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Article: Holistic, Long-Term Management of People with Relapsing Multiple Sclerosis with Cladribine Tablets: Expert Opinion from France.

Ciron, Jonathan / Bourre, Bertrand / Castelnovo, Giovanni / Guennoc, Anne Marie / De Sèze, Jérôme / Ben-Amor, Ali Frederic / Savarin, Carine / Vermersch, Patrick

Neurology and therapy

2024

Abstract: Cladribine tablets (CladT) has been available for therapeutic use in France since March 2021 for the management of highly active relapsing multiple sclerosis (RMS). This high-efficacy disease-modifying therapy (DMT) acts as an immune reconstitution ... ...

Abstract	Cladribine tablets (CladT) has been available for therapeutic use in France since March 2021 for the management of highly active relapsing multiple sclerosis (RMS). This high-efficacy disease-modifying therapy (DMT) acts as an immune reconstitution therapy. In contrast to most high-efficacy DMTs, which act via continuous immunosuppression, two short courses of oral treatment with CladT at the beginning of years 1 and 2 of treatment provide long-term control of MS disease activity in responders to treatment, without the need for any further pharmacological treatment for several years. Although the labelling for CladT does not provide guidance beyond the initial treatment courses, real-world data on the therapeutic use of CladT from registries of previous clinical trial participants and patients treated in routine practice indicate that MS disease activity is controlled for a period of years beyond this time for a substantial proportion of patients. Moreover, this clinical experience has provided useful information on how to initiate and manage treatment with CladT. In this article we, a group of expert neurologists from France, provide recommendations on the initiation of CladT in DMT-naïve patients, how to switch from existing DMTs to CladT for patients with continuing MS disease activity, how to manage patients during the first 2 years of treatment and finally, how to manage patients with or without MS disease activity in years 3, 4 and beyond after initiating treatment with CladT. We believe that optimisation of the use of CladT beyond its initial courses of treatment will maximise the benefits of this treatment, especially early in the course of MS when suppression of focal inflammation in the CNS is a clinical priority to limit MS disease progression.
Language	English
Publishing date	2024-03-15
Publishing country	New Zealand
Document type	Journal Article ; Review
ISSN	2193-8253
ISSN	2193-8253
DOI	10.1007/s40120-024-00589-7
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Article ; Online: 3.0 T prostate MRI: Visual assessment of 2D and 3D T2-weighted imaging sequences using PI-QUAL score.

Brillat-Savarin, Nina / Wu, Carine / Aupin, Laurène / Thoumin, Camille / Hamzaoui, Dimitri / Renard-Penna, Raphaële

European journal of radiology

2023 Volume 166, Page(s) 110974

Abstract: Purpose: Comparing 2D and 3D T2 weighted sequences in terms of image quality in 3.0 T MRI with readers of varied experiences, using PI-QUAL inspired criteria.: Methods: 91 male patients with suspected prostate cancer (PCa) underwent diagnostic ... ...

Abstract	Purpose: Comparing 2D and 3D T2 weighted sequences in terms of image quality in 3.0 T MRI with readers of varied experiences, using PI-QUAL inspired criteria. Methods: 91 male patients with suspected prostate cancer (PCa) underwent diagnostic prostate MRI on a 3.0 T MR system using a 32-channel phased-array torso coil before prostate biopsy. MRI protocol included 3D T2w images, axial 2D T2w images, axial diffusion-weighted images (DWI) with the corresponding ADC apparent diffusion coefficient maps, and axial dynamic contrast enhanced images. 3D T2w and 2D T2w imaging were compared by 4 radiologists using a Likert scale for image quality (overall anatomy, delineation of capsule, seminal vesicles, ejaculatory ducts, sphincter muscle, artifacts), tumor delimitation and conspicuity. Results: No significant differences in terms of overall quality between 3D and 2D T2w images were found. However 2D T2w demonstrated higher rating than 3D T2w images as for the image quality of the external capsule, sphincter muscle and ejaculatory ducts delineation (p < 0.05). Conclusion: 3D T2w sequence can't replace 2D T2w sequence, despite good quality images but it remains more prone to artifacts. Quality of 2D T2w sequences was substantially superior to 3D sequences for delineation of key structures as external capsule, sphincter muscle. The use of PI-QUAL criteria allows reproducible analysis of the quality of T2 weighted images.
MeSH term(s)	Humans ; Male ; Prostate/diagnostic imaging ; Prostate/pathology ; Magnetic Resonance Imaging/methods ; Diffusion Magnetic Resonance Imaging/methods ; Imaging, Three-Dimensional/methods ; Prostatic Neoplasms/pathology
Language	English
Publishing date	2023-07-12
Publishing country	Ireland
Document type	Journal Article
ZDB-ID	138815-0
ISSN	1872-7727 ; 0720-048X
ISSN (online)	1872-7727
ISSN	0720-048X
DOI	10.1016/j.ejrad.2023.110974
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Article: Correction: Expert Narrative Review of the Safety of Cladribine Tablets for the Management of Relapsing Multiple Sclerosis.

