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Background: This preliminary retrospective cohort study investigates the potential additive prophylactic effect of erenumab, a fully human monoclonal antibody that blocks the calcitonin gene-related peptide receptor, in combination with ongoing onabotulinumtoxin A (onaBoNT-A) treatment in patients suffering from chronic migraine., Methods: The study included 218 patients and investigated the effects of adding erenumab to the existing treatment regimen. The primary outcome was the MIDAS (Migraine Disability Assessment) score assessed 3 months after the introduction of erenumab., Results: The results indicated a significant improvement of the MIDAS score, suggesting a reduction in migraine-related disability following the addition of erenumab to onaBoNT-A. In the inter group comparison, dual therapy showed a significantly greater reduction of the MIDAS when compared to a switch from onaBoNT-A to erenumab monotherapy, but not compared to initiation of onaBoNT-A monotherapy. It is hypothesized that the observed additive effects are due to the independent modes of action of erenumab and onabotulinumtoxin A., Conclusion: This study suggests that the combination of erenumab with onaBoNT-A may offer an improved approach for the treatment of chronic migraine in selected patients. However, the results highlight the need for prospective, controlled studies to validate these findings and determine the optimal combination of treatments tailored to the individual patient., Competing Interests: TK has received travel grants from Merck, Abbvie, Ipsen, and Merz, all outside the submitted work. VK has received travel grants from Abbvie, Ipsen and Merz, all outside the submitted work. SM received honoraria for lecturing and travel expenses for attending meetings and has received financial research support from Bayer, Biogen Idec, Sanofi-Aventis, Bayer Schering, Merck Serono, Novo Nordisk, Genzyme, MSD, and Teva.PA reports grants, personal fees and non-financial support from Novartis, grants, personal fees and non-financial support from Biogen, grants, personal fees and non-financial support from Merz, personal fees and non-financial support from Teva, personal fees and non-financial support from Ipsen, from Allergan, grants, personal fees and non-financial support from Celgene, personal fees from Janssen Cilag, grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from Merck, grants and personal fees from Sanofi, personal fees from Sandoz, outside the submitted work. J-IL is Review Editor for Frontiers in Neurology and has received honoraria for speaking/consultation from Boehringer Ingelheim, Daiichi Sankyo, Allergan, Abbvie, Ipsen, Novartis, Teva, Lilly, Pfizer as well as travel grants from Allergan, Abbvie, Ipsen, Merz, Bayer, Novartis, all outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Koelsche, Nikolov, Koska, Ingwersen, Jansen, Arat, Meuth, Albrecht and Lee.)

Various studies conducted on Centaurea species indicate that the relevant plant is good source of bioactive phytochemicals. In this study, in vitro studies were used to determine bioactivity properties of methanol extract of Centaurea mersinensis - endemic species in Turkey - on extensive basis. Furthermore, the interaction of target molecules, identified for breast cancer and phytochemicals in the extract, was investigated via in silico analyses to support findings received in vitro . Scutellarin, quercimeritrin, chlorogenic acid and baicalin were primary phytochemicals in the extract. Methanol extract and scutellarin had higher cytotoxic effects against MCF-7 (IC 50 =22.17 µg/mL, and IC 50 =8.25 µM, respectively), compared to other breast cancer cell lines (MDA-MB-231, SKBR-3). The extract had strong antioxidant properties and inhibited target enzymes, especially α-amylase (371.69 mg AKE/g extract). The results of molecular docking indicate that main compounds of extract show high-strength bonding to the c-Kit tyrosine among target molecules identified in breast cancer, compared to other target molecules (MMP-2, MMP-9, VEGFR2 kinase, Aurora-A kinase, HER2). The tyrosinase kinase (1T46)-Scutellarin complex showed considerable stability in 150 ns simulation as per MD findings, and it was coherent with optimal docking findings. Docking findings and HOMO-LUMO analysis results corresponds with in vitro experiments. Medicinal properties of phytochemicals, which was determined to be suitable for oral use along with ADMET, were found to be within normal limits except for their polarity properties. In conclusion, in vitro and in silico studies indicated that the relevant plant yields promising results regarding its potential to develop novel and effective medicational products.Communicated by Ramaswamy H. Sarma.

