Metabolische Untersuchung des Knochenstoffwechsels bei Parodontitis

Die bakteriell-induzierte inflammatorische Parodontitis nimmt vor allem durch den demografischen Wandel immer mehr an Bedeutung zu. Ziel dieser Arbeit ist es, in Hinblick auf die Entstehung und Progression einer Parodontitis die Auswirkung von fettangereicherter Ernährung unter Normalgewicht näher zu beleuchten. Es wurde eine tierexperimentelle Studie mit männlichen 4 Wochen alten C57BL/6J- Mäusen durchgeführt. Diese bekamen über 16 Wochen verschiedene fettangereicherte Diäten (gesättigte oder ungesättigte Fettsäuren, Kombination) und eine nichthochfetthaltige Kontrollernährung. Die Mäuse wurden ab Woche 10 für eine parodontale Infektion mit Porphyromonas gingivalis (P.g.) oder einem Placebo über 5 Wochen 3x wöchentlich oral infiziert. Die Tiere aller Versuchsgruppen wiesen am Versuchsende Normalgewicht auf. Es wurden an Femura immunhistochemische und histomorphometrische Analysen gemacht, um die Anzahl der Osteoklasten (OK), der Osteocalcin-posititven Zellen (OCN+) und die Knochendichte zu bestimmen und somit eine Aussage über den ernährungsassoziierten systemischen Knochenstoffwechsel treffen zu können. Die Anzahl der knochenresorbierenden Osteoklasten nahm unter Palmitinsäure (PA) nach Infektion mit P.g. zu, während die knochenaufbauenenden Osteoblasten die weniger reaktive Zellgruppe darstellte. Des Weiteren konnte gezeigt werden, dass unter der gesättigten Fettsäure PA die Knochendichte signifikant abnahm gegenüber allen anderen Ernährungen. Eine Umstellung von PA auf Ölsäure (OA) konnte diesen Effekt ausgleichen. Zusammenfassend konnte gezeigt werden, dass es einen unterschiedlichen Einfluss von gesättigten und ungesättigten Fettsäuren auf den systemischen Knochenstoffwechsel auch schon bei Normalgewicht gibt. Negative Einflüsse auf die Knochenstruktur durch die gesättigte Fettsäure PA konnten durch Umstellung auf OA wieder ausgeglichen werden

Retinal Optical Coherence Tomography in Neuromyelitis Optica

Retina; Pérdida visualRetina; Visual lossRetina; Pèrdua visualBackground and Objectives To determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-seropositive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohort after previous studies have been limited by small and heterogeneous cohorts. Methods The cross-sectional Collaborative Retrospective Study on retinal optical coherence tomography (OCT) in neuromyelitis optica collected retrospective data from 22 centers. Of 653 screened participants, we included 283 AQP4-IgG–seropositive patients with NMOSD and 72 healthy controls (HCs). Participants underwent OCT with central reading including quality control and intraretinal segmentation. The primary outcome was thickness of combined ganglion cell and inner plexiform (GCIP) layer; secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA). Results Eyes with ON (NMOSD-ON, N = 260) or without ON (NMOSD-NON, N = 241) were assessed compared with HCs (N = 136). In NMOSD-ON, GCIP layer (57.4 ± 12.2 μm) was reduced compared with HC (GCIP layer: 81.4 ± 5.7 μm, p < 0.001). GCIP layer loss (−22.7 μm) after the first ON was higher than after the next (−3.5 μm) and subsequent episodes. pRNFL observations were similar. NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC. VA was greatly reduced in NMOSD-ON compared with HC eyes, but did not differ between NMOSD-NON and HC. Discussion Our results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON in NMOSD. Therapies ameliorating attack-related damage, especially during a first attack, are an unmet clinical need. Mild signs of neuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and do not suggest clinically relevant progression but need further investigation.Guthy-Jackson Charitable Foundation (GJCF) and German Research Foundation (DFG)

Exploring the Cost Effectiveness of Shared Decision Making for Choosing between Disease-Modifying Drugs for Relapsing-Remitting Multiple Sclerosis in the Netherlands:A State Transition Model

Background Up to 31% of patients with relapsing-remitting multiple sclerosis (RRMS) discontinue treatment with disease-modifying drug (DMD) within the first year, and of the patients who do continue, about 40% are nonadherent. Shared decision making may decrease nonadherence and discontinuation rates, but evidence in the context of RRMS is limited. Shared decision making may, however, come at additional costs. This study aimed to explore the potential cost-effectiveness of shared decision making for RRMS in comparison with usual care, from a (limited) societal perspective over a lifetime. Methods An exploratory economic evaluation was conducted by adapting a previously developed state transition model that evaluates the cost-effectiveness of a range of DMDs for RRMS in comparison with the best supportive care. Three potential effects of shared decision making were explored: 1) a change in the initial DMD chosen, 2) a decrease in the patient's discontinuation in using the DMD, and 3) an increase in adherence to the DMD. One-way and probabilistic sensitivity analyses of a scenario that combined the 3 effects were conducted. Results Each effect separately and the 3 effects combined resulted in higher quality-adjusted life years (QALYs) and costs due to the increased utilization of DMD. A decrease in discontinuation of DMDs influenced the incremental cost-effectiveness ratio (ICER) most. The combined scenario resulted in an ICER of euro17,875 per QALY gained. The ICER was sensitive to changes in several parameters. Conclusion This study suggests that shared decision making for DMDs could potentially be cost-effective, especially if shared decision making would help to decrease treatment discontinuation. Our results, however, may depend on the assumed effects on treatment choice, persistence, and adherence, which are actually largely unknown

