation as an immunomodulatory treatment concept. Bone marrow of plt/plt mice (lacking CCL19 and CCL21-Ser) was transplanted into atherogenic Ldlr(-/-) mice. The study demonstrated a significantly increased inflammatory cellular infiltration into the lesions of plt/plt/Ldlr(-/-) mice versus controls. Although the level of chemoattraction was increased, messenger ribonucleic acid and protein levels in thoracic aorta and serum of several proinflammatory cytokines (TNFα, IFNγ, IL-6, IL-12, and IL-17) were significantly reduced in plt/plt/Ldlr(-/-) versus control mice. Increased influx, accompanied by reduced activation of leukocytes in atherosclerotic lesion, was accompanied by increased plaque stability but unchanged lesion development. In conclusion, modulation of the chemokines CCL19 and CCL21 represents a potent immunoregulatory treatment approach, and thus represents a novel therapeutic target to stabilize atherosclerotic lesions. PMID:25473269

  18. Autoantibodies to tetraspanins (CD9, CD81 and CD82) in demyelinating diseases.

    PubMed

    Miyaji, Kazuki; Paul, Friedemann; Shahrizaila, Nortina; Umapathi, Thirugnanam; Yuki, Nobuhiro

    2016-02-15

    Tetraspanin family proteins, CD9, CD81 and CD82 are expressed in the oligodendrocytes and Schwann cells. We investigated autoantibodies to tetraspanin proteins in patients with demyelinating diseases. Sera were collected from 119 multiple sclerosis patients, 19 neuromyelitis optica, 42 acute inflammatory demyelinating polyneuropathy, 23 chronic inflammatory demyelinating polyneuropathy and 13 acute motor axonal neuropathy as well as 55 healthy controls. Few multiple sclerosis and acute inflammatory demyelinating polyneuropathy patients had autoantibodies that were weakly reactive to CD9 or CD81 but the significance is unclear. It is unlikely that these autoantibodies are pathogenic or serve as potential biomarkers in demyelinating diseases. PMID:26857499

  19. Oral Cancer and Oral Precancerous Lesions in Inflammatory Bowel Diseases: A Systematic Review.

    PubMed

    Katsanos, Konstantinos H; Roda, Giulia; Brygo, Alexandre; Delaporte, Emmanuel; Colombel, Jean-Frédéric

    2015-11-01

    Oral cancer is historically linked to well-known behavioural risk factors such as tobacco smoking and alcohol consumption. Other risk factors include age over 40, male sex, several dietary factors, nutritional deficiencies, viruses, sexually transmitted infections, human papillomavirus, chronic irritation, and possibly genetic predisposition. Precancerous lesions in the oral cavity include leukoplakia, erythroplakia, and lichen planus. Histology of oral cancer varies widely but the great majority are squamous cell carcinomas.Epidemiological studies and cancer registries have shown a consistently increased risk of oral malignancies in kidney, bone marrow, heart, or liver transplantation, in graft vs host disease, and in patients with HIV infection. Because of the increasing use of immunosuppressive drugs in patients with inflammatory bowel disease, it is useful to more accurately delineate the consequences of chronic immunosuppression to the oral cavity. Oral cancer and precancerous oral lesions in patients with inflammatory bowel disease [IBD] have been scarcely reported and reviews on the topic are lacking.We conducted a literature search using the terms and variants of all cancerous and precancerous oral manifestations of inflammatory bowel diseases. By retrieving the existing literature, it is evident that patients with IBD belong to the high-risk group of developing these lesions, a phenomenon amplified by the increasing HPV prevalence. Education on modifiable risk behaviours in patients with oral cancer is the cornerstone of prevention.Oral screening should be performed for all IBD patients, especially those who are about to start an immunosuppressant or biological drug. PMID:26163301

  20. Systemic inflammatory response reactivates immune-mediated lesions in rat brain.

    PubMed

    Serres, Sébastien; Anthony, Daniel C; Jiang, Yanyan; Broom, Kerry A; Campbell, Sandra J; Tyler, Damian J; van Kasteren, Sander I; Davis, Benjamin G; Sibson, Nicola R

    2009-04-15

    The potential association between microbial infection and reactivation of a multiple sclerosis (MS) lesion is an important issue that remains unresolved, primarily because of the absence of suitable animal models and imaging techniques. Here, we have evaluated this question in an empirical manner using immunohistochemistry and magnetic resonance imaging (MRI), before and after the induction of a systemic inflammatory response in two distinct models of MS. In a pattern-II-type focal myelin oligodendrocyte glycoprotein-experimental autoimmune encephalomyelitis model, systemic endotoxin injection caused an increase in regional cerebral blood volume (rCBV) around the lesion site after 6 h, together with a reduction in the magnetization transfer ratio of the lesioned corpus callosum. These changes were followed by an increase in the diffusion of tissue water within the lesion 24 h after endotoxin challenge and new leukocyte recruitment as revealed both immunohistochemically and by MRI tracking of ultrasmall superparamagnetic iron oxide-labeled macrophages. Importantly, we detected in vivo expression of E- and P-selectin in quiescent lesions by MRI-detectable glyconanoparticles conjugated to sialyl Lewis(X). This finding may explain, at least in part, the ability of quiescent MS lesions to rapidly reinitiate the cell recruitment processes. In a pattern-I-type delayed-type hypersensitivity response model, a similar effect of endotoxin challenge on rCBV was observed, together with delayed breakdown of the blood-brain barrier, showing that systemic infection can alter the pathogenesis of MS-like lesions regardless of lesion etiology. These findings will have important implications for the management and monitoring of individuals with MS. PMID:19369550

  1. The road to remyelination in demyelinating diseases: current status and prospects for clinical treatment.

    PubMed

    Wootla, Bharath; Watzlawik, Jens O; Denic, Aleksandar; Rodriguez, Moses

    2013-06-01

    Within CNS disorders, demyelinating diseases are among the most devastating and cost intensive due to long-term disabilities affecting relatively young patients. Multiple sclerosis, a chronic inflammatory demyelinating disease in which the persistent inhibitory microenvironment of the resident oligodendrocyte precursor cells abrogates regeneration of myelin sheaths, is the most prominent disease in the spectrum of demyelinating diseases. The essential goal is to stimulate creation of new myelin sheaths on the demyelinated axons, leading to restoration of saltatory conduction and resolving functional deficits. The past few decades witnessed significant efforts to understand the cellular interactions at the lesion site with studies suggesting efficient remyelination as a prerequisite for functional repair. Despite its proven efficacy in experimental models, immunosuppression has not had profound clinical consequences in multiple sclerosis, which argued for a paradigm shift in the design of therapeutics aiming to achieve remyelination. For example, targeting oligodendrocytes themselves may drive remyelination in the CNS. This group and others have demonstrated that natural autoreactive antibodies directed at oligodendrocyte progenitors participate in remyelination. Accordingly, the authors developed a recombinant autoreactive natural human IgM antibody with therapeutic potential for remyelination. PMID:23730884

  2. A brainstem inflammatory lesion causing REM sleep behavior disorder and sleepwalking (parasomnia overlap disorder).

    PubMed

    Limousin, Nadège; Dehais, Caroline; Gout, Olivier; Héran, Françoise; Oudiette, Delphine; Arnulf, Isabelle

    2009-10-01

    A 40-year-old woman with no prior parasomnia developed an acute inflammatory rhombencephalitis with multiple cranial nerve palsies and cerebellar ataxia, followed by myelitis 6 months later, and by an intracranial thrombophlebitis 1 month after. Between and after these episodes, she had a persistent, mild right internuclear ophtalmoplegia, a mild cerebellar ataxia, and a severe REM sleep behavior disorder (RBD) lasting for 2 years. She talked, sang and moved nightly while asleep, and injured her son (cosleeping with her) while asleep. In addition, she walked asleep nightly. During video-polysomnography, there were two arousals during slow wave sleep without abnormal behavior, while 44% of REM sleep was without chin muscle atonia with bilateral arm and leg movements. There were small hypointensities in the right pontine tegmentum and in the right dorsal medulla on T1-weighted magnetic resonance imaging, suggesting post-inflammatory lesions that persisted between acute episodes. The RBD and sleepwalking did not improve with clonazepam, but improved with melatonin 9 mg/d. The unilateral small lesion of the pontine tegmentum could be responsible for the parasomnia overlap disorder as in other rare lesional cases. PMID:19345142

  3. Optical biopsy of pre-malignant or degenerative lesions: the role of the inflammatory process

    NASA Astrophysics Data System (ADS)

    da Silva Martinho, Herculano

    2011-03-01

    Recent technological advances in fiber optics, light sources, detectors, and molecular biology have stimulated unprecedented development of optical methods to detect pathological changes in tissues. These methods, collectively termed "optical biopsy," are nondestructive in situ and real-time assays. Optical biopsy techniques as fluorescence spectroscopy, polarized light scattering spectroscopy, optical coherence tomography, confocal reflectance microscopy, and Raman spectroscopy had been extensively used to characterize several pathological tissues. In special, Raman spectroscopy technique had been able to probe several biochemical alterations due to pathology development as change in the DNA, glycogen, phospholipid, non-collagenous proteins. All studies claimed that the optical biopsy methods were able to discriminate normal and malignant tissues. However, few studies had been devoted to the discrimination of very common subtle or early pathological states as inflammatory process, which are always present on, e.g., cancer lesion border. In this work we present a systematic comparison of optical biopsy data on several kinds of lesions were inflammatory infiltrates play the role (breast, cervical, and oral lesion). It will be discussed the essential conditions for the optimization of discrimination among normal and alterated states based on statistical analysis.

  4. Possible Implication of Local Immune Response in Darier's Disease: An Immunohistochemical Characterization of Lesional Inflammatory Infiltrate

    PubMed Central

    Miracco, Clelia; Pietronudo, Francesco; Mourmouras, Vasileios; Pellegrino, Michele; Onorati, Monica; Mastrogiulio, Maria Grazia; Cantarini, Luca; Luzi, Pietro

    2010-01-01

    Cell-mediated immunity is considered to be normal in Darier's Disease (DD), an inherited skin disorder complicated by skin infections. To date, there are no investigations on the local inflammatory infiltrate in DD skin lesions. In this immunohistochemical study we characterized and quantified it, making comparisons with two other inflammatory skin disorders, that is, pemphigus vulgaris (PV) and lichen ruber planus (LRP), and with the normal skin (NSk). We found a significant (P < .05) decrease of CD1a+ Langerhans cells (LCs) in DD, compared to PV, LRP, and NSk, and of CD123+ plasmacytoid dendritic cells (pDCs), compared to PV and LRP. We hypothesize that the genetic damage of keratinocytes might result in a loss of some subsets of dendritic cells and, consequently, in an impaired local immune response, which might worsen the infections that inevitably occur in this disease. PMID:20671948

  5. Nitric Oxide-Driven Hypoxia Initiates Synovial Angiogenesis, Hyperplasia and Inflammatory Lesions in Mice

    PubMed Central

    Bao, Fei; Wu, Pei; Xiao, Na; Qiu, Frank; Zeng, Qing-Ping

    2012-01-01

    Background Rheumatoid arthritis (RA) is an inflammatory articular disease with cartilage and bone damage due to hyperplasic synoviocyte invasion and subsequent matrix protease digestion. Although monoclonal antibodies against tumor necrosis factor alpha (TNFα) have been approved for clinical use in patients with RA, desired therapeutic regimens suitable for non-responders are still unavailable because etiological initiators leading to RA remain enigmatic and unidentified. Methodology/Principal Findings Bacteria-induced arthritis (BIA) that simulates collagen-induced arthritis (CIA) is developed in mice upon daily live bacterial feeding. The morphological lesions of paw erythema and edema together with the histological alterations of synovial hyperplasia and lymphocytic infiltration emerge as the early-phase manifestations of BIA and CIA. Bacteria- or collagen-mediated global upregulation of pro-inflammatory cytokines is accompanied by the burst of nitric oxide (NO). Elevation of the serum NO level is correlated with decline of the blood oxygen saturation percentage (SpO2), reflecting a hypoxic consequence during development towards arthritis. NO-driven hypoxia is further evident from a positive relationship between NO and lactic acid (LA), an end product from glycolysis. Upregulation of hypoxia inducible factor 1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF) validates hypoxia-induced angiogenesis in the inflamed synovium of modeling mice. Administration of the NO donor compound sodium nitroprusside (SNP) causes articular inflammation by inducing synovial hypoxia. Anti-bacteria by the antibiotic cefotaxime and/or the immunosuppressant rapamycin or artesunate that also inhibits nitric oxide synthase (NOS) can abrogate NO production, mitigate hypoxia, and considerably ameliorate or even completely abort synovitis, hence highlighting that NO may serve as an initiator of inflammatory arthritis. Conclusions/Significance Like collagen, bacteria also

  6. Functional consequences of ethidium bromide demyelination of the mouse ventral spinal cord

    PubMed Central

    Kuypers, Nicholas J.; James, Kurtis T.; Enzmann, Gaby U.; Magnuson, David S.K.; Whittemore, Scott R.

    2013-01-01

    Ethidium bromide (EB) has been extensively used in the rat as a model of spinal cord demyelination. However, this lesion has not been addressed in the adult mouse, a model with unlimited genetic potential. Here we characterize behavioral function, inflammation, myelin status and axonal viability following bilateral injection of 0.20 mg/mL ethidium bromide or saline into the ventral white matter (VWM) of female C57Bl/6 mice. EB-induced VWM demyelination significantly reduced spared VWM and Basso Mouse Scale (BMS) scores persisting out to 2 months. Chronic hindlimb dysfunction was accompanied by a persistent inflammatory response (demonstrated by CD45+ immunofluorescence) and axonal loss (demonstrated by NF-M immunofluorescence and electron microscopy; EM). These cellular responses differ from the rat where inflammation resolves by 3–4 weeks and axon loss is minimal following EB demyelination. As these data suggest that EB-injection in the mouse spinal cord is a non-remyelinating lesion, we sought to ask whether wheel running could promote recovery by enhancing plasticity of local lumbar circuitry independent of remyelination. This did not occur as BMS and Treadscan® assessment revealed no significant effect of wheel running on recovery. However, this study defines the importance of descending ventral motor pathways to locomotor function in the mouse as VWM loss results in a chronic hindlimb deficit. PMID:23466931

  7. Cuprizone-induced demyelination and demyelination-associated inflammation result in different proton magnetic resonance metabolite spectra

    PubMed Central

    Praet, Jelle; Orije, Jasmien; Kara, Firat; Guglielmetti, Caroline; Santermans, Eva; Daans, Jasmijn; Hens, Niel; Verhoye, Marleen; Berneman, Zwi; Ponsaerts, Peter; Van der Linden, Annemie

    2015-01-01

    Conventional MRI is frequently used during the diagnosis of multiple sclerosis but provides only little additional pathological information. Proton MRS (1H-MRS), however, provides biochemical information on the lesion pathology by visualization of a spectrum of metabolites. In this study we aimed to better understand the changes in metabolite concentrations following demyelination of the white matter. Therefore, we used the cuprizone model, a well-established mouse model to mimic type III human multiple sclerosis demyelinating lesions. First, we identified CX3CL1/CX3CR1 signaling as a major regulator of microglial activity in the cuprizone mouse model. Compared with control groups (heterozygous CX3CR1+/− C57BL/6 mice and wild type CX3CR1+/+ C57BL/6 mice), microgliosis, astrogliosis, oligodendrocyte cell death and demyelination were shown to be highly reduced or absent in CX3CR1−/− C57BL/6 mice. Second, we show that 1H-MRS metabolite spectra are different when comparing cuprizone-treated CX3CR1−/− mice showing mild demyelination with cuprizone-treated CX3CR1+/+ mice showing severe demyelination and demyelination-associated inflammation. Following cuprizone treatment, CX3CR1+/+ mice show a decrease in the Glu, tCho and tNAA concentrations as well as an increased Tau concentration. In contrast, following cuprizone treatment CX3CR1−/− mice only showed a decrease in tCho and tNAA concentrations. Therefore, 1H-MRS might possibly allow us to discriminate demyelination from demyelination-associated inflammation via changes in Tau and Glu concentration. In addition, the observed decrease in tCho concentration in cuprizone-induced demyelinating lesions should be further explored as a possible diagnostic tool for the early identification of human MS type III lesions. Copyright © 2015 John Wiley & Sons, Ltd. PMID:25802215

  8. Astrocytic TYMP and VEGFA drive blood-brain barrier opening in inflammatory central nervous system lesions.

    PubMed

    Chapouly, Candice; Tadesse Argaw, Azeb; Horng, Sam; Castro, Kamilah; Zhang, Jingya; Asp, Linnea; Loo, Hannah; Laitman, Benjamin M; Mariani, John N; Straus Farber, Rebecca; Zaslavsky, Elena; Nudelman, German; Raine, Cedric S; John, Gareth R

    2015-06-01

    In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood-brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood-brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood-brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood-brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood-brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood-brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP as an

  9. Astrocytic TYMP and VEGFA drive blood–brain barrier opening in inflammatory central nervous system lesions

    PubMed Central

    Chapouly, Candice; Tadesse Argaw, Azeb; Horng, Sam; Castro, Kamilah; Zhang, Jingya; Asp, Linnea; Loo, Hannah; Laitman, Benjamin M.; Mariani, John N.; Straus Farber, Rebecca; Zaslavsky, Elena; Nudelman, German; Raine, Cedric S.

    2015-01-01

    In inflammatory central nervous system conditions such as multiple sclerosis, breakdown of the blood–brain barrier is a key event in lesion pathogenesis, predisposing to oedema, excitotoxicity, and ingress of plasma proteins and inflammatory cells. Recently, we showed that reactive astrocytes drive blood–brain barrier opening, via production of vascular endothelial growth factor A (VEGFA). Here, we now identify thymidine phosphorylase (TYMP; previously known as endothelial cell growth factor 1, ECGF1) as a second key astrocyte-derived permeability factor, which interacts with VEGFA to induce blood–brain barrier disruption. The two are co-induced NFκB1-dependently in human astrocytes by the cytokine interleukin 1 beta (IL1B), and inactivation of Vegfa in vivo potentiates TYMP induction. In human central nervous system microvascular endothelial cells, VEGFA and the TYMP product 2-deoxy-d-ribose cooperatively repress tight junction proteins, driving permeability. Notably, this response represents part of a wider pattern of endothelial plasticity: 2-deoxy-d-ribose and VEGFA produce transcriptional programs encompassing angiogenic and permeability genes, and together regulate a third unique cohort. Functionally, each promotes proliferation and viability, and they cooperatively drive motility and angiogenesis. Importantly, introduction of either into mouse cortex promotes blood–brain barrier breakdown, and together they induce severe barrier disruption. In the multiple sclerosis model experimental autoimmune encephalitis, TYMP and VEGFA co-localize to reactive astrocytes, and correlate with blood–brain barrier permeability. Critically, blockade of either reduces neurologic deficit, blood–brain barrier disruption and pathology, and inhibiting both in combination enhances tissue preservation. Suggesting importance in human disease, TYMP and VEGFA both localize to reactive astrocytes in multiple sclerosis lesion samples. Collectively, these data identify TYMP

  10. Paediatric UK demyelinating disease longitudinal study (PUDDLS)

    PubMed Central

    2011-01-01

    Background There is evidence that at least 5% of Multiple sclerosis (MS) cases manifest in childhood. Children with MS present with a demyelinating episode involving single or multiple symptoms prior to developing a second event (usually within two years) to then meet criteria for diagnosis. There is evidence from adult cohorts that the incidence and sex ratios of MS are changing and that children of immigrants have a higher risk for developing MS. A paediatric population should reflect the vanguard of such changes and may reflect trends yet to be observed in adult cohorts. Studying a paediatric population from the first demyelinating event will allow us to test these hypotheses, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS. Methods/Design The Paediatric UK Demyelinating Disease Longitudinal Study (PUDDLS) is a prospective longitudinal observational study which aims to determine the natural history, predictors and outcomes of childhood CNS inflammatory demyelinating diseases. PUDDLS will involve centres in the UK, and will establish a cohort of children affected with a first CNS inflammatory demyelinating event for long-term follow up by recruiting for approximately 5 years. PUDDLS will also establish a biological sample archive (CSF, serum, and DNA), allowing future hypothesis driven research. For example, the future discovery of a biomarker will allow validation within this dataset for the evaluation of novel biomarkers. Patients will also be requested to consent to be contacted in the future. A secondary aim is to collaborate internationally with the International Paediatric Multiple Sclerosis Study Group when future collaborative studies are proposed, whilst sharing a minimal anonymised dataset. PUDDLS is the second of two jointly funded studies. The first (UCID-SS) is an epidemiological surveillance study that already received ethical approvals, and started on the 1st September 2009. There is

  11. Ultrasound of Inherited vs. Acquired Demyelinating Polyneuropathies

    PubMed Central

    Zaidman, Craig M.; Harms, Matthew B.; Pestronk, Alan

    2013-01-01

    Introduction We compared features of nerve enlargement in inherited and acquired demyelinating neuropathies using ultrasound. Methods We measured median and ulnar nerve cross-sectional areas in proximal and distal regions in 128 children and adults with inherited (Charcot-Marie Tooth-1 (CMT-1) (n=35)) and acquired (Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) (n=55), Guillaine-Barre Syndrome (GBS) (n=21) and Multifocal Motor Neuropathy (MMN) (n=17)) demyelinating neuropathies. We classified nerve enlargement by degree and number of regions affected. We defined patterns of nerve enlargement as: none- no enlargement; mild-nerves enlarged but never more than twice normal; regional- nerves normal at at least one region and enlarged more than twice normal at atleast one region; diffuse- nerves enlarged at all four regions with atleast one region more than twice normal size. Results Nerve enlargement was commonly diffuse (89%) and generally more than twice normal size in CMT-1, but not (p<0.001) in acquired disorders which mostly had either no, mild or regional nerve enlargement (CIDP (64%), GBS (95%), and MMN (100%)). In CIDP, subjects treated within three months of disease onset had less nerve enlargement than those treated later. Discussion Ultrasound identified patterns of diffuse nerve enlargement can be used to screen patients suspected of having CMT-1. Normal, mildly, or regionally enlarged nerves in demyelinating polyneuropathy suggests an acquired etiology. Early treatment in CIDP may impede nerve enlargement. PMID:24101129

  12. Toll-Like Receptor 4 Expression in the Epithelium of Inflammatory Periapical Lesions.

    PubMed Central

    Leonardi, R.; Perrotta, R.E.; Musumeci, G.; Crimi, S.; dos Santos, J.N.; Rusu, M.C.; Bufo, P.; Barbato, E.; Pannone, G.

    2015-01-01

    Toll-like receptors (TLR) are essential for the innate immune response against invading pathogens and have been described in immunocompetent cells of areas affected by periapical disease. Besides initiating the inflammatory response, they also directly regulate epithelial cell proliferation and survival in a variety of settings. This study evaluates the in situ expression of TLR4 in periapical granulomas (PG) and radicular cysts, focusing on the epithelial compartment. Twenty-one periapical cysts (PC) and 10 PG were analyzed; 7 dentigerous non-inflamed follicular cyst (DC) served as control. TLR4 expression was assessed by immunohistochemistry. TLR4 immunoreaction products were detected in the epithelium of all specimens, with a higher percentage of immunostained cells in PG. Although TLR4 overexpression was detected in both PG and PC, there were differences that seemed to be related to the nature of the lesion, since in PG all epithelial cells of strands, islands and trabeculae were strongly immunoreactive for TLR4, whereas in PC only some areas of the basal and suprabasal epithelial layers were immunostained. This staining pattern is consistent with the action of TLR4: in PG it could promote formation of epithelial cell rests of Malassez and in epithelial strands and islands the enhancement of cell survival, proliferation and migration, whereas in PC TLR4 could protect the lining epithelium from extensive apoptosis. These findings go some way towards answering the intriguing question of why many epithelial strands or islands in PG and the lining epithelium of apical cysts regress after non-surgical endodontic therapy, and suggest that TLR4 plays a key role in the pathobiology of the inflammatory process related to periapical disease. PMID:26708181

  13. Demyelination and axonal preservation in a transgenic mouse model of Pelizaeus-Merzbacher disease

    PubMed Central

    Edgar, Julia M; McCulloch, Mailis C; Montague, Paul; Brown, Angus M; Thilemann, Sebastian; Pratola, Laura; Gruenenfelder, Fredrik I; Griffiths, Ian R; Nave, Klaus-Armin

    2010-01-01

    It is widely thought that demyelination contributes to the degeneration of axons and, in combination with acute inflammatory injury, is responsible for progressive axonal loss and persistent clinical disability in inflammatory demyelinating disease. In this study we sought to characterize the relationship between demyelination, inflammation and axonal transport changes using a Plp1-transgenic mouse model of Pelizaeus-Merzbacher disease. In the optic pathway of this non-immune mediated model of demyelination, myelin loss progresses from the optic nerve head towards the brain, over a period of months. Axonal transport is functionally perturbed at sites associated with local inflammation and ‘damaged’ myelin. Surprisingly, where demyelination is complete, naked axons appear well preserved despite a significant reduction of axonal transport. Our results suggest that neuroinflammation and/or oligodendrocyte dysfunction are more deleterious for axonal health than demyelination per se, at least in the short term. PMID:20091761

  14. Is disturbed clearance of apoptotic keratinocytes responsible for UVB-induced inflammatory skin lesions in systemic lupus erythematosus?

    PubMed Central

    Reefman, Esther; de Jong, Marcelus CJM; Kuiper, Hilde; Jonkman, Marcel F; Limburg, Pieter C; Kallenberg, Cees GM; Bijl, Marc

    2006-01-01

    Apoptotic cells are thought to play an essential role in the pathogenesis of systemic lupus erythematosus (SLE). We hypothesise that delayed or altered clearance of apoptotic cells after UV irradiation will lead to inflammation in the skin of SLE patients. Fifteen SLE patients and 13 controls were irradiated with two minimal erythemal doses (MEDs) of ultraviolet B light (UVB). Subsequently, skin biopsies were analysed (immuno)histologically, over 10 days, for numbers of apoptotic cells, T cells, macrophages, and deposition of immunoglobulin and complement. Additionally, to compare results with cutaneous lesions of SLE patients, 20 biopsies of lupus erythematosus (LE) skin lesions were analysed morphologically for apoptotic cells and infiltrate. Clearance rate of apoptotic cells after irradiation did not differ between patients and controls. Influx of macrophages in dermal and epidermal layers was significantly increased in patients compared with controls. Five out of 15 patients developed a dermal infiltrate that was associated with increased epidermal influx of T cells and macrophages but not with numbers of apoptotic cells or epidermal deposition of immunoglobulins. Macrophages were ingesting multiple apoptotic bodies. Inflammatory lesions in these patients were localised near accumulations of apoptotic keratinocytes similar as was seen in the majority of LE skin lesions. In vivo clearance rate of apoptotic cells is comparable between SLE patients and controls. However, the presence of inflammatory lesions in the vicinity of apoptotic cells, as observed both in UVB-induced and in LE skin lesions in SLE patients, suggests that these lesions result from an inflammatory clearance of apoptotic cells. PMID:17014704

  15. Cavitating lung lesion as a manifestation of inflammatory tumor (pseudotumor) of the lung: A case report and literature review

    PubMed Central

    Michaelides, Stylianos A.; Passalidou, Elisabeth; Bablekos, George D.; Aza, Evlambia; Goulas, George; Chorti, Maria; Nicolaou, Irene N.; Lioulias, Achilleas G.

    2014-01-01

    Patient: Female, 60 Final Diagnosis: Inflammatory pseudotumor of the lung Symptoms: Cough dry • fever Medication: — Clinical Procedure: — Specialty: — Objective: Rare disease Background: Inflammatory pseudotumor of the lung involves a benign, non-neoplastic lung lesion of unknown etiology. Case Report: We present a case of a 60-year-old female smoker who had been under intermittent immunosuppressive medication for discoid lupus, who was admitted to hospital with fever of 39.5°C of 10-day duration, not responding to an oral cephalosporin. Chest CT examination showed a cavitating opacity in the upper zone of the left lung. It was not feasible to establish a diagnosis based on clinical and laboratory testing nor based on CT scanning and bronchoscopy. Thus, the patient underwent left thoracotomy and sphenoid resection of the lesion, which was sent for biopsy. The histopathologic features aided by immunohistochemical staining proved the lesion to be an inflammatory pseudotumor of the lung. Conclusions: The case is reported because of the extremely rare radiologic presentation of the development of a lung pseudotumor emerging as a cavitated lesion, which relapsed during the follow-up period while the patient was still under immunosuppressive medication. PMID:24971159

  16. Local Injection of Lenti-BDNF at the Lesion Site Promotes M2 Macrophage Polarization and Inhibits Inflammatory Response After Spinal Cord Injury in Mice.

    PubMed

    Ji, Xin-Chao; Dang, Yuan-Yuan; Gao, Hong-Yan; Wang, Zhao-Tao; Gao, Mou; Yang, Yi; Zhang, Hong-Tian; Xu, Ru-Xiang

    2015-08-01

    There is much evidence to suggest that brain-derived neurotrophic factor (BDNF) is a prominent candidate in promoting neuroprotection, axonal regeneration, and synaptic plasticity following spinal cord injury (SCI). Although some evidence indicates that BDNF has potent anti-oxidative effects and may be involved in the regulation of the immune response, the effects of BDNF in the inflammatory response during the course of secondary damage after SCI is still unclear. The present study was designed to investigate the effects of BDNF with a special focus on their effect on macrophage polarization after SCI. Adult C57 mice underwent T10 spinal cord clip compression injury and received lenti-BDNF vector injections at the epicenter of the lesion site. Four days later, total BDNF levels were greatly increased in animals that received lenti-BDNF injections. Confocal imaging showed that more than 80 % of the lenti-virus infected cells were CD11b-positive macrophages. In addition, the expression of arginase-1 and CD206 (associated with M2 macrophage phenotype) significantly increased in the animals that received lenti-BDNF injections compared with those that received lenti-EGFP injections. On the contrary, the expression of CD16/32 and inducible nitric oxide synthase (M1 phenotype marker) was down-regulated as demonstrated using flow cytometry and immunohistochemistry. Furthermore, the production of interleukin 1β and tumor necrosis factor alpha was significantly reduced whereas the levels of interleukin 10 and interleukin 13 were elevated in subjects that received lenti-BDNF vector injections. The time course of functional recovery revealed that gradual recovery was observed in the subacute phase in lenti-BDNF group, little improvement was observed in lenti-EGFP group. At the axonal level, significant retraction of the CST axons were observed in lenti-EGFP injected animals relative to lenti-BDNF group by biotinylated dextran amine tracing. In addition, compared to lenti

  17. Alteration of synaptic connectivity of oligodendrocyte precursor cells following demyelination

    PubMed Central

    Sahel, Aurélia; Ortiz, Fernando C.; Kerninon, Christophe; Maldonado, Paloma P.; Angulo, María Cecilia; Nait-Oumesmar, Brahim

    2015-01-01

    Oligodendrocyte precursor cells (OPCs) are a major source of remyelinating oligodendrocytes in demyelinating diseases such as Multiple Sclerosis (MS). While OPCs are innervated by unmyelinated axons in the normal brain, the fate of such synaptic contacts after demyelination is still unclear. By combining electrophysiology and immunostainings in different transgenic mice expressing fluorescent reporters, we studied the synaptic innervation of OPCs in the model of lysolecithin (LPC)-induced demyelination of corpus callosum. Synaptic innervation of reactivated OPCs in the lesion was revealed by the presence of AMPA receptor-mediated synaptic currents, VGluT1+ axon-OPC contacts in 3D confocal reconstructions and synaptic junctions observed by electron microscopy. Moreover, 3D confocal reconstructions of VGluT1 and NG2 immunolabeling showed the existence of glutamatergic axon-OPC contacts in post-mortem MS lesions. Interestingly, patch-clamp recordings in LPC-induced lesions demonstrated a drastic decrease in spontaneous synaptic activity of OPCs early after demyelination that was not caused by an impaired conduction of compound action potentials. A reduction in synaptic connectivity was confirmed by the lack of VGluT1+ axon-OPC contacts in virtually all rapidly proliferating OPCs stained with EdU (50-ethynyl-20-deoxyuridine). At the end of the massive proliferation phase in lesions, the proportion of innervated OPCs rapidly recovers, although the frequency of spontaneous synaptic currents did not reach control levels. In conclusion, our results demonstrate that newly-generated OPCs do not receive synaptic inputs during their active proliferation after demyelination, but gain synapses during the remyelination process. Hence, glutamatergic synaptic inputs may contribute to inhibit OPC proliferation and might have a physiopathological relevance in demyelinating disorders. PMID:25852473

  18. [Ultrasonographic diagnosis of inflammatory neuropathies].

    PubMed

    Sugimoto, Takamichi; Ochi, Kazuhide; Hosomi, Naohisa; Matsumoto, Masayasu

    2014-03-01

    Ultrasonographic nerve enlargement has primarily been reported in patients with inflammatory neuropathies such as chronic inflammatory demyelinating polyneuropathy (CIDP), multifocal motor neuropathy, Guillain-Barre syndrome, vasculitic neuropathy and leprosy. Nerve ultrasonography is a promising diagnostic supportive tool for inflammatory neuropathies. The ultrasonographic findings that are currently useful are 1) nerve enlargement primarily suggests the existence of inflammatory or demyelinating neuropathies and 2) for patients with CIDP or demyelinating Charcot-Marie-Tooth disease, the pattern of nerve enlargement is noted, and this pattern is useful for discriminating between these diseases. More precise evidence of ultrasonographic findings for inflammatory neuropathies should be established in the future. PMID:24607946

  19. P2Y6 Receptor Potentiates Pro-Inflammatory Responses in Macrophages and Exhibits Differential Roles in Atherosclerotic Lesion Development

    PubMed Central

    Garcia, Ricardo A.; Yan, Mujing; Search, Debra; Zhang, Rongan; Carson, Nancy L.; Ryan, Carol S.; Smith-Monroy, Constance; Zheng, Joanna; Chen, Jian; Kong, Yan; Tang, Huaping; Hellings, Samuel E.; Wardwell-Swanson, Judith; Dinchuk, Joseph E.; Psaltis, George C.; Gordon, David A.; Glunz, Peter W.; Gargalovic, Peter S.

    2014-01-01

    Background P2Y6, a purinergic receptor for UDP, is enriched in atherosclerotic lesions and is implicated in pro-inflammatory responses of key vascular cell types and macrophages. Evidence for its involvement in atherogenesis, however, has been lacking. Here we use cell-based studies and three murine models of atherogenesis to evaluate the impact of P2Y6 deficiency on atherosclerosis. Methodology/Principal Findings Cell-based studies in 1321N1 astrocytoma cells, which lack functional P2Y6 receptors, showed that exogenous expression of P2Y6 induces a robust, receptor- and agonist-dependent secretion of inflammatory mediators IL-8, IL-6, MCP-1 and GRO1. P2Y6-mediated inflammatory responses were also observed, albeit to a lesser extent, in macrophages endogenously expressing P2Y6 and in acute peritonitis models of inflammation. To evaluate the role of P2Y6 in atherosclerotic lesion development, we used P2Y6-deficient mice in three mouse models of atherosclerosis. A 43% reduction in aortic arch plaque was observed in high fat-fed LDLR knockout mice lacking P2Y6 receptors in bone marrow-derived cells. In contrast, no effect on lesion development was observed in fat-fed whole body P2Y6xLDLR double knockout mice. Interestingly, in a model of enhanced vascular inflammation using angiotensin II, P2Y6 deficiency enhanced formation of aneurysms and exhibited a trend towards increased atherosclerosis in the aorta of LDLR knockout mice. Conclusions P2Y6 receptor augments pro-inflammatory responses in macrophages and exhibits a pro-atherogenic role in hematopoietic cells. However, the overall impact of whole body P2Y6 deficiency on atherosclerosis appears to be modest and could reflect additional roles of P2Y6 in vascular disease pathophysiologies, such as aneurysm formation. PMID:25360548

  20. Polycyclic Annular Lesion Masquerading as Lupus Erythematosus and Emerging as Tinea Faciei Incognito

    PubMed Central

    Kye, Heesang; Kim, Dai Hyun; Seo, Soo Hong; Ahn, Hyo Hyun; Kye, Young Chul

    2015-01-01

    Tinea incognito is a dermatophytic infection induced by immunosuppressive agents that lacks the classic features of a typical fungal infection. Although the treatment of tinea incognito is simple and relatively easy, its clinical manifestation varies and can masquerade as various skin disorders, causing misdiagnosis and thus preventing prompt and appropriate treatment. Here, we report an interesting case of tinea incognito occurring after topical steroid administration in an immunosuppressed patient with dermatitis artefacta. A 40-year-old female patient who had been taking systemic glucocorticoid for 4 years for chronic inflammatory demyelinating polyneuropathy presented with itching multiple erythematous erosive lesions on the face and upper chest for 2 months. Initial biopsy produced nonspecific findings. The skin lesion was aggravated and became polycyclic and erythematous; after azathioprine was added, her chronic inflammatory demyelinating polyneuropathy became aggravated. A second biopsy confirmed hyphae in the cornified layer. Complete remission was achieved after admonishing oral terbinafine and topical amorolfine. PMID:26082592

  1. Polycyclic Annular Lesion Masquerading as Lupus Erythematosus and Emerging as Tinea Faciei Incognito.

    PubMed

    Kye, Heesang; Kim, Dai Hyun; Seo, Soo Hong; Ahn, Hyo Hyun; Kye, Young Chul; Choi, Jae Eun

    2015-06-01

    Tinea incognito is a dermatophytic infection induced by immunosuppressive agents that lacks the classic features of a typical fungal infection. Although the treatment of tinea incognito is simple and relatively easy, its clinical manifestation varies and can masquerade as various skin disorders, causing misdiagnosis and thus preventing prompt and appropriate treatment. Here, we report an interesting case of tinea incognito occurring after topical steroid administration in an immunosuppressed patient with dermatitis artefacta. A 40-year-old female patient who had been taking systemic glucocorticoid for 4 years for chronic inflammatory demyelinating polyneuropathy presented with itching multiple erythematous erosive lesions on the face and upper chest for 2 months. Initial biopsy produced nonspecific findings. The skin lesion was aggravated and became polycyclic and erythematous; after azathioprine was added, her chronic inflammatory demyelinating polyneuropathy became aggravated. A second biopsy confirmed hyphae in the cornified layer. Complete remission was achieved after admonishing oral terbinafine and topical amorolfine. PMID:26082592

  2. Selection of non-steroidal anti-inflammatory drug and treatment regimen for sulfur mustard-induced cutaneous lesions.

    PubMed

    Plahovinsak, Jennifer L; Buccellato, Matthew A; Reid, Frances M; Graham, John S

    2016-09-01

    The inflammatory process plays an important role in sulfur mustard (HD) injury and HD pathogenesis, suggesting that anti-inflammatory treatments applied as soon as possible following HD injury may reduce tissue damage and accelerate healing. This study used the HD dermal weanling swine model to investigate the efficacy of two non-steroidal anti-inflammatory drugs, capsaicin and diclofenac, when applied in combination with the steroid, clobetasol. The therapeutic regimen was also investigated with respect to initiation of treatment post-exposure, frequency and duration. Yorkshire-cross pigs were randomly assigned to experimental groups, corresponding to all combinations of treatment (capsaicin with clobetasol or diclofenac with clobetasol), onset time (1, 2 or 4 h post-exposure), treatment duration (1, 3 or 5 days) and frequency of applications (2, 3 or 4 per day). For each animal, two sites on the ventral abdomen were exposed to 400 μL of neat HD for 8 min to achieve superficial dermal (SD) lesions and two sites were exposed to 400 μL neat HD for 30 min to achieve deep dermal (DD) lesions. Each treatment regimen was tested against a SD and a DD injury. Untreated SD and DD lesion sites served as within-animal controls. Assessments, up to one week post-challenge, included digital photographs, clinical assessments (lesion size measurements and modified Draize scoring), transepidermal water loss (TEWL), reflectance colorimetry and histopathologic evaluations that included an estimate for depth of injury and wound healing parameters. Diclofenac plus clobetasol treatment resulted in significant reductions in lesion contracture and modified Draize scores, increased barrier function (decreased TEWL), and increased healing as determined by histopathology for both SD and DD injury when compared with untreated sites and sites treated with capsaicin plus clobetasol. An increased duration of treatment from 1 to 5 days was most commonly associated with decreased

  3. [Diagnostic algorithm of a lesion of jaws bone tissues in purulent inflammatory diseases of maxillofacial region].

    PubMed

    Mubarakova, L N

    2008-01-01

    The writer detects changes of density of strontium, calcium, zinc and ratio Ca/Sr, Zn/Sr in oral liquid at examination 162 patients with acute odontogenic inflammatory diseases and 85 ill with a fracture of a mandible and at it inflammatory complication. By her is established the increase density of calcium in a stomatic liquid at all purulent-inflammatory diseases of maxillofacial area. The strontium is reduced only at an acute odontogenic osteomyelitis and odontogenic lymphadenitis complicated by a phlegmon. The ratio Ca/Sr, Zn/Sr is-augmented also only at the data diseases. PMID:18577924

  4. A Validated Model of the Pro- and Anti-Inflammatory Cytokine Balancing Act in Articular Cartilage Lesion Formation

    PubMed Central

    Wang, Xiayi; Brouillette, Marc J.; Ayati, Bruce P.; Martin, James A.

    2015-01-01

    Traumatic injuries of articular cartilage result in the formation of a cartilage lesion and contribute to cartilage degeneration and the risk of osteoarthritis (OA). A better understanding of the framework for the formation of a cartilage lesion formation would be helpful in therapy development. Toward this end, we present an age and space-structured model of articular cartilage lesion formation after a single blunt impact. This model modifies the reaction-diffusion-delay models in Graham et al. (2012) (single impact) and Wang et al. (2014) (cyclic loading), focusing on the “balancing act” between pro- and anti-inflammatory cytokines. Age structure is introduced to replace the delay terms for cell transitions used in these earlier models; we find age structured models to be more flexible in representing the underlying biological system and more tractable computationally. Numerical results show a successful capture of chondrocyte behavior and chemical activities associated with the cartilage lesion after the initial injury; experimental validation of our computational results is presented. We anticipate that our in silico model of cartilage damage from a single blunt impact can be used to provide information that may not be easily obtained through in in vivo or in vitro studies. PMID:25806365

  5. A validated model of the pro- and anti-inflammatory cytokine balancing act in articular cartilage lesion formation.

    PubMed

    Wang, Xiayi; Brouillette, Marc J; Ayati, Bruce P; Martin, James A

    2015-01-01

    Traumatic injuries of articular cartilage result in the formation of a cartilage lesion and contribute to cartilage degeneration and the risk of osteoarthritis (OA). A better understanding of the framework for the formation of a cartilage lesion formation would be helpful in therapy development. Toward this end, we present an age and space-structured model of articular cartilage lesion formation after a single blunt impact. This model modifies the reaction-diffusion-delay models in Graham et al. (2012) (single impact) and Wang et al. (2014) (cyclic loading), focusing on the "balancing act" between pro- and anti-inflammatory cytokines. Age structure is introduced to replace the delay terms for cell transitions used in these earlier models; we find age structured models to be more flexible in representing the underlying biological system and more tractable computationally. Numerical results show a successful capture of chondrocyte behavior and chemical activities associated with the cartilage lesion after the initial injury; experimental validation of our computational results is presented. We anticipate that our in silico model of cartilage damage from a single blunt impact can be used to provide information that may not be easily obtained through in in vivo or in vitro studies. PMID:25806365

  6. Fulminant Demyelinating Diseases of the Central Nervous System.

    PubMed

    Bevan, Carolyn J; Cree, Bruce A

    2015-12-01

    Fulminant demyelinating diseases of the central nervous system include acute disseminated encephalomyelitis, the related acute hemorrhagic leukoencephalitis, multiple sclerosis variants, neuromyelitis optica spectrum disorders, and idiopathic transverse myelitis. These syndromes are often managed with similar acute treatments including high-dose corticosteroids and plasmapheresis; however, long-term management varies. Although the prognosis of fulminant demyelinating disease was historically poor, outcomes today may be improved due to earlier diagnosis, rapid implementation of anti-inflammatory therapies such as high-dose corticosteroids and plasmapheresis, and improved supportive care. PMID:26595866

  7. Nandrolone decanoate and resistance exercise training favor the occurrence of lesions and activate the inflammatory response in the ventral prostate.

    PubMed

    Gomes, F C; Chuffa, L G A; Scarano, W R; Pinheiro, P F F; Fávaro, W J; Domeniconi, R F

    2016-05-01

    Age is a key factor in the development of prostatic lesions. An increase in reactive oxygen species levels occurs during aging. Furthermore, the indiscriminate use of anabolic androgenic steroids and physical exercise alter the availability of hormones and may promote the appearance of lesions. This study examined whether the use of nandrolone decanoate (ND), associated or not with resistance exercise training, affects the pathways related to the inflammatory response in the ventral prostate of adult and aged rats. Sprague-Dawley rats were distributed into eight experimental groups: sedentary with ND, sedentary without ND, exercise with ND, and exercise without ND. The animals performed resistance exercise training and received ND two times/week (5 mg/kg, i.m.) for 8 weeks. Adult rats were killed immediately following treatment completion, and aged rats remained untreated until reaching 300 days of age. The adult animals that received ND and performed resistance exercise training showed a higher occurrence of lesions with TLR4 activation. Marked IL-6 expression occurred in the group that performed resistance exercise training. The group exposed to ND showed overexpression of TLR2, TLR4, NOX1, Nrf2, TNF-α, and P38MAPK. The animals that received ND and performed training showed increase levels of NFκB, IRF3, IL-6, TNF-α, and NOX1. TLR2 and TLR4 showed no upregulation in the aged animals. The groups exercise + ND showed lesions in the adult stage and after aging, followed by molecular alterations. We concluded that nandrolone decanoate and resistance exercise training can promote the onset of prostatic tumors in the adult stage, and during aging, activating pathways involved in the inflammatory response. PMID:27011054

  8. Immunohistochemical characteristics of surfactant proteins a, B, C and d in inflammatory and tumorigenic lung lesions of f344 rats.

    PubMed

    Yokohira, Masanao; Yamakawa, Keiko; Nakano, Yuko; Numano, Takamasa; Furukawa, Fumio; Kishi, Sosuke; Ninomiya, Fumiko; Kanie, Shohei; Hitotsumachi, Hiroko; Saoo, Kousuke; Imaida, Katsumi

    2014-10-01

    Surfactant proteins (SPs), originally known as human lung surfactants, are essential to respiratory structure and function. There are 4 subtypes, SP-A, SP-B, SP-C and SP-D, with SP-A and SP-D having immunological functions, and SP-B and SP-C having physicochemical properties that reduce the surface tension at biological interfaces. In this experiment, the expressions of SP-A, SP-B, SP-C and SP-D in lung neoplastic lesions induced by N-bis (2-hydroxypropyl) nitrosamine (DHPN) and inflammatory lesions due to quartz instillation were examined and compared immunohistochemically. Formalin fixed paraffin embedded (FFPE) lung samples featuring inflammation were obtained with a rat quartz instillation model, and neoplastic lesions, hyperplasias and adenomas, were obtained with the rat DHPN-induced lung carcinogenesis model. In the rat quartz instillation model, male 10-week old F344 rats were exposed by intratracheal instillation (IT) to quartz at a dose of 2 mg/rat suspended in saline (0.2 ml) on day 0, and sacrificed on day 28. Lung tumorigenesis in F344 male rats was initiated by DHPN in drinking water for 2 weeks, and the animals were then sacrificed in week 30. Lung proliferative lesions, hyperplasias and adenomas, were observed with DHPN, and inflammation was observed with quartz. The expressions of SP-A, SP-B, SP-C and SP-D were examined immunohistochemically. SP-B and SP-C showed strong expression in lung hyperplasias and adenomas, while SP-A and SP-D were observed in mucus or exudates in inflammatory alveoli. These results suggest the possibility that SP-B and SP-C are related to lung tumorigenesis. PMID:25378802

  9. Early and widespread injury of astrocytes in the absence of demyelination in acute haemorrhagic leukoencephalitis.

    PubMed

    Robinson, Christopher A; Adiele, Reginald C; Tham, Mylyne; Lucchinetti, Claudia F; Popescu, Bogdan F G H

    2014-01-01

    Acute hemorrhagic leukoencephalitis (AHL) is a fulminant demyelinating disease of unknown etiology. Most cases are fatal within one week from onset. AHL pathology varies with the acuteness of disease. Hemorrhages, vessel fibrinoid necrosis, perivascular fibrin exudation, edema and neutrophilic inflammation are early features, while perivascular demyelination, microglial foci and myelin-laden macrophages appear later. Reactive astrocytosis is not present in early hemorrhagic non-demyelinated lesions, but is seen in older lesions. This case report presents the pathology of an AHL case with fulminant course and fatal outcome within 48 hours from presentation. Severe hemorrhages, edema and neutrophilic inflammation in the absence of circumscribed perivascular demyelination affected the temporal neocortex and white matter, hippocampus, cerebellar cortex and white matter, optic chiasm, mammillary bodies, brainstem, cranial nerve roots and leptomeninges. Perivascular end-feet and parenchymal processes of astrocytes exhibited impressive swelling in haemorrhagic but non-demyelinated white matter regions. Astrocytes were dystrophic and displayed degenerating processes. Astrocytic swellings and remnants were immunoreactive for aquaporin-4, aquaporin-1 and glial fibrillary acidic protein. These morphological changes of astrocytes consistent with injury were also observed in haemorrhagic and normal appearing cortex. Our findings reinforce that perivascular demyelination is not present early in AHL. This is the first study that highlights the early and widespread astrocytic injury in the absence of demyelination in AHL, suggesting that, similarly to neuromyelitis optica and central pontine myelinolysis, demyelination in AHL is secondary to astrocyte injury. PMID:24887055

  10. Immune-mediated demyelination--immunopathological basis for electrophysiological changes.

    PubMed

    Saida, T; Saida, K

    1982-01-01

    A focal immune-mediated demyelinating lesion of peripheral nerve was produced by intraneural injection of antiserum to galactocerebroside, a major glycosphingolipid hapten common in CNS and PNS myelin. This model provides an excellent system for correlative studies of physiological and pathological alterations in the processes of demyelination, because the time course of such changes is predictable from animal to animal. Twenty minutes after antiserum injection, Schwann cells showed focal cytoplasmic outpouching and their external mesaxons opened. Between 1 and 8 h after injection "melting," splitting, vesiculation and vacuolation of myelin became increasingly prominent at paranodal regions and Schmidt-Lantermann clefts, with concomitant degenerative changes in Schwann cell cytoplasm. Disruption of myelin in the paranodal region with detachment of the outermost paranodal myelin loops from paranodal axon resulted in an increase in nodal surface area. This seems to be the most critical anatomical alteration responsible for the early changes in propagation of nerve impulses in this antibody-mediated demyelinating lesion. Between 8 h and 3 days axons became demyelinated progressively over several internodes by macrophage phagocytosis. The onset of clinical and saltatory conduction recovery from the lesion corresponded to the appearance of 2-8 myelin lamellae around each remyelinating axon. PMID:6962042

  11. Developmental endothelial locus-1 (Del-1) is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination

    PubMed Central

    Neuwirth, Ales; Economopoulou, Matina; Chatzigeorgiou, Antonios; Chung, Kyoung-Jin; Bittner, Stefan; Lee, Seung-Hwan; Langer, Harald; Samus, Maryna; Kim, Hyesoon; Cho, Geum-Sil; Ziemssen, Tjalf; Bdeir, Khalil; Chavakis, Emmanouil; Koh, Jae-Young; Boon, Louis; Hosur, Kavita; Bornstein, Stefan R.; Meuth, Sven G.; Hajishengallis, George; Chavakis, Triantafyllos

    2014-01-01

    Inflammation in the central nervous system (CNS) and disruption of its immune privilege are major contributors to the pathogenesis of multiple sclerosis (MS) and of its rodent counterpart, experimental autoimmune encephalomyelitis (EAE). We have previously identified developmental endothelial locus-1 (Del-1) as an endogenous anti-inflammatory factor, which inhibits integrin-dependent leukocyte adhesion. Here we show that Del-1 contributes to the immune privilege status of the CNS. Intriguingly, Del-1 expression decreased in chronic active MS lesions and in the inflamed CNS in the course of EAE. Del-1-deficiency was associated with increased EAE severity, accompanied by increased demyelination and axonal loss. As compared to control mice, Del-1−/− mice displayed enhanced disruption of the blood brain barrier and increased infiltration of neutrophil granulocytes in the spinal cord in the course of EAE, accompanied by elevated levels of inflammatory cytokines, including IL-17. The augmented levels of IL-17 in Del-1-deficiency derived predominantly from infiltrated CD8+ T cells. Increased EAE severity and neutrophil infiltration due to Del-1-deficiency was reversed in mice lacking both Del-1 and IL-17-receptor, indicating a crucial role for the IL-17/neutrophil inflammatory axis in EAE pathogenesis in Del-1−/− mice. Strikingly, systemic administration of Del-1-Fc ameliorated clinical relapse in relapsing-remitting EAE. Therefore, Del-1 is an endogenous homeostatic factor in the CNS protecting from neuroinflammation and demyelination. Our findings provide mechanistic underpinnings for the previous implication of Del-1 as a candidate MS susceptibility gene and suggest that Del-1-centered therapeutic approaches may be beneficial in neuroinflammatory and demyelinating disorders. PMID:25385367

  12. Developmental endothelial locus-1 is a homeostatic factor in the central nervous system limiting neuroinflammation and demyelination.

    PubMed

    Choi, E Y; Lim, J-H; Neuwirth, A; Economopoulou, M; Chatzigeorgiou, A; Chung, K-J; Bittner, S; Lee, S-H; Langer, H; Samus, M; Kim, H; Cho, G-S; Ziemssen, T; Bdeir, K; Chavakis, E; Koh, J-Y; Boon, L; Hosur, K; Bornstein, S R; Meuth, S G; Hajishengallis, G; Chavakis, T

    2015-07-01

    Inflammation in the central nervous system (CNS) and disruption of its immune privilege are major contributors to the pathogenesis of multiple sclerosis (MS) and of its rodent counterpart, experimental autoimmune encephalomyelitis (EAE). We have previously identified developmental endothelial locus-1 (Del-1) as an endogenous anti-inflammatory factor, which inhibits integrin-dependent leukocyte adhesion. Here we show that Del-1 contributes to the immune privilege status of the CNS. Intriguingly, Del-1 expression decreased in chronic-active MS lesions and in the inflamed CNS in the course of EAE. Del-1-deficiency was associated with increased EAE severity, accompanied by increased demyelination and axonal loss. As compared with control mice, Del-1(-/-) mice displayed enhanced disruption of the blood-brain barrier and increased infiltration of neutrophil granulocytes in the spinal cord in the course of EAE, accompanied by elevated levels of inflammatory cytokines, including interleukin-17 (IL-17). The augmented levels of IL-17 in Del-1-deficiency derived predominantly from infiltrated CD8(+) T cells. Increased EAE severity and neutrophil infiltration because of Del-1-deficiency was reversed in mice lacking both Del-1 and IL-17 receptor, indicating a crucial role for the IL-17/neutrophil inflammatory axis in EAE pathogenesis in Del-1(-/-) mice. Strikingly, systemic administration of Del-1-Fc ameliorated clinical relapse in relapsing-remitting EAE. Therefore, Del-1 is an endogenous homeostatic factor in the CNS protecting from neuroinflammation and demyelination. Our findings provide mechanistic underpinnings for the previous implication of Del-1 as a candidate MS susceptibility gene and suggest that Del-1-centered therapeutic approaches may be beneficial in neuroinflammatory and demyelinating disorders. PMID:25385367

  13. Scanning acoustic microscopy for characterization of neoplastic and inflammatory lesions of lymph nodes.

    PubMed

    Miura, Katsutoshi; Nasu, Hatsuko; Yamamoto, Seiji

    2013-01-01

    A scanning acoustic microscope (SAM) imaging system calculates and color codes speed of sound (SOS). We evaluated the SAM results for lymph node imaging and compared these results with those of light microscopy (LM). SAM showed normal structures and localized/diffuse lesions of the lymph node. Our results revealed that as a rule, soft areas such as cystic necrosis presented less SOS while harder areas such as coagulative necrosis, granulomas, and fibrosis exhibited greater SOS. SOS increased according to stromal desmoplastic reactions and cellular concentration. In neoplastic lesions, statistically significant differences in SOS were observed among scirrhous carcinomas, lymphomas, and medullary carcinomas. SAM provided the following benefits over LM: (1) images reflected the tissue elasticity of each lesion, (2) digitized SOS data could be statistically comparable, (3) images were acquired in a few minutes without special staining, (4) SAM images and echographic images were comparable for clinical ultrasound imaging study. PMID:23409246

  14. Dermoscopy for the pediatric dermatologist part I: dermoscopy of pediatric infectious and inflammatory skin lesions and hair disorders.

    PubMed

    Haliasos, Elena C; Kerner, Miryam; Jaimes-Lopez, Natalia; Rudnicka, Lidia; Zalaudek, Iris; Malvehy, Josep; Hofmann-Wellenhof, Rainer; Braun, Ralph P; Marghoob, Ashfaq A

    2013-01-01

    The dermoscope allows physicians to examine the macroscopic and microscopic primary morphology of skin lesions, identify subtle clinical clues, confirm naked-eye clinical diagnoses, and monitor treatment progress while posing little threat to the young patient. This review summarizes important dermoscopic structures seen in infectious and inflammatory skin conditions and hair disorders in children. Scabies, pediculosis, phthiriasis, molluscum contagiosum, tinea nigra, and verrucae are well characterized dermoscopically by delta-shaped structures, ovoid-shaped nits, the crab louse, red corona, brown strands or spicules, and multiple densely packed papilla with a central black dot surrounded by a whitish halo, respectively. These dermoscopic structures will be discussed, focusing on the dermoscopic morphologies and dermoscopic sensitivity for diagnosis and its utility in monitoring treatment progress. Dermoscopy has also been shown to significantly improve the clinician's diagnostic and monitoring accuracy of inflammatory skin lesions such as psoriasis, which is characterized dermoscopically by uniformly distributed dotted blood vessels, and lichen planus, which is characterized by whitish lines on a purple to reddish background. Dermoscopy of the hair and scalp (trichoscopy) facilitates the differential diagnosis of hair diseases in children, including alopecia areata, trichotillomania, and tinea capitis. It can also assist in the diagnosis of multiple genetic hair shaft disorders, such as monilethrix, trichorrhexis invaginata, trichorrhexis nodosa, pili torti, and pili annulati. PMID:23405886

  15. Integrated imaging of hepatic tumors in childhood. Part II. Benign lesions (congenital, reparative, and inflammatory)

    SciTech Connect

    Miller, J.H.; Greenspan, B.S.

    1985-01-01

    The authors have encountered benign liver masses as frequently as malignant lesions in children with hepatomegaly. Lesions studied included abscesses, cavernous hemangioma/hemangioendothelioma, adenoma of glycogen storage disease, choledochal cysts, focal nodular hyperplasia, cystic hepatoblastoma, and hamartoma. An intergrated imaging protocol involving ultrasound, computed tomography, and scintigraphy proved to be more helpful than any one modality in establishing the benign or malignant nature of a hepatic neoplasm and the type of tumor, which is of particular importance when surgical exploration and/or biopsy is contraindicated.