Clavelou, Pierre / Castelnovo, Giovanni / Pourcher, Valérie / De Sèze, Jerome / Vermersch, Patrick / Ben-Amor, Ali-Frederic / Savarin, Carine / Defer, Gilles

Neurology and therapy

2023 Volume 13, Issue 1, Page(s) 255–256

Language	English
Publishing date	2023-11-19
Publishing country	New Zealand
Document type	Published Erratum
ISSN	2193-8253
ISSN	2193-8253
DOI	10.1007/s40120-023-00564-8
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Article ; Online: Fine Tuning the Cytokine Storm by IFN and IL-10 Following Neurotropic Coronavirus Encephalomyelitis.

Savarin, Carine / Bergmann, Cornelia C

Frontiers in immunology

2018 Volume 9, Page(s) 3022

Abstract: The central nervous system (CNS) is vulnerable to several viral infections including herpes viruses, arboviruses and HIV to name a few. While a rapid and effective immune response is essential to limit viral spread and mortality, this anti-viral response ...

Abstract	The central nervous system (CNS) is vulnerable to several viral infections including herpes viruses, arboviruses and HIV to name a few. While a rapid and effective immune response is essential to limit viral spread and mortality, this anti-viral response needs to be tightly regulated in order to limit immune mediated tissue damage. This balance between effective virus control with limited pathology is especially important due to the highly specialized functions and limited regenerative capacity of neurons, which can be targets of direct virus cytolysis or bystander damage. CNS infection with the neurotropic strain of mouse hepatitis virus (MHV) induces an acute encephalomyelitis associated with focal areas of demyelination, which is sustained during viral persistence. Both innate and adaptive immune cells work in coordination to control virus replication. While type I interferons are essential to limit virus spread associated with early mortality, perforin, and interferon-γ promote further virus clearance in astrocytes/microglia and oligodendrocytes, respectively. Effective control of virus replication is nonetheless associated with tissue damage, characterized by demyelinating lesions. Interestingly, the anti-inflammatory cytokine IL-10 limits expansion of tissue lesions during chronic infection without affecting viral persistence. Thus, effective coordination of pro- and anti-inflammatory cytokines is essential during MHV induced encephalomyelitis in order to protect the host against viral infection at a limited cost.
MeSH term(s)	Animals ; Central Nervous System/immunology ; Coronavirus Infections/immunology ; Coronavirus Infections/virology ; Disease Models, Animal ; Encephalomyelitis/immunology ; Encephalomyelitis/virology ; Host-Pathogen Interactions/immunology ; Interferons/immunology ; Interferons/metabolism ; Interleukin-10/immunology ; Interleukin-10/metabolism ; Mice ; Murine hepatitis virus/immunology ; Perforin/immunology ; Perforin/metabolism
Chemical Substances	IL10 protein, mouse ; Perforin (126465-35-8) ; Interleukin-10 (130068-27-8) ; Interferons (9008-11-1)
Keywords	covid19
Language	English
Publishing date	2018-12-20
Publishing country	Switzerland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.03022
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Article: Expert Narrative Review of the Safety of Cladribine Tablets for the Management of Relapsing Multiple Sclerosis.

Clavelou, Pierre / Castelnovo, Giovanni / Pourcher, Valérie / De Sèze, Jerome / Vermersch, Patrick / Ben-Amor, Ali-Frederic / Savarin, Carine / Defer, Gilles

Neurology and therapy

2023 Volume 12, Issue 5, Page(s) 1457–1476

Abstract: Cladribine tablets (CladT) is a highly active oral disease-modifying therapy (DMT) for the management of relapsing multiple sclerosis (RMS). CladT acts as an immune reconstitution therapy, in that two short courses of treatment 1 year apart have been ... ...

