Multiscale, patient-specific computational fluid dynamics models predict formation of neointimal hyperplasia in saphenous vein grafts

Stenosis due to neointimal hyperplasia (NIH) is among the major causes of peripheral graft failure. Its link to abnormal hemodynamics in the graft is complex, and isolated use of hemodynamic markers is insufficient to fully capture its progression. Here, a computational model of NIH growth is presented, establishing a link between computational fluid dynamics simulations of flow in the lumen and a biochemical model representing NIH growth mechanisms inside the vessel wall. For all three patients analyzed, NIH at proximal and distal anastomoses was simulated by the model, with values of stenosis comparable to the computed tomography scans

An in silico study of the influence of vessel wall deformation on neointimal hyperplasia progression in peripheral bypass grafts

Neointimal hyperplasia (NIH) is a major obstacle to graft patency in the peripheral arteries. A complex interaction of biomechanical factors contribute to NIH development and progression, and although haemodynamic markers such as wall shear stress have been linked to the disease, these have so far been insufficient to fully capture its behaviour. Using a computational model linking computational fluid dynamics (CFD) simulations of blood flow with a biochemical model representing NIH growth mechanisms, we analyse the effect of compliance mismatch, due to the presence of surgical stitches and/or to the change in distensibility between artery and vein graft, on the haemodynamics in the lumen and, subsequently, on NIH progression. The model enabled to simulate NIH at proximal and distal anastomoses of three patient-specific end-to-side saphenous vein grafts under two compliance-mismatch configurations, and a rigid wall case for comparison, obtaining values of stenosis similar to those observed in the computed tomography (CT) scans. The maximum difference in time-averaged wall shear stress between the rigid and compliant models was 3.4 Pa, and differences in estimation of NIH progression were only observed in one patient. The impact of compliance on the haemodynamic-driven development of NIH was small in the patient-specific cases considered

Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function

cAMP signaling in the brain mediates several higher order neural processes. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels directly bind cAMP through their cytoplasmic cyclic nucleotide binding domain (CNBD), thus playing a unique role in brain function. Neuronal HCN channels are also regulated by tetratricopeptide repeat-containing Rab8b interacting protein (TRIP8b), an auxiliary subunit that antagonizes the effects of cAMP by interacting with the channel CNBD. To unravel the molecular mechanisms underlying the dual regulation of HCN channel activity by cAMP/TRIP8b, we determined the NMR solution structure of the HCN2 channel CNBD in the cAMP-free form and mapped on it the TRIP8b interaction site. We reconstruct here the full conformational changes induced by cAMP binding to the HCN channel CNBD. Our results show that TRIP8b does not compete with cAMP for the same binding region; rather, it exerts its inhibitory action through an allosteric mechanism, preventing the cAMP-induced conformational changes in the HCN channel CNBD

Beta-lactam antibiotic offers neuroprotection in a spinal muscular atrophy model by multiple mechanisms

Spinal muscular atrophy (SMA) is the most common genetic neurodegenerative disease leading to death in childhood. SMA is characterized by the loss of spinal cord anterior horn neurons and progressive denervation of skeletal muscles. SMA is caused by deletion or mutation of the telomeric copy of human survival motor neuron gene 1 (hSMN1) and retention of the hSMN2 gene. SMA animal models are extremely useful in studying the mechanism of SMA-related motoneuronal death, and may provide an in vivo system for testing a potential SMA therapy

Sequential LASER ART and CRISPR treatments eliminate HIV-1 in a subset of infected humanized mice

