Crystal structure of ethyl (6-hydroxy-1-benzofuran-3-yl)acetate sesquihydrate

In the title hydrate, C12H12O4·1.5H2O, one of the water molecules in the asymmetric unit is located on a twofold rotation axis. The molecule of the benzofuran derivative is essentially planar (r.m.s. deviation for the non-H atoms = 0.021à ), with the ester group adopting a fully extended conformation. In the crystal, O-H�O hydrogen bonds between the water molecules and the hydroxy groups generate a centrosymmetric R6 6(12) ring motif. These R6 6(12) rings are fused, forming a one-dimensional motif extending along the c-axis direction

Immunological Mechanisms and Natalizumab Treatment in Multiple Sclerosis : Studies on lymphocytes, inflammatory markers and magnetic resonance spectroscopy

Background: Multiple sclerosis (MS) is a chronic inflammatory, demyelinating disease of the central nervous system (CNS), and a frequent cause of neurological disability among young adults. In addition to focal inflammatory demyelinated lesions, diffuse white matter pathology as well as a neurodegenerative component with accumulating axonal damage and gliosis have been demonstrated and contribute to MS disease characteristics. The inflammatory component is considered autoimmune and mediated by auto-reactive T lymphocytes together with other cell populations of the immune system and their respective products like cytokines and chemokines. Treatment with natalizumab, a monoclonal antibody directed against the α4β1-integrin (VLA-4), reduces migration of potential disease-promoting cells to the CNS. The efficacy of natalizumab in reducing relapses and MRI activity is evident, however associated effects on the immune response and the neurodegenerative component in MS are not clear. Methods: In total 72 MS patients were included, distributed among paper I-IV. We investigated effects associated with one-year natalizumab treatment in 31 MS patients regarding cytokine and chemokine levels in CSF and blood using multiplex bead assay analyses (paper I), as well as treatment effects on blood lymphocyte composition in 40 patients using flow cytometry, including functional assays of lymphocyte activation (paper II). Normal appearing white matter (NAWM) metabolite concentrations were assessed with proton magnetic resonance spectroscopy (1H-MRS) in 27 MS patients before and after one year of treatment (paper III). We also evaluated the balance between circulating T helper (Th) subsets in 33 MS patients using gene expression analyses of the CD4+ T cell related transcription factors in whole blood (paper IV). Results: One-year natalizumab treatment was associated with a marked decline in pro-inflammatory cytokines (IL-1β and IL-6) and chemokines (CXCL8, CXCL9, CXCL10 and CXCL11) intrathecally. Circulating plasma levels of some cytokines (GM-CSF, TNF, IL-6 and IL-10) also decreased after treatment. Natalizumab treatment was further associated with an increase in lymphocyte numbers of major populations in blood (total lymphocytes, T cells, T helper cells, cytotoxic T cells, NK cells and B cells). In addition, T cell responsiveness to recall antigens and mitogens was restored after treatment. As to 1H-MRS metabolite concentrations in NAWM, no change in levels were detected post-to pretreatment on a group level. However, correlation analyses between one-year change in metabolite levels (total creatine and total choline) and levels of pro-inflammatory IL-1β and CXCL8 showed a pattern of high magnitude correlation coefficients (r=0.43-0.67). Gene expression analyses demonstrated a systemically reduced expression of transcription factors related to immunoregulatory T cell populations (regulatory T cells and Th2) in relapsing MS compared with controls. Conclusions: Our findings support that an important mode of action of natalizumab is reducing lymphocyte extravasation, although cell-signalling effects through VLA-4 also may be operative. Correlation analyses between changes 1H-MRS metabolite concentrations and inflammatory markers possibly point towards an association between intrathecal inflammation and gliosis development in NAWM. Finally, gene expression analyses indicate a systemic defect at the mRNA level in relapsing MS, involving downregulation of beneficial CD4+ phenotypes

Treatment effects of fingolimod in multiple sclerosis: Selective changes in peripheral blood lymphocyte subsets.