  16. Diagnosis and treatment of chronic acquired demyelinating polyneuropathies.

    PubMed

    Latov, Norman

    2014-08-01

    Chronic neuropathies are operationally classified as primarily demyelinating or axonal, on the basis of electrodiagnostic or pathological criteria. Demyelinating neuropathies are further classified as hereditary or acquired-this distinction is important, because the acquired neuropathies are immune-mediated and, thus, amenable to treatment. The acquired chronic demyelinating neuropathies include chronic inflammatory demyelinating polyneuropathy (CIDP), neuropathy associated with monoclonal IgM antibodies to myelin-associated glycoprotein (MAG; anti-MAG neuropathy), multifocal motor neuropathy (MMN), and POEMS syndrome. They have characteristic--though overlapping--clinical presentations, are mediated by distinct immune mechanisms, and respond to different therapies. CIDP is the default diagnosis if the neuropathy is demyelinating and no other cause is found. Anti-MAG neuropathy is diagnosed on the basis of the presence of anti-MAG antibodies, MMN is characterized by multifocal weakness and motor conduction blocks, and POEMS syndrome is associated with IgG or IgA λ-type monoclonal gammopathy and osteosclerotic myeloma. The correct diagnosis, however, can be difficult to make in patients with atypical or overlapping presentations, or nondefinitive laboratory studies. First-line treatments include intravenous immunoglobulin (IVIg), corticosteroids or plasmapheresis for CIDP; IVIg for MMN; rituximab for anti-MAG neuropathy; and irradiation or chemotherapy for POEMS syndrome. A correct diagnosis is required for choosing the appropriate treatment, with the aim of preventing progressive neuropathy. PMID:24980070

  17. Multifocal Motor Neuropathy, Multifocal Acquired Demyelinating Sensory and Motor Neuropathy and Other Chronic Acquired Demyelinating Polyneuropathy Variants

    PubMed Central

    Barohn, Richard J.; Katz, Jonathan

    2014-01-01

    Chronic acquired demyelinating neuropathies (CADP) are an important group of immune neuromuscular disorders affecting myelin. These are distinct from chronic inflammatory demyelinating polyneuropathy (CIDP). Classically, CIDP is characterized by proximal and distal weakness, large fiber sensory loss, elevated cerebrospinal fluid (CSF) protein content, demyelinating changes nerve conduction studies or nerve biopsy, and response to immunomodulating treatment. In this chapter we discuss CADP with emphasis on multifocal motor neuropathy (MMN), multifocal acquired demyelinating sensory and motor neuropathy (MADSAM), distal acquired demyelinating symmetric (DADS) neuropathy and conclude with less common variants. While each of these entities has distinctive laboratory and electrodiagnostic features that aid in their diagnosis, clinical characteristics are of paramount importance in diagnosing specific conditions and determining the most appropriate therapies. Unlike CIDP, MMN is typically asymmetric and affects only the motor nerve fibers. MMN is a rare disease that presents chronically, over several years of progression affecting the arms are more commonly than the legs. Men are more likely than women to develop MMN. MADSAM should be suspected in patients who have weakness and loss of sensation in primarily one arm or leg which progresses slowly over several months to years. It is important in patient with multifocal demyelinating clinical presentation to distinguish MMN from MADSAM since corticosteroids are not effective in MMN where the mainstay of therapy is intravenous gammaglobulin (IVIg). DADS can be subdivided into DADS-M (associated woth M-protein) and DADS-I which is idioapthic. While DADS-I patients respond somewhat to immunotherapy, DADS-M patients present with distal predominant sensorimotor demyelinating neuropathy phenotype and are notoriously refractory to immunotherapies regardless of antibodies to myelin-associated glycoprotein (MAG). Our knowledge

  18. Time course of lewisite-induced skin lesions and inflammatory response in the SKH-1 hairless mouse model.

    PubMed

    Nguon, Nina; Cléry-Barraud, Cécile; Vallet, Virginie; Elbakdouri, Nacéra; Wartelle, Julien; Mouret, Stéphane; Bertoni, Marine; Dorandeu, Frédéric; Boudry, Isabelle

    2014-01-01

    Data on the toxicity of lewisite (L), a vesicant chemical warfare agent, are scarce and conflicting, and the use of the specific antidote is not without drawbacks. This study was designed to evaluate if the SKH-1 hairless mouse model was suitable to study the L-induced skin injuries. We studied the progression of lesions following exposure to L vapors for 21 days using paraclinical parameters (color, transepidermal water loss (TEWL), and biomechanical measurements), histological assessments, and biochemical indexes of inflammation. Some data were also obtained over 27 weeks. The development of lesions was similar to that reported in other models. The TEWL parameter appeared to be the most appropriate index to follow their progression. Histological analysis showed inflammatory cell infiltration and microvesications at day 1 and a complete wound closure by day 21. Biochemical studies indicated a deregulation of the levels of several cytokines and receptors involved in inflammation. An increase in the quantity of pro-matrix metalloproteinases 2 and 9 was shown as observed in other models. This suggests that the SKH-1 mouse model is relevant for the investigation of the physiopathological process of skin lesions induced by L and to screen new treatment candidates. PMID:24635178

  19. Quantifying Demyelination in NK venom treated nerve using its electric circuit model.

    PubMed

    Das, H K; Das, D; Doley, R; Sahu, P P

    2016-01-01

    Reduction of myelin in peripheral nerve causes critical demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, etc. Clinical monitoring of these diseases requires rapid and non-invasive quantification of demyelination. Here we have developed formulation of nerve conduction velocity (NCV) in terms of demyelination considering electric circuit model of a nerve having bundle of axons for its quantification from NCV measurements. This approach has been validated and demonstrated with toad nerve model treated with crude Naja kaouthia (NK) venom and also shows the effect of Phospholipase A2 and three finger neurotoxin from NK-venom on peripheral nerve. This opens future scope for non-invasive clinical measurement of demyelination. PMID:26932543

  20. Quantifying Demyelination in NK venom treated nerve using its electric circuit model

    NASA Astrophysics Data System (ADS)

    Das, H. K.; Das, D.; Doley, R.; Sahu, P. P.

    2016-03-01

    Reduction of myelin in peripheral nerve causes critical demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, etc. Clinical monitoring of these diseases requires rapid and non-invasive quantification of demyelination. Here we have developed formulation of nerve conduction velocity (NCV) in terms of demyelination considering electric circuit model of a nerve having bundle of axons for its quantification from NCV measurements. This approach has been validated and demonstrated with toad nerve model treated with crude Naja kaouthia (NK) venom and also shows the effect of Phospholipase A2 and three finger neurotoxin from NK-venom on peripheral nerve. This opens future scope for non-invasive clinical measurement of demyelination.

  1. Quantifying Demyelination in NK venom treated nerve using its electric circuit model

    PubMed Central

    Das, H. K.; Das, D.; Doley, R.; Sahu, P. P.

    2016-01-01

    Reduction of myelin in peripheral nerve causes critical demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barre syndrome, etc. Clinical monitoring of these diseases requires rapid and non-invasive quantification of demyelination. Here we have developed formulation of nerve conduction velocity (NCV) in terms of demyelination considering electric circuit model of a nerve having bundle of axons for its quantification from NCV measurements. This approach has been validated and demonstrated with toad nerve model treated with crude Naja kaouthia (NK) venom and also shows the effect of Phospholipase A2 and three finger neurotoxin from NK-venom on peripheral nerve. This opens future scope for non-invasive clinical measurement of demyelination. PMID:26932543

  2. Early loss of oligodendrocytes in human and experimental neuromyelitis optica lesions

    PubMed Central

    Wrzos, Claudia; Winkler, Anne; Metz, Imke; Kayser, Dieter M.; Thal, Dietmar R.; Wegner, Christiane; Brück, Wolfgang; Nessler, Stefan; Bennett, Jeffrey L.

    2014-01-01

    Neuromyelitis optica (NMO) is a chronic, mostly relapsing inflammatory demyelinating disease of the CNS characterized by serum anti-aquaporin 4 (AQP4) antibodies in the majority of patients. Anti-AQP4 antibodies derived from NMO patients target and deplete astrocytes in experimental models when co-injected with complement. However, the time course and mechanisms of oligodendrocyte loss and demyelination and the fate of oligodendrocyte precursor cells (OPC) have not been examined in detail. Also, no studies regarding astrocyte repopulation of experimental NMO lesions have been reported. We utilized two rat models using either systemic transfer or focal intracerebral injection of recombinant human anti-AQP4 antibodies to generate NMO-like lesions. Time-course experiments were performed to examine oligodendroglial and astroglial damage and repair. In addition, oligodendrocyte pathology was studied in early human NMO lesions. Apart from early complement-mediated astrocyte destruction, we observed a prominent, very early loss of oligodendrocytes and oligodendrocyte precursor cells (OPCs) as well as a delayed loss of myelin. Astrocyte repopulation of focal NMO lesions was already substantial after 1 week. Olig2-positive OPCs reappeared before NogoA-positive, mature oligodendrocytes. Thus, using two experimental models that closely mimic the human disease, our study demonstrates that oligodendrocyte and OPC loss is an extremely early feature in the formation of human and experimental NMO lesions and leads to subsequent, delayed demyelination, highlighting an important difference in the pathogenesis of MS and NMO. PMID:24292009

  3. Histopathology of duodenal mucosal lesions in pediatric patients with inflammatory bowel disease: statistical analysis to identify distinctive features.

    PubMed

    Hardee, Steven; Alper, Arik; Pashankar, Dinesh S; Morotti, Raffaella A

    2014-01-01

    Histopathologic lesions of the upper gastrointestinal tract (UGT) are common in inflammatory bowel disease (IBD) patients. Pediatric patients have a higher incidence of IBD-associated gastritis and duodenitis than do adults. This study aimed to identify histopathologic features of duodenal lesions in the pediatric population that are characteristic of IBD, compared to duodenal pathology of different etiopathogenesis. We performed a retrospective analysis of UGT biopsies from pediatric patients with a histopathologic diagnosis of duodenitis (0-18 years of age) over a 7-year period. We identified 40 cases of duodenitis associated with Crohn's disease (CD) and 10 cases associated with ulcerative colitis (UC) and compared the histopathologic characteristics of the duodenitis with age-matched controls consisting of 40 cases duodenitis associated with celiac disease and 40 non-Helicobacter pylori-associated (NOS) etiology duodenitis cases. The histologic features that were evaluated included presence of granulomas, duodenal cryptitis, erosion, lamina propria eosinophils, villous blunting, increased intraepithelial lymphocytes (IELs), and crypt hyperplasia, among others. Additionally, we evaluated the presence of associated gastritis in all of these groups. Statistical analysis to identify significant differences was performed using Kruskal-Wallis testing. Cryptitis was the most distinctive feature of IBD-associated duodenitis. Granulomas were exceptionally rare. The severity of villous blunting and presence of IELs was significantly different in the IBD versus the celiac group. There is a significant overlap with duodenal lesions of different etiopathogenesis, including villous blunting and eosinophilia. With the exclusion of granulomas, cryptitis seems the most distinctive feature of the duodenal lesions associated with IBD. PMID:25207874

  4. FLT PET/CT in a Case of Demyelinating Disease.

    PubMed

    Nikaki, Alexandra; Prassopoulos, Vasilios; Efthimiadou, Roxani; Tsougos, Ioannis; Georgoulias, Panagiotis

    2016-07-01

    A 32-year-old woman, with spare previous medical history, presented with neurological symptoms of numbness and diplopia. The patient underwent brain MRI, which revealed a lesion of abnormal signal in the midbrain that could be attributed to subacute stroke; however, consecutive MRIs revealed multiple lesions of abnormal signal pointing to demyelinating disease. During symptoms investigation and MRI findings assessment, the patient underwent a FLT PET/CT examination, which revealed lesions of increased FLT uptake, probably indicating active disease and blood-brain barrier disruption. PMID:27088385

  5. Tumours and inflammatory lesions of the anal canal and perianal skin revisited: an update and practical approach.

    PubMed

    Dawson, Heather; Serra, Stefano

    2015-12-01

    Tumours of the anal and perianal region are relatively rare, and clinically often interpreted as innocuous lesions, leading to frequent delays in diagnosis and adequate treatment. Although squamous cell neoplasia represents the most common entity encountered in this anatomically complex area, many conditions, both neoplastic and inflammatory, may occur. Adding to the challenge of correct diagnosis and patient management, recent years have seen major updates in the terminology of squamous cell neoplasia, created to reflect advances in our understanding of the role of human papilloma virus and unify previous terminologies used for different sites in the anogenital tract. However, squamous cell neoplasia in the anal canal and perianal region may differ in terms of histology, biological behaviour, staging and treatment. The aim of this review is to present an overview of neoplastic and non-neoplastic lesions that may be seen in this area, an update on important developments and terminology, potential pitfalls that may be encountered in routine pathology practice and a practical approach on how to resolve these issues. PMID:26602415

  6. Nodal, paranodal and juxtaparanodal axonal proteins during demyelination and remyelination in multiple sclerosis.

    PubMed

    Coman, I; Aigrot, M S; Seilhean, D; Reynolds, R; Girault, J A; Zalc, B; Lubetzki, C

    2006-12-01

    Saltatory conduction in myelinated fibres depends on the specific molecular organization of highly specialized axonal domains at the node of Ranvier, the paranodal and the juxtaparanodal regions. Voltage-gated sodium channels (Na(v)) have been shown to be deployed along the naked demyelinated axon in experimental models of CNS demyelination and in multiple sclerosis lesions. Little is known about aggregation of nodal, paranodal and juxtaparanodal constituents during the repair process. We analysed by immunohistochemistry on free-floating sections from multiple sclerosis brains the expression and distribution of nodal (Na(v) channels), paranodal (paranodin/Caspr) and juxtaparanodal (K(v) channels and Caspr2) molecules in demyelinated and remyelinated lesions. Whereas in demyelinated lesions, paranodal and juxtaparanodal proteins are diffusely distributed on denuded axons, the distribution of Na(v) channels is heterogeneous, with a diffuse immunoreactivity but also few broad Na(v) channel aggregates in all demyelinated lesions. In contrast to the demyelinated plaques, all remyelinated lesions are characterized by the detection of aggregates of Na(v) channels, paranodin/Caspr, K(v) channels and Caspr2. Our data suggest that these aggregates precede remyelination, and that Na(v) channel aggregation is the initial event, followed by aggregation of paranodal and then juxtaparanodal axonal proteins. Remyelination takes place in multiple sclerosis tissue but myelin repair is often incomplete, and the reasons for this remyelination deficit are many. We suggest that a defect of Na(v) channel aggregation might be involved in the remyelination failure in demyelinated lesions with spared axons and oligodendroglial cells. PMID:16766541

  7. Nogo Receptor Inhibition Enhances Functional Recovery following Lysolecithin-Induced Demyelination in Mouse Optic Chiasm

    PubMed Central

    Pourabdolhossein, Fereshteh; Mozafari, Sabah; Morvan-Dubois, Ghislaine; Mirnajafi-Zadeh, Javad; Lopez-Juarez, Alejandra; Pierre-Simons, Jacqueline; Demeneix, Barbara A.; Javan, Mohammad

    2014-01-01

    Background Inhibitory factors have been implicated in the failure of remyelination in demyelinating diseases. Myelin associated inhibitors act through a common receptor called Nogo receptor (NgR) that plays critical inhibitory roles in CNS plasticity. Here we investigated the effects of abrogating NgR inhibition in a non-immune model of focal demyelination in adult mouse optic chiasm. Methodology/Principal Findings A focal area of demyelination was induced in adult mouse optic chiasm by microinjection of lysolecithin. To knock down NgR levels, siRNAs against NgR were intracerebroventricularly administered via a permanent cannula over 14 days, Functional changes were monitored by electrophysiological recording of latency of visual evoked potentials (VEPs). Histological analysis was carried out 3, 7 and 14 days post demyelination lesion. To assess the effect of NgR inhibition on precursor cell repopulation, BrdU was administered to the animals prior to the demyelination induction. Inhibition of NgR significantly restored VEPs responses following optic chiasm demyelination. These findings were confirmed histologically by myelin specific staining. siNgR application resulted in a smaller lesion size compared to control. NgR inhibition significantly increased the numbers of BrdU+/Olig2+ progenitor cells in the lesioned area and in the neurogenic zone of the third ventricle. These progenitor cells (Olig2+ or GFAP+) migrated away from this area as a function of time. Conclusions/Significance Our results show that inhibition of NgR facilitate myelin repair in the demyelinated chiasm, with enhanced recruitment of proliferating cells to the lesion site. Thus, antagonizing NgR function could have therapeutic potential for demyelinating disorders such as Multiple Sclerosis. PMID:25184636

  8. Inflammatory Myofibroblastic Tumor: A Rarely Seen Submucosal Lesion of the Stomach

    PubMed Central

    Arslan, Deniz; Gündüz, Şeyda; Tural, Deniz; Uysal, Mükremin; Tatlı, Ali Murat; Başsorgun, Cumhur İbrahim; Elpek, Gülsüm Özlem; Coşkun, Hasan Şenol; Bozcuk, Hakan Şat; Savaş, Burhan

    2013-01-01

    Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal benign tumor which is generally seen in children and in young adults. It is especially located in the lungs. In histopathological examination, neoplastic fusiform cells originating from a subtype of accessory immune system cells which are called fibroblastic reticulum cells are seen (Kouichi and Youichirou, 2008). Although IMT is histopathologically benign, imaging methods show its tendency for local recurrence and invasion. In most of the cases, it may not be possible to make a distinction whether it is malign or benign. Complete surgical resection is the most important treatment method. In this study, we have discussed the findings of our case having a gastric submucosal located IMT in light of the current literatures. PMID:23573435

  9. The neural androgen receptor: a therapeutic target for myelin repair in chronic demyelination.

    PubMed

    Hussain, Rashad; Ghoumari, Abdel M; Bielecki, Bartosz; Steibel, Jérôme; Boehm, Nelly; Liere, Philippe; Macklin, Wendy B; Kumar, Narender; Habert, René; Mhaouty-Kodja, Sakina; Tronche, François; Sitruk-Ware, Regine; Schumacher, Michael; Ghandour, M Said

    2013-01-01

    Myelin regeneration is a major therapeutic goal in demyelinating diseases, and the failure to remyelinate rapidly has profound consequences for the health of axons and for brain function. However, there is no efficient treatment for stimulating myelin repair, and current therapies are limited to anti-inflammatory agents. Males are less likely to develop multiple sclerosis than females, but often have a more severe disease course and reach disability milestones at an earlier age than females, and these observations have spurred interest in the potential protective effects of androgens. Here, we demonstrate that testosterone treatment efficiently stimulates the formation of new myelin and reverses myelin damage in chronic demyelinated brain lesions, resulting from the long-term administration of cuprizone, which is toxic for oligodendrocytes. In addition to the strong effect of testosterone on myelin repair, the number of activated astrocytes and microglial cells returned to low control levels, indicating a reduction of neuroinflammatory responses. We also identify the neural androgen receptor as a novel therapeutic target for myelin recovery. After the acute demyelination of cerebellar slices in organotypic culture, the remyelinating actions of testosterone could be mimicked by 5α-dihydrotestosterone, a metabolite that is not converted to oestrogens, and blocked by the androgen receptor antagonist flutamide. Testosterone treatment also failed to promote remyelination after chronic cuprizone-induced demyelination in mice with a non-functional androgen receptor. Importantly, testosterone did not stimulate the formation of new myelin sheaths after specific knockout of the androgen receptor in neurons and macroglial cells. Thus, the neural brain androgen receptor is required for the remyelination effect of testosterone, whereas the presence of the receptor in microglia and in peripheral tissues is not sufficient to enhance remyelination. The potent synthetic

  10. Current Concepts of the Pathogenesis and Pathology of Inflammatory Lesions of the Intestine

    PubMed Central

    Shnitka, Theodor K.

    1964-01-01

    The histopathologic lesions of regional enteritis and ulcerative colitis, particularly in their early stages, are distinct and distinguishable, irrespective of the sites that are involved. Regional enteritis is characterized by lymphangiectasis, lymphedema, lymphoid hyperplasia, and granulomatous inflammation of the submucosal and subserosal layers of intestine, whereas chronic ulcerative colitis is an exudative, ulcerative disorder of the mucosal layer that commences with “crypt abscesses” and only in its later stages progresses to deeper coats of the wall. Electron microscopy of a rectal biopsy from a juvenile patient with chronic ulcerative colitis for five years disclosed a labyrinthine system of clefts and compartments between columnar, mucosal epithelial cells. Regenerated colonic epithelial cells were of primitive, germinal type and featured a “vesicular” rather than a “goblet” pattern of mucus secretion. Clusters of small “clavate fimbriae” projected from the tips of microvilli. Each of these newly recognized substructures measured 30 to 60 mμ. in diameter, and was enclosed by a tri-laminar “unit membrane”, derived from the surface plasma membrane of the cell. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6Fig. 7Fig. 8Fig. 9Fig. 10Fig. 11Fig. 12Fig. 13Fig. 14Fig. 15Fig. 16Fig. 17Fig. 18Fig. 19 PMID:14182565

  11. Inflammatory pseudotumor containing necrotizing granulomatous lesions of kidney: a hitherto undescribed entity.

    PubMed

    Terada, Tadashi

    2014-01-01

    Herein reported is a case of inflammatory pseudotumor (IPT) of kidney. It is not described in WHO, AFIP, and other books. A review of the literature revealed about 35 cases. A 76-year-old man underwent nephrectomy under clinical diagnosis of renal pelvic carcinoma. Grossly, a solid tumor was seen in renal parenchyma. Microscopically, it was composed of spindle cell tissue with inflammation and many necrotizing granulomas. Epithelioid histiocytes were abundant but giant cells were few. Lymphocytes and plasma cells were also seen. The features suggested tuberculosis (TB), but Ziehl-Neelsen stains and PCR revealed no TB bacillus. Immunohistochemistry showed that the tumor spindle cells were positive for vimentin, CD68, CD45, and Ki-67 (labeling = 18%), α-smooth muscle antigen, and NSE. Focal staining of KIT (mast cells), S100 protein (Langerhans cells), and CD10 (spindle cells) was present. IgG4 was negative. The tumor spindle cells were negative for other antigens examined. PMID:25379319

  12. Disease-specific molecular events in cortical multiple sclerosis lesions

    PubMed Central

    Wimmer, Isabella; Höftberger, Romana; Gerlach, Susanna; Haider, Lukas; Zrzavy, Tobias; Hametner, Simon; Mahad, Don; Binder, Christoph J.; Krumbholz, Markus; Bauer, Jan; Bradl, Monika

    2013-01-01

    Cortical lesions constitute an important part of multiple sclerosis pathology. Although inflammation appears to play a role in their formation, the mechanisms leading to demyelination and neurodegeneration are poorly understood. We aimed to identify some of these mechanisms by combining gene expression studies with neuropathological analysis. In our study, we showed that the combination of inflammation, plaque-like primary demyelination and neurodegeneration in the cortex is specific for multiple sclerosis and is not seen in other chronic inflammatory diseases mediated by CD8-positive T cells (Rasmussen’s encephalitis), B cells (B cell lymphoma) or complex chronic inflammation (tuberculous meningitis, luetic meningitis or chronic purulent meningitis). In addition, we performed genome-wide microarray analysis comparing micro-dissected active cortical multiple sclerosis lesions with those of tuberculous meningitis (inflammatory control), Alzheimer’s disease (neurodegenerative control) and with cortices of age-matched controls. More than 80% of the identified multiple sclerosis-specific genes were related to T cell-mediated inflammation, microglia activation, oxidative injury, DNA damage and repair, remyelination and regenerative processes. Finally, we confirmed by immunohistochemistry that oxidative damage in cortical multiple sclerosis lesions is associated with oligodendrocyte and neuronal injury, the latter also affecting axons and dendrites. Our study provides new insights into the complex mechanisms of neurodegeneration and regeneration in the cortex of patients with multiple sclerosis. PMID:23687122

  13. Saltatory conduction precedes remyelination in axons demyelinated with lysophosphatidyl choline.

    PubMed

    Smith, K J; Bostock, H; Hall, S M

    1982-04-01

    The changing electrical and morphological properties of demyelinating and remyelinating nerve fibres have been studied in rat ventral roots after intrathecal injection of lysophosphatidyl choline (LPC). The spatial distribution of electrical excitability within the lesion has been studied in undissected single fibres using high-resolution longitudinal current analysis. The distribution of excitability has been correlated with the ultrastructure of the fibres and with the distribution of the surrounding Schwann cells. Demyelinated axolemma was initially not excited, but conduction across demyelinated internodes appeared progressively from the 4th day after LPC injection. Conduction was never continuous, but proceeded via new foci of inward membrane current as early as 4 days after LPC injection, i.e. 3 days before the onset of remyelination. It is suggested that these foci (termed phi-nodes to distinguish them from the nodes of Ranvier distributed along myelinated nerve fibres) are precursors of nodes of Ranvier, and may indicate aggregates of sodium channels which form along the demyelinated axolemma prior to remyelination. PMID:6804606

  14. Dendritic Cells Are the Major Antigen Presenting Cells in Inflammatory Lesions of Murine Mycoplasma Respiratory Disease

    PubMed Central

    Sun, Xiangle; Jones, Harlan P.; Dobbs, Nicole; Bodhankar, Sheetal; Simecka, Jerry W.

    2013-01-01

    Mycoplasmas cause chronic respiratory diseases in animals and humans, and to date, development of vaccines have been problematic. Using a murine model of mycoplasma pneumonia, lymphocyte responses, specifically T cells, were shown to confer protection as well as promote immunopathology in mycoplasma disease. Because T cells play such a critical role, it is important to define the role of antigen presenting cells (APC) as these cells may influence either exacerbation of mycoplasma disease pathogenesis or enhancement of protective immunity. The roles of APC, such as dendritic cells and/or macrophages, and their ability to modulate adaptive immunity in mycoplasma disease are currently unknown. Therefore, the purpose of this study was to identify individual pulmonary APC populations that may contribute to the activation of T cell responses during mycoplasma disease pathogenesis. The present study indeed demonstrates increasing numbers of CD11c− F4/80+ cells, which contain macrophages, and more mature/activated CD11c+ F4/80− cells, containing DC, in the lungs after infection. CD11c− F4/80+ macrophage-enriched cells and CD11c+ F4/80− dendritic cell-enriched populations showed different patterns of cytokine mRNA expression, supporting the idea that these cells have different impacts on immunity in response to infection. In fact, DC containing CD11c+ F4/80− cell populations from the lungs of infected mice were most capable of stimulating mycoplasma-specific CD4+ Th cell responses in vitro. In vivo, these CD11c+F4/80− cells were co-localized with CD4+ Th cells in inflammatory infiltrates in the lungs of mycoplasma-infected mice. Thus, CD11c+F4/80− dendritic cells appear to be the major APC population responsible for pulmonary T cell stimulation in mycoplasma-infected mice, and these dendritic cells likely contribute to responses impacting disease pathogenesis. PMID:23390557

  15. Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy.

    PubMed

    Kagiava, Alexia; Sargiannidou, Irene; Theophilidis, George; Karaiskos, Christos; Richter, Jan; Bashiardes, Stavros; Schiza, Natasa; Nearchou, Marianna; Christodoulou, Christina; Scherer, Steven S; Kleopa, Kleopas A

    2016-04-26

    Inherited demyelinating peripheral neuropathies are progressive incurable diseases without effective treatment. To develop a gene therapy approach targeting myelinating Schwann cells that can be translatable, we delivered a lentiviral vector using a single lumbar intrathecal injection and a myelin-specific promoter. The human gene of interest, GJB1, which is mutated in X-linked Charcot-Marie-Tooth Disease (CMT1X), was delivered intrathecally into adult Gjb1-null mice, a genetically authentic model of CMT1X that develops a demyelinating peripheral neuropathy. We obtained widespread, stable, and cell-specific expression of connexin32 in up to 50% of Schwann cells in multiple lumbar spinal roots and peripheral nerves. Behavioral and electrophysiological analysis revealed significantly improved motor performance, quadriceps muscle contractility, and sciatic nerve conduction velocities. Furthermore, treated mice exhibited reduced numbers of demyelinated and remyelinated fibers and fewer inflammatory cells in lumbar motor roots, as well as in the femoral motor and sciatic nerves. This study demonstrates that a single intrathecal lentiviral gene delivery can lead to Schwann cell-specific expression in spinal roots extending to multiple peripheral nerves. This clinically relevant approach improves the phenotype of an inherited neuropathy mouse model and provides proof of principle for treating inherited demyelinating neuropathies. PMID:27035961

  16. Remyelination of demyelinated rat axons by transplanted mouse oligodendrocytes

    SciTech Connect

    Crang, A.J.; Blakemore, W.F. )

    1991-01-01

    The injection of the gliotoxic agent ethidium bromide (EB) into spinal white matter produces a CNS lesion in which it is possible to investigate the ability of transplanted glial cells to reconstruct a glial environment around demyelinated axons. This study demonstrates that transplanted mouse glial cells can repopulate EB lesions in rats provided tissue rejection is controlled. In X-irradiated EB lesions in cyclosporin-A-treated rats, mouse oligodendrocytes remyelinated rat axons and, together with mouse astrocytes, re-established a CNS environment. When transplanted into nonirradiated EB lesions in nude rats, mouse glial cells modulated the normal host repair by Schwann cells to remyelination by oligodendrocytes. In both X-irradiated and non-irradiated EB lesions, transplanted mouse glial cells behaved similarly to isogenic rat glial cell transplants. These findings indicate that the cell-cell interactions involved in reconstruction of a glial environment are common to both mouse and rat.

  17. Autoimmune demyelination in the central nervous system.

    PubMed

    Tabira, T

    1988-01-01

    Autoimmune demyelination was studied in EAE induced by active challenge or by transfer of effector T-cell lines or clones specific for myelin basic protein or proteolipid apoprotein. The following points became clear: (1) Proteolipid apoprotein is responsible for widespread demyelination; (2) demyelination is more significant in EAE with a more chronic disease process; (3) a single T-cell clone can mediate significant demyelination without the aid of recipient-derived T-cell populations; (4) the difference in vulnerability between axons and myelin may account for the T-cell-mediated demyelination; and (5) effector T-cell clones can be activated by allogeneic antigens. PMID:2462801

  18. Pentadecapeptide BPC 157 positively affects both non-steroidal anti-inflammatory agent-induced gastrointestinal lesions and adjuvant arthritis in rats.

    PubMed

    Sikiric, P; Seiwerth, S; Grabarevic, Z; Rucman, R; Petek, M; Jagic, V; Turkovic, B; Rotkvic, I; Mise, S; Zoricic, I; Konjevoda, P; Perovic, D; Simicevic, V; Separovic, J; Hanzevacki, M; Ljubanovic, D; Artukovic, B; Bratulic, M; Tisljar, M; Rekic, B; Gjurasin, M; Miklic, P; Buljat, G

    1997-01-01

    Besides a superior protection of the pentadecapeptide BPC 157 (an essential fragment of an organoprotective gastric juice peptide BPC) against different gastrointestinal and liver lesions, an acute anti-inflammatory and analgetic activity was also noted. Consequently, its effect on chronic inflammation lesions, such as adjuvant arthritis, and non-steroidal anti-inflammatory agents (NSAIAs)-induced gastrointestinal lesions was simultaneously studied in rats. In gastrointestinal lesions (indomethacin (30 mg/kg s.c.), aspirin (400 mg/kg i.g.) and diclofenac (125 mg/kg i.p.) studies, BPC 157 (10 micrograms or 10 ng/kg i.p.) was regularly given simultaneously and/or 1 h prior to drug application (indomethacin). In the adjuvant arthritis (tail-application of 0.2 mL of Freund's adjuvant) studies (14 days, 30 days, 1 year) BPC 157 (10 micrograms or 10 ng/kg i.p.), it was given as a single application (at 1 h either before or following the application of Freund's adjuvant) or in a once daily regimen (0-14th day, 14-30th day, 14th day-1 year). Given with the investigated NSAIAs, BPC 157 consistently reduced the otherwise prominent lesions in the stomach of the control rats, as well as the lesions in the small intestine in the indomethacin groups. In the adjuvant arthritis studies, the lesion's development seems to be considerably reduced after single pentadecapeptide medication, and even more attenuated in rats daily treated with BPC 157. As a therapy of already established adjuvant arthritis, its salutary effect consistently appeared already after 2 weeks of medication and it could be clearly seen also after 1 year of application. Taking together all these results, the data likely point to a special anti-inflammatory and mucosal integrity protective effect. PMID:9403784

  19. Effect of particle size on their accumulation in an inflammatory lesion in a dextran sulfate sodium (DSS)-induced colitis model.

    PubMed

    Watanabe, Ayaka; Tanaka, Hiroki; Sakurai, Yu; Tange, Kota; Nakai, Yuta; Ohkawara, Tatsuya; Takeda, Hiroshi; Harashima, Hideyoshi; Akita, Hidetaka

    2016-07-25

    Taking advantage of the enhanced permeation and retention (EPR) effect is a promising approach for delivering macromolecules or nanoparticles to tumors. Recent studies revealed that this strategy is also applicable for targeting other pathological lesions (i.e. inflammatory disease). In the present study, we report the optimal size of a nanoparticle for allowing the higher accumulation of a particle in an inflammatory lesion using a dextran sulfate sodium (DSS)-induced colitis model. As a nanoparticle platform, we utilized a SS-cleavable and pH-activated lipid-like material (ssPalm), that can be used to produce particles in a variety of sizes ranging from 50nm to 180nm while using the same lipid composition. In healthy mice, particle accumulation remained low regardless of size. In contrast, the accumulation in inflammatory colon tissue was enhanced depending on the progress of the inflammation. In this situation, the apparent uptake clearance accumulation of a mid-sized particle (113nm on average) was higher than that for smaller and larger (54nm and 183nm in average, respectively) ones. Therefore, controlling particle size is an important parameter for the extensive targeting of inflammatory lesion. PMID:27231121

  20. Molecular Biology, Epidemiology, and Pathogenesis of Progressive Multifocal Leukoencephalopathy, the JC Virus-Induced Demyelinating Disease of the Human Brain

    PubMed Central

    Ferenczy, Michael W.; Marshall, Leslie J.; Nelson, Christian D. S.; Atwood, Walter J.; Nath, Avindra; Khalili, Kamel

    2012-01-01

    Summary: Progressive multifocal leukoencephalopathy (PML) is a debilitating and frequently fatal central nervous system (CNS) demyelinating disease caused by JC virus (JCV), for which there is currently no effective treatment. Lytic infection of oligodendrocytes in the brain leads to their eventual destruction and progressive demyelination, resulting in multiple foci of lesions in the white matter of the brain. Before the mid-1980s, PML was a relatively rare disease, reported to occur primarily in those with underlying neoplastic conditions affecting immune function and, more rarely, in allograft recipients receiving immunosuppressive drugs. However, with the onset of the AIDS pandemic, the incidence of PML has increased dramatically. Approximately 3 to 5% of HIV-infected individuals will develop PML, which is classified as an AIDS-defining illness. In addition, the recent advent of humanized monoclonal antibody therapy for the treatment of autoimmune inflammatory diseases such as multiple sclerosis (MS) and Crohn's disease has also led to an increased risk of PML as a side effect of immunotherapy. Thus, the study of JCV and the elucidation of the underlying causes of PML are important and active areas of research that may lead to new insights into immune function and host antiviral defense, as well as to potential new therapies. PMID:22763635

  1. Classification of choroiditis based on inflammatory lesion process rather than fundus appearance: enhanced comprehension through the ICGA concepts of the iceberg and jellyfish effects.

    PubMed

    Herbort, C P; Papadia, M; Mantovani, A

    2012-04-01

    Choroidal inflammatory diseases have been classically grouped under the term of white dot syndromes (WDS), a term only based on the appearance (white-yellow dots) of inflammatory fundus lesions. This purely descriptive and vague terminology, regrouping a pot-pourri of posterior inflammatory conditions, probably came into use because the precise exploration of the choroid was not possible, and also because many of the diseases were rare and not well understood. Since the availability of indocyanine green angiography (ICGA) that allows one to explore the choroidal compartment, it became possible to understand the lesion mechanism of choroiditides and to classify this group of diseases according to their pathophysiological behaviour. It was our aim to show here that the term WDS is applied to and encompasses inflammatory conditions that are characterized by completely different lesion mechanisms and should therefore be classified separately from each other. ICGA made it possible to differentiate two types of choroiditides, including on the one hand inflammatory diseases of the choroidal stroma and on the other hand inflammatory diseases of the choriocapillaris. Unfortunately, twenty years after its advent, ICGA is still not used routinely in uveitis centres and the traditional inappropriate but overall useless term of WDS is still used, maintaining the confusion about these diseases. The aim of this work was (i) to illustrate that meaningful exploration of choroidal inflammation, mostly occult and inaccessible to usual investigations, has to be performed using ICGA, (ii) to insist on the crucial importance of ICGA in the management of choroiditis and (iii) to enhance the comprehension of the ICGA-based classification of choroiditis, by using the demonstrative and striking analogue concepts of iceberg and jellyfish effects. PMID:22495994

  2. Hepatocellular expression of a novel glycoprotein with sialylated difucosyl Lex activity in the active inflammatory lesions of chronic liver disease.

    PubMed Central

    Okada, Y.; Shimoe, T.; Muguruma, M.; Usumoto, R.; Tsuji, T.; Jinno, K.; Moriwaki, S.; Shin, S.; Hakomori, S.

    1988-01-01

    Hepatic expression of sialylated difucosyl Lex antigen (SDLex, NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-) was studied with monoclonal antibody FH6, which defines this structure. Hepatocytes in the severe form of chronic active hepatitis and liver cirrhosis strongly expressed SDLex. The antigen was only weakly and focally detected in chronic persistent hepatitis. The mild form of chronic active hepatitis showed intermediate expression. SDLex expressed along the liver cell membranes displayed a honeycomb pattern when extensively expressed in the severe form of chronic active hepatitis or in liver cirrhosis. Cytoplasmic expression was faint and focal. Preferential tissue distribution was at the periphery of the hepatic lobules where the distruction of the limiting plate was present. The antigen was also expressed in sinusoidal lining cells and polymorphonuclear cells but not in the biliary epithelia. Hepatocytes expressing SDLex did not express related carbohydrate antigens, ie, Type 2 chain N-acetyllactosamine, Lex, and sialylated Lea. On subcellular fractionation, the microsome fraction contained the majority of the antigen activity. SDS-PAGE and Western blot analysis revealed one major SDLex-active glycoprotein with an apparent molecular weight of 110 kilodaltons. This glycoprotein was different from SDLex-active glycoproteins found in the sera of cancer patients. No ganglioside showed FH6 reactivity. These results indicate that liver cells in active inflammatory lesion expressed a novel glycoprotein carrying SDLex antigen in honeycomblike membrane-associated pattern. Images Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 PMID:3341453

  3. Effects of etanercept versus sulfasalazine in early axial spondyloarthritis on active inflammatory lesions as detected by whole-body MRI (ESTHER): a 48-week randomised controlled trial

    PubMed Central

    Song, I-H; Hermann, KG; Haibel, H; Althoff, CE; Listing, J; Burmester, GR; Krause, A; Bohl-Bühler, M; Freundlich, B; Rudwaleit, M; Sieper, J

    2011-01-01

    Purpose To evaluate the potential of etanercept versus sulfasalazine to reduce active inflammatory lesions on whole-body MRI in active axial spondyloarthritis with a symptom duration of less than 5 years. Methods Patients were randomly assigned to etanercept (n=40) or sulfasalazine (n=36) treatment over 48 weeks. All patients showed active inflammatory lesions (bone marrow oedema) on MRI in either the sacroiliac joints or the spine. MRI was performed at weeks 0, 24 and 48 and was scored for active inflammatory lesions in sacroiliac joints and the spine including posterior segments and peripheral enthesitis by two radiologists, blinded for treatment arm and MRI time point. Results In the etanercept group, the reduction of the sacroiliac joint score from 7.7 at baseline to 2.0 at week 48 was significantly (p=0.02) larger compared with the sulfasalazine group from 5.4 at baseline to 3.5 at week 48. A similar difference in the reduction of inflammation was found in the spine from 2.2 to 1.0 in the etanercept group versus from 1.4 to 1.3 in the sulfasalazine group between baseline and week 48, respectively (p=0.01). The number of enthesitic sites also improved significantly from 26 to 11 in the etanercept group versus 24 to 26 in the sulfasalazine group (p=0.04 for difference). 50% of patients reached clinical remission in the etanercept group versus 19% in the sulfasalazine group at week 48. Conclusion In patients with early axial spondyloarthritis active inflammatory lesions detected by whole-body MRI improved significantly more in etanercept versus sulfasalazine-treated patients. This effect correlated with a good clinical response in the etanercept group. PMID:21372193

  4. Enzyme-labeled Antigen Method: Development and Application of the Novel Approach for Identifying Plasma Cells Locally Producing Disease-specific Antibodies in Inflammatory Lesions

    PubMed Central

    Mizutani, Yasuyoshi; Shiogama, Kazuya; Onouchi, Takanori; Sakurai, Kouhei; Inada, Ken-ichi; Tsutsumi, Yutaka

    2016-01-01

    In chronic inflammatory lesions of autoimmune and infectious diseases, plasma cells are frequently observed. Antigens recognized by antibodies produced by the plasma cells mostly remain unclear. A new technique identifying these corresponding antigens may give us a breakthrough for understanding the disease from a pathophysiological viewpoint, simply because the immunocytes are seen within the lesion. We have developed an enzyme-labeled antigen method for microscopic identification of the antigen recognized by specific antibodies locally produced in plasma cells in inflammatory lesions. Firstly, target biotinylated antigens were constructed by the wheat germ cell-free protein synthesis system or through chemical biotinylation. Next, proteins reactive to antibodies in tissue extracts were screened and antibody titers were evaluated by the AlphaScreen method. Finally, with the enzyme-labeled antigen method using the biotinylated antigens as probes, plasma cells producing specific antibodies were microscopically localized in fixed frozen sections. Our novel approach visualized tissue plasma cells that produced 1) autoantibodies in rheumatoid arthritis, 2) antibodies against major antigens of Porphyromonas gingivalis in periodontitis or radicular cyst, and 3) antibodies against a carbohydrate antigen, Strep A, of Streptococcus pyogenes in recurrent tonsillitis. Evaluation of local specific antibody responses expectedly contributes to clarifying previously unknown processes in inflammatory disorders. PMID:27006517

  5. Other noninfectious inflammatory disorders.

    PubMed

    Rovira, Álex; Auger, Cristina; Rovira, Antoni

    2016-01-01

    Idiopathic inflammatory-demyelinating diseases (IIDDs) represent a broad spectrum of central nervous system (CNS) disorders, including monophasic, multiphasic, and progressive disorders that range from highly localized forms to multifocal or diffuse variants. In addition to the classic multiple sclerosis (MS) phenotypes, several MS variants have been described, which can be differentiated on the basis of severity, clinical course, and lesion distribution. Other forms of IIDD are now recognized as distinct entities and not MS variants, such as acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorders. The CNS can also be affected by a variety of inflammatory diseases. These include primary angiitis of the CNS (PACNS), a rare disorder specifically targeting the CNS vasculature, and various systemic conditions which, among other organs and systems, can also affect the CNS, such as systemic vasculitis and sarcoidosis. The diagnosis of PACNS is difficult, as this condition may be confused with reversible cerebral vasoconstriction syndrome (RCVS), a term comprising a group of conditions characterized by prolonged but reversible vasoconstriction of the cerebral arteries. Magnetic resonance imaging of the brain and spine is the radiologic technique of choice for diagnosing these disorders, and, together with the clinical and laboratory findings, enables a prompt and accurate diagnosis. PMID:27432677

  6. Eosinophil Granule Proteins ECP and EPX as Markers for a Potential Early-Stage Inflammatory Lesion in Female Genital Schistosomiasis (FGS)

    PubMed Central

    Randrianasolo, Bodo Sahondra; Ravoniarimbinina, Pascaline; Ravaoalimalala, Vololomboahangy Elisabeth; Leutscher, Peter; Kjetland, Eyrun Floerecke; Vennervald, Birgitte Jyding

    2014-01-01

    Background Genital granulomas induced by Schistosoma haematobium eggs can manifest as different lesion types visible by colposcopy; rubbery papules (RP), homogenous sandy patches (HSP) and grainy sandy patches (GSP). Pronounced tissue eosinophilia is a candidate marker for active S. haematobium pathology, as viable schistosome egg granulomas often are eosinophil rich. Here it was investigated whether eosinophil granule proteins ECP (eosinophil cationic protein) and EPX (eosinophil protein-X) in urine and genital lavage can be used as markers for active FGS lesions. Methods Uro-genital samples from 118 Malagasy women were analysed for ECP and EPX by standard sandwich avidin/biotin amplified ELISA. Principal findings The women with RP lesions had significantly higher levels of ECP and EPX in both lavage and urine. Furthermore, women with RP lesions were significantly younger than those with GSP. This could indicate that RP lesions might be more recently established and thus represent an earlier inflammatory lesion stage. Conclusion ECP in genital lavage might be a future tool aiding the identification of FGS pathology at a stage where reversibility remains a possibility following praziquantel treatment. PMID:25033206

  7. Non-steroidal anti-inflammatory drug indometacin enhances endogenous remyelination.

    PubMed

    Preisner, Anna; Albrecht, Stefanie; Cui, Qiao-Ling; Hucke, Stephanie; Ghelman, Julia; Hartmann, Christine; Taketo, Makoto Mark; Antel, Jack; Klotz, Luisa; Kuhlmann, Tanja

    2015-08-01

    Multiple sclerosis is the most frequent demyelinating disease in the CNS that is characterized by inflammatory demyelinating lesions and axonal loss, the morphological correlate of permanent clinical disability. Remyelination does occur, but is limited especially in chronic disease stages. Despite effective immunomodulatory therapies that reduce the number of relapses the progressive disease phase cannot be prevented. Therefore, promotion of neuroprotective and repair mechanisms, such as remyelination, represents an attractive additional treatment strategy. A number of pathways have been identified that may contribute to impaired remyelination in MS lesions, among them the Wnt/β-catenin pathway. Here, we demonstrate that indometacin, a non-steroidal anti-inflammatory drug (NSAID) that has been also shown to modulate the Wnt/β-catenin pathway in colorectal cancer cells promotes differentiation of primary human and murine oligodendrocytes, myelination of cerebellar slice cultures and remyelination in cuprizone-induced demyelination. Our in vitro experiments using GSK3β inhibitors, luciferase reporter assays and oligodendrocytes expressing a mutant, dominant stable β-catenin indicate that the mechanism of action of indometacin depends on GSK3β activity and β-catenin phosphorylation. Indometacin might represent a promising treatment option to enhance endogenous remyelination in MS patients. PMID:25943886

  8. Local overexpression of interleukin-11 in the central nervous system limits demyelination and enhances remyelination.

    PubMed

    Maheshwari, Anurag; Janssens, Kris; Bogie, Jeroen; Van Den Haute, Chris; Struys, Tom; Lambrichts, Ivo; Baekelandt, Veerle; Stinissen, Piet; Hendriks, Jerome J A; Slaets, Helena; Hellings, Niels

    2013-01-01

    Demyelination is one of the pathological hallmarks of multiple sclerosis (MS). To date, no therapy is available which directly potentiates endogenous remyelination. Interleukin-11 (IL-11), a member of the gp130 family of cytokines, is upregulated in MS lesions. Systemic IL-11 treatment was shown to ameliorate clinical symptoms in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. IL-11 modulates immune cells and protects oligodendrocytes in vitro. In this study, the cuprizone-induced demyelination mouse model was used to elucidate effects of IL-11 on de- and remyelination, independent of the immune response. Prophylactic-lentiviral- (LV-) mediated overexpression of IL-11 in mouse brain significantly limited acute demyelination, which was accompanied with the preservation of CC1(+) mature oligodendrocytes (OLs) and a decrease in microglial activation (Mac-2(+)). We further demonstrated that IL-11 directly reduces myelin phagocytosis in vitro. When IL-11 expressing LV was therapeutically applied in animals with extensive demyelination, a significant enhancement of remyelination was observed as demonstrated by Luxol Fast Blue staining and electron microscopy imaging. Our results indicate that IL-11 promotes maturation of NG2(+) OPCs into myelinating CC1(+) OLs and may thus explain the enhanced remyelination. Overall, we demonstrate that IL-11 is of therapeutic interest for MS and other demyelinating diseases by limiting demyelination and promoting remyelination. PMID:23818742

  9. Local Overexpression of Interleukin-11 in the Central Nervous System Limits Demyelination and Enhances Remyelination

    PubMed Central

    Maheshwari, Anurag; Janssens, Kris; Bogie, Jeroen; Van Den Haute, Chris; Struys, Tom; Lambrichts, Ivo; Baekelandt, Veerle; Stinissen, Piet; Hendriks, Jerome J. A.; Hellings, Niels

    2013-01-01

    Demyelination is one of the pathological hallmarks of multiple sclerosis (MS). To date, no therapy is available which directly potentiates endogenous remyelination. Interleukin-11 (IL-11), a member of the gp130 family of cytokines, is upregulated in MS lesions. Systemic IL-11 treatment was shown to ameliorate clinical symptoms in experimental autoimmune encephalomyelitis (EAE), an animal model of MS. IL-11 modulates immune cells and protects oligodendrocytes in vitro. In this study, the cuprizone-induced demyelination mouse model was used to elucidate effects of IL-11 on de- and remyelination, independent of the immune response. Prophylactic-lentiviral- (LV-) mediated overexpression of IL-11 in mouse brain significantly limited acute demyelination, which was accompanied with the preservation of CC1+ mature oligodendrocytes (OLs) and a decrease in microglial activation (Mac-2+). We further demonstrated that IL-11 directly reduces myelin phagocytosis in vitro. When IL-11 expressing LV was therapeutically applied in animals with extensive demyelination, a significant enhancement of remyelination was observed as demonstrated by Luxol Fast Blue staining and electron microscopy imaging. Our results indicate that IL-11 promotes maturation of NG2+ OPCs into myelinating CC1+ OLs and may thus explain the enhanced remyelination. Overall, we demonstrate that IL-11 is of therapeutic interest for MS and other demyelinating diseases by limiting demyelination and promoting remyelination. PMID:23818742

  10. IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination

    PubMed Central

    Kang, Zizhen; Liu, Liping; Spangler, Roo; Spear, Charles; Wang, Chenhui; Gulen, Muhammet Fatih; Veenstra, Mike; Ouyang, Wenjun; Ransohoff, Richard M.; Li, Xiaoxia

    2012-01-01

    Cuprizone inhibits mitochondrial function and induces demyelination in the corpus callosum which resembles pattern III lesions in multiple sclerosis (MS) patients. However, the molecular and cellular mechanism by which cuprizone induces demyelination remains unclear. Interleukin-17 (IL-17) secreted by T helper 17 (Th17) cells and γδT cells are essential in the development of experimental autoimmune encephalomyelitis (EAE). In this study, we examined the importance of IL-17 signaling in cuprizone-induced demyelination. We found that mice deficient in IL-17A, IL-17RC and adaptor protein Act1 (of IL-17R) all had reduced demyelination accompanied by lessened microglial and polydendrocyte cellular reactivity compared to that in wild-type mice in response to cuprizone feeding, demonstrating the essential role of IL-17-induced Act1-mediated signaling in cuprizone-induced demyelination. Importantly, specific deletion of Act1 in astrocytes reduced the severity of tissue injury in this model, indicating the critical role of CNS resident cells in the pathogenesis of cuprizone-induced demyelination. In cuprizone-fed mice IL-17 was produced by CNS CD3+ T cells suggesting a source of IL-17 in CNS upon cuprizone treatment. PMID:22699909

  11. IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination.

    PubMed

    Kang, Zizhen; Liu, Liping; Spangler, Roo; Spear, Charles; Wang, Chenhui; Gulen, Muhammet Fatih; Veenstra, Mike; Ouyang, Wenjun; Ransohoff, Richard M; Li, Xiaoxia

    2012-06-13

    Cuprizone inhibits mitochondrial function and induces demyelination in the corpus callosum, which resembles pattern III lesions in multiple sclerosis patients. However, the molecular and cellular mechanism by which cuprizone induces demyelination remains unclear. Interleukin-17 (IL-17) secreted by T helper 17 cells and γδT cells are essential in the development of experimental autoimmune encephalomyelitis. In this study, we examined the importance of IL-17 signaling in cuprizone-induced demyelination. We found that mice deficient in IL-17A, IL-17 receptor C (IL-17RC), and adaptor protein Act1 (of IL-17R) all had reduced demyelination accompanied by lessened microglial and polydendrocyte cellular reactivity compared with that in wild-type mice in response to cuprizone feeding, demonstrating the essential role of IL-17-induced Act1-mediated signaling in cuprizone-induced demyelination. Importantly, specific deletion of Act1 in astrocytes reduced the severity of tissue injury in this model, indicating the critical role of CNS resident cells in the pathogenesis of cuprizone-induced demyelination. In cuprizone-fed mice, IL-17 was produced by CNS CD3(+) T cells, suggesting a source of IL-17 in CNS upon cuprizone treatment. PMID:22699909

  12. Influenza Vaccine-Induced CNS Demyelination in a 50-Year-Old Male

    PubMed Central

    Sacheli, Aaron; Bauer, Raymond

    2014-01-01

    Patient: Male, 50 Final Diagnosis: Acute post-vaccination CNS demyelinating disorder Symptoms: Blurred vision • hemiparesis • hemiplegia • hypertonia • itching • paresthesia Medication: — Clinical Procedure: MRI Specialty: Neurology Objective: Rare disease Background: There are several categories of primary inflammatory demyelinating disorders, which comprise clinically similar neurologic sequelae. Of interest, clinically isolated syndrome (CIS) and acute disseminated encephalomyelitis (ADEM) are 2 demyelinating conditions of the central nervous system (CNS), whose clinical similarity pose a significant challenge to definitive diagnosis. Yet, both remain important clinical considerations in patients with neurologic signs and symptoms in the context of recent vaccination. Case Report: We report a case of a 50-year-old Caucasian male with a course of progressive, focal, neurologic deficits within 24 h after receiving the influenza vaccine. Subsequent work-up revealed the possibility of an acute central nervous system (CNS) demyelinating episode secondary to the influenza vaccine, best described as either CIS or ADEM. Conclusions: Case reports of CNS demyelination following vaccinations have been previously noted, most often occurring in the context of recent influenza vaccination. This report serves to document a case of CNS demyelination occurring 24 h after influenza vaccination in a middle-aged patient, and will describe some salient features regarding the differential diagnosis of CIS and ADEM, as well as their potential management. PMID:25175754

  13. Are electrophysiological criteria useful in distinguishing childhood demyelinating neuropathies?

    PubMed

    Potulska-Chromik, Anna; Ryniewicz, Barbara; Aragon-Gawinska, Karolina; Kabzinska, Dagmara; Seroka, Andrzej; Lipowska, Marta; Kaminska, Anna M; Kostera-Pruszczyk, Anna

    2016-03-01

    Childhood chronic inflammatory demyelinating polyneuropathy (CIDP) needs to be differentiated from hereditary neuropathy. We aimed to validate existing CIDP nerve conduction study (NCS) criteria in a group of children with demyelinating neuropathies of chronic or subacute onset. Retrospective analysis of clinical and NCS results in 18 children with CIDP, 7 with hereditary neuropathy with pressure palsy (HNPP), and 24 with Charcot-Marie-Tooth 1a (CMT1a). AAN and EFNS electrodiagnostic CIDP criteria were fulfilled in 17 of 18 CIDP, 3 of 7 HNPP, and 23 of 24 CMT1a patients. A distal compound muscle action potential (dCMAP) of >9 ms was observed in 14 of 18 CIDP patients but not in any patients with HNPP. Abnormal median/normal sural SNAP (AMNS) and a 10 m/s difference between conduction velocities (CV) of two corresponding nerves were not observed in any CMT1a patients. NCS in CMT1a, HNPP, and CIDP reflect demyelination. dCMAP duration, sensory AMNS, and a 10 m/s CV difference parameter are most useful in the differential diagnosis of pediatric CIDP. PMID:26663344

  14. Radial Diffusivity Predicts Demyelination in ex-vivo Multiple Sclerosis Spinal Cords

    PubMed Central

    Klawiter, Eric C.; Schmidt, Robert E.; Trinkaus, Kathryn; Liang, Hsiao-Fang; Budde, Matthew D.; Naismith, Robert T.; Song, Sheng-Kwei; Cross, Anne H.; Benzinger, Tammie L.

    2011-01-01

    Objective Correlation of diffusion tensor imaging (DTI) with histochemical staining for demyelination and axonal damage in multiple sclerosis (MS) ex vivo human cervical spinal cords. Background In MS, demyelination, axonal degeneration, and inflammation contribute to disease pathogenesis to variable degrees. Based upon in vivo animal studies with acute injury and histopathologic correlation, we hypothesized that DTI can differentiate between axonal and myelin pathologies within humans. Methods DTI was performed at 4.7 Tesla on 9 MS and 5 normal control fixed cervical spinal cord blocks following autopsy. Sections were then stained for Luxol fast blue (LFB), Bielschowsky silver, and hematoxylin and eosin (H&E). Regions of interest (ROIs) were graded semi-quantitatively as normal myelination, mild (<50%) demyelination, or moderate-severe (>50%) demyelination. Corresponding axonal counts were manually determined on Bielschowsky silver. ROIs were mapped to co-registered DTI parameter slices. DTI parameters evaluated included standard quantitative assessments of apparent diffusion coefficient (ADC), relative anisotropy (RA), axial diffusivity and radial diffusivity. Statistical correlations were made between histochemical gradings and DTI parameters using linear mixed models. Results: Within ROIs in MS subjects, increased radial diffusivity distinguished worsening severities of demyelination. Relative anisotropy was decreased in the setting of moderate-severe demyelination compared to normal areas and areas of mild demyelination. Radial diffusivity, ADC, and RA became increasingly altered within quartiles of worsening axonal counts. Axial diffusivity did not correlate with axonal density (p=0.091). Conclusions Increased radial diffusivity can serve as a surrogate for demyelination. However, radial diffusivity was also altered with axon injury, suggesting that this measure is not pathologically specific within chronic human MS tissue. We propose that radial diffusivity

  15. Tumefactive demyelinating disease with isolated spinal cord involvement

    PubMed Central

    Kirsch, Claudia F

    2014-01-01

    Tumefactive multiple sclerosis (TMS) is an unusual variant of demyelinating disease. TMS has a variable and unknown progression and presents with features similar to a neoplasm making the determination a diagnostic challenge to clinicians. This report presents one of the very few reported cases of isolated spinal cord TMS, and the second case to describe TMS of the lower spinal cord, given that the lesions are typically cervical. This case study presents a diagnostic approach based on clinical, laboratory, and imaging characteristics, as well as sheds some light on the response to therapy and disease evolution. PMID:25298871

  16. Fingolimod Attenuates Splenocyte-Induced Demyelination in Cerebellar Slice Cultures

    PubMed Central

    Pritchard, Adam J.; Mir, Anis K.; Dev, Kumlesh K.

    2014-01-01

    The family of sphingosine-1-phosphate receptors (S1PRs) is G-protein-coupled, comprised of subtypes S1PR1-S1PR5 and activated by the endogenous ligand S1P. The phosphorylated version of Fingolimod (pFTY720), an oral therapy for multiple sclerosis (MS), induces S1PR1 internalisation in T cells, subsequent insensitivity to S1P gradients and sequestering of these cells within lymphoid organs, thus limiting immune response. S1PRs are also expressed in neuronal and glial cells where pFTY720 is suggested to directly protect against lysolecithin-induced deficits in myelination state in organotypic cerebellar slices. Of note, the effect of pFTY720 on immune cells already migrated into the CNS, prior to treatment, has not been well established. We have previously found that organotypic slice cultures do contain immune cells, which, in principle, could also be regulated by pFTY720 to maintain levels of myelin. Here, a mouse organotypic cerebellar slice and splenocyte co-culture model was thus used to investigate the effects of pFTY720 on splenocyte-induced demyelination. Spleen cells isolated from myelin oligodendrocyte glycoprotein immunised mice (MOG-splenocytes) or from 2D2 transgenic mice (2D2-splenocytes) both induced demyelination when co-cultured with mouse organotypic cerebellar slices, to a similar extent as lysolecithin. As expected, in vivo treatment of MOG-immunised mice with FTY720 inhibited demyelination induced by MOG-splenocytes. Importantly, in vitro treatment of MOG- and 2D2-splenocytes with pFTY720 also attenuated demyelination caused by these cells. In addition, while in vitro treatment of 2D2-splenocytes with pFTY720 did not alter cell phenotype, pFTY720 inhibited the release of the pro-inflammatory cytokines such as interferon gamma (IFNγ) and interleukin 6 (IL6) from these cells. This work suggests that treatment of splenocytes by pFTY720 attenuates demyelination and reduces pro-inflammatory cytokine release, which likely contributes to enhanced

  17. MMP1-1607 polymorphism increases the risk for periapical lesion development through the upregulation MMP-1 expression in association with pro-inflammatory milieu elements

    PubMed Central

    TROMBONE, Ana Paula Favaro; CAVALLA, Franco; SILVEIRA, Elcia Maria Varize; ANDREO, Camile Bermejo; FRANCISCONI, Carolina Favaro; FONSECA, Angélica Cristina; LETRA, Ariadne; SILVA, Renato Menezes; GARLET, Gustavo Pompermaier

    2016-01-01

    ABSTRACT Increased matrix metalloproteinases (MMPs) activity is a hallmark of periapical granulomas. However, the factors underlying the MMPs expression modulation in healthy and diseased periapical tissues remains to be determined. Objective In this study, we evaluated the association between the MMP1-1607 polymorphism (rs1799750) and pro-inflammatory milieu elements with MMP-1 mRNA levels in vivo. Material and Methods MMP1-1607 SNP and the mRNA levels of MMP-1, TNF-a, IFN-g, IL-17A, IL-21, IL-10, IL-4, IL-9, and FOXp3 were determined via RealTimePCR in DNA/RNA samples from patients presenting periapical granulomas (N=111, for both genotyping and expression analysis) and control subjects (N=214 for genotyping and N=26 for expression analysis). The Shapiro-Wilk, Fisher, Pearson, Chi-square ordinal least squares regression tests were used for data analysis (p<0.05 was considered statistically significant). Results The MMP1-1607 1G/2G and 1G/2G+2G/2G genotypes were significantly more prevalent in the patients than in controls, comprising a risk factor for periapical lesions development. MMP-1 mRNA levels were higher in periapical lesions than in healthy periodontal ligament samples, as well as higher in active than in inactive lesions. The polymorphic allele 2G carriers presented a significantly higher MMP-1 mRNA expression when compared with the 1G/1G genotype group. The ordered logistic regression demonstrated a significant correlation between the genetic polymorphism and the expression levels of MMP-1. Additionally, the pro- and anti-inflammatory cytokines IL-17A, IFN-g, TNF-a, IL-21, IL-10, IL-9, and IL-4 were significant as complementary explanatory variables of MMP-1 expression. Conclusion The MMP1-1607 SNP was identified as a risk factor for periapical lesions development, possibly due to its association with increased MMP-1 mRNA levels in periapical lesions. The MMP-1 expression is also under the control of the inflammatory milieu elements, being the

  18. Oligodendrocyte Lineage Cells in Chronic Demyelination of Multiple Sclerosis Optic Nerve.

    PubMed

    Jennings, Alison Ruth; Carroll, William M

    2015-09-01

    Reports that chronically demyelinated multiple sclerosis brain and spinal cord lesions contained immature oligodendrocyte lineage cells have generated major interest aimed at the potential for promotion of endogenous repair. Despite the prominence of the optic nerve as a lesion site and its importance in clinical disease assessment, no detailed studies of multiple sclerosis-affected optic nerve exist. This study aims to provide insight into the cellular pathology of chronic demyelination in multiple sclerosis through direct morphological and immunohistochemical analysis of optic nerve in conjunction with observations from an experimental cat optic nerve model of successful remyelination. Myelin staining was followed by immunohistochemistry to differentially label neuroglia. Digitally immortalized sections were then analyzed to generate quantification data and antigenic phenotypes including maturational stages within the oligodendrocyte lineage. It was found that some chronically demyelinated multiple sclerosis optic nerve lesions contained oligodendroglial cells and that heterogeneity existed in the presence of myelin sheaths, oligodendrocyte maturational stages and extent of axonal investment. The findings advance our understanding of oligodendrocyte activity in chronically demyelinated human optic nerve and may have implications for studies aimed at enhancement of endogenous repair in multiple sclerosis. PMID:25175564

  19. Promotion of Remyelination by Sulfasalazine in a Transgenic Zebrafish Model of Demyelination

    PubMed Central

    Kim, Suhyun; Lee, Yun-Il; Chang, Ki-Young; Lee, Dong-Won; Cho, Sung Chun; Ha, Young Wan; Na, Ji Eun; Rhyu, Im Joo; Park, Sang Chul; Park, Hae-Chul

    2015-01-01

    Most of the axons in the vertebrate nervous system are surrounded by a lipid-rich membrane called myelin, which promotes rapid conduction of nerve impulses and protects the axon from being damaged. Multiple sclerosis (MS) is a chronic demyelinating disease of the CNS characterized by infiltration of immune cells and progressive damage to myelin and axons. One potential way to treat MS is to enhance the endogenous remyelination process, but at present there are no available treatments to promote remyelination in patients with demyelinating diseases. Sulfasalazine is an anti-inflammatory and immune-modulating drug that is used in rheumatology and inflammatory bowel disease. Its anti-inflammatory and immunomodulatory properties prompted us to test the ability of sulfasalazine to promote remyelination. In this study, we found that sulfasalazine promotes remyelination in the CNS of a transgenic zebrafish model of NTR/MTZ-induced demyelination. We also found that sulfasalazine treatment reduced the number of macrophages/microglia in the CNS of demyelinated zebrafish larvae, suggesting that the acceleration of remyelination is mediated by the immunomodulatory function of sulfasalazine. Our data suggest that temporal modulation of the immune response by sulfasalazine can be used to overcome MS by enhancing myelin repair and remyelination in the CNS. PMID:26549504

  20. Chronic demyelinating peripheral neuropathy in cerebrotendinous xanthomatosis.

    PubMed

    Argov, Z; Soffer, D; Eisenberg, S; Zimmerman, Y

    1986-07-01

    Three siblings with chemically proved cerebrotendinous xanthomatosis presented with typical neurological manifestations of dementia and spinocerebellar disorder. Electrodiagnostic tests revealed demyelinating neuropathy in all three. Sural nerve biopsies showed loss of myelinated large fibers, marked Schwann cell proliferation, and onion bulb formation. Teased-fiber preparations confirmed the occurrence of segmental demyelination and remyelination. We suggest that demyelinating neuropathy is part of the neurological spectrum of cerebrotendinous xanthomatosis and should be considered in the differential diagnosis of a recessively inherited motor and sensory neuropathy. PMID:3017187

  1. Progressive Injury in Chronic Multiple Sclerosis Lesions Is Gender-Specific: A DTI Study

    PubMed Central

    Klistorner, Alexander; Wang, Chenyu; Yiannikas, Con; Graham, Stuart L.; Parratt, John; Barnett, Michael H.

