Lacking P2X7-receptors protects substantia nigra dopaminergic neurons and hippocampal-related cognitive performance from the deleterious effects of high-fat diet exposure in adult male mice

BackgroundDietary fat consumption, involved in the pathogenesis of insulin resistance and impaired glucose metabolism, is linked with decline in cognitive functions, dementia, and development of Parkinson’s disease and Alzheimer’s disease. Mature IL-1β, requiring the activation of the P2X7 receptor (P2X7R)-inflammasome complex, is an important mediator of neuroinflammation. The aim of the study was to test whether P2X7R activation might interfere with systemic and cerebral metabolic homeostasis.MethodsWe treated WT and P2X7R KO mice with a high-fat diet (HFD) for 16 weeks, evaluating the effects on the Substantia Nigra and Hippocampus, target areas of damage in several forms of cognitive impairment.ResultsHFD-treated WT and P2X7R KO mice showed a different brain mRNA profile of Insulin and Igf-1, with these genes and relative receptors, more expressed in KO mice. Unlike P2X7R KO mice, WT mice treated with HFD displayed a diameter reduction in dopaminergic neurons in the Substantia Nigra, accompanied by an increased IBA1 expression in this area; they also showed poor performances during Y-Maze and Morris Water Maze, tasks involving Hippocampus activity. Conversely, Parkin, whose reduction might promote neuronal cell death, was increased in the brain of P2X7R KO animals.ConclusionWe report for the first time that HFD induces damage in dopaminergic neurons of the Substantia Nigra and a Hippocampus-related worse cognitive performance, both attenuated in the absence of P2X7R. The involved mechanisms might differ in the two brain areas, with a predominant role of inflammation in the Substantia Nigra and a metabolic derangement in the Hippocampus

Gut-derived metabolites mediating cognitive development in 5-year-old children: Early-life transplant in mice has lasting effects throughout adulthood

The gut microbiota has been causally linked to cognitive development. We aimed to identify metabolites mediating its effect on cognitive development, and foods or nutrients related to most promising metabolites. Faeces from 5-year-old children (DORIAN-PISAC cohort, including 90 general population families with infants, 42/48 females/males, born in 2011-2014) were transplanted (FMT) into C57BL/6 germ-free mice. Children and recipient mice were stratified by cognitive phenotype, or based on protective metabolites. Food frequency questionnaires were obtained in children. Cognitive measurements in mice included five Y-maze tests until 23 weeks post-FMT, and (at 23 weeks) PET-CT for brain metabolism and radiodensity, and ultrasound-based carotid vascular indices. Children (faeces, urine) and mice (faeces, plasma) metabolome was measured by 1H NMR spectroscopy, and the faecal microbiota was profiled in mice by 16S rRNA amplicon sequencing. Cognitive scores of children and recipient mice were correlated. FMT-dependent modifications of brain metabolism were observed. Mice receiving FMT from high-cognitive or protective metabolite-enriched children developed superior cognitive-behavioural performance. A panel of metabolites, namely xanthine, hypoxanthine, formate, mannose, tyrosine, phenylalanine, glutamine, was found to mediate the gut-cognitive axis in donor children and recipient mice. Vascular indices partially explained the metabolite-to-phenotype relationships. Children's consumption of legumes, whole-milk yogurt and eggs, and intake of iron, zinc and vitamin D appeared to support protective gut metabolites. Overall, metabolites involved in inflammation, purine metabolism and neurotransmitter synthesis mediate the gut-cognitive axis, and holds promise for screening. The related dietary and nutritional findings offer leads to microbiota-targeted interventions for cognitive protection, with long-lasting effects

Organosilicon phantom for photoacoustic imaging

Photoacoustic imaging is an emerging technique. Although commercially available photoacoustic imaging systems currently exist, the technology is still in its infancy. Therefore, the design of stable phantoms is essential to achieve semiquantitative evaluation of the performance of a photoacoustic system and can help optimize the properties of contrast agents. We designed and developed a polydimethylsiloxane (PDMS) phantom with exceptionally fine geometry; the phantom was tested using photoacoustic experiments loaded with the standard indocyanine green dye and compared to an agar phantom pattern through polyethylene glycol-gold nanorods. The linearity of the photoacoustic signal with the nanoparticle number was assessed. The signal-to-noise ratio and contrast were employed as image quality parameters, and enhancements of up to 50 and up to 300%, respectively, were measured with the PDMS phantom with respect to the agar one. A tissue-mimicking (TM)-PDMS was prepared by adding TiO2 and India ink; photoacoustic tests were performed in order to compare the signal generated by the TM-PDMS and the biological tissue. The PDMS phantom can become a particularly promising tool in the field of photoacoustics for the evaluation of the performance of a PA system and as a model of the structure of vascularized soft tissues. (C) 2015 Society of Photo-Optical Instrumentation Engineers (SPIE

Antitumoral effects of attenuated Listeria monocytogenes in a genetically engineered mouse model of melanoma