Immunometabolic capacities of nutritional fatty acids in regulation of inflammatory bone cell interaction and systemic impact of periodontal infection

IntroductionNovel preventive strategies in periodontal disease target the bacterial-induced inflammatory host response to reduce associated tissue destruction. Strategies focus on the modulation of tissue-destroying inflammatory host response, particularly the reduction of inflammation and promotion of resolution. Thereby, nutrition is a potent immunometabolic non-pharmacological intervention. Human studies have demonstrated the benefit of olive oil-containing Mediterranean-style diets (MDs), the main component of which being mono-unsaturated fatty acid (FA) oleic acid (OA (C18:1)). Hence, nutritional OA strengthened the microarchitecture of alveolar trabecular bone and increased circulating pro-resolving lipid mediators following bacterial inoculation with periodontal pathogen Porphyromonas gingivalis, contrary to saturated FA palmitic acid (PA (C16:0)), which is abundant in Western-style diets. Additionally, the generalized distribution of inflammatory pathway mediators can occur in response to bacterial infection and compromise systemic tissue metabolism and bone homeostasis distant from the side of infection. Whether specific FA-enriched nutrition and periodontal inoculation are factors in systemic pathology that can be immune-modulatory targeted through dietary substitution is unknown and of clinical relevance.MethodsNormal-weight C57BL/6-mice received OA-or PA-enriched diets (PA-ED, OA-ED, PA/OA-ED) or a normal-standard diet (n=12/group) for 16 weeks and were orally infected with P. gingivalis/placebo to induce periodontal disease. Using histomorphometry and LC-MS/MS, systemic bone morphology, incorporated immunometabolic FA-species, serological markers of bone metabolism, and stress response were determined in addition to bone cell inflammation and interaction in vitro.ResultsIn contrast to OA-ED, PA-ED reduced systemic bone microarchitecture paralleled by increased lipotoxic PA-containing metabolite accumulation in bone. Substitution with OA reversed the bone-destructive impact of PA, which was accompanied by reduced diacylglycerols (DAG) and saturated ceramide levels. Further, PA-associated reduction in mineralization activity and concomitant pro-inflammatory activation of primary osteoblasts were diminished in cultures where PA was replaced with OA, which impacted cellular interaction with osteoclasts. Additionally, PA-ED increased osteoclast numbers in femurs in response to oral P. gingivalis infection, whereas OA-ED reduced osteoclast occurrence, which was paralleled by serologically increased levels of the stress-reducing lipokine PI(18:1/18:1).ConclusionOA substitution reverses the bone-destructive and pro-inflammatory effects of PA and eliminates incorporated lipotoxic PA metabolites. This supports Mediterranean-style OA-based diets as a preventive intervention to target the accumulation of PA-associated lipotoxic metabolites and thereby supports systemic bone tissue resilience after oral bacterial P. gingivalis infection

Persistent anthrax as a major driver of wildlife mortality in a tropical rainforest

Anthrax is a globally important animal disease and zoonosis. Despite this, our current knowledge of anthrax ecology is largely limited to arid ecosystems, where outbreaks are most commonly reported. Here we show that the dynamics of an anthrax-causing agent, Bacillus cereus biovar anthracis, in a tropical rainforest have severe consequences for local wildlife communities. Using data and samples collected over three decades, we show that rainforest anthrax is a persistent and widespread cause of death for a broad range of mammalian hosts. We predict that this pathogen will accelerate the decline and possibly result in the extirpation of local chimpanzee (Pan troglodytes verus) populations. We present the epidemiology of a cryptic pathogen and show that its presence has important implications for conservation

On the reproducibility of extrusion-based bioprinting: round robin study on standardization in the field