    2016-01-01

    Objective To evaluate the longitudinal integrity of white matter tracts in patients with relapsing remitting multiple sclerosis (RRMS) as determined by changes in diffusivity indices of lesional and non-lesional white matter in the optic radiation over 12 months. Methods The optic radiation (OR) was identified in sixty RRMS patients using probabilistic tractography. MS lesions were segmented on FLAIR T2 images and a lesion mask was intersected with the co-registered OR. Lesions within the OR were identified in 39 patients. Voxel-based analysis of axial diffusivity (AD) and radial diffusivity (RD) within OR lesions and non-lesional normal appearing white matter (NAWM) was performed at baseline and 12 months in 34 patients (five patients excluded due to new OR lesions). Results Both RD and AD demonstrated much higher values within the lesions compared with non-lesional NAWM. There was a significant (p<0.001) increase of lesional AD and RD during the follow-up period. This increase, however, was driven almost entirely by the male cohort, in which a significantly greater change in both AD (M-2.7%, F-0.9%) and RD (M-4.6%, F-0.7%) was observed during the follow-up period. Non-lesional NAWM also demonstrated an increase in both AD and RD, albeit on a much lesser scale (1.0% and 0.6% respectively). In contradistinction to lesions, the diffusivity change in non-lesional NAWM was similar between sexes. Conclusions The evolution of AD and RD in chronic MS lesions over 12 months suggests ongoing inflammatory demyelinating activity accompanied by axonal loss. In addition, our findings are consistent with the recently observed trend of more rapid clinical progression in males and establish a potential in vivo biomarker of gender dichotomy by demonstrating a significantly faster rate of microstructural change in the chronic lesions of male patients with MS. PMID:26901540

  2. Early burn wound excision and skin grafting postburn trauma restores in vivo neutrophil delivery to inflammatory lesions

    SciTech Connect

    Tchervenkov, J.I.; Epstein, M.D.; Silberstein, E.B.; Alexander, J.W.

    1988-12-01

    This study assessed the effect of early vs delayed postburn wound excision and skin grafting on the in vivo neutrophil delivery to a delayed-type hypersensitivity (DTH) reaction and a bacterial skin lesion (BSL). Male Lewis rats were presensitized to keyhole-limpet hemocyanin. Group 1 comprised sham controls. Groups 2 through 4 were given a 30% 3 degrees scald burn, but the burn wounds were excised, and skin was grafted on days 1, 3, and 7, respectively, after the burn. Group 5 comprised burn controls. Twelve days after burn trauma, all rats were injected at different intervals (during a 24-hour period) with a trio of intradermal injections of keyhole-limpet hemocyanin, Staphylococcus aureus 502A, and saline at different sites. In vivo neutrophil delivery to these dermal lesions was determined by injecting indium in 111 oxyquinoline-labeled neutrophils isolated from similarly treated groups of rats. Neutrophil delivery to DTH and BSL lesions was restored to normal by excision and skin grafting of the burn wound one day after burn trauma. Waiting three days after burn trauma to excise and skin graft the wound partially, but not completely, restored the in vivo neutrophil delivery to DTH and BSL lesions. Waiting one week to excise and skin graft a burn wound resulted in no improvement in neutrophil delivery to DTH and BSL dermal lesions. It was concluded that burn wound excision and skin grafting immediately after burn trauma restored in vivo neutrophil delivery to a BSL and DTH dermal lesion. This may, in part, explain the beneficial effect of early aggressive burn wound debridement in patients with burn injuries.

  3. Antibodies to gliomedin cause peripheral demyelinating neuropathy and the dismantling of the nodes of Ranvier.

    PubMed

    Devaux, Jérôme J

    2012-10-01

    Guillain-Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are conditions that affect peripheral nerves. The mechanisms that underlie demyelination in these neuropathies are unknown. Recently, we demonstrated that the node of Ranvier is the primary site of the immune attack in patients with GBS and CIDP. In particular, GBS patients have antibodies against gliomedin and neurofascin, two adhesion molecules that play a crucial role in the formation of nodes of Ranvier. We demonstrate that immunity toward gliomedin, but not neurofascin, induced a progressive neuropathy in Lewis rats characterized by conduction defects and demyelination in spinal nerves. The clinical symptoms closely followed the titers of anti-gliomedin IgG and were associated with an important deposition of IgG at nodes. Furthermore, passive transfer of antigliomedin IgG induced a severe demyelinating condition and conduction loss. In both active and passive models, the immune attack at nodes occasioned the loss of the nodal clusters for gliomedin, neurofascin-186, and voltage-gated sodium channels. These results indicate that primary immune reaction against gliomedin, a peripheral nervous system adhesion molecule, can be responsible for the initiation or progression of the demyelinating form of GBS. Furthermore, these autoantibodies affect saltatory propagation by dismantling nodal organization and sodium channel clusters. Antibodies reactive against nodal adhesion molecules thus likely participate in the pathologic process of GBS and CIDP. PMID:22885108

  4. Primary intraosseous atypical inflammatory meningioma presenting as a lytic skull lesion: Case report with review of literature.

    PubMed

    Bohara, Sangita; Agarwal, Swapnil; Khurana, Nita; Pandey, P N

    2016-01-01

    Primary extradural meningiomas of the skull comprise 1% of all meningiomas, and lytic skull meningiomas are still rarer and are said to be more aggressive. We present a case of 38-year-old male with an extradural tumor which on histopathological examination showed features of inflammatory atypical meningioma (WHO Grade II). The intense inflammatory nature of osteolytic primary intraosseous meningioma has not been reported before. This entity deserves special mention because of the need for adjuvant therapy and proper follow-up. PMID:27510685

  5. Example based lesion segmentation

    NASA Astrophysics Data System (ADS)

    Roy, Snehashis; He, Qing; Carass, Aaron; Jog, Amod; Cuzzocreo, Jennifer L.; Reich, Daniel S.; Prince, Jerry; Pham, Dzung

    2014-03-01

    Automatic and accurate detection of white matter lesions is a significant step toward understanding the progression of many diseases, like Alzheimer's disease or multiple sclerosis. Multi-modal MR images are often used to segment T2 white matter lesions that can represent regions of demyelination or ischemia. Some automated lesion segmentation methods describe the lesion intensities using generative models, and then classify the lesions with some combination of heuristics and cost minimization. In contrast, we propose a patch-based method, in which lesions are found using examples from an atlas containing multi-modal MR images and corresponding manual delineations of lesions. Patches from subject MR images are matched to patches from the atlas and lesion memberships are found based on patch similarity weights. We experiment on 43 subjects with MS, whose scans show various levels of lesion-load. We demonstrate significant improvement in Dice coefficient and total lesion volume compared to a state of the art model-based lesion segmentation method, indicating more accurate delineation of lesions.

  6. Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9.

    PubMed

    Lindner, Maren; Thümmler, Katja; Arthur, Ariel; Brunner, Sarah; Elliott, Christina; McElroy, Daniel; Mohan, Hema; Williams, Anna; Edgar, Julia M; Schuh, Cornelia; Stadelmann, Christine; Barnett, Susan C; Lassmann, Hans; Mücklisch, Steve; Mudaliar, Manikhandan; Schaeren-Wiemers, Nicole; Meinl, Edgar; Linington, Christopher

    2015-07-01

    Remyelination failure plays an important role in the pathophysiology of multiple sclerosis, but the underlying cellular and molecular mechanisms remain poorly understood. We now report actively demyelinating lesions in patients with multiple sclerosis are associated with increased glial expression of fibroblast growth factor 9 (FGF9), which we demonstrate inhibits myelination and remyelination in vitro. This inhibitory activity is associated with the appearance of multi-branched 'pre-myelinating' MBP+ / PLP+ oligodendrocytes that interact with axons but fail to assemble myelin sheaths; an oligodendrocyte phenotype described previously in chronically demyelinated multiple sclerosis lesions. This inhibitory activity is not due to a direct effect of FGF9 on cells of the oligodendrocyte lineage but is mediated by factors secreted by astrocytes. Transcriptional profiling and functional validation studies demonstrate that these include effects dependent on increased expression of tissue inhibitor of metalloproteinase-sensitive proteases, enzymes more commonly associated with extracellular matrix remodelling. Further, we found that FGF9 induces expression of Ccl2 and Ccl7, two pro-inflammatory chemokines that contribute to recruitment of microglia and macrophages into multiple sclerosis lesions. These data indicate glial expression of FGF9 can initiate a complex astrocyte-dependent response that contributes to two distinct pathogenic pathways involved in the development of multiple sclerosis lesions. Namely, induction of a pro-inflammatory environment and failure of remyelination; a combination of effects predicted to exacerbate axonal injury and loss in patients. PMID:25907862

  7. Protective Effect of a cAMP Analogue on Behavioral Deficits and Neuropathological Changes in Cuprizone Model of Demyelination.

    PubMed

    Vakilzadeh, Gelareh; Khodagholi, Fariba; Ghadiri, Tahereh; Darvishi, Marzieh; Ghaemi, Amir; Noorbakhsh, Farshid; Gorji, Ali; Sharifzadeh, Mohammad

    2015-08-01

    Multiple sclerosis (MS) is an inflammatory demyelinating disease that leads to neuronal cell loss. Cyclic AMP and its analogs are well known to decrease inflammation and apoptosis. In the present study, we examined the effects of bucladesine, a cell-permeable analogue of cyclic adenosine monophosphate (cAMP), on myelin proteins (PLP, PMP-22), inflammation, and apoptotic, as well as anti-apoptotic factors in cuprizone model of demyelination. C57BL/6J mice were fed with chow containing 0.2% copper chelator cuprizone or vehicle by daily oral gavage for 5 weeks to induce reversible demyelination predominantly of the corpus callosum. Bucladesine was administered intraperitoneally at different doses (0.24, 0.48, or 0.7 μg/kg body weight) during the last 7 days of 5-week cuprizone treatment. Bucladesine exhibited a protective effect on myelination. Furthermore, bucladesine significantly decreased the production of interleukin-6 pro-inflammatory mediator as well as nuclear factor-κB activation and reduced the mean number of apoptotic cells compared to cuprizone-treated mice. Bucladesine also decreased production of caspase-3 as well as Bax and increased Bcl-2 levels. Our data revealed that enhancement of intracellular cAMP prevents demyelination and plays anti-inflammatory and anti-apoptotic properties in mice cuprizone model of demyelination. This suggests the modulation of intracellular cAMP as a potential target for treatment of MS. PMID:25128030

  8. Supramaximal Stimulus Intensity as a Diagnostic Tool in Chronic Demyelinating Neuropathy.

    PubMed

    Parker, Vivien; Warman Chardon, Jodi; Mills, Julie; Goldsmith, Claire; Bourque, Pierre R

    2016-01-01

    Objective. The ability to correctly identify chronic demyelinating neuropathy can have important therapeutic and prognostic significance. The stimulus intensity value required to obtain a supramaximal compound muscle action potential amplitude is a commonly acquired data point that has not been formally assessed as a diagnostic tool in routine nerve conduction studies to identify chronic neuropathies. We postulated that this value was significantly elevated in chronic demyelinating neuropathy. Methods. We retrospectively reviewed electrophysiology laboratory records to compare the stimulus intensity values recorded during median and ulnar motor nerve conduction studies. The groups studied included normal controls (n = 42) and the following diagnostic categories: chronic inflammatory demyelinating neuropathy (CIDP) (n = 20), acquired inflammatory demyelinating neuropathy (AIDP) (n = 13), Charcot Marie Tooth (CMT) type 1 or 4C (n = 15), carpal tunnel syndrome (CTS) (n = 11), and amyotrophic lateral sclerosis (ALS) (n = 18). Results. Supramaximal intensities were significantly higher in patients with CMT (median nerve: 43.4 mA) and CIDP (median nerve: 38.9 mA), whereas values similar to normal controls (median nerve: 25.3 mA) were obtained in ALS, CTS, and AIDP. Conclusions. Supramaximal stimulus intensity may be used as an additional criterion to identify the pathophysiology of neuropathy. We postulate that endoneurial hypertrophic changes may increase electrical impedance and thus the threshold of excitation at nodes of Ranvier. PMID:27413732

  9. Supramaximal Stimulus Intensity as a Diagnostic Tool in Chronic Demyelinating Neuropathy

    PubMed Central

    Parker, Vivien; Warman Chardon, Jodi; Mills, Julie; Goldsmith, Claire; Bourque, Pierre R.

    2016-01-01

    Objective. The ability to correctly identify chronic demyelinating neuropathy can have important therapeutic and prognostic significance. The stimulus intensity value required to obtain a supramaximal compound muscle action potential amplitude is a commonly acquired data point that has not been formally assessed as a diagnostic tool in routine nerve conduction studies to identify chronic neuropathies. We postulated that this value was significantly elevated in chronic demyelinating neuropathy. Methods. We retrospectively reviewed electrophysiology laboratory records to compare the stimulus intensity values recorded during median and ulnar motor nerve conduction studies. The groups studied included normal controls (n = 42) and the following diagnostic categories: chronic inflammatory demyelinating neuropathy (CIDP) (n = 20), acquired inflammatory demyelinating neuropathy (AIDP) (n = 13), Charcot Marie Tooth (CMT) type 1 or 4C (n = 15), carpal tunnel syndrome (CTS) (n = 11), and amyotrophic lateral sclerosis (ALS) (n = 18). Results. Supramaximal intensities were significantly higher in patients with CMT (median nerve: 43.4 mA) and CIDP (median nerve: 38.9 mA), whereas values similar to normal controls (median nerve: 25.3 mA) were obtained in ALS, CTS, and AIDP. Conclusions. Supramaximal stimulus intensity may be used as an additional criterion to identify the pathophysiology of neuropathy. We postulate that endoneurial hypertrophic changes may increase electrical impedance and thus the threshold of excitation at nodes of Ranvier. PMID:27413732

  10. Autoimmune antigenic targets at the node of Ranvier in demyelinating disorders.

    PubMed

    Stathopoulos, Panos; Alexopoulos, Harry; Dalakas, Marinos C

    2015-03-01

    Mounting evidence suggests that autoantibodies contribute to the pathogenesis of demyelination in the PNS and CNS. Rapid reversal of electrophysiological blockade after plasmapheresis or intravenous immunoglobulin treatment for acute or chronic inflammatory demyelinating polyneuropathy is more likely to result from removal or neutralization of an antibody that impairs saltatory conduction than from remyelination. Although up to 30% of patients with acute or chronic inflammatory demyelinating polyneuropathy harbour autoantibodies, specific antigens have been identified in no more than 13% of cases. To date, autoantigens identified at the node of Ranvier include neurofascin 186, gliomedin and possibly moesin in the nodal domain, and contactin-1, Caspr1 and neurofascin 155 in the paranodal domain. In some patients with multiple sclerosis, paranodal CNPase and juxtaparanodal contactin-2 trigger a humoral response. This Review explores the molecular anatomy of the node of Ranvier, focusing on proteins with extracellular domains that could serve as antigens. The clinical implications of node-specific antibody responses are addressed, and the best approaches to identify antibodies that target nodal proteins are highlighted. Also discussed are the roles of these antibodies as either secondary, disease-exacerbating responses, or as a primary effector mechanism that defines demyelination or axonal degeneration at the node, identifies disease subtypes or determines response to treatments. PMID:25623793

  11. Promoting remyelination: utilizing a viral model of demyelination to assess cell-based therapies

    PubMed Central

    Marro, Brett S; Blanc, Caroline A; Loring, Jeanne F; Cahalan, Michael D; Lane, Thomas E

    2014-01-01

    Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS. While a broad range of therapeutics effectively reduce the incidence of focal white matter inflammation and plaque formation for patients with relapse-remitting forms of MS, a challenge within the field is to develop therapies that allow for axonal protection and remyelination. In the last decade, growing interest has focused on utilizing neural precursor cells (NPCs) to promote remyelination. To understand how NPCs function in chronic demyelinating environments, several excellent pre-clinical mouse models have been developed. One well accepted model is infection of susceptible mice with neurotropic variants of mouse hepatitis virus (MHV) that undergo chronic demyelination exhibiting clinical and histopathologic similarities to MS patients. Combined with the possibility that an environmental agent such as a virus could trigger MS, the MHV model of demyelination presents a relevant mouse model to assess the therapeutic potential of NPCs transplanted into an environment in which inflammatory-mediated demyelination is established. PMID:25245576

  12. Multiple Colon Ulcers with Typical Small Intestinal Lesions Induced by Non-Steroidal Anti-Inflammatory Drugs.

    PubMed

    Akashi, Momoko; Ando, Takayuki; Hamashima, Takeru; Yoshita, Hiroki; Nanjo, Sohachi; Mihara, Hiroshi; Fujinami, Haruka; Kajiura, Shinya; Nishikawa, Jun; Miura, Yoshiaki; Hosokawa, Ayumu; Sugiyama, Toshiro

    2015-01-01

    The diagnosis of NSAID-induced colon ulcers is difficult when the distribution or endoscopic findings are not typical. An 83-year-old woman was transferred to our hospital for hemorrhagic diarrhea. Colonoscopy showed multiple ulcers in the entire colon, particularly longitudinal ulcers in the transverse colon. These were unusual for NSAID-induced colopathy, although she had been on meloxicam. However, capsule endoscopy revealed multiple scars and erosions, characteristic of NSAIDs users. The final diagnosis was NSAID-induced enteropathy, and all lesions were in remission after meloxicam discontinuation. We herein emphasize the value of an endoscopic assessment of the entire digestive tract in the diagnosis of NSAID-induced mucosal lesions. PMID:26278290

  13. Gliopathy of Demyelinating and Non-Demyelinating Strains of Mouse Hepatitis Virus

    PubMed Central

    Kenyon, Lawrence C.; Biswas, Kaushiki; Shindler, Kenneth S.; Nabar, Manasi; Stout, Marjorie; Hingley, Susan T.; Grinspan, Judith B.; Das Sarma, Jayasri

    2015-01-01

    Demyelination in the central nervous system induced by neurovirulent strains of Mouse Hepatitis Virus (MHV) is mediated by the viral spike glycoprotein, but it is not clear whether the mechanism of this disease pathology involves direct viral infection of oligodendrocytes. Detailed studies of glial cell tropism of MHV are presented, demonstrating that direct MHV infection of oligodendrocytes differs between demyelinating (RSA59) and non-demyelinating (RSMHV2) viral strains both in vitro and in vivo. Our results indicate that direct injury of mature oligodendrocytes is an important mechanism of virus-induced demyelination. In vivo, RSA59 infection was identified in spinal cord gray and white matter, but infected oligodendrocytes were restricted to white matter. In contrast, RSMHV2 infection was restricted to gray matter neurons and was not localized to oligodendrocytes. In vitro, RSA59 can infect both oligodendrocyte precursors and differentiated oligodendrocytes, whereas RSMHV2 can infect oligodendrocyte precursors but not differentiated oligodendrocytes. Viral spreading through axonal means to white matter and release of the demyelinating strain MHV at the nerve end is critical for oligodendrocytes infection and subsequent demyelination. Understanding the mechanisms by which known viruses effect demyelination in this animal model has important therapeutic implications in the treatment of human demyelinating disease. PMID:26733813

  14. High-Fat Diet Promotion of Endometriosis in an Immunocompetent Mouse Model is Associated With Altered Peripheral and Ectopic Lesion Redox and Inflammatory Status.

    PubMed

    Heard, Melissa E; Melnyk, Stepan B; Simmen, Frank A; Yang, Yanqing; Pabona, John Mark P; Simmen, Rosalia C M

    2016-07-01

    Endometriosis is a benign gynecological condition that causes considerable morbidity due to associated infertility, debilitating pelvic pain and inflammatory dysfunctions. Diet is a highly modifiable risk factor for many chronic diseases, but its contribution to endometriosis has not been extensively investigated, due partly to the paradoxical inverse association between obesity and disease incidence. Nevertheless, chronic exposure to dietary high-fat intake has been linked to greater systemic inflammation and oxidative stress, both features of women with endometriosis. Here, we evaluated the effects of a high-fat diet (HFD) (45% fat kcal) on endometriosis progression using an immunocompetent mouse model where ectopic lesion incidence was induced in wild-type recipients by ip administration of endometrial fragments from transcription factor Krüppel-like factor 9-null donor mice. We show that HFD significantly increased ectopic lesion numbers in recipient mice with no significant weight gain and modifications in systemic ovarian steroid hormone and insulin levels, relative to control diet-fed (17% fat kcal) mice. HFD promotion of lesion establishment was associated with reductions in stromal estrogen receptor 1 isoform and progesterone receptor expression, increased F4/80-positive macrophage infiltration, higher stromal but not glandular epithelial proliferation, and enhanced expression of proinflammatory and prooxidative stress pathway genes. Lesion-bearing HFD-fed mice also displayed higher peritoneal fluid TNFα and elevated local and systemic redox status than control diet-fed counterparts. Our results suggest that HFD intake exacerbates endometriosis outcome in the absence of ovarian dysfunction and insulin resistance in mice and warrants further consideration with respect to clinical management of endometriosis progression and recurrence in nonobese patients. PMID:27175969

  15. Remote acute demyelination after focal proton radiation therapy for optic nerve meningioma.

    PubMed

    Redjal, Navid; Agarwalla, Pankaj K; Dietrich, Jorg; Dinevski, Nikolaj; Stemmer-Rachamimov, Anat; Nahed, Brian V; Loeffler, Jay S

    2015-08-01

    We present a unique patient with delayed onset, acute demyelination that occurred distant to the effective field of radiation after proton beam radiotherapy for an optic nerve sheath meningioma. The use of stereotactic radiotherapy as an effective treatment modality for some brain tumors is increasing, given technological advances which allow for improved targeting precision. Proton beam radiotherapy improves the precision further by reducing unnecessary radiation to surrounding tissues. A 42-year-old woman was diagnosed with an optic nerve sheath meningioma after initially presenting with vision loss. After biopsy of the lesion to establish diagnosis, the patient underwent stereotactic proton beam radiotherapy to a small area localized to the tumor. Subsequently, the patient developed a large enhancing mass-like lesion with edema in a region outside of the effective radiation field in the ipsilateral frontal lobe. Given imaging features suggestive of possible primary malignant brain tumor, biopsy of this new lesion was performed and revealed an acute demyelinating process. This patient illustrates the importance of considering delayed onset acute demyelination in the differential diagnosis of enhancing lesions in patients previously treated with radiation. PMID:25937571

  16. One calcitriol dose transiently increases Helios+ FoxP3+ T cells and ameliorates autoimmune demyelinating disease.

    PubMed

    Nashold, Faye E; Nelson, Corwin D; Brown, Lauren M; Hayes, Colleen E

    2013-10-15

    Multiple sclerosis (MS) is an incurable inflammatory demyelinating disease. We investigated one calcitriol dose plus vitamin D3 (calcitriol/+D) as a demyelinating disease treatment in experimental autoimmune encephalomyelitis (EAE). Evidence that calcitriol-vitamin D receptor pathway deficits may promote MS, and data showing calcitriol enhancement of autoimmune T cell apoptosis provided the rationale. Whereas vitamin D3 alone was ineffective, calcitriol/+D transiently increased central nervous system (CNS) Helios(+)FoxP3(+) T cells and sustainably decreased CNS T cells, pathology, and neurological deficits in mice with EAE. Calcitriol/+D, which was more effective than methylprednisolone, has potential for reversing inflammatory demyelinating disease safely and cost-effectively. PMID:23968560

  17. Preventive Effects of Tocotrienol on Stress-Induced Gastric Mucosal Lesions and Its Relation to Oxidative and Inflammatory Biomarkers

    PubMed Central

    Nur Azlina, Mohd Fahami; Ibrahim, Ibrahim Abdel Aziz

    2015-01-01

    This study aimed to investigate the possible gastroprotective effect of tocotrienol against water-immersion restraint stress (WIRS) induced gastric ulcers in rats by measuring its effect on gastric mucosal nitric oxide (NO), oxidative stress, and inflammatory biomarkers. Twenty-eight male Wistar rats were randomly assigned to four groups of seven rats. The two control groups were administered vitamin-free palm oil (vehicle) and the two treatment groups were given omeprazole (20 mg/kg) or tocotrienol (60 mg/kg) orally. After 28 days, rats from one control group and both treated groups were subjected to WIRS for 3.5 hours once. Malondialdehyde (MDA), NO content, and superoxide dismutase (SOD) activity were assayed in gastric tissue homogenates. Gastric tissue SOD, iNOS, TNF-α and IL1-β expression were measured. WIRS increased the gastric MDA, NO, and pro-inflammatory cytokines levels significantly when compared to the non-stressed control group. Administration of tocotrienol and omeprazole displayed significant protection against gastric ulcers induced by exposure to WIRS by correction of both ulcer score and MDA content. Tissue content of TNF-α and SOD activity were markedly reduced by the treatment with tocotrienol but not omeprazole. Tocotrienol significantly corrected nitrite to near normal levels and attenuated iNOS gene expression, which was upregulated in this ulcer model. In conclusion, oral supplementation with tocotrienol provides a gastroprotective effect in WIRS-induced ulcers. Gastroprotection is mediated through 1) free radical scavenging activity, 2) the increase in gastric mucosal antioxidant enzyme activity, 3) normalisation of gastric mucosal NO through reduction of iNOS expression, and 4) attenuation of inflammatory cytokines. In comparison to omeprazole, it exerts similar effectiveness but has a more diverse mechanism of protection, particularly through its effect on NO, SOD activity, and TNF-α. PMID:26465592

  18. Intravenous Administration of Human ES-derived Neural Precursor Cells Attenuates Cuprizone-induced CNS Demyelination

    PubMed Central

    Crocker, Stephen J.; Bajpai, Ruchi; Moore, Craig S.; Frausto, Ricardo F.; Brown, Graham D.; Pagarigan, Roberto R.; Whitton, J. Lindsay; Terskikh, Alexey V.

    2011-01-01

    Aims Previous studies have demonstrated the therapeutic potential for human embryonic stem cell-derived neural precursor cells (hES-NPCs) in autoimmune and genetic animal models of demyelinating diseases. Herein, we tested whether intravenous (i.v) administration of hES-NPCs would impact central nervous system (CNS) demyelination in a cuprizone model of demyelination. Methods C57Bl/6 mice were fed cuprizone (0.2%) for two weeks and then separated into two groups that either received an i.v. injection of hES-NPCs or i.v. administration of media without these cells. After an additional two weeks of dietary cuprizone treatment, CNS tissues were analyzed for detection of transplanted cells and differences in myelination in the region of the corpus callosum (CC). Results Cuprizone-induced demyelination in the CC was significantly reduced in mice treated with hES-NPCs compared with cuprizone-treated controls that did not receive stem cells. hES-NPCs were identified within the brain tissues of treated mice and revealed migration of transplanted cells into the CNS. A limited number of human cells were found to express the mature oligodendrocyte marker, O1, or the astrocyte marker, GFAP. Reduced apoptosis and attenuated microglial and astrocytic responses were also observed in the CC of hES-NPC-treated mice. Conclusions These findings indicated that systemically-administered hES-NPCs migrated from circulation into a demyelinated lesion within the CNS and effectively reduced demyelination. Observed reductions in astrocyte and microglial responses, and (c) the benefit of hES-NPC treatment in this model of myelin injury was not obviously accountable to tissue replacement by exogenously administered cells. PMID:21276029

  19. Increased levels of myelin basic protein transcripts in virus-induced demyelination.

    PubMed

    Kristensson, K; Holmes, K V; Duchala, C S; Zeller, N K; Lazzarini, R A; Dubois-Dalcq, M

    In multiple sclerosis, a demyelinating disease of young adults, there is a paucity of myelin repair in the central nervous system (CNS) which is necessary for the restoration of fast saltatory conduction in axons. Consequently, this relapsing disease often causes marked disability. In similar diseases of small rodents, however, remyelination can be quite extensive, as in the demyelinating disease caused by the A59 strain of mouse hepatitis virus (MHV-A59), a coronavirus of mice. To investigate when and where oligodendrocytes are first triggered to repair CNS myelin in such disease, we have used a complementary DNA probe specific for one major myelin protein gene, myelin basic protein (MBP), which hybridizes with the four forms of MBP messenger RNA in rodents. Using Northern blot and in situ hybridization techniques, we previously found that MBP mRNA is first detected at about 5 days after birth, peaks at 18 days and progressively decreases to 25% of the peak levels in the adult. We now report that in spinal cord sections of adult animals with active demyelination and inflammatory cells, in situ hybridization reveals a dramatic increase in probe binding to MBP-specific mRNA at 2-3 weeks after virus inoculation and before remyelination can be detected by morphological methods. This increase of MBP-specific mRNA is found at the edge of the demyelinating area and extends into surrounding areas of normal-appearing white matter. Thus, in situ hybridization with myelin-specific probes appears to be a useful method for detecting the timing, intensity and location of myelin protein gene reactivation preceding remyelination. This method could be used to elucidate whether such a reactivation occurs in multiple sclerosis brain tissue. Our results suggest that in mice, glial cells react to a demyelinating process with widespread MBP mRNA synthesis which may be triggered by a diffusible factor released in the demyelinated areas. PMID:2426599

  20. Nociception and inflammatory hyperalgesia evaluated in rodents using infrared laser stimulation after Trpv1 gene knockout or resiniferatoxin lesion.

    PubMed

    Mitchell, Kendall; Lebovitz, Evan E; Keller, Jason M; Mannes, Andrew J; Nemenov, Michael I; Iadarola, Michael J

    2014-04-01

    TRPV1 is expressed in a subpopulation of myelinated Aδ and unmyelinated C-fibers. TRPV1+ fibers are essential for the transmission of nociceptive thermal stimuli and for the establishment and maintenance of inflammatory hyperalgesia. We have previously shown that high-power, short-duration pulses from an infrared diode laser are capable of predominantly activating cutaneous TRPV1+ Aδ-fibers. Here we show that stimulating either subtype of TRPV1+ fiber in the paw during carrageenan-induced inflammation or following hind-paw incision elicits pronounced hyperalgesic responses, including prolonged paw guarding. The ultrapotent TRPV1 agonist resiniferatoxin (RTX) dose-dependently deactivates TRPV1+ fibers and blocks thermal nociceptive responses in baseline or inflamed conditions. Injecting sufficient doses of RTX peripherally renders animals unresponsive to laser stimulation even at the point of acute thermal skin damage. In contrast, Trpv1-/- mice, which are generally unresponsive to noxious thermal stimuli at lower power settings, exhibit withdrawal responses and inflammation-induced sensitization using high-power, short duration Aδ stimuli. In rats, systemic morphine suppresses paw withdrawal, inflammatory guarding, and hyperalgesia in a dose-dependent fashion using the same Aδ stimuli. The qualitative intensity of Aδ responses, the leftward shift of the stimulus-response curve, the increased guarding behaviors during carrageenan inflammation or after incision, and the reduction of Aδ responses with morphine suggest multiple roles for TRPV1+ Aδ fibers in nociceptive processes and their modulation of pathological pain conditions. PMID:24434730

  1. Reduction in Serum Aquaporin-4 Antibody Titers During Development of a Tumor-Like Brain Lesion in a Patient With Neuromyelitis Optica: A Serum Antibody–Consuming Effect?

    PubMed Central

    Aboulenein-Djamshidian, Fahmy; Höftberger, Romana; Waters, Patrick; Krampla, Wolfgang; Lassmann, Hans; Budka, Herbert; Vincent, Angela; Kristoferitsch, Wolfgang

    2015-01-01

    Abstract Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the CNS with severe involvement of the optic nerve and spinal cord. Highly specific serum IgG autoantibodies (NMO-IgG) that react with aquaporin-4 (AQP4), the most abundant CNS water channel protein, are found in patients with NMO. However, in vivo evidence combining the results of AQP4 antibody serum levels and brain pathology is lacking. We report a patient with NMO whose AQP4 antibody levels decreased simultaneously with clinical deterioration caused by the development of a tumor-like brain lesion. In the seminecrotic biopsied brain lesion, there was activated complement complex, whereas only very scattered immunoreactivity to AQP4 protein was detectable. The decrease in serum AQP4 antibody levels and the loss of AQP4 in the tumor-like lesion could represent a “serum antibody–consuming effect” during lesion formation. PMID:25668569

  2. The EIIIA domain from astrocyte‐derived fibronectin mediates proliferation of oligodendrocyte progenitor cells following CNS demyelination

    PubMed Central

    Stoffels, Josephine M. J.; Hoekstra, Dick; Franklin, Robin J. M.

    2014-01-01

    Central nervous system remyelination by oligodendrocyte progenitor cells (OPCs) ultimately fails in the majority of multiple sclerosis (MS) lesions. Remyelination benefits from transient expression of factors that promote migration and proliferation of OPCs, which may include fibronectin (Fn). Fn is present in demyelinated lesions in two major forms; plasma Fn (pFn), deposited following blood‐brain barrier disruption, and cellular Fn, synthesized by resident glial cells and containing alternatively spliced domains EIIIA and EIIIB. Here, we investigated the distinctive roles that astrocyte‐derived Fn (aFn) and pFn play in remyelination. We used an inducible Cre‐lox recombination strategy to selectively remove pFn, aFn or both from mice, and examined the impact on remyelination of toxin‐induced demyelinated lesions of spinal cord white matter. This approach revealed that astrocytes are a major source of Fn in demyelinated lesions. Furthermore, following aFn conditional knockout, the number of OPCs recruited to the demyelinated lesion decreased significantly, whereas OPC numbers were unaltered following pFn conditional knockout. However, remyelination completed normally following conditional knockout of aFn and pFn. Both the EIIIA and EIIIB domains of aFn were expressed following demyelination, and in vitro assays demonstrated that the EIIIA domain of aFn mediates proliferation of OPCs, but not migration. Therefore, although the EIIIA domain from aFn mediates OPC proliferation, aFn is not essential for successful remyelination. Since previous findings indicated that astrocyte‐derived Fn aggregates in chronic MS lesions inhibit remyelination, aFn removal may benefit therapeutic strategies to promote remyelination in MS. GLIA 2015;63:242–256 PMID:25156142

  3. Investigation of Functional Activity of Cells in Granulomatous Inflammatory Lesions from Mice with Latent Tuberculous Infection in the New Ex Vivo Model

    PubMed Central

    2013-01-01

    The new ex vivo model system measuring functional input of individual granuloma cells to formation of granulomatous inflammatory lesions in mice with latent tuberculous infection has been developed and described in the current study. Monolayer cultures of cells that migrated from individual granulomas were established in the proposed culture settings for mouse spleen and lung granulomas induced by in vivo exposure to BCG vaccine. The cellular composition of individual granulomas was analyzed. The expression of the leukocyte surface markers such as phagocytic receptors CD11b, CD11c, CD14, and CD16/CD32 and the expression of the costimulatory molecules CD80, CD83, and CD86 were tested as well as the production of proinflammatory cytokines (IFNγ and IL-1α) and growth factors (GM-CSF and FGFb) for cells of individual granulomas. The colocalization of the phagocytic receptors and costimulatory molecules in the surface microdomains of granuloma cells (with and without acid-fast BCG-mycobacteria) has also been detected. It was found that some part of cytokine macrophage producers have carried acid-fast mycobacteria. Detected modulation in dynamics of production of pro-inflammatory cytokines, growth factors, and leukocyte surface markers by granuloma cells has indicated continued processes of activation and deactivation of granuloma inflammation cells during the latent tuberculous infection progress in mice. PMID:24198843

  4. Technetium-99m HM-PAO-labeled leukocytes in detection of inflammatory lesions: Comparison with gallium-67 citrate

    SciTech Connect

    Vorne, M.; Soini, I.; Lantto, T.; Paakkinen, S. )

    1989-08-01

    Forty-three patients with suspected benign, inflammatory, or infectious diseases were imaged with ({sup 99m}Tc)HM-PAO-labeled leukocytes and ({sup 67}Ga)citrate. Technetium-99m leukocytes showed 22 true-positive, no false-positive, 19 true-negative, and two false-negative findings and ({sup 67}Ga)citrate 23, 7, 12 and 1, respectively. The sensitivity, specificity, and accuracy values with {sup 99m}Tc leukocytes were 92%, 100%, and 95%, and with ({sup 67}Ga)citrate 96%, 63%, and 81%. Technetium-99m leukocyte scintigraphy has a promising future in comparison with ({sup 67}Ga)citrate because of the ready availability of ({sup 99m}Tc)HM-PAO, the good image quality, more rapid results (within few hours), and the lower radiation exposure to the patient with {sup 99m}Tc leukocytes. The usefulness of {sup 99m}Tc leukocytes in chronic osteomyelitis needs further evaluation.

  5. Restless Leg Syndrome in Different Types of Demyelinating Neuropathies: A Single-Center Pilot Study

    PubMed Central

    Luigetti, Marco; Del Grande, Alessandra; Testani, Elisa; Bisogni, Giulia; Losurdo, Anna; Giannantoni, Nadia Mariagrazia; Mazza, Salvatore; Sabatelli, Mario; Della Marca, Giacomo

    2013-01-01

    Objective: to determine the prevalence of restless legs syndrome (RLS) in a cohort of patients with demyelinating neuropathies. Methods: Patients were retrospectively recruited from our cohort of different forms of demyelinating neuropathies, including chronic inflammatory demyelinating neuropathy (CIDP), Charcot-Marie-Tooth 1A (CMT1A), and hereditary neuropathy with liability to pressure palsies (HNPP) referred to our Department of Neurology in a 10-year period. The validated 4-item RLS questionnaire was used for diagnosis of RLS. All patients with RLS who fulfilled criteria underwent a suggested immobilization test to confirm the diagnosis. A group of outpatients referred to the sleep disorders unit and data from published literature were used as controls. Results: Prevalence of RLS in demyelinating neuropathy group was higher than prevalence observed in control population (p = 0.0142) or in the literature data (p = 0.0007). In particular, in comparison with both control population and literature data, prevalence of RLS was higher in CIDP group (p = 0.0266 and p = 0.0063, respectively) and in CMT1A group (p = 0.0312 and p = 0.0105, respectively), but not in HNPP (p = 1.000 and p = 0.9320, respectively). Conclusions: our study confirms a high prevalence of RLS in inflammatory neuropathies as CIDP and, among inherited neuropathies, in CMT1A but not in HNPP. Considering that this is only a small cohort from a single-center retrospective experience, the link between RLS and neuropathy remains uncertain, and larger multicenter studies are probably needed to clarify the real meaning of the association between RLS and neuropathy. Citation: Luigetti M; Del Grande A; Testani E; Bisogni G; Losurdo A; Giannantoni NM; Mazza S; Sabatelli M; Della Marca G. Restless leg syndrome in different types of demyelinating neuropathies: a single-center pilot study. J Clin Sleep Med 2013;9(9):945-949. PMID:23997707

  6. [Demyelinating diseases in children with acute neurological symptoms].

    PubMed

    Olofsson, Isa Amalie; Skov, Liselotte; Miranda, Maria Jose

    2015-12-01

    Demyelinating diseases in children is a broad group of illnesses, which affect the central nervous system. Demyelinating diseases can be monophasic or chronic and comprise acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, multiple sclerosis and neuromyelitis optica. Demyelinating diseases are rare, but it is important for the physician to recognize these diseases, as well as to understand the differential diagnoses. This review summarizes the current knowledge of demyelinating disorders in children, focusing on an approach to diagnosis and management. PMID:26651911

  7. No evidence for chronic demyelination in spared axons following spinal cord injury in a mouse

    PubMed Central

    Lasiene, Jurate; Shupe, Larry; Perlmutter, Steve; Horner, Philip

    2008-01-01

    The pattern of remyelination after traumatic spinal cord injury remains elusive, with animal and human studies reporting partial to complete demyelination followed by incomplete remyelination. In the present study, we found that spared rubrospinal tract (RST) axons of passage traced with actively transported dextrans and examined caudally to the lesion twelve weeks after mouse spinal cord contusion injury were fully remyelinated. Spared axons exhibited a marginally reduced myelin thickness and significantly shorter internodes. Contactin-associated protein (CASPR) and Kv1.2 channels were used to identify internodes and paranodal protein distribution properties were used as an index of myelin integrity. This is the first time the CNS myelin internode length was measured in a mouse. To better understand the significance of shortened internodes and thinner myelin in spared axons, we modeled conduction properties using McIntyre’s et al. model of myelinated axons. Mathematical modeling predicted a 21% decrease in the conduction velocity of remyelinated RST axons due to shortened internodes. To determine whether demyelination could be present on axons exhibiting a pathological transport system we utilized the retroviral reporter system. Virally delivered GFP unveiled a small population of dystrophic RST axons that persist chronically with evident demyelination or abnormal remyelination. Collectively these data show that lasting demyelination in spared axons is rare and that remyelination of axons of passage occurs in the chronically injured mouse spinal cord. PMID:18400887

  8. Impact of different ratios of Omega-6 polyundaturated fatty acids to eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA) on atherosclerotic lesion formation and inflammatory factors in the LDL receptor knockout mouse

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective was to assess the effect of different ratios of omega-6 to EPA plus DHA on atherosclerotic lesion formation and plasma inflammatory markers in LDLr-/- mice. Mice (n=10/group) were fed the following diets for 32 weeks: high fat (20% w/w) without EPA and DHA (HF omega-6), and high fat wi...

  9. The sphingosine 1-phosphate receptor agonist FTY720 is neuroprotective after cuprizone-induced CNS demyelination

    PubMed Central

    Slowik, A; Schmidt, T; Beyer, C; Amor, S; Clarner, T; Kipp, M

    2015-01-01

    BACKGROUND AND PURPOSE Modulation of the sphingosine 1-phosphate receptor is an approved treatment for relapsing multiple sclerosis because of its anti-inflammatory effect of retaining lymphocytes within the lymph nodes. Here, we evaluated the potential of an agonist at this receptor, FTY720 (fingolimod), to activate the promyelinating pathways within the brain to encourage remyelination and neuroprotection. EXPERIMENTAL APPROACH In this study, we used the cuprizone model in male C57BL/6 mice and tested the promyelinating and neuroprotective effects of FTY720 after acute and chronic toxin-induced experimental demyelination. We used histological, immunohistochemical and gene expression methods. KEY RESULTS The midline of the corpus callosum was severely demyelinated after acute and chronic cuprizone-induced demyelination. Robust endogenous remyelination was evident after acute, but impaired after chronic, demyelination. FTY720 treatment modestly accelerated myelin recovery after acute but not chronic cuprizone exposure. Markers of gliosis (astrocyte and microglia activation) were not affected by FTY720 treatment. Remarkably, the accumulation of amyloid precursor protein-positive spheroids in axons was less distinct in FTY720-treated animals, indicating that this compound alleviated ongoing axonal damage. CONCLUSIONS AND IMPLICATIONS We show that even during endogenous remyelination, axonal degeneration continued at a low level, accumulating over time. This continuous neurodegenerative process was ameliorated by FTY720 treatment. FTY720 preserved CNS integrity by direct interaction with brain resident cells, the actions of which are still to be defined. PMID:25220526

  10. Treatment Responsiveness in CIDP Patients with Diabetes Is Associated with Higher Degrees of Demyelination

    PubMed Central

    Abraham, Alon; Alabdali, Majed; Qrimli, Mohammad; Albulaihe, Hana; Breiner, Ari; Barnett, Carolina; Katzberg, Hans D.; Lovblom, Leif E.; Perkins, Bruce A.; Bril, Vera

    2015-01-01

    Introduction Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is one of several chronic treatable acquired demyelinating neuropathies. Objectives To explore the association between the degree of demyelination in CIDP, and treatment responsiveness. Methods A retrospective chart review of CIDP subjects assessed between 1997 and 2013 was performed to compare treatment responsiveness using different sets of criteria. Results 99 CIDP patients were included, 34 with diabetes mellitus (DM). Treatment responsiveness was higher in CIDP-DM fulfilling 1 or more EFNS/PNS criteria, (63% vs. 31%, p = 0.03), and in CIDP+DM fulfilling 2 or more criteria (89% vs. 36%, p = 0.01). Nonetheless, treatment responsiveness in CIDP+DM had the highest odds ratio (3.73, p = 0.01). Similar results were also shown in simplified uniform study criteria, with 10% cut off values for CIDP-DM, compared to 30% for CIDP+DM. Conclusion In CIDP+DM, higher degrees of demyelination are associated with treatment responsiveness, implying the need to adjust current criteria in these patients. PMID:26461125

  11. Environmental and genetic factors in pediatric inflammatory demyelinating diseases.

    PubMed

    Waubant, Emmanuelle; Ponsonby, Anne-Louise; Pugliatti, Maura; Hanwell, Heather; Mowry, Ellen M; Hintzen, Rogier Q

    2016-08-30

    The onset of multiple sclerosis (MS) occurs in childhood in about 5% of all patients with MS. The disease in adults has a complex genetic and environmental inheritability. One of the main risk factors, also confirmed in pediatric MS, is HLA DRB1*1501 In addition to genetic factors, a large part of disease susceptibility in adults is conferred by environmental risk factors such as low vitamin D status, exposure to cigarette smoking, and remote Epstein-Barr virus (EBV) infection. In children, both exposure to cigarette smoking and prior EBV infection have been reported consistently as risk factors for MS. The role of vitamin D remains to be confirmed in this age category. Finally, although very likely critical in disease processes, few gene-environment interactions and epigenetic changes have been reported for adult and pediatric MS susceptibility. Of interest, some of the risk factors for MS have also been associated with disease course modification, such as low 25(OH) vitamin D serum levels in pediatric and adult MS. Age is also a clear disease modifier of clinical, CSF, and MRI phenotype in children with the disease. Finally, although much has yet to be unraveled regarding molecular processes at play in MS, there is a larger gap in our knowledge of genetic and environmental risk factors for pediatric neuromyelitis optica spectrum disorders and acute disseminated encephalomyelitis and only collaborative studies will answer those questions. PMID:27572857

  12. Dysautonomic polyneuropathy as a variant of chronic inflammatory "demyelinating" polyneuropathy?

    PubMed

    Wolf, Hans-Heinrich; Kornhuber, Malte Erich; Weis, Joachim; Posa, Andreas

    2016-08-01

    This report describes the clinical course over almost one decade of a male patient presenting with immune-mediated pure autonomic neuropathy resembling a distinct variant of chronic dysimmune polyneuropathies. We suppose autoantibodies directed against epitopes on autonomic axons or neurons causative for the symptoms. PMID:27379500

  13. Aggregation of MBP in chronic demyelination

    PubMed Central

    Frid, Kati; Einstein, Ofira; Friedman-Levi, Yael; Binyamin, Orli; Ben-Hur, Tamir; Gabizon, Ruth

    2015-01-01

    Objectives Misfolding of key disease proteins to an insoluble state is associated with most neurodegenerative conditions, such as prion, Parkinson, and Alzheimer’s diseases. In this work, and by studying animal models of multiple sclerosis, we asked whether this is also the case for myelin basic protein (MBP) in the late and neurodegenerative phases of demyelinating diseases. Methods To this effect, we tested whether MBP, an essential myelin component, present prion-like properties in animal models of MS, as is the case for Cuprizone-induced chronic demyelination or chronic phases of Experimental Autoimmune Encephalomyelitis (EAE). Results We show here that while total levels of MBP were not reduced following extensive demyelination, part of these molecules accumulated thereafter as aggregates inside oligodendrocytes or around neuronal cells. In chronic EAE, MBP precipitated concomitantly with Tau, a marker of diverse neurodegenerative conditions, including MS. Most important, analysis of fractions from Triton X-100 floatation gradients suggest that the lipid composition of brain membranes in chronic EAE differs significantly from that of naïve mice, an effect which may relate to oxidative insults and subsequently prevent the appropriate insertion and compaction of new MBP in the myelin sheath, thereby causing its misfolding and aggregation. Interpretation Prion-like aggregation of MBP following chronic demyelination may result from an aberrant lipid composition accompanying this pathological status. Such aggregation of MBP may contribute to neuronal damage that occurs in the progressive phase of MS. PMID:26273684

  14. Bone marrow transplantation in the rat. III. Structure of the liver inflammatory lesion in acute graft-versus-host disease

    SciTech Connect

    Leszczynski, D.; Renkonen, R.; Haeyry, P.

    1985-08-01

    The liver is a major parenchymal target organ of acute graft-versus-host disease (aGVHD) after bone marrow transplantation in the rat. The authors have analyzed the nature of cellular infiltrates in the liver using monoclonal antibodies against white cell subsets and investigated the anatomic distribution of the inflammatory cell subsets inside the liver parenchyma. Several types of white cells are present in a normal control liver: In the portal area the T-helper (Th) cells predominate, (surface) immunoglobulin-expressing B cells are present in ample numbers, and most of the phagocytes are Ia-positive. In the central vein area the T-suppressor/killer cells (Tsk) dominate, no B cells are present, and most of the phagocytes are Ia-negative. During aGVHD the number of T cells increases rapidly in the portal area; and after an initial strong increase, the Th/Tsk ratio decreases but remains still above 1. In the central vein area there is also an increase in the number of T cells, compared with that in the syngeneic recipient, but the Th/Tsk ratio rapidly decreases and remains uniformly below 1. During aGVHD the B cells entirely disappear from the portal area, whereas a small but distinct number of mature plasma cells with intracellular immunoglobulin appear in the central vein area. Following irradiation the Ia-positive phagocytic cells entirely disappear from the portal area and decrease distinctly in number in the central vein area. During aGVHD the number of Ia-positive phagocytes increases again in both locations. In the central vein area the positive phagocytes are seen over the background level, and, concomitantly, the Ia-negative phagocytes disappear.

  15. Vesicular demyelination induced by raised intracellular calcium.

    PubMed

    Smith, K J; Hall, S M; Schauf, C L

    1985-11-01

    Incubation of nerve with high concentrations of the divalent cation ionophore A23187 produces myelin vesiculation (Schlaepfer 1977). This observation has now been extended using segments of rat ventral or dorsal root incubated with high (19 microM, 10 micrograms/ml) or low (1-1.5 microM) concentrations of A23187, or another divalent ionophore, ionomycin. Low concentrations of A23187 induced no vesiculation within a 2-h period. However, subsequent incubation of these roots in fresh, ionophore-free medium for 20 h, resulted in a prominent vesicular demyelination at the Schmidt-Lanterman incisures and paranodes of many fibres. At this time (22 h) the Schwann cells associated with some demyelinating internodes appeared vital upon ultrastructural examination: the cells also excluded the nuclear dye nigrosin. High concentrations of A23187 induced a similar vesicular demyelination in affected fibres within only 15-20 min. While the Schwann cells continued to exclude nigrosin for a further 4 h, their ultrastructural appearance indicated that they were probably in the early stages of necrosis. Incubation of moribund root with the ionophore produced no myelin vesiculation. At all ionophore concentrations, the myelin vesiculation was dependent upon the presence of extracellular Ca2+, and could be modulated in severity by varying this concentration. Other divalent cations (Ba2+, Co2+, Mg2+, Mn2+, Ni2+, Sr2+) could not substitute for Ca2+. The vesiculation induced by A23187 could be entirely prevented by the addition of Zn2+ (greater than or equal to 1 microM), Ni2+ (greater than or equal to 1-10 microM), Co2+ (greater than or equal to 100 microM) or Mn2+ (greater than or equal to 100 microM) to the bathing medium. A23187 applied to only part of an isolated internode resulted in a localization of the myelin disruption to that region. Ionomycin (greater than or equal to 1 microM), an ionophore with a greater selectivity for Ca2+ than A23187, also induced a prompt Ca2+-dependent

  16. Mitochondria as crucial players in demyelinated axons: lessons from neuropathology and experimental demyelination.

    PubMed

    Campbell, Graham R; Mahad, Don J

    2011-01-01

    Mitochondria are the most efficient producers of energy in the form of ATP. Energy demands of axons, placed at relatively great distances from the neuronal cell body, are met by mitochondria, which when functionally compromised, produce reactive oxygen species (ROS) in excess. Axons are made metabolically efficient by myelination, which enables saltatory conduction. The importance of mitochondria for maintaining the structural integrity of myelinated axons is illustrated by neuroaxonal degeneration in primary mitochondrial disorders. When demyelinated, the compartmentalisation of ion channels along axons is disrupted. The redistribution of electrogenic machinery is thought to increase the energy demand of demyelinated axons. We review related studies that focus on mitochondria within unmyelinated, demyelinated and dysmyelinated axons in the central nervous system. Based on neuropathological observations we propose the increase in mitochondrial presence within demyelinated axons as an adaptive process to the increased energy need. An increased presence of mitochondria would also increase the capacity to produce deleterious agents such as ROS when functionally compromised. Given the lack of direct evidence of a beneficial or harmful effect of mitochondrial changes, the precise role of increased mitochondrial presence within axons due to demyelination needs to be further explored in experimental demyelination in-vivo and in-vitro. PMID:21331147

  17. Differences in Membrane Properties in Simulated Cases of Demyelinating Neuropathies: Internodal Focal Demyelinations without Conduction Block

    PubMed Central

    Daskalova, M. S.; Alexandrov, A. S.

    2006-01-01

    The membrane properties (intracellular, extracellular, electrotonic potentials, strength-duration time constants, rheobasic currents and recovery cycles), which can now be measured in healthy subjects and patients with demyelinating neuropathies, are investigated in simulated cases of focal reduction (70%) of the myelin sheath in one, two and three successive internodal segments along the length of human motor fibres. The internodally focally demyelinated cases (termed as IFD1, IFD2 and IFD3, respectively) are simulated using our previous double cable model of the fibres. The results show that the intracellular potentials are with reduced amplitude and slowed conduction velocity in the vicinity of demyelinated segments, however the segmental conduction block is not achieved. The radial decline of the extracellular potential amplitudes slightly increases with the increase of the radial distance and demyelination. In contrast, the electrotonic potentials, strength-duration time constants and rheobases are normal. In the recovery cycles, the refractoriness, supernormality and less late subnormality are close to the normal, showing that the pathology is relatively minor. The obtained abnormalities in the potentials and excitability properties provide new information about the pathophysiology of the demyelinated human motor axons and can be observed in vivo in patients with acquired demyelinating neuropathies. PMID:19669452

  18. Differences in Membrane Properties in Simulated Cases of Demyelinating Neuropathies: Internodal Focal Demyelinations with Conduction Block

    PubMed Central

    Daskalova, M. S.; Alexandrov, A. S.

    2006-01-01

    The aim of this study is to investigate the membrane properties (potentials and axonal excitability indices) in the case of myelin wrap reduction (96%) in one, two and three consecutive internodes along the length of human motor nerve fibre. The internodally focally demyelinated cases (termed as IFD1, IFD2 and IFD3, respectively, with one, two and three demyelinated internodes are simulated using our previous double cable model of the fibre. The progressively greater increase of focal loss of myelin lamellae blocks the invasion of the intracellular potentials into the demyelinated zones. For all investigated cases, the radial decline of the extracellular potential amplitudes increases with the increase of the radial distance and demyelination, whereas the electrotonic potentials show a decrease in the slow part of the depolarizing and hyperpolarizing responses. The time constants are shorter and the rheobases higher for the IFD2 and IFD3 cases than for the normal case. In the recovery cycles, the same cases have less refractoriness, greater supernormality and less late subnormality than the normal case. The simulated membrane abnormalities can be observed in vivo in patients with demyelinating forms of Guillain-Barré syndrome. The study provides new information about the pathophysiology of acquired demyelinating neuropathies. PMID:19669456

  19. Inflammatory response in serrated precursor lesions of the colon classified according to WHO entities, clinical parameters and phenotype–genotype correlation

    PubMed Central

    Atreya, Raja; Aust, Daniela; Baretton, Gustavo; Eck, Matthias; Erlenbach‐Wünsch, Katharina; Hartmann, Arndt; Lugli, Alessandro; Stöhr, Robert; Vieth, Michael; Wirsing, Anna M; Zlobec, Inti; Katzenberger, Tiemo

    2016-01-01

    Abstract Studies on traditional serrated adenoma (TSA) and sessile serrated adenoma with dysplasia (SSA‐D) are rare due to the low frequency of these lesions, which are well defined by the latest WHO classification. However, introducing new morphological criteria such as intra‐epithelial lymphocytes (IELs) might facilitate colorectal polyp diagnoses. Additionally, the phenotype–genotype correlation needs to be updated as the terminology has repeatedly changed. This study analysed 516 polyps, consisting of 118 classical adenomas (CAD), 116 hyperplastic polyps (HPP), 179 SSAs, 41 SSA‐Ds, and 62 TSAs. The lesions were analysed in relation to the patients’ clinical parameters including gender, age, localisation, and size. The inflammatory background of the polyps was quantified and BRAF and KRAS mutations as well as MLH1 and CDKN2A promoter methylation were assessed. In multivariate analyses, an increase in IELs was an independent and robust new criterion for the diagnosis of SSA‐D (p < 0.001). Superficial erosions and acute neutrophil granulocytes led to reactive changes potentially resembling dysplasia. KRAS and BRAF mutations were associated with CAD/TSA and HPP/SSA, respectively. However, almost half of TSAs had a BRAF mutation and were KRAS wild type. CDKN2A seems to precede MLH1 hyper‐methylation within the serrated carcinogenesis model. The genotyping of WHO‐based entities – and especially SSA – has sharpened in comparison to previously published data. TSAs can be sub‐grouped according to their mutation status. Of note, the higher number of IELs in SSA‐D reflects their close relationship to colorectal cancers with micro‐satellite instability. Therefore, IELs might represent a new diagnostic tool for SSA‐D.

