253 research outputs found
Generation of novel immunoprophylactic and immunotherapeutic antimicrobial approaches
No full textLa presente tesi, intitolata “Generation of novel immunoprophylactic and immunotherapeutic antimicrobial approaches”, analizza nuovi approcci immunoprofilattici e immunoterapeutici al fine di sviluppare strategie innovative per il miglioramento delle risposte immunitarie contro le infezioni.
La prima sezione analizza l’utilizzo dei cristalli di acido urico (Monosodium Urate, MSU crystals) come adiuvanti per potenziare l'efficacia del vaccino di Calmette-Guérin (Bacillo di Calmette-Guérin, BCG) contro la tubercolosi (TB). La stimolazione con i cristalli di acido urico promuove la risposta innata antimicobatterica, migliorando la maturazione dei fagolisosomi nei macrofagi infettati da Mycobacterium tuberculosis (MTB).
Inoltre, la stimolazione dei macrofagi con MSU aumenta significativamente l'attivazione immunitaria, stimolando la produzione di specie reattive dell'ossigeno (ROS) e il rilascio di citochine pro-infiammatorie, come l'interleuchina-1β.
L’utilizzo di MSU come adiuvante nella vaccinazione antitubercolare con il BCG ha dimostrato un aumento della protezione contro MTB in modelli murini, suggerendo che tale approccio potrebbe rappresentare un significativo progresso nella vaccinazione antitubercolare.
La seconda parte della tesi si focalizza sull’utilizzo di liposomi, particelle lipidiche sferiche, come veicoli per la somministrazione mirata di molecole immunomodulanti.
I liposomi sono stati studiati per la loro capacità di modulare l'acidificazione intracellulare e intrafagosomale nei macrofagi infettati.
La stimolazione con liposomi contenenti secondi messaggeri lipidici (come l’acido fosfatidico, fosfatidil-inositolo-3-fosfato; fosfatidil-inositolo-5-fosfato) favorisce la risposta antimicobatterica stimolando l'attivazione delle vie metaboliche che promuovono la produzione di ROS e la maturazione del fagolisosoma, aumentando così l'eliminazione intracellulare dei patogeni e suggerendo l’uso potenziale dei liposomi come strumenti immunoterapeutici innovativi.
Conclusioni:
I risultati di questa tesi forniscono una base scientifica per lo sviluppo di nuove terapie immunoprofilattiche e immunoterapeutiche al fine di proporre soluzioni innovative per il miglioramento della risposta immunitaria contro patogeni infettivi
Hair analysis for beta‐blockers and calcium‐channel blockers by using liquid chromatography‐tandem mass spectrometry as a tool for monitoring adherence to antihypertensive therapy
No full textAdherence to therapy is the key to a successful therapeutic intervention, especially in cardiovascular diseases in which a lack of adherence may have serious consequences in terms morbidity and/or mortality. In this context, hair analysis can be an excellent tool to monitor adherence to therapy. Indeed, drugs present in blood are incorporated into the hair matrix, where drugs and metabolites can stay unaltered for a long time protected from metabolism and degradation. In the present study, a simple, specific, and sensitive ultra-high performance liquid-chromatography-tandem mass spectrometry (UHPLC-MS/MS) method set up to determine in human hair seven beta-blockers (viz., metoprolol, sotalol, labetalol, atenolol, nebivolol, bisoprolol, and nadolol) and two calcium-channel blockers (lercanidipine and amlodipine), which are widely prescribed to treat medium-to-severe hypertensive conditions. The optimized method was successfully validated in terms of accuracy, repeatability, reproducibility, matrix effect and extraction recovery. Moreover, the applicability of the method was evaluated by analyzing 34 real samples of hair obtained from patients under long-term therapy with calcium channel blockers and beta-blockers
Hair analysis as a new tool to monitor adherence to long‐term therapy to statins
No full text: Statins are cholesterol-lowering medications which are widely prescribed as first-line treatment for hyperlipidemia, against high blood cholesterol aimed at reducing the risk of atherosclerotic diseases. Notwithstanding their undoubted efficacy, the needed long-term treatment with these drugs is characterized by a high percentage of dropout. Consequently, an effective tool to verify the patients' compliance to statin therapy is needed. In this context, the analysis for drugs and drug metabolites in the hair may represent an almost ideal tool because, according to a sound body of forensic toxicological literature, concentrations in the hair matrix reflect the chronic intake of drugs and pharmaceuticals. In this light, in the present study, a novel, specific and sensitive ultra-performance liquid chromatography-tandem mass spectrometry method has been developed to determine six statins and their metabolites (namely atorvastatin, (p)α-OH-atorvastatin-lactone, (o)α-OH-atorvastatin-lactone, rosuvastatin, N-desmethyl rosuvastatin and pravastatin) in human hair. After optimization, the method was successfully validated in terms of selectivity, linearity, sensitivity, precision, accuracy, stability and matrix effect. Moreover, the practical applicability of this method for verifying adherence to statin therapy was assessed by testing samples of hair collected from subjects under long-term therapy with statins
Platelet-Derived Extracellular Vesicles as Target of Antiplatelet Agents. What Is the Evidence?
