Part I: Role of incretin hormones and DPP-IV inhibitors on the control of vascular homeostasis in physiological conditions and their involvement in vascular diseases Part II: Sphingolipid de novo pathway is a novel regulator of vascular homeostasis

The first part of this scientific work has been focused on the role of Dipeptidyl-Peptidase IV (DPP-IV) inhibitors in vascular homeostasis regulation. DPP-IV inhibitors represent a class of antidiabetic drugs. By increasing the physiological levels of incretin hormones, as GLP-1 and GIP, DPP-IV inhibitors sustain the release of insulin and the control of circulating plasma glucose levels. It has been shown that DPP-IV inhibitors are able to improve vascular function independently to their ability in controlling blood glucose levels. Hyperglycemic condition damages endothelium layer with consequent impairment of eNOS/NO-mediated control on vessels homeostasis leading to vascular dysfunction. We demonstrated that Linagliptin, a DPP-IV inhibitor, by interfering with the protein–protein interaction CAV-1/eNOS, led to an increased eNOS availability, thus enhancing NO production. This mechanism accounts for the beneficial vascular effect of Linagliptin that is independent from glucose control and GLP-1/GLP-1R interaction. In the context of endothelial dysfunction, the second part of this work reveals sphingolipid de novo biosynthesis as a necessary pathway to preserve endothelial cell-dependent regulation of vascular tone and BP homeostasis. Sphingolipids represent important components of plasma membrane as well as bioactive molecules. Sphingolipid de novo biosynthesis tightly regulates the physiological levels of sphingolipids. Serine-Palmitoyl Transferase (SPT) represents the first rate-limiting enzyme of this pathway, and we demonstrated that downregulation of endothelial de novo sphingolipid biosynthesis, by deletion of SPT, increases BP and impairs endothelial cell functions. Thus, endothelial-derived sphingolipids are important in the regulation of endothelial-dependent BP homeostasis. Alterations of their levels below or above a physiological range leads to alteration in vascular tone and BP regulation

A Bayesian approach for controlling structural displacements

Bayesian Networks represent one of the most powerful and effective tools for knowledge acquisition in the observation of physical phenomena affected by randomness and uncertainties. The methodology is the result of several developments concerning the Bayesian statistical theory and permits, by inference, to update the statistics describing physical variables by the observation of experimental evidences. In general, Bayesian Networks have become a very popular and versatile approach in problem solving strategies because of their capability in enhancing the status of knowledge of a physical problem domain and to characterize expected outcomes. In particular, this work presents a strategy performing the Bayesian updating of the mechanical and geometrical properties of a steel structure. Based on high-precision topographical measurements, such a strategy has the purpose of accurately estimating the structural displacements expected during the structural life-cycle

Vascular effects of linagliptin in non-obese diabetic mice are glucose-independent and involve positive modulation of the endothelial nitric oxide synthase (eNOS)/caveolin-1 (CAV-1) pathway

Aim: To test the effect of linagliptin in non-obese diabetic (NOD) mice, a murine model of type 1 diabetes, to unveil a possible direct cardiovascular action of dipeptidyl peptidase 4 (DPP-4) inhibitors beyond glycaemia control. Methods: NOD mice were grouped according to glycosuria levels as NODI: none; NODII: high; NODIII: severe. Linagliptin treatment was initiated once they reached NODII levels. Vascular reactivity was assessed ex vivo on aorta harvested from mice upon reaching NODIII level. In a separate set of experiments, the effect of linagliptin was tested directly in vitro on vessels harvested from untreated NODIII, glucagon-like peptide-1 (GLP-1) receptor knockout and soluble guanylyl cyclase-α1 knockout mice. Molecular and cellular studies were performed on endothelial and endothelial nitric oxide synthase (eNOS)-transfected cells. Results: In this ex vivo vascular study, endothelium-dependent vasorelaxation was ameliorated and eNOS/nitric oxide (NO)/soluble guanylyl cyclase (sGC) signalling was enhanced. In the in vitro vascular study, linagliptin exerted a direct vasodilating activity on vessels harvested from both normo- or hyperglycaemic mice. The effect was independent from GLP-1/GLP-1 receptor (GLP-1R) interaction and required eNOS/NO/sGC pathway activation. Molecular studies performed on endothelial cells show that linagliptin rescues eNOS from caveolin-1 (CAV-1)-binding in a calcium-independent manner. Conclusion: Linagliptin, by interfering with the protein-protein interaction CAV-1/eNOS, led to an increased eNOS availability, thus enhancing NO production. This mechanism accounts for the vascular effect of linagliptin that is independent from glucose control and GLP-1/GLP-1R interaction

Cortical recruitment and functional dynamics in postural control adaptation and habituation during vibratory proprioceptive stimulation