  20. Recurrent asymptomatic demyelinating disease following 13-cis-retinoic acid exposure

    PubMed Central

    Okuda, Darin T; Prados, Michael D

    2009-01-01

    We report a case of multifocal demyelination within the central nervous system in a patient being treated for a left hemispheric gemnistocytic astrocytoma with radiation therapy and chemotherapy, comprising temozolomide (360 mg/day—days 1–5 every 28 days) and 13-cis-retinoic acid (100 mg/m2/day—separated into two doses administered every 12 h on days 1 through 21 every 28 days). Five months into her first round of chemotherapy, brain magnetic resonance imaging (MRI) demonstrated multifocal regions of T2 prolongation with associated gadolinium enhancement within the right cerebral hemisphere. Spectroscopic data were consistent with demyelination rather than neoplasia. Despite the incidentally identified radiological progression, new neurological symptoms were not described. Interval resolution of the demyelinating lesions was observed in the years following the discontinuance of her chemotherapy regimen with reactivation of the previously observed lesions and the development of new T2 foci 6 months into her second round of re-treatment for tumour progression 5 years later. PMID:21901115

  1. Directional diffusivity as a magnetic resonance (MR) biomarker in demyelinating disease

    NASA Astrophysics Data System (ADS)

    Benzinger, Tammie L. S.; Cross, Anne H.; Xu, Junqian; Naismith, Robert; Sun, Shu-Wei; Song, Sheng-Kwei

    2007-09-01

    Directional diffusivities derived from diffusion tensor magnetic resonance imaging (DTI) measurements describe water movement parallel to (λ ||, axial diffusivity) and perpendicular to (λ⊥radial diffusivity) axonal tracts. λ || and λ⊥ have been shown to differentially detect axon and myelin abnormalities in several mouse models of central nervous system white matter pathology in our laboratory. These models include experimental autoimmune encephalomyelitis (EAE), (1) myelin basic protein mutant mice with dysmyelination and intact axons, (2) cuprizone-induced demyelination, and remyelination, with reversible axon injury (2, 3) and a model of retinal ischemia in which retinal ganglion cell death is followed by Wallerian degeneration of optic nerve, with axonal injury preceding demyelination. (4) Decreased λ|| correlates with acute axonal injury and increased λ⊥ indicates myelin damage. (4) More recently, we have translated this approach to human MR, investigating acute and chronic optic neuritis in adults with multiple sclerosis, brain lesions in adults with multiple sclerosis, and acute disseminated encephalomyelitis (ADEM) in children. We are also investigating the use of this technique to probe the underlying structural change of the cervical spinal cord in acute and chronic T2- hyperintense lesions in spinal stenosis, trauma, and transverse myelitis. In each of these demyelinating diseases, the discrimination between axonal and myelin injury which we can achieve has important prognostic and therapeutic implications. For those patients with myelin injury but intact axons, early, directed drug therapy has the potential to prevent progression to axonal loss and permanent disability.

  2. Species-specific inflammatory responses as a primary component for the development of glomerular lesions in mice and monkeys following chronic administration of a second-generation antisense oligonucleotide.

    PubMed

    Frazier, Kendall S; Sobry, Cécile; Derr, Victoria; Adams, Mike J; Besten, Cathaline Den; De Kimpe, Sjef; Francis, Ian; Gales, Tracy L; Haworth, Richard; Maguire, Shaun R; Mirabile, Rosanna C; Mullins, David; Palate, Bernard; Doorten, Yolanda Ponstein-Simarro; Ridings, James E; Scicchitano, Marshall S; Silvano, Jérémy; Woodfine, Jennie

    2014-07-01

    Chronic administration of drisapersen, a 2'-OMe phosphorothioate antisense oligonucleotide (AON) to mice and monkeys resulted in renal tubular accumulation, with secondary tubular degeneration. Glomerulopathy occurred in both species with species-specific characteristics. Glomerular lesions in mice were characterized by progressive hyaline matrix accumulation, accompanied by the presence of renal amyloid and with subsequent papillary necrosis. Early changes involved glomerular endothelial hypertrophy and degeneration, but the chronic glomerular amyloid and hyaline alterations in mice appeared to be species specific. An immune-mediated mechanism for the glomerular lesions in mice was supported by early inflammatory changes including increased expression of inflammatory cytokines and other immunomodulatory genes within the renal cortex, increased stimulation of CD68 protein, and systemic elevation of monocyte chemotactic protein 1. In contrast, kidneys from monkeys given drisapersen chronically showed less severe glomerular changes characterized by increased mesangial and inflammatory cells, endothelial cell hypertrophy, and subepithelial and membranous electron-dense deposits, with ultrastructural and immunohistochemical characteristics of complement and complement-related fragments. Lesions in monkeys resembled typical features of C3 glomerulopathy, a condition described in man and experimental animals to be linked to dysregulation of the alternative complement pathway. Thus, inflammatory/immune mechanisms appear critical to glomerular injury with species-specific sensitivities for mouse and monkey. The lower observed proinflammatory activity in humans as compared to mice and monkeys may reflect a lower risk of glomerular injury in patients receiving AON therapy. PMID:24292388

  3. SURF1 deficiency causes demyelinating Charcot-Marie-Tooth disease

    PubMed Central

    Ghezzi, Daniele; Chassagne, Maïté; Mayençon, Martine; Padet, Sylvie; Melchionda, Laura; Rouvet, Isabelle; Lannes, Béatrice; Bozon, Dominique; Latour, Philippe; Zeviani, Massimo; Mousson de Camaret, Bénédicte

    2013-01-01

    Objective: To investigate whether mutations in the SURF1 gene are a cause of Charcot-Marie-Tooth (CMT) disease. Methods: We describe 2 patients from a consanguineous family with demyelinating autosomal recessive CMT disease (CMT4) associated with the homozygous splice site mutation c.107-2A>G in the SURF1 gene, encoding an assembly factor of the mitochondrial respiratory chain complex IV. This observation led us to hypothesize that mutations in SURF1 might be an unrecognized cause of CMT4, and we investigated SURF1 in a total of 40 unrelated patients with CMT4 after exclusion of mutations in known CMT4 genes. The functional impact of c.107-2A>G on splicing, amount of SURF1 protein, and on complex IV activity and assembly was analyzed. Results: Another patient with CMT4 was found to harbor 2 additional SURF1 mutations. All 3 patients with SURF1-associated CMT4 presented with severe childhood-onset neuropathy, motor nerve conduction velocities <25 m/s, and lactic acidosis. Two patients had brain MRI abnormalities, including putaminal and periaqueductal lesions, and developed cerebellar ataxia years after polyneuropathy. The c.107-2A>G mutation produced no normally spliced transcript, leading to SURF1 absence. However, complex IV remained partially functional in muscle and fibroblasts. Conclusions: We found SURF1 mutations in 5% of families (2/41) presenting with CMT4. SURF1 should be systematically screened in patients with childhood-onset severe demyelinating neuropathy and additional features such as lactic acidosis, brain MRI abnormalities, and cerebellar ataxia developing years after polyneuropathy. PMID:24027061

  4. Ligation of the Jugular Veins Does Not Result in Brain Inflammation or Demyelination in Mice

    PubMed Central

    Wojtkiewicz, Gregory R.; Pulli, Benjamin; Iwamoto, Yoshiko; Ueno, Takuya; Waterman, Peter; Truelove, Jessica; Oklu, Rahmi; Chen, John W.

    2012-01-01

    An alternative hypothesis has been proposed implicating chronic cerebrospinal venous insufficiency (CCSVI) as a potential cause of multiple sclerosis (MS). We aimed to evaluate the validity of this hypothesis in a controlled animal model. Animal experiments were approved by the institutional animal care committee. The jugular veins in SJL mice were ligated bilaterally (n = 20), and the mice were observed for up to six months after ligation. Sham-operated mice (n = 15) and mice induced with experimental autoimmune encephalomyelitis (n = 8) were used as negative and positive controls, respectively. The animals were evaluated using CT venography and 99mTc-exametazime to assess for structural and hemodynamic changes. Imaging was performed to evaluate for signs of blood-brain barrier (BBB) breakdown and neuroinflammation. Flow cytometry and histopathology were performed to assess inflammatory cell populations and demyelination. There were both structural changes (stenosis, collaterals) in the jugular venous drainage and hemodynamic disturbances in the brain on Tc99m-exametazime scintigraphy (p = 0.024). In the JVL mice, gadolinium MRI and immunofluorescence imaging for barrier molecules did not reveal evidence of BBB breakdown (p = 0.58). Myeloperoxidase, matrix metalloproteinase, and protease molecular imaging did not reveal signs of increased neuroinflammation (all p>0.05). Flow cytometry and histopathology also did not reveal increase in inflammatory cell infiltration or population shifts. No evidence of demyelination was found, and the mice remained without clinical signs. Despite the structural and hemodynamic changes, we did not identify changes in the BBB permeability, neuroinflammation, demyelination, or clinical signs in the JVL group compared to the sham group. Therefore, our murine model does not support CCSVI as a cause of demyelinating diseases such as multiple sclerosis. PMID:22457780

  5. Analysis of inflammatory periimplant lesions during a 12-week period of undisturbed plaque accumulation--a comparison between flapless and flap surgery in the mini-pig.

    PubMed

    Mueller, Cornelia K; Thorwarth, Michael; Schultze-Mosgau, Stefan

    2012-04-01

    This study's aim was to clarify the influence of soft tissue management on the development of periimplant infection. Four weeks after removal of all maxillary premolars in 12 mini-pigs, four BEGO Semados RI implants were inserted in each maxillary quadrant. Employing a split-mouth design, one quadrant was randomized to flapless insertion while the contralateral side was chosen for flap surgery. Following 1, 2, 4 and 12 weeks of transmucosal implant, healing biopsies were retrieved from the periimplant soft tissue and subjected to further analysis. Histomorphometrically, a significant reduction of transmigration of polymorphonuclear neutrophils (week 1, p = 0.007; week 2, p = 0.021; week 4, p = 0.023; week 12, p = 0.013) as well as the density of the subepithelial inflammatory infiltrates (week 1, p = 0.007; week 2, p = 0.046; week 4, p = 0.003; week 12, p = 0.032) was verified following flapless surgery. Quantification of inducible nitric oxide synthase showed significantly reduced expression in the flapless group 2 (p = 0.027), 4 (p = 0.005) and 12 (p = 0.004) weeks post-insertion. Analysis of CD31 and collagen I immunostained sections revealed more regular capillary distribution as well as higher vessel and collagen density in the flapless group. The data of the present study indicate that flapless placement reduces the incidence of inflammatory periimplant soft tissue lesions during a 12-week period. Considering the beneficial effects of flapless placement on early soft tissue healing and stability, the technique might be preferred in case of an uncomplicated locoregional anatomy with sufficient hard and soft tissue. However, this positive effect might disappear after manipulation of the implant and soft tissue during impression taking or try in of the prosthodontic supraconstruction. PMID:22186942

  6. Anthocyanins suppress the secretion of proinflammatory mediators and oxidative stress, and restore ion pump activities in demyelination.

    PubMed

    Carvalho, Fabiano B; Gutierres, Jessié M; Bohnert, Crystiani; Zago, Adriana M; Abdalla, Fátima H; Vieira, Juliano M; Palma, Heloisa E; Oliveira, Sara M; Spanevello, Roselia M; Duarte, Marta M; Lopes, Sonia T A; Aiello, Graciane; Amaral, Marta G; Pippi, Ney Luis; Andrade, Cinthia M

    2015-04-01

    The aim of this study was to investigate the protective effect of anthocyanins (ANT) on oxidative and inflammatory parameters, as well as ion pump activities, in the pons of rats experimentally demyelinated with ethidium bromide (EB). Rats were divided in six groups: control, ANT 30 mg/kg, ANT 100 mg/kg, EB (0.1%), EB plus ANT 30 mg/kg and EB plus ANT 100 mg/kg. The EB cistern pons injection occurred on the first day. On day 7, there was a peak in the demyelination. During the 7 days, the animals were treated once per day with vehicle or ANT. It was observed that demyelination reduced Na(+),K(+)-ATPase and Ca(2+)-ATPase activities and increased 4-hydroxynonenal, malondialdehyde, protein carbonyl and NO2plus NO3 levels. In addition, a depletion of glutathione reduced level/nonprotein thiol content and a decrease in superoxide dismutase activity were also seen. The dose of 100 mg/kg showed a better dose-response to the protective effects. The demyelination did not affect the neuronal viability but did increase the inflammatory infiltrate (myeloperoxidase activity) followed by an elevation in interleukin (IL)-1β, IL-6, tumor necrosis factor-α and interferon-γ levels. ANT promoted a reduction in cellular infiltration and proinflammatory mediators. Furthermore, ANT restored the levels of IL-10. Luxol fast blue staining confirmed the loss of myelin in the EB group and the protective effect of ANT 100 mg/kg. In conclusion, this study was the first to show that ANT are able to restore ion pump activities and protect cellular components against the inflammatory and oxidative damages induced by demyelination. PMID:25632845

  7. B Cell, Th17, and Neutrophil Related Cerebrospinal Fluid Cytokine/Chemokines Are Elevated in MOG Antibody Associated Demyelination

    PubMed Central

    Kothur, Kavitha; Wienholt, Louise; Tantsis, Esther M; Earl, John; Bandodkar, Sushil; Prelog, Kristina; Tea, Fiona; Ramanathan, Sudarshini; Brilot, Fabienne; Dale, Russell C.

    2016-01-01

    Background Myelin oligodendrocyte glycoprotein antibody (MOG Ab) associated demyelination represents a subgroup of autoimmune demyelination that is separate from multiple sclerosis and aquaporin 4 IgG-positive NMO, and can have a relapsing course. Unlike NMO and MS, there is a paucity of literature on immunopathology and CSF cytokine/chemokines in MOG Ab associated demyelination. Aim To study the differences in immunopathogenesis based on cytokine/chemokine profile in MOG Ab-positive (POS) and -negative (NEG) groups. Methods We measured 34 cytokines/chemokines using multiplex immunoassay in CSF collected from paediatric patients with serum MOG Ab POS [acute disseminated encephalomyelitis (ADEM = 8), transverse myelitis (TM = 2) n = 10] and serum MOG Ab NEG (ADEM = 5, TM = 4, n = 9) demyelination. We generated normative data using CSF from 20 non-inflammatory neurological controls. Results The CSF cytokine and chemokine levels were higher in both MOG Ab POS and MOG Ab NEG demyelination groups compared to controls. The CSF in MOG Ab POS patients showed predominant elevation of B cell related cytokines/chemokines (CXCL13, APRIL, BAFF and CCL19) as well as some of Th17 related cytokines (IL-6 AND G-CSF) compared to MOG Ab NEG group (all p<0.01). In addition, patients with elevated CSF MOG antibodies had higher CSF CXCL13, CXCL12, CCL19, IL-17A and G-CSF than patients without CSF MOG antibodies. Conclusion Our findings suggest that MOG Ab POS patients have a more pronounced CNS inflammatory response with elevation of predominant humoral associated cytokines/chemokines, as well as some Th 17 and neutrophil related cytokines/chemokines suggesting a differential inflammatory pathogenesis associated with MOG antibody seropositivity. This cytokine/chemokine profiling provides new insight into disease pathogenesis, and improves our ability to monitor inflammation and response to treatment. In addition, some of these molecules may represent potential immunomodulatory targets

  8. Blocking mitochondrial calcium release in Schwann cells prevents demyelinating neuropathies

    PubMed Central

    Berthelot, Jade; Jiner, Jennifer; Perrin-Tricaud, Claire; Fernando, Ruani; Chrast, Roman; Lenaers, Guy

    2016-01-01

    Schwann cells produce myelin sheath around peripheral nerve axons. Myelination is critical for rapid propagation of action potentials, as illustrated by the large number of acquired and hereditary peripheral neuropathies, such as diabetic neuropathy or Charcot-Marie-Tooth diseases, that are commonly associated with a process of demyelination. However, the early molecular events that trigger the demyelination program in these diseases remain unknown. Here, we used virally delivered fluorescent probes and in vivo time-lapse imaging in a mouse model of demyelination to investigate the underlying mechanisms of the demyelination process. We demonstrated that mitochondrial calcium released by voltage-dependent anion channel 1 (VDAC1) after sciatic nerve injury triggers Schwann cell demyelination via ERK1/2, p38, JNK, and c-JUN activation. In diabetic mice, VDAC1 activity was altered, resulting in a mitochondrial calcium leak in Schwann cell cytoplasm, thereby priming the cell for demyelination. Moreover, reduction of mitochondrial calcium release, either by shRNA-mediated VDAC1 silencing or pharmacological inhibition, prevented demyelination, leading to nerve conduction and neuromuscular performance recovery in rodent models of diabetic neuropathy and Charcot-Marie-Tooth diseases. Therefore, this study identifies mitochondria as the early key factor in the molecular mechanism of peripheral demyelination and opens a potential opportunity for the treatment of demyelinating peripheral neuropathies. PMID:26878172

  9. Changed distribution of sodium channels along demyelinated axons.

    PubMed

    England, J D; Gamboni, F; Levinson, S R; Finger, T E

    1990-09-01

    Voltage-gated sodium channels are largely localized to the nodes of Ranvier in myelinated axons, providing a physiological basis for saltatory conduction. What happens to these channels in demyelinated axons is not known with certainty. Experimentally demyelinated axons were examined by using a well-characterized, polyclonal antibody directed against sodium channels. Immunocytochemical and radioimmunoassay data were consistent with the distribution of an increased number of sodium channels along segments of previously internodal axon. These findings affirm the plasticity of sodium channels in demyelinated axolemma and may be relevant to understanding how axons recover conduction after demyelination. PMID:2168559

  10. Abnormal endothelial tight junctions in active lesions and normal-appearing white matter in multiple sclerosis.

    PubMed

    Plumb, Jonnie; McQuaid, Stephen; Mirakhur, Meenakshi; Kirk, John

    2002-04-01

    Blood-brain barrier (BBB) breakdown, demonstrable in vivo by enhanced MRI is characteristic of new and expanding inflammatory lesions in relapsing-remitting and chronic progressive multiple sclerosis (MS). Subtle leakage may also occur in primary progressive MS. However, the anatomical route(s) of BBB leakage have not been demonstrated. We investigated the possible involvement of interendothelial tight junctions (TJ) by examining the expression of TJ proteins (occludin and ZO-1 ) in blood vessels in active MS lesions from 8 cases of MS and in normal-appearing white (NAWM) matter from 6 cases. Blood vessels (10-50 per frozen section) were scanned using confocal laser scanning microscopy to acquire datasets for analysis. TJ abnormalities manifested as beading, interruption, absence or diffuse cytoplasmic localization of fluorescence, or separation of junctions (putative opening) were frequent (affecting 40% of vessels) in oil-red-O-positive active plaques but less frequent in NAWM (15%), and in normal (< 2%) and neurological controls (6%). Putatively "open" junctions were seen in vessels in active lesions and in microscopically inflamed vessels in NAWM. Dual fluorescence revealed abnormal TJs in vessels with pre-mortem serum protein leakage. Abnormal or open TJs, associated with inflammation may contribute to BBB leakage in enhancing MRI lesions and may also be involved in subtle leakage in non-enhancing focal and diffuse lesions in NAWM. BBB disruption due to tight junctional pathology should be regarded as a significant form of tissue injury in MS, alongside demyelination and axonopathy. PMID:11958369

  11. Astrocyte-derived VEGF-A drives blood-brain barrier disruption in CNS inflammatory disease.

    PubMed

    Argaw, Azeb Tadesse; Asp, Linnea; Zhang, Jingya; Navrazhina, Kristina; Pham, Trinh; Mariani, John N; Mahase, Sean; Dutta, Dipankar J; Seto, Jeremy; Kramer, Elisabeth G; Ferrara, Napoleone; Sofroniew, Michael V; John, Gareth R

    2012-07-01

    In inflammatory CNS conditions such as multiple sclerosis (MS), current options to treat clinical relapse are limited, and more selective agents are needed. Disruption of the blood-brain barrier (BBB) is an early feature of lesion formation that correlates with clinical exacerbation, leading to edema, excitotoxicity, and entry of serum proteins and inflammatory cells. Here, we identify astrocytic expression of VEGF-A as a key driver of BBB permeability in mice. Inactivation of astrocytic Vegfa expression reduced BBB breakdown, decreased lymphocyte infiltration and neuropathology in inflammatory and demyelinating lesions, and reduced paralysis in a mouse model of MS. Knockdown studies in CNS endothelium indicated activation of the downstream effector eNOS as the principal mechanism underlying the effects of VEGF-A on the BBB. Systemic administration of the selective eNOS inhibitor cavtratin in mice abrogated VEGF-A-induced BBB disruption and pathology and protected against neurologic deficit in the MS model system. Collectively, these data identify blockade of VEGF-A signaling as a protective strategy to treat inflammatory CNS disease. PMID:22653056

  12. Molecular Mechanisms of Inherited Demyelinating Neuropathies

    PubMed Central

    SCHERER, STEVEN S.; WRABETZ, LAWRENCE

    2008-01-01

    The past 15 years have witnessed the identification of more than 25 genes responsible for inherited neuropathies in humans, many associated with primary alterations of the myelin sheath. A remarkable body of work in patients, as well as animal and cellular models, has defined the clinical and molecular genetics of these illnesses and shed light on how mutations in associated genes produce the heterogeneity of dysmyelinating and demyelinating phenotypes. Here, we review selected recent developments from work on the molecular mechanisms of these disorders and their implications for treatment strategies. PMID:18803325

  13. Pre-Existing Mature Oligodendrocytes Do Not Contribute to Remyelination following Toxin-Induced Spinal Cord Demyelination

    PubMed Central

    Crawford, Abbe H.; Tripathi, Richa B.; Foerster, Sarah; McKenzie, Ian; Kougioumtzidou, Eleni; Grist, Matthew; Richardson, William D.; Franklin, Robin J.M.

    2016-01-01

    Remyelination is the regenerative response to demyelination. Although the oligodendrocyte progenitor is established as the major source of remyelinating cells, there is no conclusive evidence on whether mature, differentiated oligodendrocytes can also contribute to remyelination. Using two different inducible myelin-CreER mouse strains in which mature oligodendrocytes were prelabeled by the expression of membrane-bound Green fluorescent protein, we found that after focal spinal cord demyelination, the surrounding surviving labeled oligodendrocytes did not proliferate but remained at a consistent density. Furthermore, existing (prelabeled) oligodendrocytes showed no evidence of incorporation or migration into the lesioned area, or of process extension from the peripheral margins into the lesion. Thus, mature oligodendrocytes do not normally contribute to remyelination and are therefore not a promising target for regenerative therapy. PMID:26773350

  14. Demyelinating Guillain-Barré syndrome recurs more frequently than axonal subtypes.

    PubMed

    Notturno, Francesca; Kokubun, Norito; Sekiguki, Yukari; Nagashima, Takahide; De Lauretis, Angelo; Yuki, Nobuhiro; Kuwabara, Satoshi; Uncini, Antonino

    2016-06-15

    Guillain-Barré syndrome (GBS) is considered a monophasic disorder yet recurrences occur in up to 6% of patients. We retrospectively studied an Italian-Japanese population of 236 GBS and 73 Miller Fisher syndrome (MFS) patients and searched for factors which may be associated with recurrence. A recurrent patient was defined as having at least two episodes that fulfilled the diagnostic criteria for GBS and MFS with an identifiable recovery after each episode and a minimum of 2months between episodes. Preceding Campylobacter jejuni (C. jejuni) infection and antiganglioside antibodies were also assessed. Seven (3%) recurrent GBS and one (1.4%) recurrent MFS patients were identified. In the individual patient the clinical features during episodes were usually similar varying in severity whereas the preceding infection differed. None of the patients had GBS in one episode and MFS in the recurrence or vice versa. Recurrent GBS patients, compared with monophasic GBS, did not have preceding diarrhea at the first episode and considering the electrophysiological subtypes, acute inflammatory demyelinating polyneuropathies recurred more frequently than axonal GBS (6.5% vs 0.9%, p=0.04). In conclusion in a GBS population with a balanced number of demyelinating and axonal subtypes less frequent diarrhea and demyelination at electrophysiology were associated with recurrence. PMID:27206890

  15. [A case of asymmetric demyelinating neuropathy in a patient with chronic graft-versus-host disease].

    PubMed

    Matsumoto, Hideyuki; Seki, Naoko; Yamamoto, Tomotaka; Oshima, Kumi; Asai, Takashi; Motokura, Toru; Ugawa, Yoshikazu; Goto, Jun; Tsuji, Shoji

    2005-10-01

    A 47-year-old man, who suffered from acute lymphocytic leukemia at 45 years old and was treated with hematopoietic stem cell transplantation at 46 years old after the induction of complete remission by the standard chemotherapy, developed the symptoms of chronic graft-versus-host disease (cGVHD) such as dry eyes, dry mouth, skin thickening, skin scaling, skin pigmentation and impaired liver function. He was admitted to our hospital because of the acute development of diplopia and weakness of his left upper extremity accompanying with the exacerbation of other symptoms of cGVHD. Neurological examinations revealed the right abducens nerve palsy and asymmetric muscular weakness of the extremities; the proximal part of the left upper extremity and the distal part of the right upper extremity were markedly involved. Neurophysiological studies including magnetic motor root stimulation revealed demyelinating neuropathy specifically involving the motor nerves. On the basis of these findings, a diagnosis of peripheral neuropathy associated with cGVHD was made. Nighteen reports are available on peripheral neuropathy in cGVHD patients, but to date little is known about the pathophysiology of this condition. Most of those patients have been diagnosed as having symmetric demyelinating polyneuropathy, such as Guillain-Barré syndrome or chronic inflammatory demyelinating polyneuropathy. In this study, contrary to previous reports, the asymmetric involvement of motor nerves is noteworthy. Accumulation and further analyses of the cases like the present case are necessary to elucidate the pathogenesis of peripheral neuropathy in cGVHD. PMID:16318371

  16. A New Model of Cuprizone-Mediated Demyelination/Remyelination

    PubMed Central

    Sachs, Hilary H.; Bercury, Kathryn K.; Popescu, Daniela C.; Narayanan, S. Priya

    2014-01-01

    In the central nervous system, demyelinating diseases, such as multiple sclerosis, result in devastating long-term neurologic damage, in part because of the lack of effective remyelination in the adult human brain. One model used to understand the mechanisms regulating remyelination is cuprizone-induced demyelination, which allows investigation of remyelination mechanisms in adult animals following toxin-induced demyelination. Unfortunately, the degree of demyelination in the cuprizone model can vary, which complicates understanding the process of remyelination. Previous work in our laboratory demonstrated that the Akt/mTOR pathway regulates active myelination. When given to young postnatal mice, the mTOR inhibitor, rapamycin, inhibits active myelination. In the current study, the cuprizone model was modified by the addition of rapamycin during cuprizone exposure. When administered together, cuprizone and rapamycin produced more complete demyelination and provided a longer time frame over which to investigate remyelination than treatment with cuprizone alone. The consistency in demyelination will allow a better understanding of the mechanisms initiating remyelination. Furthermore, the slower rate of remyelination provides a longer window of time in which to investigate the diverse contributing factors that regulate remyelination. This new model of cuprizone-induced demyelination could potentially aid in identification of new therapeutic targets to enhance remyelination in demyelinating diseases. PMID:25290063

  17. A new model of cuprizone-mediated demyelination/remyelination.

    PubMed

    Sachs, Hilary H; Bercury, Kathryn K; Popescu, Daniela C; Narayanan, S Priya; Macklin, Wendy B

    2014-01-01

    In the central nervous system, demyelinating diseases, such as multiple sclerosis, result in devastating long-term neurologic damage, in part because of the lack of effective remyelination in the adult human brain. One model used to understand the mechanisms regulating remyelination is cuprizone-induced demyelination, which allows investigation of remyelination mechanisms in adult animals following toxin-induced demyelination. Unfortunately, the degree of demyelination in the cuprizone model can vary, which complicates understanding the process of remyelination. Previous work in our laboratory demonstrated that the Akt/mTOR pathway regulates active myelination. When given to young postnatal mice, the mTOR inhibitor, rapamycin, inhibits active myelination. In the current study, the cuprizone model was modified by the addition of rapamycin during cuprizone exposure. When administered together, cuprizone and rapamycin produced more complete demyelination and provided a longer time frame over which to investigate remyelination than treatment with cuprizone alone. The consistency in demyelination will allow a better understanding of the mechanisms initiating remyelination. Furthermore, the slower rate of remyelination provides a longer window of time in which to investigate the diverse contributing factors that regulate remyelination. This new model of cuprizone-induced demyelination could potentially aid in identification of new therapeutic targets to enhance remyelination in demyelinating diseases. PMID:25290063

  18. MHC II expression in the CNS after long-term demyelination

    SciTech Connect

    Cannella, B.; Aquino, D.A.; Raine, C.S.

    1995-07-01

    The ability of chronically demyelinated central nervous system (CNS) tissue to express major histocompatibility complex (MHC) class II molecules has been measured in mouse spinal cord cultures exposed for 1 and 3 weeks to demyelinating anti-white matter (WM) serum. From previous studies, It was known that after 3 weeks of demyelination in vitro, such cultures are incapable of remyelination. In the present report, MHC II levels were evaluated by immunocytochemistry and by Western and Northern blots. The results have shown that after both 1 and 3 weeks of exposure to myelinotoxic anti-WM serum, the cultures retained the ability to express MHC II and this could be further upregulated by incubation with interferon {gamma} (IFN{gamma}). Control groups showed increased expression of MHC II with age. By immunocytochemistry, all groups of cultures expressed high levels of MHC II and all groups showed upregulation after IFN{gamma} treatment. Anti-WM-treated cultures demonstrated slightly higher levels of MHC II than controls. Morphologically, the MHC II expression was associated with the surface of astrocytes. Semiquantitative analysis by Western blotting confirmed the increase in class II MHC expression in the long-term treated cultures after IFN{gamma} exposure, revealing no differences between anti-WM-treated and complement-treated cultures. This was also supported by Northern blotting which showed similar mRNA levels in both groups. These findings suggest that long-term demyelinated CNS tissue still possesses the ability to interact with CD4{sup +} T cells, observations of significance to the expansion of the chronic multiple sclerosis lesion. 50 refs., 6 figs., 2 tabs.

  19. The role of axonopathy in the mechanisms of development of demyelination processes in the central and peripheral nervous system.

    PubMed

    Merkulov, Yu A; Zavalishin, I A; Merkulova, D M

    2009-01-01

    The role of axonopathy in the development of demyelinating processes in the CNS and peripheral nervous system was addressed in studies of 43 patients with multiple sclerosis (MS) and 144 patients with chronic inflammatory demyelinating polyneuropathy (CIDPN). Patients with MS were found to have foci of reduced MRI intensity in the T1 regime ("black holes," present in 28%) and regional atrophy of the cerebral cortex (in 46%), which showed a significant association with the degree of invalidity on the EDSS (Kendall tau = 0.38 and 0.43; p = 0.038 and 0.021, respectively). The mean fatigue score on the FSS was 4.9 (3.6; 5.4). A significant increase in the central conduction time on the background of fatigue (p = 0.016), along with an absence of signs of impaired reliability of neuromuscular transmission and an absence of past-activation phenomena, suggested that central mechanisms were predominant in the formation of fatigue phenomena in MS. In addition, 34.9% of patients with MS showed signs of peripheral nervous system involvement, while the clinical-electrophysiological pattern in 12.5% of patients with CIDPN showed signs of CNS involvement. These data widen existing concepts of the mechanisms of formation of axonopathy in the CNS, based on evidence for the development of axon-demyelinating processes in CIDPN, which is the most accessible model of demyelination for study using contemporary neurophysiological methods. PMID:19089637

  20. Disruption of neurofascin localization reveals early changes preceding demyelination and remyelination in multiple sclerosis.

    PubMed

    Howell, O W; Palser, A; Polito, A; Melrose, S; Zonta, B; Scheiermann, C; Vora, A J; Brophy, P J; Reynolds, R

    2006-12-01

    Saltatory conduction in the nervous system is enabled through the intimate association between the leading edge of the myelin sheath and the axonal membrane to demarcate the node of Ranvier. The 186 kDa neuron specific isoform of the adhesion molecule neurofascin (Nfasc186) is required for the clustering of voltage gated Na+ channels at the node, whilst the 155 kDa glial specific isoform (Nfasc155) is required for the assembly of correct paranodal junctions. In order to understand the relationship between these vital structures and how they are affected in multiple sclerosis we have examined the expression of Nfasc155 and Nfasc186 in areas of inflammation, demyelination and remyelination from post-mortem brains. Fourteen cases of neuropathologically confirmed multiple sclerosis (8 female and 6 male; post-mortem delay 7-24 h; age 37-77 years; and disease duration 15-40 years), comprising 20 tissue blocks with 32 demyelinating or remyelinating lesions, were used in this study. A significant early alteration in Nfasc155+ paranodal structures occurs within and adjacent to actively demyelinating white matter lesions that are associated with damaged axons. Shaker-type Kv1.2 channels, normally located distally to the paranode, overlapped with the disrupted Nfasc155+ structures. In the absence of Nfasc155, Kv1.2 channels abutted normally clustered Nfasc186+ nodes, indicating that complete disruption of the paranodal structure and movement of Kv1.2 channels precede alterations at the node itself. Within areas of partial remyelination, a number of atypical triple-Nfasc155+ structures were noted that may represent transient oligodendrocyte-axonal contacts during the process of myelin repair or aberrant interactions. Within shadow plaques discretely clustered Na+v, Nfasc186+ and Nfasc155+ domains indicated the restoration of normal nodal architecture. The alterations in oligodendrocyte Nfasc155 expression that accompany inflammation and demyelination suggest an ongoing

  1. Sentinel lesions of primary CNS lymphoma.

    PubMed Central

    Alderson, L; Fetell, M R; Sisti, M; Hochberg, F; Cohen, M; Louis, D N

    1996-01-01

    Some patients ultimately diagnosed with primary CNS lymphoma (PCNSL) have transient symptomatic contrast enhancing lesions. These "sentinel lesions" of PCNSL recede spontaneously or with corticosteroid treatment and present an important diagnostic dilemma because they show variable, but non-diagnostic histopathological features. Four previously healthy, immunocompetent patients aged 49 to 58 years had contrast enhancing intraparenchymal brain lesions. Before biopsy, three of the four were treated with corticosteroids. Initial biopsies showed demyelination with axonal sparing in two, non-specific inflammation in one, and normal brain in one. Infiltrating lymphocytes predominantly expressed T cell markers with rare B cells. All four patients recovered within two to four weeks after the initial biopsy and imaging studies showed resolution of the lesions. The CSF was normal in three of the four patients tested; oligoclonal bands were absent in both of the two tested. After seven to 11 months, each patient developed new symptomatic lesions in a different region of the brain, biopsy of which showed a B cell PCNSL. The mechanism of spontaneous involution of sentinel lesions is not understood, but may represent host immunity against the tumour. Sentinel lesions of PCNSL should be considered in patients with contrast enhancing focal parenchymal lesions that show non-specific or demyelinative histopathological changes. Close clinical and radiographic follow up is essential if PCNSL is to be diagnosed early in such patients. Images PMID:8558135

  2. Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

    PubMed Central

    Ohno, Nobuhiko; Chiang, Hao; Mahad, Don J.; Kidd, Grahame J.; Liu, LiPing; Ransohoff, Richard M.; Sheng, Zu-Hang; Komuro, Hitoshi; Trapp, Bruce D.

    2014-01-01

    Axonal degeneration is a primary cause of permanent neurological disability in individuals with the CNS demyelinating disease multiple sclerosis. Dysfunction of axonal mitochondria and imbalanced energy demand and supply are implicated in degeneration of chronically demyelinated axons. The purpose of this study was to define the roles of mitochondrial volume and distribution in axonal degeneration following acute CNS demyelination. We show that the axonal mitochondrial volume increase following acute demyelination of WT CNS axons does not occur in demyelinated axons deficient in syntaphilin, an axonal molecule that immobilizes stationary mitochondria to microtubules. These findings were supported by time-lapse imaging of WT and syntaphilin-deficient axons in vitro. When demyelinated, axons deficient in syntaphilin degenerate at a significantly greater rate than WT axons, and this degeneration can be rescued by reducing axonal electrical activity with the Na+ channel blocker flecainide. These results support the concept that syntaphilin-mediated immobilization of mitochondria to microtubules is required for the volume increase of axonal mitochondria following acute demyelination and protects against axonal degeneration in the CNS. PMID:24958879

  3. Desert hedgehog is a mediator of demyelination in compression neuropathies.

    PubMed

    Jung, James; Frump, Derek; Su, Jared; Wang, Weiping; Mozaffar, Tahseen; Gupta, Ranjan

    2015-09-01

    The secreted protein desert hedgehog (dhh) controls the formation of the nerve perineurium during development and is a key component of Schwann cells that ensures peripheral nerve survival. We postulated that dhh may play a critical role in maintaining myelination and investigated its role in demyelination-induced compression neuropathies by using a post-natal model of a chronic nerve injury in wildtype and dhh(-/-) mice. We evaluated demyelination using electrophysiological, morphological, and molecular approaches. dhh transcripts and protein are down-regulated early after injury in wild-type mice, suggesting an intimate relationship between the hedgehog pathway and demyelination. In dhh(-/-) mice, nerve injury induced more prominent and severe demyelination relative to their wild-type counterparts, suggesting a protective role of dhh. Alterations in nerve fiber characteristics included significant decreases in nerve conduction velocity, increased myelin debris, and substantial decreases in internodal length. Furthermore, in vitro studies showed that dhh blockade via either adenovirus-mediated (shRNA) or pharmacological inhibition both resulted in severe demyelination, which could be rescued by exogenous Dhh. Exogenous Dhh was protective against this demyelination and maintained myelination at baseline levels in a custom in vitro bioreactor to applied biophysical forces to myelinated DRG/Schwann cell co-cultures. Together, these results demonstrate a pivotal role for dhh in maintaining myelination. Furthermore, dhh signaling reveals a potential target for therapeutic intervention to prevent and treat demyelination of peripheral nerves in compression neuropathies. PMID:25936873

  4. Extracellular potentials of myelinated and demyelinated human motor nerve fibres.

    PubMed

    Stephanova, D I; Daskalova, M

    2003-12-01

    The extracellular potentials of myelinated and demyelinated human motor nerve fibres in an unbounded volume conductor are studied. Using our previous double-cable models of normal and demyelinated human fibres, the spatial and temporal intracellular potentials are calculated in the cases of point polarization and adaptation of the fibres. The intracellular potentials are then used as input to a line source model that allows to calculate the corresponding spatial and temporal extracellular potentials at various radial distances in the surrounding volume conductor. Four fibre demyelinations (termed as internodal focal\\systematic and paranodal focal\\systematic demyelinations, respectively) are studied. In all investigated cases, the radial decline of the peak-to-peak amplitude of the extracellular potential depends on the radial distance of the field point and increases with the increase of the distance. The results are consistent with the interpretation that the considerably different spatial and temporal distributions of the extracellular potentials depend not only on the cable properties of the fibres, but on the methods of fibre stimulation. In the case of fibre adaptation, the temporal extracellular potentials in the normal and demyelinated cases correspond well with electromyograms (EMGs) from healthy subjects and patients with demyelinated disorders as reported in the literature. Simulation results indicate that the models used are rather promising tools in studying the main properties of compound action potentials in patients with demyelinated disorders which up till now have not been sufficiently well understood. PMID:14717030

  5. Combined central and peripheral demyelination: Clinical features, diagnostic findings, and treatment.

    PubMed

    Cortese, A; Franciotta, D; Alfonsi, E; Visigalli, N; Zardini, E; Diamanti, L; Prunetti, P; Osera, C; Gastaldi, M; Berzero, G; Pichiecchio, A; Piccolo, G; Lozza, A; Piscosquito, G; Salsano, E; Ceroni, M; Moglia, A; Bono, G; Pareyson, D; Marchioni, E

    2016-04-15

    Combined central and peripheral demyelination (CCPD) is rare, and current knowledge is based on case reports and small case series. The aim of our study was to describe the clinical features, diagnostic results, treatment and outcomes in a large cohort of patients with CCPD. Thirty-one patients entered this retrospective, observational, two-center study. In 20 patients (65%) CCPD presented, after an infection, as myeloradiculoneuropathy, encephalopathy, cranial neuropathy, length-dependent peripheral neuropathy, or pseudo-Guillain-Barré syndrome. Demyelinating features of peripheral nerve damage fulfilling European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) electrodiagnostic criteria for CIDP were found in 23 patients (74%), and spatial dissemination of demyelinating lesions on brain MRI fulfilling the 2010 McDonald criteria for multiple sclerosis (MS) in 11 (46%). Two thirds of the patients had a relapsing or progressive disease course, usually related to the appearance of new spinal cord lesions or worsening of the peripheral neuropathy, and showed unsatisfactory responses to high-dose corticosteroids and intravenous immunoglobulins. The clinical presentation of CCPD was severe in 22 patients (71%), who were left significantly disabled. Our data suggest that CCPD has heterogeneous features and shows frequent post-infectious onset, primary peripheral nervous system or central nervous system involvement, a monophasic or chronic disease course, inadequate response to treatments, and a generally poor outcome. We therefore conclude that the current diagnostic criteria for MS and CIDP may not fully encompass the spectrum of possible manifestations of CCPD, whose pathogenesis remains largely unknown. PMID:27000248

  6. Time-Dependent Progression of Demyelination and Axonal Pathology in MP4-Induced Experimental Autoimmune Encephalomyelitis

    PubMed Central

    Stormanns, Eva R.; Recks, Mascha S.; Kuerten, Stefanie

    2015-01-01

    Background Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) characterized by inflammation, demyelination and axonal pathology. Myelin basic protein/proteolipid protein (MBP-PLP) fusion protein MP4 is capable of inducing chronic experimental autoimmune encephalomyelitis (EAE) in susceptible mouse strains mirroring diverse histopathological and immunological hallmarks of MS. Limited availability of human tissue underscores the importance of animal models to study the pathology of MS. Methods Twenty-two female C57BL/6 (B6) mice were immunized with MP4 and the clinical development of experimental autoimmune encephalomyelitis (EAE) was observed. Methylene blue-stained semi-thin and ultra-thin sections of the lumbar spinal cord were assessed at the peak of acute EAE, three months (chronic EAE) and six months after onset of EAE (long-term EAE). The extent of lesional area and inflammation were analyzed in semi-thin sections on a light microscopic level. The magnitude of demyelination and axonal damage were determined using electron microscopy. Emphasis was put on the ventrolateral tract (VLT) of the spinal cord. Results B6 mice demonstrated increasing demyelination and severe axonal pathology in the course of MP4-induced EAE. In addition, mitochondrial swelling and a decrease in the nearest neighbor neurofilament distance (NNND) as early signs of axonal damage were evident with the onset of EAE. In semi-thin sections we observed the maximum of lesional area in the chronic state of EAE while inflammation was found to a similar extent in acute and chronic EAE. In contrast to the well-established myelin oligodendrocyte glycoprotein (MOG) model, disease stages of MP4-induced EAE could not be distinguished by assessing the extent of parenchymal edema or the grade of inflammation. Conclusions Our results complement our previous ultrastructural studies of B6 EAE models and suggest that B6 mice immunized with different antigens constitute

  7. Oligodendrocyte ablation as a tool to study demyelinating diseases

    PubMed Central

    Pajoohesh-Ganji, Ahdeah; Miller, Robert H.

    2016-01-01

    Multiple sclerosis (MS) is an autoimmune mediated neurodegenerative disease characterized by demyelination and oligodendrocyte (OL) loss in the central nervous system and accompanied by local inflammation and infiltration of peripheral immune cells. Although many risk factors and symptoms have been identified in MS, the pathology is complicated and the cause remains unknown. It is also unclear whether OL apoptosis precedes the inflammation or whether the local inflammation is the cause of OL death and demyelination. This review briefly discusses several models that have been developed to specifically ablate oligodendrocytes in an effort to separate the effects of demyelination from inflammation. PMID:27482202

  8. Oligodendrocyte ablation as a tool to study demyelinating diseases.

    PubMed

    Pajoohesh-Ganji, Ahdeah; Miller, Robert H

    2016-06-01

    Multiple sclerosis (MS) is an autoimmune mediated neurodegenerative disease characterized by demyelination and oligodendrocyte (OL) loss in the central nervous system and accompanied by local inflammation and infiltration of peripheral immune cells. Although many risk factors and symptoms have been identified in MS, the pathology is complicated and the cause remains unknown. It is also unclear whether OL apoptosis precedes the inflammation or whether the local inflammation is the cause of OL death and demyelination. This review briefly discusses several models that have been developed to specifically ablate oligodendrocytes in an effort to separate the effects of demyelination from inflammation. PMID:27482202

  9. Experimental Demyelination and Remyelination of Murine Spinal Cord by Focal Injection of Lysolecithin

    PubMed Central

    Keough, Michael B.; Jensen, Samuel K.; Yong, V. Wee

    2015-01-01

    Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system characterized by plaque formation containing lost oligodendrocytes, myelin, axons, and neurons. Remyelination is an endogenous repair mechanism whereby new myelin is produced subsequent to proliferation, recruitment, and differentiation of oligodendrocyte precursor cells into myelin-forming oligodendrocytes, and is necessary to protect axons from further damage. Currently, all therapeutics for the treatment of multiple sclerosis target the aberrant immune component of the disease, which reduce inflammatory relapses but do not prevent progression to irreversible neurological decline. It is therefore imperative that remyelination-promoting strategies be developed which may delay disease progression and perhaps reverse neurological symptoms. Several animal models of demyelination exist, including experimental autoimmune encephalomyelitis and curprizone; however, there are limitations in their use for studying remyelination. A more robust approach is the focal injection of toxins into the central nervous system, including the detergent lysolecithin into the spinal cord white matter of rodents. In this protocol, we demonstrate that the surgical procedure involved in injecting lysolecithin into the ventral white matter of mice is fast, cost-effective, and requires no additional materials than those commercially available. This procedure is important not only for studying the normal events involved in the remyelination process, but also as a pre-clinical tool for screening candidate remyelination-promoting therapeutics. PMID:25867716

  10. Multiple sclerosis: a role for astroglia in active demyelination suggested by class II MHC expression and ultrastructural study.

    PubMed

    Lee, S C; Moore, G R; Golenwsky, G; Raine, C S

    1990-03-01

    Central nervous system (CNS) tissue was studied by immunocytochemistry and electron microscopy from three cases of multiple sclerosis (MS) in which evidence of ongoing myelin breakdown could be documented. The study focussed upon the role of glial cells in the pathogenesis of demyelination. In acute MS, demyelination involved the vesicular dissolution of myelin from intact axons and a paucity of fibrillary astrogliosis. Foamy macrophages, many of them probably derived from transformed and recently proliferated microglia, contained recognizable myelin debris and lipid droplets and were abundant throughout the lesions. These cells formed the major phagocytic population and stained positively for class II major histocompatibility complex antigens (HLA-DR; Ia). In acute MS lesions, rounded astrocytes were encountered which possessed membrane-bound compartments enclosing phagocytosed fragments of myelin basic protein-positive debris. Despite the superficial resemblance of these cells to foamy macrophages, the presence of intermediate filaments, glycogen granules and diffuse glial fibrillary acidic protein positivity supported an astroglial identity. Astrocyte processes were involved in myelin removal and invested recently demyelinated axons. Hypertrophic fibrous astrocytes were common in chronic active lesions, were capable of myelin degradation and on occasion, contained myelin debris attached to clathrin-coated pits. These astrocytes were sometimes Ia+. Oligodendrocytes were depleted from the center of active lesions but were numerous at the lesion margin, suggesting survival and proliferation. They stained positively for myelin-associated glycoprotein, a marker for immature oligodendrocytes. However, they were invariably Ia-. The findings confirm and further support a role for the astrocyte as both an antigen presenting cell and a phagocyte in the CNS during MS. PMID:2307980

  11. Diffusion-Weighted Magnetic Resonance Imaging Characterization of White Matter Injury Produced by Axon-Sparing Demyelination and Severe Contusion Spinal Cord Injury in Rats.

    PubMed

    Talbott, Jason F; Nout-Lomas, Yvette S; Wendland, Michael F; Mukherjee, Pratik; Huie, J Russell; Hess, Christopher P; Mabray, Marc C; Bresnahan, Jacqueline C; Beattie, Michael S

    2016-05-15

    Alterations in magnetic resonance imaging (MRI)-derived measurements of water diffusion parallel (D∥) and perpendicular (D⊥) to white matter tracts have been specifically attributed to pathology of axons and myelin, respectively. We test the hypothesis that directional diffusion measurements can distinguish between axon-sparing chemical demyelination and severe contusion spinal cord white matter injury. Adult rats received either unilateral ethidium bromide (EB) microinjections (chemical demyelination) into the lateral funiculus of the spinal cord at C5 or were subjected to unilateral severe contusion spinal cord injury (SCI). Diffusion MRI metrics in the lateral funiculus were analyzed at early and late time-points following injury and correlated with histology. Early EB-demyelination resulted in a significant elevation in D⊥ and significant reduction in D∥ at the injury epicenter, with histological evidence of uniform axon preservation. Alterations in D⊥ and D∥ at the epicenter of early EB-demyelination were not significantly different from those observed with severe contusion at the epicenter, where histology demonstrated severe combined axonal and myelin injury. Diffusion abnormalities away from the injury epicenter were seen with contusion injury, but not with EB-demyelination. Chronic EB lesions underwent endogenous remyelination with normalization of diffusion metrics, whereas chronic contusion resulted in persistently altered diffusivities. In the early setting, directional diffusion measurements at the injury epicenter associated with chemical demyelination are indistinguishable from those seen with severe contusive SCI, despite dramatic pathologic differences between injury models. Caution is advised in interpretation of diffusion metrics with respect to specific white matter structural alterations. Diffusion analysis should not be limited to the epicenter of focal spinal lesions as alterations marginal to the epicenter are useful for

  12. Dynamic impact of brief electrical nerve stimulation on the neural immune axis-polarization of macrophages toward a pro-repair phenotype in demyelinated peripheral nerve.

    PubMed

    McLean, Nikki A; Verge, Valerie M K

    2016-09-01

    Demyelinating peripheral nerves are infiltrated by cells of the monocyte lineage, including macrophages, which are highly plastic, existing on a continuum from pro-inflammatory M1 to pro-repair M2 phenotypic states. Whether one can therapeutically manipulate demyelinated peripheral nerves to promote a pro-repair M2 phenotype remains to be elucidated. We previously identified brief electrical nerve stimulation (ES) as therapeutically beneficial for remyelination, benefits which include accelerated clearance of macrophages, making us theorize that ES alters the local immune response. Thus, the impact of ES on the immune microenvironment in the zone of demyelination was examined. Adult male rat tibial nerves were focally demyelinated via 1% lysophosphatidyl choline (LPC) injection. Five days later, half underwent 1 hour 20 Hz sciatic nerve ES proximal to the LPC injection site. ES had a remarkable and significant impact, shifting the macrophage phenotype from predominantly pro-inflammatory/M1 toward a predominantly pro-repair/M2 one, as evidenced by an increased incidence of expression of M2-associated phenotypic markers in identified macrophages and a decrease in M1-associated marker expression. This was discernible at 3 days post-ES (8 days post-LPC) and continued at the 5 day post-ES (10 days post-LPC) time point examined. ES also affected chemokine (C-C motif) ligand 2 (CCL2; aka MCP-1) expression in a manner that correlated with increases and decreases in macrophage numbers observed in the demyelination zone. The data establish that briefly increasing neuronal activity favorably alters the immune microenvironment in demyelinated nerve, rapidly polarizing macrophages toward a pro-repair phenotype, a beneficial therapeutic concept that may extend to other pathologies. GLIA 2016;64:1546-1561. PMID:27353566

  13. Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy.

    PubMed

    Vendrely, Aurélie; Bienvenu, Boris; Gasnault, Jacques; Thiebault, Jean Baptiste; Salmon, Dominique; Gray, Françoise

    2005-04-01

    HAART-induced immune restoration is beneficial for patients with AIDS-related progressive multifocal leukoencephalopathy (PML). However, in rare instances, an immune-reconstitution inflammatory syndrome (IRIS) may cause paradoxical clinical deterioration. We report the neuropathological study of an AIDS patient who presented with progressive cognitive deterioration; CD4(+) count was 117 and the HIV viral load >10(4); imaging showed non-enhancing lesions consistent with PML. Following initiation of HAART, CD4(+) was 300 and HIV viral load <10(3), but his neurological symptoms continued to deteriorate. Imaging revealed an increase in the size and number of lesions and enhancement of all the lesions. A stereotactic biopsy showed severe inflammatory and demyelinating lesions with marked infiltration by macrophages and T lymphocytes in the absence of a detectable infectious agent. Despite high doses of steroids, the patient died 3 months after admission. Autopsy showed two types of lesions: (1) active inflammatory PML changes with abundant JC virus, and intraparenchymal and perivascular infiltration by T lymphocytes, and (2) acute perivenous leukoencephalitis devoid of JC virus. Most lymphocytes were CD8(+) lymphocytes; CD4(+) lymphocytes were virtually absent. Two pathological reactions were associated with the paradoxical clinical deterioration related to dysregulation of the immune response characteristic of IRIS in PML: (1) an accentuation of JCV infection, and (2) a nonspecific acute perivenous leukoencephalitis. We suggest that both these types of lesions are due to an imbalance of CD8(+)/CD4(+) T cells, with massive infiltration of the cerebral parenchyma by CD8(+) cytotoxic T lymphocytes in the absence of sufficient CD4(+) response. Better understanding of the mechanisms of the IRIS may enable prevention or cure of this severe, sometimes fatal complication of HAART. PMID:15739098

  14. Overlapping demyelinating syndromes and anti-NMDA receptor encephalitis

    PubMed Central

    Titulaer, Maarten J.; Höftberger, Romana; Iizuka, Takahiro; Leypoldt, Frank; McCracken, Lindsey; Cellucci, Tania; Benson, Leslie A.; Shu, Huidy; Irioka, Takashi; Hirano, Makito; Singh, Gagandeep; Calvo, Alvaro Cobo; Kaida, Kenichi; Morales, Pamela S.; Wirtz, Paul W.; Yamamoto, Tomotaka; Reindl, Markus; Rosenfeld, Myrna R.; Graus, Francesc; Saiz, Albert; Dalmau, Josep

    2014-01-01

    Objective To report the clinical, radiological, and immunological association of demyelinating disorders with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Methods Clinical and radiological analysis of a cohort of 691 patients with anti-NMDAR encephalitis. Determination of antibodies to NMDAR, aquaporin-4 (AQP4) and myelin oligodendrocyte glycoprotein (MOG) was performed using brain immunohistochemistry and cell-based assays. Results Twenty-three of 691 patients with anti-NMDAR encephalitis had prominent MRI and/or clinical features of demyelination. Group 1 included 12 patients in whom anti-NMDAR encephalitis was preceded or followed by independent episodes of NMO-spectrum disorder (5 cases, 4 anti-AQP4-positive), or brainstem or multifocal demyelinating syndromes (7 cases, all anti-MOG-positive). Group 2 included 11 patients in whom anti-NMDAR encephalitis occurred simultaneously with MRI and symptoms compatible with demyelination (5 AQ4-positive, 2 MOG-positive). Group 3 (136 controls) included 50 randomly selected patients with typical anti-NMDAR encephalitis, 56 with NMO, and 30 with multiple sclerosis: NMDAR-antibodies were detected only in the 50 anti-NMDAR patients, MOG-antibodies in 3/50 anti-NMDAR and 1/56 NMO patients, and AQP4-antibodies in 48/56 NMO and 1/50 anti-NMDAR patients (p<0.0001 for all comparisons with Groups 1 and 2). Most patients improved with immunotherapy, but compared with anti-NMDAR encephalitis the demyelinating episodes required more intensive therapy and resulted in more residual deficits. Only 1/23 NMDAR patients with signs of demyelination had ovarian teratoma compared with 18/50 anti-NMDAR controls (p=0.011) Interpretation Patients with anti-NMDAR encephalitis may develop concurrent or separate episodes of demyelinating disorders, and conversely patients with NMO or demyelinating disorders with atypical symptoms (e.g., dyskinesias, psychosis) may have anti-NMDAR encephalitis. PMID:24700511

  15. Acute Demyelinating Disease after Oral Therapy with Herbal Extracts

    PubMed Central

    Kostianovsky, Alex; Maskin, Patricio; Noriega, María M.; Soler, Cristina; Bonelli, Ignacio; Riley, Claire S.; O'Connor, Kevin C.; Saubidet, Cristi´n López; Alvarez, Paulino A.

    2011-01-01

    Central nervous system demyelinating processes such as multiple sclerosis and acute disseminated encephalomyelitis constitute a group of diseases not completely understood in their physiopathology. Environmental and toxic insults are thought to play a role in priming autoimmunity. The aim of the present report is to describe a case of acute demyelinating disease with fatal outcome occurring 15 days after oral exposure to herbal extracts. PMID:21738505

  16. In Patients with Coronary Artery Disease and Type 2 Diabetes, SIRT1 Expression in Circulating Mononuclear Cells Is Associated with Levels of Inflammatory Cytokines but Not with Coronary Lesions

    PubMed Central

    Li, Yuanmin; Ni, Jing; Guo, Rong; Li, Weiming

    2016-01-01

    While SIRT1 is significantly associated with atherosclerosis and diabetic complications, its relevance to coronary lesions in patients with coronary artery disease and type 2 diabetes has not been specifically investigated. Thus, we assessed SIRT1 expression in peripheral blood mononuclear cells in these patients. We found that SIRT1 expression did not significantly correlate with syntax scores from coronary angiography (p > 0.05). Notably, plasma levels of the inflammatory cytokines tumor necrosis factor-α, monocyte chemoattractant protein-1, and high-sensitivity C-reactive protein were markedly higher in diabetic patients (p < 0.05). In addition, SIRT1 expression was negatively correlated with levels of these cytokines, as well as that of interleukin-6 (p < 0.05). In summary, the data indicate that SIRT1 expression in peripheral blood mononuclear cells is significantly correlated with inflammatory cytokines levels in patients with coronary artery disease and type 2 diabetes but not with the severity of coronary lesions. PMID:27123454

  17. Evaluation of Parotid Lesions.

    PubMed

    Kuan, Edward C; Mallen-St Clair, Jon; St John, Maie A

    2016-04-01

    The differential diagnosis of a parotid lesion is broad, and the otolaryngologist must consider inflammatory, neoplastic, autoimmune, traumatic, infectious, or congenital causes. A comprehensive history and physical examination, in conjunction with judicious use of radiographic imaging (MRI, computed tomography, ultrasonography, nuclear medicine studies), laboratory studies, and pathologic analysis (fine-needle aspiration, core biopsy, incisional biopsy), facilitates making an accurate diagnosis. This article reviews the key history and physical elements and adjunctive diagnostic tools available for working up parotid lesions. PMID:26902978

  18. Oxidative Stress and Neurobiology of Demyelination.

    PubMed

    Ljubisavljevic, Srdjan

    2016-01-01

    Despite a large amount of research which aims at defining the pathophysiology of human demyelination (i.e., multiple sclerosis), etiological bases of disease have been unknown so far. The point of intersection of all assumed etiological factors, which are mainly based upon immunological cascades, is neuroinflammation. The precise definition of the place and role of all pathogenetic factors in the occurrence and development of the disease is of crucial importance for understanding the clinical nature and for finding more effective therapeutic options. There are few studies whose results give more precise data about the role and the importance of other factors in neuroinflammation, besides immunological ones, with regard to clinical and paraclinical correlates of the disease. The review integrates results found in previously performed studies which have evaluated oxidative stress participation in early and late neuroinflammation. The largest number of studies indicates that the use of antioxidants affects the change of neuroinflammation course under experimental conditions, which is reflected in the reduction of the severity and the total reversibility in clinical presentation of the disease, the faster achieving of remission, and the delayed and slow course of neuroinflammation. Therapies based on the knowledge of redox biology targeting free radical generation hold great promise in modulation of the neuroinflammation and its clinical presentations. PMID:25502298

  19. Piecemeal degranulation of mast cells in the inflammatory eyelid lesions of interleukin-4 transgenic mice. Evidence of mast cell histamine release in vivo by diamine oxidase-gold enzyme-affinity ultrastructural cytochemistry.