Objective: Myasthenia gravis (MG) is the most common autoimmune disorder affecting the neuromuscular junction. However, evidence shaping treatment decisions, particularly for treatment-refractory cases, is sparse. Both rituximab and eculizumab may be considered as therapeutic options for refractory MG after insufficient symptom control by standard immunosuppressive therapies., Methods: In this retrospective observational study, we included 57 rituximab-treated and 20 eculizumab-treated patients with MG to compare the efficacy of treatment agents in generalised, therapy-refractory anti-acetylcholine receptor antibody (anti-AChR-ab)-mediated MG with an observation period of 24 months. Change in the quantitative myasthenia gravis (QMG) score was defined as the primary outcome parameter. Differences between groups were determined in an optimal full propensity score matching model., Results: Both groups were comparable in terms of clinical and demographic characteristics. Eculizumab was associated with a better outcome compared with rituximab, as measured by the change of the QMG score at 12 and 24 months of treatment. Minimal manifestation of disease was more frequently achieved in eculizumab-treated patients than rituximab-treated patients at 12 and 24 months after baseline. However, the risk of myasthenic crisis (MC) was not ameliorated in either group., Interpretation: This retrospective, observational study provides the first real-world evidence supporting the use of eculizumab for the treatment of refractory, anti-AChR-ab positive MG. Nonetheless, the risk of MC remained high and prompts the need for intensified monitoring and further research effort aimed at this vulnerable patient cohort., Competing Interests: Competing interests: CN reports no conflicts of interest. CBS reports no conflicts of interest. FS received speaking honoraria from Biogen and Alexion. MP received speaker honoraria and travel/accommodation/meeting expenses from Novartis. LR-N reports no disclosures. NM reports no conflicts of interest. PM is on the Advisory Board of HealthNextGen and has equity interest in the company. His research is funded by the Bundesministerium für Bildung und Forschung (BMBF), the European Union, the Else Kröner-Fresenius Stiftung, the Volkswagen Stiftung and the Einstein Foundation Berlin. AG reports no conflicts of interest. HS reports no conflicts of interest. MS reports no conflicts of interest. BB received travel grants and/or training expenses from Bayer Vital GmbH, IpsenPharma GmbH, Norvartis, Biogen GmbH and Genzyme, as well as lecture fees from Ipsen Pharma GmbH, Alexion Pharma GmbH, Merck, Sanofi Genzyme and Roche. AT reports on conflicts of interest. TH received speaker honoraria and advisor honoraria from Alexion, Argenx, Biogen, Roche, Sanofi-Genzyme, Novartis and Hormosan. SS reports no conflicts of interest. SV reports no conflicts of interest. AM received speaker honoraria, consulting services and/or research support research from Alexion, argnx, GRIFOLS, Hormosan, Janssen, Octapharma, UCB and Vitaccess. He serves as chairman of the medical advisory board of the German Myasthenia Gravis Society. HW receives honoraria for acting as a member of Scientific Advisory Boards, Biogen, Evgen, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG and Sanofi-Aventis as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche, Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Genzyme, TEVA and WebMD Global. HW is acting as a paid consultant for AbbVie, Actelion, Biogen, IGES, Johnson & Johnson, Novartis, Roche, Sanofi-Aventis and the Swiss Multiple Sclerosis Society. His research is funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, Fresenius Foundation, the European Union, Hertie Foundation, NRW Ministry of Education and Research, Interdisciplinary Center for Clinical Studies (IZKF) Muenster and RE Children’s Foundation, Biogen, GlaxoSmithKline GmbH, Roche Pharma AG, Sanofi-Genzyme. SGM receives honoraria for lecturing, and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS and Teva. His research is funded by the German Ministry for Education and Research (BMBF), Bundesinstitut für Risikobewertung (BfR), Deutsche Forschungsgemeinschaft (DFG), Deutsche Multiple Sklerose Gesellschaft (DMSG), Else Kröner Fresenius Foundation, Gemeinsamer Bundesausschuss (G-BA), German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and Alexion, Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, HERZ Burgdorf, Merck Serono, Novartis, ONO Pharma, Roche and Teva. HW receives honoraria for acting as a member of Scientific Advisory Boards, Biogen, Evgen, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Roche Pharma AG and Sanofi-Aventis as well as speaker honoraria and travel support from Alexion, Biogen, Cognomed, F. Hoffmann-La Roche, Gemeinnützige Hertie-Stiftung, Merck Serono, Novartis, Roche Pharma AG, Genzyme, TEVA and WebMD Global. TR reports grants from German Ministry of Education, Science, Research and Technology, grants and personal fees from Sanofi-Genzyme and Alexion; personal fees from Biogen, Roche and Teva; personal fees and non-financial support from Merck Serono, outside the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Myasthenic crisis (MC) and disease exacerbation in myasthenia gravis (MG) are associated with significant lethality and continue to impose a high disease burden on affected patients. Therefore, we sought to determine potential predictors for MC and exacerbation as well as to identify factors affecting outcome., Methods: We examined a retrospective, observational cohort study of patients diagnosed with MG between 2000 and 2021 with a mean follow-up of 62.6 months after diagnosis from eight tertiary hospitals in Germany. A multivariate Cox regression model with follow-up duration as the time variable was used to determine independent risk factors for MC and disease exacerbation., Results: 815 patients diagnosed with MG according to national guidelines were included. Disease severity at diagnosis (quantitative MG score or Myasthenia Gravis Foundation of America class), the presence of thymoma and anti-muscle specific tyrosine kinase-antibodies were independent predictors of MC or disease exacerbation. Patients with minimal manifestation status 12 months after diagnosis had a lower risk of MC and disease exacerbation than those without. The timespan between diagnosis and the start of immunosuppressive therapy did not affect risk. Patients with a worse outcome of MC were older, had higher MGFA class before MC and at admission, and had lower vital capacity before and at admission. The number of comorbidities, requirement for intubation, prolonged mechanical ventilation, and MC triggered by infection were associated with worse outcome. No differences between outcomes were observed comparing treatments with IVIG (intravenous immunoglobulin) vs. plasma exchange vs. IVIG together with plasma exchange., Conclusions: MC and disease exacerbations inflict a substantial burden of disease on MG patients. Disease severity at diagnosis and antibody status predicted the occurrence of MC and disease exacerbation. Intensified monitoring with emphasis on the prevention of infectious complications could be of value to prevent uncontrolled disease in MG patients., (© 2022. The Author(s).)