BACKGROUND:Treatment with fingolimod reduces inflammation in multiple sclerosis (MS) by inhibiting lymphocyte egress from lymph nodes. We aimed to map, in detail, the alterations in peripheral blood lymphocyte subpopulations in relation to clinical outcome in MS patients treated with fingolimod. METHODS:Paired blood samples from relapsing-remitting MS patients (n = 19) were collected before and after one year of treatment with fingolimod (0.5 mg/day). Absolute counts and relative proportions of a broad set of T- B- and NK-cell subsets were analyzed by flow cytometry. Blood samples from 18 healthy controls were used for baseline comparisons. RESULTS:Treatment with fingolimod markedly decreased the absolute numbers of all major lymphocyte subsets, except for NK cells. The reduction was most pronounced within the T helper (Th) and B cell populations (p<0.001). By phenotyping differentiation status of T cells, dramatic reductions within the naïve and central memory (CM) cell populations were found (p<0.001), while a less pronounced reduction was observed among effector memory (EM) cells (p<0.001). The numbers of regulatory T cells (Tregs) were also decreased (p<0.001), but to a lesser extent than other T cell populations, resulting in a relative preservation of Tregs with a memory phenotype (p = 0.002). CONCLUSIONS:Our results confirm that fingolimod therapy markedly reduces lymphocyte counts in peripheral blood of MS patients. Subgroup analysis of T cells showed that naïve and CM Th cells were the most profoundly affected and that memory Tregs were relatively preserved

Correspondence address:

Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal flui

Dimethyl fumarate treatment in relapsing remitting MS changes the inflammatory CSF protein profile by a prominent decrease in T-helper 1 immunity

Background: Dimethyl fumarate (DMF) is a common treatment for multiple sclerosis (MS), but its mechanisms of action are not fully understood. Targeted proteomics offers insights into effects of DMF and biomarkers for treatment responses.Objectives: To assess influence of DMF on inflammation-and neuro-associated proteins in plasma and cerebro-spinal fluid (CSF) in MS and to reveal biomarkers for predicting treatment responses.Methods: Using the high-sensitivity and high-specificity method of proximity extension assay (PEA), we measured 182 inflammation-and neuro-associated proteins in paired plasma (n = 28) and CSF (n = 12) samples before and after one year of DMF treatment. Disease activity was evaluated through clinical examination and MRI. Statistical tests, network analysis, and regression models were used.Results: Several proteins including T-helper 1 (Th1)-associated proteins (CXCL10, CXCL11, granzyme A, IL-12p70, lymphotoxin-alpha) were consistently decreased in CSF, while IL-7 was increased after one year of treatment. The changes in plasma protein levels did not follow the same pattern as in CSF. Logistic regression models identified potential biomarker candidates (including plexins and neurotrophins) for prediction of treatment response.Conclusions: DMF treatment induced prominent changes in CSF proteins, consistently reducing Th1-associated pro-inflammatory proteins. Neurodegeneration-related CSF proteins were able to predict treatment response. Protein biomarkers hold promise for personalized medicine.Funding Agencies|Swedish Research Council [2018-02776, 2021-03092]; European Union [813863]; MIIC (Medical Infection and Inflammation Center, Linkoping University and Region Ostergotland, Sweden); ALF Grants, Region Ostergotland, Sweden</p

Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal fluid

Natalizumab exerts impressive therapeutic effects in patients with multiple sclerosis (MS). The proposed main mode of action is reducing transmigration of leukocytes into the CNS, but other immunological effects may also be operative. Cytokines and chemokines are involved in the regulation of inflammatory responses and may reflect the disease process in MS. The objective of this study was to evaluate the effects of natalizumab treatment on cytokine and chemokine profiles systemically and intrathecally in multiple sclerosis. We used luminex to analyse a panel of cytokines (IL-1 beta, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, TNF-alpha, IFN-gamma, GM-CSF) and chemokines (CXCL9, CXCL10, CXCL11, CCL17, CCL22) in blood and cerebrospinal fluid (CSF) from 31 patients with relapsing MS before and after one year of natalizumab treatment. There was a marked decline in CSF levels of cytokines and chemokines, thus including pro-inflammatory cytokines (IL-1 beta, IL-6 and IL-8) as well as chemokines associated with both Th1 (CXCL9, CXCL10, CXCL11) and Th2 (CCL22). Circulating plasma levels of some cytokines (GM-CSF, TNF-alpha, IL-6 and IL-10) also decreased after one year of treatment. This is the first study to show that natalizumab treatment is associated with a global decline in cytokine and chemokine levels at a protein level. This finding was most pronounced in CSF, in line with the reduced transmigration of cells into CNS, whereas reduction in plasma levels indicates other possible mechanisms of natalizumab treatment.Original Publication: Johan Mellergård, Måns Edström, Magnus Vrethem, Jan Ernerudh and Charlotte Dahle, Natalizumab treatment in multiple sclerosis: marked decline of chemokines and cytokines in cerebrospinal fluid, 2010, MULTIPLE SCLEROSIS, (16), 2, 208-217. http://dx.doi.org/10.1177/1352458509355068 Copyright: SAGE Publications http://www.uk.sagepub.com/</p

An Increase in B cell and Cytotoxic NK cell Proportions and Increased T cell Responsiveness in Blood of Natalizumab-treated Multiple Sclerosis Patients

Background Changes in the peripheral blood lymphocyte composition probably both mediate and reflect the effects of natalizumab treatment in multiple sclerosis, with implications for treatment benefits and risks. Objectives To assess changes in circulating lymphocyte subpopulation compositions and T-cell responses during natalizumab treatment. Material and methods A broad panel of markers for blood lymphocyte populations, including states of activation and co-stimulation as well as T-cell responses to recall antigens and mitogens, was assessed by flow cytometry in 40 patients with relapsing multiple sclerosis before and after one-year natalizumab treatment. Results Absolute numbers of all major populations of lymphocytes increased after treatment, most markedly for NK- and B-cells. The fraction of both memory and presumed regulatory B-cell subsets increased, as did CD3-CD56dim cytotoxic NK-cells, whereas CD3-CD56bright regulatory NK-cells decreased. Treatment was also associated with a restored T-cell responsiveness to recall antigens and mitogens. Conclusions Our data confirms that natalizumab treatment increases the number of lymphocytes in blood, likely mirroring the expression of VLA-4 being highest on NK- and B-cells. This supports reduction of lymphocyte extravasation as a main mode of action, although the differential composition of lymphocyte subpopulations suggests cell-signalling effects may also be operative. The systemic increase in T-cell responsiveness reflects the increase in numbers, and while augmenting anti-infectious responses systemically, localized responses become correspondingly decreased

http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-102974 Increased B Cell and Cytotoxic NK Cell Proportions and Increased T Cell Responsiveness in Blood of Natalizumab-Treated Multiple Sclerosis Patients

Background: Changes in the blood lymphocyte composition probably both mediate and reflect the effects of natalizumab treatment in multiple sclerosis, with implications for treatment benefits and risks. Methods: A broad panel of markers for lymphocyte populations, including states of activation and co-stimulation, as well as functional T cell responses to recall antigens and mitogens, were assessed by flow cytometry in 40 patients with relapsing multiple sclerosis before and after one-year natalizumab treatment. Results: Absolute numbers of all major lymphocyte populations increased after treatment, most markedly for NK an

Non-Bacterial Thrombotic Endocarditis : A Presentation of COVID-19

The SARS-CoV-2 virus is a newly emergent pathogen first identified in Wuhan, China, and responsible for the COVID-19 global pandemic. In this case report we describe a manifestation of non-bacterial thrombotic endocarditis with continuous peripheral embolization in a COVID-19-positive patient. The patient responded well to high-dose LMWH treatment with cessation of the embolic process

Phenotypic characteristics of CD19+ B cell and CD3^-CD56+ NK cell subpopulations in MS patients before and after one year of natalizumab treatment (pre and post, respectively).

<p>p<0.01 is considered statistically significant. Comparisons are pairwise. Bars show mean values, whiskers denote SD.</p