Computational study of resting state network dynamics

Lo scopo di questa tesi è quello di mostrare, attraverso una simulazione con il software The Virtual Brain, le più importanti proprietà della dinamica cerebrale durante il resting state, ovvero quando non si è coinvolti in nessun compito preciso e non si è sottoposti a nessuno stimolo particolare. Si comincia con lo spiegare cos’è il resting state attraverso una breve revisione storica della sua scoperta, quindi si passano in rassegna alcuni metodi sperimentali utilizzati nell’analisi dell’attività cerebrale, per poi evidenziare la differenza tra connettività strutturale e funzionale. In seguito, si riassumono brevemente i concetti dei sistemi dinamici, teoria indispensabile per capire un sistema complesso come il cervello. Nel capitolo successivo, attraverso un approccio ‘bottom-up’, si illustrano sotto il profilo biologico le principali strutture del sistema nervoso, dal neurone alla corteccia cerebrale. Tutto ciò viene spiegato anche dal punto di vista dei sistemi dinamici, illustrando il pionieristico modello di Hodgkin-Huxley e poi il concetto di dinamica di popolazione. Dopo questa prima parte preliminare si entra nel dettaglio della simulazione. Prima di tutto si danno maggiori informazioni sul software The Virtual Brain, si definisce il modello di network del resting state utilizzato nella simulazione e si descrive il ‘connettoma’ adoperato. Successivamente vengono mostrati i risultati dell’analisi svolta sui dati ricavati, dai quali si mostra come la criticità e il rumore svolgano un ruolo chiave nell'emergenza di questa attività di fondo del cervello. Questi risultati vengono poi confrontati con le più importanti e recenti ricerche in questo ambito, le quali confermano i risultati del nostro lavoro. Infine, si riportano brevemente le conseguenze che porterebbe in campo medico e clinico una piena comprensione del fenomeno del resting state e la possibilità di virtualizzare l’attività cerebrale

Statistical characterization of cultured neural networks activity recorded via MEA

In questa tesi si sono analizzate le attività di neuroni in coltura accoppiati con un Multi-Electrode Array (MEA) a 60 canali. Le reti neurali in vitro sono influenzate da diversi fattori, come la densità di coltura, l'età e l'animale di provenienza dei neuroni. Lo scopo di questa tesi è quello di caratterizzare questa variabilità attraverso varie analisi statistiche. Utilizzando un software sviluppato in Python si sono estratte 40 misure per descrivere un ampio spettro delle attività delle cellule, come lo spiking e i network bursts. Sono state caratterizzate le distribuzioni statistiche di queste feature, ed una analisi PCA per vedere la segregazione dei dati nelle classi considerate. Sono poi state implementate una analisi con K-Means Clustering e una classificazione mediante Random Forest, per caratterizzare la separazione spontanea e mediante label dei vari tipi di misurazioni. É stato studiato anche l'effetto del sottocampionamento temporale sulle misure, determinando che anche con un quarto della serie temporale disponibile si sono potute estrarre misure significative. Un altro tipo di sottocampionamento preso in considerazione è stato quello spaziale. Anche qui le misure si sono dimostrate robuste riducendo il numero di elettrodi da cui estrarre il segnale, fino ad un minimo di 10 elettrodi. Questa analisi della robustezza alla variabilità e al sottocampionamento delle misure di attività spontanea di reti di neuroni in vitro mediante setup MEA é utile per studiare gli effetti di sostanze chimiche, stimoli elettrici o malattie sulle colture nervose

Robustness of a bisimulation-type faster-than preorder

TACS is an extension of CCS where upper time bounds for delays can be specified. Luettgen and Vogler defined three variants of bismulation-type faster-than relations and showed that they all three lead to the same preorder, demonstrating the robustness of their approach. In the present paper, the operational semantics of TACS is extended; it is shown that two of the variants still give the same preorder as before, underlining robustness. An explanation is given why this result fails for the third variant. It is also shown that another variant, which mixes old and new operational semantics, can lead to smaller relations that prove the same preorder.Comment: Express Worksho