The outcome of three-dimensional (3D) bioprinting heavily depends, amongst others, on the interaction between the developed bioink, the printing process, and the printing equipment. However, if this interplay is ensured, bioprinting promises unmatched possibilities in the health care area. To pave the way for comparing newly developed biomaterials, clinical studies, and medical applications (i.e. printed organs, patient-specific tissues), there is a great need for standardization of manufacturing methods in order to enable technology transfers. Despite the importance of such standardization, there is currently a tremendous lack of empirical data that examines the reproducibility and robustness of production in more than one location at a time. In this work, we present data derived from a round robin test for extrusion-based 3D printing performance comprising 12 different academic laboratories throughout Germany and analyze the respective prints using automated image analysis (IA) in three independent academic groups. The fabrication of objects from polymer solutions was standardized as much as currently possible to allow studying the comparability of results from different laboratories. This study has led to the conclusion that current standardization conditions still leave room for the intervention of operators due to missing automation of the equipment. This affects significantly the reproducibility and comparability of bioprinting experiments in multiple laboratories. Nevertheless, automated IA proved to be a suitable methodology for quality assurance as three independently developed workflows achieved similar results. Moreover, the extracted data describing geometric features showed how the function of printers affects the quality of the printed object. A significant step toward standardization of the process was made as an infrastructure for distribution of material and methods, as well as for data transfer and storage was successfully established

On the reproducibility of extrusion-based bioprinting: round robin study on standardization in the field

The outcome of three-dimensional (3D) bioprinting heavily depends, amongst others, on the interaction between the developed bioink, the printing process, and the printing equipment. However, if this interplay is ensured, bioprinting promises unmatched possibilities in the health care area. To pave the way for comparing newly developed biomaterials, clinical studies, and medical applications (i.e. printed organs, patient-specific tissues), there is a great need for standardization of manufacturing methods in order to enable technology transfers. Despite the importance of such standardization, there is currently a tremendous lack of empirical data that examines the reproducibility and robustness of production in more than one location at a time. In this work, we present data derived from a round robin test for extrusion-based 3D printing performance comprising 12 different academic laboratories throughout Germany and analyze the respective prints using automated image analysis (IA) in three independent academic groups. The fabrication of objects from polymer solutions was standardized as much as currently possible to allow studying the comparability of results from different laboratories. This study has led to the conclusion that current standardization conditions still leave room for the intervention of operators due to missing automation of the equipment. This affects significantly the reproducibility and comparability of bioprinting experiments in multiple laboratories. Nevertheless, automated IA proved to be a suitable methodology for quality assurance as three independently developed workflows achieved similar results. Moreover, the extracted data describing geometric features showed how the function of printers affects the quality of the printed object. A significant step toward standardization of the process was made as an infrastructure for distribution of material and methods, as well as for data transfer and storage was successfully established

Expression of a Neuroendocrine Gene Signature in Gastric Tumor Cells from CEA 424-SV40 Large T Antigen-Transgenic Mice Depends on SV40 Large T Antigen

A large fraction of murine tumors induced by transgenic expression of SV40 large T antigen (SV40 TAg) exhibits a neuroendocrine phenotype. It is unclear whether SV40 TAg induces the neuroendocrine phenotype by preferential transformation of progenitor cells committed to the neuroendocrine lineage or by transcriptional activation of neuroendocrine genes. To address this question we analyzed CEA424-SV40 TAg-transgenic mice that develop spontaneous tumors in the antral stomach region. Immunohistology revealed expression of the neuroendocrine marker chromogranin A in tumor cells. By ELISA an 18-fold higher level of serotonin could be detected in the blood of tumor-bearing mice in comparison to nontransgenic littermates. Transcriptome analyses of antral tumors combined with gene set enrichment analysis showed significant enrichment of genes considered relevant for human neuroendocrine tumor biology. This neuroendocrine gene signature was also expressed in 424GC, a cell line derived from a CEA424-SV40 TAg tumor, indicating that the tumor cells exhibit a similar neuroendocrine phenotype also in vitro. Treatment of 424GC cells with SV40 TAg-specific siRNA downregulated expression of the neuroendocrine gene signature. SV40 TAg thus appears to directly induce a neuroendocrine gene signature in gastric carcinomas of CEA424-SV40 TAg-transgenic mice. This might explain the high incidence of neuroendocrine tumors in other murine SV40 TAg tumor models. Since the oncogenic effect of SV40 TAg is caused by inactivation of the tumor suppressor proteins p53 and RB1 and loss of function of these proteins is commonly observed in human neuroendocrine tumors, a similar mechanism might cause neuroendocrine phenotypes in human tumors

Persistent anthrax as a major driver of wildlife mortality in a tropical rainforest

Anthrax is a globally important animal disease and zoonosis. Despite this, our current knowledge of anthrax ecology is largely limited to arid ecosystems, where outbreaks are most commonly reported. Here we show that the dynamics of an anthrax-causing agent, Bacillus cereus biovar anthracis, in a tropical rainforest have severe consequences for local wildlife communities. Using data and samples collected over three decades, we show that rainforest anthrax is a persistent and widespread cause of death for a broad range of mammalian hosts. We predict that this pathogen will accelerate the decline and possibly result in the extirpation of local chimpanzee (Pan troglodytes verus) populations. We present the epidemiology of a cryptic pathogen and show that its presence has important implications for conservation