Nebivolol: haemodynamic effects and clinical significance of combined beta-blockade and nitric oxide release.

Nebivolol is a third-generation beta-adrenergic receptor antagonist (beta-blocker) with high selectivity for beta(1)-adrenergic receptors. In addition, it causes vasodilatation via interaction with the endothelial L-arginine/nitric oxide (NO) pathway. This dual mechanism of action underlies many of the haemodynamic properties of nebivolol, which include reductions in heart rate and blood pressure (BP), and improvements in systolic and diastolic function. With respect to BP lowering, the NO-mediated effects cause a reduction in peripheral vascular resistance and an increase in stroke volume with preservation of cardiac output. Flow-mediated dilatation and coronary flow reserve are also increased during nebivolol administration. Other haemodynamic effects include beneficial effects on pulmonary artery pressure, pulmonary wedge pressure, exercise capacity and left ventricular ejection fraction. In addition, nebivolol does not appear to have adverse effects on lipid metabolism and insulin sensitivity like traditional beta-blockers. The documented beneficial haemodynamic effects of nebivolol are translated into improved clinical outcomes in patients with hypertension or heart failure. In patients with hypertension, the incidence of bradycardia with nebivolol is often lower than that with other currently available beta-blockers. This, along with peripheral vasodilatation and NO-induced benefits such as antioxidant activity and reversal of endothelial dysfunction, should facilitate better protection from cardiovascular events. In addition, nebivolol has shown an improved tolerability profile, particularly with respect to events commonly associated with beta-blockers, such as fatigue and sexual dysfunction. Data from SENIORS (Study of the Effects of Nebivolol Intervention on Outcomes and Rehospitalization in Seniors with Heart Failure) showed that significantly fewer nebivolol versus placebo recipients experienced the primary endpoint of all-cause mortality or cardiovascular hospitalization. The benefits of nebivolol therapy were shown to be cost effective. Thus, nebivolol is an effective and well tolerated agent with benefits over and above those of traditional beta-blockade because of its effects on NO release, which give it unique haemodynamic effects, cardioprotective activity and a good tolerability profile

An Innovative Lipidomic Workflow to Investigate the Lipid Profile in a Cystic Fibrosis Cell Line

Altered lipid metabolism has been associated to cystic fibrosis disease, which is characterized by chronic lung inflammation and various organs dysfunction. Here, we present the validation of an untargeted lipidomics approach based on high-resolution mass spectrometry aimed at identifying those lipid species that unequivocally sign CF pathophysiology. Of n.13375 mass spectra recorded on cystic fibrosis bronchial epithelial airways epithelial cells IB3, n.7787 presented the MS/MS data, and, after software and manual validation, the final number of annotated lipids was restricted to n.1159. On these lipids, univariate and multivariate statistical approaches were employed in order to select relevant lipids for cellular phenotype discrimination between cystic fibrosis and HBE healthy cells. In cystic fibrosis IB3 cells, a pervasive alteration in the lipid metabolism revealed changes in the classes of ether-linked phospholipids, cholesterol esters, and glycosylated sphingolipids. Through functions association, it was evidenced that lipids variation involves the moiety implicated in membrane composition, endoplasmic reticulum, mitochondria compartments, and chemical and biophysical lipids properties. This study provides a new perspective in understanding the pathogenesis of cystic fibrosis and strengthens the need to use a validated mass spectrometry-based lipidomics approach for the discovery of potential biomarkers and perturbed metabolism

A Novel Approach by SPME-GC/MS for the Determination of gammahydroxybutyric acid (GHB) in Urine Samples after Conversion into gamma-butyrolactone (GBL)