    PubMed

    Dvorak, A M; Tepper, R I; Weller, P F; Morgan, E S; Estrella, P; Monahan-Earley, R A; Galli, S J

    1994-06-15

    We used light and electron microscopy to analyze the eyelid inflammation that develops in transgenic mice that overexpress interleukin-4 (IL-4; Tepper et al, Cell 62:457, 1990). Analysis of alkaline Giemsa-stained plastic sections examined by light microscopy (Dvorak et al, J Exp Med 132:558, 1970), as well as by routine transmission electron microscopy, indicated that the mast cells in the inflammatory eyelid lesions were undergoing piecemeal degranulation, a form of secretion in which the cells' cytoplasmic granules exhibit characteristic morphologic changes that are thought to be associated with the prolonged, vesicle-mediated release of the granules' constituents. Moreover, by using a newly reported enzyme affinity-gold method, which stains histamine based on binding to diamine oxidase-gold (Dvorak et al, J Histochem Cytochem 41:787, 1993), we show that these activated mast cells had released much of their histamine content. The eyelid lesions also exhibited increased numbers of mast cells; interstitial fibrosis, particularly around cutaneous nerves and blood vessels; activated fibroblasts; focal axonal damage; venules with endothelial cells containing numerous vesiculo-vacuolar organelles; and infiltrates of neutrophils and eosinophils. Our findings illustrate that overexpression of the IL-4 gene in vivo can result in eyelid lesions associated with piecemeal degranulation of mast cells, as well as tissue fibrosis and a variety of other pathologic changes. These results also represent the first direct morphologic evidence for histamine secretion by mast cells in vivo. PMID:7515717

  20. Hearing disorders in brainstem lesions.

    PubMed

    Celesia, Gastone G

    2015-01-01

    Auditory processing can be disrupted by brainstem lesions. It is estimated that approximately 57% of brainstem lesions are associated with auditory disorders. However diseases of the brainstem usually involve many structures, producing a plethora of other neurologic deficits, often relegating "auditory symptoms in the background." Lesions below or within the cochlear nuclei result in ipsilateral auditory-processing abnormalities detected in routine testing; disorders rostral to the cochlear nuclei may result in bilateral abnormalities or may be silent. Lesions in the superior olivary complex and trapezoid body show a mixture of ipsilateral, contralateral, and bilateral abnormalities, whereas lesions of the lateral lemniscus, inferior colliculus, and medial geniculate body do not affect peripheral auditory processing and result in predominantly subtle contralateral abnormalities that may be missed by routine auditory testing. In these cases psychophysical methods developed for the evaluation of central auditory function should be employed (e.g., dichotic listening, interaural time perception, sound localization). The extensive connections of the auditory brainstem nuclei not only are responsible for binaural interaction but also assure redundancy in the system. This redundancy may explain why small brainstem lesions are sometimes clinically silent. Any disorder of the brainstem (e.g., neoplasms, vascular disorders, infections, trauma, demyelinating disorders, neurodegenerative diseases, malformations) that involves the auditory pathways and/or centers may produce hearing abnormalities. PMID:25726288

  1. TREM2 regulates microglial cell activation in response to demyelination in vivo

    PubMed Central

    Cantoni, Claudia; Bollman, Bryan; Licastro, Danilo; Xie, Mingqiang; Mikesell, Robert; Schmidt, Robert; Yuede, Carla M.; Galimberti, Daniela; Olivecrona, Gunilla; Klein, Robyn S.; Cross, Anne H.; Otero, Karel; Piccio, Laura

    2015-01-01

    Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2−/−) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2−/− microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2−/− microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. PMID:25631124

  2. Autophagic myelin destruction by schwann cells during wallerian degeneration and segmental demyelination.

    PubMed

    Jang, So Young; Shin, Yoon Kyung; Park, So Young; Park, Joo Youn; Lee, Hye Jeong; Yoo, Young Hyun; Kim, Jong Kuk; Park, Hwan Tae

    2016-05-01

    As lysosomal hydrolysis has long been suggested to be responsible for myelin clearance after peripheral nerve injury, in this study, we investigated the possible role of autophagolysosome formation in myelin phagocytosis by Schwann cells and its final contribution to nerve regeneration. We found that the canonical formation of autophagolysosomes was induced in demyelinating Schwann cells after injury, and the inhibition of autophagy via Schwann cell-specific knockout of the atg7 gene or pharmacological intervention of lysosomal function caused a significant delay in myelin clearance. However, Schwann cell dedifferentiation, as demonstrated by extracellular signal-regulated kinase activation and c-Jun induction, and redifferentiation were not significantly affected, and thus the entire repair program progressed normally in atg7 knockout mice. Finally, autophagic Schwann cells were also found during segmental demyelination in a mouse model of inflammatory peripheral neuropathy. Together, our findings suggest that autophagy is the self-myelin destruction mechanism of Schwann cells, but mechanistically, it is a process distinct from Schwann cell plasticity for nerve repair. GLIA 2016;64:730-742. PMID:26712109

  3. 17 β-estradiol Protects Male Mice from Cuprizone-induced Demyelination and Oligodendrocyte Loss

    PubMed Central

    Taylor, Lorelei C; Puranam, Kasturi; Gilmore, Wendy; Ting, Jenny P-Y.; Matsushima, G.K.

    2010-01-01

    In addition to regulating reproductive functions in the brain and periphery, estrogen has trophic and neuroprotective functions in the central nervous system (CNS). Estrogen administration has been demonstrated to provide protection in several animal models of CNS disorders, including stroke, brain injury, epilepsy, Parkinson’s disease, Alzheimer’s disease, age-related cognitive decline and multiple sclerosis. Here, we use a model of toxin-induced oligodendrocyte death which results in demyelination, reactive gliosis, recruitment of oligodendrocyte precursor cells and subsequent remyelination to study the potential benefit of 17β-estradiol (E2) administration in male mice. The results indicate that E2 partially ameliorates loss of oligodendrocytes and demyelination in the corpus callosum. This protection is accompanied by a delay in microglia accumulation as well as reduced mRNA expression of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFα), and insulin-like growth factor-1 (IGF-1). E2 did not significantly alter the accumulation of astrocytes or oligodendrocyte precursor cells, or remyelination. These data obtained from a toxin-induced, T cell-independent model using male mice provide an expanded view of the beneficial effects of estrogen on oligodendrocyte and myelin preservation. PMID:20347981

  4. Ozone Therapy in Ethidium Bromide-Induced Demyelination in Rats: Possible Protective Effect.

    PubMed

    Salem, Neveen A; Assaf, Naglaa; Ismail, Manal F; Khadrawy, Yasser A; Samy, Mohga

    2016-08-01

    Multiple sclerosis, an autoimmune inflammatory disease of the central nervous system, is characterized by excessive demyelination. The study aimed to investigate the possible protective effect of ozone (O3) therapy in ethidium bromide (EB)-induced demyelination in rats either alone or in combination with corticosteroids in order to decrease the dose of steroid therapy. Rats were divided into Group (1) normal control rats received saline, Group (2) Sham-operated rats received saline, Group (3) Sham-operated rats received vehicle (oxygen), Group (4) EB-treated rats received EB, Group (5) EB-treated rats received O3, Group (6) EB-treated rats received methylprednisolone (MP), and Group (7) EB-treated rats received half the dose of MP concomitant with O3. EB-treated rats showed a significant increase in the number of footfalls in the grid walk test, decreased brain GSH, and paraoxonase-1 enzyme activity, whereas brain MDA, TNF-α, IL-1β, INF-γ, Cox-2 immunoreactivity, and p53 protein levels were increased. A significant decline in brain serotonin, dopamine, norepinephrine, and MBP immunoreactivity was also reported. Significant improvement of the above-mentioned parameters was demonstrated with the administration of either MP or O3, whereas best amelioration was achieved by combining half the dose of MP with ozone. PMID:26467344

  5. Erythromelalgia-like presentation of chronic acquired demyelinating polyneuropathy in a setting of past alcohol abuse.

    PubMed

    Chuquilin, Miguel; Dhand, Upinder K

    2016-02-01

    Erythromelalgia may be primary or secondary to an underlying medical condition. Association with small fiber neuropathy and axonal large fiber peripheral neuropathy has been described. Erythromelalgia in the setting of acquired demyelinating neuropathy has not been reported. We report a 52-year-old woman with severe erythromelalgia, pain and burning, progressive weakness, hyporeflexia and distal pan-sensory deficits. Cerebrospinal fluid protein was 219 mg/dL. Nerve conduction study revealed extreme (ten-fold) prolongation of distal motor latencies, markedly slow motor nerve conduction, reduced terminal latency index, reduced distal compound muscle action potential (CMAP) amplitude, possible conduction blocks, and distal denervation. Treatment with intravenous immunoglobulin, prednisone and azathioprine resulted in marked clinical and electrophysiological improvement. Our patient fulfills the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP); however, the unique electrodiagnostic features and presentation with erythromelalgia may represent a CIDP variant or a novel dysimmune neuropathy, or may partly be related to neurotoxic effects of prior alcohol abuse. PMID:26804376

  6. Sphingosine-1-phosphate receptor antagonism enhances proliferation and migration of engrafted neural progenitor cells in a model of viral-induced demyelination.

    PubMed

    Blanc, Caroline A; Grist, Jonathan J; Rosen, Hugh; Sears-Kraxberger, Ilse; Steward, Oswald; Lane, Thomas E

    2015-10-01

    The oral drug FTY720 affects sphingosine-1-phosphate (S1P) signaling on targeted cells that bear the S1P receptors S1P1, S1P3, S1P4, and S1P5. We examined the effect of FTY720 treatment on the biology of mouse neural progenitor cells (NPCs) after transplantation in a viral model of demyelination. Intracerebral infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in an acute encephalomyelitis, followed by demyelination similar in pathology to the human demyelinating disease, multiple sclerosis. We have previously reported that intraspinal transplantation of mouse NPCs into JHMV-infected animals resulted in selective colonization of demyelinated lesions, preferential differentiation into oligodendroglia accompanied by axonal preservation, and increased remyelination. Cultured NPCs expressed transcripts for S1P receptors S1P1, S1P2, S1P3, S1P4, and S1P5. FTY720 treatment of cultured NPCs resulted in increased mitogen-activated protein kinase phosphorylation and migration after exposure to the chemokine CXCL12. Administration of FTY720 to JHMV-infected mice resulted in enhanced migration and increased proliferation of transplanted NPCs after spinal cord engraftment. FTY720 treatment did not improve clinical disease, diminish neuroinflammation or the severity of demyelination, nor increase remyelination. These findings argue that FTY720 treatment selectively increases NPC proliferation and migration but does not either improve clinical outcome or enhance remyelination after transplantation into animals in which immune-mediated demyelination is initiated by the viral infection of the central nervous system. PMID:26435414

  7. Noninfectious penile lesions.

    PubMed

    Teichman, Joel M H; Sea, Jason; Thompson, Ian M; Elston, Dirk M

    2010-01-15

    Family physicians commonly diagnose and manage penile cutaneous lesions. Noninfectious lesions may be classified as inflammatory and papulosquamous (e.g., psoriasis, lichen sclerosus, angiokeratomas, lichen nitidus, lichen planus), or as neoplastic (e.g., carcinoma in situ, invasive squamous cell carcinoma). The clinical presentation and appearance of the lesions guide the diagnosis. Psoriasis presents as red or salmon-colored plaques with overlying scales, often with systemic lesions. Lichen sclerosus presents as a phimotic, hypopigmented prepuce or glans penis with a cellophane-like texture. Angiokeratomas are typically asymptomatic, well-circumscribed, red or blue papules, whereas lichen nitidus usually produces asymptomatic pinhead-sized, hypopigmented papules. The lesions of lichen planus are pruritic, violaceous, polygonal papules that are typically systemic. Carcinoma in situ should be suspected if the patient has velvety red or keratotic plaques of the glans penis or prepuce, whereas invasive squamous cell carcinoma presents as a painless lump, ulcer, or fungating irregular mass. Some benign lesions, such as psoriasis and lichen planus, can mimic carcinoma in situ or squamous cell carcinoma. Biopsy is indicated if the diagnosis is in doubt or neoplasm cannot be excluded. The management of benign penile lesions usually involves observation or topical corticosteroids; however, neoplastic lesions generally require surgery. PMID:20082512

  8. Overcoming failure to repair demyelination in EAE: gamma-secretase inhibition of Notch signaling.

    PubMed

    Jurynczyk, Maciej; Jurewicz, Anna; Bielecki, Bartosz; Raine, Cedric S; Selmaj, Krzysztof

    2008-02-15

    In multiple sclerosis (MS), myelin destroyed by the immune attack is not effectively repaired by oligodendrocytes (OLs) and MS foci eventually undergo glial scarring. Although oligodendrocyte precursor cells (OPCs) are normally recruited to the lesion areas, they fail to mature and remyelinate the damaged fibers. Activation of the Notch pathway has been shown to inhibit OPC differentiation and to hamper their ability to produce myelin during CNS development. We have recently shown that inhibition of gamma-secretase within the CNS of SJL/J mice with experimental autoimmune encephalomyelitis (EAE) blocks Notch pathway activation in OLs, promotes remyelination, reduces axonal damage and significantly enhances clinical recovery from the disease. Our results suggest that inhibiting the non-myelin permissive environment maintained by Notch pathways within the mature CNS offers a new strategy for treating autoimmune demyelination, including MS. PMID:17949754

  9. A novel and robust conditioning lesion induced by ethidium bromide

    PubMed Central

    Hollis, Edmund R; Ishiko, Nao; Tolentino, Kristine; Doherty, Ernest; Rodriguez, Maria J.; Calcutt, Nigel A.; Zou, Yimin

    2015-01-01

    Molecular and cellular mechanisms underlying the peripheral conditioning lesion remain unsolved. We show here that injection of a chemical demyelinating agent, ethidium bromide, into the sciatic nerve induces a similar set of regeneration-associated genes and promotes a 2.7-fold greater extent of sensory axon regeneration in the spinal cord than sciatic nerve crush. We found that more severe peripheral demyelination correlates with more severe functional and electrophysiological deficits, but more robust central regeneration. Ethidium bromide injection does not activate macrophages at the demyelinated sciatic nerve site, as observed after nerve crush, but briefly activates macrophages in the dorsal root ganglion. This study provides a new method for investigating the underlying mechanisms of the conditioning response and suggests that loss of the peripheral myelin may be a major signal to change the intrinsic growth state of adult sensory neurons and promote regeneration. PMID:25541322

  10. Anti-inflammatory Therapy With Simvastatin Improves Neuroinflammation and CNS Function in a Mouse Model of Metachromatic Leukodystrophy.

    PubMed

    Stein, Axel; Stroobants, Stijn; Gieselmann, Volkmar; D'Hooge, Rudi; Matzner, Ulrich

    2015-07-01

    Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by a functional deficiency of the lysosomal enzyme arylsulfatase A. The prevailing late-infantile variant of MLD is characterized by widespread and progressive demyelination of the central nervous system (CNS) causing death during childhood. In order to gain insight into the pathomechanism of the disease and to identify novel therapeutic targets, we analyzed neuroinflammation in two mouse models reproducing a mild, nondemyelinating, and a more severe, demyelinating, variant of MLD, respectively. Microgliosis and upregulation of cytokine/chemokine levels were clearly more pronounced in the demyelinating model. The analysis of the temporal cytokine/chemokine profiles revealed that the onset of demyelination is preceded by a sustained elevation of the macrophage inflammatory protein (MIP)-1α followed by an upregulation of MIP-1β, monocyte chemotactic protein (MCP)-1, and several interleukins. The tumor necrosis factor (TNF)-α remains unchanged. Treatment of the demyelinating mouse model with the nonsteroidal anti-inflammatory drug simvastatin reduced neuroinflammation, improved the swimming performance and ataxic gait, and retarded demyelination of the spinal cord. Our data suggest that neuroinflammation is causative for demyelination in MLD mice and that anti-inflammatory treatment might be a novel therapeutic option to improve the CNS function of MLD patients. PMID:25896249

  11. Vitamin D3 attenuates oxidative stress and cognitive deficits in a model of toxic demyelination

    PubMed Central

    Tarbali, Sepideh; Khezri, Shiva

    2016-01-01

    Objective(s): Multiple sclerosis (MS) is a demyelinating disease. The prevalence of MS is highest where environmental supplies of vitamin D are low. Cognitive deficits have been observed in patients with MS. Oxidative damage may contribute to the formation of MS lesions. Considering the involvement of hippocampus in MS, an attempt is made in this study to investigate the effects of vitamin D3 on behavioral process and the oxidative status in the dorsal hippocampus (CA1 area) following the induction of experimental demyelination in rats. Materials and Methods: Animals were divided into six groups. Control group: animals received no surgery and treatment; saline group: animals received normal saline; sham group: animals received 150 μl sesame oil IP; vitamin D3 group: animals received 5 μg/kg vitamin D3 IP; lysophosphatidyl choline (LPC) group (toxic demyelination’s model): animals received LPC by stereotaxic intra-hippocampal injection of 2 μl LPC in CA1 area; Vitamin D3- treated group: animals were treated with vitamin D3 at doses of 5 μg/kg IP for 7 and 21 days post lesion. The spatial memory, biochemical parameters including catalase (CAT) activities and lipid peroxidation levels were investigated. Results: Animals in LPC group had more deficits in spatial memory than the control group in radial arm maze. Vitamin D3 significantly improved spatial memory compared to LPC group. Also, results indicated that vitamin D3 caused a decrease in lipid peroxidation levels and an increase in CAT activities. Conclusion: Current findings suggest that vitamin D3 may have a protective effect on cognitive deficits and oxidative stress in toxic demyelination’s model. PMID:27096068

  12. Probiotics Lactobacillus plantarum and bifidobacterium B94: cognitive function in demyelinated model

    PubMed Central

    Goudarzvand, Mahdi; Rasouli koohi, Samira; Khodaii, Zohreh; Soleymanzadeh Moghadam, Somayeh

    2016-01-01

    Background: Multiple Sclerosis (MS) is a disease of the immune system that creates damage of Learning and memory in that. Using probiotic supplements is recommended for preventing MS disease and improving memory. This study aimed to investigate the effect of Lactobacillus plantarum (LP) and bifidobacterium B94 (BB94), on acquisition phase of spatial memory in the local demyelination of rats` hippocampus. Methods: In this study, 32 male Wistar rats were divided into control, damage group and treatment groups. Treatment groups were including (LP) and (BB94). After the induction of demyelination by 3 μl of EB into the right dentate gyrus of the hippocampus in treatment groups, 1.5×108 probiotic bacteria were administered by gavage for 28 days. Data was analyzed using one-way ANOVA and Tukey post-hoc tests (p≤0.05). Results: Findings demonstrated that injection of EB caused a significant increase in traveled distance (p<0.01) and also escape latency (p<0.05) compared with control group. Also, effect administrations of (LP) and (BB94) on traveled distance and escape latency were reviewed, and it was determined that administration of them do not cause significant reduction in the traveled distance compared with the lesion group. Also mentioned probiotics has no significant effect on swimming speed compared with lesion and saline groups. Conclusion: According to some studies, probiotics have a positive impact on improving the performance of spatial memory and learning, although the results of the current study could not indicate finality of this assumption. It seems that more researches is needed on this subject. PMID:27579282

  13. Hypervascular liver lesions.

    PubMed

    Kamaya, Aya; Maturen, Katherine E; Tye, Grace A; Liu, Yueyi I; Parti, Naveen N; Desser, Terry S

    2009-10-01

    Hypervascular hepatocellular lesions include both benign and malignant etiologies. In the benign category, focal nodular hyperplasia and adenoma are typically hypervascular. In addition, some regenerative nodules in cirrhosis may be hypervascular. Malignant hypervascular primary hepatocellular lesions include hepatocellular carcinoma, fibrolamellar carcinoma, and peripheral cholangiocarcinoma. Vascular liver lesions often appear hypervascular because they tend to follow the enhancement of the blood pool; these include hemangiomas, arteriovenous malformations, angiosarcomas, and peliosis. While most gastrointestinal malignancies that metastasize to the liver will appear hypovascular on arterial and portal-venous phase imaging, certain cancers such as metastatic neuroendocrine tumors (including pancreatic neuroendocrine tumors, carcinoid, and gastrointestinal stromal tumors) tend to produce hypervascular metastases due to the greater recruitment of arterial blood supply. Finally, rare hepatic lesions such as glomus tumor and inflammatory pseudotumor may have a hypervascular appearance. PMID:19842564

  14. Absence of CCL2 and CCL3 Ameliorates Central Nervous System Grey Matter But Not White Matter Demyelination in the Presence of an Intact Blood-Brain Barrier.

    PubMed

    Janssen, Katharina; Rickert, Mira; Clarner, Tim; Beyer, Cordian; Kipp, Markus

    2016-04-01

    A broad spectrum of diseases is characterized by myelin abnormalities, oligodendrocyte pathology, and concomitant glia activation, among multiple sclerosis (MS). Our knowledge regarding the factors triggering gliosis and demyelination is scanty. Chemokines are pivotal for microglia and astrocyte activation and orchestrate critical steps during the formation of central nervous system (CNS) demyelinating lesions. Redundant functions of chemokines complicate, however, the study of their functional relevance. We used the cuprizone model to study redundant functions of two chemokines, CCL2/MCP1 and CCL3/MIP1α, which are critically involved in the pathological process of cuprizone-induced demyelination. First, we generated a mutant mouse strain lacking functional genes of both chemokines and demonstrated that double-mutant animals are viable, fertile, and do not present with gross abnormalities. Astrocytes and peritoneal macrophages, cultured form tissues of these animals did neither express CCL2 nor CCL3. Exposure to cuprizone resulted in increased CCL2 and CCL3 brain levels in wild-type but not mutant animals. Cuprizone-induced demyelination, oligodendrocyte loss, and astrogliosis were significantly ameliorated in the cortex but not corpus callosum of chemokine-deficient animals. In summary, we provide a novel powerful model to study the redundant function of two important chemokines. Our study reveals that chemokine function in the CNS redounds to region-specific pathophysiological events. PMID:25663168

  15. Pregnancy modulates precursor cell proliferation in a murine model of focal demyelination.

    PubMed

    Haddady, S; Low, H P; Billings-Gagliardi, S; Riskind, P N; Schwartz, W J

    2010-05-19

    In mice, pregnancy has been shown to have a beneficial effect on the endogenous repair of focal lysolecithin-induced CNS demyelinative lesions, enhancing the genesis of new oligodendrocytes and the degree of remyelination. To identify local cells undergoing mitosis in response to such lesions, we examined the time course of phospho-histone H3 (PH3) and myelin basic protein (MBP) expression by immunohistochemistry. After lysolecithin injection into the corpus callosum of virgin female mice, the number of dividing cells peaked about 48 h after injection and declined gradually to baseline by day 7; in pregnant mice, this initial peak was unchanged, but a new delayed peak on day 4 was induced. Colocalization data using PH3 and NG2 proteoglycan, or bromodeoxyuridine (BrdU) and oligodendrocyte transcription factor 1 (Olig1), suggested that about 75% of the proliferating cells on day 2, and about 40% of the cells on day 4, were likely of oligodendrocyte lineage; these differential percentages were of the same magnitude in both virgin and pregnant animals. Notably, the heightened proliferative response to focal lysolecithin injection during pregnancy was specific to gestational stage (early, but not late) and to lesion location (in the corpus callosum of the periventricular forebrain, but not in the caudal cerebellar peduncle of the hindbrain). PMID:20197083

  16. Influence of laser irradiation on demyelination of nervous fibers

    NASA Astrophysics Data System (ADS)

    Melnik, Nataly O.; Plaksij, Yu. S.; Mamilov, Serge A.

    2000-11-01

    Problem demyelinating diseases from actual in modern of neurology. Main disease of this group - multiple sclerosis, which morphological manifestation is the process demyelineation - disintegration of myelin, which covers axial cylinders of nervous filaments. The outcome of such damage is violation of realization of nervous impulses, dissonance of implement and coordination functions. Most typical the feature of a multiple sclerosis is origin of repeated remissions, which compact with indication remyelination. In development of disease the large role is played by modifications of immunological of a reactivity of an organism. The purpose of the title is development of new methods of treatment of a multiple sclerosis because of lasertherapy. For thsi purpose the influence of a laser exposure on demyelination and remyelination processes will be investigated, is investigated pathological fabrics at microscopic and submicroscopic levels. The study of proceses demyelination and remyelination will be conducted on experimental animals (rats), which are sick experimental allergic encephalomyelitis (EAE), that is the most adequate model of a multiple sclerosis. The patients' EAE animals will be subjected to treatment by a laser exposure. For want of it there will be determinate optimum lengths of waves, dozes and modes of laser radiation.

  17. Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis

    PubMed Central

    Wang, Yong; Sun, Peng; Wang, Qing; Trinkaus, Kathryn; Schmidt, Robert E.; Naismith, Robert T.; Song, Sheng-Kwei

    2015-01-01

    Axon injury/loss, demyelination and inflammation are the primary pathologies in multiple sclerosis lesions. Despite the prevailing notion that axon/neuron loss is the substrate of clinical progression of multiple sclerosis, the roles that these individual pathological processes play in multiple sclerosis progression remain to be defined. An imaging modality capable to effectively detect, differentiate and individually quantify axon injury/loss, demyelination and inflammation, would not only facilitate the understanding of the pathophysiology underlying multiple sclerosis progression, but also the assessment of treatments at the clinical trial and individual patient levels. In this report, the newly developed diffusion basis spectrum imaging was used to discriminate and quantify the underlying pathological components in multiple sclerosis white matter. Through the multiple-tensor modelling of diffusion weighted magnetic resonance imaging signals, diffusion basis spectrum imaging resolves inflammation-associated cellularity and vasogenic oedema in addition to accounting for partial volume effects resulting from cerebrospinal fluid contamination, and crossing fibres. Quantitative histological analysis of autopsied multiple sclerosis spinal cord specimens supported that diffusion basis spectrum imaging-determined cellularity, axon and myelin injury metrics closely correlated with those pathologies identified and quantified by conventional histological staining. We demonstrated in healthy control subjects that diffusion basis spectrum imaging rectified inaccurate assessments of diffusion properties of white matter tracts by diffusion tensor imaging in the presence of cerebrospinal fluid contamination and/or crossing fibres. In multiple sclerosis patients, we report that diffusion basis spectrum imaging quantitatively characterized the distinct pathologies underlying gadolinium-enhanced lesions, persistent black holes, non-enhanced lesions and non-black hole lesions, a

  18. Differentiation and quantification of inflammation, demyelination and axon injury or loss in multiple sclerosis.

    PubMed

    Wang, Yong; Sun, Peng; Wang, Qing; Trinkaus, Kathryn; Schmidt, Robert E; Naismith, Robert T; Cross, Anne H; Song, Sheng-Kwei

    2015-05-01

    Axon injury/loss, demyelination and inflammation are the primary pathologies in multiple sclerosis lesions. Despite the prevailing notion that axon/neuron loss is the substrate of clinical progression of multiple sclerosis, the roles that these individual pathological processes play in multiple sclerosis progression remain to be defined. An imaging modality capable to effectively detect, differentiate and individually quantify axon injury/loss, demyelination and inflammation, would not only facilitate the understanding of the pathophysiology underlying multiple sclerosis progression, but also the assessment of treatments at the clinical trial and individual patient levels. In this report, the newly developed diffusion basis spectrum imaging was used to discriminate and quantify the underlying pathological components in multiple sclerosis white matter. Through the multiple-tensor modelling of diffusion weighted magnetic resonance imaging signals, diffusion basis spectrum imaging resolves inflammation-associated cellularity and vasogenic oedema in addition to accounting for partial volume effects resulting from cerebrospinal fluid contamination, and crossing fibres. Quantitative histological analysis of autopsied multiple sclerosis spinal cord specimens supported that diffusion basis spectrum imaging-determined cellularity, axon and myelin injury metrics closely correlated with those pathologies identified and quantified by conventional histological staining. We demonstrated in healthy control subjects that diffusion basis spectrum imaging rectified inaccurate assessments of diffusion properties of white matter tracts by diffusion tensor imaging in the presence of cerebrospinal fluid contamination and/or crossing fibres. In multiple sclerosis patients, we report that diffusion basis spectrum imaging quantitatively characterized the distinct pathologies underlying gadolinium-enhanced lesions, persistent black holes, non-enhanced lesions and non-black hole lesions, a

  19. Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington's disease: role of CB1 and CB2 receptors.

    PubMed

    Valdeolivas, Sara; Satta, Valentina; Pertwee, Roger G; Fernández-Ruiz, Javier; Sagredo, Onintza

    2012-05-16

    We have investigated whether a 1:1 combination of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, is neuroprotective in Huntington's disease (HD), using an experimental model of this disease generated by unilateral lesions of the striatum with the mitochondrial complex II inhibitor malonate. This toxin damages striatal neurons by mechanisms that primarily involve apoptosis and microglial activation. We monitored the extent of this damage and the possible preservation of the striatal parenchyma by treatment with a Sativex-like combination of phytocannabinoids using different histological and biochemical markers. Results were as follows: (i) malonate increased the volume of edema measured by in vivo NMR imaging and the Sativex-like combination of phytocannabinoids partially reduced this increase; (ii) malonate reduced the number of Nissl-stained cells, while enhancing the number of degenerating cells stained with FluoroJade-B, and the Sativex-like combination of phytocannabinoids reversed both effects; (iii) malonate caused a strong glial activation (i.e., reactive microglia labeled with Iba-1, and astrogliosis labeled with GFAP) and the Sativex-like combination of phytocannabinoids attenuated both responses; and (iv) malonate increased the expression of inducible nitric oxide synthase and the neurotrophin IGF-1, and both responses were attenuated after the treatment with the Sativex-like combination of phytocannabinoids. We also wanted to establish whether targets within the endocannabinoid system (i.e., CB(1) and CB(2) receptors) are involved in the beneficial effects induced in this model by the Sativex-like combination of phytocannabinoids. This we did using selective antagonists for both receptor types (i.e., SR141716 and AM630) combined with the Sativex-like phytocannabinoid combination. Our results indicated that the effects of this

  20. Long-term safety of ivermectin 1% cream vs azelaic acid 15% gel in treating inflammatory lesions of rosacea: results of two 40-week controlled, investigator-blinded trials.

    PubMed

    Stein Gold, Linda; Kircik, Leon; Fowler, Joseph; Jackson, J Mark; Tan, Jerry; Draelos, Zoe; Fleischer, Alan; Appell, Melanie; Steinhoff, Martin; Lynde, Charles; Sugarman, Jeffrey; Liu, Hong; Jacovella, Jean

    2014-11-01

    Papulopustular rosacea (PPR) is characterized by facial erythema and inflammatory lesions believed to be primarily caused by dysregulation of the innate immune system. More recent evidence also suggests that Demodex folliculorum mites may contribute to the etiology of PPR. Ivermectin (IVM) 1% cream is a novel topical treatment developed to treat PPR. Two phase 3 trials have demonstrated that IVM 1% cream was significantly better than vehicle at investigator global assessment (IGA) success rate and lesion reductions and that it was safe and well tolerated. Two 40-week extension studies of those trials were conducted to assess the long-term safety of IVM 1% cream vs azelaic acid (AzA) 15% gel. Subjects originally treated with IVM 1% continued on IVM 1% and those originally treated with vehicle switched to AzA 15% gel. IVM 1% cream was safe throughout the study with a lower incidence of related adverse events (AEs) compared to AzA 15% gel. No subjects in the IVM 1% cream group discontinued either study due to a related AE. IVM 1% also continued to be efficacious during the 40-week extension studies as the percentage of subjects with IGA scores of clear or almost clear was higher at the end of the study compared to baseline. The results of these 40-week extension studies support the use of IVM 1% cream as a long-term therapy for PPR as IVM 1% cream was shown to be safe and effective for up to 52 weeks of total treatment. PMID:25607706

  1. Fingolimod (FTY720) Enhances Remyelination Following Demyelination of Organotypic Cerebellar Slices

    PubMed Central

    Miron, Veronique E.; Ludwin, Samuel K.; Darlington, Peter J.; Jarjour, Andrew A.; Soliven, Betty; Kennedy, Timothy E.; Antel, Jack P.

    2010-01-01

    Remyelination, which occurs subsequent to demyelination, contributes to functional recovery and is mediated by oligodendrocyte progenitor cells (OPCs) that have differentiated into myelinating cells. Therapeutics that impact remyelination in the CNS could be critical determinants of long-term functional outcome in multiple sclerosis (MS). Fingolimod is a S1P receptor modulator in MS clinical trials due to systemic anti-inflammatory properties, yet may impact cells within the CNS by crossing the blood-brain barrier. Previous studies using isolated dissociated cultures indicate that neural cells express S1P receptors and respond to receptor engagement. Our objective was to assess the effects of fingolimod on myelin-related processes within a multicellular environment that maintains physiological cell-cell interactions, using organotypic cerebellar slice cultures. Fingolimod treatment had no impact on myelin under basal conditions. Fingolimod treatment subsequent to lysolecithin-induced demyelination enhanced remyelination and process extension by OPCs and mature oligodendrocytes, while increasing microglia numbers and immunoreactivity for the astrocytic marker glial fibrillary acidic protein. The number of phagocytosing microglia was not increased by fingolimod. Using S1P receptor specific agonists and antagonists, we determined that fingolimod-induced effects on remyelination and astrogliosis were mediated primarily through S1P3 and S1P5, whereas enhanced microgliosis was mediated through S1P1 and S1P5. Taken together, these data demonstrate that fingolimod modulates multiple neuroglial cell responses, resulting in enhanced remyelination in organotypic slice cultures that maintain the complex cellular interactions of the mammalian brain. PMID:20413685

  2. Inhibition of LINGO-1 promotes functional recovery after experimental spinal cord demyelination.

    PubMed

    Zhang, Yongjie; Zhang, Yi Ping; Pepinsky, Blake; Huang, Guanrong; Shields, Lisa B E; Shields, Christopher B; Mi, Sha

    2015-04-01

    Blocking LINGO-1 has been shown to enhance remyelination in the rat lysolecithin-induced focal spinal cord demyelination model. We used transcranial magnetic motor-evoked potentials (tcMMEPs) to assess the effect of blocking LINGO-1 on recovery of axonal function in a mouse lysolecithin model at 1, 2 and 4weeks after injury. The role of LINGO-1 was assessed using LINGO-1 knockout (KO) mice and in wild-type mice after intraperitoneal administration of anti-LINGO-1 antagonist monoclonal antibody (mAb3B5). Response rates (at 2 and 4weeks) and amplitudes (at 4weeks) were significantly increased in LINGO-1 KO and mAb3B5-treated mice compared with matched controls. The latency of potentials at 4weeks was significantly shorter in mAb3B5-treated mice compared with controls. Lesion areas in LINGO-1 KO and mAb3B5-treated mice were reduced significantly compared with matched controls. The number of remyelinated axons within the lesions was increased and the G-ratios of the axons were decreased in both LINGO-1 KO and mAb3B5-treated mice compared with matched controls. These data provide morphometric and functional evidence of enhancement of remyelination associated with antagonism of LINGO-1. PMID:25681574

  3. An unusual demyelinating neuropathy in a patient with Waardenburg's syndrome.

    PubMed

    Jacobs, J M; Wilson, J

    1992-01-01

    We present clinical and laboratory data from a patient with Waardenburg's syndrome type II comprising iris heterochromia and deafness, complicated by Hirschsprung's disease--a known association--and an unusual demyelinating peripheral neuropathy--a unique association. The neuropathy is characterised by excessive focal folding of myelin sheaths. It is our view that, although both disorders could represent the consequences of neural crest embryopathy, it is more likely that they are associated by chance. PMID:1636383

  4. Periaxin mutations cause a broad spectrum of demyelinating neuropathies.

    PubMed

    Takashima, Hiroshi; Boerkoel, Cornelius F; De Jonghe, Peter; Ceuterick, Chantal; Martin, Jean-Jacques; Voit, Thomas; Schröder, J-Michael; Williams, Anna; Brophy, Peter J; Timmerman, Vincent; Lupski, James R

    2002-06-01

    Previous studies have demonstrated that apparent loss-of-function mutations in the periaxin gene cause autosomal recessive Dejerine-Sottas neuropathy or severe demyelinating Charcot-Marie-Tooth disease. In this report, we extend the associated phenotypes with the identification of two additional families with novel periaxin gene mutations (C715X and R82fsX96) and provide detailed neuropathology. Each patient had marked sensory involvement; two siblings with a homozygous C715X mutation had much worse sensory impairment than motor impairment. Despite early disease onset, these siblings with the C715X mutation had relatively slow disease progression and adult motor impairment typical of classic demyelinating Charcot-Marie-Tooth neuropathy. In contrast, a patient with the homozygous R82fsX96 mutation had a disease course consistent with Dejerine-Sottas neuropathy. The neuropathology of patients in both families was remarkable for demyelination, onion bulb and occasional tomacula formation with focal myelin thickening, abnormalities of the paranodal myelin loops, and focal absence of paranodal septate-like junctions between the terminal loops and axon. Our study indicates a prominent sensory neuropathy resulting from periaxin gene mutations and suggests a role for the carboxyl terminal domain of the periaxin protein. PMID:12112076

  5. Inflammatory mediators and modulators released in organ culture from rabbit skin lesions produced in vivo by sulfur mustard. III. Electrophoretic protein fractions, trypsin-inhibitory capacity, alpha 1-proteinase inhibitor, and alpha 1- and alpha 2-macroglobulin proteinase inhibitors of culture fluids and serum.

    PubMed Central

    Harada, S.; Dannenberg, A. M.; Vogt, R. F.; Myrick, J. E.; Tanaka, F.; Redding, L. C.; Merkhofer, R. M.; Pula, P. J.; Scott, A. L.

    1987-01-01

    This is the third report in a series on the inflammatory mediators and modulators released in organ culture from skin lesions of various ages, which were produced in vivo in rabbits by the military vesicant, sulfur mustard (SM). It describes the electrophoretic protein fractions and trypsin-inhibitory capacities of the various culture fluids and the amounts of alpha 1-proteinase inhibitor and alpha-macroglobulin proteinase inhibitors in these fluids. With one-dimensional electrophoresis, the albumin and beta-globulin fractions of protein in culture fluids varied little with the development and healing of the SM lesions. These fractions proportionally resembled the corresponding fractions found in serum. The alpha 1-globulin fraction was proportionally smaller than the corresponding fractions of serum as the lesions healed. The alpha 2-globulin fraction was proportionally smaller than the corresponding fractions of serum at all stages of lesion development and healing. The gamma-globulin fraction was proportionally larger as the lesions healed. With two-dimensional electrophoresis, about 68%, 46%, and 35% of the protein spots in culture fluids from representative 1-day and 6-day SM lesions and normal skin, respectively, matched those from serum. In each case, the large, diffuse, serum albumin spot represented about two-thirds of the protein present. Thus, gravimetrically, in normal skin and in both developing and healing lesions, the extracellular proteins were 80-90% of serum origin. The trypsin-inhibitory capacity (TIC) per milligram protein in the culture fluids of healing lesions was markedly less than the TIC per milligram protein in the fluids of peak lesions. This decrease correlates well with the decrease found in the alpha 1-globulin fraction, which contains alpha 1-antiproteinase (alpha 1-PI) (and alpha 1-macroglobulin [alpha 1M] in rabbits). The alpha 1PI and the alpha 1M-alpha 2M proteinase inhibitors were identified in the culture fluids by means of

  6. The Multiple Sclerosis Degradome: Enzymatic Cascades in Development and Progression of Central Nervous System Inflammatory Disease

    PubMed Central

    Scarisbrick, I.A.

    2014-01-01

    An array of studies implicate different classes of protease and their endogenous inhibitors in multiple sclerosis (MS) pathogenesis based on expression patterns in MS lesions, sera, and/or cerebrospinal fluid (CSF). Growing evidence exists regarding their mechanistic roles in inflammatory and neurodegenerative aspects of this disease. Proteolytic events participate in demyelination, axon injury, apoptosis, and development of the inflammatory response including immune cell activation and extravasation, cytokine and chemokine activation/inactivation, complement activation, and epitope spreading. The potential significance of proteolytic activity to MS therefore relates not only to their potential use as important biomarkers of disease activity, but additionally as prospective therapeutic targets. Experimental data indicate that understanding the net physiological consequence of altered protease levels in MS development and progression necessitates understanding protease activity in the context of substrates, endogenous inhibitors, and proteolytic cascade interactions, which together make up the MS degradome. This review will focus on evidence regarding the potential physiologic role of those protease families already identified as markers of disease activity in MS; that is, the metallo-, serine, and cysteine proteases. PMID:18219817

  7. Immunocytochemical investigations of sodium channels along nodal and internodal portions of demyelinated axons.

    PubMed

    England, J D; Levinson, S R; Shrager, P

    1996-08-01

    Voltage-gated sodium channels are largely localized to the nodes of Ranvier in myelinated axons, providing the physiological basis for saltatory conduction. Studies using antisodium channel antibodies have shown that along demyelinated axons sodium channels form new distributions. The nature of this changed distribution appears to vary with the time course and mechanism of demyelination. In chronic demyelination, sodium channels increase in number and redistribute along previously internodal axon segments. In chronic demyelination produced by doxorubicin, the increase in sodium channels appeared independently of Schwann cells, suggesting increased neuronal synthesis. In acute demyelination produced by lysolecithin new clusters of sodium channels developed but only in association with the edges of remyelinating Schwann cells, which appeared to control the distribution and mobility of the channels. These findings affirm the plasticity of sodium channels in demyelinated axons and are relevant to understanding how these axons recover conduction. PMID:8837020

  8. Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis.

    PubMed

    Pelisch, Nicolas; Dan, Takashi; Ichimura, Atsuhiko; Sekiguchi, Hiroki; Vaughan, Douglas E; van Ypersele de Strihou, Charles; Miyata, Toshio

    2015-01-01

    Multiple sclerosis (MS) is characterized by inflammatory demyelination and deposition of fibrinogen in the central nervous system (CNS). Elevated levels of a critical inhibitor of the mammalian fibrinolitic system, plasminogen activator inhibitor 1 (PAI-1) have been demonstrated in human and animal models of MS. In experimental studies that resemble neuroinflammatory disease, PAI-1 deficient mice display preserved neurological structure and function compared to wild type mice, suggesting a link between the fibrinolytic pathway and MS. We previously identified a series of PAI-1 inhibitors on the basis of the 3-dimensional structure of PAI-1 and on virtual screening. These compounds have been reported to provide a number of in vitro and in vivo benefits but none was tested in CNS disease models because of their limited capacity to penetrate the blood-brain barrier (BBB). The existing candidates were therefore optimized to obtain CNS-penetrant compounds. We performed an in vitro screening using a model of BBB and were able to identify a novel, low molecular PAI-1 inhibitor, TM5484, with the highest penetration ratio among all other candidates. Next, we tested the effects on inflammation and demyelination in an experimental allergic encephalomyelitis mice model. Results were compared to either fingolimod or 6α-methylprednisolone. Oral administration of TM5484 from the onset of signs, ameliorates paralysis, attenuated demyelination, and axonal degeneration in the spinal cord of mice. Furthermore, it modulated the expression of brain-derived neurotrophic factor, which plays a protective role in neurons against various pathological insults, and choline acetyltransferase, a marker of neuronal density. Taken together, these results demonstrate the potential benefits of a novel PAI-1 inhibitor, TM5484, in the treatment of MS. PMID:25915660

  9. Plasminogen Activator Inhibitor-1 Antagonist TM5484 Attenuates Demyelination and Axonal Degeneration in a Mice Model of Multiple Sclerosis

    PubMed Central

    Pelisch, Nicolas; Dan, Takashi; Ichimura, Atsuhiko; Sekiguchi, Hiroki; Vaughan, Douglas E.; van Ypersele de Strihou, Charles; Miyata, Toshio

    2015-01-01

    Multiple sclerosis (MS) is characterized by inflammatory demyelination and deposition of fibrinogen in the central nervous system (CNS). Elevated levels of a critical inhibitor of the mammalian fibrinolitic system, plasminogen activator inhibitor 1 (PAI-1) have been demonstrated in human and animal models of MS. In experimental studies that resemble neuroinflammatory disease, PAI-1 deficient mice display preserved neurological structure and function compared to wild type mice, suggesting a link between the fibrinolytic pathway and MS. We previously identified a series of PAI-1 inhibitors on the basis of the 3-dimensional structure of PAI-1 and on virtual screening. These compounds have been reported to provide a number of in vitro and in vivo benefits but none was tested in CNS disease models because of their limited capacity to penetrate the blood-brain barrier (BBB). The existing candidates were therefore optimized to obtain CNS-penetrant compounds. We performed an in vitro screening using a model of BBB and were able to identify a novel, low molecular PAI-1 inhibitor, TM5484, with the highest penetration ratio among all other candidates. Next, we tested the effects on inflammation and demyelination in an experimental allergic encephalomyelitis mice model. Results were compared to either fingolimod or 6α-methylprednisolone. Oral administration of TM5484 from the onset of signs, ameliorates paralysis, attenuated demyelination, and axonal degeneration in the spinal cord of mice. Furthermore, it modulated the expression of brain-derived neurotrophic factor, which plays a protective role in neurons against various pathological insults, and choline acetyltransferase, a marker of neuronal density. Taken together, these results demonstrate the potential benefits of a novel PAI-1 inhibitor, TM5484, in the treatment of MS. PMID:25915660

  10. Multi-glycoside of Tripterygium wilfordii Hook. f. ameliorates imiquimod-induced skin lesions through a STAT3-dependent mechanism involving the inhibition of Th17-mediated inflammatory responses

    PubMed Central

    Zhao, Jingxia; Di, Tingting; Wang, Yan; Liu, Xin; Liang, Daiying; Zhang, Guangzhong; Li, Ping

    2016-01-01

    Multi-glycoside of Tripterygium wilfordii Hook. f. (GTW) possesses anti-inflammatory and immunosuppressive properties, and has been used as a traditional treatment for psoriasis for many years, although the underlying immunological mechanisms remain poorly understood. The T helper (Th)17 cell response is considered to play a major role in the pathogenesis of psoriasis. Th17 cells are implicated in the mechanism of pathogenesis of imiquimod (IMQ)-induced skin inflammation. Using a mouse model, we demonstrated that GTW protected mice from developing psoriasis-like lesions induced by topical IMQ administration. This protection was associated with significantly decreased mRNA levels of Th17 cytokines such as interleukin (IL)-17A, IL-17F and IL-22 in mouse skin samples as well as fewer IL-17-secreting splenic CD4+ lymphocytes in IMQ-exposed mice. There were no significant effects on the proportion of CD4+ interferon (IFN)-γ+ T cells, CD4+IL-4+ T cells and CD4+CD25+Foxp3+ Treg cells in the spleen cells. Taken together with the unchanged mRNA levels of Th1 cytokine IFN-γ, Th2 cytokine IL-4 and Treg cytokine IL-10 in IMQ-exposed mouse skin following GTW administration, our findings suggest that the immunosuppressive effect of GTW in psoriasis is exerted mainly on Th17 cells, rather than on Th1, Th2 or Treg cells. Furthermore, we showed that GTW suppressed Th17 function through the inhibition of STAT3 phosphorylation. These results have the potential to pave the way for the use of GTW as an agent for the treatment of psoriasis. PMID:27431437

  11. Multi-glycoside of Tripterygium wilfordii Hook. f. ameliorates imiquimod-induced skin lesions through a STAT3-dependent mechanism involving the inhibition of Th17-mediated inflammatory responses.

    PubMed

    Zhao, Jingxia; Di, Tingting; Wang, Yan; Liu, Xin; Liang, Daiying; Zhang, Guangzhong; Li, Ping

    2016-09-01

    Multi-glycoside of Tripterygium wilfordii Hook. f.(GTW) possesses anti-inflammatory and immunosuppressive properties, and has been used as a traditional treatment for psoriasis for many years, although the underlying immunological mechanisms remain poorly understood. The T helper (Th)17 cell response is considered to play a major role in the pathogenesis of psoriasis. Th17 cells are implicated in the mechanism of pathogenesis of imiquimod (IMQ)‑induced skin inflammation. Using a mouse model, we demonstrated that GTW protected mice from developing psoriasis-like lesions induced by topical IMQ administration. This protection was associated with significantly decreased mRNA levels of Th17 cytokines such as interleukin (IL)-17A, IL-17F and IL-22 in mouse skin samples as well as fewer IL-17-secreting splenic CD4+ lymphocytes in IMQ-exposed mice. There were no significant effects on the proportion of CD4+ interferon (IFN)-γ+ T cells, CD4+IL-4+ T cells and CD4+CD25+Foxp3+ Treg cells in the spleen cells. Taken together with the unchanged mRNA levels of Th1 cytokine IFN-γ, Th2 cytokine IL-4 and Treg cytokine IL-10 in IMQ-exposed mouse skin following GTW administration, our findings suggest that the immunosuppressive effect of GTW in psoriasis is exerted mainly on Th17 cells, rather than on Th1, Th2 or Treg cells. Furthermore, we showed that GTW suppressed Th17 function through the inhibition of STAT3 phosphorylation. These results have the potential to pave the way for the use of GTW as an agent for the treatment of psoriasis. PMID:27431437

  12. Near-infrared reflectance spectroscopy as a novel method to detect demyelination in rat sciatic nerve in vivo

    NASA Astrophysics Data System (ADS)

    Radhakrishnan, Harsha; Senapati, Arun; Peng, Yuan Bo; Kashyap, Dheerendra; Liu, Hanli

    2005-04-01

    This study was done to use near infrared (NIR) spectroscopy to bring out differences in the anatomical substructures in the rat spinal cord and further to differentiate scattering between demyelinated and normal sciatic nerves in rat models, thereby exploring a new methodology to localize MS (multiple Sclerosis) lesions in vivo for animal studies. The experimental setup consisted of a tungsten light source, CCD array spectrometer, and bifurcated optical fibers for light delivery and detection of back scattered light from tissue. The measurement system was calibrated with reflectance standard. The spinal cord of 14 rats was exposed by laminectomy, and the measurements were taken on 8 points at intervals of 1 mm on the right and left lumbar-sacral regions and the central blood vessel. For measurements on the sciatic nerve, the spinal nerves of 84 rats were ligated according to the Chung Model. Measurements were taken on five points on both the ligated and the control nerve side after 1, 4, 7 and 14 days. The reduced scattering coefficient, μs', was found to be higher in the lumbar-sacral regions (34.17 +/- 2.05 cm-1) than that near the central blood vessel (19.9 +/- 3.8 cm-1). Statistically, there was significant difference in scattering between the control side and the ligated side on postoperative days 4, 7, and 14. This study shows a promising diagnostic value in the future for monitoring of demyelinated CNS (central nervous system) diseases, like Multiple Sclerosis.

  13. Myelin Oligodendrocyte Glycoprotein-Associated Pediatric Central Nervous System Demyelination: Clinical Course, Neuroimaging Findings, and Response to Therapy.

    PubMed

    Thulasirajah, Salini; Pohl, Daniela; Davila-Acosta, Jorge; Venkateswaran, Sunita

    2016-08-01

    Under the umbrella of pediatric-acquired demyelinating syndromes, there is a multitude of disorders, including optic neuritis, transverse myelitis, acute disseminated encephalomyelitis (ADEM), multiple sclerosis (MS), and neuromyelitis optica spectrum disorders (NMOSD). Due to overlapping clinical and magnetic resonance imaging (MRI) features, it can be challenging to provide an accurate diagnosis. In view of therapeutic and prognostic implications, an early and reliable diagnosis is however of utmost importance. Recent studies of myelin oligodendrocyte glycoprotein (MOG) identify MOG, as a promising target for antibody-mediated demyelination and a biomarker for a relatively benign and non-MS disease course. We describe the clinical and MRI presentation of five children presenting with an acute, severe central nervous system inflammatory disease involving the brain and spinal cord, all of whom were positive for MOG-IgG antibody. Encephalopathy was uncommon at presentation and all had quick resolution of symptoms with intravenous steroid and intravenous immunoglobulin (IVIG) treatment. All patients recovered well, and have been treated with IVIG to potentially prevent relapses. PMID:27128728

  14. Brain lesions in mallard ducklings from parents fed methylmercury

    USGS Publications Warehouse

    Heinz, G.H.; Locke, L.N.

    1976-01-01

    Methylmercury dicyandiamide was fed to mallard ducks at 3 ppm mercury. Mercury accumulated in the eggs to an average of 7.18 and 5.46 ppm on a wet-weight basis in 2 successive years. Mercury in the eggs is believed to have caused brain lesions in the hatched ducklings. Lesions included demyelination, neuron shrink-age, necrosis, and hemorrhage in the meninges overlying the cerebellum. Brains of dead ducklings contained an average of 6.17 and 5.19 ppm mercury on a wet-weight basis in 2 successive years.

  15. Mesenteric inflammatory myofibroblastic tumors

    PubMed Central

    Chaudhary, Poras

    2015-01-01

    Inflammatory myofibroblastic tumors (IMTs), also known as inflammatory pseudotumors and inflammatory fibrosarcomas, are uncommon mesenchymal tumors composed of myofibroblastic spindle cells admixed with lymphocytes, plasma cells and eosinophils. Once thought to be reactive, these lesions are now considered to be neoplastic. These tumors can occur throughout the body, most commonly in the lung, mesentery and omentum. Patients commonly present with painless abdominal mass or with intestinal obstruction. IMTs may be multicentric, have a high local recurrence rate and may metastasize in rare cases. The lesions show wide variability in their histologic features and cellularity, and marked inflammatory infiltration, predominantly of plasmatocytes and lymphocytes, and occasionally neutrophils and eosinophils. Anaplastic lymphoma kinase (ALK) rearrangements and/or ALK1 and p80 immunoreactivity are reported in 33-67% of the tumors. Owing to the rarity of these lesions, there are no specific imaging findings that distinguish IMTs from other mesenteric masses. Complete surgical resection is the treatment of choice. Local recurrence rates are high, and re-excision is the preferred therapy for local recurrences. ALK-positive tumors show good response to ALK inhibitors. Current knowledge and comprehensive review of the available literature on IMTs is herein presented. PMID:25608706

  16. Advanced MRI and staging of multiple sclerosis lesions.

    PubMed

    Absinta, Martina; Sati, Pascal; Reich, Daniel S

    2016-06-01

    Over the past few decades, MRI-based visualization of demyelinated CNS lesions has become pivotal to the diagnosis and monitoring of multiple sclerosis (MS). In this Review, we outline current efforts to correlate imaging findings with the pathology of lesion development in MS, and the pitfalls that are being encountered in this research. Multimodal imaging at high and ultra-high magnetic field strengths is yielding biologically relevant insights into the pathophysiology of blood-brain barrier dynamics and both active and chronic inflammation, as well as mechanisms of lesion healing and remyelination. Here, we parallel the results in humans with advances in imaging of a primate model of MS - experimental autoimmune encephalomyelitis (EAE) in the common marmoset - in which demyelinated lesions resemble their human counterparts far more closely than do EAE lesions in the rodent. This approach holds promise for the identification of innovative biological markers, and for next-generation clinical trials that will focus more on tissue protection and repair. PMID:27125632

  17. Demyelinizing neurological disease after treatment with tumor necrosis factor alpha-inhibiting agents in a rheumatological outpatient clinic: description of six cases.

    PubMed

    Theibich, Ali; Dreyer, Lene; Magyari, Melinda; Locht, Henning

    2014-05-01

    Biological treatment with inhibitors of the pro-inflammatory cytokine TNF-alpha has dramatically improved the disease course of several chronic rheumatologic conditions. Adverse events (AEs) are primarily infections and hypersensitivity reactions. Demyelinizing neurological symptoms resembling multiple sclerosis (MS) have been described as a rare AE. During about 10-year use of anti TNF-alpha, the Danish Medicines Agency has recorded eight cases of MS like AEs. The objective of this study was to estimate the incidence of demyelinizing AEs both in the central and peripheral nervous system after treatment with anti TNF-alpha in a cohort of patients from a large rheumatologic outpatient clinic in Copenhagen. In a 4-year period from January 2008 to December 2011, approximately 550 patients annually were undergoing treatment with anti TNF-alpha inhibitors in our department. We collected data on all patients who developed neurological symptoms during this time period. We found six patients with signs of demyelinizing neurological disorders: four resembling MS, one MS-like condition, and one multifocal motor neuropathy. During a relatively short time period, we found a remarkably high number of neurological demyelinizing AEs probably linked to anti TNF-alpha treatment. The AEs were not associated with a single anti TNF-alpha agent and were thus presumably a class effect. The data presented suggest that neurological AEs may be underreported. We advocate that physicians handling patients during treatment with TNF inhibitors are aware of this potentially serious AE and report these events to the proper medical authorities. PMID:24202614

  18. Immunohistochemical and morphometrical studies on myelin breakdown in the demyelination (dmy) mutant rat.

    PubMed

    Kuwamura, Mitsuru; Kanehara, Toshiko; Tokuda, Satoko; Kumagai, Daijiro; Yamate, Jyoji; Kotani, Takao; Nakane, Yoshifumi; Kuramoto, Takashi; Serikawa, Tadao

    2004-10-01

    The demyelination (dmy) rat is a unique mutant exhibiting severe myelin breakdown in the central nervous system (CNS). In this study, we conducted immunohistochemical and morphometrical investigations in the dmy rat. From around 6 weeks of age, the affected rats developed ataxia especially in the hindlimbs. Afterwards, ataxia worsened rapidly, resulting in complete paralysis of the hindlimbs and recumbency. Histopathology at 7 to 10 weeks of age revealed myelin destruction throughout the white matter of the CNS in the dmy rats. The most severely affected lesions were distributed in the corpus callosum, capsula interna, striatum, subcortical white matter, cerebellar peduncle, and ventral and lateral parts of the spinal cord. Immunohistochemistry demonstrated prominent astrogliosis and many ED-1 positive macrophages in the myelin-destructed areas. Until the 4th week, no significant differences in myelin thickness and fiber diameter were found between dmy and control rats. However, from 5 weeks of age, myelin thickness of residual myelinated fibers in dmy rats became significantly less than that in controls. These data indicated that the dmy phenotype shows a prolonged period of myelin destruction, suggesting that dmy mutation affects the adequate maintenance of myelin. PMID:15353220

  19. A spectrum of inflammation and demyelination in acute disseminated encephalomyelitis (ADEM) of children.

    PubMed

    Esposito, Susanna; Di Pietro, Giada Maria; Madini, Barbara; Mastrolia, Maria Vincenza; Rigante, Donato

    2015-10-01

    Acute disseminated encephalomyelitis (ADEM) is an inflammatory demyelinating disease of the central nervous system that involves multifocal areas of the white matter, rarely the gray matter and spinal cord, mainly affecting children and mostly occurring 1-2weeks after infections or more rarely after vaccinations. Though a specific etiologic agent is not constantly identified, to evaluate carefully patient's clinical history and obtain adequate samples for the search of a potential ADEM causal agent is crucial. In the case of a prompt diagnosis and adequate treatment, most children with ADEM have a favorable outcome with full recovery, but in the case of diagnostic delays or inappropriate treatment some patients might display neurological sequelae and persistent deficits or even show an evolution to multiple sclerosis. The suspicion of ADEM rises on a clinical basis and derives from systemic and neurologic signs combined with magnetic resonance imaging of the central nervous system. Other advanced imaging techniques may help an appropriate differential diagnosis and definition of exact disease extension. Although there is no standardized protocol or management for ADEM, corticosteroids, intravenous immunoglobulin, and plasmapheresis have been successfully used. There is no marker that permits to identify the subset of children with worse prognosis and future studies should try to detect any biological clue for prevision of neurologic damage as well as should optimize treatment strategies using an approach based on the effective risk of negative evolution. PMID:26079482

  20. Demyelinizing Neurological Disease after Treatment with Tumor Necrosis Factor-α Antagonists

    PubMed Central

    Bruè, Claudia; Mariotti, Cesare; Rossiello, Ilaria; Saitta, Andrea; Giovannini, Alfonso

    2016-01-01

    Purpose Demyelinizing neurological disease is a rare complication after treatment with tumor necrosis factor (TNF)α antagonists. We report on a case of multiple sclerosis after TNFα antagonist treatment and discuss its differential diagnosis. Methods This is an observational case study. Results A 48-year-old male was referred to Ophthalmology in January 2015 for an absolute scotoma in the superior quadrant of the visual field in his right eye. Visual acuity was 20/50 in the right eye and 20/20 in the left. Fundus examination was unremarkable bilaterally. Spectral domain optical coherence tomography revealed a normal macular retina structure. Visual field examination revealed a superior hemianopsia in the right eye. Head magnetic resonance imaging showed findings compatible with optic neuritis. The visual evoked potentials confirmed the presence of optic neuritis. The patient had been under therapy with adalimumab since January 2014, for Crohn's disease. Suspension of adalimumab was recommended, and it was substituted with tapered deltacortene, from 1 mg/kg/day. After 1 month, the scotoma was resolved completely. Conclusions TNFα antagonists can provide benefit to patients with inflammatory autoimmune diseases. However, they can also be associated with severe adverse effects. Therefore, adequate attention should be paid to neurological abnormalities in patients treated with TNFα antagonists. PMID:27504093

  1. Digesting the emerging role for the gut microbiome in central nervous system demyelination.

    PubMed

    Joscelyn, Jennifer; Kasper, Lloyd H

    2014-10-01

    The fields of microbiology, immunology, neurology and nutrition are rapidly converging, as advanced sequencing and genomics-based methodologies have enabled the mapping out of the microbial diversity of humans for the first time. Bugs, guts, brains and behavior were once believed to be separate domains of clinical practice and research; however, recent observations in our understanding of the microbiome indicate that the boundaries between domains are becoming permeable. This permeability is multidirectional: Biological systems are operating simultaneously in a vastly complex and interconnected web. Understanding the microbiome-gut-brain axis will entail fleshing out the mechanisms by which transduction across each domain occurs, allowing us ultimately to appreciate the role of commensal organisms in shaping and modulating host immunity. This article will highlight animal and human research to date, as well as highlight directions for future research. We speculate that the gut microbiome is potentially the premier environmental risk factor mediating inflammatory central nervous system demyelination, in particular multiple sclerosis. PMID:25070675

  2. Pediatric acquired CNS demyelinating syndromes: Features associated with multiple sclerosis.

    PubMed

    Hintzen, Rogier Q; Dale, Russell C; Neuteboom, Rinze F; Mar, Soe; Banwell, Brenda

    2016-08-30

    Approximately one-third of children with an acquired demyelinating syndrome (ADS) will be diagnosed with multiple sclerosis (MS), either at onset according to the 2010 McDonald criteria, or on the basis of clinical or MRI evidence of relapsing disease, in the majority of patients within 2-4 years. ADS in adolescents, female patients, and patients with polyfocal deficits is associated with the highest likelihood of MS, while children with acute disseminated encephalomyelitis, those with documented preceding infection, and ADS presentation in young children more commonly portends a monophasic outcome. While pediatric MS associates with similar genetic risk alleles as have been documented in adult-onset MS, such associations are not diagnostically valuable at the individual level. The presence of antibodies directed against aquaporin-4 strongly supports a diagnosis of neuromyelitis optica, and should be assayed in children manifesting with severe optic neuritis, longitudinally extensive myelitis, or brainstem/hypothalamic syndromes. Further research will determine whether other antibody signatures are indicative of relapsing demyelination distinct from MS. PMID:27572864

  3. Gut Commensalism, Cytokines, and Central Nervous System Demyelination

    PubMed Central

    Ochoa-Repáraz, Javier; Kasper, Lloyd H.

    2014-01-01

    There is increasing support for the importance of risk factors such as genetic makeup, obesity, smoking, vitamin D insufficiency, and antibiotic exposure contributing to the development of autoimmune diseases, including human multiple sclerosis (MS). Perhaps the greatest environmental risk factor associated with the development of immune-mediated conditions is the gut microbiome. Microbial and helminthic agents are active participants in shaping the immune systems of their hosts. This concept is continually reinforced by studies in the burgeoning area of commensal-mediated immunomodulation. The clinical importance of these findings for MS is suggested by both their participation in disease and, perhaps of greater clinical importance, attenuation of disease severity. Observations made in murine models of central nervous system demyelinating disease and a limited number of small studies in human MS suggest that immune homeostasis within the gut microbiome may be of paramount importance in maintaining a disease-free state. This review describes three immunological factors associated with the gut microbiome that are central to cytokine network activities in MS pathogenesis: T helper cell polarization, T regulatory cell function, and B cell activity. Comparisons are drawn between the regulatory mechanisms attributed to first-line therapies and those described in commensal-mediated amelioration of central nervous system demyelination. PMID:25084177

  4. Deimination restores inner retinal visual function in murine demyelinating disease

    PubMed Central

    Enriquez-Algeciras, Mabel; Ding, Di; Mastronardi, Fabrizio G.; Marc, Robert E.; Porciatti, Vittorio; Bhattacharya, Sanjoy K.