Increased serum OPG in atrophic nonunion shaft fractures

Background Bone repair alteration is hypothesized for nonunion fracture pathogenesis. Since it is involved in osteoclast regulation, the RANK/RANKL/OPG system (receptor activator of nuclear factor kB/its ligand/osteoprotegerin) may play a role. Materials and methods Serum OPG, free RANKL, bone alkaline phosphatase (BAP), osteocalcin (OC), and urinary deoxypyridinoline (DPD) were determined in 16 male patients (20\u201339 years) with long bone atrophic nonunion fractures. Serum markers were also measured in 18 agematched male controls who healed from the same type of fractures within six months, and in 14 age-matched male controls who were healing from the same fractures one month after injury. One-way ANOVA and Bonferroni\u2019s test were used for statistical analysis. Results Only OPG was significantly higher (0.56 sd 0.11 ng/ml) in the patients compared to healed (0.26 sd 0.04 ng/ml; P\0.001) and healing (0.29 sd 0.09 ng/ml; P\0.001) controls. The patients\u2019 DPD levels were normal. No correlations were found between bone markers and the characteristics of the subjects in all groups. Conclusions A normal steady state of bone metabolism seems to be present in patients with atrophic nonunion fractures, despite the high serum OPG. The reason for the inability of the patients\u2019 OPG to inhibit osteoclastic activity is unknown. Osteoblast activity also appears normal, so another cellular source of OPG can be hypothesized

Qualitative and quantitative analysis of doctor-patient interactions during andrological consultations

Although a trustworthy connection between doctor and patient is crucial in clinical practice, it could be hindered by different cultural and linguistic backgrounds. Moreover, an effective doctor-patient interaction could be even more challenging in andrological fields, in which psychological and social components are predominant

Refractory and 17p-deleted chronic lymphocytic leukemia: improving survival with pathway inhibitors and allogeneic stem cell transplantation.

ABSTRACT Refractory/early relapsed and 17p deletion/p53 mutation (del(17p)/TP53mut)-positive chronic lymphocytic leukemia (CLL) has been conventionally considered a high-risk disease, potentially eligible for treatment with allogeneic stem cell transplantation (alloSCT). In this multicenter retrospective analysis of 157 patients, we compared the outcomes of patients with high-risk CLL treated with alloSCT, a B-cell receptor pathway inhibitor (BCRi), and both. Seventy-one patients were treated with BCRis, 67 patients underwent reduced-intensity conditioning alloSCT, and 19 received alloSCT with a BCRi before and/or after transplantation. Inverse probability of treatment weighting analyses were performed to compare the alloSCT and no-alloSCT groups; in the 2 groups, 5-year OS, PFS, and cumulative incidence of nonrelapse mortality (NRM) and relapse were 40% versus 60% (P = .096), 34% versus 17% (P = .638), 28% versus 5% (P = .016), and 38% versus 83% (P = .005), respectively. Patients treated with alloSCT plus BCRi had a 3-year OS of 83%. The 3-year OS and NRM by year of alloSCT, including patients treated with BCRi, were 53% and 17% in 2000 to 2007, 55% and 30% in 2008 to 2012, and 72% and 18% in 2013 to 2018. In conclusion, the combination of pathway inhibitors and alloSCT is feasible and may further improve the outcome of high-risk CLL patients

Reduced lysosomal acid lipase activity in blood and platelets is associated with nonalcoholic fatty liver disease

OBJECTIVES: To investigate whether blood total lysosomal acid lipase activity (BT-LAL) levels are uniquely associated with the noncirrhotic and cirrhotic stages of nonalcoholic fatty liver disease (NAFLD) and with protection from NAFLD in metabolically/genetically predisposed subjects and a normal liver. To clarify which enzyme-carrying circulating cells are involved in reduced BT-LAL of NAFLD.METHODS: In a cross-sectional study, BT-LAL was measured by a fluorigenic method in patients with NAFLD (n = 118), alcoholic (n = 116), and hepatitis C virus-related disease (n = 49), in 103 controls with normal liver and in 58 liver transplant recipients. Intracellular platelet and leukocyte LAL was measured in 14 controls and 28 patients with NAFLD.RESULTS: Compared with controls, (i) BT-LAL and LAL in platelets, but not in leukocytes, were progressively reduced in noncirrhotic NAFLD and in nonalcoholic steatohepatitis-related cirrhosis; (ii) platelet and leukocyte counts did not differ in patients with noncirrhotic NAFLD; and (iii) BT-LAL did not differ in alcoholic and hepatitis C virus noncirrhotic patients. BT-LAL progressively increased in controls with metabolic syndrome features according to their PNPLA3 rs738409 steatosis-associated variant status (II vs IM vs MM), and their BT-LAL was higher than that of noncirrhotic NAFLD, only when carriers of the PNPLA3 unfavorable alleles were considered. Liver transplant recipients with de novo NAFLD compared with those without de novo NAFLD had lower BT-LAL.DISCUSSION: LAL in blood and platelets is progressively and uniquely reduced in NAFLD according to disease severity. High BT-LAL is associated with protection from NAFLD occurrence in subjects with metabolic and genetic predisposition. Low LAL in platelets and blood could play a pathogenetic role in NAFLD

