There is concern about the threat that nanoplastics (NPs) may pose to both wildlife and humans. This thesis explores the mechanisms of toxicity of polystyrene nanoparticles (PS-NPs) in chicken... Show moreThere is concern about the threat that nanoplastics (NPs) may pose to both wildlife and humans. This thesis explores the mechanisms of toxicity of polystyrene nanoparticles (PS-NPs) in chicken embryo. In Chapter 1, I review the literature on MPs and NPs, and their potential risks to humans and animals. In Chapter 2, I show that the exposure of chicken embryos to PS-NPs produces malformations in the neural tube, eyes, and tail. Chapter 3 details the heart malformations caused by PS-NPs. I propose that the mechanisms of PS-NP toxicity include the selective binding of PS-NPs to neural crest cells, leading to the death and impaired migration of those cells (Chapter 4). My data support this model, indicating that most of the malformations I observe are in organs that depend for their normal development on neural crest cells. My findings are a matter of concern given the large and growing burden of nanoplastics in the environment, and the fact that they are being considered as drug-delivery agents in nanomedicine. They also suggest that NPs may pose a potential health risk to the developing embryo. Further work is needed to determine how PS-NPs become distributed in the body. Show less
Jia, Y.; Wang, M.; Lambers, P.H.; Andel, T.R. van 2024
Objectives To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis.Methods Two phase 3,... Show moreObjectives To investigate the efficacy and safety of otilimab, an antigranulocyte-macrophage colony-stimulating factor antibody, in patients with active rheumatoid arthritis.Methods Two phase 3, double-blind randomised controlled trials including patients with inadequate responses to methotrexate (contRAst 1) or conventional synthetic/biologic disease-modifying antirheumatic drugs (cs/bDMARDs; contRAst 2). Patients received background csDMARDs. Through a testing hierarchy, subcutaneous otilimab (90/150 mg once weekly) was compared with placebo for week 12 endpoints (after which, patients receiving placebo switched to active interventions) or oral tofacitinib (5 mg two times per day) for week 24 endpoints. Primary endpoint: proportion of patients achieving an American College of Rheumatology response ≥20% (ACR20) at week 12.Results The intention-to-treat populations comprised 1537 (contRAst 1) and 1625 (contRAst 2) patients. Primary endpoint: proportions of ACR20 responders were statistically significantly greater with otilimab 90 mg and 150 mg vs placebo in contRAst 1 (54.7% (p=0.0023) and 50.9% (p=0.0362) vs 41.7%) and contRAst 2 (54.9% (p<0.0001) and 54.5% (p<0.0001) vs 32.5%). Secondary endpoints: in both trials, compared with placebo, otilimab increased the proportion of Clinical Disease Activity Index (CDAI) low disease activity (LDA) responders (not significant for otilimab 150 mg in contRAst 1), and reduced Health Assessment Questionnaire-Disability Index (HAQ-DI) scores. Benefits with tofacitinib were consistently greater than with otilimab across multiple endpoints. Safety outcomes were similar across treatment groups.Conclusions Although otilimab demonstrated superiority to placebo in ACR20, CDAI LDA and HAQ-DI, improved symptoms, and had an acceptable safety profile, it was inferior to tofacitinib. Show less
Wang, M.; Rücklin, M.; Poelmann, R.E.; Mooij, C.L. de; Fokkema, M.; Lamers, G.E.M.; ... ; Richardson, M.K. 2023
Nanomaterials are widespread in the human environment as pollutants, and are being actively developed for use in human medicine. We have investigated how the size and dose of polystyrene... Show moreNanomaterials are widespread in the human environment as pollutants, and are being actively developed for use in human medicine. We have investigated how the size and dose of polystyrene nanoparticles affects malformations in chicken embryos, and have characterized the mechanisms by which they interfere with normal development. We find that nanoplastics can cross the embryonic gut wall. When injected into the vitelline vein, nanoplastics become distributed in the circulation to multiple organs. We find that the exposure of embryos to polystyrene nanoparticles produces malformations that are far more serious and extensive than has been previously reported. These malformations include major congenital heart defects that impair cardiac function. We show that the mechanism of toxicity is the selective binding of polystyrene nanoplastics nanoparticles to neural crest cells, leading to the death and impaired migration of those cells. Consistent with our new model, most of the malformations seen in this study are in organs that depend for their normal development on neural crest cells. These results are a matter of concern given the large and growing burden of nanoplastics in the environment. Our findings suggest that nanoplastics may pose a health risk to the developing embryo. Show less
Ji, Y.; De Deyn, G.B.; Zhang, N.; Xu, H.; Wang, M.; Bezemer, T.M. 2023