    2013-01-01

    Progressive loss of visual function frequently accompanies demyelinating diseases such as multiple sclerosis (MS) and is hypothesized to be the result of damage to the axons and soma of neurons. Here, we show that dendritic impairment is also involved in these diseases. Deimination, a posttranslational modification, was reduced in the retinal ganglion cell layer of MS patients and in a transgenic mouse model of MS (ND4 mice). Reduced deimination accompanied a decrease in inner retinal function in ND4 mice, indicating loss of vision. Local restoration of deimination dramatically improved retinal function and elongation of neurites in isolated neurons. Further, neurite length was decreased by downregulation of deimination or siRNA knockdown of the export-binding protein REF, a primary target for deimination in these cells. REF localized to dendrites and bound selective mRNAs and translation machinery to promote protein synthesis. Thus, protein deimination and dendritic outgrowth play key roles in visual function and may be a general feature of demyelinating diseases. PMID:23281397

  5. Phosphatidic acid mediates demyelination in Lpin1 mutant mice

    PubMed Central

    Nadra, Karim; de Preux Charles, Anne-Sophie; Médard, Jean-Jacques; Hendriks, William T.; Han, Gil-Soo; Grès, Sandra; Carman, George M.; Saulnier-Blache, Jean-Sébastien; Verheijen, Mark H.G.; Chrast, Roman

    2008-01-01

    Lipids play crucial roles in many aspects of glial cell biology, affecting processes ranging from myelin membrane biosynthesis to axo-glial interactions. In order to study the role of lipid metabolism in myelinating glial cells, we specifically deleted in Schwann cells the Lpin1 gene, which encodes the Mg2+-dependent phosphatidate phosphatase (PAP1) enzyme necessary for normal triacylglycerol biosynthesis. The affected animals developed pronounced peripheral neuropathy characterized by myelin degradation, Schwann cell dedifferentiation and proliferation, and a reduction in nerve conduction velocity. The observed demyelination is mediated by endoneurial accumulation of the substrate of the PAP1 enzyme, phosphatidic acid (PA). In addition, we show that PA is a potent activator of the MEK–Erk pathway in Schwann cells, and that this activation is required for PA-induced demyelination. Our results therefore reveal a surprising role for PA in Schwann cell fate determination and provide evidence of a direct link between diseases affecting lipid metabolism and abnormal Schwann cell function. PMID:18559480

  6. Gut commensalism, cytokines, and central nervous system demyelination.

    PubMed

    Telesford, Kiel; Ochoa-Repáraz, Javier; Kasper, Lloyd H

    2014-08-01

    There is increasing support for the importance of risk factors such as genetic makeup, obesity, smoking, vitamin D insufficiency, and antibiotic exposure contributing to the development of autoimmune diseases, including human multiple sclerosis (MS). Perhaps the greatest environmental risk factor associated with the development of immune-mediated conditions is the gut microbiome. Microbial and helminthic agents are active participants in shaping the immune systems of their hosts. This concept is continually reinforced by studies in the burgeoning area of commensal-mediated immunomodulation. The clinical importance of these findings for MS is suggested by both their participation in disease and, perhaps of greater clinical importance, attenuation of disease severity. Observations made in murine models of central nervous system demyelinating disease and a limited number of small studies in human MS suggest that immune homeostasis within the gut microbiome may be of paramount importance in maintaining a disease-free state. This review describes three immunological factors associated with the gut microbiome that are central to cytokine network activities in MS pathogenesis: T helper cell polarization, T regulatory cell function, and B cell activity. Comparisons are drawn between the regulatory mechanisms attributed to first-line therapies and those described in commensal-mediated amelioration of central nervous system demyelination. PMID:25084177

  7. Iron and copper in progressive demyelination--New lessons from Skogholt's disease.

    PubMed

    Aspli, Klaus Thanke; Flaten, Trond Peder; Roos, Per M; Holmøy, Trygve; Skogholt, Jon H; Aaseth, Jan

    2015-01-01

    The pathophysiological mechanisms of progressive demyelinating disorders including multiple sclerosis are incompletely understood. Increasing evidence indicates a role for trace metals in the progression of several neurodegenerative disorders. The study of Skogholt disease, a recently discovered demyelinating disease affecting both the central and peripheral nervous system, might shed some light on the mechanisms underlying demyelination. Cerebrospinal fluid iron and copper concentrations are about four times higher in Skogholt patients than in controls. The transit into cerebrospinal fluid of these elements from blood probably occurs in protein bound form. We hypothesize that exchangeable fractions of iron and copper are further transferred from cerebrospinal fluid into myelin, thereby contributing to the pathogenesis of demyelination. Free or weakly bound iron and copper ions may exert their toxic action on myelin by catalyzing production of oxygen radicals. Similarities to demyelinating processes in multiple sclerosis and other myelinopathies are discussed. PMID:25563774

  8. Vascular Lesions.

    PubMed

    Jahnke, Marla N

    2016-08-01

    Vascular lesions in childhood are comprised of vascular tumors and vascular malformations. Vascular tumors encompass neoplasms of the vascular system, of which infantile hemangiomas (IHs) are the most common. Vascular malformations, on the other hand, consist of lesions due to anomalous development of the vascular system, including the capillary, venous, arterial, and lymphatic systems. Capillary malformations represent the most frequent type of vascular malformation. IHs and vascular malformations tend to follow relatively predictable growth patterns in that IHs grow then involute during early childhood, whereas vascular malformations tend to exhibit little change. Both vascular tumors and vascular malformations can demonstrate a wide range of severity and potential associated complications necessitating specialist intervention when appropriate. Evaluation and treatment of the most common types of vascular lesions are discussed in this article. [Pediatr Ann. 2016;45(8):e299-e305.]. PMID:27517358

  9. Anti-inflammatory mechanisms of IFN-γ studied in experimental autoimmune encephalomyelitis reveal neutrophils as a potential target in multiple sclerosis

    PubMed Central

    Miller, Nichole M.; Wang, Jun; Tan, Yanping; Dittel, Bonnie N.

    2015-01-01

    Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) mediated by T helper (h)1 and/or Th17 CD4 T cells that drive inflammatory lesion development along with demyelination and neuronal damage. Defects in immune regulatory mechanisms are thought to play a role in the pathogenesis of MS. While an early clinical trial indicated that IFN-γ administration was detrimental to MS, studies in the mouse model of MS, experimental autoimmune encephalomyelitis (EAE), indicated that IFN-γ exhibits a number of anti-inflammatory properties within the CNS. These mechanisms include inhibition of IL-17 production, induction of regulatory T cells, T cell apoptosis and regulation of chemokine production. Mice deficient in IFN-γ or its receptor were instrumental in deciphering the anti-inflammatory properties of IFN-γ in the CNS. In particular, they revealed that IFN-γ is a major regulator of neutrophil recruitment into the CNS, which by a variety of mechanisms including disruption of the blood-brain-barrier (BBB) and production of reactive oxygen species are thought to contribute to the onset and progression of EAE. Neutrophils were also shown to be instrumental in EAE relapses. To date neutrophils have not been appreciated as a driver of MS, but more recently based largely on strong EAE data this view is being reevaluated by some investigators in the field. PMID:26347600

  10. Nonsurgical management of periapical lesions

    PubMed Central

    Fernandes, Marina; de Ataide, Ida

    2010-01-01

    Periapical lesions develop as sequelae to pulp disease. They often occur without any episode of acute pain and are discovered on routine radiographic examination. The incidence of cysts within periapical lesions varies between 6 and 55%. The occurrence of periapical granulomas ranges between 9.3 and 87.1%, and of abscesses between 28.7 and 70.07%. It is accepted that all inflammatory periapical lesions should be initially treated with conservative nonsurgical procedures. Studies have reported a success rate of up to 85% after endodontic treatment of teeth with periapical lesions. A review of literature was performed by using electronic and hand searching methods for the nonsurgical management of periapical lesions. Various methods can be used in the nonsurgical management of periapical lesions: the conservative root canal treatment, decompression technique, active nonsurgical decompression technique, aspiration-irrigation technique, method using calcium hydroxide, Lesion Sterilization and Repair Therapy, and the Apexum procedure. Monitoring the healing of periapical lesions is essential through periodic follow-up examinations. PMID:21217952

  11. [Progressive Multifocal Leukoencephalopathy with Inflammatory Reactions].

    PubMed

    Shishido-Hara, Yukiko; Uchihara, Toshiki; Sanjo, Nobuo

    2016-04-01

    Progressive multifocal leukoencephalopathy (PML) is a demyelinating disorder caused by reactivation of the JC virus associated with impaired host immunity. However, PML may occur even without an evident cause of immunosuppression. In such cases, JC virus DNA in cerebrospinal fluid (CSF) may not be detectable with polymerase chain reactions (PCR), and a brain biopsy may be performed. Pathology may exhibit marked inflammatory reactions around the JC virus-infected cells, although typical intranuclear viral inclusions would rarely be seen. Atypical inflammation in patients with PML likely an indication of the host's immune-response against the virus. this is usually observed in those with relatively-mild immunosuppression with favorable prognosis. Here, we describe cases of PML that exhibited inflammatory reactions; a recent topic, PML with immune reconstruction inflammatory syndrome (IRIS), will also be discussed. PMID:27056866

  12. Differential expression of matrix metalloproteinase and tissue inhibitor of matrix metalloproteinase genes in the mouse central nervous system in normal and inflammatory states.

    PubMed Central

    Pagenstecher, A.; Stalder, A. K.; Kincaid, C. L.; Shapiro, S. D.; Campbell, I. L.

    1998-01-01

    Matrix metalloproteinases (MMPs) are implicated in the pathogenesis of inflammatory disorders of the central nervous system (CNS) whereas the contribution of the major endogenous counter-regulators of MMPs, the tissue inhibitors of the matrix metalloproteinases (TIMPs), is unclear. We investigated the temporal and spatial expression patterns in the CNS of nine MMP genes and three TIMP genes in normal mice, in mice with EAE, and in transgenic mice with astrocyte (glial fibrillary acidic protein)-targeted expression of the cytokines interleukin-3 (macrophage/microglial demyelinating disease), interleukin-6 (neurodegenerative disease), or tumor necrosis factor-alpha (lymphocytic encephalomyelitis). In normal mice, the MMPs MT1-MMP, stromelysin 3, and gelatinase B were expressed at low levels, whereas high expression of TIMP-2 and TIMP-3 was observed predominantly in neurons and in the choroid plexus, respectively. In EAE and the transgenic mice, significant induction or up-regulation of various MMP genes was observed, the pattern of which was somewhat specific for each of the models, and there was significant induction of TIMP-1. In situ localization experiments revealed a dichotomy between MMP expression that was restricted to leukocytes and possibly microglia within inflammatory lesions and TIMP-1 expression that was observed in activated astrocytes circumscribing the lesions. These findings demonstrate specific spatial and temporal regulation in the expression of individual MMP and TIMP genes in the CNS in normal and inflammatory states. The distinct localization of TIMP-1 and MMP expression during CNS inflammation suggests a dynamic state in which the interplay between these gene products may determine both the size and resolution of the destructive inflammatory focus. Images Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 PMID:9502415

  13. A case of chronic inflammatory demyelinating polyneuropathy with reversible alternating diaphragmatic paralysis: case study.

    PubMed

    Haji, Kavi; Butler, Ernest; Royse, Colin

    2015-12-01

    Respiratory failure requiring mechanical ventilation has been reported in patients with bilateral diaphragmatic paralysis due to CIDP. We report a case of CIDP that progressed to respiratory failure with normal chest radiography despite unilateral diaphragmatic paralysis. This manifestation would have been missed if ultrasound was not employed. PMID:26490681

  14. Hock lesions and free-stall design.

    PubMed

    Weary, D M; Taszkun, I

    2000-04-01

    We compared the prevalence and severity of skin lesions on the hocks of lactating dairy cows in southern British Columbia, comparing 20 farms using three common bedding surfaces: sawdust, sand, and geotextile mattresses. Skin lesions were scored at five positions on the hock. For each position we noted if the lesion showed inflammatory attributes, and then assigned a severity score. Of the 1752 lactating cows scored, 1267 cows (73%) had at least one hock lesion. Of those cows with lesions, 87% had lesions on both legs, 76% had lesions on more than one location on the hock, and 78% had a lesion of at least moderate severity (i.e., evidence of skin breakage or an area of hair loss >10 cm2). Lesions were most prevalent on farms that used geotextile mattresses (91% of cows) and least common on farms that used sand (24% of cows). Moreover, lesions on cows from farms using mattresses were more numerous and more severe than those on cows from sand-bedded farms. The prevalence and severity of lesions on farms using sawdust was intermediate. Lesions also varied in relation to location on the hock. For farms using geotextile mattresses, lesions were more common and more severe on the lateral surfaces of both the tuber calcis and the tarsal joint. On farms using sawdust, lesions were common on the dorsal surface of the tuber calcis and the lateral surfaces of both the tuber calcis and the tarsal joint. Lesions were rare on all five positions for cows from sand-bedded farms. Among the 10 farms sampled using sawdust, we found a significant negative relationship between the length of the stall and severity of lesions. For cows with lesions, the number and severity of lesions increased with age. PMID:10791785

  15. Demyelination increases axonal stationary mitochondrial size and the speed of axonal mitochondrial transport

    PubMed Central

    Kiryu-Seo, Sumiko; Ohno, Nobuhiko; Kidd, Grahame J.; Komuro, Hitoshi; Trapp, Bruce D.

    2010-01-01

    Axonal degeneration contributes to permanent neurological disability in inherited and acquired diseases of myelin. Mitochondrial dysfunction has been proposed as a major contributor to this axonal degeneration. It remains to be determined, however, if myelination, demyelination or remyelination alter the size and distribution of axonal mitochondrial stationary sites or the rates of axonal mitochondrial transport. Using live myelinated rat dorsal root ganglion (DRG) cultures, we investigated whether myelination and lysolecithin-induced demyelination affect axonal mitochondria. Myelination increased the size of axonal stationary mitochondrial sites by 2.3 fold. Following demyelination, the size of axonal stationary mitochondrial sites was increased by an additional 2.2 fold and the transport velocity of motile mitochondria was increased by 47%. These measures returned to the levels of myelinated axons following remyelination. Demyelination induced activating transcription factor (ATF) 3 in DRG neurons. Knockdown of neuronal ATF3 by shRNA abolished the demyelination-induced increase in axonal mitochondrial transport and increased nitrotyrosine immunoreactivity in axonal mitochondria, suggesting that neuronal ATF3 expression and increased mitochondrial transport protect demyelinated axons from oxidative damage. In response to insufficient ATP production, demyelinated axons increase the size of stationary mitochondrial sites and thereby balance ATP production with the increased energy needs of nerve conduction. PMID:20463228

  16. [Foot lesions].

    PubMed

    Stelzner, C; Schellong, S; Wollina, U; Machetanz, J; Unger, L

    2013-11-01

    The foot is the target organ of a variety of internal diseases. Of upmost importance is the diabetic foot syndrome (DFS). Its complex pathophysiology is driven by the diabetic neuropathy, a vastly worsening effect is contributed by infection and ischemia. Seemingly localised lesions have the potential for phlegmone and septicaemia if not diagnosed and drained early. The acral lesions of peripheral artery occlusive disease (PAOD) have unique features as well. However, their life-threatening potential is lower than that of DFS even if the limb is critical. Notably, isolated foot lesions with a mere venous cause may arise from insufficient perforator veins; the accompanying areas of haemosiderosis will lead the diagnostic path. Cholesterol embolization (blue toe syndrome, trash foot) elicits a unique clinical picture and will become more frequent with increasing numbers of catheter-based procedures. Finally, descriptions are given of podagra and of foot mycosis as disease entities not linked to perfusion. The present review focuses on the depiction of disease and its diagnosis, leaving therapeutic considerations untouched. PMID:24114468

  17. Effects of Reducing Suppressors of Cytokine Signaling-3 (SOCS3) Expression on Dendritic Outgrowth and Demyelination after Spinal Cord Injury

    PubMed Central

    Park, Keun Woo; Lin, Ching-Yi; Li, Kevin; Lee, Yu-Shang

    2015-01-01

    Suppressors of cytokine signaling-3 (SOCS3) is associated with limitations of nerve growth capacity after injury to the central nervous system. Although genetic manipulations of SOCS3 can enhance axonal regeneration after optic injury, the role of SOCS3 in dendritic outgrowth after spinal cord injury (SCI) is still unclear. The present study investigated the endogenous expression of SOCS3 and its role in regulating neurite outgrowth in vitro. Interleukin-6 (IL-6) induces SOCS3 expression at the mRNA and protein levels in neuroscreen-1 (NS-1) cells. In parallel to SOCS3 expression, IL-6 induced tyrosine phosphorylation of signal transducer and activator of transcription 3 (STAT3) in NS-1 cells. Lentiviral delivery of short hairpin RNA (shSOCS3) (Lenti-shSOCS3) to decrease SOCS3 expression into NS-1 cells enhanced IL-6-induced tyrosine phosphorylation of STAT3 (P-STAT3 Tyr705) and promoted neurite outgrowth. In addition, we determined if reduction of SOCS3 expression by microinjection of Lenti-shSOCS3 into spinal cord enhances dendrite outgrowth in spinal cord neurons after SCI. Knocking down of SOCS3 in spinal cord neurons with Lenti-shSOCS3 increased complete SCI-induced P-STAT3 Tyr705. Immunohistochemical analysis showed that complete SCI induced a significant reduction of microtubule association protein 2-positive (MAP-2+) dendrites in the gray and white matter at 1 and 4 weeks after injury. The SCI-induced reduction of MAP-2+ dendrites was inhibited by infection with Lenti-shSOCS3 in areas both rostral and caudal to the lesion at 1 and 4 weeks after complete SCI. Furthermore, shSOCS3 treatment enhanced up-regulation of growth associated protein-43 (GAP-43) expression, which co-localized with MAP-2+ dendrites in white matter and with MAP-2+ cell bodies in gray matter, indicating Lenti-shSOCS3 may induce dendritic regeneration after SCI. Moreover, we demonstrated that Lenti-shSOCS3 decreased SCI-induced demyelination in white matter of spinal cord both rostral and

  18. Comparison of two fat-suppressed magnetic resonance imaging pulse sequences to standard t2-weighted images for brain parenchymal contrast and lesion detection in dogs with inflammatory intracranial disease.

    PubMed

    Young, Benjamin D; Mankin, Joseph M; Griffin, John F; Fosgate, Geoffrey T; Fowler, Jennifer L; Levine, Jonathan M

    2015-01-01

    T2-weighted (T2w) sequences are commonly relied upon in magnetic resonance imaging protocols for the detection of brain lesions in dogs. Previously, the effect of fluid suppression via fluid-attenuated inversion recovery (FLAIR) has been compared to T2-weighting with mixed results. Short tau inversion recovery (STIR) has been reported to increase the detection of some CNS lesions in people. The purpose of the current study was to evaluate the effect of fat suppression on brain parenchymal contrast resolution and lesion detection in dogs. We compared three sequences: T2w images, STIR, and T2w FLAIR with chemical fat suppression (T2-FLAIR-FS) in dogs with meningoencephalitis. Dogs with meningoencephalitis and dogs with idiopathic epilepsy were retrospectively identified and anonymized. Evaluators recorded the presence or absence of lesions within 12 predetermined brain regions on randomized sequences, viewing and scoring each sequence individually. Additionally, signal-to-noise ratios, contrast-to-noise ratios, and relative contrast (RC) were measured in a reference population. Short tau inversion recovery sequences had the highest RC between gray and white matter. While descriptively more lesions were identified by evaluators on T2-FLAIR-FS images, there was no statistical difference in the relative sensitivity of lesion detection between the sequences. Nor was there a statistical difference in false lesion detection within our reference population. Short tau inversion recovery may be favored for enhanced anatomic contrast depiction in brain imaging. No benefit of the inclusion of a fat-suppressed T2-FLAIR sequence was found. PMID:25395066

  19. A review of MRI evaluation of demyelination in cuprizone murine model

    NASA Astrophysics Data System (ADS)

    Krutenkova, E.; Pan, E.; Khodanovich, M.

    2015-11-01

    The cuprizone mouse model of non-autoimmune demyelination reproduces some phenomena of multiple sclerosis and is appropriate for validation and specification of a new method of non-invasive diagnostics. In the review new data which are collected using the new MRI method are compared with one or more conventional MRI tools. Also the paper reviewed the validation of MRI approaches using histological or immunohistochemical methods. Luxol fast blue histological staining and myelin basic protein immunostaining is widespread. To improve the accuracy of non-invasive conventional MRI, multimodal scanning could be applied. The new quantitative MRI method of fast mapping of the macromolecular proton fraction is a reliable biomarker of myelin in the brain and can be used for research of demyelination in animals. To date, a validation of MPF method on the CPZ mouse model of demyelination is not performed, although this method is probably the best way to evaluate demyelination using MRI.

  20. Auraptene induces oligodendrocyte lineage precursor cells in a cuprizone-induced animal model of demyelination.

    PubMed

    Nakajima, Mitsunari; Shimizu, Risei; Furuta, Kohei; Sugino, Mami; Watanabe, Takashi; Aoki, Rui; Okuyama, Satoshi; Furukawa, Yoshiko

    2016-05-15

    We investigated the effects of auraptene on mouse oligodendroglial cell lineage in an animal model of demyelination induced by cuprizone. Auraptene, a citrus coumarin, was intraperitoneally administered to mice fed the demyelinating agent cuprizone. Immunohistochemical analysis of the corpus callosum and/or Western blotting analysis of brain extracts revealed that cuprizone reduced immunoreactivity for myelin-basic protein, a marker of myelin, whereas it increased immunoreactivity to platelet derived-growth factor receptor-α, a marker of oligodendrocyte precursor cells. Administration of auraptene enhanced the immunoreactivity to oligodendrocyte transcription factor 2, a marker of oligodendrocyte precursor cells and oligodendrocyte lineage precursor cells, but had no effect on immunoreactivity to myelin-basic protein or platelet-derived growth factor receptor-α. These findings suggest that auraptene promotes the production of oligodendrocyte lineage precursor cells in an animal model of demyelination and may be useful for individuals with demyelinating diseases. PMID:26944297

  1. Demyelination as a rational therapeutic target for ischemic or traumatic brain injury.

    PubMed

    Shi, Hong; Hu, Xiaoming; Leak, Rehana K; Shi, Yejie; An, Chengrui; Suenaga, Jun; Chen, Jun; Gao, Yanqin

    2015-10-01

    Previous research on stroke and traumatic brain injury (TBI) heavily emphasized pathological alterations in neuronal cells within gray matter. However, recent studies have highlighted the equal importance of white matter integrity in long-term recovery from these conditions. Demyelination is a major component of white matter injury and is characterized by loss of the myelin sheath and oligodendrocyte cell death. Demyelination contributes significantly to long-term sensorimotor and cognitive deficits because the adult brain only has limited capacity for oligodendrocyte regeneration and axonal remyelination. In the current review, we will provide an overview of the major causes of demyelination and oligodendrocyte cell death following acute brain injuries, and discuss the crosstalk between myelin, axons, microglia, and astrocytes during the process of demyelination. Recent discoveries of molecules that regulate the processes of remyelination may provide novel therapeutic targets to restore white matter integrity and improve long-term neurological recovery in stroke or TBI patients. PMID:25819104

  2. A review of MRI evaluation of demyelination in cuprizone murine model

    SciTech Connect

    Krutenkova, E. Pan, E.; Khodanovich, M.

    2015-11-17

    The cuprizone mouse model of non-autoimmune demyelination reproduces some phenomena of multiple sclerosis and is appropriate for validation and specification of a new method of non-invasive diagnostics. In the review new data which are collected using the new MRI method are compared with one or more conventional MRI tools. Also the paper reviewed the validation of MRI approaches using histological or immunohistochemical methods. Luxol fast blue histological staining and myelin basic protein immunostaining is widespread. To improve the accuracy of non-invasive conventional MRI, multimodal scanning could be applied. The new quantitative MRI method of fast mapping of the macromolecular proton fraction is a reliable biomarker of myelin in the brain and can be used for research of demyelination in animals. To date, a validation of MPF method on the CPZ mouse model of demyelination is not performed, although this method is probably the best way to evaluate demyelination using MRI.

  3. Axon membrane remodeling in the lead-induced demyelinating neuropathy of the rat.

    PubMed

    Coria, F; Berciano, M T; Berciano, J; Lafarga, M

    1984-01-23

    Single-teased fibers stained with the ferric ion-ferrocyanide method allowed us to study axonal remodeling in the lead-induced demyelinating neuropathy of the rat. Our findings, in agreement with recent physiological data, pointed to a transitory reorganization of the demyelinated axons to maintain impulse conduction until remyelination and formation of new cytochemically normal nodes had restored a secure saltatory conduction. PMID:6320964

  4. Visual hallucinations and pontine demyelination in a child: possible REM dissociation?

    PubMed

    Vita, Maria Gabriella; Batocchi, Anna Paola; Dittoni, Serena; Losurdo, Anna; Cianfoni, Alessandro; Stefanini, Maria Chiara; Vollono, Catello; Della Marca, Giacomo; Mariotti, Paolo

    2008-12-15

    An 11 year-old-boy acutely developed complex visual and acoustic hallucinations. Hallucinations, consisting of visions of a threatening, evil character of the Harry Potter saga, persisted for 3 days. Neurological and psychiatric examinations were normal. Ictal EEG was negative. MRI documented 3 small areas of hyperintense signal in the brainstem, along the paramedian and lateral portions of pontine tegmentum, one of which showed post-contrast enhancement. These lesions were likely of inflammatory origin, and treatment with immunoglobulins was started. Polysomnography was normal, multiple sleep latency test showed a mean sleep latency of 8 minutes, with one sleep-onset REM period. The pontine tegmentum is responsible for REM sleep regulation, and contains definite "REM-on" and "REM-off" regions. The anatomical distribution of the lesions permits us to hypothesize that hallucinations in this boy were consequent to a transient impairment of REM sleep inhibitory mechanisms, with the appearance of dream-like hallucinations during wake. PMID:19110890

  5. Effects of deep heating provided by therapeutic ultrasound on demyelinating nerves

    PubMed Central

    Aydin, Elif; Tastaban, Engin; Omurlu, Imran Kurt; Turan, Yasemin; Şendur, Ömer Faruk

    2016-01-01

    [Purpose] Physiotherapeutic heating agents are classified into two groups: superficial-heating agents and deep-heating agents. Therapeutic ultrasound is a deep-heating agent used to treat various musculosketal disorders. Numerous studies have attempted to determine the impact of ultrasound on healthy nerve conduction parameters. However, the instantaneous effects of deep heating via ultrasound on demyelinating nerves do not appear to have been described previously. The present study aimed to assess and compare the impact of ultrasound on demyelinating nerve and healthy nerve conduction parameters. [Subjects and Methods] Carpal tunnel syndrome was used as a focal demyelination model. Thirty-two hands of 25 participants with carpal tunnel syndrome were enrolled in the study. Ultrasound parameters were 3.3 MHz, 1.0 W/cm2, 8 minutes, and continuous wave. Electrodiagnostic studies were performed initially, at the midpoint (4th min), and immediately after (8th min) ultrasound application. [Results] Reduced motor conduction velocity was found in demyelinating nerves at the 4th and 8th minutes. Ulnar nerve onset latency was significantly prolonged in the 8th minute recording, compared to the initial value. There were no significant differences in relative velocity and latency changes between demyelinating and normal nerves. [Conclusion] Deep heating via ultrasound may inversely affect conduction velocity in demyelinating nerves. PMID:27190467

  6. Molecular imaging of cerebrovascular lesions.

    PubMed

    Chalouhi, Nohra; Jabbour, Pascal; Magnotta, Vincent; Hasan, David

    2014-04-01

    Inflammation is a key component in the pathogenesis of cerebrovascular lesions. Two agents have emerged as promising possibilities for imaging cerebrovascular lesions. These agents are ferumoxytol and myeloperoxidase (MPO)-specific paramagnetic magnetic resonance (MR) contrast agent. Ferumoxytol is an iron oxide nanoparticle coated by a carbohydrate shell that is used in MRI studies as an inflammatory marker as it is cleared by macrophages. Ferumoxytol-enhanced MRI allows noninvasive assessment of the inflammatory status of cerebral aneurysms and arteriovenous malformations and, possibly, may differentiate "unstable" lesions that require early intervention from "stable" lesions that can be safely observed. Several pilot studies have also suggested that MPO-specific paramagnetic MR contrast agent, di-5-hydroxytryptamide of gadopentetate dimeglumine, may allow imaging of inflammation in the wall of saccular aneurysms in animal models. However, studies in human subjects have yet to be performed. In this paper, we review current data regarding ferumoxytol-enhanced MRI and MPO-specific paramagnetic MR contrast agent and discuss current and future applications. PMID:24323714

  7. High bone turnover assessed by 18F-fluoride PET/CT in the spine and sacroiliac joints of patients with ankylosing spondylitis: comparison with inflammatory lesions detected by whole body MRI

    PubMed Central

    2012-01-01

    Background This study compares the frequency and distribution of increased activity on 18 F-fluoride PET/CT with the presence of bone marrow edema on whole-body MR imaging in the spine and sacroiliac joints (SIJ) of patients with active ankylosing spondylitis (AS). Methods Ten patients (6 men and 4 women), between 30 and 58 years old (median 44) with active AS, were prospectively examined with both whole-body MRI and 18 F-fluoride PET/CT. Patients fulfilled modified NY criteria and had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of at least 4. Increased radiotracer uptake in PET/CT and bone marrow edema in whole-body MRI of spine and SIJ was evaluated independently by two blinded observers for each modality. Kappa statistics were used to compare interobserver agreement as well as scores of consensus reading of the two imaging modalities. Results Analysis of interobserver agreement for PET/CT yielded a kappa value of 0.68 for spinal lesions and of 0.88 for SIJ lesions. The corresponding kappa values for the MRI modality were 0.64 and 0.93, respectively. More spinal lesions were detected by MRI in comparison to PET/CT (68 vs. 38), whereas a similar number of SIJ quadrants scored positive in both modalities (19 vs. 17). Analysis of agreement of lesion detection between both imaging modalities yielded a kappa value of only 0.25 for spinal lesions and of 0.64 for SIJ lesions. Conclusion Increased 18 F-fluoride uptake in PET/CT is only modestly associated with bone marrow edema on MRI in the spine and SIJ of patients with AS, suggesting different aspects of bone involvement in AS. PMID:22788874

  8. [2013: what's new in inflammatory neuropathies].

    PubMed

    Kuntzer, T

    2014-12-01

    Several high-quality publications were published in 2013 and some major trials studies were started. In Guillain-Barré syndrome, events included the launch of IGOS and a better understanding of diagnostic limits, the effect of influenza vaccination, and better care, but uncertainty remains about analgesics. A new mouse model was also described. In chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), diagnostic pitfalls can be recalled. Our knowledge of underlying pathophysiological processes has improved, and the value of monitoring with function and deficit scores has been demonstrated. IVIG can sometimes be effective longer than expected, but CIDP remains sensitive to corticosteroids, particularly with the long-term beneficial effects of megadose dexamethasone. The impact of fingolimod remains to be demonstrated in an ongoing trial. Advances concerning multifocal motor neuropathy, inflammatory plexopathy, and neuropathy with anti -MAG activity are discussed but treatments already recognized as effective should not be changed. Imaging of peripheral nerve progresses. PMID:25459118

  9. Short myelitis lesions in aquaporin-4-IgG-positive neuromyelitis optica spectrum

    PubMed Central

    Flanagan, Eoin P.; Weinshenker, Brian G.; Krecke, Karl N.; Lennon, Vanda A.; Lucchinetti, Claudia F.; McKeon, Andrew; Wingerchuk, Dean M.; Shuster, Elizabeth A.; Jiao, Yujuan; Horta, Erika S.; Pittock, Sean J.

    2015-01-01

    Importance Short transverse myelitis (STM, <3 vertebral segments) is considered non-characteristic of neuromyelitis optica spectrum disorders (NMOSD). Poor recognition of the potential for STM to occur in NMOSD may lead to increased disability from delay in diagnosis and appropriate treatment. Objectives To determine the frequency of short lesions at the initial myelitis manifestation of NMOSD, and to compare the demographic, clinical and radiological characteristics of aquaporin-4-IgG (AQP4-IgG) seropositive and seronegative STM. Design, Setting, Participants We reviewed the records and images of Mayo Clinic AQP4-IgG positive NMOSD patients identified from 1996-2014. Inclusion criteria were: 1) first TM episode; 2) MRI performed ≤90 days from symptom onset; 3) Spinal cord T2-hyperintense lesion <3 vertebral segments; 4) AQP4-IgG seropositivity; 5) final diagnosis NMO or NMOSD. Patients with an initial longitudinally extensive transverse myelitis (LETM) were excluded (n=151). Patients with STM, seronegative for AQP4-IgG, among an Olmsted County population-based cohort of inflammatory demyelinating disorders of the central nervous system were used as a control group. Main Outcomes and Measures Delay to diagnosis in months, clinical and radiological characteristics and disability measured by ambulatory status. Results Twenty-five AQP4-IgG seropositive patients with an initial STM were included, representing 14% of initial myelitis episodes among NMOSD patients. The STM episode was: the first manifestation of NMOSD in 10 patients (40%); preceded by optic neuritis in 13 patients (52%); and preceded by a nausea and vomiting episode in 2 (8%). In comparison to the excluded NMOSD patients with an initial LETM, delay to diagnosis/treatment was greater when initial lesions were short (p=0.016). In AQP4-IgG positive STM cases subsequent myelitis episodes were longitudinally extensive in 92%. Attributes more common in aquaporin-4-IgG-positive STM patients than in 27

  10. Chronic Severe Hyponatremia and Cardiopulmonary Bypass: Avoiding Osmotic Demyelination Syndrome.

    PubMed

    Canaday, Susan; Rompala, John; Rowles, John; Fisher, Josh; Holt, David

    2015-12-01

    Serum sodium concentration affects every cell in the body with respect to cellular tonicity. Hyponatremia is the most frequent electrolyte abnormality encountered, occurring at clinical admission in 22% of elderly patients. Any rapid correction of chronic severe hyponatremia can result in rapid cellular shrinking due to loss of intracellular free water. This is commonly associated with paralysis and severe brain damage due to osmotic demyelination syndrome (ODS). ODS occurs because the body has the ability to compensate for cellular fluid shifts due to chronic hyponatremia (by a decrease in brain concentration of several ions, amino acids, and organic osmolytes). Thus, the neurons are often at a functional state of fluid balance despite the sodium imbalance. The initiation of cardiopulmonary bypass (CPB) can introduce between 1 and 2 L of priming solution containing a normal sodium concentration creating a rapid rise in sodium concentration within the extracellular fluid. This abrupt change establishes a situation where intracellular free water can be lost resulting in cellular shrinking and ODS. In presenting this case study, we hope to add to the current literature with a specific isotonic approach to treating the chronically severe hyponatremic patient pre-CPB, during CPB, and post-CPB. PMID:26834285

  11. Oligodendrocyte death results in immune-mediated CNS demyelination

    PubMed Central

    Traka, Maria; Podojil, Joseph R; McCarthy, Derrick P; Miller, Stephen D; Popko, Brian

    2016-01-01

    Although multiple sclerosis is a common neurological disorder, the origin of the autoimmune response against myelin, which is the characteristic feature of the disease, remains unclear. To investigate whether oligodendrocyte death could cause this autoimmune response, we examined the oligodendrocyte ablation Plp1-CreERT;ROSA26-eGFP-DTA (DTA) mouse model. Approximately 30 weeks after recovering from oligodendrocyte loss and demyelination, DTA mice develop a fatal secondary disease characterized by extensive myelin and axonal loss. Strikingly, late-onset disease was associated with increased numbers of T lymphocytes in the CNS and myelin oligodendrocyte glycoprotein (MOG)-specific T cells in lymphoid organs. Transfer of T cells derived from DTA mice to naive recipients resulted in neurological defects that correlated with CNS white matter inflammation. Furthermore, immune tolerization against MOG ameliorated symptoms. Overall, these data indicate that oligodendrocyte death is sufficient to trigger an adaptive autoimmune response against myelin, suggesting that a similar process can occur in the pathogenesis of multiple sclerosis. PMID:26656646

  12. [Development and regeneration of oligodendrocytes: therapeutic perspectives in demyelinating diseases].

    PubMed

    Dubois-Dalcq, M

    2005-01-01

    The function of the central nervous system (CNS) is in great part depending on glial cells as, for instance, radial glial cells give rise to cortical neurons, and oligodendrocytes synthesize an immense specialized membrane that enwraps axons to make myelin internodes. Myelin allows fast saltatory conduction of action potentials along myelinated nerve tracts and assures the survival of axons. Oligodendrocytes precursors (OP) emerge during development, first in the spinal cord and later in the telencephalon from multipotential neural precursors in germinative zones around the cerebral ventricles. Morphogens and specific growth factors stimulate the growth, migration and survival of OPs toward axons, culminating in myelination. Such precursors can be isolated from human brain and persist in the adult CNS, allowing some degree of remyelination in the course of a demyelinating disease caused by an infectious agent or inflammation such as multiple sclerosis (MS). These remyelinating cells can recapitulate some molecular events of myelination while new OPs are generated by neural stem cells in the subventricular zones and niches. This natural repair process often decreases with time in man, raising questions about the appropriateness of rodent animal models where remyelination is robust. The challenge today in MS is to develop a pharmacology of myelin repair by endogenous precursors which, if successful, might be more likely to result in clinical benefits than transplantation of myelin-forming cells, shown to be so efficient in rodent models. PMID:16768245

  13. Kinetics of lung lesion development and pro-inflammatory cytokine response in pigs with vaccine-associated enhanced respiratory disease induced by challenge with pandemic (2009) A/H1N1 influenza virus

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The objective of this report was to characterize the enhanced clinical disease and lung lesions observed in pigs vaccinated with inactivated H1N2 swine delta-cluster influenza A virus and challenged with pandemic 2009 A/H1N1 human influenza virus. Eighty-four, six-week-old, crossbred pigs were rand...

  14. Chronic inflammatory polyneuropathy

    MedlinePlus

    ... nerves outside the brain or spinal cord ( peripheral neuropathy ). Polyneuropathy means several nerves are involved. It usually ... demyelinating polyneuropathy (CIDP) is the most common chronic neuropathy caused by an abnormal immune response. CIDP occurs ...

  15. TNFR2 Deficiency Acts in Concert with Gut Microbiota To Precipitate Spontaneous Sex-Biased Central Nervous System Demyelinating Autoimmune Disease.

    PubMed

    Miller, Patrick G; Bonn, Michael B; Franklin, Craig L; Ericsson, Aaron C; McKarns, Susan C

    2015-11-15

    TNF-α antagonists provide benefit to patients with inflammatory autoimmune disorders such as Crohn's disease, rheumatoid arthritis, and ankylosing spondylitis. However, TNF antagonism unexplainably exacerbates CNS autoimmunity, including multiple sclerosis and neuromyelitis optica. The underlying mechanisms remain enigmatic. We demonstrate that TNFR2 deficiency results in female-biased spontaneous autoimmune CNS demyelination in myelin oligodendrocyte glycoprotein-specific 2D2 TCR transgenic mice. Disease in TNFR2(-/-) 2D2 mice was associated with CNS infiltration of T and B cells as well as increased production of myelin oligodendrocyte glycoprotein-specific IL-17, IFN-γ, and IgG2b. Attenuated disease in TNF(-/-) 2D2 mice relative to TNFR2(-/-) 2D2 mice identified distinctive roles for TNFR1 and TNFR2. Oral antibiotic treatment eliminated spontaneous autoimmunity in TNFR2(-/-) 2D2 mice to suggest role for gut microbiota. Illumina sequencing of fecal 16S rRNA identified a distinct microbiota profile in male TNFR2(-/-) 2D2 that was associated with disease protection. Akkermansia muciniphila, Sutterella sp., Oscillospira sp., Bacteroides acidifaciens, and Anaeroplasma sp. were selectively more abundant in male TNFR2(-/-) 2D2 mice. In contrast, Bacteroides sp., Bacteroides uniformis, and Parabacteroides sp. were more abundant in affected female TNFR2(-/-) 2D2 mice, suggesting a role in disease causation. Overall, TNFR2 blockade appears to disrupt commensal bacteria-host immune symbiosis to reveal autoimmune demyelination in genetically susceptible mice. Under this paradigm, microbes likely contribute to an individual's response to anti-TNF therapy. This model provides a foundation for host immune-microbiota-directed measures for the prevention and treatment of CNS-demyelinating autoimmune disorders. PMID:26475926

  16. Analysis of the host transcriptome from demyelinating spinal cord of murine coronavirus-infected mice.

    PubMed

    Elliott, Ruth; Li, Fan; Dragomir, Isabelle; Chua, Ming Ming W; Gregory, Brian D; Weiss, Susan R

    2013-01-01

    Persistent infection of the mouse central nervous system (CNS) with mouse hepatitis virus (MHV) induces a demyelinating disease pathologically similar to multiple sclerosis and is therefore used as a model system. There is little information regarding the host factors that correlate with and contribute to MHV-induced demyelination. Here, we detail the genes and pathways associated with MHV-induced demyelinating disease in the spinal cord. High-throughput sequencing of the host transcriptome revealed that demyelination is accompanied by numerous transcriptional changes indicative of immune infiltration as well as changes in the cytokine milieu and lipid metabolism. We found evidence that a Th1-biased cytokine/chemokine response and eicosanoid-derived inflammation accompany persistent MHV infection and that antigen presentation is ongoing. Interestingly, increased expression of genes involved in lipid transport, processing, and catabolism, including some with known roles in neurodegenerative diseases, coincided with demyelination. Lastly, expression of several genes involved in osteoclast or bone-resident macrophage function, most notably TREM2 and DAP12, was upregulated in persistently infected mouse spinal cord. This study highlights the complexity of the host antiviral response, which accompany MHV-induced demyelination, and further supports previous findings that MHV-induced demyelination is immune-mediated. Interestingly, these data suggest a parallel between bone reabsorption by osteoclasts and myelin debris clearance by microglia in the bone and the CNS, respectively. To our knowledge, this is the first report of using an RNA-seq approach to study the host CNS response to persistent viral infection. PMID:24058676

  17. A comparative study of experimental mouse models of central nervous system demyelination

    PubMed Central

    Dumitrascu, Oana M.; Mott, Kevin R.; Ghiasi, Homayon

    2014-01-01

    Several mouse models of multiple sclerosis (MS) are now available. We have established a mouse model, in which ocular infection with a recombinant HSV-1 that expresses murine IL-2 constitutively (HSV-IL-2) causes CNS demyelination in different strains of mice. This model differs from most other models in that it represents a mixture of viral and immune triggers. In the present study, we directly compared MOG35–55, MBP35–47, and PLP190–209 models of EAE with our HSV-IL-2-induced MS model. Mice with HSV-IL-2-induced and MOG-induced demyelinating diseases demonstrated a similar pattern and distribution of demyelination in their brain, spinal cord, and optic nerves. In contrast, no demyelination was detected in the optic nerves of MBP- and PLP-injected mice. IFN-β injections significantly reduced demyelination in brains of all groups, in the spinal cords of the MOG and MBP groups, and completely blocked it in the spinal cords of the PLP and HSV-IL-2 groups as well as in optic nerves of MOG and HSV-IL-2 groups. In contrast to IFN-β treatment, IL-12p70 protected the HSV-IL-2 group from demyelination, while IL-4 was not effective at all in preventing demyelination. MOG-injected mice showed clinical signs of paralysis and disease-related mortality whereas mice in the other treatment groups did not. Collectively, the results indicate that the HSV-IL-2 model and the MOG model complement each other and, together, provide unique insights into the heterogeneity of human MS. PMID:24718267

  18. A comparative study of experimental mouse models of central nervous system demyelination.

    PubMed

    Dumitrascu, O M; Mott, K R; Ghiasi, H

    2014-06-01

    Several mouse models of multiple sclerosis (MS) are now available. We have established a mouse model, in which ocular infection with a recombinant HSV-1 that expresses murine interleukin (IL)-2 constitutively (HSV-IL-2) causes central nervous system demyelination in different strains of mice. This model differs from most other models, in which it represents a mixture of viral and immune triggers. In the present study, we directly compared MOG35-55, MBP35-47 and PLP190-209 models of experimental autoimmune encephalitis with our HSV-IL-2-induced MS model. Mice with HSV-IL-2- and myelin oligodendrocyte glycoprotein (MOG)-induced demyelinating diseases demonstrated a similar pattern and distribution of demyelination in their brain, spinal cord (SC) and optic nerves (ONs). In contrast, no demyelination was detected in the ONs of myelin basic protein (MBP)- and proteolipid protein (PLP)-injected mice. Interferon-β (IFN-β) injections significantly reduced demyelination in brains of all groups, in the SCs of the MOG and MBP groups, and completely blocked it in the SCs of the PLP and HSV-IL-2 groups as well as in ONs of MOG and HSV-IL-2 groups. In contrast to IFN-β treatment, IL-12p70 protected the HSV-IL-2 group from demyelination, whereas IL-4 was not effective at all in preventing demyelination. MOG-injected mice showed clinical signs of paralysis and disease-related mortality, whereas mice in the other treatment groups did not. Collectively, the results indicate that the HSV-IL-2 model and the MOG model complement each other and, together, provide unique insights into the heterogeneity of human MS. PMID:24718267

  19. Inflammatory pseudotumor of spleen

    PubMed Central

    Rajabi, Parvin; Noorollahi, Hasan; Hani, Mohsen; Bagheri, Marzie

    2014-01-01

    Inflammatory pseudotumor (IPT) is an uncommon tumor and its occurrence in spleen is rare. This tumor is composed of proliferation of spindle cells of unknown origin and etiology that mimic other tumors at clinical and histological evaluation. The most surmising etiology is Epstein Barr virus (EBV) and the most suspected origin is myofibroblasts, hence its synonym is “inflammatory myofibroblastic tumor.” The clinical appearance of tumor is related to its location but the most ones are abdominal pain, fever and weight loss. Surgical removal for this lesion is treatment of choice and there is few reported case with recurrence and metastasis. Herein we report a 63-year-old female patient with and abdominal discomfort that primary paraclinical investigations had been showed splenic mass and therefore surgical treatment was performed for her. Microscopic examination suggest some different diagnosis such as IPT, thus immunohistochemical staining was perform to confirm the diagnosis and rule out the others. PMID:24592376

  20. Increased interleukin-6 correlates with myelin oligodendrocyte glycoprotein antibodies in pediatric monophasic demyelinating diseases and multiple sclerosis.

    PubMed

    Horellou, Philippe; Wang, Min; Keo, Vixra; Chrétien, Pascale; Serguera, Ché; Waters, Patrick; Deiva, Kumaran

    2015-12-15

    Acquired demyelinating syndromes (ADS) in children evolve either as a monophasic disease diagnosed as acute demyelinating encephalomyelitis (ADEM), transverse myelitis (TM) or optic neuritis (ON), or a multiphasic one with several relapses most often leading to the diagnosis of multiple sclerosis (MS) or neuromyelitis optica (NMO). These neuroinflammatory disorders are increasingly associated with autoantibodies against proteins such as aquaporin-4 in rare instances, and more frequently against myelin oligodendrocyte glycoprotein (MOG). Recently, in adult NMO patients, C5a levels were shown to be elevated in cerebrospinal fluid (CSF) during acute exacerbation. We investigated the CSF levels of anaphylatoxins and pro-inflammatory cytokines, and plasma MOG antibodies in onset samples from children with ADS. Thirty four children presenting with a first episode of ADS, 17 with monophasic ADS (9 with ADEM, 4 with TM and 4 with ON) and 17 with MS, who had paired blood and CSF samples at onset were included and compared to 12 patients with other non-inflammatory neurological disorders (OND). Cytokines and anaphylatoxins in CSF were measured by Cytometric Bead Array immunoassay. MOG antibody titers in plasma were tested by flow cytometry using a stable cell line expressing full-length human MOG. We found a significant increase in C5a levels in the CSF of patients with monophasic ADS (n=17) compared to OND (n=12, p=0.0036) and to MS (n=17, p=0.0371). The C5a levels in MS were higher than in OND without reaching significance (p=0.2). CSF IL-6 levels were significantly increased in monophasic ADS compared to OND (p=0.0027) and to MS (p=0.0046). MOG antibody plasma levels were significantly higher in monophasic ADS (p<0.0001) and, to a lesser extent, in MS compared to OND (p=0.0023). Plasma MOG antibodies and CSF IL-6 levels were significantly correlated (r=0.51, p=0.018). CSF C5a and IL-6 levels are increased in monophasic ADS but not in MS when compared to OND, suggesting

  1. The Effect of Melatonin on Behavioral, Molecular, and Histopathological Changes in Cuprizone Model of Demyelination.

    PubMed

    Vakilzadeh, Gelareh; Khodagholi, Fariba; Ghadiri, Tahereh; Ghaemi, Amir; Noorbakhsh, Farshid; Sharifzadeh, Mohammad; Gorji, Ali

    2016-09-01

    Multiple sclerosis (MS) is an autoimmune, demyelinating disease of the central nervous system. The protective effects of melatonin (MLT) on various neurodegenerative diseases, including MS, have been suggested. In the present study, we examined the effect of MLT on demyelination, apoptosis, inflammation, and behavioral dysfunctions in the cuprizone toxic model of demyelination. C57BL/6J mice were fed a chaw containing 0.2 % cuprizone for 5 weeks and received two doses of MLT (50 and 100 mg/kg) intraperitoneally for the last 7 days of cuprizone diet. Administration of MLT improved motor behavior deficits induced by cuprizone diet. MLT dose-dependently decreased the mean number of apoptotic cells via decreasing caspase-3 and Bax as well as increasing Bcl-2 levels. In addition, MLT significantly enhanced nuclear factor-κB activation and decreased heme oxygenase-1 level. However, MLT had no effect on interleukin-6 and myelin protein production. Our data revealed that MLT improved neurological deficits and enhanced cell survival but was not able to initiate myelin production in the cuprizone model of demyelination. These findings may be important for the design of potential MLT therapy in demyelinating disorders, such as MS. PMID:26310973

  2. [Ion channels and demyelination: basis of a treatment of experimental autoimmune encephalomyelitis (EAE) by potassium channel blockers].

    PubMed

    Devaux, J; Beeton, C; Béraud, E; Crest, M

    2004-05-01

    Voltage-gated potassium channels (Kv channels) are ion channels, openings of which provide an outward flow of potassium ions repolarising the cell. In neurons, Kv channels play a crucial role in action potential repolarisation and in shaping neuronal excitability. In non-excitable cells, such as T lymphocytes, Kv channels and calcium-activated K+ channels (KCa channels) determine the driving force for Ca2+ entry. During T cell activation the calcium entry depolarises the cell and increases the cytosolic calcium concentration, which in return activates Kv and KCa channels. K+ channel opening repolarises the cell and drives the membrane potential to a negative voltage. The roles of Kv channels in nervous and immune systems have been investigated here by means of a rat experimental autoimmune disease of the central nervous system, the experimental autoimmune encephalomyelitis (EAE). EAE is characterised clinically by paralysis, and pathologically by inflammatory cell infiltrations into the brain and the spinal cord. Among the inflammatory cells, T lymphocytes play a major role. Hence, EAE can be adoptively transferred into syngenic animals by the injection of T cells reactive to myelin antigens. During adoptive-EAE, somato-sensory evoked potentials recorded along the spinal tracts decrease in amplitude and axonal propagation is disrupted. We have analysed the consequences of Kv channels blockade by peptidyl toxins on central nerve conduction, on T cell activation and on the time course of EAE. In rat optic nerves, Kv channels have been identified up from postnatal day 1. Their blockade by kaliotoxin (a scorpion toxin) or by dendrotoxin-I (a snake toxin) enlarges the compound action potentials, demonstrating the participation of Kv channels to spike repolarisation. This effect disappears at adult age due to the sequestration of Kv channels under the myelin, in the paranodal regions. During acute demyelination by lysophosphatidyl-choline, the surface area of compound

  3. Endoneurial content of lead related to the onset and severity of segmental demyelination. [Rats

    SciTech Connect

    Windebank, A.J.; McCall, J.T.; Hunder, H.G.; Dyck, P.J.

    1980-11-01

    The endoneurial lead and water content was serially evaluated in the nerves of rats fed lead carbonate and related to the onset and severity of segmental demyelination and remyelination. Lead began to accumulate significantly in the endoneurium by 5 days, reached a maximum level by 34 days, and then fell to the perineurial level by 3 months. The water content of endoneurium did not become significantly increased until the 50th day. Extensive teased fiber grading of pathologic abnormalities carried out on the same animals showed that segmental demyelination began between the 20th and 35th days and worsened progressively. This provides the first evidence that high endoneurial lead concentration precedes segmental demyelination and nerve edema. It suggests that the random Schwann cell damage is more likely to be due to a direct toxic effect of lead rather than a factor associated with edema or increased endoneurial pressure.

  4. Therapeutic Approach to the Management of Pediatric Demyelinating Disease: Multiple Sclerosis and Acute Disseminated Encephalomyelitis.

    PubMed

    Brenton, J Nicholas; Banwell, Brenda L

    2016-01-01

    Acquired pediatric demyelinating diseases manifest acutely with optic neuritis, transverse myelitis, acute disseminated encephalomyelitis, or with various other acute deficits in focal or polyfocal areas of the central nervous system. Patients may experience a monophasic illness (as in the case of acute disseminated encephalomyelitis) or one that may manifest as a chronic, relapsing disease [e.g., multiple sclerosis (MS)]. The diagnosis of pediatric MS and other demyelinating disorders of childhood has been facilitated by consensus statements regarding diagnostic definitions. Treatment of pediatric MS has been modeled after data obtained from clinical trials in adult-onset MS. There are now an increasing number of new therapeutic agents for MS, and many will be formally studied for use in pediatric patients. There are important efficacy and safety concerns regarding the use of these therapies in children and young adults. This review will discuss acute management as well as chronic immunotherapies in acquired pediatric demyelination. PMID:26496907

  5. [Synovial tumors and tumor-like lesions].

    PubMed

    Doepfer, A-K; Meurer, A

    2015-10-01

    Synovial tumors comprise a variety of lesions, including those with benign and aggressive neoplastic changes as well as inflammatory causes. In this article we focus on neoplastic tumors. Synovial tumors with other etiologies, such as sarcoidosis, granuloma, synovitis, or gouty arthritis, are not dealt with here. Through a precise differentiation between these disease entities can an optimization of treatment be achieved. PMID:26370407

  6. Progressive oil-spot-like lesion in multiple sclerosis.

    PubMed

    Petrescu, A

    1981-01-01

    The demyelinating lesion in MS being characterised by an evolutive polymorphism, led to different opinions about the identification of the hypercellularity. The present work deals with data concerning the abundance and the early appearance of macrophages (M) within the lesion, studied with lipid histochemistry methods. The disposition of 3 various types of previously described M, with different lipid content, demonstrates the progressive centrifugal evolution of the recent lesion. At the edge the M are filled exclusively with intensely Baker (phospholipids) stained myelinic granules whereas inside they have a mixed myelinic and sudano-osmiophylic (esterocholesterolic) composition as revealed by Sudan red, Oil rd, Otan and Schultz methods. Surrounding vessels, in the centre of the lesion, M contain exclusively sudano-osmiophylic (esterocholesterolic) granules and crystals. This arrangement of M as to AGE is due to the progressive disintegrative cycle of phagocyted myelin: the youngest at the edge and those undergoing myelin disintegration towards the centre. It is demonstrative for the progressive and centrifugally oil-spot-like extension of the lesion and might explain the round-shape of the small lesions which stop their extension without any morphological correlations. PMID:6939231

  7. Putaminal alteration in multiple sclerosis patients with spinal cord lesions.

    PubMed

    Zimmermann, Hilga; Rolfsnes, Hans O; Montag, Swantje; Wilting, Janine; Droby, Amgad; Reuter, Eva; Gawehn, Joachim; Zipp, Frauke; Gröger, Adriane

    2015-10-01

    Typical multiple sclerosis (MS) lesions occur in the brain as well as in the spinal cord. However, two extreme magnetic resonance imaging phenotypes appear occasionally: those with predominantly spinal cord lesions (MS + SL) and those with cerebral lesions and no detectable spinal lesions (MS + CL). We assessed whether morphological differences can be found between these two extreme phenotypes. We examined 19 patients with MS + SL, 18 with MS + CL and 20 controls. All subjects were examined using magnetic resonance imaging, including anatomical and diffusion tensor imaging sequences. Voxel-based morphologic and regions of interest-based analyses and tract-based spatial statistics were performed. Patients also underwent neuropsychological testing. Demographic, clinical and neuropsychological characteristics did not differ between MS + SL and MS + CL patients. Patients with MS + SL showed significantly larger putamen volumes than those with MS + CL which correlated negatively with disability. Compared to controls, only MS + CL revealed clear cortical and deep gray matter atrophy, which correlated with cerebral lesion volume. Additionally, extensive white matter microstructural damage was found only in MS + CL compared to MS + SL and controls in the tract-based spatial statistics. Higher putamen volumes in MS + SL could suggest compensatory mechanisms in this area responsible for motor control. Widely reduced fractional anisotropy values in MS + CL were caused by higher cerebral lesion volume and thus presumably stronger demyelination, which subsequently leads to higher global gray matter atrophy. PMID:25971605

  8. Pain and spinal cord imaging measures in children with demyelinating disease

    PubMed Central

    Barakat, Nadia; Gorman, Mark P.; Benson, Leslie; Becerra, Lino; Borsook, David

    2015-01-01

    Pain is a significant problem in diseases affecting the spinal cord, including demyelinating disease. To date, studies have examined the reliability of clinical measures for assessing and classifying the severity of spinal cord injury (SCI) and also to evaluate SCI-related pain. Most of this research has focused on adult populations and patients with traumatic injuries. Little research exists regarding pediatric spinal cord demyelinating disease. One reason for this is the lack of reliable and useful approaches to measuring spinal cord changes since currently used diagnostic imaging has limited specificity for quantitative measures of demyelination. No single imaging technique demonstrates sufficiently high sensitivity or specificity to myelin, and strong correlation with clinical measures. However, recent advances in diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) measures are considered promising in providing increasingly useful and specific information on spinal cord damage. Findings from these quantitative imaging modalities correlate with the extent of demyelination and remyelination. These techniques may be of potential use for defining the evolution of the disease state, how it may affect specific spinal cord pathways, and contribute to the management of pediatric demyelination syndromes. Since pain is a major presenting symptom in patients with transverse myelitis, the disease is an ideal model to evaluate imaging methods to define these regional changes within the spinal cord. In this review we summarize (1) pediatric demyelinating conditions affecting the spinal cord; (2) their distinguishing features; and (3) current diagnostic and classification methods with particular focus on pain pathways. We also focus on concepts that are essential in developing strategies for the detection, monitoring, treatment and repair of pediatric myelitis. PMID:26509120

  9. In vitro analysis of the oligodendrocyte lineage in mice during demyelination and remyelination

    SciTech Connect

    Armstrong, R.; Friedrich, V.L. Jr.; Holmes, K.V.; Dubois-Dalcq, M. )

    1990-09-01

    A demyelinating disease induced in C57B1/6N mice by intracranial injection of a coronavirus (murine hepatitis virus strain A59) is followed by functional recovery and efficient CNS myelin repair. To study the biological properties of the cells involved in this repair process, glial cells were isolated and cultured from spinal cords of these young adult mice during demyelination and remyelination. Using three-color immunofluorescence combined with (3H)thymidine autoradiography, we have analyzed the antigenic phenotype and mitotic potential of individual glial cells. We identified oligodendrocytes with an antibody to galactocerebroside, astrocytes with an antibody to glial fibrillary acidic protein, and oligodendrocyte-type 2 astrocyte (O-2A) progenitor cells with the O4 antibody. Cultures from demyelinated tissue differed in several ways from those of age-matched controls: first, the total number of O-2A lineage cells was strikingly increased; second, the O-2A population consisted of a higher proportion of O4-positive astrocytes and cells of mixed oligodendrocyte-astrocyte phenotype; and third, all the cell types within the O-2A lineage showed enhanced proliferation. This proliferation was not further enhanced by adding PDGF, basic fibroblast growth factor (bFGF), or insulin-like growth factor I (IGF-I) to the defined medium. However, bFGF and IGF-I seemed to influence the fate of O-2A lineage cells in cultures of demyelinated tissue. Basic FGF decreased the percentage of cells expressing galactocerebroside. In contrast, IGF-I increased the relative proportion of oligodendrocytes. Thus, O-2A lineage cells from adult mice display greater phenotypic plasticity and enhanced mitotic potential in response to an episode of demyelination. These properties may be linked to the efficient remyelination achieved in this demyelinating disease.