Abstract	Cladribine tablets (CladT) is a highly active oral disease-modifying therapy (DMT) for the management of relapsing multiple sclerosis (RMS). CladT acts as an immune reconstitution therapy, in that two short courses of treatment 1 year apart have been shown to suppress disease activity for a prolonged period in most patients, without need for continued DMT. Each course of CladT induces a profound reduction in B lymphocytes that recovers over months, and serious lymphopenia (Grade 3-4) is uncommon. Smaller reductions in levels of T lymphocytes occur slightly later: on average, these remain within the normal range and repopulate progressively. A larger effect occurs on CD8 vs. CD4 cells. Reactivation of latent or opportunistic infections (e.g. varicella zoster, tuberculosis) is mostly associated with very low lymphocyte counts (< 200/mm
Language	English
Publishing date	2023-06-29
Publishing country	New Zealand
Document type	Journal Article ; Review
ISSN	2193-8253
ISSN	2193-8253
DOI	10.1007/s40120-023-00496-3
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Article ; Online: Viral-induced suppression of self-reactive T cells: Lessons from neurotropic coronavirus-induced demyelination.

Savarin, Carine / Bergmann, Cornelia C

Journal of neuroimmunology

2017 Volume 308, Page(s) 12–16

Abstract: Genetic and environmental factors, i.e. infections, have been proposed to contribute to disease induction and relapsing events in multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS). While research has mainly ... ...

Abstract	Genetic and environmental factors, i.e. infections, have been proposed to contribute to disease induction and relapsing events in multiple sclerosis (MS), an autoimmune demyelinating disease of the central nervous system (CNS). While research has mainly focused on virus associated autoimmune activation, less is known about prevention of autoimmunity, especially following resolving infections associated with CNS tissue damage. This review discusses novel insights on control of self-reactive (SR) T cells activated during neurotropic coronavirus-induced demyelination. A new concept is introduced that SR T cells can be dampened by distinct regulatory mechanisms in the periphery and the CNS, thereby preventing autoimmune disease.
MeSH term(s)	Animals ; Autoimmunity ; CD4-Positive T-Lymphocytes/physiology ; Coronavirus/pathogenicity ; Coronavirus Infections/complications ; Demyelinating Diseases/immunology ; Demyelinating Diseases/pathology ; Demyelinating Diseases/virology ; Humans ; Lymphocyte Activation
Keywords	covid19
Language	English
Publishing date	2017-01-11
Publishing country	Netherlands
Document type	Journal Article ; Review ; Research Support, N.I.H., Extramural
ZDB-ID	8335-5
ISSN	1872-8421 ; 0165-5728
ISSN (online)	1872-8421
ISSN	0165-5728
DOI	10.1016/j.jneuroim.2017.01.003
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Jg. 1995 - 2021: Lesesall (1.OG)
ab Jg. 2022: Lesesaal (EG)

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Article ; Online: Trem2 deficiency impairs recovery and phagocytosis and dysregulates myeloid gene expression during virus-induced demyelination.

Hwang, Mihyun / Savarin, Carine / Kim, Jihye / Powers, Jennifer / Towne, Natasha / Oh, Hyunsuk / Bergmann, Cornelia C

Journal of neuroinflammation

2022 Volume 19, Issue 1, Page(s) 267

Abstract: Background: Triggering receptor expressed on myeloid cells 2 (Trem2) plays a protective role in neurodegenerative diseases. By contrast, Trem2 functions can exacerbate tissue damage during respiratory viral or liver infections. We, therefore, ... ...