No full textPlatelet-derived large extracellular vesicles (often referred to as microparticles in the field of cardiovascular disease) have been identified as effector in the atherothrombotic process, therefore representing a target of pharmacological intervention of potential interest. Despite that, limited evidence is so far available concerning the effects of antiplatelet agents on the release of platelet-derived extracellular vesicles. In the present narrative review, the mechanisms leading to vesiculation in platelets and the pathophysiological processes implicated will be discussed. This will be followed by a summary of the present evidence concerning the effects of antiplatelet agents under experimental conditions and in clinical settings
Risk of obstructive sleep apnea among health workers: results of a screening in a large Italian University Hospital
No full textPurposeObstructive sleep apnea (OSA) is a common respiratory sleep disorder, related to increased mortality, poor quality of life, and higher risk of work accidents and injuries. Studies on the risk of OSA (rOSA) among health workers (HW) are scant. The aims of this study were to investigate this issue in a large University Hospital and to assess the effectiveness of a screening program.MethodsThe STOP-BANG questionnaire (SBQ) was sent via e-mail to the 5031 HW employed at the University Hospital of Verona. HW who completed the SBQ were classified at low, moderate, and high rOSA. HW at high rOSA were invited to undergo nocturnal polygraphy. The determinants of rOSA were studied by non-parametric Kruskal-Wallis test, Pearson's chi-squared, and multinomial logistic model.ResultsOf 5031 HW, 1564 (31.1%) completed the online questionnaire. Responders with low, moderate, and high rOSA were 72.7%, 13.7%, and 13.6%. Male gender, older age, and higher body mass index (BMI) were significant predictors of high rOSA, as expected. Physicians had the lowest probability of being in the high-risk category. Polygraphy was performed in 64 subjects. The positive predictive value of the self-administered SBQ was 68.8% (95%C.I. 55.9-79.8%) but raised to 96.9% (95%C.I. 89.2-99.6%) when re-administered by medical staff.ConclusionSBQ showed its effectiveness as a screening tool in detecting undiagnosed OSA in HW. Systematic screening for OSA in work settings could allow early diagnosis and treatment, reducing short- and long-term health effects of OSA
Direct and specific analysis of nitrite and nitrate in biological and non-biological samples by capillary ion analysis for the rapid identification of fatal intoxications with sodium nitrite
No full textIn recent years, a significant increase of reports about suicidal cases due to intentional sodium nitrite intake has been described. In the forensic pathology context, the strategy to approach intoxication cases by sodium nitrite, without any preliminary information or hint, is not straightforward. Indeed, in a number of cases the lack of crime scene data and/or specific pathological signs makes difficult the identification of nitrite poisoning. Moreover, the analytical determination of nitrite in blood is challenging, due to its rapid oxidization to nitrate by hemoglobin. Although several methods have been proposed for the clinical analysis of nitrate and/or nitrite in biological samples, none of these is specifically focused on the determination of these ions in cadaveric samples. Consequently, the diagnosis of nitrite fatal intoxication is still based on methemoglobin analysis. The present paper reports the optimization and validation of an analytical method of capillary ion analysis (CIA) with UV detection, for the determination of nitrite and nitrate in biological fluids and its application to two authentic cases of death by nitrite intake. The analyses were carried out in a bare fused-silica capillary (75 μm inner diameter) using 100 mM sodium tetraborate (pH 9.24) as background electrolyte and applying a voltage of - 15 kV between the capillary ends. The detection was obtained by direct UV absorption recorded at 214 nm wavelength. Bromide was used as the internal standard. Linearity was established in the range of 0.25-5 mmol/L). Reproducibility (intraday and day-to-day) was characterized by relative standard deviations (RSDs) 14.7% for peak areas. The method was applied to the determination of nitrite and nitrate in two real forensic cases, where high concentrations of nitrate were found in cadaveric blood samples (6.5 and 4.4 mmol/L, respectively). Nitrite was found only in trace amounts, due to the instability of this ion in cadaveric blood where it is oxidized to nitrate. The present method represents a new tool for the direct and rapid determination of nitrite and nitrate in cases of forensic interest, and thus offers a diagnostic tool more sensitive and precise than the need methemoglobin analysis
