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  • 1
    Online Resource
    Online Resource
    Intravenous methadone causes acute toxic and delayed inflammatory encephalopathy with persistent neurocognitive impairments
    Springer Science and Business Media LLC ; 2021
    In:  BMC Neurology Vol. 21, No. 1 ( 2021-12)
    Details
    In: BMC Neurology, Springer Science and Business Media LLC, Vol. 21, No. 1 ( 2021-12)
    Abstract: The mu-opioid agonist methadone is administered orally and used in opioid detoxification and in the treatment of moderate-to-severe pain. Acute oral methadone–use and –abuse have been associated with inflammatory and toxic central nervous system (CNS) damage in some cases and cognitive deficits can develop in long-term methadone users. In contrast, reports of intravenous methadone adverse effects are rare. Case presentation Here, we report a patient who developed acute bilateral hearing loss, ataxia and paraparesis subsequently to intravenous methadone-abuse. While the patient gradually recovered from these deficits, widespread magnetic resonance imaging changes progressed and delayed-onset encephalopathy with signs of cortical dysfunction persisted. This was associated with changes in the composition of monocyte and natural killer cell subsets in the cerebrospinal fluid. Conclusion This case suggests a potential bi-phasic primary toxic and secondary inflammatory CNS damage induced by intravenous methadone.
    Type of Medium: Online Resource
    ISSN: 1471-2377
    URL: Article
    DOI: 10.1186/s12883-021-02108-9
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2041347-6
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  • 2
    Online Resource
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    Blockade of inhibitory killer cell immunoglobulin-like receptors and IL-2 triggering reverses the functional hypoactivity of tumor-derived NK-cells in glioblastomas
    Springer Science and Business Media LLC ; 2022
    In:  Scientific Reports Vol. 12, No. 1 ( 2022-04-26)
    Details
    In: Scientific Reports, Springer Science and Business Media LLC, Vol. 12, No. 1 ( 2022-04-26)
    Abstract: Killer cell immunoglobulin-like receptors (KIRs) comprise a group of highly polymorphic inhibitory receptors which are specific for classical HLA class-I molecules. Peripheral blood and freshly prepared tumor cell suspensions (n = 60) as well as control samples (n = 32) were investigated for the distribution, phenotype, and functional relevance of CD158ab/KIR2DL1,-2/3 expressing NK-cells in glioblastoma (GBM) patients. We found that GBM were scarcely infiltrated by NK-cells that preferentially expressed CD158ab/KIR2DL1,-2/3 as inhibitory receptors, displayed reduced levels of the activating receptors CD335/NKp46, CD226/DNAM-1, CD159c/NKG2C, and showed diminished capacity to produce IFN-γ and perforin. Functional hypoactivity of GBM-derived NK-cells persisted despite IL-2 preactivation. Blockade with a specific KIR2DL-1,2/3 monoclonal antibody reversed NK-cell inhibition and significantly enhanced degranulation and IFN-γ production of IL-2 preactivated NK-cells in the presence of primary GBM cells and HLA-C expressing but not HLA class-I deficient K562 cells. Additional analysis revealed that significant amounts of IL-2 could be produced by tumor-derived CD4 + and CD8 + CD45RA - memory T-cells after combined anti-CD3/anti-CD28 stimulation. Our data indicate that both blockade of inhibitory KIR and IL-2 triggering of tumor-derived NK-cells are necessary to enhance NK-cell responsiveness in GBM.