Abstract	Background: Triggering receptor expressed on myeloid cells 2 (Trem2) plays a protective role in neurodegenerative diseases. By contrast, Trem2 functions can exacerbate tissue damage during respiratory viral or liver infections. We, therefore, investigated the role of Trem2 in a viral encephalomyelitis model associated with prominent Th1 mediated antiviral immunity leading to demyelination. Methods: Wild-type (WT) and Trem2 deficient (Trem2 Results: BMDM recruited to SCs in response to infection highly upregulated Trem2 mRNA compared to microglia coincident with viral control. Trem2 deficiency did not alter disease onset or severity, but impaired clinical recovery after onset of demyelination. Disease progression in Trem2 Conclusions: Trem2 deficiency during viral-induced demyelination dysregulates expression of other select genes regulating phagocytic pathways and lipid metabolism, with distinct effects on microglia and BMDM. The ultimate failure to remove damaged myelin is reminiscent of toxin or autoimmune cell-induced demyelination models and supports that Trem2 function is regulated by sensing tissue damage including a dysregulated lipid environment in very distinct inflammatory environments.
MeSH term(s)	Animals ; Mice ; Brain/metabolism ; Phagocytosis/genetics ; Microglia/metabolism ; Demyelinating Diseases/chemically induced ; Disease Progression ; Gene Expression ; Membrane Glycoproteins/genetics ; Membrane Glycoproteins/metabolism ; Receptors, Immunologic/genetics ; Receptors, Immunologic/metabolism
Chemical Substances	Trem2 protein, mouse ; Membrane Glycoproteins ; Receptors, Immunologic
Language	English
Publishing date	2022-11-04
Publishing country	England
Document type	Journal Article
ZDB-ID	2156455-3
ISSN	1742-2094 ; 1742-2094
ISSN (online)	1742-2094
ISSN	1742-2094
DOI	10.1186/s12974-022-02629-1
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Article: Distinct Gene Profiles of Bone Marrow-Derived Macrophages and Microglia During Neurotropic Coronavirus-Induced Demyelination.

Savarin, Carine / Dutta, Ranjan / Bergmann, Cornelia C

Frontiers in immunology

2018 Volume 9, Page(s) 1325

Abstract: Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal loss. Demyelinating lesions are associated with infiltrating T lymphocytes, bone marrow-derived macrophages (BMDM), ... ...

Abstract	Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterized by demyelination and axonal loss. Demyelinating lesions are associated with infiltrating T lymphocytes, bone marrow-derived macrophages (BMDM), and activated resident microglia. Tissue damage is thought to be mediated by T cell produced cytokines and chemokines, which activate microglia and/or BMDM to both strip myelin and produce toxic factors, ultimately damaging axons and promoting disability. However, the relative contributions of BMDM and microglia to demyelinating pathology are unclear, as their identification in MS tissue is difficult due to similar morphology and indistinguishable surface markers when activated. The CD4 T cell-induced autoimmune murine model of MS, experimental autoimmune encephalitis (EAE), in which BMDM are essential for demyelination, has revealed pathogenic and repair-promoting phenotypes associated with BMDM and microglia, respectively. Using a murine model of demyelination induced by a gliatropic coronavirus, in which BMDM are redundant for demyelination, we herein characterize gene expression profiles of BMDM versus microglia associated with demyelination. While gene expression in CNS infiltrating BMDM was upregulated early following infection and subsequently sustained, microglia expressed a more dynamic gene profile with extensive mRNA upregulation coinciding with peak demyelination after viral control. This delayed microglia response comprised a highly pro-inflammatory and phagocytic profile. Furthermore, while BMDM exhibited a mixed phenotype of M1 and M2 markers, microglia repressed the vast majority of M2-markers. Overall, these data support a pro-inflammatory and pathogenic role of microglia temporally remote from viral control, whereas BMDM retained their gene expression profile independent of the changing environment. As demyelination is caused by multifactorial insults, our results highlight the plasticity of microglia in responding to distinct inflammatory settings, which may be relevant for MS pathogenesis.
Keywords	covid19
Language	English
Publishing date	2018
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2018.01325
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Article ; Online: Blockade of sustained tumor necrosis factor in a transgenic model of progressive autoimmune encephalomyelitis limits oligodendrocyte apoptosis and promotes oligodendrocyte maturation.

Valentin-Torres, Alice / Savarin, Carine / Barnett, Joslyn / Bergmann, Cornelia C

Journal of neuroinflammation

2018 Volume 15, Issue 1, Page(s) 121

Abstract: Background: Tumor necrosis factor (TNF) is associated with several neurodegenerative disorders including multiple sclerosis (MS). Although TNF-targeted therapies have been largely unsuccessful in MS, recent preclinical data suggests selective soluble ... ...