Panax notoginseng (PN) is a Chinese medicinal herb that is traditionally used to treat inflammation and immune-related diseases. Its major active constituents are saponins, the types and levels of... Show morePanax notoginseng (PN) is a Chinese medicinal herb that is traditionally used to treat inflammation and immune-related diseases. Its major active constituents are saponins, the types and levels of which can be changed in the process of steaming. These differences in saponins are causally relevant to the differences in the therapeutic efficacies of raw and steamed PN. In this study, we have prepared the extracts of steamed PN (SPNE) with 70% ethanol and investigated their immunomodulatory effect using a zebrafish tail-fin amputation model. A fingerprint-effect relationship analysis was performed to uncover active constituents of SPNE samples related to the inhibitory effect on neutrophil number. The results showed that SPNE significantly inhibited the neutrophil number at the amputation site of zebrafish larvae. And SPNE extracts steamed at higher temperatures and for longer time periods showed a stronger inhibitory effect. Ginsenosides Rh-1, Rk(3), Rh-4, 20(S)-Rg(3), and 20(R)-Rg(3), of which the levels were increased along with the duration of steaming, were found to be the major active constituents contributing to the neutrophil-inhibiting effect of SPNE. By additionally investigating the number of neutrophils in the entire tail of zebrafish larvae and performing TUNEL assays, we found that the decreased number of neutrophils at the amputation site was due to both the inhibition of their migration and apoptosis-inducing effects of the ginsenosides in SPNE on neutrophils. Among them, Rh-1 and 20(R)-Rg(3) did not affect the number of neutrophils at the entire tail, suggesting that they only inhibit the migration of neutrophils. In contrast, ginsenosides Rk(3), Rh-4, 20(S)-Rg(3), and SPNE did not only inhibit the migration of neutrophils but also promoted neutrophilic cell death. In conclusion, this study sheds light on how SPNE, in particular the ginsenosides it contains, plays a role in immune modulation. Show less
Arends, S.; Drenthen, J.; Bergh, P. van den; Franssen, H.; Hadden, R.D.M.; Islam, B.; ... ; Cornblath, D.R. 2022
Objective: To describe the heterogeneity of electrodiagnostic (EDx) studies in Guillain-Barre syndrome (GBS) patients collected as part of the International GBS Outcome Study (IGOS). Methods:... Show moreObjective: To describe the heterogeneity of electrodiagnostic (EDx) studies in Guillain-Barre syndrome (GBS) patients collected as part of the International GBS Outcome Study (IGOS). Methods: Prospectively collected clinical and EDx data were available in 957 IGOS patients from 115 centers. Only the first EDx study was included in the current analysis. Results: Median timing of the EDx study was 7 days (interquartile range 4-11) from symptom onset. Methodology varied between centers, countries and regions. Reference values from the responding 103 centers were derived locally in 49%, from publications in 37% and from a combination of these in the remaining 15%. Amplitude measurement in the EDx studies (baseline-to-peak or peak-to-peak) differed from the way this was done in the reference values, in 22% of motor and 39% of sensory conduction. There was marked variability in both motor and sensory reference values, although only a few outliers accounted for this. Conclusions: Our study showed extensive variation in the clinical practice of EDx in GBS patients among IGOS centers across the regions. Significance: Besides EDx variation in GBS patients participating in IGOS, this diversity is likely to be present in other neuromuscular disorders and centers. This underlines the need for standardization of EDx in future multinational GBS studies.(c) 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Show less
Background and aim: Chinese Materia Medica (CMM) is subject to changes over time. Investigating changes in botanical ingredients, applications, plant parts used as well as name changes over time,... Show moreBackground and aim: Chinese Materia Medica (CMM) is subject to changes over time. Investigating changes in botanical ingredients, applications, plant parts used as well as name changes over time, contribute to the understanding of the history and development of CMM. Materials and methods: This study compares four historic collections of CMM, located in Europe, compiled between 1700 and the late 19th century, with a list of contemporary CMM marketed in Europe. Results: More than 1700 specimens within these five collections. The dominant families are Fabaceae (5.3-7.2%) and Asteraceae (4.1-5.7%), while half of the medicinal parts are represented by roots or rhizomes and fruits and/or seeds. Their importance has been stable in a time span of 300 years. The proportion of animal and mineral drugs gradually decreased over time. 14 plant species appeared in all five collections. A total of 47 species are shared between the three more recent collections and the modern trade list. Among these common species, most medicinal parts remain unchanged, but for several species the used plant parts changed or new medicinal plant parts appeared. All common species have unanimously been used in ancient classical TCM formulae and/or Chinese patent medicines. Conclusions: Over more than 300 years, the main body of CMM has hardly changed, with regard to plant taxa and plant parts used. The most prominent changes are related to conservation issues of threatened species, health safety and the discovery of new pharmacological applications of well-known species. Analyzing physical specimens from historic CMM collections complements literature-based research. (c) 2021 Center for Food and Biomolecules, National Taiwan University. Production and hosting by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/ licenses/by-nc-nd/4.0/). Show less
