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Cardiovascular inflammaging: mechanisms, consequences, and therapeutic perspectives
Get PDFBoth aging and systemic inflammation are major risk factors for cardiovascular disease. This review summarizes the interrelationship of aging and inflammation—known as inflammaging—and the consequences for cardiovascular health. We discuss mechanisms including epigenetic modification, mitochondrial dysfunction, cellular senescence, and gut dysbiosis, many of which are themselves interrelated. Increasing understanding of inflammaging provides an array of biomarkers, some of which are now recommended in international guidelines. We also discuss therapeutic strategies aiming to modify the process of inflammaging and improve cardiovascular disease outcomes, either with immunomodulating agents or with therapies targeted at specific mechanisms, such as senolytics, telomerase activators, and pre- and probiotic supplementation. We conclude that inflammaging is a key part of cardiovascular aging and provides encouraging opportunities for new therapies
Tph2 deficiency leads to alterations in social adjustment and socio-affective communication in neonatal rats: no rescue effect of communal nesting
Get PDFDeficiency of tryptophan hydroxylase 2 (TPH2), the rate-limiting enzyme for serotonin (5-hydroxytryptamine, 5-HT) synthesis in the brain, was repeatedly reported to cause impairments in socio-affective communication and maternal affiliation across species, including mice, rats, and monkeys. We recently applied a rescue protocol in the Tph2 knockout rat model and demonstrated that communal nesting ameliorates maternal affiliation impairments. Interestingly, however, this rescue strategy did not lead to improvements in socio-affective communication and was associated with an aggravated growth retardation phenotype in Tph2-deficient offspring. In the present study, we aimed to gain deeper insight into the interplay between socio-affective communication, nesting condition, and test context. To this aim, we studied Tph2(−/−) knockout, Tph2(+/−) heterozygous, and Tph2(+/+) wildtype rat pups of both sexes, randomly assigned to standard versus communal nesting. We performed detailed spectrographic analyses and compared the emission of isolation-induced ultrasonic vocalizations under social test conditions, i.e., the maternal preference test and the homing test, to non-social test conditions, i.e., the isolation box test. Our results show that Tph2 deficiency causes prominent alterations in isolation-induced ultrasonic calling linked to reduced maternal responsiveness, including changes in acoustic features, e.g., increased call duration but reduced frequency modulation. Remarkably, irrespective of communal nesting, Tph2(−/−) pups typically displayed either no evidence for social adjustment or even changes opposite to Tph2(+/+) littermates, suggesting a reduction and/or delay in the capability and/or motivation to appropriately adjust to changes in the social environment. Such alterations in social adjustment likely contribute to growth retardation through reduced quality of mother-pup interactions
Reproducibility of late gadolinium enhancement quantification techniques in ischemic and non-ischemic heart diseases (ReLate study)
Get PDFBACKGROUND: Late gadolinium enhancement (LGE) assessed by cardiovascular magnetic resonance (CMR) is an established metric for risk stratification and therapeutic guidance. However, consensus on the optimal technique for quantifying left ventricular (LV) LGE extent remains lacking. This study aimed to identify the most reliable method for quantifying LGE in chronic myocardial infarction (CMI), hypertrophic cardiomyopathy (HCM), and inflammatory heart disease (IHD). METHODS: A retrospective analysis was conducted on 285 prospectively enrolled patients (CMI: n = 98; HCM: n = 91; IHD: n = 96). LV LGE images in short-axis orientation were analyzed twice by the same reader. The most reliable LGE quantification technique was defined as the one achieving the highest intra-observer reproducibility. A two-step study design was implemented: in the pilot phase ( n = 90), three quantification methods were compared: full width at half maximum (FWHM), signal threshold vs. reference mean using 2–6 standard deviations (n-SD), and manual thresholding. Techniques demonstrating the lowest variability were then applied in a validation cohort ( n = 195). A mixed model for repeated measures was used to estimate mean differences. Equivalence was confirmed if the 95% confidence interval (CI) for the mean difference remained within predefined margins. RESULTS: In CMI, FWHM demonstrated the highest reproducibility, with a mean difference of 0.47% (95% CI: −0.40 to 1.35). In HCM, both the 5-SD and 6-SD techniques showed the highest reproducibility, with mean differences of 0.06% (95% CI: −1.28 to 1.39) and −0.16% (95% CI: −1.50 to 1.17), respectively. In IHD, the 5-SD and 6-SD techniques achieved the highest reproducibility, with mean differences of −0.72% (95% CI: −1.54 to 0.11) and −0.71% (95% CI: −1.54 to 0.11). CONCLUSION: The distribution and pattern of LGE influence the reproducibility of its quantification. FWHM provided the highest intra-observer reproducibility for sharply demarcated scars, as seen in CMI. For more diffuse fibrosis patterns, such as in HCM and IHD, both the 5-SD and 6-SD techniques offered similarly reproducible performance