Objective. Maintaining upright posture is a complex task governed by the integration of afferent sensorimotor and visual information with compensatory neuromuscular reactions. The objective of the present work was to characterize the visual dependency and functional dynamics of cortical activation during postural control. Approach. Proprioceptic vibratory stimulation of calf muscles at 85 Hz was performed to evoke postural perturbation in open-eye (OE) and closed-eye (CE) experimental trials, with pseudorandom binary stimulation phases divided into four segments of 16 stimuli. 64-channel EEG was recorded at 512 Hz, with perturbation epochs defined using bipolar electrodes placed proximal to each vibrator. Power spectra variation and linearity analysis was performed via fast Fourier transformation into six frequency bands (Δ, 0.5–3.5 Hz; θ, 3.5–7.5 Hz; α, 7.5–12.5 Hz; β, 12.5–30 Hz; γlow, 30–50 Hz; and γhigh, 50–80 Hz). Finally, functional connectivity assessment was explored via network segregation and integration analyses. Main results. Spectra variation showed waveform and vision-dependent activation within cortical regions specific to both postural adaptation and habituation. Generalized spectral variation yielded significant shifts from low to high frequencies in CE adaptation trials, with overall activity suppressed in habituation; OE trials showed the opposite phenomenon, with both adaptation and habituation yielding increases in spectral power. Finally, our analysis of functional dynamics reveals novel cortical networks implicated in postural control using EEG source-space brain networks. In particular, our reported significant increase in local θ connectivity May signify the planning of corrective steps and/or the analysis of falling consequences, while α band network integration results reflect an inhibition of error detection within the cingulate cortex, likely due to habituation. Significance. Our findings principally suggest that specific cortical waveforms are dependent upon the availability of visual feedback, and we furthermore present the first evidence that local and global brain networks undergo characteristic modification during postural control

Partial response to first generation SSA guides the choice and predict the outcome of second line therapy in acromegaly

Treatment of acromegaly resistant to first generation somatostatin analogues (first gen-SSA) is often difficult. We aimed to investigate the role of partial response and resistance to first gen-SSA in the choice of second line treatments and their outcomes

Análisis visual de datos multidimensionales

El objetivo de la visualización es comunicar información de una manera gráfica, interactiva y comprensible. La visualización de datos multivariados, en particular, es un campo de investigación activo con una gran aplicación en diversas áreas. En el análisis de conjuntos de datos multidimensionales, las cuestiones relacionadas con la detección de eventos, correlaciones, patrones y tendencias, desempeñan un papel cada vez más importante. A medida que aumenta la dimensionalidad de los datos, la realización de una visualización eficaz se vuelve cada vez más compleja ya que muchas técnicas tradicionales solo pueden generar vistas parciales de los datos [3, 11, 12, 13], imposibilitando la detección de posibles relaciones entre todas las variables involucradas en el proceso. Por lo tanto, tener un conjunto de metáforas visuales y técnicas de visualización relacionadas, es muy útil para nuestro análisis. Estas representaciones deben poder transmitir de manera efectiva las características del espacio de información e inspirar el descubrimiento. En este contexto, el objetivo general es contribuir al desarrollo de tecnologías en torno al análisis visual de datos multidimensionales. En esta línea en particular, nos centraremos en la aplicación de estas nuevas tecnologías en el campo de la geología, pero estos métodos son extensibles a diferentes disciplinas.Eje: Computación gráfica, imágenes y visualización.Red de Universidades con Carreras en Informátic

Pensareal futuro. Percorsi di orientamento alle scelte post-diploma

La scelta del futuro, che sia di un’occupazione o di un percorso di studi uni-versitario, è il momento che per un giovane segna l’inizio del passaggio all’età adulta. Per uno studente che si affaccia al diploma rappresenta spesso una fase critica della vita, che il più delle volte lo coglie impreparato e smarrito. Per questo l’orientamento diviene una parte integrante del processo educati-vo e formativo che supporta i giovani a prendere coscienza di sé e a far fronte in modo consapevole alle scelte che si trovano ad affrontare in particolari fasi di transizione della loro vita. Ma non è esclusivamente una questione che riguarda il singolo. Accompagnare lo studente nel suo progetto personale e professionale signifi ca soprattutto agire su un piano individuale, ma in una prospettiva sociale; signifi ca immaginare una società futura capace di con-trastare l’abbandono scolastico e la dispersione universitaria, di limitare la distanza tra scuola e realtà socio-economiche e il mismatch tra formazione e lavoro e, quindi, di ridurre il fenomeno dei Not in Education, Employment or Training. Ma perché sia effi cace è necessario che si confi guri come un per-corso di cooperazione tra i diversi attori e i diversi mondi che concorrono alla formazione e all’educazione del giovane – scuola, università, famiglia, mondo del lavoro, territorio, istituzioni, aziende; in altre parole, un sistema integrato di orientamento che pone al centro il giovane e le sue attitudini e lo accom-pagna nell’elaborazione del suo progetto di vita.Il volume parte da questa convinzione. Alla luce delle direttive europee e della conseguente riforma dell’orientamento contenuta nel Piano Nazionale di Ripresa e Resilienza, si è sentita la necessità di raccogliere in un unico testo esperienze e punti di vista di studiosi che, con uno sguardo sull’attuale con-testo sociale, culturale ed economico, si raccontano da differenti angolazioni, avanzando ipotesi sui possibili percorsi per favorire e agevolare le scelte dei giovani. Esperienze a confronto, dunque, che messe in connessione fornisco-no un quadro complesso ma coerente della centralità dell’orientamento nella costruzione dei possibili futuri individuali e sociali e offrono indicazioni su procedure di specifi che proposte innovative

