Extended Identification of Mechanical Parameters and Boundary Conditions by Digital Image Correlation

Abstract This paper represents a further contribution to the study of identification procedures for material mechanics resting on kinematic measurements provided by 2D Digital Image Correlation (DIC) at the microscale. Reference is made to non-conventional experiments on adhesively bonded assemblies industrially manufactured for aerospace applications. For calibration purposes a local approach is considered under plane stress conditions, focusing on a small sub-domain on the sample surface, in which mixed mode debonding is monitored. As a novelty, both the (cohesive) mechanical parameters of the interface and the actual boundary conditions prescribed at different time instants during the test are considered as unknowns to be estimated on the basis of full-field data. In this way, data smoothing and parameter identification procedures, so far usually performed in a sequence, are tackled simultaneously in a coupled framework. Since the inverse problem generalized as mentioned above turns out to be severely ill-posed, suitable regularizing provisions are applied, concerning the a priori regularity of (kinematic) displacement fields, from which boundary data are sampled, and the equilibrium (Neumann) conditions along the cracked part of the interface

Selective inhibition of phosphodiesterase 4D increases tau phosphorylation at Ser214 residue

Tau is a protein that normally participates in the assembly and stability of microtubules. However, it can form intraneuronal hyperphosphorylated aggregates that are hallmarks of Alzheimer's disease and other neurodegenerative disorders known as tauopathies. Tau can be phosphorylated by multiple kinases at several sites. Among such kinases, the cAMP-dependent protein kinase A (PKA) phosphorylates tau at Ser214 (pTAU-S214), an event that was shown to reduce the pathological assembly of the protein. Given that the neuronal cAMP/PKA-activated cascade is involved in synaptic plasticity and memory, and that cAMP-enhancing strategies demonstrated promising therapeutic potential for the treatment of cognitive deficits, we investigated the impact of cAMP on pTAU-S214 in N2a cells and rat hippocampal slices. Our results confirm that the activation of adenylyl cyclase increases pTAU-S214 in both model systems and, more interestingly, this effect is mimicked by GEBR-7b, a phosphodiesterase 4D inhibitor with proven pro-cognitive efficacy in rodents

MicroRNA-155 influences B-cell function through PU.1 in rheumatoid arthritis

MicroRNA-155 (miR-155) is an important regulator of B cells in mice. B cells have a critical role in the pathogenesis of rheumatoid arthritis (RA). Here we show that miR-155 is highly expressed in peripheral blood B cells from RA patients compared with healthy individuals, particularly in the IgD-CD27- memory B-cell population in ACPA+ RA. MiR-155 is highly expressed in RA B cells from patients with synovial tissue containing ectopic germinal centres compared with diffuse synovial tissue. MiR-155 expression is associated reciprocally with lower expression of PU.1 at B-cell level in the synovial compartment. Stimulation of healthy donor B cells with CD40L, anti-IgM, IL-21, CpG, IFN-α, IL-6 or BAFF induces miR-155 and decreases PU.1 expression. Finally, inhibition of endogenous miR-155 in B cells of RA patients restores PU.1 and reduces production of antibodies. Our data suggest that miR-155 is an important regulator of B-cell activation in RA

Mobilization of Hematopoietic Stem Cells with Lenograstim in Healthy Donors: Efficacy and Safety Analysis According to Donor Age

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Studio della mammella con protesi in tomosintesi