Elimination of HIV-1 requires clearance and removal of integrated proviral DNA from infected cells and tissues. Here, sequential long-acting slow-effective release antiviral therapy (LASER ART) and CRISPR-Cas9 demonstrate viral clearance in latent infectious reservoirs in HIV-1 infected humanized mice. HIV-1 subgenomic DNA fragments, spanning the long terminal repeats and the Gag gene, are excised in vivo, resulting in elimination of integrated proviral DNA; virus is not detected in blood, lymphoid tissue, bone marrow and brain by nested and digital-droplet PCR as well as RNAscope tests. No CRISPR-Cas9 mediated off-target effects are detected. Adoptive transfer of human immunocytes from dual treated, virus-free animals to uninfected humanized mice fails to produce infectious progeny virus. In contrast, HIV-1 is readily detected following sole LASER ART or CRISPR-Cas9 treatment. These data provide proof-of-concept that permanent viral elimination is possible

Activity and safety of NGR-hTNF, a selective vascular-targeting agent, in previously treated patients with advanced hepatocellular carcinoma

Background:Hepatocellular carcinoma (HCC) is a highly vascularised and poor-prognosis tumour. NGR-hTNF is a vascular-targeting agent consisting of human tumour necrosis factor-alpha fused to the tumour-homing peptide NGR, which is able to selectively bind an aminopeptidase N overexpressed on tumour blood vessels.Methods:Twenty-seven patients with advanced-stage disease resistant to either locoregional (59%; range, 1-3), systemic treatments (52%; range, 1-3) or both (33%) received NGR-hTNF 0.8 gm-2 once every 3 weeks. The primary aim of the study was progression-free survival (PFS).Results:No grade 3-4 treatment-related toxicities were noted. Common toxicity included mild-to-moderate, short-lived chills (63%). Median PFS was 2.3 months (95% CI: 1.7-2.9). A complete response ongoing after 20 months was observed in a sorafenib-refractory patient and a partial response in a Child-Pugh class-B patient, yielding a response rate of 7%. Six patients (22%) experienced stable disease. The disease control rate (DCR) was 30% and was maintained for a median PFS time of 4.3 months. Median survival was 8.9 months (95% CI: 7.5-10.2). In a subset of 12 sorafenib-resistant patients, the response rate was 8% and the median survival was 9.5 months.Conclusion:NGR-hTNF was well tolerated and showed single-agent activity in HCC. Further investigation in HCC is of interest

HIV-1 specific IgA detected in vaginal secretions of HIV uninfected women participating in a microbicide trial in Southern Africa are primarily directed toward gp120 and gp140 specificities.

CAPRISA, 2014.Abstract available in pdf

Depressione post-natale : studio pilota sui fattori di rischio in un gruppo di donne del Nord Italia

Aim. This research aimed to study the risk factors which predispose women to post partum depression. This study was conducted on women from a rural province in northern Italy. Methods. The women enrolled in the study were interviewed and completed the Symptom Checklist 90-R (SCL 90R) and Edinburgh Postnatal Depression Scale (EPDS) scales at 12 weeks of pregnancy and at 12 weeks post partum. Interviews prior to birth were focused on the emotional significance of pregnancy while interviews after birth were on the relationships with the partner and the family and on the birthing experience. Results. Two groups emerged, a low risk group and a medium-high risk group. Conclusion. Prenatal fears, the birthing experience and post partum stress involving caring for the newborn child, concurrent with specific personality traits are the greatest risk factors forpost partum depression

Un modello di ripartenza post Covid per i territori fragili di montagna. Il caso di TWIN

La recente pandemia ha riportato i territori montani al centro dei dibattiti politici e accademici, fornendo un’importante occasione per pensare a un progetto di ripartenza. Con la prospettiva di valorizzare il potenziale montano, il turismo post-Covid può farsi promotore di una rigenerazione complessiva, di luoghi e comunità. In quest’ottica il binomio turismo lento su linea (sentieri, cammini e ciclabili) e inclusione sociale può diventare un’opportunità per una strategia unitaria di rilancio dei territori. Per esplorare questa possibilità viene analizzato il caso del progetto Trekking Walking Cycling for Inclusion (twin), un modello replicabile, pensato per trasformare le fragilità in punto di forza