Apnee ostruttive nel sonno negli operatori sanitari: risultati di uno screening in un ospedale universitario italiano
No full textLe Apnee Ostruttive del Sonno (OSA) sono caratterizzate da episodi di ostruzione delle prime vie aeree, associati a desaturazione ed attivazione del sistema adrenergico. Presentano alta prevalenza nella popolazione generale e possono essere correlate a sonnolenza diurna, ipertensione arteriosa ed alterazioni cognitive. Tuttavia, sono ancora ampiamente sotto-diagnosticate, anche per l’insufficienza di politiche di screening nelle popolazioni ad alto rischio (1). Ad oggi gli studi in ambito occupazionale hanno riguardato quasi esclusivamente il settore dei trasporti, mentre pochi dati sono disponibili sugli operatori della Sanità (OS
Reduction of Excessive Dietary Sodium Consumption: Effectiveness of a Prevention Intervention among Health Workers in a Large Italian Hospital
No full textExcessive salt consumption is one of the leading causes of high blood pressure. Worldwide salt intake largely exceeds the WHO recommended amount. This study aimed to evaluate the prevalence of high salt consumers and the effectiveness of a short-term workplace educational intervention among health workers. An online survey, assessing daily salt consumption through the MINISAL-SIIA questionnaire, was sent to the 4911 health workers employed by the University Hospital of Verona, Italy. Health workers who had a high (total score ≥ 10) or moderate (total score = 8/9) salt consumption associated with obesity or arterial hypertension were invited to undergo a medical examination and a short individual counselling session. A total of 1665 health workers (34.0%) completed the online questionnaire; 40.9% and 12.6% had moderate and high salt intake, respectively. High salt intake was more prevalent in men, current and past smokers, and obese and overweight subjects. In 95 participants completing the clinical phase, median daily salt consumption decreased from 10 (p25–p75 8–11) to 7 g (6–8) (p < 0.001), systolic blood pressure from 130 (120–140) to 120 (120–130) mmHg and weight from 78 (62–87) to 75 (62–86) kg. More than half of health workers had an excessive salt intake. However, a brief educational intervention in the healthcare working setting can substantially reduce unhealthy dietary habits, fostering weight loss and blood pressure control. Studies with a longer follow-up are needed to evaluate the persistence over time of these effects
Automatic Prostate Volume estimation on Transabdominal Ultrasound using Deep Neural Networks
No full textProstate cancer is the most commonly diagnosed cancer in the Netherlands. Accurate assessment of the prostate volume (PV) is a crucial step in prostate cancer (PCa) screening and risk-stratification. In standard clinical care, the PV is obtained by measuring the prostate dimensions with the aid of transrectal ultrasound (TRUS). However, rectal examination is characterised with patient discomfort, for which the feasibility of transabdominal ultrasound (TAUS) is explored, as a more accessible and patient-friendly alternative. However, manual PV measurements are prone to inter-observer variability and require operator training. This study aims to improve the accessibility, complexity, and robustness of PV measurements by developing a framework to automatically estimate the PV based on TAUS acquisitions. The primary components of the framework comprise two deep neural networks, developed for prostate segmentation on axial and sagittal TAUS images, and an algorithm that extracts the prostate's diameters on which the PV is calculated.During this study, a new prostate dataset is developed, comprising sagittal and transverse TAUS image acquisitions of 100 participants, and reference PV measurements based on TRUS and MRI are collected. First, the feasibility of TAUS for manual PV estimation is explored, and the inter-method agreement between TAUS, TRUS and MRI is analysed in Bland Altman diagrams. Additionally, all TAUS acquisitions are assessed on image quality. Secondly, three deep neural networks (using the nnU-Net framework) are developed to segment the prostate on sagittal and/or axial TAUS images. All models, are trained and validated on TAUS image data of 52 participants. Additionally, an algorithm is designed to predict the prostate diameters when prostate segmentations serve as input. To this extend, the PV is estimated according to the widely used Ellipsoid formula. The proposed algorithm is evaluated on input ground-truth segmentations of 42 participants. Essentially, the segmentation models combined