OBJECTIVE Optimization of a low-dose protocol with Tomosynthesis technique for the study of breast with prosthesis during the screening process. INTRODUCTION TO THE STUDY  Guidelines in both Italy, UK and US agree that 2D mammography, in the presence of prostheses, does not offer a reliable diagnosis and therefore invite clinicians to perform the Eklund maneuver. Due to the typical radiopacity of implants, Tomosynthesis is not currently the technique of choice for screening this type of breast. In this study, we wanted to experiment a protocol in which Tomosynthesis can be used to provide more diagnostic information even in the presence of breast implants, reconciling the technical, methodological and dosimetric aspects. MATERIALS AND METHODS  A total of 53 women who joined the breast screening program reserved for women with prostheses aged between 50 and 74 years, in the ASL Roma 1, were enrolled in this study. These women were asked for consent to acquire the images also with Tomosynthesis. In a first group of 15 women, using a standard configuration for the automatic exposure control algorithm (AEC), present on the IMS Giotto Class mammography unit, eight projections were acquired: four with digital mammography with prosthesis included and four in Tomosynthesis with Eklund's maneuver. A low-dose configuration of the AEC was activated in a second group of 38 women. The average age of the women who took part in the study was between 50 and 65. One woman returned to the screening program 10 years after the quadrantectomy. RESULTS  From the analysis and comparison of the data acquired in the different study modes, it emerged that the study in Mammography mode, with only four projections with prosthesis included, with standard exposure meter, is associated with an average glandular dose of 7.5 mGy. If the Eklund maneuver is also performed in Tomosynthesis mode, the woman is exposed to an average of 11 mGy in total. A low-dose configuration of the AEC, for the eight projections, also acquired in tomosynthesis, is associated with an average glandular dose equal to 9.2 mGy total. This dedicated configuration allows to lower the dose by 15%, while maintaining adequate image quality. DISCUSSION At the present time, Tomosynthesis for the study of breasts with prostheses is not considered a valid diagnostic test yet, mainly due to the encumbrance of the prosthesis. However, the results of this test seem to highlight the possibility to use it effectively. CONCLUSIONS The study methodology tested is based on the best practices and on the most innovative technologies specifically designed for mammography. This methodology was able to improve the accuracy of screening tests, guarantee a controlled glandular dose and an adequate iconographic result. By disseminating this methodology, we may be able to increase the qualitative level of performance in the identified target.OBIETTIVO Ottimizzazione di un protocollo a bassa dose con tecnica Tomosintesi per lo studio delle mammelle con protesi, nel percorso di screening. INTRODUZIONE ALLO STUDIO le linee guida in Italia, in UK e negli Stati Uniti concordano che la mammografia 2D, in presenza di protesi, non offra una diagnosi affidabile e pertanto invitano ad effettuare anche la manovra di Eklund. A causa della tipica radiopacità delle protesi, la Tomosintesi, attualmente, non rappresenta la tecnica di elezione per lo screening di questo tipo di mammelle. Abbiamo voluto sperimentare un protocollo in cui sia possibile utilizzare la Tomosintesi per dare maggiori informazioni diagnostiche anche in presenza di protesi mammarie, conciliando l’aspetto tecnico, metodologico e dosimetrico. MATERIALI E METODI Sono state arruolate in totale 53 donne che hanno aderito al programma di screening della mammella, riservato a donne con protesi di età compresa tra i 50 ed i 74 anni, nella ASL Roma 1. A queste donne è stato chiesto il consenso di acquisire le immagini anche con la Tomosintesi. In un primo gruppo di 15 donne, utilizzando una configurazione standard per l’algoritmo di controllo automatico dell’esposizione (AEC) presente sul mammografo IMS Giotto Class, sono state acquisite otto proiezioni, di cui quattro con mammografia digitale con protesi inclusa, e quattro in Tomosintesi con manovra di Eklund. In un secondo gruppo di 38 donne si è attivata una configurazione a bassa dose dell’AEC. L’età media delle donne che hanno fatto parte dello studio è compresa tra i 50 ed i 65 anni. Una donna rientrava nel programma di screening dopo 10 anni dall’intervento di quadrantectomia. RISULTATI Dall’analisi e dal confronto dei dati acquisiti nelle diverse modalità di studio è emerso che allo studio in modalità Mammografia, con le sole quattro proiezioni a protesi inclusa, con esposimetro standard, è associata una dose media ghiandolare di 7.5 mGy. Se si effettua anche la manovra di Eklund in modalità Tomosintesi si espone la donna ad una media di 11 mGy totali. Ad una configurazione a bassa dose dell’AEC, per le otto proiezioni, acquisite anche in tomosintesi, è associata una dose media ghiandolare pari a 9,2 mGy totali.  Questa configurazione dedicata consente di abbassare la dose del 15%, mantenendo adeguata la qualità delle immagini. DISCUSSIONE Al momento attuale la Tomosintesi per lo studio delle mammelle con protesi non è ancora considerata un valido test diagnostico, principalmente a causa dell’ingombro della protesi; tuttavia, i risultati di questo test sembrano rendere ipotizzabile un suo efficace utilizzo. CONCLUSIONI La metodica di studio sperimentata è basata sulle migliori pratiche e sulle più innovative tecnologie appositamente progettate per la mammografia. Si è dimostrata in grado di migliorare l’accuratezza dei test di screening, ha garantito una dose ghiandolare controllata ed un risultato iconografico adeguato. Diffondendo tale metodologia potremmo essere in grado di aumentare il livello qualitativo delle prestazioni nel target identificato