Fingolimod (FTY) is a disease modifying therapy for relapsing remitting multiple sclerosis (RRMS) which can lead to severe lymphopenia requiring therapy discontinuation in order to avoid adverse events. However, this can result in severe disease reactivation occasionally presenting with tumefactive demyelinating lesions (TDLs). TDLs, which are thought to originate from a massive re-entry of activated lymphocytes into the central nervous system, are larger than 2 cm in diameter and may feature mass effect, perifocal edema, and gadolinium enhancement. In these cases, it can be challenging to exclude important differential diagnoses for TDLs such as progressive multifocal leukoencephalopathy (PML) or other opportunistic infections. Here, we present the case of a 26-year-old female patient who suffered a massive rebound with TDLs following FTY discontinuation with primarily neuropsychiatric symptoms despite persisting lymphopenia. Two cycles of seven plasmaphereses each were necessary to achieve remission and ocrelizumab was used for long-term stabilization., Competing Interests: PA received compensation for serving on Scientific Advisory Boards for Allergan, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche. He received speaker honoraria and travel support from Allergan, Bayer Vital GmbH, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, Roche and research support from Allergan, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche. OA has received grant support from Bayer, Biogen, Novartis, and Sanofi and consultancy or speaking fees and fees for serving on steering committees from Bayer, Biogen, Celgene, Medimmune, Merck, Novartis, Roche, Sanofi, and Teva. PK was supported by the Stifterverband/Novartisstiftung. SM received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research was funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology and by Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. DK received travel grants from GeNeuro and Merck, refund of congress participation fees from GeNeuro, Merck and Servier, consulting fees from Grifols, payment for lectures from Grifols, support for research projects from Teva and was funded by the Deutsche Forschungsgemeinschaft (DFG) while carrying research on human endogenous retroviruses at Cleveland Clinic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Koska, Förster, Brouzou, Arat, Albrecht, Aktas, Küry, Meuth and Kremer.)

Perceived ethnic discrimination is known to decrease minorities' life satisfaction. This research investigates the extent to which minorities' local and transnational co-ethnic social ties mitigate the negative effects of perceived discrimination on life satisfaction. Put differently, focusing on the experiences of Turkish and Moroccan minorities, we discuss whether co-ethnic social ties, both locally and transnationally embedded, can be considered as coping mechanisms against perceived discrimination. Furthermore, we investigate whether these mechanisms work differently for first- and second-generation minorities. Using Netherlands Longitudinal Life-course Study, we reveal that perceived discrimination is positively associated with local co-ethnic social ties in Netherlands which consequently predicts higher life satisfaction for both generations. Surprisingly, we also show that only among the second generation perceived discrimination is associated with stronger transnational co-ethnic social ties, but not the first generation. Having these transnational ties however are beneficial for life satisfaction of both generations. Consequently, we highlight the importance of recognizing transnational embeddedness of minorities and studying the effects transnational co-ethnic social ties on subjective well-being outcomes especially for second-generation minorities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Arat and Bilgili.)