Einführung eines Schwerpunktes Neuroimmunologie in der Neurologie – Positionspapier der DGN-Kommission für Neuroimmunologie [Introduction of a neuroimmunology specialisation in neurology: position paper of the German Neurological Society Commission for Neuroimmunology]
Get PDFDie Deutsche Gesellschaft für Neurologie (DGN) möchte die strukturierte Weiterbildung im gesamten Bereich neuroimmunologischer Erkrankungen und damit die Sicherung der Qualität ärztlicher Berufsausübung in diesem wachsenden Feld sicherstellen. Daher hat sie ihre Klinische Kommission „Neuroimmunologie“ damit beauftragt, entsprechend der Musterweiterbildungsordnung (MWBO) der Bundesärztekammer (BÄK) einen Entwurf für einen „Schwerpunkt Neuroimmunologie“ zu erarbeiten. Die zunehmende Komplexität und das rasch wachsende Spektrum neuroimmunologischer Erkrankungen erfordern eine strukturierte und standardisierte Weiterbildung innerhalb der Neurologie.
Die Kommission stellt hier nachfolgend ihren Vorschlag auf Grundlage der MWBO 2018 [1] der BÄK vor, um ihn mit möglichst vielen Mitgliedern der DGN zu diskutieren. Im Vorfeld ist bereits eine Abstimmung mit benachbarten Fachdisziplinen und Organisationen erfolgt, aus der sich konkrete Vorschläge ergeben haben, die in den nachfolgenden Entwurf eingeflossen sind. Dabei ist die diskutierte Implementierung eines Schwerpunktes Neuroimmunologie auf ausgesprochen positive Zustimmung gestoßen und alle kontaktierten Organisationen haben ihre Unterstützung in der weiteren Ausgestaltung zugesichert.
Dieses Positionspapier beschreibt die fachliche Notwendigkeit, die rechtlichen Voraussetzungen, die strukturellen Rahmenbedingungen und die konkret geplanten Inhalte einer Schwerpunktweiterbildung Neuroimmunologie gemäß den Vorgaben der MWBO. Es richtet sich an neurologisch tätige Ärztinnen und Ärzte, Fachgesellschaften sowie gesundheitspolitische EntscheidungsträgerInnen. Abschließend wird der mögliche weitere Weg hin zum Schwerpunkt Neuroimmunologie skizziert
Membrane-distal part of extracellular domain of the Fap2 autotransporter adhesin from Fusobacterium nucleatum ATCC23726
No full textCaspase-6 is a non-apoptotic effector of shear-induced morphological adaptation in pulmonary artery endothelial cells in vitro
Get PDFCaspases are known for their roles in cell death and inflammation. However, emerging evidence suggests they also mediate non-lethal processes, governed by a finely tuned balance of localization, activity, kinetics, and substrate availability. Given that many caspase substrates are implicated in mechanoadaptive processes, we investigated if caspases contribute to morphological adaptation of human pulmonary artery endothelial cells to fluid shear stress and other morphology-altering stimuli in vitro. Using selective inhibitors, we screened all major caspases for a role in endothelial cell adaptation to unidirectional laminar shear stress (15 dyn/cm(2), 72 h). Selective inhibition of caspase-6, but not other caspases, impaired morphological shear adaptation. Only 5.5% of caspase-6-inhibited cells shear-adapted vs. 75.2% of vector controls. Live-cell FRET imaging revealed progressive caspase-6 activation starting at 18 h of shear stress, coinciding with the onset of morphological remodeling. The active caspase-6 localized predominantly perinuclearly, while caspase-3 remained inactive throughout shear exposure. Caspase-6 inhibition did not affect elongation in response to alternative biomechanical or biochemical stimuli, including uniaxial cyclic stretch (5%, 1 Hz), spatial confinement on narrow micropatterned RGD-lines, or TNF-α stimulation, nor did it impair cell adhesion, directed migration, wound healing, or barrier recovery after wounding. Our study uncovers a previously unidentified role of caspase-6 as a non-apoptotic, mechanosensitive effector specifically required for shear-induced morphological adaptation of pulmonary artery endothelial cells, highlighting a novel regulatory axis in vascular mechanoadaptation
A computational model elucidates the effects of oncogene-induced expression alterations on the energy metabolism of neuroblastoma