Attenuated Listeria monocytogenes (Lmat-LLO) represents a valuable anticancer vaccine and drug delivery platform. Here we show that in vitro Lmat-LLO causes ROS production and, in turn, apoptotic killing of a wide variety of melanoma cells, irrespectively of their stage, mutational status, sensitivity to BRAF inhibitors or degree of stemness. We also show that, when administered in the therapeutic setting to Braf/Pten genetically engineered mice, Lmat-LLO causes a strong decrease in the size and volume of primary melanoma tumors, as well as a reduction of the metastatic burden. At the molecular level, we confirm that the anti-melanoma activity exerted in vivo by Lmat-LLO depends also on its ability to potentiate the immune response of the organism against the infected tumor. Our data pave the way to the preclinical testing of listeria-based immunotherapeutic strategies against metastatic melanoma, using a genetically engineered mouse rather than xenograft models

Carotid Ultrasound Boundary Study (CUBS): An Open Multicenter Analysis of Computerized Intima–Media Thickness Measurement Systems and Their Clinical Impact

[Abstract] Common carotid intima–media thickness (CIMT) is a commonly used marker for atherosclerosis and is often computed in carotid ultrasound images. An analysis of different computerized techniques for CIMT measurement and their clinical impacts on the same patient data set is lacking. Here we compared and assessed five computerized CIMT algorithms against three expert analysts’ manual measurements on a data set of 1088 patients from two centers. Inter- and intra-observer variability was assessed, and the computerized CIMT values were compared with those manually obtained. The CIMT measurements were used to assess the correlation with clinical parameters, cardiovascular event prediction through a generalized linear model and the Kaplan–Meier hazard ratio. CIMT measurements obtained with a skilled analyst's segmentation and the computerized segmentation were comparable in statistical analyses, suggesting they can be used interchangeably for CIMT quantification and clinical outcome investigation. To facilitate future studies, the entire data set used is made publicly available for the community at http://dx.doi.org/10.17632/fpv535fss7.

Arterial pressure changes monitoring with a new precordial noninvasive sensor

<p>Abstract</p> <p>Background</p> <p>Recently, a cutaneous force-frequency relation recording system based on first heart sound amplitude vibrations has been validated. A further application is the assessment of Second Heart Sound (S2) amplitude variations at increasing heart rates. The aim of this study was to assess the relationship between second heart sound amplitude variations at increasing heart rates and hemodynamic changes.</p> <p>Methods</p> <p>The transcutaneous force sensor was positioned in the precordial region in 146 consecutive patients referred for exercise (n = 99), dipyridamole (n = 41), or pacing stress (n = 6). The curve of S2 peak amplitude variation as a function of heart rate was computed as the increment with respect to the resting value.</p> <p>Results</p> <p>A consistent S2 signal was obtained in all patients. Baseline S2 was 7.2 ± 3.3 m<it>g</it>, increasing to 12.7 ± 7.7 m<it>g </it>at peak stress. S2 percentage increase was + 133 ± 104% in the 99 exercise, + 2 ± 22% in the 41 dipyridamole, and + 31 ± 27% in the 6 pacing patients (p < 0.05). Significant determinants of S2 amplitude were blood pressure, heart rate, and cardiac index with best correlation (R = .57) for mean pressure.</p> <p>Conclusion</p> <p>S2 recording quantitatively documents systemic pressure changes.</p

Post-exercise contractility, diastolic function, and pressure: Operator-independent sensor-based intelligent monitoring for heart failure telemedicine

<p>Abstract</p> <p>Background</p> <p>New sensors for intelligent remote monitoring of the heart should be developed. Recently, a cutaneous force-frequency relation recording system has been validated based on heart sound amplitude and timing variations at increasing heart rates.</p> <p>Aim</p> <p>To assess sensor-based post-exercise contractility, diastolic function and pressure in normal and diseased hearts as a model of a wireless telemedicine system.</p> <p>Methods</p> <p>We enrolled 150 patients and 22 controls referred for exercise-stress echocardiography, age 55 ± 18 years. The sensor was attached in the precordial region by an ECG electrode. Stress and recovery contractility were derived by first heart sound amplitude vibration changes; diastolic times were acquired continuously. Systemic pressure changes were quantitatively documented by second heart sound recording.</p> <p>Results</p> <p>Interpretable sensor recordings were obtained in all patients (feasibility = 100%). Post-exercise contractility overshoot (defined as increase > 10% of recovery contractility vs exercise value) was more frequent in patients than controls (27% vs 8%, p < 0.05). At 100 bpm stress heart rate, systolic/diastolic time ratio (normal, < 1) was > 1 in 20 patients and in none of the controls (p < 0.01); at recovery systolic/diastolic ratio was > 1 in only 3 patients (p < 0.01 vs stress). Post-exercise reduced arterial pressure was sensed.</p> <p>Conclusion</p> <p>Post-exercise contractility, diastolic time and pressure changes can be continuously measured by a cutaneous sensor. Heart disease affects not only exercise systolic performance, but also post-exercise recovery, diastolic time intervals and blood pressure changes – in our study, all of these were monitored by a non-invasive wearable sensor.</p