Clinical characteristics and risk factors associated with COVID-19 severity in patients with haematological malignancies in Italy: a retrospective, multicentre, cohort study

Several small studies on patients with COVID-19 and haematological malignancies are available showing a high mortality in this population. The Italian Hematology Alliance on COVID-19 aimed to collect data from adult patients with haematological malignancies who required hospitalisation for COVID-19

Post COVID-19 irritable bowel syndrome

Objectives: The long-term consequences of COVID-19 infection on the gastrointestinal tract remain unclear. Here, we aimed to evaluate the prevalence of gastrointestinal symptoms and post-COVID-19 disorders of gut-brain interaction after hospitalisation for SARS-CoV-2 infection. Design: GI-COVID-19 is a prospective, multicentre, controlled study. Patients with and without COVID-19 diagnosis were evaluated on hospital admission and after 1, 6 and 12 months post hospitalisation. Gastrointestinal symptoms, anxiety and depression were assessed using validated questionnaires. Results: The study included 2183 hospitalised patients. The primary analysis included a total of 883 patients (614 patients with COVID-19 and 269 controls) due to the exclusion of patients with pre-existing gastrointestinal symptoms and/or surgery. At enrolment, gastrointestinal symptoms were more frequent among patients with COVID-19 than in the control group (59.3% vs 39.7%, p<0.001). At the 12-month follow-up, constipation and hard stools were significantly more prevalent in controls than in patients with COVID-19 (16% vs 9.6%, p=0.019 and 17.7% vs 10.9%, p=0.011, respectively). Compared with controls, patients with COVID-19 reported higher rates of irritable bowel syndrome (IBS) according to Rome IV criteria: 0.5% versus 3.2%, p=0.045. Factors significantly associated with IBS diagnosis included history of allergies, chronic intake of proton pump inhibitors and presence of dyspnoea. At the 6-month follow-up, the rate of patients with COVID-19 fulfilling the criteria for depression was higher than among controls. Conclusion: Compared with controls, hospitalised patients with COVID-19 had fewer problems of constipation and hard stools at 12 months after acute infection. Patients with COVID-19 had significantly higher rates of IBS than controls. Trial registration number: NCT04691895

Serum Albumin Is Inversely Associated With Portal Vein Thrombosis in Cirrhosis

We analyzed whether serum albumin is independently associated with portal vein thrombosis (PVT) in liver cirrhosis (LC) and if a biologic plausibility exists. This study was divided into three parts. In part 1 (retrospective analysis), 753 consecutive patients with LC with ultrasound-detected PVT were retrospectively analyzed. In part 2, 112 patients with LC and 56 matched controls were entered in the cross-sectional study. In part 3, 5 patients with cirrhosis were entered in the in vivo study and 4 healthy subjects (HSs) were entered in the in vitro study to explore if albumin may affect platelet activation by modulating oxidative stress. In the 753 patients with LC, the prevalence of PVT was 16.7%; logistic analysis showed that only age (odds ratio [OR], 1.024; P = 0.012) and serum albumin (OR, -0.422; P = 0.0001) significantly predicted patients with PVT. Analyzing the 112 patients with LC and controls, soluble clusters of differentiation (CD)40-ligand (P = 0.0238), soluble Nox2-derived peptide (sNox2-dp; P < 0.0001), and urinary excretion of isoprostanes (P = 0.0078) were higher in patients with LC. In LC, albumin was correlated with sCD4OL (Spearman's rank correlation coefficient [r(s)], -0.33; P < 0.001), sNox2-dp (r(s), -0.57; P < 0.0001), and urinary excretion of isoprostanes (r(s), -0.48; P < 0.0001) levels. The in vivo study showed a progressive decrease in platelet aggregation, sNox2-dp, and urinary 8-iso prostaglandin F2 alpha-III formation 2 hours and 3 days after albumin infusion. Finally, platelet aggregation, sNox2-dp, and isoprostane formation significantly decreased in platelets from HSs incubated with scalar concentrations of albumin. Conclusion: Low serum albumin in LC is associated with PVT, suggesting that albumin could be a modulator of the hemostatic system through interference with mechanisms regulating platelet activation