The Marburg variant of multiple sclerosis (Marburg MS) is the most aggressive form of MS, often leading to death soon after onset. Here we describe the case of a 26-year-old Marburg MS patient presenting with severe neurological deficits requiring intensive care. In spite of more than 100 gadolinium-enhancing MRI lesions, the patient recovered almost completely upon high-dose cyclophosphamide (HiCy) rescue treatment (four consecutive days with 50 mg/kg/day, cumulative absolute dose of 14 g). Following the acute treatment, her disease was stabilized by B cell depletion using ocrelizumab. Clinical amelioration was reflected by a decrease of MRI activity and a marked decline of serum neurofilament light chain levels. HiCy rescue treatment followed by ocrelizumab as a maintenance therapy prevented permanent disability and achieved an almost complete clinical and drastic radiological improvement in this Marburg MS patient., Competing Interests: PA received compensation for serving on scientific advisory boards for Allergan, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche. He received speaker honoraria and travel support from Allergan, Bayer Vital GmbH, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche and research support from Allergan, Biogen, Celgene, Ipsen, Merck Serono, Merz Pharmaceuticals, Novartis, and Roche. OA has received grant support from Bayer, Biogen, Novartis, and Sanofi and consultancy or speaking fees and fees for serving on steering committees from Bayer, Biogen, Celgene, Medimmune, Merck, Novartis, Roche, Sanofi, and Teva. PK was supported by Stifterverband/Novartisstiftung. SM received honoraria for lecturing and travel expenses for attending meetings from Almirall, Amicus Therapeutics Germany, Bayer Health Care, Biogen, Celgene, Diamed, Genzyme, MedDay Pharmaceuticals, Merck Serono, Novartis, Novo Nordisk, ONO Pharma, Roche, Sanofi-Aventis, Chugai Pharma, QuintilesIMS, and Teva. His research was funded by the German Ministry for Education and Research (BMBF), Deutsche Forschungsgemeinschaft (DFG), Else Kröner Fresenius Foundation, German Academic Exchange Service, Hertie Foundation, Interdisciplinary Center for Clinical Studies (IZKF) Muenster, German Foundation Neurology, Almirall, Amicus Therapeutics Germany, Biogen, Diamed, Fresenius Medical Care, Genzyme, Merck Serono, Novartis, ONO Pharma, Roche, and Teva. DK received travel grants from GeNeuro and Merck, refund of congress participation fees from GeNeuro, Merck, and Servier, consulting fees from Grifols, payment for lectures from Grifols, and support for research projects from Teva and was funded by the Deutsche Forschungsgemeinschaft (DFG) while carrying research on human endogenous retroviruses at Cleveland Clinic. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Koska, Förster, Brouzou, Hatami, Arat, Aytulun, Albrecht, Aktas, Küry, Meuth and Kremer.)

A series of novel chiral 14 urea, thiourea and squaramide stereoisomers possessing carbohydrate backbones as well as amide functional groups was synthesized and characterized by their, 1 H NMR, 13 C NMR, FT-IR, HRMS, optical rotation, and melting points. Their antiproliferative activities were investigated against HeLa and PC3 cell lines. The compounds 9, 11 and 12 showed better activities at 25 μM against PC3 cell line with respect to the standard 5-fluorouracil (5-FU). Especially, the compounds 9 and 11 showed higher activities than the standard 5-FU even at low concentration (5 μM) against HeLa cell line. IC 50 results also confirm these activities. The compounds 9, 10 and 11 have the IC 50 values of 1.10 μM, 1.51 μM and 1.02 μM, respectively while 5-FU has 2.51 μM. Moreover, their cytotoxicity tests have proven that their viabilities were in between 50% and 100%., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Purpose: To investigate the effects of penile tourniquet (PT) application on bacterial adhesion to urothelium., Methods: Fifty-six rats were allocated into control group (CG), sham group (SG), PT group (PTG). No intervention was applied in CG. A 5mm-length urethral repair was performed in SG and PTG. In PTG, a 10-min duration of PT was applied during the procedure and the tissue oxygenation monitor was used to adjust the same degree of ischemia in all subjects. Samples were examined for wound healing parameters and tissue levels of inflammatory markers, eNOS, e-selectin, and ICAM-1antibodies. The adhesion of Escherichia coli to urothelium was investigated with in vitro adhesion assay., Results: Inflammation was higher and wound healing was worse in SG than CG and in PTG in comparison to CG and SG (p<0.05). The endothelial damage, as shown by eNOS expression, was significantly higher in PTG compared to CG and SG (p<0.05). The staining with ICAM-1 and e-selectin antibodies, showing increased inflammatory response to bacterial adhesion, was significantly higher in PTG compared to CG and SG (p<0.05). In vitro urethral cell proliferation was achieved only in CG and SG revealing significantly increased adhesion in SG compared to CG (p<0.05). The PT application caused endothelial corruption and prevented cell proliferation in cell culture., Conclusion: The PT application does not improve wound healing and increases bacterial adhesion molecules in penile tissue. The in vitro assays showed that PT causes severe endothelial damage and inhibits endothelial cell proliferation., (Copyright © 2017 Elsevier Inc. All rights reserved.)