with the proposed algorithm result in a framework to automatically estimate the PV on TAUS. Finally, it is tested on unseen TAUS acquisitions of 17 participants, whereby the predicted PV is compared to reference PV measurements on MRI. Our results show an average volume difference of 3.0 ± 17.6 ml when manual PV estimation on TAUS is compared to MRI. When manual PV estimation on TRUS is compared to MRI, an average volume difference of 12.3 ± 18.8 ml is obtained. The developed segmentations models segment the middle region of the prostate on TAUS with an average DSC = 0.91 ± 0.06 and DSC = 0.83 ± 0.09 for axial and sagittal TAUS images respectively. When the entire prostate region was evaluated, a lower model performance was observed, whereby the prostate was segmented with a DSC of 0.76 ± 0.09 in the axial imaging-plane and DSC of 0.68 ± 0.21 in the sagittal imaging-plane. The algorithm for automatic diameter extraction showed good correspondence with manually assigned prostate diameters on TAUS. When the segmentation models and the algorithm are utilised for automatic PV estimation, an average volume difference of 2.5 ± 10.2 ml was observed, compared to MRI reference volumes. Ultimately the PV was predicted with a volume difference < 25 compared to MRI in 14 out of 17 test cases. The results of this study show that it is possible to obtain PV measurements using TAUS that are comparable to those obtained with MRI. Moreover, the variability related to PV measurements using TAUS seem unrelated to TAUS image quality, indicating that manual PV measurements can be performed, even when unfavorable patient characteristics limit the image quality. Still, it is important to note that proper operator training for TAUS examination is essential. The proposed framework for automatic PV estimation on TAUS acquisitions shows good correspondence with MRI reference volumes. Thus expanding the possibilities of PCa risk-stratification, whereby robust, and straightforward PV estimations are desired. In order to adopt the framework for standard clinical care, further research is required on a larger cohort to investigate the generalizability of the framework and ensure reliable results on all future patients.TM30004; 35 ECTSTechnical Medicine | Imaging and Interventio
Circadian melatonin and temperature taus in delayed sleep-wake phase disorder and non-24-hour sleep-wake rhythm disorder patients: An ultradian constant routine study
No full textFerguson, SA ORCiD: 0000-0002-9682-7971Our objectives were to investigate the period lengths (i.e., taus) of the endogenous core body temperature rhythm and melatonin rhythm in delayed sleep-wake phase disorder patients (DSWPD) and non-24-h sleep-wake rhythm disorder patients (N24SWD) compared with normally entrained individuals. Circadian rhythms were measured during an 80-h ultradian modified constant routine consisting of 80 ultrashort 1-h "days" in which participants had 20-min sleep opportunities alternating with 40 min of enforced wakefulness. We recruited a community-based sample of 26 DSWPD patients who met diagnostic criteria (17 males, 9 females; age, 21.85 ± 4.97 years) and 18 healthy controls (10 males, 8 females; age, 23.72 ± 5.10 years). Additionally, 4 full-sighted patients (3 males, 1 female; age, 25.75 ± 4.99 years) were diagnosed with N24SWD and included as a discrete study group. Ingestible core temperature capsules were used to record minute temperatures that were averaged to obtain 80 hourly data points. Salivary melatonin concentration was assessed every half-hour to determine time of dim light melatonin onset at the beginning and end of the 80-h protocol. DSWPD patients had significantly longer melatonin rhythm taus (24 h 34 min ± 17 min) than controls (24 h 22 min ± 15 min, p = 0.03, d = 0.70). These results were further supported by longer temperature rhythm taus in DSWPD patients (24 h 34 min ± 26 min) relative to controls (24 h 13 min ± 15 min, p = 0.01, d = 0.80). N24SWD patients had even longer melatonin (25 h ± 19 min) and temperature (24 h 52 min ± 17 min) taus than both DSWPD (p = 0.007, p = 0.06) and control participants (p < 0.001, p = 0.02, respectively). Between 12% and 19% of the variance in DSWPD patients' sleep timing could be explained by longer taus. This indicates that longer taus of circadian rhythms may contribute to the DSWPD patients' persistent tendency to delay, their frequent failure to respond to treatment, and their relapse following treatment. Additionally, other factors can contribute to misalignments in DSWPD and N24SWD disorders. © 2016 The Author(s).Associated Grant:Australian Research Council Discovery ProjectAssociated Grant Code:DP12010140
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