Fatal Takotsubo syndrome in critical COVID-19 related pneumonia

COVID-19 can involve several organs and systems, often with indirect and poorly clarified mechanisms. Different presentations of myocardial injury have been reported, with variable degrees of severity, often impacting on the prognosis of COVID-19 patients. The pathogenic mechanisms underlying cardiac damage in SARS-CoV-2 infection are under active investigation. We report the clinical and autopsy findings of a fatal case of Takotsubo Syndrome occurring in an 83-year-old patient with COVID-19 pneumonia. The patient was admitted to Emergency Department with dyspnea, fever and diarrhea. A naso-pharyngeal swab test for SARS-CoV-2 was positive. In the following week his conditions worsened, requiring intubation and deep sedation. While in the ICU, the patient suddenly showed ST segment elevation. Left ventricular angiography showed decreased with hypercontractile ventricular bases and mid-apical ballooning, consistent with diagnosis of Takotsubo syndrome (TTS). Shortly after the patient was pulseless. After extensive resuscitation maneuvers, the patient was declared dead. Autopsy revealed a subepicardial hematoma, in absence of myocardial rupture. On histology, the myocardium showed diffuse edema, multiple foci of contraction band necrosis in both ventricles and occasional coagulative necrosis of single cardiac myocytes. Abundant macrophages CD68+ were detected in the myocardial interstitium. The finding of diffuse contraction band necrosis supports the pathogenic role of increased catecholamine levels; the presence of a significant interstitial inflammatory infiltrate, made up by macrophages, remains of uncertain significance

Metabolomic fingerprinting of renal disease progression in Bardet-Biedl syndrome reveals mitochondrial dysfunction in kidney tubular cells.

Chronic kidney disease (CKD) is a major clinical sign of patients with Bardet-Biedl syndrome (BBS), especially in those carrying BBS10 mutations. Twenty-nine patients with BBS and 30 controls underwent a serum-targeted metabolomic analysis. In vitro studies were conducted in two kidney-derived epithelial cell lines, where Bbs10 was stably deleted (IMCD3-Bbs10-/-cells) and over-expressed. The CKD status affected plasmatic metabolite fingerprinting in both patients with BBS and controls. Specific phosphatidylcholine and acylcarnitines discriminated eGFR decline only in patients with BBS. IMCD3-Bbs10-/ cells displayed intracellular lipidaccumulation, reduced mitochondrial potential membrane and citrate synthase staining. Mass-Spectrometry-based analysis revealed that human BBS10 interacted with six mitochondrial proteins, in vitro. In conclusion, renal dysfunction correlated with abnormal phosphatidylcholine and acylcarnitines plasma levels in patients with BBS; in vitro, Bbs10 depletion caused mitochondrial defects while human BBS10 interacted with several mitochondria-related proteins, suggesting an unexplored role of this protein

Memory-enhancing effects of GEBR-32a, a new PDE4D inhibitor holding promise for the treatment of Alzheimer\u2019s disease.