  10. Laquinimod prevents cuprizone-induced demyelination independent of Toll-like receptor signaling

    PubMed Central

    Menken, Lena; Hayardeny, Liat; Hanisch, Uwe-Karsten; Brück, Wolfgang

    2016-01-01

    Objective: To test whether Toll-like receptor (TLR) signaling plays a key role for reduced nuclear factor B (NF-κB) activation after laquinimod treatment in the model of cuprizone-induced demyelination, oligodendrocyte apoptosis, inflammation, and axonal damage. Methods: Ten-week-old C57BL/6J, TLR4−/−, and MyD88−/− mice received 0.25% cuprizone for 6 weeks and were treated daily with 25 mg/kg laquinimod or vehicle. After 6 weeks of demyelination, extent of demyelination, oligodendrocyte density, microglia infiltration, and axonal damage were analyzed in the corpus callosum. Additionally, we analyzed primary mouse astrocytes from C57BL/6J, TLR4−/−, MyD88−/−, and TRIF−/− mice for alteration in NF-κB signaling. Results: Vehicle-treated controls from C57BL/6J, TLR4−/−, and MyD88−/− mice displayed extensive callosal demyelination as well as microglial activation. In contrast, mice treated with 25 mg/kg laquinimod showed mainly intact callosal myelin. The demyelination score was significantly higher in all untreated mice compared to mice treated with laquinimod. There were significantly fewer APP-positive axonal spheroids, Mac3-positive macrophages/microglia, and less oligodendrocyte apoptosis in the corpus callosum of laquinimod-treated mice in comparison to untreated controls. Stimulated primary mouse astrocytes from laquinimod-treated groups show reduced NF-κB activation compared to vehicle-treated controls. Conclusions: Our results confirm that laquinimod prevents demyelination in the cuprizone mouse model for multiple sclerosis via downregulation of NF-κB activation. This laquinimod effect, however, does not involve upstream Toll-like receptor signaling. PMID:27231712

  11. Spatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model.

    PubMed

    Tagge, Ian; O'Connor, Audrey; Chaudhary, Priya; Pollaro, Jim; Berlow, Yosef; Chalupsky, Megan; Bourdette, Dennis; Woltjer, Randy; Johnson, Mac; Rooney, William

    2016-01-01

    Cuprizone administration in mice provides a reproducible model of demyelination and spontaneous remyelination, and has been useful in understanding important aspects of human disease, including multiple sclerosis. In this study, we apply high spatial resolution quantitative MRI techniques to establish the spatio-temporal patterns of acute demyelination in C57BL/6 mice after 6 weeks of cuprizone administration, and subsequent remyelination after 6 weeks of post-cuprizone recovery. MRI measurements were complemented with Black Gold II stain for myelin and immunohistochemical stains for associated tissue changes. Gene expression was evaluated using the Allen Gene Expression Atlas. Twenty-five C57BL/6 male mice were split into control and cuprizone groups; MRI data were obtained at baseline, after 6 weeks of cuprizone, and 6 weeks post-cuprizone. High-resolution (100 μm isotropic) whole-brain coverage magnetization transfer ratio (MTR) parametric maps demonstrated concurrent caudal-to-rostral and medial-to-lateral gradients of MTR decrease within corpus callosum (CC) that correlated well with demyelination assessed histologically. Our results show that demyelination was not limited to the midsagittal line of the corpus callosum, and also that opposing gradients of demyelination occur in the lateral and medial CC. T2-weighted MRI gray/white matter contrast was strong at baseline, weak after 6 weeks of cuprizone treatment, and returned to a limited extent after recovery. MTR decreases during demyelination were observed throughout the brain, most clearly in callosal white matter. Myelin damage and repair appear to be influenced by proximity to oligodendrocyte progenitor cell populations and exhibit an inverse correlation with myelin basic protein gene expression. These findings suggest that susceptibility to injury and ability to repair vary across the brain, and whole-brain analysis is necessary to accurately characterize this model. Whole-brain parametric mapping

  12. Spatio-Temporal Patterns of Demyelination and Remyelination in the Cuprizone Mouse Model

    PubMed Central

    Tagge, Ian; O’Connor, Audrey; Chaudhary, Priya; Pollaro, Jim; Berlow, Yosef; Chalupsky, Megan; Bourdette, Dennis; Woltjer, Randy; Johnson, Mac; Rooney, William

    2016-01-01

    Cuprizone administration in mice provides a reproducible model of demyelination and spontaneous remyelination, and has been useful in understanding important aspects of human disease, including multiple sclerosis. In this study, we apply high spatial resolution quantitative MRI techniques to establish the spatio-temporal patterns of acute demyelination in C57BL/6 mice after 6 weeks of cuprizone administration, and subsequent remyelination after 6 weeks of post-cuprizone recovery. MRI measurements were complemented with Black Gold II stain for myelin and immunohistochemical stains for associated tissue changes. Gene expression was evaluated using the Allen Gene Expression Atlas. Twenty-five C57BL/6 male mice were split into control and cuprizone groups; MRI data were obtained at baseline, after 6 weeks of cuprizone, and 6 weeks post-cuprizone. High-resolution (100μm isotropic) whole-brain coverage magnetization transfer ratio (MTR) parametric maps demonstrated concurrent caudal-to-rostral and medial-to-lateral gradients of MTR decrease within corpus callosum (CC) that correlated well with demyelination assessed histologically. Our results show that demyelination was not limited to the midsagittal line of the corpus callosum, and also that opposing gradients of demyelination occur in the lateral and medial CC. T2-weighted MRI gray/white matter contrast was strong at baseline, weak after 6 weeks of cuprizone treatment, and returned to a limited extent after recovery. MTR decreases during demyelination were observed throughout the brain, most clearly in callosal white matter. Myelin damage and repair appear to be influenced by proximity to oligodendrocyte progenitor cell populations and exhibit an inverse correlation with myelin basic protein gene expression. These findings suggest that susceptibility to injury and ability to repair vary across the brain, and whole-brain analysis is necessary to accurately characterize this model. Whole-brain parametric mapping across

  13. Renal lesions of nondomestic felids.

    PubMed

    Newkirk, K M; Newman, S J; White, L A; Rohrbach, B W; Ramsay, E C

    2011-05-01

    To comprehensively evaluate the occurrence of renal lesions in a variety of nondomestic felids, necropsy cases from 1978 to 2008 were reviewed from a municipal zoo and a large cat sanctuary for those in which the kidneys were examined histologically. Seventy exotic felids were identified (25 tigers, 18 lions, 6 cougars, 5 leopards, 3 snow leopards, 3 clouded leopards, 3 Canadian lynx, 2 ocelots, 2 bobcats, 2 cheetahs, 1 jaguar), and their histologic renal lesions were evaluated and compared. The most common lesion was tubulointerstitial nephritis (TIN); 36 of 70 (51%) cats were affected to some degree. Lymphocytic interstitial nephritis was the most common lesion in the tigers (9 of 25, 36%) and was rarely seen in other species. Although the renal pelvis was not available for all cats, 28 of 47 (60%) had some degree of lymphocytic pyelitis. There was no significant association between the presence of pyelitis and that of TIN. Only 1 cat had pyelonephritis. Renal papillary necrosis was present in 13 of 70 (19%) cats and was significantly associated with historical nonsteroidal anti-inflammatory drug treatment (odds ratio, 7.1; 95% confidence interval, 1.9 to 26.8). Only 1 cat (lion) had amyloid accumulation, and it was restricted to the corticomedullary junction. Primary glomerular lesions were absent in all cats. Intraepithelial pigment was identified in many of the cats but was not correlated with severity of TIN. Despite several previous reports describing primary glomerular disease or renal amyloidosis in exotic felids, these lesions were rare to absent in this population. PMID:20876911

  14. Variable histopathology of discovertebral lesion (spondylodiscitis) of ankylosing spondylitis.

    PubMed

    Agarwal, A K; Reidbord, H E; Kraus, D R; Eisenbeis, C H

    1990-01-01

    Extensive discovertebral lesion is an infrequent complication of long-standing ankylosing spondylitis. Reported histopathological descriptions vary from predominantly inflammatory to fibrous granulation with reactive bone formation. We report variable histological findings in four symptomatic patients with extensive discovertebral lesions who required spinal fusion. PMID:2347137

  15. Effects of pyrethroid molecules on rat nerves in vitro: potential to reverse temperature-sensitive conduction block of demyelinated peripheral axons

    PubMed Central

    Lees, George

    1998-01-01

    Prolongation of action potentials by cooling or pharmacological treatment can restore conduction in demyelinated axons. We have assessed the ability of pyrethroids (in vitro) to modify action potential kinetics and to reverse conduction block in lesioned peripheral nerve. Fast Na+ currents were isolated in mammalian neuroblastoma (NIE115). Pyrethroids (4 μM) concurrently slowed inactivation and produced a spectrum of pronounced tail currents: s-bioallethrin (duration 12.2±7 ms), permethrin (24.2±3 ms) and deltamethrin (2230±100 ms). Deltamethrin (5 μM) effected a slowly developing depression of compound action potential (CAP) amplitude in peroneal nerve trunks (P<0.05). Permethrin produced no net effect on CAP amplitude, area or repolarization time. s-Bioallethrin (5 μM) enhanced CAP area, time for 90% repolarization and induced regenerative activity in a subpopulation of axons. Tibial nerve trunks were demyelinated by lysolecithin (2 μl) injection: 6–14 days later, slowly-conducting axons in the CAP (and peri-axonal microelectrode recordings) were selectively blocked by warming to 37°C. At 37°C, s-bioallethrin (45 min, 5 μM) produced much greater after-potentials in lesioned nerves than in uninjected controls: area (P<0.05) and relative amplitude ratios (P<0.0001) were significantly altered. In 3 of 4 cells (single-unit recording), s-bioallethrin restored conduction through axons exhibiting temperature-dependent block by raising blocking temperature (by 1.5 to >3°C) and reducing refractory period. s-Bioallethrin induced temperature-dependent regenerative activity only in a sub-population of axons even after prolonged superfusion (>1 h). It was concluded that pyrethroids differentially alter Na+ current kinetics and action potential kinetics. The effects of s-bioallethrin are consistent with reversal of conduction block by demyelinated axons but regenerative/ectopic firing even in normal cells is likely to underpin its acknowledged

  16. Inflammatory pseudotumour of the maxilla.

    PubMed

    Kichenaradjou, A; Barrett, A W; Norris, P; Rowell, N; Newman, L

    2016-09-01

    Inflammatory pseudotumour (IP), also known as inflammatory myofibroblastic tumour (IMT), is a rare lesion of the maxillofacial skeleton and a diagnosis by exclusion. We describe three cases which affected the maxilla, two women and one man of ages 67, 56 and 70 years at presentation. All showed the typical, rather non-specific histopathological features. IgG4-positive plasma cells varied greatly in prominence, and none of the three lesions expressed ALK-1. Both women responded to steroids and radiotherapy, though one also required azathioprine. Despite maxillectomy, radiotherapy, steroids and cyclophosphamide, the man suffered intracranial spread and succumbed to persistent disease. The cases described here demonstrate the clinicopathological difficulties presented by this entity and its aggressive, unpredictable behaviour. PMID:27052813

  17. Imaging of noninfectious inflammatory disorders of the spinal cord.

    PubMed

    Klein, Joshua P

    2016-01-01

    Myelitis, or inflammation of the spinal cord, produces a characteristic clinical syndrome. Among the many causes of myelitis are the prototypical demyelinating diseases multiple sclerosis and neuromyelitis optica, each of which has distinct clinical, pathologic, and radiographic features. Less distinct are the myelitides associated with systemic autoimmune conditions like sarcoidosis and lupus. Nondemyelinating conditions such as arachnoiditis, dural arteriovenous fistula, and tumor infiltration may also produce inflammation of the spinal cord. The objective of this review is to aid the clinician in the radiographic diagnosis of noninfectious inflammatory diseases of the spinal cord. PMID:27430439

  18. CXCR4 Signaling Regulates Remyelination by Endogenous Oligodendrocyte Progenitor Cells in a Viral Model of Demyelination

    PubMed Central

    CARBAJAL, KEVIN S.; MIRANDA, JUAN L.; TSUKAMOTO, MICHELLE R.; LANE, THOMAS E.

    2016-01-01

    Following intracranial infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV), susceptible mice will develop widespread myelin destruction that results in pathological and clinical outcomes similar to those seen in humans with the demyelinating disease Multiple Sclerosis (MS). Partial remyelination and clinical recovery occurs during the chronic phase following control of viral replication yet the signaling mechanisms regulating these events remain enigmatic. Here we report the kinetics of proliferation and maturation of oligodendrocyte progenitor cells (OPCs) within the spinal cord following JHMV-induced demyelination and that CXCR4 signaling contributes to the maturation state of OPCs. Following treatment with AMD3100, a specific inhibitor of CXCR4, mice recovering from widespread demyelination exhibit a significant (P < 0.01) increase in the number of OPCs and fewer (P < 0.05) mature oligodendrocytes compared with HBSS-treated animals. These results suggest that CXCR4 signaling is required for OPCs to mature and contribute to remyelination in response to JHMV-induced demyelination. To assess if this effect is reversible and has potential therapeutic benefit, we pulsed mice with AMD3100 and then allowed them to recover. This treatment strategy resulted in increased numbers of mature oligodendrocytes, enhanced remyelination, and improved clinical outcome. These findings highlight the possibility to manipulate OPCs in order to increase the pool of remyelination-competent cells that can participate in recovery. PMID:21830237

  19. The Anti-Aging Protein Klotho Enhances Remyelination Following Cuprizone-Induced Demyelination.

    PubMed

    Zeldich, Ella; Chen, Ci-Di; Avila, Robin; Medicetty, Satish; Abraham, Carmela R

    2015-10-01

    The current study examined whether overexpression of Klotho (KL) in transgenic mice can enhance remyelination following cuprizone-induced demyelination and improves the clinical outcome in experimental autoimmune encephalomyelitis (EAE). Demyelination was achieved by feeding transgenic mice overexpressing the transmembrane form of Klotho (KL-OE) and wild-type (WT) littermates cuprizone-containing chow for 6 weeks. The animals were then allowed to remyelinate for 3 weeks. Paraphenylenediamine staining and platelets-derived growth factor receptor α (PDGFRα) and glutathione S-transferase pi (GSTpi) immunohistochemistry were performed on corpus callosum (CC) sections for quantification of myelin and progenitor and mature oligodendrocytes, respectively. The EAE model was induced with the MOG35-55 peptide. The animals were scored daily for clinical symptoms for 30 days. Following 6 weeks of demyelination, both KL-OE mice and WT littermates demonstrated almost complete and comparable demyelination of the CC. However, the level of spontaneous remyelination was increased approximately two-fold in KL-OE mice, although no significant differences in the numbers of PDGFRα and GSTpi-positive cells were observed. Following EAE induction, Klotho overexpression did not affect the clinical scores, likely due to the different roles Klotho plays in the brain and spinal cord. Thus, increasing Klotho expression should be considered as a therapy for enhancing remyelination in the brains of individuals with multiple sclerosis. PMID:26067431

  20. A novel model of demyelination and remyelination in a GFP-transgenic zebrafish.

    PubMed

    Fang, Yangwu; Lei, Xudan; Li, Xiang; Chen, Yanan; Xu, Fei; Feng, Xizeng; Wei, Shihui; Li, Yuhao

    2014-01-01

    Demyelinating diseases consist of a variety of autoimmune conditions in which the myelin sheath is damaged due to genetic and/or environmental factors. During clinical treatment, some patients undergo partial remyelination, especially during the early disease stages. However, the mechanisms that regulate demyelination remain unclear. The myelin structure, myelin formation and myelin-related gene expression are highly conserved between mammals and zebrafish. Therefore, the zebrafish is an ideal model organism to study myelination. In this study, we generated a transgenic zebrafish Tg(mbp:nfsB-egfp) expressing a fusion protein composed of enhanced green fluorescent protein (EGFP) and NTR from the myelin basic protein (mbp) promoter. Tg(mbp:nfsB-egfp) expressed NTR-EGFP reproducibly and hereditarily in oligodendrocytes along the spinal cord. Treatment of zebrafish larvae Tg(mbp:nfsB-egfp) with metronidazole (Mtz) resulted in the selective ablation of oligodendrocytes and led to demyelination, accompanied by behavioral changes, including decreased total movement distance, velocity, total movement time and fast movement time. After withdrawal of Mtz for a seven day recovery period, the expression of EGFP and MBP protein was observed again which indicates remyelination. Additionally, locomotor capacity was restored. Collectively, Tg(mbp:nfsB-egfp), a heritable and stable transgenic line, provides a novel, powerful tool to study the mechanisms of demyelination and remyelination. PMID:25527642

  1. TREM2 sustains microglial expansion during aging and response to demyelination.

    PubMed

    Poliani, Pietro Luigi; Wang, Yaming; Fontana, Elena; Robinette, Michelle L; Yamanishi, Yoshinori; Gilfillan, Susan; Colonna, Marco

    2015-05-01

    Microglia contribute to development, homeostasis, and immunity of the CNS. Like other tissue-resident macrophage populations, microglia express the surface receptor triggering receptor expressed on myeloid cells 2 (TREM2), which binds polyanions, such as dextran sulphate and bacterial LPS, and activates downstream signaling cascades through the adapter DAP12. Individuals homozygous for inactivating mutations in TREM2 exhibit demyelination of subcortical white matter and a lethal early onset dementia known as Nasu-Hakola disease. How TREM2 deficiency mediates demyelination and disease is unknown. Here, we addressed the basis for this genetic association using Trem2(-/-) mice. In WT mice, microglia expanded in the corpus callosum with age, whereas aged Trem2(-/-) mice had fewer microglia with an abnormal morphology. In the cuprizone model of oligodendrocyte degeneration and demyelination, Trem2(-/-) microglia failed to amplify transcripts indicative of activation, phagocytosis, and lipid catabolism in response to myelin damage. As a result, Trem2(-/-) mice exhibited impaired myelin debris clearance, axonal dystrophy, oligodendrocyte reduction, and persistent demyelination after prolonged cuprizone treatment. Moreover, myelin-associated lipids robustly triggered TREM2 signaling in vitro, suggesting that TREM2 may directly sense lipid components exposed during myelin damage. We conclude that TREM2 is required for promoting microglial expansion during aging and microglial response to insults of the white matter. PMID:25893602

  2. Promotion of remyelination by polyclonal immunoglobulin in Theiler's virus-induced demyelination and in multiple sclerosis.

    PubMed Central

    van Engelen, B G; Miller, D J; Pavelko, K D; Hommes, O R; Rodriguez, M

    1994-01-01

    Spontaneous remyelination occurs in experimental models of demyelination and in patients with multiple sclerosis, although to a limited extent. This enables the search for factors that promote remyelination. Using the Theiler's virus model of central nervous system demyelination, promotion of remyelination was observed after passive transfer of CNS-specific antiserum and transfer of CNS-specific purified immunoglobulin. Mouse polyclonal immunoglobulin from normal non-syngeneic mice, comparable with the human immunoglobulin preparation, also promotes CNS remyelination in the Theiler's virus model of multiple sclerosis. These experimental findings further bridge the gap with a pilot study that suggests clinical improvement after polyclonal immunoglobulin administration, possibly due to remyelination, in some multiple sclerosis patients with stable, steroid-unresponsive optic neuritis. In view of these experimental and clinical data, the physiological role of myelin in demyelination and remyelination is discussed, and the role of IgG solely as a deleterious molecule in the pathophysiology of multiple sclerosis and experimental demyelination is addressed. PMID:7964859

  3. FGF2 and FGFR1 signaling regulate functional recovery following cuprizone demyelination.

    PubMed

    Mierzwa, Amanda J; Zhou, Yong-Xing; Hibbits, Norah; Vana, Adam C; Armstrong, Regina C

    2013-08-26

    In demyelinating diseases, such as multiple sclerosis, remyelination offers the potential to recover function of viable denuded axons by restoring saltatory conduction and/or protecting from further damage. Mice with genetic reduction of fibroblast growth factor 2 (Fgf2) or Fgf receptor 1 (Fgfr1) exhibit dramatically improved remyelination following experimental demyelination with cuprizone. The current studies are the first to test neurobehavioral outcomes with these gene deletions that improved remyelination. The cuprizone protocols used did not produce overt abnormalities but did reduce bilateral sensorimotor coordination (complex wheel task) and increase sociability (two chamber apparatus with novel mouse). A significant effect of genotype was observed on the complex wheel task but not in the sociability apparatus. Specifically, complex wheel velocities for Fgf2 nulls improved significantly after removal of cuprizone from the diet. This improvement in Fgf2 null mice occurred following either acute (6 weeks) or chronic (12 weeks) demyelination. Plp/CreERT:Fgfr1(fl/fl) mice administered tamoxifen at 10 weeks of cuprizone treatment to induce Fgfr1 knockdown also showed improved recovery of running velocities on the complex wheels. Therefore, constitutive deletion of Fgf2 or Fgfr1 knockdown in oligodendrocyte lineage cells is sufficient to overcome impairment of sensorimotor coordination after cuprizone demyelination. PMID:23684572

  4. Skin-derived neural precursors competitively generate functional myelin in adult demyelinated mice

    PubMed Central

    Mozafari, Sabah; Laterza, Cecilia; Roussel, Delphine; Bachelin, Corinne; Marteyn, Antoine; Deboux, Cyrille; Martino, Gianvito; Evercooren, Anne Baron-Van

    2015-01-01

    Induced pluripotent stem cell–derived (iPS-derived) neural precursor cells may represent the ideal autologous cell source for cell-based therapy to promote remyelination and neuroprotection in myelin diseases. So far, the therapeutic potential of reprogrammed cells has been evaluated in neonatal demyelinating models. However, the repair efficacy and safety of these cells has not been well addressed in the demyelinated adult CNS, which has decreased cell plasticity and scarring. Moreover, it is not clear if these induced pluripotent–derived cells have the same reparative capacity as physiologically committed CNS-derived precursors. Here, we performed a side-by-side comparison of CNS-derived and skin-derived neural precursors in culture and following engraftment in murine models of adult spinal cord demyelination. Grafted induced neural precursors exhibited a high capacity for survival, safe integration, migration, and timely differentiation into mature bona fide oligodendrocytes. Moreover, grafted skin–derived neural precursors generated compact myelin around host axons and restored nodes of Ranvier and conduction velocity as efficiently as CNS-derived precursors while outcompeting endogenous cells. Together, these results provide important insights into the biology of reprogrammed cells in adult demyelinating conditions and support use of these cells for regenerative biomedicine of myelin diseases that affect the adult CNS. PMID:26301815

  5. Hes3 expression in the adult mouse brain is regulated during demyelination and remyelination.

    PubMed

    Toutouna, Louiza; Nikolakopoulou, Polyxeni; Poser, Steven W; Masjkur, Jimmy; Arps-Forker, Carina; Troullinaki, Maria; Grossklaus, Sylvia; Bosak, Viktoria; Friedrich, Ulrike; Ziemssen, Tjalf; Bornstein, Stefan R; Chavakis, Triantafyllos; Androutsellis-Theotokis, Andreas

    2016-07-01

    Hes3 is a component of the STAT3-Ser/Hes3 Signaling Axis controlling the growth and survival of neural stem cells and other plastic cells. Pharmacological activation of this pathway promotes neuronal rescue and behavioral recovery in models of ischemic stroke and Parkinson's disease. Here we provide initial observations implicating Hes3 in the cuprizone model of demyelination and remyelination. We focus on the subpial motor cortex of mice because we detected high Hes3 expression. This area is of interest as it is impacted both in human demyelinating diseases and in the cuprizone model. We report that Hes3 expression is reduced at peak demyelination and is partially restored within 1 week after cuprizone withdrawal. This raises the possibility of Hes3 involvement in demyelination/remyelination that may warrant additional research. Supporting a possible role of Hes3 in the maintenance of oligodendrocyte markers, a Hes3 null mouse strain shows lower levels of myelin basic protein in undamaged adult mice, compared to wild-type controls. We also present a novel method for culturing the established oligodendrocyte progenitor cell line oli-neu in a manner that maintains Hes3 expression as well as its self-renewal and differentiation potential, offering an experimental tool to study Hes3. Based upon this approach, we identify a Janus kinase inhibitor and dbcAMP as powerful inducers of Hes3 gene expression. We provide a new biomarker and cell culture method that may be of interest in demyelination/remyelination research. PMID:27018293

  6. Anti-MOG antibody: The history, clinical phenotype, and pathogenicity of a serum biomarker for demyelination.

    PubMed

    Ramanathan, Sudarshini; Dale, Russell C; Brilot, Fabienne

    2016-04-01

    Myelin oligodendrocyte glycoprotein (MOG) is a protein exclusively expressed on the surface of oligodendrocytes and myelin in the central nervous system. MOG has been identified as a putative candidate autoantigen and autoantibody target in demyelination for almost three decades, with extensive literature validating its role in murine models of experimental autoimmune encephalomyelitis. Seminal studies using murine anti-MOG antibodies have highlighted the fact that antibodies that target epitopes of native MOG in its conformational state, rather than linearized or denature`d MOG, are biologically relevant. However, the relevance of anti-MOG antibodies in humans has been difficult to decipher over the years due to varying methods of detection as well as the fact that it was assumed that these antibodies would be clinically associated with multiple sclerosis. There is now international consensus that anti-MOG antibodies are important in both pediatric and adult demyelination, and the clinical association of MOG antibody-associated demyelination has been refined to include acute disseminated encephalomyelitis, relapsing and bilateral optic neuritis, and transverse myelitis. Anti-MOG antibodies are now thought not to be associated with multiple sclerosis in adults. Patients with MOG antibody-associated demyelination appear to have a unique clinical, radiological, and therapeutic profile, which represents a major advance in their diagnosis and management. It is imperative to understand whether anti-MOG antibodies are indeed pathogenic, and if so, their mechanisms of action. As it has become apparent that there are differences in MOG epitope binding between species, translation of animal studies to human demyelination should be analyzed in this context. Further work is required to identify the specific epitope binding sites in human disease and pathogenic mechanisms of anti-MOG antibodies, as well optimal therapeutic strategies to improve prognosis and minimize

  7. Successful treatment of cutaneous lesions of dermatomyositis with topical pimecrolimus.

    PubMed

    Kim, Ji Eun; Jeong, Myeong Gil; Lee, Ha Eun; Ko, Joo Yeon; Ro, Young Suck

    2011-08-01

    Dermatomyositis (DM) is an idiopathic inflammatory process characterized by proximal muscle weakness and cutaneous lesions, such as the Gottron's sign, heliotrope rash, and erythematous photosensitive rash. Administration of systemic agents for the treatment of underlying systemic diseases leads to remission of the cutaneous lesions in many cases. However, cutaneous lesions may remain refractory to treatment. Pimecrolimus is a calcineurin inhibitor with combined anti-inflammatory and immunomodulatory activity. It has high affinity to the skin and low permeation potential, even in patients with acute skin inflammation and in those undergoing post-topical corticosteroid therapy. We herein report two DM patients whose cutaneous lesions were refractory to conventional treatment but showed dramatic response to topical pimecrolimus. The clinical outcomes suggest that topical pimecrolimus may be a good therapeutic alternative for the management of the cutaneous lesions of DM. PMID:21909206

  8. A new venture with sclerotherapy in an oral vascular lesion.

    PubMed

    Sitra, G; Kayalvizhi, E B; Sivasankari, T; Vishwanath, R

    2014-12-01

    Vascular malformations are one of the most common lesions of the oral cavity. The lesion may be a congenital malformation observed in neonates or arteriovenous malformation observed in adults. Various surgical and medical managements are possible for vascular lesions which include surgical excision, laser therapy, cryotherapy, selective embolization, intralesional sclerosing agents, β-blockers and steroid therapy. Here we report a case of oral vascular lesion where intralesional injection with 30 mg/ml of sodium tetradecyl sulfate (STS) was given, which resulted in local complications with severe inflammatory response including pain, swelling, and surface ulceration that remained for 2 weeks. Sclerotherapy with STS still remain an effective agent in treating benign oral vascular lesions and provides alternative or support for surgical methods. Sometimes it can lead to undesirable complications like allergic reactions, local inflammatory response, etc. PMID:25538471

  9. Hematolymphoid lesions of the sinonasal tract.

    PubMed

    Crane, Genevieve M; Duffield, Amy S

    2016-03-01

    Various hematolymphoid lesions involve the sinonasal tract, including aggressive B, T, and NK-cell neoplasms; myeloid sarcoma; low-grade lymphomas; indolent T-lymphoblastic proliferations; and Rosai-Dorfman disease. Differentiating aggressive lymphomas from non-hematopoietic neoplasms such as poorly differentiated squamous cell carcinoma, olfactory neuroblastoma, or sinonasal undifferentiated carcinoma may pose diagnostic challenges. In addition, the necrosis, vascular damage, and inflammatory infiltrates that are associated with some hematolymphoid disorders can result in misdiagnosis as infectious, autoimmune, or inflammatory conditions. Here, we review hematolymphoid disorders involving the sinonasal tract including their key clinical and histopathologic features. PMID:26472692

  10. Retrospective study of biopsied head and neck lesions in a cohort of referral Taiwanese patients

    PubMed Central

    2014-01-01

    Introduction A study of the whole spectrum of biopsied head and neck (HN) diseases in Taiwan has not yet been performed. Therefore, the current study aimed to provide updated information about HN lesions in a cohort of referral Taiwanese patients for histopathological examination. Methods HN lesions (2000–2011) in patients with records of age, sex, and histological diagnoses were retrieved from the Oral Pathology Department of the institution. These lesions were classified into four main categories: tumor/tumor-like reactive lesions, cystic/pseudocystic lesions, inflammatory/infective lesions, and others/miscellaneous lesions. Results A total of 37,210 HN lesions were included in the current study. Most of these lesions were distributed in the group of tumor/tumor-like reactive lesions, followed by the groups of inflammatory/infective lesions, cystic/pseudocystic lesions, and others/miscellaneous lesions. Squamous cell carcinoma was the most common HN lesion, and was also the most frequent malignant lesion among the referral patients. Conclusion It was worthy of note that squamous cell carcinoma and oral potentially malignant disorders comprised high percentages of all HN lesions for the present cohort of referral patients. PMID:25047214

  11. The complement system contributes to the pathology of experimental autoimmune encephalomyelitis by triggering demyelination and modifying the antigen-specific T and B cell response.

    PubMed

    Hundgeburth, Lorenz C; Wunsch, Marie; Rovituso, Damiano; Recks, Mascha S; Addicks, Klaus; Lehmann, Paul V; Kuerten, Stefanie

    2013-03-01

    So far, studies of the human autoimmune disease multiple sclerosis (MS) have largely been hampered by the absence of a pathogenic B cell component in its animal model, experimental autoimmune encephalomyelitis (EAE). To overcome this shortcoming, we have previously introduced the myelin basic protein (MBP)-proteolipid protein (PLP) MP4-induced EAE, which is B cell and autoantibody-dependent. Here we show that MP4-immunized wild-type C57BL/6 mice displayed a significantly lower disease incidence when their complement system was transiently depleted by a single injection of cobra venom factor (CVF) prior to immunization. Considering the underlying pathomechanism, our data suggest that the complement system is crucial for MP4-specific antibodies to trigger CNS pathology. Demyelinated lesions in the CNS were colocalized with complement depositions. In addition, B cell deficient JHT mice reconstituted with MP4-reactive serum showed significantly attenuated clinical and histological EAE after depletion of complement by CVF. The complement system was also critically involved in the generation of the MP4-specific T and B cell response: in MP4-immunized wild-type mice treated with CVF the MP4-specific cytokine and antibody response was significantly attenuated compared to untreated wild-type mice. Taken together, we propose two independent mechanisms by which the complement system can contribute to the pathology of autoimmune encephalomyelitis. Our data corroborate the role of complement in triggering antibody-dependent demyelination and antigen-specific T cell immunity and also provide first evidence that the complement system can modify the antigen-specific B cell response in EAE and possibly MS. PMID:23352967

  12. Loss of Myelin Basic Protein Function Triggers Myelin Breakdown in Models of Demyelinating Diseases.

    PubMed

    Weil, Marie-Theres; Möbius, Wiebke; Winkler, Anne; Ruhwedel, Torben; Wrzos, Claudia; Romanelli, Elisa; Bennett, Jeffrey L; Enz, Lukas; Goebels, Norbert; Nave, Klaus-Armin; Kerschensteiner, Martin; Schaeren-Wiemers, Nicole; Stadelmann, Christine; Simons, Mikael

    2016-07-12

    Breakdown of myelin sheaths is a pathological hallmark of several autoimmune diseases of the nervous system. We employed autoantibody-mediated animal models of demyelinating diseases, including a rat model of neuromyelitis optica (NMO), to target myelin and found that myelin lamellae are broken down into vesicular structures at the innermost region of the myelin sheath. We demonstrated that myelin basic proteins (MBP), which form a polymer in between the myelin membrane layers, are targeted in these models. Elevation of intracellular Ca(2+) levels resulted in MBP network disassembly and myelin vesiculation. We propose that the aberrant phase transition of MBP molecules from their cohesive to soluble and non-adhesive state is a mechanism triggering myelin breakdown in NMO and possibly in other demyelinating diseases. PMID:27346352

  13. Remyelination by Resident Oligodendrocyte Precursor Cells in a Xenopus laevis Inducible Model of Demyelination.

    PubMed

    Sekizar, Sowmya; Mannioui, Abdelkrim; Azoyan, Loris; Colin, Catherine; Thomas, Jean-Léon; Du Pasquier, David; Mallat, Michel; Zalc, Bernard

    2015-01-01

    We have generated a Xenopus laevis transgenic line, MBP-GFP-NTR, allowing conditional ablation of myelin-forming oligodendrocytes. In this transgenic line the transgene is driven by the proximal portion of the myelin basic protein regulatory sequence, specific to mature oligodendrocytes. The transgene protein is formed by the green fluorescent protein reporter fused to the Escherichia coli nitroreductase (NTR) selection enzyme. The NTR enzyme converts the innocuous prodrug metronidazole (MTZ) to a cytotoxin. Ablation of oligodendrocytes by MTZ treatment of the tadpole induced demyelination, and here we show that myelin debris are subsequently eliminated by microglial cells. After cessation of MTZ treatment, remyelination proceeded spontaneously. We questioned the origin of remyelinating cells. Our data suggest that Sox10+ oligodendrocyte precursor cells (OPCs), which are already present in the optic nerve prior to the experimentally induced demyelination, are responsible for remyelination, and this required only minimal (if any) cell division of OPCs. © 2015 S. Karger AG, Basel. PMID:25896276

  14. [Phenotypes of Charcot-Marie-Tooth Syndrome and Differential Diagnosis Focused in Inflammatory Neuropathies].

    PubMed

    Iijima, Masahiro

    2016-01-01

    Charcot-Marie-Tooth disease (CMT), the most frequent form of inherited neuropathy, is a genetically heterogeneous syndrome of the peripheral nervous system with a rather homologous clinical phenotype (slowly progressive distal weakness and muscle atrophy, skeletal deformities, and areflexia in each limb). CMT1 is the autosomal-dominant demyelinating form, and CMT1A (mostly PMP22 duplication) is the most frequent subtype, followed by CMTX1, HNPP (hereditary neuropathy with liability to pressure palsies), CMT1B, or CMT2. As CMT is characterized by slowly progressive motor and sensory disturbances in each limb, it could be misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP) occasionally. Some points can distinguish demyelinating CMT from CIDP. CMT1 patients do not show the conduction block that is frequent in CIDP. In addition, ultrasonographic findings are useful because CMT1 suggests diffuse enlargement of peripheral nerves, whereas CIDP is characterized by asymmetrical or focal enlargement of peripheral nerves. Some CMT1 cases show favorable responses to immunomodulating therapeutics such as corticosteroids, IVIg, and plasma exchange. Such CIDP-like CMT1 (especially CMT1B or CMT2A) shows moderate to high levels of cerebrospinal fluid protein and infiltrated inflammatory macrophages. PMID:26764297

  15. Activity-dependent excitability changes in normal and demyelinated rat spinal root axons.

    PubMed Central

    Bostock, H; Grafe, P

    1985-01-01

    Myelinated nerve fibres with a reduced safety factor for conduction due to demyelination are easily blocked by trains of impulses. To find out why, in vivo recordings from rat ventral root fibres demyelinated with diphtheria toxin have been supplemented with in vivo and in vitro recordings from normal fibres. Despite a small rise in extracellular potassium activity, normal fibres were invariably hyperpolarized by intermittent trains of impulses. This hyperpolarization resulted in an increase in threshold and also in an enhancement of the depolarizing after-potential and the superexcitable period. Replacement of NaCl in the extracellular solution by LiCl completely blocked both the membrane hyperpolarization and the threshold increase which were normally observed during intermittent trains of impulses. At demyelinated nodes which were blocked by trains of impulses (10-50 Hz), conduction block was preceded by a rise in threshold current and in an increase in internodal conduction time, but by no detectable reduction in the outward current generated by the preceding node. It was found possible to prevent the threshold from changing during a train by automatic adjustment of a d.c. polarizing current. This 'threshold clamp' prevented the conduction failure and virtually abolished the changes in internodal conduction time. The threshold changes were attributed to hyperpolarization, as in normal fibres, since (a) the polarizing current required to prevent them was always a depolarizing current, and (b) they were accompanied by an increase in superexcitability. The post-tetanic depression that can follow continuous trains of impulses was attributed to the combination of increased threshold and enhanced superexcitable period due to hyperpolarization. It is concluded that the susceptibility of these demyelinated fibres to impulse trains is not due to a membrane depolarization induced by extracellular potassium accumulation but to a membrane hyperpolarization as a consequence

  16. Thyroid hormone alleviates demyelination induced by cuprizone through its role in remyelination during the remission period.

    PubMed

    Zhang, Mao; Zhan, Xiao L; Ma, Zi Y; Chen, Xing S; Cai, Qi Y; Yao, Zhong X

    2015-09-01

    Multiple sclerosis (MS) is a disease induced by demyelination in the central nervous system, and the remission period of MS is crucial for remyelination. In addition, abnormal levels of thyroid hormone (TH) have been identified in MS. However, in the clinic, insufficient attention has been paid to the role of TH in the remission period. Indeed, TH not only functions in the development of the brain but also affects myelination. Therefore, it is necessary to observe the effect of TH on remyelination during this period. A model of demyelination induced by cuprizone (CPZ) was used to observe the function of TH in remyelination during the remission period of MS. Through weighing and behavioral tests, we found that TH improved the physical symptoms of mice impaired by CPZ. Supplementation of TH led to the repair of myelin as detected by immunohistochemistry and western blot. In addition, a sufficient TH supply resulted in an increase in myelinated axons without affecting myelin thickness and g ratio in the corpus callosum, as detected by electron microscopy. Double immunostaining with myelin basic protein and neurofilament 200 (NF200) showed that the CPZ-induced impairment of axons was alleviated by TH. Conversely, insufficient TH induced by 6-propyl-2-thiouracil resulted in the enlargement of mitochondria. Furthermore, we found that an adequate supply of TH promoted the proliferation and differentiation of oligodendrocyte lineage cells by immunofluorescence, which was beneficial to remyelination. Further, we found that TH reduced the number of astrocytes without affecting microglia. Conclusively, it was shown that TH alleviated demyelination induced by CPZ by promoting the development of oligodendrocyte lineage cells and remyelination. The critical time for remyelination is the remission period of MS. TH plays a significant role in alleviating demyelination during the remission period in the clinical treatment of MS. PMID:25577802

  17. A Unified Frequency Domain Model to Study the Effect of Demyelination on Axonal Conduction

    PubMed Central

    Chaubey, Saurabh; Goodwin, Shikha J.

    2016-01-01

    Multiple sclerosis is a disease caused by demyelination of nerve fibers. In order to determine the loss of signal with the percentage of demyelination, we need to develop models that can simulate this effect. Existing time-based models does not provide a method to determine the influences of demyelination based on simulation results. Our goal is to develop a system identification approach to generate a transfer function in the frequency domain. The idea is to create a unified modeling approach for neural action potential propagation along the length of an axon containing number of Nodes of Ranvier (N). A system identification approach has been used to identify a transfer function of the classical Hodgkin–Huxley equations for membrane voltage potential. Using this approach, we model cable properties and signal propagation along the length of the axon with N node myelination. MATLAB/Simulink platform is used to analyze an N node-myelinated neuronal axon. The ability to transfer function in the frequency domain will help reduce effort and will give a much more realistic feel when compared to the classical time-based approach. Once a transfer function is identified, the conduction as a cascade of each linear time invariant system-based transfer function can be modeled. Using this approach, future studies can model the loss of myelin in various parts of nervous system. PMID:27103847

  18. A Unified Frequency Domain Model to Study the Effect of Demyelination on Axonal Conduction.

    PubMed

    Chaubey, Saurabh; Goodwin, Shikha J

    2016-01-01

    Multiple sclerosis is a disease caused by demyelination of nerve fibers. In order to determine the loss of signal with the percentage of demyelination, we need to develop models that can simulate this effect. Existing time-based models does not provide a method to determine the influences of demyelination based on simulation results. Our goal is to develop a system identification approach to generate a transfer function in the frequency domain. The idea is to create a unified modeling approach for neural action potential propagation along the length of an axon containing number of Nodes of Ranvier (N). A system identification approach has been used to identify a transfer function of the classical Hodgkin-Huxley equations for membrane voltage potential. Using this approach, we model cable properties and signal propagation along the length of the axon with N node myelination. MATLAB/Simulink platform is used to analyze an N node-myelinated neuronal axon. The ability to transfer function in the frequency domain will help reduce effort and will give a much more realistic feel when compared to the classical time-based approach. Once a transfer function is identified, the conduction as a cascade of each linear time invariant system-based transfer function can be modeled. Using this approach, future studies can model the loss of myelin in various parts of nervous system. PMID:27103847

  19. Correlation Between Daam2 Expression Changes and Demyelination in Guillain-Barre Syndrome.

    PubMed

    Cui, Quanquan; Xie, Peng

    2016-07-01

    Wnt signaling has been implicated in developmental and regenerative myelination of the CNS and PNS. The present translational investigation was undertaken to assess whether a soluble factor like Wnt may be responsible for the critically important skeletal muscle neuromuscular junction-Schwann cell communication. Specifically, three key aspects were examined: (a) whether the expression of Daam2, disheveled-associated activator of morphogenesis, a key Wnt signaling downstream effector, and PIP5K is changed in the demyelinating conditions and under different stages of progress of clinical recovery of patients with Guillain-Barre syndrome; (b) whether critical protein interactions of Daam2 with disheveled and Arf6 are changed; and (c) whether expression of c-Jun/Krox, a key negative regulator of remyelination, is changed. Daam2 was elevated in acute presentation in GB syndrome. Reduction occurred with clinical improvement of the patients. With progressive clinical improvement, c-Jun/Krox expression significantly reduced with time. Wnt signaling likely causes immediate early gene activation and transcriptional shutdown of factors critical for formation and maintenance of myelination. Whether the findings of the present study are specific to pathophysiology of demyelination in acute infectious polyradiculopathy and multiple sclerosis or a generalized aspect of demyelinating diseases merits to be examined in future studies. PMID:26293489

  20. Absence of Multiple Sclerosis and Demyelinating Diseases among Lacandonians, a Pure Amerindian Ethnic Group in Mexico.

    PubMed

    Flores, Jose; González, Silvia; Morales, Ximena; Yescas, Petra; Ochoa, Adriana; Corona, Teresa

    2012-01-01

    Multiple Sclerosis (MS) is a highly polymorphic disease characterized by different neurologic signs and symptoms. In MS, racial and genetic factors may play an important role in the geographic distribution of this disease. Studies have reported the presence of several protective alleles against the development of autoimmune disorders. In the case of MS, however, they help define MS as a complex disease, and confirm the importance of environmental agents as an independent variable not associated with ethnicity. We carried out an on-site epidemiological study to confirm the absence of MS or NMO among Lacandonians, a pure Amerindian ethnic group in Mexico. We administered a structured interview to 5,372 Lacandonians to assess by family background any clinical data consistent with the presence of a prior demyelinating event. Every participating subject underwent a comprehensive neurological examination by a group of three members of the research team with experience in the diagnosis and treatment of demyelinating disorders to detect clinical signs compatible with a demyelinating disease. We did not find any clinical signs compatible with multiple sclerosis among study participants. PMID:22973516

  1. Intraventricular injections of mesenchymal stem cells activate endogenous functional remyelination in a chronic demyelinating murine model

    PubMed Central

    Cruz-Martinez, P; González-Granero, S; Molina-Navarro, M M; Pacheco-Torres, J; García-Verdugo, J M; Geijo-Barrientos, E; Jones, J; Martinez, S

    2016-01-01

    Current treatments for demyelinating diseases are generally only capable of ameliorating the symptoms, with little to no effect in decreasing myelin loss nor promoting functional recovery. Mesenchymal stem cells (MSCs) have been shown by many researchers to be a potential therapeutic tool in treating various neurodegenerative diseases, including demyelinating disorders. However, in the majority of the cases, the effect was only observed locally, in the area surrounding the graft. Thus, in order to achieve general remyelination in various brain structures simultaneously, bone marrow-derived MSCs were transplanted into the lateral ventricles (LVs) of the cuprizone murine model. In this manner, the cells may secrete soluble factors into the cerebrospinal fluid (CSF) and boost the endogenous oligodendrogenic potential of the subventricular zone (SVZ). As a result, oligodendrocyte progenitor cells (OPCs) were recruited within the corpus callosum (CC) over time, correlating with an increased myelin content. Electrophysiological studies, together with electron microscopy (EM) analysis, indicated that the newly formed myelin correctly enveloped the demyelinated axons and increased signal transduction through the CC. Moreover, increased neural stem progenitor cell (NSPC) proliferation was observed in the SVZ, possibly due to the tropic factors released by the MSCs. In conclusion, the findings of this study revealed that intraventricular injections of MSCs is a feasible method to elicit a paracrine effect in the oligodendrogenic niche of the SVZ, which is prone to respond to the factors secreted into the CSF and therefore promoting oligodendrogenesis and functional remyelination. PMID:27171265

  2. Absence of Multiple Sclerosis and Demyelinating Diseases among Lacandonians, a Pure Amerindian Ethnic Group in Mexico

    PubMed Central

    Flores, Jose; González, Silvia; Morales, Ximena; Yescas, Petra; Ochoa, Adriana; Corona, Teresa

    2012-01-01

    Multiple Sclerosis (MS) is a highly polymorphic disease characterized by different neurologic signs and symptoms. In MS, racial and genetic factors may play an important role in the geographic distribution of this disease. Studies have reported the presence of several protective alleles against the development of autoimmune disorders. In the case of MS, however, they help define MS as a complex disease, and confirm the importance of environmental agents as an independent variable not associated with ethnicity. We carried out an on-site epidemiological study to confirm the absence of MS or NMO among Lacandonians, a pure Amerindian ethnic group in Mexico. We administered a structured interview to 5,372 Lacandonians to assess by family background any clinical data consistent with the presence of a prior demyelinating event. Every participating subject underwent a comprehensive neurological examination by a group of three members of the research team with experience in the diagnosis and treatment of demyelinating disorders to detect clinical signs compatible with a demyelinating disease. We did not find any clinical signs compatible with multiple sclerosis among study participants. PMID:22973516

  3. Peripheral mechanisms of neuropathic pain – involvement of lysophosphatidic acid receptor-mediated demyelination

    PubMed Central

    Ueda, Hiroshi

    2008-01-01

    Recent advances in pain research provide a clear picture for the molecular mechanisms of acute pain; substantial information concerning plasticity that occurs during neuropathic pain has also become available. The peripheral mechanisms responsible for neuropathic pain are found in the altered gene/protein expression of primary sensory neurons. With damage to peripheral sensory fibers, a variety of changes in pain-related gene expression take place in dorsal root ganglion neurons. These changes, or plasticity, might underlie unique neuropathic pain-specific phenotype modifications – decreased unmyelinated-fiber functions, but increased myelinated A-fiber functions. Another characteristic change is observed in allodynia, the functional change of tactile to nociceptive perception. Throughout a series of studies, using novel nociceptive tests to characterize sensory-fiber or pain modality-specific nociceptive behaviors, it was demonstrated that communication between innocuous and noxious sensory fibers might play a role in allodynia mechanisms. Because neuropathic pain in peripheral and central demyelinating diseases develops as a result of aberrant myelination in experimental animals, demyelination seems to be a key mechanism of plasticity in neuropathic pain. More recently, we discovered that lysophosphatidic acid receptor activation initiates neuropathic pain, as well as possible peripheral mechanims of demyelination after nerve injury. These results lead to further hypotheses of physical communication between innocuous Aβ- and noxious C- or Aδ-fibers to influence the molecular mechanisms of allodynia. PMID:18377664

  4. Inflammatory glaucoma

    PubMed Central

    Bodh, Sonam A.; Kumar, Vasu; Raina, Usha K.; Ghosh, B.; Thakar, Meenakshi

    2011-01-01

    Glaucoma is seen in about 20% of the patients with uveitis. Anterior uveitis may be acute, subacute, or chronic. The mechanisms by which iridocyclitis leads to obstruction of aqueous outflow include acute, usually reversible forms (e.g., accumulation of inflammatory elements in the intertrabecular spaces, edema of the trabecular lamellae, or angle closure due to ciliary body swelling) and chronic forms (e.g., scar formation or membrane overgrowth in the anterior chamber angle). Careful history and follow-up helps distinguish steroid-induced glaucoma from uveitic glaucoma. Treatment of combined iridocyclitis and glaucoma involves steroidal and nonsteroidal antiinflammatory agents and antiglaucoma drugs. However, glaucoma drugs can often have an unpredictable effect on intraocular pressure (IOP) in the setting of uveitis. Surgical intervention is required in case of medical failure. Method of Literature Search: Literature on the Medline database was searched using the PubMed interface. PMID:21713239

  5. A method for histopathological study of the multifocal nature of spinal cord lesions in murine experimental autoimmune encephalomyelitis

    PubMed Central

    Boyden, Alexander W.; Leidinger, Mariah R.; Lambertz, Allyn M.; Ofori-Amanfo, Georgina; Naumann, Paul W.; Goeken, J. Adam; Karandikar, Nitin J.

    2016-01-01

    Experimental autoimmune encephalomyelitis (EAE) is a well-established mouse model for multiple sclerosis and is characterized by infiltration of mononuclear cells and demyelination within the central nervous system along with the clinical symptoms of paralysis. EAE is a multifocal and random disease, which sometimes makes histopathologic analysis of lesions difficult as it may not be possible to predict where lesions will occur, especially when evaluating cross sections of spinal cord. Consequently, lesions may be easily missed due to limited sampling in traditional approaches. To evaluate the entire length of the spinal cord while maintaining anatomic integrity, we have developed a method to section the cord within the decalcified spinal column, which allows for the study of the multifocal nature of this disease and also minimizes handling artifact. HE and Luxol fast blue staining of these spinal cord sections revealed a paucity of lesions in some areas, while others showed marked inflammation and demyelination. The percentage of spinal cord affected by EAE was evaluated at four separate areas of longitudinally sectioned cord and it varied greatly within each animal. Immunohistochemical staining of in situ spinal cords which had undergone decalcification was successful for key immuno-markers used in EAE research including CD3 for T cells, B220 for B cells and F4/80 for murine macrophages. This method will allow investigators to look at the entire spinal cord on a single slide and evaluate the spinal cord with and without classic EAE lesions. PMID:26855861

  6. COMMON LESIONS OF THE URETHRA IN WOMEN

    PubMed Central

    Burkland, Carl E.

    1952-01-01

    Urethral disease in women and girls often is overlooked. As the urine may seem to be normal as determined by repeated urinalysis, the symptoms—urinary frequency and burning—may be attributed entirely to other pelvic disease or to functional disorder. Since erroneous diagnosis may lead to unnecessary procedures or to neglect of treatment with consequent development of severe disease in the kidneys or ureters, it is important to consider urethral lesions as a possible cause in any case of abdominal discomfort in women. The most common lesions of the urethra in women are urethritis, stricture, caruncle, inflammatory polyps and cysts, prolapse of the urethra, and diverticulum. In some cases diagnosis can be made simply on the basis of inspection and palpation. In others more extensive diagnostic procedures must be carried out in order that treatment may be definitive. The methods of treatment, varying with the nature of the lesion, are outlined herein. PMID:14905285

  7. Mitochondrial dysfunction is an important cause of neurological deficits in an inflammatory model of multiple sclerosis.

    PubMed

    Sadeghian, Mona; Mastrolia, Vincenzo; Rezaei Haddad, Ali; Mosley, Angelina; Mullali, Gizem; Schiza, Dimitra; Sajic, Marija; Hargreaves, Iain; Heales, Simon; Duchen, Michael R; Smith, Kenneth J

    2016-01-01

    Neuroinflammation can cause major neurological dysfunction, without demyelination, in both multiple sclerosis (MS) and a mouse model of the disease (experimental autoimmune encephalomyelitis; EAE), but the mechanisms remain obscure. Confocal in vivo imaging of the mouse EAE spinal cord reveals that impaired neurological function correlates with the depolarisation of both the axonal mitochondria and the axons themselves. Indeed, the depolarisation parallels the expression of neurological deficit at the onset of disease, and during relapse, improving during remission in conjunction with the deficit. Mitochondrial dysfunction, fragmentation and impaired trafficking were most severe in regions of extravasated perivascular inflammatory cells. The dysfunction at disease onset was accompanied by increased expression of the rate-limiting glycolytic enzyme phosphofructokinase-2 in activated astrocytes, and by selective reduction in spinal mitochondrial complex I activity. The metabolic changes preceded any demyelination or axonal degeneration. We conclude that mitochondrial dysfunction is a major cause of reversible neurological deficits in neuroinflammatory disease, such as MS. PMID:27624721

  8. Interrelationship between Periapical Lesion and Systemic Metabolic Disorders

    PubMed Central

    Sasaki, Hajime; Hirai, Kimito; Martins, Christine Men; Furusho, Hisako; Battaglino, Ricardo; Hashimoto, Koshi

    2016-01-01

    Periapical periodontitis, also known as periapical lesion, is a common dental disease, along with periodontitis (gum disease). Periapical periodontitis is a chronic inflammatory disease, caused by endodontic infection, and its development is regulated by the host immune/inflammatory response. Metabolic disorders, which are largely dependent on life style such as eating habits, have been interpreted as a “metabolically-triggered” low-grade systemic inflammation and may interact with periapical periodontitis by triggering immune modulation. The host immune system is therefore considered the common fundamental mechanism of both disease conditions. An elevated inflammatory state caused by metabolic disorders can impact the clinical outcome of periapical lesions and interfere with wound healing after endodontic treatment. Although additional well-designed clinical studies are needed, periapical lesions appear to affect insulin sensitivity and exacerbate non-alcoholic steatohepatitis. Immune regulatory cytokines produced by various cell types, including immune cells and adipose tissue, play an important role in this interrelationship. PMID:26881444

  9. Lobulated capillary haemangioma: a common lesion in an uncommon site

    PubMed Central

    Varma, Siddhartha; Gangavati, Rashmi; Sundaresh, K J; Mallikarjuna, Rachappa

    2013-01-01

    Pyogenic granuloma (PG) is a well-known localised granulation tissue overgrowth. It remains an aetiopathological enigma, with trauma, inflammatory and infectious agents being the suspected causative factors. It is a relatively common benign mucocutaneous lesion occurring intraorally or extraorally and is more common in women in the second decade of their lives than in men. Although it is a common lesion it may present with varying clinical features that sometimes may mimic more serious lesions such as malignancies. The clinical diagnosis of such lesion can be quite challenging. This case report drives attention towards the uncommon location of PG of lobular capillary haemangioma type occurring on anterior palate. Surgical excision of the lesion was planned because of the discomfort attributed to large size of the lesion and hindrance in mastication. PMID:23417947

  10. In vivo and in vitro models of demyelinating disease. XVII. The infectious process in athymic rats inoculated with JHM virus.

    PubMed

    Sorensen, O; Saravani, A; Dales, S

    1987-02-01

    Wistar Lewis (WL), Long Evans (LE) and other rat strains develop complete resistance to CNS disease when inoculated intracerebrally with murine hepatitis JHM virus (JHMV) after the 10th day of age. Two types of studies were conducted to ascertain the involvement of the cellular immune system in development of resistance. Immunosuppression of WL rats with cyclosporin A (CsA) following onset of the age-related resistance demonstrated that this drug was partially able to abrogate resistance. In the other studies nude (rnu/rnu) rats, their heterozygous (rnu/+) litter mates and genetically related LE rats of various ages were challenged with JHMV. The rnu/+ and LE animals became completely resistant before the age of weaning, whereas some rnu/rnu rats, challenged as late as 70 days of age, showed disease symptoms--albeit after a long latent period. These observations indicated that the cellular immune system plays an important role in suppressing the disease process in the CNS. When the infection of nude rats was initiated on or after the 15th day of life, the histological lesions were generally small and present in both grey and white matter but were seldom seen in the spinal cord. Mononuclear infiltrates were evident throughout the CNS. In some nude rats there was massive mononuclear cell infiltration towards the meningies and into ventricular spaces. By contrast in mu/+, LE and WL rats with late-onset disease symptoms, demyelinating-type lesions were confined to the white matter and only minor infiltration of mononuclear cells was evident. JHMV RNA was detectable by dot-blotting analysis in the CNS of both paralysed and asymptomatic rnu/rnu and rnu/+ rats, but less RNA was usually detected in heterozygous animals. In-situ hybridization with cDNA probes for JHMV RNA showed that neurons in the hippocampus and cerebellum, as well as cells in the white matter, were frequently infected. The present data indicate that in the rat T cells have an important function in

  11. Ghost cell lesions

    PubMed Central

    Rajesh, E.; Jimson, Sudha; Masthan, K. M. K.; Balachander, N.

    2015-01-01

    Ghost cells have been a controversy for a long time. Ghost cell is a swollen/enlarged epithelial cell with eosnophilic cytoplasm, but without a nucleus. In routine H and E staining these cells give a shadowy appearance. Hence these cells are also called as shadow cells or translucent cells. The appearance of these cells varies from lesion to lesion involving odontogenic and nonodontogenic lesions. This article review about the origin, nature and significance of ghost cells in different neoplasms. PMID:26015694

  12. [Surprising white lesions].

    PubMed

    Nolte, J W; van der Waal, I

    2011-09-01

    A 46-year-old man appeared with white lesions of the oral cavity. A previously taken biopsy revealed no classifying diagnosis and treatment with mouth rinse produced no improvement. A new biopsy was taken, on which the pathologist performed additional tests. This resulted in the diagnosis 'syphilis'. The patient was treated with benzylpenicillin and the oral white lesions disappeared. Although nowadays syphilis is rare, special attention is required when noticing these kinds of lesions of the oral cavity. PMID:21957637

  13. Subcutaneous immunoglobulin in treating inflammatory neuromuscular disorders

    PubMed Central

    Yoon, Min-Suk; Gold, Ralf

    2015-01-01

    Objective: Intravenous immunoglobulin administration has long been used in the treatment of autoimmune neuromuscular disorders. Immunoglobulins may be administered by intramuscular, intravenous or subcutaneous routes. Methods: This is a report on the long-term clinical follow up of six patients with inflammatory neuromuscular disorders, that is, three chronic inflammatory demyelinating polyneuropathy (CIDP), one multifocal motor neuropathy (MMN), one inclusion body myositis (IBM) and one myasthenia gravis (MG), treated with subcutaneous immunoglobulins for a mean of 3.25 years. Results: One MMN and two CIDP patients received a weekly dose of subcutaneous immunoglobulins equivalent to intravenous immunoglobulin. One CIDP patient received a 50% dose reduction, the IBM patient received a 30% reduction and the MG patient a 20% reduction. The lower dose chosen in the majority of patients was based not only on clinical effects, but also on studies of primary immunodeficiency syndromes. One patient with CIDP showed clinical fluctuation, which was successfully treated with an adaptation of the dose of subcutaneous immunoglobulins, while the remaining patients with neuromuscular disorders had a stable clinical course for 2 years. No serious side effects were observed. Conclusions: Our results suggest that subcutaneous immunoglobulins can be an attractive alternative therapy in autoimmune neuromuscular disorders. PMID:26136842

  14. Asymptomatic pontine and extra-pontine lesions in a patient with end-stage renal disease.

    PubMed

    Yadav, Raj Kanwar; Das, Chandan J; Bagchi, Soumita; Agarwal, Sanjay

    2016-03-01

    Osmotic demyelination syndrome leading to central pontine/extra-pontine myelinolysis (CPM/EPM) occurs mainly in patients with history of alcohol abuse, malnourishment, following liver transplantation and less commonly, in association with other systemic diseases. Asymptomatic CPM/EPM is rare. Patients with end-stage renal disease (ESRD) who develop CPM/EPM are usually symptomatic with florid neurologic manifestations. Herein, we present a patient with ESRD on maintenance hemodialysis who was incidentally detected to have pontine and extra-pontine lesions suggestive of myelinolysis without any neurologic signs or symptoms. PMID:26997398

  15. Inflammatory myoglandular polyp causing hematochezia.

    PubMed

    Hirasaki, Shoji; Okuda, Masato; Kudo, Kenichiro; Suzuki, Seiyuu; Shirakawa, Atsuko

    2008-09-14

    A case of inflammatory myoglandular polyp (IMGP) causing hematochezia is reported. The patient was a 33-year-old man who visited our hospital for further evaluation of hematochezia. Colonoscopy revealed a red, hard, spherical peduncular polyp with erosion and mucous exudation, about 20 mm in diameter, in the descending colon. Excluding the polyp, there was no lesion in the colorectum. Endoscopic polypectomy was performed. Histological examination of the specimen revealed inflammatory granulation tissue in the lamina propria, proliferation of smooth muscle, and hyperplastic glands with variable cystic changes. This polyp was diagnosed as an IMGP. The symptom of hematochezia was resolved after endoscopic resection. Our case shows that treatment is necessary for IMGP if intestinal bleeding occurs and endoscopists should be aware of the endoscopic characteristics of IMGP. PMID:18785292

  16. Demyelination induces transport of ribosome-containing vesicles from glia to axons: evidence from animal models and MS patient brains.

