Therapeutic resistance of cerebral secondary tumours largely depends on unique aspects linked to the neurovascular unit, especially cerebral endothelial cells and astrocytes. By using advanced microscopy techniques, here we explored novel mechanisms related to the neurovascular unit during extravasation and proliferation of triple negative breast cancer cells in the brain. Metastatic mammary carcinoma cells arrested and elongated within one hour in cerebral microvessels, but their number decreased by almost 80% in the first two days. Interestingly, malignant cells induced vasoconstriction and development of intraluminal endothelial plugs, which isolated invading cells from the circulation. During diapedesis – which usually took place on day four and five after inoculation of the tumour cells – continuity of cerebral endothelial tight junctions remained intact, indicating migration of cancer cells through the transcellular pathway. In addition, metastatic cells induced formation of multiluminal vessels and claudin-5-positive endothelial blebs. However, even severe endothelial blebbing could be reversed and the vessel morphology was restored shortly after the tumour cells completed transendothelial migration. Similar to neuro-inflammatory leukocytes, tumour cells migrated not only through the endothelial layer, but through the glia limitans perivascularis as well. Nevertheless, along with the growth of metastatic lesions by co-option of pre-existing capillaries, astrocytes and astrocyte end-feet were gradually expelled from the vessels to the border of the tumour. Taken together, we identified previously unknown mechanisms involved in the reaction of brain resident cells to invading breast cancer cells. Our results contribute to a better understanding of the complex cross-talk between tumour cells and host cells in the brain, which is essential for the identification of new therapeutic targets in this devastating disease.

Background: Non-spherical titanium dioxide (TiO₂) nanoparticles have been increasingly applied in various biomedical and technological fields. Their toxicological characterization is, however, less complete than that of roundish nanoparticles. Materials and Methods: Anatase form TiO₂ nanorods, ca. 15x65 nm in size, were applied to cultured astrocytes in vitro and to the airways of young adult Wistar rats in vivo in 5, 10, and 8 mg/kg BW dose for altogether 28 days. Presence of nanorods and cellular damage was investigated in the astrocytes and in rat lungs and kidneys. Functional damage of the nervous system was studied by electrophysiological methods. Results: The treated astrocytes showed loss of viability without detectable apoptosis. In rats, TiO₂ nanorods applied to the airways reached the blood and various organs including the lungs, kidneys, and the central nervous system. In lung and kidney samples, nanorods were observed within (partly damaged) phagolysosomes and attached to organelles, and apoptotic cell death was also detected. In cortical and peripheral electrophysiological activity, alterations corresponding to energy shortage (resulting possibly from mitochondrial damage) and astrocytic dysfunction were detected. Local titanium levels and relative weight of the investigated organs, apoptotic cell death in the lungs and kidneys, and changes in the central and peripheral nervous activity were mostly proportional to the applied doses, and viability loss of the cultured astrocytes was also dose-dependent, suggesting causal relationship of treatments and effects. Conclusion: Based on localization of the visualized nanorods, on neuro-functional changes, and on literature data, the toxic mechanism involved mitochondrial damage, oxidative stress, and apoptotic cell death. These indicate potential human toxicity and occupational risk in case of exposure to rod-shaped TiO₂ nanoparticles.

ChatGPT, a general artificial intelligence, has been recognized as a powerful tool in scientific writing and programming but its use as a medical tool is largely overlooked. The general accessibility, rapid response time and comprehensive training database might enable ChatGPT to serve as a diagnostic augmentation tool in certain clinical settings. The diagnostic process in neurology is often challenging and complex. In certain time-sensitive scenarios, rapid evaluation and diagnostic decisions are needed, while in other cases clinicians are faced with rare disorders and atypical disease manifestations. Due to these factors, the diagnostic accuracy in neurology is often suboptimal. Here we evaluated whether ChatGPT can be utilized as a valuable and innovative diagnostic augmentation tool in various neurological settings. We used synthetic data generated by neurological experts to represent descriptive anamneses of patients with known neurology-related diseases, then the probability for an appropriate diagnosis made by ChatGPT was measured. To give clarity to the accuracy of the AI-determined diagnosis, all cases have been cross-validated by other experts and general medical doctors as well. We found that ChatGPT-determined diagnostic accuracy (ranging from 68.5% ± 3.28% to 83.83% ± 2.73%) can reach the accuracy of other experts (81.66% ± 2.02%), furthermore, it surpasses the probability of an appropriate diagnosis if the examiner is a general medical doctor (57.15% ± 2.64%). Our results showcase the efficacy of general artificial intelligence like ChatGPT as a diagnostic augmentation tool in medicine. In the future, AI-based supporting tools might be useful amendments in medical practice and help to improve the diagnostic process in neurology.