Jia, Y.; Lei, L.; Luo, X.; Zhao, Z.; Wang, M.; Andel, T.R. van 2020
Most psycholinguistic models of speech production agree on an earlier semantic processing stage and a later word-form encoding stage. Using a logographic language, Mandarin Chinese, Zhang and... Show moreMost psycholinguistic models of speech production agree on an earlier semantic processing stage and a later word-form encoding stage. Using a logographic language, Mandarin Chinese, Zhang and Weekes [2009. Orthographic facilitation effects on spoken word production: Evidence from Chinese. Language and Cognitive Processes, 24(7–8), 1082–1096. https://doi.org/10.1080/ 01690960802042133] reported an early effect of orthography in a picture-word-interference study and suggested orthography affects speech production via a lexical-semantic pathway at an early stage. This early orthographic effect without co-occurrence of phonological effect, however, was not replicated [Zhao, La Heij, & Schiller, 2012. Orthographic and phonological facilitation in speech production: New evidence from picture naming in Chinese. Acta Psychologica, 139(2), 272–280. https://doi.org/10.1016/j.actpsy.2011.12.001]. The present study aimed to dissociate further the semantic and phonological representations from orthography by using simplex Chinese characters. The results of Experiment 1 and 2 revealed an orthographic effect but only at a similar point in time as the phonological effect, both of which followed the semantic effect. Our results thus raise further doubts about the role of orthography at the conceptual level of speech planning and lend new evidence to a two-step model of speech production. Show less
The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that... Show moreThe cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder. Show less
Xiong, Y.; Zhang, Z.; Zhang, Y.; Cui, X.; Yang, Y.; Duijn, A. van; ... ; Wang, C. 2020
Background The benefits of surgery for symptomatic spinal metastases have been demonstrated, largely based on series of patients undergoing debulking and instrumentation operations. However, as... Show moreBackground The benefits of surgery for symptomatic spinal metastases have been demonstrated, largely based on series of patients undergoing debulking and instrumentation operations. However, as cancer treatments improve and overall survival lengths increase, the incidence of recurrent spinal cord compression after debulking may increase. The aim of the current paper is to document the postoperative evolution of neurological function, pain, and quality of life following debulking and instrumentation in the Global Spine Tumor Study Group (GSTSG) database. Methods The GSTSG database is a prospective multicenter data repository of consecutive patients that underwent surgery for a symptomatic spinal metastasis. For the present analysis, patients were selected from the database that underwent decompressive debulking surgery with instrumentation. Preoperative tumor type, Tomita and Tokuhashi scores, EQ-5D, Frankel, Karnofsky, and postoperative complications, survival, EQ-5D, Frankel, Karnofsky, and pain numeric rating scores (NRS) at 3, 6, 12, and 24 months were analyzed. Results A total of 914 patients underwent decompressive debulking surgery with instrumentation and had documented follow-up until death or until 2 years post surgery. Median preoperative Karnofsky performance index was 70. A total of 656 patients (71.8%) had visceral metastases and 490 (53.6%) had extraspinal bone metastases. Tomita scores were evenly distributed above (49.1%) and below or equal to 5 (50.9%), and Tokuhashi scores almost evenly distributed below or equal to 8 (46.3%) and above 8 (53.7%). Overall, 12-month survival after surgery was 56.3%. The surgery resulted in EQ-5D health status improvement and NRS pain reduction that was maintained throughout follow-up. Frankel scores improved at first follow-up in 25.0% of patients, but by 12 months neurological deterioration was observed in 18.8%. Conclusion We found that palliative debulking and instrumentation surgeries were performed throughout all Tomita and Tokuhashi categories. These surgeries reduced pain scores and improved quality of life up to 2 years after surgery. After initial improvement, a proportion of patients experienced neurological deterioration by 1 year, but the majority of patients remained stable. Show less
Jia, Y.; Sun, M.; Shi, Y.; Zhu, Z.; Wijk, E. van; Wijk, R. van; ... ; Wang, M. 2020