Diastolic time – frequency relation in the stress echo lab: filling timing and flow at different heart rates

A cutaneous force-frequency relation recording system based on first heart sound amplitude vibrations has been recently validated. Second heart sound can be simultaneously recorded in order to quantify both systole and diastole duration

Dynamic Arterial-Ventricular Coupling

Il sistema cardiovascolare è un sistema intrinsecamente accoppiamento ed eccezionalmente complesso in cui ventricolo sinistro e arterie sistemiche interagiscono tra loro. Variazioni nelle proprietà del sistema arterioso inevitabilmente influenzano la funzione cardiaca. D'altro canto, cambiamenti nelle proprietà del ventricolo sinistro possono influenzare il flusso arterioso. Lo studio dell'interazione tra il ventricolo sinistro e il sistema arterioso, noto come accoppiamento arterio-ventricolare (che può essere matematicamente espresso come EA/ELV, dove EA e ELV sono rispettivamente le elastanze arteriosa e ventricolare) è necessario non solo per comprendere gli aspetti fisiologici del sistema cardiovascolare, ma ha anche la sua importanza in diagnosi e prevenzione. Tuttavia, in passato, gli studi si sono concentrati sui due sistemi come se essi agissero distintamente. Inoltre, il sistema cardiovascolare è solitamente studiato a riposo, sia in condizioni sane che patologiche, senza tenere conto del fatto che un sistema può funzionare in modo diverso a riposo o al picco di uno stress. Al momento, solo pochi studi hanno esaminato i cambiamenti dell’accoppiamento arterio-ventricolare e dei suoi componenti durante l'esercizio, principalmente a causa della mancanza di metodologie affidabili per valutare EA e ELV in condizioni dinamiche, come durante una prova da sforzo. La riserva funzionale di EA/ELV, EA ed ELV, definita come la differenza tra i valori di questi parametri al picco dell'esercizio rispetto al valore basale (cioè le sue variazioni dinamiche), è un modo ottimale per descrivere le variazioni dinamiche di questi biomarcatori. Tuttavia, lo studio di queste interazioni richiede lo sviluppo di approcci metodologici innovativi. In questo lavoro di tesi, la valutazione delle alterazioni di EA/ELV è stata ottenuta mediante stima di EA e ELV per mezzo di tecnologia MEMS. In tal modo è stato possibile rilevare la riserva funzionale di ELV mediante un accelerometro percutaneo posizionato sul torace di soggetti sottoposti a stress test. Infatti, in passato, abbiamo dimostrato l’esistenza di un forte rapporto come delta percentuale tra valori basali e picco di forza di contrazione iso-volumica rilevata dal sensore e rapporto di pressione sistolica su volume sistolico, ottenuto con ecografia, il quale a sua volta costituisce una buona stima della ELV. Inoltre, la letteratura riporta che le variazioni di EA indotte da esercizio sono progressivamente e intensità-dipendente controllate dal cambiamento della sola compliance arteriosa, ovvero l’aumento di EA durante l'esercizio (in media) corrisponde esclusivamente all'aumento della rigidità arteriosa. La velocità di propagazione dell'onda di polso carotidea (cPWV) è considerata un buon marker surrogato per stimare la rigidità carotidea e, più in generale, i suoi cambiamenti nel corso dell'esercizio riflettono i cambiamenti della rigidità arteriosa globale. In questo modo, si potrebbe ottenere una valutazione dei cambiamenti di EA semplicemente monitorando i cambiamenti in cPWV. A questo scopo, sono state sviluppate due piattaforme hardware personalizzate comprese di supporto software in grado di controllare i sensori accelerometrici MEMS che acquisiscono il segnale fisiologico dal cuore (legata alla forza di contrattilità cardiaca) e dal sistema vascolare (legato alla rigidità arteriosa). In seguito, è stato condotto uno studio pilota arruolando 20 soggetti giovani e 10 più anziani, in cui è stata effettuata la misura e analisi della riserva funzionale di EA/ELV durante lo stress indotto su cicloergometro. I risultati ottenuti sono molto promettenti perché confermato i pochi risultati già presenti in letteratura, ma dimostrano anche la consistenza, fattibilità e affidabilità del metodo proposto. In futuro, il lavoro si orienterà alla diffusione del metodo proposto per consentire un’ampia adozione del modello proposto per la valutazione dell’accoppiamento arterio-ventricolare in condizioni dinamiche, durante stress test ed esercizio fisico. In questo modo, sarà possibile sfruttare in maniera ampia tutti i vantaggi offerti dallo studio della riserva funzionale del parametro EA/ELV in diverse condizioni fisiopatologiche per mezzo di studi epidemiologici, attraverso l’adozione di piani di prevenzione delle malattie cardiovascolari e tramite lo sviluppo di applicazioni per il fitness e il benessere della persona