The quantitative determination of gamma-hydroxybutyric acid (GHB) in urine samples is very important to assess illicit intake or administration. To this end we evaluated several analytical methods: headspace gas-chromatography coupled to flame ionization detection (HS-GC/FID), headspace gas-chromatography coupled to mass spectrometry (HS-GC/MS), headspace gas-chromatography coupled to solid phase microextraction and mass spectrometry (HS-SPME-GC/MS). All these methods were endowed with a not sufficient sensitivity, and then we moved to solid phase microextraction coupled to gas-chromatography with mass spectrometry detection (SPME-GC/MS). At first, GHB was extracted from urine with an organic solvent and analyzed after derivatization. Under these conditions, however, there was a partial overlapping between the chromatographic peak of GHB and that of urea, also extracted by the organic solvent. Then we decided to change analytical approach and to convert GHB to gamma-butyrolactone (GBL), which is not an endogenous compound. A SPME method was optimized and validated for the determination of GBL. The limit of detection (LOD) of the method resulted to be 0.25 \u3bcg/mL for GBL, corresponding to 0.5 \u3bcg/mL for GHB. The lower limit of quantification (LLOQ) was 0.4 \u3bcg/mL for GBL and 0.8 \u3bcg/mL for GHB. The LLOQ of the method resulted 10 times lower than the endogenous level, thus allowing to distinguish between physiological conditions and exogenous assumption

Applicazione di Reti Neurali Artificiali (ANN) sulla rilevazione del dolore postoperatorio in ambito ortopedico per l’individuazione di algoritmi di valutazione obbiettiva