Background: We have previous evidence that in anesthetized dogs the inorganic sodium nitrite protects against the severe ventricular arrhythmias, resulting from coronary artery occlusion and reperfusion, when administered 24 h before. The present study aimed to examine, whether in this effect changes in mitochondrial morphology and function would play a role. Methods: Thirty dogs were infused intravenously either with saline (n = 15) or sodium nitrite (0.2 μmol/kg/min; n = 15) for 20 min, and 24 h later, 10 dogs from each group were subjected to a 25 min period of occlusion and then reperfusion of the left anterior descending coronary artery. The severity of ischaemia and ventricular arrhythmias were examined in situ. Left ventricular tissue samples were collected either before the occlusion (5 saline and 5 nitrite treated dogs) or, in dogs subjected to occlusion, 2 min after reperfusion. Changes in mitochondrial morphology, in complex I and complex II-dependent oxidative phosphorylation (OXPHOS), in ATP, superoxide, and peroxynitrite productions were determined. Results: The administration of sodium nitrite 24 h before ischemia/reperfusion significantly attenuated the severity of ischaemia, and markedly reduced the number and incidence of ventricular arrhythmias. Nitrite also attenuated the ischaemia and reperfusion (I/R)-induced structural alterations, such as reductions in mitochondrial area, perimeter, and Feret diameter, as well as the increase in mitochondrial roundness. The administration of nitrite, however, enhanced the I/R-induced reduction in the mitochondrial respiratory parameters; compared to the controls, 24 h after the infusion of nitrite, there were further significant decreases, e.g., in the complex I-dependent OXPHOS (by −20 vs. −53%), respiratory control ratio (by −14 vs. −61%) and in the P/E control coupling ratio (by 2 vs. −36%). Nitrite also significantly reduced the I/R-induced generation of superoxide, without substantially influencing the ATP production. Conclusions: The results suggest that sodium nitrite may have an effect on the mitochondria; it preserves the mitochondrial structure and modifies the mitochondrial function, when administered 24 h prior to I/R. We propose that nitrite affects primary the phosphorylation system (indicated by the decreased P/E ratio), and the reduction in superoxide production would result from the subsequent suppression of the ROS producing complexes; an effect which may certainly contribute to the antiarrhythmic effect of nitrite.

In an earlier study, signs of commencing degeneration of spinal motor neurons were induced in mice with short-term intraperitoneal injections of immunoglobulin G (IgG) taken from patients with amyotrophic lateral sclerosis (ALS). Since in that study, neither weakness nor loss of motor neurons was noted, to test whether the ALS IgG in this paradigm has the potential to evoke relentless degeneration of motor neurons, treatment with repeated injections over a longer period was carried out. Mice were systematically injected intraperitoneally with serum taken from ALS patients over a 75-day period. At selected time points, the isometric force of the limbs, number of spinal motor neurons and their intracellular calcium levels were determined. Furthermore, markers of glial activation and the motoneuronal uptake of human IgG were monitored. During this period, gliosis and progressive motoneuronal degeneration developed, which led to gradual loss of spinal motor neurons, more than 40% at day 21, along with decreasing muscle strength in the limbs. The inclusion-like accumulation of IgG appeared in the perikarya with the increase of intracellular calcium in the cell bodies and motor nerve terminals. Our results demonstrate that ALS serum can transfer motor neuron disease to mice.