    Type of Medium: Online Resource
    ISSN: 2045-2322
    URL: Article
    DOI: 10.1038/s41598-022-10680-4
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2615211-3
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  • 3
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    Online Resource
    Alemtuzumab-induced immune phenotype and repertoire changes: implications for secondary autoimmunity
    Oxford University Press (OUP) ; 2022
    In:  Brain Vol. 145, No. 5 ( 2022-06-03), p. 1711-1725
    Details
    In: Brain, Oxford University Press (OUP), Vol. 145, No. 5 ( 2022-06-03), p. 1711-1725
    Abstract: Alemtuzumab is a monoclonal antibody that causes rapid depletion of CD52-expressing immune cells. It has proven to be highly efficacious in active relapsing–remitting multiple sclerosis; however, the high risk of secondary autoimmune disorders has greatly complicated its use. Thus, deeper insight into the pathophysiology of secondary autoimmunity and potential biomarkers is urgently needed. The most critical time points in the decision-making process for alemtuzumab therapy are before or at Month 12, where the ability to identify secondary autoimmunity risk would be instrumental. Therefore, we investigated components of blood and CSF of up to 106 multiple sclerosis patients before and after alemtuzumab treatment focusing on those critical time points. Consistent with previous reports, deep flow cytometric immune-cell profiling (n = 30) demonstrated major effects on adaptive rather than innate immunity, which favoured regulatory immune cell subsets within the repopulation. The longitudinally studied CSF compartment (n = 18) mainly mirrored the immunological effects observed in the periphery. Alemtuzumab-induced changes including increased numbers of naïve CD4+ T cells and B cells as well as a clonal renewal of CD4+ T- and B-cell repertoires were partly reminiscent of haematopoietic stem cell transplantation; in contrast, thymopoiesis was reduced and clonal renewal of T-cell repertoires after alemtuzumab was incomplete. Stratification for secondary autoimmunity did not show clear immununological cellular or proteomic traits or signatures associated with secondary autoimmunity. However, a restricted T-cell repertoire with hyperexpanded T-cell clones at baseline, which persisted and demonstrated further expansion at Month 12 by homeostatic proliferation, identified patients developing secondary autoimmune disorders (n = 7 without secondary autoimmunity versus n = 5 with secondary autoimmunity). Those processes were followed by an expansion of memory B-cell clones irrespective of persistence, which we detected shortly after the diagnosis of secondary autoimmune disease. In conclusion, our data demonstrate that (i) peripheral immunological alterations following alemtuzumab are mirrored by longitudinal changes in the CSF; (ii) incomplete T-cell repertoire renewal and reduced thymopoiesis contribute to a proautoimmune state after alemtuzumab; (iii) proteomics and surface immunological phenotyping do not identify patients at risk for secondary autoimmune disorders; (iv) homeostatic proliferation with disparate dynamics of clonal T- and B-cell expansions are associated with secondary autoimmunity; and (v) hyperexpanded T-cell clones at baseline and Month 12 may be used as a biomarker for the risk of alemtuzumab-induced autoimmunity.
    Type of Medium: Online Resource
    ISSN: 0006-8950 , 1460-2156
    URL: Article
    DOI: 10.1093/brain/awac064
    RVK:
    XA 10000
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2022
    detail.hit.zdb_id: 1474117-9
    SSG: 12
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  • 4
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    The Innate Immune Response Characterizes Posterior Reversible Encephalopathy Syndrome
    Springer Science and Business Media LLC ; 2021
    In:  Journal of Clinical Immunology Vol. 41, No. 6 ( 2021-08), p. 1229-1240
    Details
    In: Journal of Clinical Immunology, Springer Science and Business Media LLC, Vol. 41, No. 6 ( 2021-08), p. 1229-1240
    Abstract: While posterior reversible encephalopathy syndrome (PRES) is often characterized by an inflammatory cerebrospinal-fluid (CSF) profile, knowledge of immune cell patterns in PRES is lacking. Thus, we retrospectively characterized CSF and peripheral blood (PB) from 15 PRES patients, which we analyzed by multidimensional flow cytometry (FC). Results were compared to 72 controls, as well as to 9 patients with progressive multifocal leukoencephalopathy (PML, as a relevant differential diagnosis) and 15 multiple sclerosis patients (MS, as a classical neuroinflammatory disorder), respectively. Total protein level in CSF from PRES patients was elevated compared to that in controls, but not to MS and PML. In-depth FC analysis revealed no differences for adaptive immune cells (B cells, plasma cells, CD4 + , and CD8 + T cells) in PB or CSF of PRES compared to controls. In contrast, we observed alterations of the adaptive immune response in CSF of PML and MS compared to PRES, indicating that the adaptive immune response is not a driver of disease in PRES. Indeed, PRES was characterized by an innate immune response with CD14 ++ /CD16 + (intermediate) monocytes elevated in PB and CSF, while CD14 ++ /CD16 − (classical) monocytes were decreased in PB from PRES patients as compared to controls. Levels of CD14 ++ /CD16 + monocytes correlated with the duration of hospital stay as a surrogate marker for disease severity in PRES patients. Our findings argue for a role of innate rather than adaptive immunity in the pathophysiology of PRES. The observed shift in monocyte subsets might provide valuable diagnostic clues for the clinical management of these patients.