Nel nostro reparto afferiscono circa 700 fratture di femore anno, mentre circa 400 risultano i ricoveri di protesica in elezione. Il trattamento del dolore riveste importanza in quanto condizionante il trattamento riabilitativo e l\u2019outcame, in relazione anche al controllo della risposta alla terapia per i soggetti meno responsivi. Abbiamo pensato di applicare strumenti di AI per individuare una risposta utile alle gestione del sintomo dolore. In questo contesto, sia gli algoritmi di machine learning (2), sia le reti neurali artificiali (1) possono rappresentare un supporto a: un'efficace intervento precoce; l\u2019identificazione di gruppi a rischio; l\u2019elaborazione della diagnosi (3); l\u2019ottimizzazione temporale ed economica delle azioni proattive e reattive (\u201cTecnologie cognitive e nuove strategie di realt\ue0 virtuale nel paziente anziano: diagnosi, prognosi e recupero funzionale\u201d Folgieri SIMFER2017). A seconda della dimensione e della complessit\ue0 dei dati, \ue8 possibile applicare differenti algoritmi di AI. In particolare, le Reti Neurali Artificiali (ANN) appaiono adatte allo studio per la peculiare capacit\ue0 di generalizzazione anche a fronte di dati incompleti, in una sorta di \u201cinsight\u201d, che le rende adatte all\u2019ambito considerato per la capacit\ue0 delle ANN di apprendere da esempi, in assenza di esplicita descrizione del problema. Dati gli input, le ANN possono determinare (relazione input-output) il peso dei criteri componenti la scala ricercata individuando il minimo sottoinsieme di parametri utili. Materiali e metodi Il campione analizzato consta di 65 pazienti di et\ue0 compresa tra i 45 e i 90 anni, di cui 30 di sesso maschile. Sono stati collezionati 45 parametri tra anamnesi, diagnosi, terapia, abitudini alimentari, stile di vita, stato neuropsicologico. I dati sono stati analizzati con una rete neurale artificiale (ANN) supervisionata con algoritmo di backpropagation. La rete presenta 44 neuroni di input, un hidden layer composto da cinque neuroni e un neurone di uscita. Il target error \ue8 risultato 0.01, mentre l\u2019average training error \ue8 stato di 0.0099. Una Rete Neurale \ue8 utilizzata per classificare un set di osservazioni composte da n differenti variabili. I neuroni (nodi), che rappresentano l\u2019unit\ue0 di base per processare i segnali, sono organizzati in strati (layer). Nello strato di input ogni neurone accetta un singolo e genera un valore di output che sar\ue0 usato quale input per i neuroni del livello successivo. Per il neurone j strato ricevente, il net input \ue8 calcolato mediante la formula: netj= 11_i\u2592\u3016WijIi \u3017 (1) Ii \ue8 il segnale dal neurone i dello strato che invia il segnale, netj \ue8 il segnale raccolto dal neurone ricevente j , e wi,j \ue8 il peso da sommare una volta moltiplicato per il corrispondente segnale ricevuto dal neruone di input. Il neurone ricevente crea l\u2019attivazione in risposta al segnale netj . Nel caso della rete neurale sviluppata, l\u2019attivazione avviene mediante la funzione sigmoidale: 1/(1+e^(-netj) ) (2) L\u2019attivazione diviene l\u2019input per lo strato successive. Le equazioni (1) e (2) possono essere usate per processare nuovamente il segnale. I processi di raccolta e attivazione continuano finch\ue9 i segnali finali raggiungono lo strato di output. Attraverso l\u2019algoritmo feedforward, la rete calcola i pesi per i nodi di input e per quelli nascosti verso i nodi di output. I pesi sono determinati tramite algoritmo di addestramento di back propagation (BP), l\u2019algoritmo si ferma quando il valore della funzione errore arriva alla soglia prevista. L\u2019algoritmo di back propagation seleziona i pesi iniziali in modo random e confronta l\u2019output ottenuto con il risultato atteso. La differenza tra questi valori \ue8 valutata mediante la mean squared error. Una volta che tutte le osservazioni sono state presentate alla rete, i pesi vengono modificati in accordo alla delta rule generalizzata, in modo che l\u2019errore totale sia distribuito tra i vari nodi della rete. Un sottoinsieme di dati di training viene utilizzato per ottenere i pesi ottimali iniziali. Discussione e risultati Il target error \ue8 stato impostato 0.01, e l\u2019average training error \ue8 risultato 0.0099. I risultati ottenuti, sebbene preliminari, sembrano consentire di individuare: i parametri significativi per misurazioni obiettive e meno soggettive; la graduazione del rischio, in relazione alla manifestazione di stati dolorosi acuti. Dai 45 parametri inizialmente utilizzati sono state selezionate tra le 9 e le 8 variabili realmente incidenti sull\u2019algoritmo di graduazione. Conclusioni A fronte di un ampliamento del campione analizzato, pensiamo di rivalutare il numero dei parametri mentre l\u2019ANN sviluppata potrebbe permettere di individuare: parametri significativi per l\u2019individuazione del rischio e l\u2019ottimizzazione della terapia graduazione obiettiva del trattamento del dolore Bibliografia Baxt, W. G. (1995). Application of artificial neural networks to clinical medicine. The lancet, 346(8983), 1135-1138. Kononenko, I. (2001). Machine learning for medical diagnosis: history, state of the art and perspective. Artificial Intelligence in medicine, 23(1), 89-109. Lucchiari, C., Folgieri, R., & Pravettoni, G. (2014). Fuzzy cognitive maps: a tool to improve diagnostic decisions. Diagnosis, 1(4), 289-293. Rojas R. (1996), Neural Networks, Springer-Verlag, Berlin. Buscema, M. (1998). Back propagation neural networks. Substance use & misuse, 33(2), 233-270. Kantardzic M. (2011), Data mining: concepts, models, methods, and algorithms, John Wiley & Son

Inhibition of Sphingolipid Synthesis as a Phenotype-Modifying Therapy in Cystic Fibrosis

Cystic Fibrosis (CF) is an inherited disease associated with a variety of mutations affecting the CFTR gene. A deletion of phenylalanine 508 (F508) affects more than 70% of patients and results in unfolded proteins accumulation, originating a proteinopathy responsible for inflammation, impaired trafficking, altered metabolism, cholesterol and lipids accumulation, impaired autophagy at the cellular level. Lung inflammation has been extensively related to the accumulation of the lipotoxin ceramide. We recently proved that inhibition of ceramide synthesis by Myriocin reduces inflammation and ameliorates the defence response against pathogens infection, which is downregulated in CF. Here, we aim at demonstrating the mechanisms of Myriocin therapeutic effects in Cystic Fibrosis broncho-epithelial cells