Abstract	Background: Tumor necrosis factor (TNF) is associated with several neurodegenerative disorders including multiple sclerosis (MS). Although TNF-targeted therapies have been largely unsuccessful in MS, recent preclinical data suggests selective soluble TNF inhibition can promote remyelination. This has renewed interest in regulation of TNF signaling in demyelinating disease, especially given the limited treatment options for progressive MS. Using a mouse model of progressive MS, this study evaluates the effects of sustained TNF on oligodendrocyte (OLG) apoptosis and OLG precursor cell (OPC) differentiation. Methods: Induction of experimental autoimmune encephalomyelitis (EAE) in transgenic mice expressing a dominant-negative interferon-γ receptor under the human glial fibrillary acidic protein promoter (GFAPγR1Δ) causes severe non-remitting disease associated with sustained TNF. Therapeutic effects in GFAPγR1Δ mice treated with anti-TNF compared to control antibody during acute EAE were evaluated by assessing demyelinating lesion size, remyelination, OLG apoptosis, and OPC differentiation. Results: More severe and enlarged demyelinating lesions in GFAPγR1Δ compared to wild-type (WT) mice were associated with increased OLG apoptosis and reduced differentiated CC1 Conclusion: Our data implicate that IFNγ signaling to astrocytes is essential to limit a detrimental positive feedback loop of TNF and ET-1 production, which increases OLG apoptosis and impairs OPC differentiation. Interference of this cycle by TNF blockade promotes repair independent of TNFR2 and supports selective TNF targeting to mitigate progressive forms of MS.
MeSH term(s)	Animals ; Antibodies/therapeutic use ; Apoptosis/genetics ; Calcium-Binding Proteins/metabolism ; Cytokines/metabolism ; Disease Models, Animal ; Encephalomyelitis, Autoimmune, Experimental/drug therapy ; Encephalomyelitis, Autoimmune, Experimental/etiology ; Encephalomyelitis, Autoimmune, Experimental/genetics ; Encephalomyelitis, Autoimmune, Experimental/pathology ; Freund's Adjuvant/toxicity ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/genetics ; Green Fluorescent Proteins/genetics ; Green Fluorescent Proteins/metabolism ; Humans ; Interferon-gamma/genetics ; Interferon-gamma/metabolism ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Microfilament Proteins/metabolism ; Mutation/genetics ; Nerve Tissue Proteins/metabolism ; Oligodendroglia/pathology ; Tumor Necrosis Factor-alpha/immunology ; Tumor Necrosis Factor-alpha/metabolism ; beta-Galactosidase/metabolism
Chemical Substances	Aif1 protein, mouse ; Antibodies ; Calcium-Binding Proteins ; Cytokines ; IFNG protein, mouse ; Microfilament Proteins ; Nerve Tissue Proteins ; Tumor Necrosis Factor-alpha ; Green Fluorescent Proteins (147336-22-9) ; Interferon-gamma (82115-62-6) ; Freund's Adjuvant (9007-81-2) ; beta-Galactosidase (EC 3.2.1.23)
Language	English
Publishing date	2018-04-24
Publishing country	England
Document type	Journal Article
ISSN	1742-2094
ISSN (online)	1742-2094
DOI	10.1186/s12974-018-1164-y
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Article: Differential Regulation of Self-reactive CD4

Savarin, Carine / Bergmann, Cornelia C / Hinton, David R / Stohlman, Stephen A

Frontiers in immunology

2016 Volume 7, Page(s) 370

Abstract: Viral infections have long been implicated as triggers of autoimmune diseases, including multiple sclerosis (MS), a central nervous system (CNS) inflammatory demyelinating disorder. Epitope spreading, molecular mimicry, cryptic antigen, and bystander ... ...

Abstract	Viral infections have long been implicated as triggers of autoimmune diseases, including multiple sclerosis (MS), a central nervous system (CNS) inflammatory demyelinating disorder. Epitope spreading, molecular mimicry, cryptic antigen, and bystander activation have been implicated as mechanisms responsible for activating self-reactive (SR) immune cells, ultimately leading to organ-specific autoimmune disease. Taking advantage of coronavirus JHM strain of mouse hepatitis virus (JHMV)-induced demyelination, this study demonstrates that the host also mounts counteractive measures to specifically limit expansion of endogenous SR T cells. In this model, immune-mediated demyelination is associated with induction of SR T cells after viral control. However, their decline during persisting infection, despite ongoing demyelination, suggests an active control mechanism. Antigen-specific IL-10-secreting CD4
Keywords	covid19
Language	English
Publishing date	2016
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2016.00370
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