    PubMed

    Shakhbazau, Antos; Schenk, Geert J; Hay, Curtis; Kawasoe, Jean; Klaver, Roel; Yong, V Wee; Geurts, Jeroen J G; van Minnen, Jan

    2016-06-01

    Glial cells were previously proven capable of trafficking polyribosomes to injured axons. However, the occurrence of such transfer in the general pathological context, such as demyelination-related diseases, needs further evidence. Since this may be a yet unidentified universal contributor to axonal survival, we study putative glia-axonal ribosome transport in response to demyelination in animal models and patients in both peripheral and central nervous system. In the PNS we investigate whether demyelination in a rodent model has the potential to induce ribosome transfer. We also probe the glia-axonal ribosome supply by implantation of transgenic Schwann cells engineered to produce fluorescent ribosomes in the same demyelination model. We furthermore examine the presence of axonal ribosomes in mouse experimental autoimmune encephalomyelitis (EAE), a well-established model for multiple sclerosis (MS), and in human MS autopsy brain material. We provide evidence for increased axonal ribosome content in a pharmacologically demyelinated sciatic nerve, and demonstrate that at least part of these ribosomes originate in the transgenic Schwann cells. In the CNS one of the hallmarks of MS is demyelination, which is associated with severe disruption of oligodendrocyte-axon interaction. Here, we provide evidence that axons from spinal cords of EAE mice, and in the MS human brain contain an elevated amount of axonal ribosomes compared to controls. Our data provide evidence that increased axonal ribosome content in pathological axons is at least partly due to glia-to-axon transfer of ribosomes, and that demyelination in the PNS and in the CNS is one of the triggers capable to initiate this process. PMID:27115494

  17. Preinvasive lesions

    Cancer.gov

    This definition is for allocation of lesions with preinvasive/borderline properties. It is currently aimed at newly identified neoplasms, which may be similar to those described in humans. In mouse pathology, many adenomas may be preinvasive/borderline lesions. However, their inclusion in the preinvasive category can be justified only upon development of better diagnostic criteria.

  18. Bovine colostrum against gut inflammatory lesions in preterm pigs

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Bovine colostrum is rich in bioactive factors and may prevent necrotizing enterocolitis (NEC) in pre-term neonates. We hypothesized that both native and sterilized, heat-treated colostrum protect neonates against NEC following preterm birth and formula feeding. Further, we aimed to investigate if pr...

  19. The local immune response in ulcerative lesions of Buruli disease

    PubMed Central

    Kiszewski, A E; Becerril, E; Aguilar, L D; Kader, I T A; Myers, W; Portaels, F; Hernàndez Pando, R

    2006-01-01

    Buruli disease (BU) is a progressive necrotic and ulcerative disease of the skin and subcutaneous tissue caused by Mycobacterium ulcerans. BU is considered the third most common mycobacterial disease after tuberculosis and leprosy. Three clinical stages of the cutaneous lesions have been described in BU: pre-ulcerative, ulcerative and healed lesions. In this study we used immunohistochemistry and automated morphometry to determine the percentage of macrophages and of CD4/CD8 lymphocytes and their expression of interferon (IFN)-γ, interleukin (IL)-10, tumour necrosis factor (TNF)-α and transforming growth factor (TGF)-β. Expression of these cytokines was correlated with the inflammatory response evaluated by histopathology. All the studied BU ulcerative cases showed extensive necrosis and chronic inflammation. The most important feature was the presence or absence of granulomas co-existing with a mixed pro-inflammatory/anti-inflammatory cytokine balance. When granulomas were present significantly higher expression of IFN-γ was seen, whereas in ulcerative lesions without granulomas there was increased expression of IL-10 and significantly higher bacillary counts. These features correlated with the chronicity of the lesions; longer-lasting lesions showed granulomas. Thus, granulomas were absent from relatively early ulcerative lesions, which contained more bacilli and little IFN-γ, suggesting that at this stage of the disease strong suppression of the protective cellular immune response facilitates proliferation of bacilli. PMID:16487243

  20. Imaging Pediatric Vascular Lesions.

    PubMed

    Nguyen, Tuyet A; Krakowski, Andrew C; Naheedy, John H; Kruk, Peter G; Friedlander, Sheila Fallon

    2015-12-01

    Vascular anomalies are commonly encountered in pediatric and dermatology practices. Most of these lesions are benign and easy to diagnose based on history and clinical exam alone. However, in some cases the diagnosis may not be clear. This may be of particular concern given that vascular anomalies may occasionally be associated with an underlying syndrome, congenital disease, or serious, life-threatening condition. Defining the type of vascular lesion early and correctly is particularly important to determine the optimal approach to management and treatment of each patient. The care of pediatric patients often requires collaboration from a multitude of specialties including pediatrics, dermatology, plastic surgery, radiology, ophthalmology, and neurology. Although early characterization of vascular lesions is important, consensus guidelines regarding the evaluation and imaging of vascular anomalies does not exist to date. Here, the authors provide an overview of pediatric vascular lesions, current classification systems for characterizing these lesions, the various imaging modalities available, and recommendations for appropriate imaging evaluation. PMID:26705446

  1. Imaging Pediatric Vascular Lesions

    PubMed Central

    Nguyen, Tuyet A.; Krakowski, Andrew C.; Naheedy, John H.; Kruk, Peter G.

    2015-01-01

    Vascular anomalies are commonly encountered in pediatric and dermatology practices. Most of these lesions are benign and easy to diagnose based on history and clinical exam alone. However, in some cases the diagnosis may not be clear. This may be of particular concern given that vascular anomalies may occasionally be associated with an underlying syndrome, congenital disease, or serious, life-threatening condition. Defining the type of vascular lesion early and correctly is particularly important to determine the optimal approach to management and treatment of each patient. The care of pediatric patients often requires collaboration from a multitude of specialties including pediatrics, dermatology, plastic surgery, radiology, ophthalmology, and neurology. Although early characterization of vascular lesions is important, consensus guidelines regarding the evaluation and imaging of vascular anomalies does not exist to date. Here, the authors provide an overview of pediatric vascular lesions, current classification systems for characterizing these lesions, the various imaging modalities available, and recommendations for appropriate imaging evaluation. PMID:26705446

  2. Extragastric Dieulafoy's lesion

    PubMed Central

    Gauci, James; Galea, Samuel; Galea, Joseph; Schembri, Mark

    2014-01-01

    A 74-year-old man on warfarin for aortic valve replacement presented with recurrent episodes of melaena. An initial oesophagogastroduodenoscopy (OGD) was normal, as were red cell scanning and colonoscopy. It was a third OGD that revealed the cause of the melaena—a vascular lesion in the duodenum, at the junction between D1 and D2. An extragastric Dieulafoy's lesion was diagnosed, and the lesion was injected with epinephrine and tattooed. Over the following months, episodes of bleeding recurred despite further attempts at injection. Percutaneous radiologically assisted embolisation of the gastroduodenal artery, and eventually duodenotomy and oversuturing of the lesion were performed to no avail. The patient has undergone over 10 endoscopies, and has received over 70 units of packed red cells to date, since his initial presentation 6 years ago. Attempts to stop the bleeding permanently have been difficult, highlighting the complexity of managing such a lesion. PMID:25216921

  3. A 5 year retrospective study of biopsied jaw lesions with the assessment of concordance between clinical and histopathological diagnoses

    PubMed Central

    Peker, Elif; Öğütlü, Faruk; Karaca, İnci Rana; Gültekin, Elif Sibel; Çakır, Merve

    2016-01-01

    Introduction: The jaw can be affected by several lesions that manifest in the oral cavity, but little is known about their distribution patterns in various populations. Aims and Objectives: This study presents the frequency and distribution of biopsied jaw lesions recorded in Faculty of Dentistry and gathers the information including provisional and final diagnosis of the lesions. Material and Methods: Biopsy of 1938 lesions (2008–2013) was reviewed and 1473 lesions were included in this study. The provisional diagnosis and histopathological validations of lesions were compared. Data on the location of the lesion, as well as patient demographics, were also evaluated. The lesions were divided into three major groups as 1 - developmental/reactive and inflammatory lesions of the jaw, 2 - cystic lesion and 3 - tumor and tumor-like lesions. Statistical Analysis: The variables were recorded and analysed using descriptive statistics. Results and Observations: Three hundred and ninety-six lesions were in Group 1 and periapical granuloma was the most frequent diagnosis. Seven hundred and eighty-nine lesions were in Group 2 and the radicular cyst was the most frequent diagnosis. Two hundred and eighty-eight lesions were in Group 3 and the keratocystic odontogenic tumor was the most frequent. Two hundred and ninety-one biopsied lesions were in disagreement with respect to the diagnoses on clinical and histopathological examination. Conclusion: Consequently, a provisional diagnosis of some of the malignant lesions was reactive, inflammatory, cystic or benign lesions, therefore the importance of evaluation of the specimen is emphasized. PMID:27194866

  4. The role of pro- and anti-inflammatory cytokines in the pathogenesis of spontaneous canine CNS diseases.

    PubMed

    Spitzbarth, I; Baumgärtner, W; Beineke, A

    2012-06-15

    Dogs are comparatively frequently affected by various spontaneously occurring inflammatory and degenerative central nervous system (CNS) conditions, and immunopathological processes are a hallmark of the associated neuropathology. Due to the low regenerative capacity of the CNS a sophisticated understanding of the underlying molecular basis for disease initiation, progression and remission in canine CNS diseases represents a prerequisite for the development of novel therapeutical approaches. In addition, as many spontaneous canine CNS diseases share striking similarities with their human counterpart, knowledge about the immune pathogenesis may in part be translated for a better understanding of certain human diseases. In addition to cytokine-driven differentiation of peripheral leukocytes including different subsets of T cells recent research suggests a pivotal role of these mediators also in phenotype polarization of resident glial cells. Cytokines thus represent the key mediators of the local and systemic immune response in CNS diseases and their orchestration significantly decides on either lesion progression or remission. The aim of the present review is to summarize the growing number of data focusing on the molecular basis of the immune response during spontaneous canine CNS diseases and to detail the effect of cytokines on the immune pathogenesis of selected idiopathic, infectious, and traumatic canine CNS diseases. Steroid-responsive meningitis arteritis (SRMA) represents a unique idiopathic disease of leptomeningeal blood vessels characterized by excessive IgA secretion into the cerebrospinal fluid. Recent reports have given sophisticated insights into the cytokine-driven, immune-mediated pathogenesis of SRMA that is characterized by a biased T helper 2 cell response. Canine distemper associated leukoencephalitis represents an important spontaneously occurring disease that allows investigations on the basic pathogenesis of immune-mediated myelin loss. It

  5. Myelin Loss Does Not Lead to Axonal Degeneration in a Long-Lived Model of Chronic Demyelination

    PubMed Central

    Smith, Chelsey M.; Cooksey, Elizabeth; Duncan, Ian D.

    2014-01-01

    Current dogma suggests that chronically demyelinated axons are at risk for degeneration, with axonal loss resulting in permanent disability in myelin disease. However, the trophic role of the myelin sheath in long-term axonal survival is incompletely understood. Previous observations of the effect of dysmyelination or demyelination on axonal survival in the myelin mutants has been limited because of their short life span. In this study, we used the Long–Evans shaker (les) rat, which can live up to 9 months, to study axonal health and survival after chronic demyelination. At 2 weeks, ~29% of medium and ~47% of large fiber axons are myelinated in les spinal cord. However, by 3 months, no medium and ~<1% of large-diameter axons retain myelin. After demyelination, axons have a reduced-caliber, abnormal neurofilament distribution and an increase in mitochondrial number. However, there are no signs of axonal degeneration in les rats up to 9 months. Instead, there is a profound increase in oligodendrocytes, which were found to express BDNF, NT-3, and IGF-1. Importantly, this study provides in vivo evidence that mature glial cells produce various neurotrophic factors that may aid in the survival of axons after chronic demyelination. PMID:23392698

  6. The cyclooxygenase-2 pathway via the PGE2 EP2 receptor contributes to oligodendrocytes apoptosis in cuprizone-induced demyelination

    PubMed Central

    Palumbo, Sara; Toscano, Christopher D.; Parente, Laura; Weigert, Roberto; Bosetti, Francesca

    2011-01-01

    Cyclooxygenases (COX)-1 and -2 are key enzymes required for the conversion of arachidonic acid (AA) to eicosanoids, potent mediators of inflammation. In patients with multiple sclerosis (MS), COX-2 derived prostaglandins (PGs) are elevated in the cerebrospinal fluid and COX-2 is upregulated in demyelinating plaques. However, it is not known whether COX-2 activity contributes to oligodendrocyte death. In cuprizone-induced demyelination, oligodendrocyte apoptosis and a concomitant increase in the gene expression of COX-2 and PGE2-EP2 receptor precede histological demyelination. COX-2 and EP2 receptor were expressed by oligodendrocytes, suggesting a causative role for the COX-2/EP2 pathway in the initiation of oligodendrocyte death and demyelination. COX-2 gene deletion, chronic treatment with the COX-2 selective inhibitor celecoxib, or with the EP2 receptor antagonist AH6809 reduced cuprizone-induced oligodendrocyte apoptosis, the degree of demyelination and motor dysfunction. These data indicate that the PGE2 EP2 receptor contributes to oligodendrocyte apoptosis and open possible new therapeutic approaches for MS. PMID:21699540

  7. Disparate Effects of Mesenchymal Stem Cells in Experimental Autoimmune Encephalomyelitis and Cuprizone-Induced Demyelination

    PubMed Central

    Glenn, Justin D.; Smith, Matthew D.; Kirby, Leslie A.; Baxi, Emily G.; Whartenby, Katharine A

    2015-01-01

    Mesenchymal stem cells (MSCs) are pleiotropic cells with potential therapeutic benefits for a wide range of diseases. Because of their immunomodulatory properties they have been utilized to treat autoimmune diseases such as multiple sclerosis (MS), which is characterized by demyelination. The microenvironment surrounding MSCs is thought to affect their differentiation and phenotype, which could in turn affect the efficacy. We thus sought to dissect the potential for differential impact of MSCs on central nervous system (CNS) disease in T cell mediated and non-T cell mediated settings using the MOG35–55 experimental autoimmune encephalomyelitis (EAE) and cuprizone-mediated demyelination models, respectively. As the pathogeneses of MS and EAE are thought to be mediated by IFNγ-producing (TH1) and IL-17A-producing (TH17) effector CD4+ T cells, we investigated the effect of MSCs on the development of these two key pathogenic cell groups. Although MSCs suppressed the activation and effector function of TH17 cells, they did not affect TH1 activation, but enhanced TH1 effector function and ultimately produced no effect on EAE. In the non- T cell mediated cuprizone model of demyelination, MSC administration had a positive effect, with an overall increase in myelin abundance in the brain of MSC-treated mice compared to controls. These results highlight the potential variability of MSCs as a biologic therapeutic tool in the treatment of autoimmune disease and the need for further investigation into the multifaceted functions of MSCs in diverse microenvironments and the mechanisms behind the diversity. PMID:26407166

  8. Azotemia protects the brain from osmotic demyelination on rapid correction of hyponatremia.

    PubMed

    Dhrolia, Murtaza F; Akhtar, Syed F; Ahmed, Ejaz; Naqvi, Anwar; Rizvi, Adeeb

    2014-05-01

    Osmotic demyelination syndrome (ODS) is a dreadful, irreversible and well-recognized clinical entity that classically occurs after rapid correction of hyponatremia. However, it has been observed that when hyponatremia is rapidly corrected in azotemic patients by hemodialysis (HD), patients do not necessarily develop ODS. We studied the effect of inadvertent rapid correction of hyponatremia with HD in patients with azotemia. Fifty-two azotemic patients, who underwent HD at the Sindh Institute of Urology and Transplantation, having pre-HD serum sodium level <125 mEq/L and post-HD serum sodium levels that increased by ≥12 mEq/L from their pre-dialysis level, were studied. Serum sodium was analyzed before and within 24 h after a HD session. HD was performed using bicarbonate solution, with the sodium concentration being 140 meq/L. The duration of the dialysis session was based on the discretion of the treating nephrologist. Patients were examined for any neurological symptoms or signs before and after HD and for up to two weeks. Magnetic resonance imaging was performed in required cases. None of the 52 patients with azotemia, despite inadvertent rapid correction of hyponatremia with HD, developed ODS. This study suggests that patients with azotemia do not develop ODS on rapid correction of hyponatremia by HD, which suggests a possible protective role of azotemia on the brain from osmotic demyelination. However, the mechanism by which azotemia protects the brain from demyelination in humans is largely hypothetical and further studies are needed to answer this question. PMID:24821152

  9. Inducible Expression of CXCL1 within the Central Nervous System Amplifies Viral-Induced Demyelination

    PubMed Central

    Marro, Brett S.; Grist, Jonathan J.

    2016-01-01

    The functional role of the ELR+ chemokine CXCL1 in host defense and disease following infection of the CNS with the neurotropic JHM strain of mouse hepatitis virus (JHMV) was examined. Mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within glial fibrillary acidic protein–positive cells were generated and this allowed for selectively increasing CNS expression of CXCL1 in response to JHMV infection and evaluating the effects on neuroinflammation, control of viral replication, and demyelination. Inducible expression of CNS-derived CXCL1 resulted in increased levels of CXCL1 protein within the serum, brain, and spinal cord that correlated with increased frequency of Ly6G+CD11b+ neutrophils present within the CNS. Elevated levels of CXCL1 did not influence the generation of virus-specific T cells, and there was no difference in control of JHMV replication compared with control mice, indicating that T cell infiltration into the CNS is CXCL1-independent. Sustained CXCL1 expression within the CNS resulted in increased mortality that correlated with elevated neutrophil infiltration, diminished numbers of mature oligodendrocytes, and an increase in the severity of demyelination. Neutrophil ablation in CXCL1-transgenic mice reduced the severity of demyelination in mice, arguing for a role for these cells in white matter damage. Collectively, these findings illustrate that sustained CXCL1 expression amplifies the severity of white matter damage and that neutrophils can contribute to this process in a model of viral-induced neurologic disease. PMID:26773148

  10. Inducible Expression of CXCL1 within the Central Nervous System Amplifies Viral-Induced Demyelination.

    PubMed

    Marro, Brett S; Grist, Jonathan J; Lane, Thomas E

    2016-02-15

    The functional role of the ELR(+) chemokine CXCL1 in host defense and disease following infection of the CNS with the neurotropic JHM strain of mouse hepatitis virus (JHMV) was examined. Mice in which expression of CXCL1 is under the control of a tetracycline-inducible promoter active within glial fibrillary acidic protein-positive cells were generated and this allowed for selectively increasing CNS expression of CXCL1 in response to JHMV infection and evaluating the effects on neuroinflammation, control of viral replication, and demyelination. Inducible expression of CNS-derived CXCL1 resulted in increased levels of CXCL1 protein within the serum, brain, and spinal cord that correlated with increased frequency of Ly6G(+)CD11b(+) neutrophils present within the CNS. Elevated levels of CXCL1 did not influence the generation of virus-specific T cells, and there was no difference in control of JHMV replication compared with control mice, indicating that T cell infiltration into the CNS is CXCL1-independent. Sustained CXCL1 expression within the CNS resulted in increased mortality that correlated with elevated neutrophil infiltration, diminished numbers of mature oligodendrocytes, and an increase in the severity of demyelination. Neutrophil ablation in CXCL1-transgenic mice reduced the severity of demyelination in mice, arguing for a role for these cells in white matter damage. Collectively, these findings illustrate that sustained CXCL1 expression amplifies the severity of white matter damage and that neutrophils can contribute to this process in a model of viral-induced neurologic disease. PMID:26773148

  11. An uncommon cause of bifacial weakness and non-length-dependent demyelinating neuropathy

    PubMed Central

    Nagappa, Madhu; Taly, Arun B.; Mahadevan, Anita; Pooja, Mailankody; Bindu, Parayil Sankaran; Chickabasaviah, Yasha T.; Gayathri, Narayanappa; Sinha, Sanjib

    2015-01-01

    Tangier disease is a rare metabolic disorder that causes neuropathy in half of the affected individuals. We present the clinical, electrophysiological, and histopathological findings in a middle-aged gentleman of Tangier disease who was initially diagnosed as leprosy and treated with antileprosy drugs. The presence of a demyelinating electrophysiology in a patient with predominant upper limb involvement and facial diplegia should raise the suspicion of Tangier disease. Estimation of serum lipids should form a part of routine evaluation in order to avoid misdiagnosis. PMID:26713019

  12. Radiographic and Pathologic Manifestations of Uncommon and Rare Pulmonary Lesions.

    PubMed

    Pfeifer, Kyle; Mian, Ali; Adebowale, Adeniran; Alomari, Ahmed; Kalra, Vivek; Krejci, Elise; Shin, Myung Soo

    2016-05-01

    Pulmonary opacities/nodules are common findings on computed tomography examinations, which may represent an underlying infections or malignancy. However, not every pulmonary nodule or opacity represents malignancy or infection. We present a pictorial essay illustrating common as well as obscure noninfectious, nonmalignant pulmonary lesions. Lesions discussed include organizing pneumonia, Langerhans cell histiocytosis, pulmonary amyloidosis, hyalinizing granuloma, tumourlet (benign localized neuroendocrine cell proliferations), atypical alveolar hyperplasia, inflammatory myofibroblastic tumour, papillary alveolar adenoma, plasma cell granuloma, juvenile xanthogranuloma, and sclerosing hemangiomas. We discuss the clinical presentation, prevalence, radiographic clues, pathology, and diagnostic pitfalls of these rare lesions. PMID:26690551

  13. Frequency of different oral lesions in children and adolescents in Babol, Northern Iran

    PubMed Central

    Siadati, Sepideh; Seyedmajidi, Maryam; Sharbatdaran, Majid

    2013-01-01

    Background: Few studies regarding oral lesions of children and adolescents were reported in the medical literature. The aim of this study was to determine the frequency of these lesions in patients from birth to 20 years old in Babol, Northern Iran. Methods: The slides of all cases of oral lesions in children and adolescents, between 1990 and 2012 were obtained from the pathology archives of Shahid Beheshti Hospital and School of Dentistry, Babol University of Medical Sciences in Iran. The lesions were categorized as follows: cystic lesions, tumor/tumor-like lesions and inflammatory/reactive lesions. The data were collected and analyzed. Results: The 244 retrieved cases accounted for 27% of total oral biopsies (8956) were performed during this period. Male to female ratio was 0.8. Inflammatory / reactive category (61.9%), tumor/ tumor-like category (23%) and cystic category (15.2%) were in order of frequency. Mucocele was seen in 55 (35.8%) of 151 cases of inflammatory/ reactive, centeral giant cell granoloma (CGCG) in 15 (26.8%) of 56 tumor/ tumor like and radicular cyst in 14 (37.9%) of 37 cystic lesions. Conclusion: Our findings indicate that mucocele, CGCG and radicular cyst were frequent lesions in inflammatory / reactive, tumor / tumor like and cystic categories, respectively in our region. PMID:24294472

  14. Multimodal coherent anti-Stokes Raman scattering microscopy reveals microglia-associated myelin and axonal dysfunction in multiple sclerosis-like lesions in mice

    NASA Astrophysics Data System (ADS)

    Imitola, Jaime; Côté, Daniel; Rasmussen, Stine; Xie, X. Sunney; Liu, Yingru; Chitnis, Tanuja; Sidman, Richard L.; Lin, Charles. P.; Khoury, Samia J.

    2011-02-01

    Myelin loss and axonal degeneration predominate in many neurological disorders; however, methods to visualize them simultaneously in live tissue are unavailable. We describe a new imaging strategy combining video rate reflectance and fluorescence confocal imaging with coherent anti-Stokes Raman scattering (CARS) microscopy tuned to CH2 vibration of myelin lipids, applied in live tissue of animals with chronic experimental autoimmune encephalomyelitis (EAE). Our method allows monitoring over time of demyelination and neurodegeneration in brain slices with high spatial resolution and signal-to-noise ratio. Local areas of severe loss of lipid signal indicative of demyelination and loss of the reflectance signal from axons were seen in the corpus callosum and spinal cord of EAE animals. Even in myelinated areas of EAE mice, the intensity of myelin lipid signals is significantly reduced. Using heterozygous knock-in mice in which green fluorescent protein replaces the CX3CR1 coding sequence that labels central nervous system microglia, we find areas of activated microglia colocalized with areas of altered reflectance and CARS signals reflecting axonal injury and demyelination. Our data demonstrate the use of multimodal CARS microscopy for characterization of demyelinating and neurodegenerative pathology in a mouse model of multiple sclerosis, and further confirm the critical role of microglia in chronic inflammatory neurodegeneration.

  15. Oral Lesions in Neonates

    PubMed Central

    Rao, Roopa S; Majumdar, Barnali; Jafer, Mohammed; Maralingannavar, Mahesh; Sukumaran, Anil

    2016-01-01

    ABSTRACT Oral lesions in neonates represent a wide range of diseases often creating apprehension and anxiety among parents. Early examination and prompt diagnosis can aid in prudent management and serve as baseline against the future course of the disease. The present review aims to enlist and describe the diagnostic features of commonly encountered oral lesions in neonates. How to cite this article: Patil S, Rao RS, Majumdar B, Jafer M, Maralingannavar M, Sukumaran A. Oral Lesions in Neonates. Int J Clin Pediatr Dent 2016;9(2):131-138. PMID:27365934

  16. Oral Lesions in Neonates.

    PubMed

    Patil, Shankargouda; Rao, Roopa S; Majumdar, Barnali; Jafer, Mohammed; Maralingannavar, Mahesh; Sukumaran, Anil

    2016-01-01

    Oral lesions in neonates represent a wide range of diseases often creating apprehension and anxiety among parents. Early examination and prompt diagnosis can aid in prudent management and serve as baseline against the future course of the disease. The present review aims to enlist and describe the diagnostic features of commonly encountered oral lesions in neonates. How to cite this article: Patil S, Rao RS, Majumdar B, Jafer M, Maralingannavar M, Sukumaran A. Oral Lesions in Neonates. Int J Clin Pediatr Dent 2016;9(2):131-138. PMID:27365934

  17. Retinal lesions in septicemia.

    PubMed

    Neudorfer, M; Barnea, Y; Geyer, O; Siegman-Igra, Y

    1993-12-15

    We explored the association between septicemia and specific retinal lesions in a prospective controlled study. Hemorrhages, cotton-wool spots, or Roth's spots were found in 24 of 101 septicemic patients (24%), compared to four of 99 age- and gender-matched control patients (4%) (P = .0002). There was no significant association between types of organisms or focus of infection and the presence of specific lesions. Histologic examination of affected eyes disclosed cytoid bodies in the nerve fiber layer without inflammation. A definite association between septicemia and retinal lesions was found and indicates the need for routine ophthalmoscopy in septicemic patients. PMID:8250076

  18. Oral Inflammatory Myofibroblastic Tumor: Case Report and Review of Literature

    PubMed Central

    Binmadi, Nada O; Packman, Harold; Papadimitriou, John C; Scheper, Mark

    2011-01-01

    Inflammatory myofibroblastic tumor (IMT) is a rarely described tumor of unknown etiology and pathogenesis. It occurs primarily in the lungs, but has occurred in other extra-pulmonary sites. Histologically these lesions appear as an inflammatory infiltrate within a variably myofibrotic background. Current evidence shows that inflammatory myofibroblastic tumors are neoplastic processes resulting from chromosomal translocations that often cause an overexpression of ALK kinase, which is often assessed using immunohistochemical studies. Currently, the biological behavior of oral inflammatory myofibroblastic tumor is still uncertain. This article describes the clinical, histological, and operative features of a case of IMT of the oral cavity. PMID:21566695

  19. Inflammatory bowel disease: An increased risk factor for neurologic complications

    PubMed Central

    Morís, Germán

    2014-01-01

    Only a very few systematic studies have investigated the frequency of neurologic disorders in patients with Crohn’s disease (CD) and ulcerative colitis (UC), which are the two main types of inflammatory bowel disease (IBD). Results have been inconsistent and variable, owing to differences in case-finding methods and evaluated outcomes in different studies. The most frequent neurologic manifestations reported in CD and UC populations are cerebrovascular disease (with either arterial or venous events), demyelinating central nervous system disease, and peripheral neuropathy (whether axonal or demyelinating); however, the literature describes numerous nervous system disorders as being associated with IBD. The pathogenesis of nervous system tissue involvement in IBD has yet to be elucidated, although it seems to be related to immune mechanisms or prothrombotic states. The recently-introduced tumor necrosis factor (TNF) inhibitors have proven successful in controlling moderate to severe IBD activity. However, severe neurologic disorders associated with TNF inhibitors have been reported, which therefore raises concerns regarding the effect of anti-TNF-α antibodies on the nervous system. Although neurological involvement associated with IBD is rarely reported, gastroenterologists should be aware of the neurologic manifestations of IBD in order to provide early treatment, which is crucial for preventing major neurologic morbidity. PMID:24574797

  20. Inflammatory Pseudotumors After Stem Cell Transplantation

    PubMed Central

    Tufan, Asli; Bahat, Gulistan

    2015-01-01

    Inflammatory pseudotumors (IPT) are rare tumors that occur in various organs and tissues. The clinical picture varies from the more frequent benign lesions to rare malignant tumors with distant metastases. IPTs associated with hematopoietic stem cell transplantation (HSCT) is rarely reported. In this article, we review the reports of IPT after HSCT. We also review the possible factors involved in the pathogenesis. IPT may be rare but they are a potentially serious complication of HSCT. A knowledge of these entities and insistence on a definitive biopsy of mass lesions in the post-HSCT period can avoid unnecessary treatment such as radical surgery, chemotherapy or radiotherapy. PMID:26487930

  1. MR colonography in inflammatory bowel disease.

    PubMed

    Rimola, Jordi; Ordás, Ingrid

    2014-02-01

    MR colonography has a high diagnostic accuracy for detecting Crohn disease (CD) activity and determining the extent and severity of lesions. In the setting of stricturing CD, MR colonography can provide a detailed map of the lesions, which is useful for clinical decision making. MR colonography can be used as an alternative to conventional colonoscopy in the setting of CD, or as a complementary tool in selected patients with ulcerative colitis. This article reviews the spectrum of MR colonography findings in colonic inflammatory bowel disease and discusses the potential applications and limitations of MR colonography. PMID:24238130

  2. Talar Dome Lesion

    MedlinePlus

    ... be helpful in reducing the pain and inflammation. Physical therapy . Range-of-motion and strengthening exercises are beneficial once the lesion is adequately healed. Physical therapy may also include techniques to reduce pain and ...

  3. Uterine Vascular Lesions

    PubMed Central

    Vijayakumar, Abhishek; Srinivas, Amruthashree; Chandrashekar, Babitha Moogali; Vijayakumar, Avinash

    2013-01-01

    Vascular lesions of the uterus are rare; most reported in the literature are arteriovenous malformations (AVMs). Uterine AVMs can be congenital or acquired. In recent years, there has been an increasing number of reports of acquired vascular lesions of the uterus following pregnancy, abortion, cesarean delivery, and curettage. It can be seen from these reports that there is confusion concerning the terminology of uterine vascular lesions. There is also a lack of diagnostic criteria and management guidelines, which has led to an increased number of unnecessary invasive procedures (eg, angiography, uterine artery embolization, hysterectomy for abnormal vaginal bleeding). This article familiarizes readers with various vascular lesions of the uterus and their management. PMID:24340126

  4. Multiple Osteolytic Lesions

    PubMed Central

    Vinayachandran, Divya; Sankarapandian, Sathasivasubramanian

    2013-01-01

    Several systemic diseases initially present with various oral manifestations. Investigation of these oral symptoms may at times lead to the diagnosis of grave underlying life-threatening conditions. We present one such case, where the patient manifested with gross enlargement of the mandible, along with lesions in the lower limbs. These lesions were the initial manifestation and on further investigations the patient was diagnosed with multiple myeloma. PMID:24516769

  5. Role of FNAC in the diagnosis of intraosseous jaw lesions

    PubMed Central

    Goyal, Surbhi; Kotru, Mrinalini; Gupta, Neelima

    2015-01-01

    Background FNAC of intraosseous jaw lesions has not been widely utilized for diagnosis due to rarity and diversity of these lesions, limited experience and lack of well established cytological features. Aim of the study was to determine the role of FNAC in the diagnosis of intraosseous jaw swellings. Material and Methods 42 patients underwent FNAC over a period of 7 years (2007-2013), of which 37 (88.1%) aspirates were diagnostic. Histopathology correlation was available in 33 cases and diagnostic accuracy of FNAC was calculated. Results Lesions were categorized into inflammatory 3, cysts/hamartomas 15 and neoplasms 19. Mandibular and maxillary involvement was seen in 21 and 16 patients respectively. Of these, benign cysts and malignant lesions were commonest, accounting for 27% lesions (10 cases) each. One case of cystic ameloblastoma was misdiagnosed as odontogenic cyst on cytology. Overall, sensitivity and specificity of FNAC were 94.7% and 100% respectively with a diagnostic accuracy of 97.3%. Definitive categorization of giant cell lesions, fibro-osseous lesions, odontogenic tumors and cystic lesions was not feasible on FNAC. Conclusions FNAC is a simple, safe and minimally invasive first line investigation which can render an accurate preoperative diagnosis of intraosseous jaw lesions, especially the malignant ones in the light of clinic-radiological correlation. Key words: Jaw swellings, intraosseous, FNAC. PMID:25662547

  6. Quetiapine Inhibits Microglial Activation by Neutralizing Abnormal STIM1-Mediated Intercellular Calcium Homeostasis and Promotes Myelin Repair in a Cuprizone-Induced Mouse Model of Demyelination

    PubMed Central

    Wang, Hanzhi; Liu, Shubao; Tian, Yanping; Wu, Xiyan; He, Yangtao; Li, Chengren; Namaka, Michael; Kong, Jiming; Li, Hongli; Xiao, Lan

    2015-01-01

    Microglial activation has been considered as a crucial process in the pathogenesis of neuroinflammation and psychiatric disorders. Several antipsychotic drugs (APDs) have been shown to display inhibitory effects on microglial activation in vitro, possibly through the suppression of elevated intracellular calcium (Ca2+) concentration. However, the exact underlying mechanisms still remain elusive. In this study, we aimed to investigate the inhibitory effects of quetiapine (Que), an atypical APD, on microglial activation. We utilized a chronic cuprizone (CPZ)-induced demyelination mouse model to determine the direct effect of Que on microglial activation. Our results showed that treatment with Que significantly reduced recruitment and activation of microglia/macrophage in the lesion of corpus callosum and promoted remyelination after CPZ withdrawal. Our in vitro studies also confirmed the direct effect of Que on lipopolysaccharide (LPS)-induced activation of microglial N9 cells, whereby Que significantly inhibited the release of nitric oxide (NO) and tumor necrosis factor α (TNF-α). Moreover, we demonstrated that pretreatment with Que, neutralized the up-regulation of STIM1 induced by LPS and declined both LPS and thapsigargin (Tg)-induced store-operated Ca2+ entry (SOCE). Finally, we found that pretreatment with Que significantly reduced the translocation of nuclear factor kappa B (NF-κB) p65 subunit from cytoplasm to nuclei in LPS-activated primary microglial cells. Overall, our data suggested that Que may inhibit microglial activation by neutralization of the LPS-induced abnormal STIM1-mediated intercellular calcium homeostasis. PMID:26732345

  7. Adult DRG Stem/Progenitor Cells Generate Pericytes in the Presence of Central Nervous System (CNS) Developmental Cues, and Schwann Cells in Response to CNS Demyelination.

    PubMed

    Vidal, Marie; Maniglier, Madlyne; Deboux, Cyrille; Bachelin, Corinne; Zujovic, Violetta; Baron-Van Evercooren, Anne

    2015-06-01

    It has been proposed that the adult dorsal root ganglia (DRG) harbor neural stem/progenitor cells (NPCs) derived from the neural crest. However, the thorough characterization of their stemness and differentiation plasticity was not addressed. In this study, we investigated adult DRG-NPC stem cell properties overtime, and their fate when ectopically grafted in the central nervous system. We compared them in vitro and in vivo to the well-characterized adult spinal cord-NPCs derived from the same donors. Using micro-dissection and neurosphere cultures, we demonstrate that adult DRG-NPCs have quasi unlimited self-expansion capacities without compromising their tissue specific molecular signature. Moreover, they differentiate into multiple peripheral lineages in vitro. After transplantation, adult DRG-NPCs generate pericytes in the developing forebrain but remyelinating Schwann cells in response to spinal cord demyelination. In addition, we show that axonal and endothelial/astrocytic factors as well astrocytes regulate the fate of adult DRG-NPCs in culture. Although the adult DRG-NPC multipotency is restricted to the neural crest lineage, their dual responsiveness to developmental and lesion cues highlights their impressive adaptive and repair potentials making them valuable targets for regenerative medicine. PMID:25786382

  8. Interleukin-1β and Interleukin-1 Receptor Antagonist Appear in Grey Matter Additionally to White Matter Lesions during Experimental Multiple Sclerosis

    PubMed Central

    Wierinckx, Anne; Bol, John G. J. M.; Binnekade, Rob; Tilders, Fred J. H.; Van Dam, Anne-Marie

    2013-01-01

    Background Multiple sclerosis (MS) has been mainly attributed to white matter (WM) pathology. However, recent evidence indicated the presence of grey matter (GM) lesions. One of the principal mediators of inflammatory processes is interleukin-1β (IL-1β), which is known to play a role in MS pathogenesis. It is unknown whether IL-1β is solely present in WM or also in GM lesions. Using an experimental MS model, we questioned whether IL-1β and the IL-1 receptor antagonist (IL-1ra) are present in GM in addition to affected WM regions. Methods The expression of IL-1β and IL-1ra in chronic-relapsing EAE (cr-EAE) rats was examined using in situ hybridization, immunohistochemistry and real-time PCR. Rats were sacrificed at the peak of the first disease phase, the trough of the remission phase, and at the peak of the relapse. Histopathological characteristics of CNS lesions were studied using immunohistochemistry for PLP, CD68 and CD3 and Oil-Red O histochemistry. Results IL-1β and IL-ra expression appears to a similar extent in affected GM and WM regions in the brain and spinal cord of cr-EAE rats, particularly in perivascular and periventricular locations. IL-1β and IL-1ra expression was dedicated to macrophages and/or activated microglial cells, at sites of starting demyelination. The time-dependent expression of IL-1β and IL-1ra revealed that within the spinal cord IL-1β and IL-1ra mRNA remained present throughout the disease, whereas in the brain their expression disappeared during the relapse. Conclusions The appearance of IL-1β expressing cells in GM within the CNS during cr-EAE may explain the occurrence of several clinical deficits present in EAE and MS which cannot be attributed solely to the presence of IL-1β in WM. Endogenously produced IL-1ra seems not capable to counteract IL-1β-induced effects. We put forward that IL-1β may behold promise as a target to address GM, in addition to WM, related pathology in MS. PMID:24376764

  9. Physiological Dynamics in Demyelinating Diseases: Unraveling Complex Relationships through Computer Modeling

    PubMed Central

    Coggan, Jay S.; Bittner, Stefan; Stiefel, Klaus M.; Meuth, Sven G.; Prescott, Steven A.

    2015-01-01

    Despite intense research, few treatments are available for most neurological disorders. Demyelinating diseases are no exception. This is perhaps not surprising considering the multifactorial nature of these diseases, which involve complex interactions between immune system cells, glia and neurons. In the case of multiple sclerosis, for example, there is no unanimity among researchers about the cause or even which system or cell type could be ground zero. This situation precludes the development and strategic application of mechanism-based therapies. We will discuss how computational modeling applied to questions at different biological levels can help link together disparate observations and decipher complex mechanisms whose solutions are not amenable to simple reductionism. By making testable predictions and revealing critical gaps in existing knowledge, such models can help direct research and will provide a rigorous framework in which to integrate new data as they are collected. Nowadays, there is no shortage of data; the challenge is to make sense of it all. In that respect, computational modeling is an invaluable tool that could, ultimately, transform how we understand, diagnose, and treat demyelinating diseases. PMID:26370960

  10. Nerve Demyelination Increases Metabotropic Glutamate Receptor Subtype 5 Expression in Peripheral Painful Mononeuropathy

    PubMed Central

    Ko, Miau-Hwa; Hsieh, Yu-Lin; Hsieh, Sung-Tsang; Tseng, To-Jung

    2015-01-01

    Wallerian degeneration or nerve demyelination, arising from spinal nerve compression, is thought to bring on chronic neuropathic pain. The widely distributed metabotropic glutamate receptor subtype 5 (mGluR5) is involved in modulating nociceptive transmission. The purpose of this study was to investigate the potential effects of mGluR5 on peripheral hypersensitivities after chronic constriction injury (CCI). Sprague-Dawley rats were operated on with four loose ligatures around the sciatic nerve to induce thermal hyperalgesia and mechanical allodynia. Primary afferents in dermis after CCI exhibited progressive decreases, defined as partial cutaneous denervation; importantly, mGluR5 expressions in primary afferents were statistically increased. CCI-induced neuropathic pain behaviors through the intraplantar injections of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective mGluR5 antagonist, were dose-dependently attenuated. Furthermore, the most increased mGluR5 expressions in primary afferents surrounded by reactive Schwann cells were observed at the distal CCI stumps of sciatic nerves. In conclusion, these results suggest that nerve demyelination results in the increases of mGluR5 expression in injured primary afferents after CCI; and further suggest that mGluR5 represents a main therapeutic target in developing pharmacological strategies to prevent peripheral hypersensitivities. PMID:25739080

  11. Selective vulnerability of peripheral nerves in avian riboflavin deficiency demyelinating polyneuropathy.

    PubMed

    Cai, Z; Blumbergs, P C; Finnie, J W; Manavis, J; Thompson, P D

    2009-01-01

    Riboflavin (vitamin B2) deficiency in young chickens produces a demyelinating peripheral neuropathy. In this study, day-old broiler meat chickens were fed a riboflavin-deficient diet (1.8 mg/kg) and killed on posthatch days 6, 11, 16, 21, and 31, while control chickens were given a conventional diet containing 5.0 mg/kg riboflavin. Pathologic changes were found in sciatic, cervical, and lumbar spinal nerves of riboflavin-deficient chickens from day 11 onwards, characterized by endoneurial oedema, hypertrophic Schwann cells, tomacula (redundant myelin swellings), demyelination/remyelination, lipid deposition, and fibroblastic onion bulb formation. Similar changes were also found in large and medium intramuscular nerves, although they were less severe in the latter. However, by contrast, ventral and dorsal spinal nerve roots, distal intramuscular nerves, and subcutaneous nerves were normal at all time points examined. These findings demonstrate, for the first time, that riboflavin deficiency in young, rapidly growing chickens produces selective injury to peripheral nerve trunks, with relative sparing of spinal nerve roots and distal nerve branches to muscle and skin. These novel findings suggest that the response of Schwann cells in peripheral nerves with riboflavin deficiency differs because either there are subsets of these cells in, or there is variability in access of nutrients to, different sites within the nerves. PMID:19112122

  12. The spatial distribution of excitability and membrane current in normal and demyelinated mammalian nerve fibres.

    PubMed Central

    Bostock, H; Sears, T A; Sherratt, R M

    1983-01-01

    Thresholds to electrical stimulation have been recorded, concurrently with the membrane currents of conducted impulses, at many positions along undissected single fibres in rat spinal roots. In normal myelinated fibres, distinct threshold minima invariably coincided with sites of inward current generation, and were therefore identified as nodes of Ranvier. Between nodes, the thresholds rose by an order of magnitude. At normal nodes, the charge thresholds were linearly related to stimulus duration, as predicted by computer simulations of a model myelinated fibre (Bostock, 1983). The strength-duration time constants averaged 64.9 +/- 8.3 microseconds (mean +/- S.D.) at 37 degrees C, and had a Q10 of 1/1.39. They were relatively insensitive to changes in inter-electrode distance, or to partial anaesthetization with tetrodotoxin. In fibres treated with diphtheria toxin 6-8 days previously, to induce paranodal or segmental demyelination, threshold minima were found both at nodes and in internodal regions generating inward membrane current. In these fibres strength-duration curves were of the same general form as at normal nodes, but with strength-duration time constants increased at widened nodes (up to 350 microseconds) and at excitable internodes (600-725 microseconds). Comparison with the computer model indicated that these changes were most likely due to exposure of axon membrane with a time constant much longer than that of the normal nodal membrane. In none of the demyelinated fibres examined have we found any evidence of hyperexcitability. PMID:6312029

  13. From demyelination to remyelination: the road toward therapies for spinal cord injury.

    PubMed

    Papastefanaki, Florentia; Matsas, Rebecca

    2015-07-01

    Myelin integrity is crucial for central nervous system (CNS) physiology while its preservation and regeneration after spinal cord injury (SCI) is key to functional restoration. Disturbance of nodal organization acutely after SCI exposes the axon and triggers conduction block in the absence of overt demyelination. Oligodendrocyte (OL) loss and myelin degradation follow as a consequence of secondary damage. Here, we provide an overview of the major biological events and underlying mechanisms leading to OL death and demyelination and discuss strategies to restrain these processes. Another aspect which is critical for SCI repair is the enhancement of endogenously occurring spontaneous remyelination. Recent findings have unveiled the complex roles of innate and adaptive immune responses in remyelination and the immunoregulatory potential of the glial scar. Moreover, the intimate crosstalk between neuronal activity, oligodendrogenesis and myelination emphasizes the contribution of rehabilitation to functional recovery. With a view toward clinical applications, several therapeutic strategies have been devised to target SCI pathology, including genetic manipulation, administration of small therapeutic molecules, immunomodulation, manipulation of the glial scar and cell transplantation. The implementation of new tools such as cellular reprogramming for conversion of one somatic cell type to another or the use of nanotechnology and tissue engineering products provides additional opportunities for SCI repair. Given the complexity of the spinal cord tissue after injury, it is becoming apparent that combinatorial strategies are needed to rescue OLs and myelin at early stages after SCI and support remyelination, paving the way toward clinical translation. PMID:25731941

  14. A Mutation in PMP2 Causes Dominant Demyelinating Charcot-Marie-Tooth Neuropathy

    PubMed Central

    Hyun, Young Se; Kwak, Geon; Choi, Yu-Ri; Yeo, Ha Kyung; Jwa, Dong Hwan; Kim, Eun Ja; Mo, Won Min; Nam, Soo Hyun; Kim, Sung Min; Yoo, Jeong Hyun; Koo, Heasoo; Park, Hwan Tae; Chung, Ki Wha; Choi, Byung-Ok

    2016-01-01

    Charcot-Marie-Tooth disease (CMT) is a heterogeneous group of peripheral neuropathies with diverse genetic causes. In this study, we identified p.I43N mutation in PMP2 from a family exhibiting autosomal dominant demyelinating CMT neuropathy by whole exome sequencing and characterized the clinical features. The age at onset was the first to second decades and muscle atrophy started in the distal portion of the leg. Predominant fatty replacement in the anterior and lateral compartment was similar to that in CMT1A caused by PMP22 duplication. Sural nerve biopsy showed onion bulbs and degenerating fibers with various myelin abnormalities. The relevance of PMP2 mutation as a genetic cause of dominant CMT1 was assessed using transgenic mouse models. Transgenic mice expressing wild type or mutant (p.I43N) PMP2 exhibited abnormal motor function. Electrophysiological data revealed that both mice had reduced motor nerve conduction velocities (MNCV). Electron microscopy revealed that demyelinating fibers and internodal lengths were shortened in both transgenic mice. These data imply that overexpression of wild type as well as mutant PMP2 also causes the CMT1 phenotype, which has been documented in the PMP22. This report might expand the genetic and clinical features of CMT and a further mechanism study will enhance our understanding of PMP2-associated peripheral neuropathy. PMID:26828946

  15. Direct profiling of myelinated and demyelinated regions in mouse brain by imaging mass spectrometry

    NASA Astrophysics Data System (ADS)

    Ceuppens, Ruben; Dumont, Debora; van Brussel, Leen; van de Plas, Babs; Daniels, Ruth; Noben, Jean-Paul; Verhaert, Peter; van der Gucht, Estel; Robben, Johan; Clerens, Stefan; Arckens, Lutgarde

    2007-02-01

    One of the newly developed imaging mass spectrometry (IMS) technologies utilizes matrix-assisted laser desorption/ionization (MALDI) mass spectrometry to map proteins in thin tissue sections. In this study, we evaluated the power of MALDI IMS as we developed it in our (Bruker) MALDI TOF (Reflex IV) and TOF-TOF (Ultraflex II) systems to study myelin patterns in the mouse central nervous system under normal and pathological conditions. MALDI IMS was applied to assess myelin basic protein (MBP) isoform-specific profiles in different regions throughout the mouse brain. The distribution of ions of m/z 14,144 and 18,447 displayed a striking resemblance with white matter histology and were identified as MBP isoform 8 and 5, respectively. In addition, we demonstrated a significant reduction of the MBP-8 peak intensity upon MALDI IMS analysis of focal ethidium bromide-induced demyelinated brain areas. Our MS images were validated by immunohistochemistry using MBP antibodies. This study underscores the potential of MALDI IMS to study the contribution of MBP to demyelinating diseases.

  16. Petrous Apex Lesions

    PubMed Central

    Amedee, Ronald G.; Gianoli, Gerard J.; Mann, Wolf J.

    1994-01-01

    The purpose of this article is to detail our experience in treating 69 patients over the past 6 years with pathologic processes involving the petrous apex. These included 25 (36%) primary petrous apex lesions, 40 (58%) lesions that involved the petrous apex by direct invasion from an adjacent region, and four (6%) lesions that were the result of metastatic spread from a distant site. Although lesions of the petrous apex are uncommon, they may present significant morbidity to the patient. The symptoms elicited by these lesions are usually vague and nonlocalizing in the early stages but may progress to include multiple cranial neuropathies. Successful results are contingent on early diagnosis, which requires a high index of suspicion and use of appropriate imaging modalities. Thorough preoperative assessment with use of computed tomography, magnetic resonance imaging, and carotid arteriography is essential to plan the surgical approach. We present this collection of patients in order to aid in the further preoperative characterization of the differences in primary and secondary lesions of the petrous apex. PMID:17170919

  17. Colorectal Subepithelial Lesions

    PubMed Central

    2015-01-01

    Most of subepithelial lesion (SEL) being identified was accidentally discovered as small bulging lesion covered with normal mucosa from endoscopic screening. The type of treatment and prognosis vary depending on the type of tumor, it would be crucial to perform an accurate differential diagnosis. Since the differentiation of SEL relied on the indirect findings observed from the mucosal surface using an endoscopy only in the past, it was able to confirm the presence of lesion only but difficult to identify complex detailed nature of the lesion. However, after the endoscopic ultrasonography (EUS) was introduced, it became possible to identify extrinsic compression, and size of intramural tumors, internal properties and contour so that it gets possible to have differential diagnosis of lesions and prediction on the lesion whether it is malignant or benign. In addition, the use of EUS-guided fine needle aspiration and EUS-guided core biopsy made it possible to make histological differential diagnosis. This study intended to investigate endoscopic and EUS findings, histological diagnosis, treatment regimen and impression of colorectal SELs. PMID:26240803

  18. Significance of gray matter brain lesions in multiple sclerosis and neuromyelitis optica.

    PubMed

    Kawachi, Izumi; Nishizawa, Masatoyo

    2015-10-01

    Multiple sclerosis (MS) and neuromyelitis optica (NMO) are the two main autoimmune diseases of the CNS. In patients with NMO, the target antigen is aquaporin-4 (AQP4), the most abundant water channel protein in the CNS. AQP4 is mainly expressed on astrocytic endfoot processes at the blood-brain barrier and in subpial and subendymal regions. MS and NMO are distinct diseases, but they have some common clinical features: both have long been considered autoimmune diseases that primarily affect the white matter (WM). However, because WM demyelination by itself cannot explain the full extent of the clinical disabilities, including cognitive decline in patients with MS and NMO, renewed interest in gray matter (GM) pathology in MS and NMO is emerging. Important hallmarks of WM and GM lesions in MS and NMO may differentially influence neuronal degeneration and demyelination in the brain and spinal cord, given different detrimental effects, including cytokine diffusion, disruption of water homeostasis associated with or without AQP4 (the target antigen in NMO) dynamics, or other unidentified mechanisms. An increase in knowledge of the structure of GM and WM lesions in MS and NMO will result in more targeted therapeutic approaches to these two diseases. PMID:26079808

  19. [Non-neoplastic lesions of the mediastinum].

    PubMed

    Tzankov, A

    2016-09-01

    The mediastinum is a complex body region of limited space but containing numerous organs of different embryonic origins. A variety of lesions that are difficult to distinguish from each other can occur here. Non-neoplastic lesions of the mediastinum represent important differential diagnostic pitfalls to mediastinal tumors, clinically, radiologically and histopathologically. It is important to bear these lesions in mind and to adequately verify or exclude them before starting further differential diagnostic considerations on mediastinal neoplasms. The most common non-neoplastic lesions in this region include cysts and lymphadenopathies. Mediastinal cysts result from abnormal events in the branching of the tracheobronchial tree, the pharyngeal pouches, the primary intestines, the pleuropericardial membranes and the brain meninges or are complications of inflammatory and hydrostatic processes. The histogenesis of the lining epithelium and the cyst wall structure are decisive for the exact classification. The histopathologically most prevalent patterns of mediastinal lymphadenopathies are those accompanied by increased histiocytes and Castleman's disease. Sclerosis is a non-specific reaction pattern of the mediastinum and can be associated with many processes; therefore, when establishing the diagnosis of sclerosing mediastinitis, several differential diagnoses have to be excluded. Simple thymic hyperplasia can be accompanied by considerable increase in organ size with severe local symptoms, while follicular thymic hyperplasia is often associated with myasthenia gravis and represents the most common findings in non-thymoma thymectomy specimens. PMID:27465275

  20. [Acute hepatic lesion caused by Giardia lamblia].

    PubMed

    Sotto, A; Alvarez, J L; García, B; Pomar, F; Cendán, A

    1990-01-01

    A study was made of 20 rats infested by Giardia muris in which a histologic study was made of the liver, as well as of 25 patients with giardiasis and elevated alanine-aminotransferase levels. Patients with positive A or B hepatitis markers, cholelithiasis or history of drug or alcohol use were excluded. Tests of liver function and liver biopsy were performed and antiparasite therapy was given during three months of follow-up, after which the liver biopsy was repeated. Humoral alterations were compared to those of 30 patients with acute viral hepatitis (15 type A and 15 type B) over the same periods of time. In 20% of the rats, nonspecific liver lesions were found. In the patients liver enzymes and the thymol test normalized a month after treatment and serum bile acids became normal in the third month. The liver biopsy demonstrated hepatic damage in 94% of the patients (in 20 cases cell lesions and in 12 cases inflammatory lesions) which regressed in the third month, the follow-up biopsy being normal after eradication of the parasite was confirmed. The comparative study with viral hepatitis showed highly significant differences in all the variables studied during the follow-up stage. Emphasis is placed on the importance of this lesion and its differential diagnosis to prevent its progression to chronic liver disease. PMID:2334580

  1. Aorta Atherosclerosis Lesion Analysis in Hyperlipidemic Mice

    PubMed Central

    Mohanta, Sarajo; Yin, Changjun; Weber, Christian; Hu, Desheng; Habenicht, Andreas JR

    2016-01-01

    Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries. Apolipoprotein E-deficient (ApoE-/-) mice are used as experimental models to study human atherosclerosis. ApoE-/- mice are constitutively hyperlipidemic and develop intima plaques that resemble human plaques. Various issues including experimental design for lesion analysis, dietary conditions, isolation of the aorta, staining methods, morphometry, group size, age, the location within the arterial tree, and statistical analyses are important parameters that need to be addressed to obtain robust data. Here, we provide detailed methods to quantify aorta atherosclerosis. PMID:27366759

  2. [Inflammatory myofibroblastic tumours of the bladder].

    PubMed

    Dakir, Mohamed; Taha, Abdellatif; Attar, Hicham; Sarf, Ismail; Aboutaib, Rachid; Moussaoui, Ali; Meziane, Fathi

    2004-12-01

    The inflammatory myofibroblastic tumour of the bladder is a rare benign affection that interests mainly young adults. Its etiopathogeny remains unknown, but its tumoral origin was evocated recently by Griffin (1999), incriminating a chromosomic abnormality involving the ALK gene. We will discuss the etiopathogenic, anatopathological and therapeutical aspects of this lesion for which the diagnosis is histological and the treatment remains conservative with a good prognosis. PMID:15751423

  3. Meniscal Ramp Lesions

    PubMed Central

    Chahla, Jorge; Dean, Chase S.; Moatshe, Gilbert; Mitchell, Justin J.; Cram, Tyler R.; Yacuzzi, Carlos; LaPrade, Robert F.

    2016-01-01

    Meniscal ramp lesions are more frequently associated with anterior cruciate ligament (ACL) injuries than previously recognized. Some authors suggest that this entity results from disruption of the meniscotibial ligaments of the posterior horn of the medial meniscus, whereas others support the idea that it is created by a tear of the peripheral attachment of the posterior horn of the medial meniscus. Magnetic resonance imaging (MRI) scans have been reported to have a low sensitivity, and consequently, ramp lesions often go undiagnosed. Therefore, to rule out a ramp lesion, an arthroscopic evaluation with probing of the posterior horn of the medial meniscus should be performed. Several treatment options have been reported, including nonsurgical management, inside-out meniscal repair, or all-inside meniscal repair. In cases of isolated ramp lesions, a standard meniscal repair rehabilitation protocol should be followed. However, when a concomitant ACL reconstruction (ACLR) is performed, the rehabilitation should follow the designated ACLR postoperative protocol. The purpose of this article was to review the current literature regarding meniscal ramp lesions and summarize the pertinent anatomy, biomechanics, diagnostic strategies, recommended treatment options, and postoperative protocol. PMID:27504467

  4. The Protective Effects of Areca catechu Extract on Cognition and Social Interaction Deficits in a Cuprizone-Induced Demyelination Model

    PubMed Central

    He, Jue; Hartle, Kelly; Wang, Wenqiang; Li, XinMin

    2015-01-01

    Schizophrenia is a serious psychiatric illness with an unclear cause. One theory is that demyelination of white matter is one of the main pathological factors involved in the development of schizophrenia. The current study evaluated the protective effects of Areca catechu nut extract (ANE) on a cuprizone-induced demyelination mouse model. Two doses of ANE (1% and 2%) were administered orally in the diet for 8 weeks. Animals subjected to demyelination showed impaired spatial memory and less social activity. In addition, mice subjected to demyelination displayed significant myelin damage in cortex and demonstrated a higher expression of NG2 and PDGFRα and AMPK activation. ANE treatment not only significantly enhanced cognitive ability and social activity, but also protected myelin against cuprizone toxicity by promoting oligodendrocyte precursor cell (OPC) differentiation. In addition, ANE treatment demonstrated significant dephosphorylation of AMPKα, indicating a regulatory role for ANE in schizophrenia. This study showed that ANE treatment may enhance cognitive ability and social activity by facilitating OPC differentiation and protecting against myelin damage in cortex. Results also suggest the AMPK signaling pathway may be involved in this process. PMID:25815032

  5. Inflammatory Choroidal Neovascularization

    PubMed Central

    Neri, Piergiorgi; Lettieri, Marta; Fortuna, Cinzia; Manoni, Mara; Giovannini, Alfonso

    2009-01-01

    Purpose and Methods: Choroidal neovascularization (CNV) can be a severe sight-threatening sequela, which can be secondary to both infectious and noninfectious uveitis. This review summarizes the different diseases associated with CNV, highlighting new treatment modalities and the possible strategies, which could be applied for the therapy of this occurrence. Results: Since CNV can often originate from posterior pole lesions and can be hard to identify, an accurate examination is mandatory in order to identify the correct diagnosis. In the majority of cases, fluorescein angiography (FA), indocyanine green angiography (ICGA) and optical coherence tomography (OCT) enable the determination of the clinical characteristics of the CNV. An infectious disease should be looked for to include a suitable therapy when available. The treatment strategy for CNV secondary to noninfectious uveal inflammations should be directed at controlling the inflammatory process. Systemic corticosteroids with or without immunosuppressive agents are indicated even when the CNV occurs with apparently inactive uveitis: Chronic subclinical inflammation can be the basis for the pathogenesis of CNV. Additional therapies aimed directly at the neovascular process, such as the intravitreal anti-Vascular Endothelial Growth Factor (VEGF) agents, are recommended particularly when the therapy shows an insufficient response. Conclusion: CNV secondary to uveitis is a severe sequela leading to significant visual impairment. ICGA is mandatory in order to obtain relevant information about the choroidal status. Several therapeutic options have been considered, but no guidelines are provided at the moment. Moreover, the current data are still only based on case reports or small series. For such reasons, further trials are mandatory to validate the preliminary available results. PMID:20404991

  6. Jaw Intraosseous Lesions Biopsied Extracted From 1998 to 2010 in an Iranian Population

    PubMed Central

    Jamshidi, Shokoofeh; Shojaei, Setareh; Roshanaei, Ghodratollah; Modabbernia, Shirin; Bakhtiary, Esmaeel

    2015-01-01

    Background: Jaw bones might be potential locations for different lesions. Differences in prevalence and the type of lesions can help in designing and programming prevention procedures in health care centers. Objectives: The aim of the present study was to evaluate the prevalence of intraosseous lesions in the jaws of patients referred to diagnostic and therapeutic centers in Hamadan during 1990-2010. Patients and Methods: This cross-sectional descriptive analytical study was carried o