The genomic and transcriptional landscape of primary central nervous system lymphoma

Primary lymphomas of the central nervous system (PCNSL) are mainly diffuse large B-cell lymphomas (DLBCLs) confined to the central nervous system (CNS). Molecular drivers of PCNSL have not been fully elucidated. Here, we profile and compare the whole-genome and transcriptome landscape of 51 CNS lymphomas (CNSL) to 39 follicular lymphoma and 36 DLBCL cases outside the CNS. We find recurrent mutations in JAK-STAT, NFkB, and B-cell receptor signaling pathways, including hallmark mutations in MYD88 L265P (67%) and CD79B (63%), and CDKN2A deletions (83%). PCNSLs exhibit significantly more focal deletions of HLA-D (6p21) locus as a potential mechanism of immune evasion. Mutational signatures correlating with DNA replication and mitosis are significantly enriched in PCNSL. TERT gene expression is significantly higher in PCNSL compared to activated B-cell (ABC)-DLBCL. Transcriptome analysis clearly distinguishes PCNSL and systemic DLBCL into distinct molecular subtypes. Epstein-Barr virus (EBV)+ CNSL cases lack recurrent mutational hotspots apart from IG and HLA-DRB loci. We show that PCNSL can be clearly distinguished from DLBCL, having distinct expression profiles, IG expression and translocation patterns, as well as specific combinations of genetic alterations

Extracellular Matrix Remodeling in the Retina and Optic Nerve of a Novel Glaucoma Mouse Model

Glaucoma is a neurodegenerative disease that is characterized by the loss of retinal ganglion cells (RGC) and optic nerve fibers. Increased age and intraocular pressure (IOP) elevation are the main risk factors for developing glaucoma. Mice that are heterozygous (HET) for the mega-karyocyte protein tyrosine phosphatase 2 (PTP-Meg2) show chronic and progressive IOP elevation, severe RGCs loss, and optic nerve damage, and represent a valuable model for IOP-dependent primary open-angle glaucoma (POAG). Previously, evidence accumulated suggesting that glaucomatous neurodegeneration is associated with the extensive remodeling of extracellular matrix (ECM) molecules. Unfortunately, little is known about the exact ECM changes in the glaucomatous retina and optic nerve. Hence, the goal of the present study was to comparatively explore ECM alterations in glaucomatous PTP-Meg2 HET and control wild type (WT) mice. Due to their potential relevance in glaucomatous neurodegeneration, we specifically analyzed the expression pattern of the ECM glycoproteins fibronectin, laminin, tenascin-C, and tenascin-R as well as the proteoglycans aggrecan, brevican, and members of the receptor protein tyrosine phosphatase beta/zeta (RPTPβ/ζ) family. The analyses were carried out in the retina and optic nerve of glaucomatous PTP-Meg2 HET and WT mice using quantitative real-time PCR (RT-qPCR), immunohistochemistry, and Western blot. Interestingly, we observed increased fibronectin and laminin levels in the glaucomatous HET retina and optic nerve compared to the WT group. RT-qPCR analyses of the laminins α4, β2 and γ3 showed an altered isoform-specific regulation in the HET retina and optic nerve. In addition, an upregulation of tenascin-C and its interaction partner RPTPβ/ζ/phosphacan was found in glaucomatous tissue. However, comparable protein and mRNA levels for tenascin-R as well as aggrecan and brevican were observed in both groups. Overall, our study showed a remodeling of various ECM components in the glaucomatous retina and optic nerve of PTP-Meg2 HET mice. This dysregulation could be responsible for pathological processes such as neovascularization, inflammation, and reactive gliosis in glaucomatous neurodegeneration

Association between Oral Health-Related Quality of Life in People with Rare Diseases and Their Satisfaction with Dental Care in the Health System of the Federal Republic of Germany

Background: The aim of this study was to examine the current dental care situation in Germany from the perspective of those affected by a rare disease, especially concerning their satisfaction with the German dental health care system, and thus assess the relationship between their perspective and their oral health-related quality of life (OHRQoL). Methods: A questionnaire regarding their experiences with the dental assistance and the health care system, such as the OHIP-14, was sent to the member associations of the organization of self-help groups for rare diseases ACHSE e.V. The correlation between OHIP-14 values and patient’s perspective was statistically analyzed by the non-parametric Tau de Kendall test (p < 0.05). Results: There was a statistically significant correlation between the OHIP score and the patient’s perspective regarding dental assistance and health care system (p < 0.05). For those surveyed who were satisfied with the support of the health care system, an average OHIP score of 8.54 ± 10.45 points (range: 0–48) was determined. The group that did not feel sufficiently supported by the health care system had an average OHIP score of 16.07 ± 13.43 points (range: 0–56). Discussion: The majority of respondents with rare diseases are dissatisfied with the German health care system and its support with regard to dental care