Get PDFAlterations in energy metabolism are recognized as a hallmark of cancer. Experimental evidence shows that oncogenes play a key role in the reprogramming of metabolism. In neuroblastoma, the oncogene MYCN, a main risk factor of poor prognosis, has been demonstrated to lead to expression changes in numerous glycolytic enzymes. It is not clear whether all these targets are required and how they jointly shape metabolic responses. Here we use a computational modeling approach to dissect the effects of MYCN targets on the pathway individually and in combination. We develop the first mathematical model of the energy metabolism in neuroblastoma cells based on our published experimental data. The analysis shows that overall, MYCN overexpression leads to Warburg-like flux alterations. However, individual MYCN targets can have opposing and sometimes unexpected effects. Interestingly, not all of them contribute to notable flux alterations, at least with regard to glycolysis. Moreover, our model predicts a potential bistability of cellular metabolism with a low-flux state likely representing a non-proliferative state. Overall, our study emphasizes that perturbations such as expression changes should be analysed in the context of realistic pathway models, in which specific interactions and complex regulations are captured
A vascular-associated fibroblastic cell controls pancreatic islet immunity
Get PDFThe immune protection of pancreatic β cells has three layers: anatomical, with their distribution in 1 million islets; central, with the thymic deletion of β cell-specific T cells; and peripheral, with inhibitory cellular networks. The failure of the latter leads to most spontaneous type 1 diabetes and all diabetes induced by checkpoint inhibitor therapy. Because CD4 T cells initiate disease, major histocompatibility complex (MHC) class II-expressing cells are central to the onset. In non-diabetic mouse and human islets, two such cells were detected outside of the islet boundaries near the efferent post-capillary venules: one related to the vasculature and a fibroblast referred to as a "vascular-associated fibroblast" (VAF). Functionally, primary VAFs spontaneously presented islet antigens to CD4 T cells and expressed high levels of inhibitory B7 receptors and no costimulatory receptors. VAFs induced anergy in primary pre-activated anti-islet CD4 T cells. VAFs are likely important to protect the endocrine pancreas from autoimmunity
The best available pupil response predicts neurological outcome following cardiac arrest-a prospective cohort study
Get PDFBACKGROUND: Early neuroprognostication after cardiac arrest (CA) remains challenging. Manual pupillary light reflex assessments can be inconsistent, leading to interest in automated, quantitative pupillometry. This study used the better Neurological Pupil Index (NPi) and pupillary percentage values from bilateral measurements for neuroprognostication following CA. METHODS: We evaluated 90 adult survivors of in- and out-of-hospital CA admitted to a medical ICU at a tertiary care university hospital in Berlin. Automated pupillometry was performed every 8 hours for 5 days post-admission using the NeurOptics NPi-100 pupillometer. The better measurement from either eye was selected for analysis. Outcomes at hospital discharge were classified as good (cerebral performance category scale [CPC] 1–2) or poor (CPC 3–5) using the Pittsburgh CPC scale. RESULTS: Patients with favorable neurological outcomes consistently showed higher NPi values ( P 3.0). A receiver operating characteristic analysis of the pupillary percentage change revealed a threshold of 16% to discriminate between the prespecified outcome groups. CONCLUSION: Higher NPi values and/or greater pupillary diameter changes of the better reading in bilateral measurements were associated with favorable neurological outcomes after CA. However, previously proposed cutoff thresholds could not be confirmed in our cohort
Functional connectivity is linked to symbolic BOLD patterns: replication, extension, and clinical application of the human 'complexome'
No full textFunctional connectivity (FC) quantifies the temporal coherence of blood-oxygen-level-dependent (BOLD) signals across brain regions. Recently, the information-theoretic “complexome” framework has linked FC to coinciding ‘complexity drops’: transient moments in which regional BOLD signals simultaneously become regular. Here, we replicate this relationship in an independent dataset and extend the framework by (i) integrating it with signal cofluctuation analysis through edge-timeseries, (ii) extending the previous binary concept of simultaneous complexity drops to a continuous, threshold-free calculation, (iii) providing evidence of clinical relevance in the model disease of anti-N-methyl-D-aspartate-receptor encephalitis, and (iv) deriving a novel measure of pairwise dissimilarity in local BOLD patterns. This ‘index of pattern incongruency’ (IPI) explains clinically relevant FC reductions and maps onto novel associations with cognition. These findings show that global FC is closely related to local patterns within underlying BOLD signals, strengthening the link between complexity dynamics and the brain’s functional organization as a large-scale network