    Type of Medium: Online Resource
    ISSN: 0271-9142 , 1573-2592
    URL: Article
    DOI: 10.1007/s10875-021-01033-3
    RVK:
    XA 10000
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2016755-6
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  • 5
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    Increased Intrathecal B and Plasma Cells in Patients With Anti-IgLON5 Disease : A Case Series
    Ovid Technologies (Wolters Kluwer Health) ; 2022
    In:  Neurology - Neuroimmunology Neuroinflammation Vol. 9, No. 2 ( 2022-03), p. 00-
    Details
    In: Neurology - Neuroimmunology Neuroinflammation, Ovid Technologies (Wolters Kluwer Health), Vol. 9, No. 2 ( 2022-03), p. 00-
    Abstract: Despite detection of autoantibodies, anti-IgLON5 disease was historically considered a tau-associated neurodegenerative disease, with limited treatment options and detrimental consequences for the patients. Observations in increasing case numbers hint toward underlying inflammatory mechanisms that, early detection provided, open a valuable window of opportunity for therapeutic intervention. We aimed to further substantiate this view by studying the CSF of patients with anti-IgLON5. Methods We identified 11 patients with anti-IgLON5 from our database and compared clinical, MRI, and CSF findings with a cohort of 20 patients with progressive supranuclear palsy (PSP) (as a noninflammatory tauopathy) and 22 patients with functional neurologic disorder. Results Patients with anti-IgLON5 show inflammatory changes in routine CSF analysis, an increase in B-lymphocyte frequency, and the presence of plasma cells in comparison to the PSP-control group and functional neurologic disease controls. Patients with intrathecal plasma cells showed a clinical response to rituximab. Discussion Our findings indicate the importance of inflammatory mechanisms, in particular in early and acute anti-IgLON5 cases, which may support the use of immune-suppressive treatments in these cases. The main limitation of the study is the small number of cases due to the rarity of the disease.
    Type of Medium: Online Resource
    ISSN: 2332-7812
    URL: Article
    DOI: 10.1212/NXI.0000000000001137
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2022
    detail.hit.zdb_id: 2767740-0
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  • 6
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    Immunoadsorption versus double-dose methylprednisolone in refractory multiple sclerosis relapses
    Springer Science and Business Media LLC ; 2022
    In:  Journal of Neuroinflammation Vol. 19, No. 1 ( 2022-09-07)
    Details
    In: Journal of Neuroinflammation, Springer Science and Business Media LLC, Vol. 19, No. 1 ( 2022-09-07)
    Abstract: Intravenous methylprednisolone is the standard treatment for a multiple sclerosis relapse; however, this fails to improve symptoms in up to one quarter of patients. Immunoadsorption is an accepted treatment for refractory relapses, but prospective comparator-controlled studies are missing. Methods In this observational study, patients with steroid-refractory acute multiple sclerosis relapses receiving either six courses of tryptophan-immunoadsorption or double-dose methylprednisolone therapy were analysed. Outcomes were evaluated at discharge and three months later. Immune profiling of blood lymphocytes and proteomic analysis were performed by multi-parameter flow cytometry and Olink analysis, respectively (NCT04450030). Results 42 patients were enrolled (methylprednisolone: 26 patients; immunoadsorption: 16 patients). For determination of the primary outcome, treatment response was stratified according to relative function system score changes (“full/best” vs. “average” vs. “worse/none”). Upon discharge, the adjusted odds ratio for any treatment response (“full/best” + ”average” vs. “worse/none”) was 10.697 favouring immunoadsorption ( p  = 0.005 compared to methylprednisolone). At follow-up, the adjusted odds ratio for the best treatment response (“full/best” vs. “average” + ”worse/none”) was 103.236 favouring IA patients ( p  = 0.001 compared to methylprednisolone). Similar results were observed regarding evoked potentials and quality of life outcomes, as well as serum neurofilament light-chain levels. Flow cytometry revealed a profound reduction of B cell subsets following immunoadsorption, which was closely correlated to clinical outcomes, whereas methylprednisolone had a minimal effect on B cell populations. Immunoadsorption treatment skewed the blood cytokine network, reduced levels of B cell-related cytokines and reduced immunoglobulin levels as well as levels of certain coagulation factors. Interpretation Immunoadsorption demonstrated favourable outcomes compared to double-dose methylprednisolone. Outcome differences were significant at discharge and follow-up. Further analyses identified modulation of B cell function as a potential mechanism of action for immunoadsorption, as reduction of B cell subsets correlated with clinical improvement.