Sodium-glucose cotransporter 2 inhibitors antagonize lipotoxicity in human myeloid angiogenic cells and ADP-dependent activation in human platelets: Potential relevance to prevention of cardiovascular events

Background: The clear evidence of cardiovascular benefits in cardiovascular outcome trials of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in type 2 diabetes might suggest an effect on atherosclerotic plaque vulnerability and/or thrombosis, in which myeloid angiogenic cells (MAC) and platelets (PLT) are implicated. We tested the effects of SGLT2i on inflammation and oxidant stress in a model of stearic acid (SA)-induced lipotoxicity in MAC and on PLT activation. The possible involvement of the Na+/H+ exchanger (NHE) was also explored. Method: MAC and PLT were isolated from peripheral blood of healthy subjects and incubated with/without SGLT2i [empagliflozin (EMPA) and dapagliflozin (DAPA) 1-100 μM] to assess their effects on SA (100 μM)-induced readouts of inflammation, oxidant stress and apoptosis in MAC and on expression of PLT activation markers by flow-cytometry after ADP-stimulation. Potential NHE involvement was tested with amiloride (aspecific NHE inhibitor) or cariporide (NHE1 inhibitor). Differences among culture conditions were identified using one-way ANOVA or Friedman test. Results: NHE isoforms (1,5-9), but not SGLT2 expression, were expressed in MAC and PLT. EMPA and DAPA (100 μM) significantly reduced SA-induced inflammation (IL1β, TNFα, MCP1), oxidant stress (SOD2, TXN, HO1), but not apoptosis in MAC. EMPA and DAPA (both 1 μM) reduced PLT activation (CD62p and PAC1 expression). SGLT2i effects were mimicked by amiloride, and only partially by cariporide, in MAC, and by both inhibitors in PLT. Conclusions: EMPA and DAPA ameliorated lipotoxic damage in stearate-treated MAC, and reduced ADP-stimulated PLT activation, potentially via NHE-inhibition, thereby pointing to plaque stabilization and/or thrombosis inhibition as potential mechanism(s) involved in SGLT2i-mediated cardiovascular protection

Vertical Transmission of Pneumocystis jirovecii in Humans

This study is part of the project “Pneumocystis Pathogenomics: Unravelling the Colonization-to-Disease Shift,” a Coordination Action supported by the European Commission (ERANET PathoGenoMics). This study was partially supported by the Spanish Ministry of Health (FIS 03/1743). M.A.M.-C. and C.d.l.H. were supported by the Spanish Ministry of Health (FIS CP-04/217 and FIS CM-04/146).Ye

Absorption, Pharmacokinetics, and Urinary Excretion of Pyridines After Consumption of Coffee and Cocoa-Based Products Containing Coffee in a Repeated Dose, Crossover Human Intervention Study

Scope: The present study assesses the absorption, pharmacokinetics, and urinary excretion of coffee pyridines and their metabolites after daily regular exposure to specific dosages of coffee or cocoa-based products containing coffee (CBPCC), considering different patterns of consumption. Methods and results: In a three-arm, crossover, randomized trial, 21 volunteers are requested to randomly consume for 1 month: one cup of espresso coffee per day, three cups of espresso coffee per day, or one cup of espresso coffee plus two CBPCC twice per day. The last day of the one-month treatment, blood and urine samples are collected for 24 h. Trigonelline, N-methylpyridinium, N-methylnicotinamide, and N-methyl-4-pyridone-5-carboxamide are quantified. Trigonelline and N-methylpyridinium absorption curves and 24-h urinary excretion reflect the daily consumption of different servings of coffee or CBPCC, showing also significant differences in main pharmacokinetic parameters. Moreover, inter-subject variability due to sex and smoking is assessed, showing sex-related differences in the metabolism of trigonelline and smoking-related ones for N-methylpyridinium. Conclusion: The daily exposure to coffee pyridines after consumption of different coffee dosages in a real-life setting is established. This data will be useful for future studies aiming at evaluating the bioactivity of coffee-derived circulating metabolites in cell experiments, mimicking more realistic experimental conditions