Memory loss characterizes several neurodegenerative disorders, including Alzheimer’s disease (AD). Inhibition of type 4 phosphodiesterase (PDE4) and elevation of cyclic adenosine monophosphate (cAMP) has emerged as a promising therapeutic approach to treat cognitive deficits. However, PDE4 exists in several isoforms and pan inhibitors cannot be used in humans due to severe emesis. Here, we present GEBR-32a, a new PDE4D full inhibitor that has been characterized both in vitro and in vivo using biochemical, electrophysiological and behavioural analyses. GEBR-32a efficiently enhances cAMP in neuronal cultures and hippocampal slices. In vivo pharmacokinetic analysis shows that GEBR-32a is rapidly distributed within the central nervous system with a very favourable brain/blood ratio. Specific behavioural tests (object location and Y-maze continuous alternation tasks) demonstrate that this PDE4D inhibitor is able to enhance memory in AD transgenic mice and concomitantly rescues their hippocampal long-term potentiation deficit. Of great relevance, our preliminary toxicological analysis indicates that GEBR-32a is not cytotoxic and genotoxic, and does not seem to possess emetic-like side effects. In conclusion, GEBR-32a could represent a very promising cognitive-enhancing drug with a great potential for the treatment of Alzheimer’s disease

Global longitudinal strain at rest predicts significant coronary artery stenosis in patients with peripheral arterial disease

Abstract Funding Acknowledgements Type of funding sources: None. Background Critical peripheral artery disease (PAD) is expression of systemic chronic atherosclerosis, it being often associated with cardiovascular events. The assessment of global longitudinal strain (GLS) at rest by speckle tracking echocardiography could be useful to unmask significant coronary artery disease (CAD) in asymptomatic PAD patients. Purpose To determine whether resting GLS is able to predict significant coronary artery stenosis in PAD patients selected for peripheral or carotid angiography. Methods One-hundred three clinically relevant PAD patients (M/F = 76/27, age = 66.8 ± 10,2 years, 72 with significant lower limb artery stenosis and 31 with carotid artery stenosis ≥50%), asymptomatic for CAD, underwent standard echo-Doppler exam at rest, comprehensive of GLS analysis, prior peripheral and coronary angiography. Information on cardiovascular (CV) risk factors and comorbidities were collected. Patients with know CAD and previous myocardial infarction, left ventricular (LV) ejection fraction < 50% and inadequate echocardiographic imaging were excluded. According to the results of coronary angiography, patients were divided in two groups: with significant coronary artery stenosis (>50% of obstruction. n = 73) and without significant coronary artery lesions (n = 30). Results No intergroup difference in the prevalence of CV risk factors and comorbidities was found. Age, body mass index and blood pressure were comparable between the two groups. LV ejection fraction (59.9 ± 4.2% in patients with significant coronary stenosis vs. 60.2 ± 4.7% in those without coronary stenosis, p = 0.75) and wall motion score index (1.02 ± 0.09 vs 1.03 ± 0.09 respectively, p = 0.67) did not differ significantly. Conversely, GLS was lower in patients with significant coronary artery stenosis than in those without (21.6 ± 2.7% vs. 22.8 ± 2%, p < 0.02) (Figure 1). This difference remained significant comparing the carotid subgroup with coronary stenosis vs. those without (p < 0.05) whereas it did not achieve the statistical significance in patients with lower limb artery lesions (p = 0.42). Conclusion In PAD patients, GLS at rest shoes the capability in identifying patients at higher probability of significant coronary artery stenosis. This involves in particular patients with carotid artery stenosis. GLS might be helpful to select patients who need to extend the peripheral angiographic evaluation to the coronary tree