    Type of Medium: Online Resource
    ISSN: 1742-2094
    URL: Article
    DOI: 10.1186/s12974-022-02583-y
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2156455-3
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  • 7
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    Characterization of Extracranial Giant Cell Arteritis with Intracranial Involvement and its Rapidly Progressive Subtype
    Wiley ; 2021
    In:  Annals of Neurology Vol. 90, No. 1 ( 2021-07), p. 118-129
    Details
    In: Annals of Neurology, Wiley, Vol. 90, No. 1 ( 2021-07), p. 118-129
    Abstract: The objective of this study was to characterize patients with extracranial giant cell arteritis with intracranial involvement. Methods In a multicenter retrospective study, we included 31 patients with systemic giant cell arteritis (GCA) with intracranial involvement. Clinical characteristics, pattern of arterial involvement, and cytokine profiles were assessed. Patients with GCA without intracranial involvement (n = 17), and with intracranial atherosclerosis (n = 25) served as controls. Results Erythrocyte sedimentation rate (ESR) was elevated in 18 patients (69.2%) with and in 16 patients (100%) without intracranial involvement ( p  = 0.02). Headache was complained by 15 patients (50.0%) with and 13 patients (76.5%) without intracranial involvement ( p  = 0.03). Posterior circulation arteries were affected in 26 patients (83.9%), anterior circulation arteries in 17 patients (54.8%), and both territories in 12 patients (38.7%). Patients with GCA had vertebral artery stenosis proximal and, in contrast, patients with atherosclerosis distal to the origin of posterior inferior cerebellar artery (PICA). Among patients with GCA with intracranial involvement, 11 patients (37.9%) had a rapid progressive disease course characterized by short‐term recurrent ischemic events. The median modified Rankin Scale (mRS) at follow‐up in these patients was 4 (interquartile range [IQR] = 2.0–6.0) and 4 patients (36.4%) died. Vessel wall expression of IL‐6 and IL‐17 was significantly increased in patients with rapid progressive course. Interpretation Typical characteristics of GCA, headache, and an elevated ESR, are frequently absent in patients with intracranial involvement. However, differentiation of intracranial GCA from atherosclerosis can be facilitated by the typical pattern of vertebral artery stenosis. About one‐third of patients with intracranial GCA had a rapid progressive course with poor outcome. IL‐17 and IL‐6 may represent potential future treatment targets. ANN NEUROL 2021;90:118–129
    Type of Medium: Online Resource
    ISSN: 0364-5134 , 1531-8249
    URL: Issue
    URL: Article
    DOI: 10.1002/ana.v90.1
    DOI: 10.1002/ana.26101
    Language: English
    Publisher: Wiley
    Publication Date: 2021
    detail.hit.zdb_id: 2037912-2
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  • 8
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    Resident human dermal γδT-cells operate as stress-sentinels: Lessons from the hair follicle
    Elsevier BV ; 2021
    In:  Journal of Autoimmunity Vol. 124 ( 2021-11), p. 102711-
    Details
    In: Journal of Autoimmunity, Elsevier BV, Vol. 124 ( 2021-11), p. 102711-
    Type of Medium: Online Resource
    ISSN: 0896-8411
    URL: Article
    DOI: 10.1016/j.jaut.2021.102711
    RVK:
    XA 52099
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 1468989-3
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  • 9
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    Natural Killer Cells Are Present in Rag1−/− Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke
    Springer Science and Business Media LLC ; 2022
    In:  Translational Stroke Research Vol. 13, No. 1 ( 2022-02), p. 197-211
    Details
    In: Translational Stroke Research, Springer Science and Business Media LLC, Vol. 13, No. 1 ( 2022-02), p. 197-211
    Abstract: Rag1 −/− mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1 −/− mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1 null IL2rg null (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1 −/− and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1 −/− NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1 −/− were comparable in number and function to those in WT mice. Rag1 −/− mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1 −/− controls. Our results indicate that NK cells from Rag1 −/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.
    Type of Medium: Online Resource
    ISSN: 1868-4483 , 1868-601X
    URL: Article
    DOI: 10.1007/s12975-021-00923-3
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
    detail.hit.zdb_id: 2541897-X
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  • 10
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    Pro-inflammatory Vδ1+T-cells infiltrates are present in and around the hair bulbs of non-lesional and lesional alopecia areata hair follicles
    Elsevier BV ; 2020
    In:  Journal of Dermatological Science Vol. 100, No. 2 ( 2020-11), p. 129-138
    Details
    In: Journal of Dermatological Science, Elsevier BV, Vol. 100, No. 2 ( 2020-11), p. 129-138
    Type of Medium: Online Resource
    ISSN: 0923-1811
    URL: Article
    DOI: 10.1016/j.jdermsci.2020.09.001
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2020
    detail.hit.zdb_id: 2026237-1
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