Left internal thoracic artery−radial artery composite grafts as the technique of choice for myocardial revascularization in elderly patients: a prospective randomized evaluation

AbstractObjectivesThe technique of choice for myocardial revascularization in elderly patients remains a debated issue. We evaluated the potential advantages of the use of left internal thoracic artery-radial artery composite grafts compared with conventional coronary artery bypass grafts in elderly patients.MethodsWe prospectively enrolled 160 patients aged more than 70 years scheduled to undergo isolated myocardial revascularization. Patients were assigned at random to group 1, 80 patients undergoing total arterial revascularization (left internal thoracic artery on left anterior descending coronary artery plus radial artery), or group 2, 80 patients undergoing standard coronary artery bypass graft surgery (left internal thoracic artery on left anterior descending coronary artery plus saphenous veins). The radial artery was used in all cases as a composite Y-graft.ResultsPreoperative characteristics and risk factors (EuroSCORE: group 1 = 7.9 vs group 2 = 8.1), number of grafted coronary vessels (group 1 = 2.4 vs group 2 = 2.5), aortic crossclamping time (group 1 = 37 ± 7 minutes vs group 2 = 38 ± 7 minutes), ventilation time (group 1 = 22 ± 12 hours vs group 2 = 23 ± 11 hours), intensive care unit stay (group 1 = 39 ± 10 hours vs group 2 = 40 ± 9 hours), and hospital mortality (group 1 = 3.8% vs group 2 = 5%) were comparable between the groups. Comparison between the 2 groups in terms of early postoperative complications showed a higher incidence of cerebrovascular accidents in group 2 (group 1 = 0 patients vs group 2 = 4 patients, 5%). At a mean follow-up of 16 ± 3 months, patients in group 1 showed superior clinical results with a lower incidence of graft occlusion (group 1 = 2 vs group 2 = 11; P = .06) and angina recurrence (group 1 = 2 patients vs group 2 = 12 patients; P = .03). Multivariate analysis identified saphenous vein grafts as independent predictors for graft occlusion and angina recurrence.ConclusionsLeft internal thoracic artery-radial artery composite grafts proved to be a safe procedure in elderly patients. It improved the clinical outcome, providing a significantly higher graft patency rate and a lower incidence of late cardiac events

A performance score of the quality of inpatient diabetes care is a marker of clinical outcomes and suggests a cause-effect relationship between hypoglycaemia and the risk of in-hospital mortality

Aims: To build a tool to assess the management of inpatients with diabetes mellitus and to investigate its relationship, if any, with clinical outcomes. Materials and methods: A total of 678 patients from different settings, Internal Medicine (IMU, n = 255), General Surgery (GSU, n = 230) and Intensive Care (ICU, n = 193) Units, were enrolled. A work-flow of clinical care of diabetes was created according to guidelines. The workflow was divided into five different domains: (a) initial assessment; (b) glucose monitoring; (c) medical therapy; (d) consultancies; (e) discharge. Each domain was assessed by a performance score (PS), computed as the sum of the scores achieved in a set of indicators of clinical appropriateness, management and patient empowerment. Appropriate glucose goals were included as intermediate phenotypes. Clinical outcomes included: hypoglycaemia, survival rate and clinical conditions at discharge. Results: The total PS and those of initial assessment and glucose monitoring were significantly lower in GSU with respect to IMU and ICU (P <.0001). The glucose monitoring PS was associated with lower risk of hypoglycaemia (OR = 0.55; P <.0001), whereas both the PSs of glucose monitoring and medical therapy resulted associated with higher in-hospital survival only in the IMU ward (OR = 6.67 P =.001 and OR = 2.38 P =.03, respectively). Instrumental variable analysis with the aid of PS of glucose monitoring showed that hypoglycaemia may play a causal role in in-hospital mortality (P =.04). Conclusions: The quality of in-hospital care of diabetes may affect patient outcomes, including glucose control and the risk of hypoglycaemia, and through the latter it may influence the risk of in-hospital mortality