Oral Health-Related Quality of Life in People with Rare Hereditary Connective Tissue Disorders: Marfan Syndrome

Background: The aim of this study was to analyze data on oral health-related quality of life (OHRQoL) in people with Marfan syndrome and to obtain information on the diagnosis period, orthodontic treatment, and oral symptoms. Methods: A questionnaire was developed consisting of open questions and the standardized German version of the OHIP-14 (Oral Health Impact Profile) questionnaire for the evaluation of OHRQoL. The age of diagnosis, time period from the first signs of the disease to diagnosis, and OHIP-values were compared between male and female participants. Additionally, the OHIP-values between participants who were orthodontically treated and those who were not treated were assessed. The statistical analysis was performed using the Mann⁻Whitney test with a significance level at p = 0.05. Results: A total of 51 questionnaires were evaluated, which included 34 female and 17 male participants. Overall, 84% of respondents reported oral symptoms. Male respondents tended to diagnose the disease earlier (p = 0.00), with a smaller period between the first symptom and the diagnosis (p = 0.04). The OHIP-14 score was gender-neutral at 13.65 ± 13.53 points. Conclusion: In Marfan syndrome, many years (12.01 ± 11.61) elapse between the onset of first symptoms and correct diagnosis of the disease. People with Marfan syndrome have a worse OHRQoL than do the general population

Extracellular matrix remodeling in the retina and optic nerve of a novel glaucoma mouse model

Glaucoma is a neurodegenerative disease that is characterized by the loss of retinal ganglion cells (RGC) and optic nerve fibers. Increased age and intraocular pressure (IOP) elevation are the main risk factors for developing glaucoma. Mice that are heterozygous (HET) for the mega-karyocyte protein tyrosine phosphatase 2 (PTP-Meg2) show chronic and progressive IOP elevation, severe RGCs loss, and optic nerve damage, and represent a valuable model for IOP-dependent primary open-angle glaucoma (POAG). Previously, evidence accumulated suggesting that glaucomatous neurodegeneration is associated with the extensive remodeling of extracellular matrix (ECM) molecules. Unfortunately, little is known about the exact ECM changes in the glaucomatous retina and optic nerve. Hence, the goal of the present study was to comparatively explore ECM alterations in glaucomatous PTP-Meg2 HET and control wild type (WT) mice. Due to their potential relevance in glaucomatous neurodegeneration, we specifically analyzed the expression pattern of the ECM glycoproteins fibronectin, laminin, tenascin-C, and tenascin-R as well as the proteoglycans aggrecan, brevican, and members of the receptor protein tyrosine phosphatase beta/zeta (RPTP$\beta$/$\zeta$) family. The analyses were carried out in the retina and optic nerve of glaucomatous PTP-Meg2 HET and WT mice using quantitative real-time PCR (RT-qPCR), immunohistochemistry, and Western blot. Interestingly, we observed increased fibronectin and laminin levels in the glaucomatous HET retina and optic nerve compared to the WT group. RT-qPCR analyses of the laminins $\alpha$4, $\beta$2 and $\gamma$3 showed an altered isoform-specific regulation in the HET retina and optic nerve. In addition, an upregulation of tenascin-C and its interaction partner RPTP$\beta$/$\zeta$/phosphacan was found in glaucomatous tissue. However, comparable protein and mRNA levels for tenascin-R as well as aggrecan and brevican were observed in both groups. Overall, our study showed a remodeling of various ECM components in the glaucomatous retina and optic nerve of PTP-Meg2 HET mice. This dysregulation could be responsible for pathological processes such as neovascularization, inflammation, and reactive gliosis in glaucomatous neurodegeneration

Challenges and opportunities for Zimbabwean exports arising from environmental requirements in Europe