Impact of social determinants on antiretroviral therapy access and outcomes entering the era of universal treatment for people living with HIV in Italy

Background: Social determinants are known to be a driving force of health inequalities, even in high income countries. Aim of our study was to determine if these factors can limit antiretroviral therapy (ART) access, outcome and retention in care of people living with HIV (PLHIV) in Italy. Methods: All ART naïve HIV+ patients (pts) of Italian nationality enrolled in the ICONA Cohort from 2002 to 2016 were included. The association of socio-demographic characteristics (age, sex, risk factor for HIV infection, educational level, occupational status and residency area) with time to: ART initiation (from the first positive anti-HIV test), ART regimen discontinuation, and first HIV-RNA < 50 cp/mL, were evaluated by Cox regression analysis, Kaplan Meier method and log-rank test. Results: A total of 8023 HIV+ pts (82% males, median age at first pos anti-HIV test 36 years, IQR: 29-44) were included: 6214 (77.5%) started ART during the study period. Women, people who inject drugs (PWID) and residents in Southern Italy presented the lowest levels of education and the highest rate of unemployment compared to other groups. Females, pts aged > 50 yrs., unemployed vs employed, and people with lower educational levels presented the lowest CD4 count at ART initiation compared to other groups. The overall median time to ART initiation was 0.6 years (yrs) (IQR 0.1-3.7), with a significant decrease over time [2002-2006 = 3.3 yrs. (0.2-9.4); 2007-2011 = 1.0 yrs. (0.1-3.9); 2012-2016 = 0.2 yrs. (0.1-2.1), p < 0.001]. By multivariate analysis, females (p < 0.01) and PWID (p < 0.001), presented a longer time to ART initiation, while older people (p < 0.001), people with higher educational levels (p < 0.001), unemployed (p = 0.02) and students (p < 0.001) were more likely to initiate ART. Moreover, PWID, unemployed vs stable employed, and pts. with lower educational levels showed a lower 1-year probability of achieving HIV-RNA suppression, while females, older patients, men who have sex with men (MSM), unemployed had higher 1-year risk of first-line ART discontinuation. Conclusions: Despite median time to ART start decreased from 2002 to 2016, socio-demographic factors still contribute to disparities in ART initiation, outcome and durability

An Italian Multicenter Study on the Epidemiology of Respiratory Syncytial Virus During SARS-CoV-2 Pandemic in Hospitalized Children

Since the beginning of 2020, a remarkably low incidence of respiratory virus hospitalizations has been reported worldwide. We prospectively evaluated 587 children, aged <12 years, admitted for respiratory tract infections from 1 September 2021 to 15 March 2022 in four Italian pediatric hospitals to assess the burden of respiratory viruses during the COVID-19 pandemic in Italy. At admission, a Clinical Respiratory Score was assigned and nasopharyngeal or nasal washing samples were collected and tested for respiratory viruses. Total admissions increased from the second half of October 2021 to the first half of December 2021 with a peak in early November 2021. The respiratory syncytial virus (RSV) incidence curve coincided with the total hospitalizations curve, occurred earlier than in the pre-pandemic years, and showed an opposite trend with respect to the incidence rate of SARS-CoV-2. Our results demonstrated an early peak in pediatric hospitalizations for RSV. SARS-CoV-2 may exhibit a competitive pressure on other respiratory viruses, most notably RSV

Cervical cancer screening in women vaccinated against human papillomavirus infection: Recommendations from a consensus conference

In Italy, the cohorts of women who were offered Human papillomavirus (HPV) vaccination in 2007/08 will reach the age (25 years) for cervical cancer (CC) screening from 2017. The simultaneous shift from cytology-based screening to HPV test-based screening gives the opportunity for unprecedented reorganisation of CC prevention. The ONS (National Screening Monitoring Centre) Directive and the GISCi (Italian Group for Cervical Screening) identified the consensus conference as the most suitable method for addressing this topic. A summary of consensus recommendations is reported here. The main objective was to define the best screening methods in girls vaccinated against HPV and the knowledge required for defining evidence-based screening strategies. A Jury made recommendations about questions and proposals formulated by a panel of experts representative of Italian scientific societies involved in CC prevention and based on systematic reviews of literature and evidence. The Jury considered changing the screening protocols for girls vaccinated in their twelfth year as appropriate. Tailored screening protocols based on vaccination status could be replaced by \u201cone size fits all\u201d protocols only when a herd immunity effect has been reached. Vaccinated women should start screening at age 30, instead of 25, with HPV test. Furthermore, there is a strong rationale for applying longer intervals for re-screening HPV negative women than the currently recommended 5 years, but research is needed to determine the optimal screening time points. For non-vaccinated women and for women vaccinated in their fifteenth year or later, the current protocol should be kept