Umweltfragen spielen aus zwei Gruenden eine immer bedeutendere Rolle im internationalen Geschaeft: (1) In den Industrielaendern existiert eine staendig wachsende Anzahl von umweltfreundlichen bzw. -vertraeglichen Produktstandards, die sowohl von den heimischen Produzenten als auch von Importeuren zu beruecksichtigen sind; (2) Die Nachfrage der Verbraucher nach umweltvertraeglichen und gesunden Produkten steigt staendig. Die Studie untersucht diesen Trend und die daraus resultierenden Probleme am Beispiel Simbabwes und seinen Export von Textilien, Lederwaren, Holz und Nahrungsmitteln nach Europa. Die Ergebnisse der Studie zeigen, dass die Unternehmen dieser Branchen die Anforderungen und Vorstellungen der Europaeer noch weitgehend als koloniale Zumutungen erleben und sich ein Bewusstsein nur langsam entwickelt, dass hier ertragreiche Alternativen und Entwicklungsmoeglichkeiten liegen. (pre)German title: Herausforderungen und Gelegenheiten fuer den Export Zimbabwes durch Umweltanforderungen in EuropaAvailable from UuStB Koeln(38)-980106448 / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Optic Nerve Degeneration after Retinal Ischemia/Reperfusion in a Rodent Model

Retinal ischemia is a common pathomechanism in many ocular disorders such as age-related macular degeneration (AMD), diabetic retinopathy, glaucoma or retinal vascular occlusion. Several studies demonstrated that ischemia/reperfusion (I/R) leads to morphological and functional changes of different retinal cell types. However, little is known about the ischemic effects on the optic nerve. The goal of this study was to evaluate these effects. Ischemia was induced by raising the intraocular pressure (IOP) in one eye of rats to 140 mmHg for 1 h followed by natural reperfusion. After 21 days, histological as well as quantitative real-time PCR (qRT-PCR) analyses of optic nerves were performed. Ischemic optic nerves showed an infiltration of cells and also degeneration with signs of demyelination. Furthermore, a migration and an activation of microglia could be observed histologically as well as on mRNA level. In regard to macroglia, a trend toward gliosis could be noted after ischemia induction by vimentin staining. Additionally, an up-regulation of glial fibrillary acidic protein (GFAP) mRNA was found in ischemic optic nerves. Counting of oligodendrocyte transcription factor 2 positive (Olig2+) cells revealed a decrease of oligodendrocytes in the ischemic group. Also, myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) mRNA expression was down-regulated after induction of I/R. On immunohistological level, a decrease of MOG was detectable in ischemic optic nerves as well. In addition, SMI-32 stained neurofilaments of longitudinal optic nerve sections showed a strong structural damage of the ischemic optic nerves in comparison to controls. Consequently, retinal ischemia impacts optic nerve degeneration. These findings could help to better understand the course of destruction in the optic nerve after an ischemic insult. Especially for therapeutic studies, the optic nerve is important because of its susceptibility to be damaged as a result to retinal ischemic injury and also its connecting function between the eye and the brain. So, future drug screenings should target not only the retina, but also the functionality and structure of the optic nerve. In the future, these results could lead to the development of new therapeutic strategies for treatment of ischemic injury

Transfer of the Experimental Autoimmune Glaucoma Model from Rats to Mice—New Options to Study Glaucoma Disease

Studies have suggested an involvement of the immune system in glaucoma. Hence, a rat experimental autoimmune glaucoma model (EAG) was developed to investigate the role of the immune response. Here, we transferred this model into mice. Either 0.8 mg/mL of the optic nerve antigen homogenate (ONA; ONA 0.8) or 1.0 mg/mL ONA (ONA 1.0) were injected in 129/Sv mice. Controls received sodium chloride. Before and 6 weeks after immunization, the intraocular pressure (IOP) was measured. At 6 weeks, retinal neurons, glia cells, and synapses were analyzed via immunohistology and quantitative real-time PCR (RT-qPCR). Additionally, optic nerves were examined. The IOP stayed in the normal physiological range throughout the study (p > 0.05). A significant reduction of retinal ganglion cells (RGCs) was noted in both immunized groups (p < 0.001). Remodeling of glutamatergic and GABAergic synapses was seen in ONA 1.0 retinas. Furthermore, both ONA groups revealed optic nerve degeneration and macrogliosis (all: p < 0.001). An increase of activated microglia was noted in ONA retinas and optic nerves (p < 0.05). Both ONA concentrations led to RGC loss and optic nerve degeneration. Therefore, the EAG model was successfully transferred from rats to mice. In further studies, transgenic knockout mice can be used to investigate the pathomechanisms of glaucoma more precisely