New perspectives for transcatheter aortic valve implantation: the "coup d'essai" of bicuspid aortic valves

Outline of the thesis The thesis is divided in four parts. Part I: Aortic valve disease and innovation in percutaneous treatment by transcatheter aortic valve implantation. In this first section of the thesis we present some research projects published in the field of transcatheter aortic valve replacement in general population, describing the progress of this percutaneous technique during the past years until nowadays practice. In this section there are some considerations about TAVI in particular scenarios and procedural settings requiring dedicated technical adjustments. Part II: TAVI in a complex anatomical setting: Bicuspid Aortic Valve management and percutaneous treatment. In this second section we collected research papers focused on the challenging anatomy of bicuspid aortic valves (BAV) undergoing TAVI treatment for aortic stenosis (AS). In contemporary TAVI practice BAV anatomy still represents a challenge for percutaneous treatment. This section is the real focus of the three years of PhD research, since the complexity of the topic and the time required for data collection and analysis. Moreover, this part represents the result of an International collaboration and knowledge sharing among renowned centres for the percutaneous treatment of aortic disease. Part III: Imaging for TAVI in Bicuspid Aortic Valve. This section includes research papers investigating the role of imaging, in particular of multi-sliced computed tomography (MSCT), in BAV patients undergoing TAVI procedure, considering the lack of standardized protocols for sizing and device choice in this complex aortic valve anatomy. Part IV: Discussion and Conclusions. The last part of the thesis is a discussion of the presented topics with some conclusions

The glutaminase-dependent acid resistance system. Qualitative and quantitative assays and analysis of its distribution in enteric bacteria

Neutralophilic bacteria have developed several strategies to overcome the deleterious effects of acid stress. In particular, the amino acid-dependent systems are widespread, with their activities overlapping, covering a rather large pH range, from 6 to <2. Recent reports showed that an acid resistance (AR) system relying on the amino acid glutamine (AR2_Q), the most readily available amino acid in the free form, is operative in Escherichia coli, Lactobacillus reuteri and some Brucella species. This system requires a glutaminase active at acidic pH and the antiporter GadC to import L-glutamine and export either glutamate (the glutamine deamination product) or GABA. The latter occurs when the deamination of glutamine to glutamate, via acid-glutaminase (YbaS/GlsA), is coupled to the decarboxylation of glutamate to GABA, via glutamate decarboxylase (GadB), a structural component of the glutamate-dependent AR (AR2) system, together with GadC. Taking into account that AR2_Q could be widespread in bacteria and that until now assays based on ammonium ion detection were typically employed, this work was undertaken with the aim to develop assays that allow a straightforward identification of the acid-glutaminase activity in permeabilised bacterial cells (qualitative assay) as well as a sensitive method (quantitative assay) to monitor in the pH range 2.5-4.0 the transport of the relevant amino acids in vivo. The qualitative assay is colorimetric, rapid and reliable and provides several additional information, such as co-occurrence of AR2 and AR2_Q in the same bacterial species and assessment of the growth conditions that support maximal expression of glutaminase at acidic pH. The quantitative assay is HPLC-based and allows to concomitantly measure the uptake of glutamine and the export of glutamate and/or GABA via GadC in vivo and depending on the external pH. Finally, an extensive bioinformatic genome analysis shows that the gene encoding the glutaminase involved in AR2_Q is often nearby or in operon arrangement with the genes coding for GadC and GadB. Overall, our results indicate that AR2_Q is likely to be of prominent importance in the AR of enteric bacteria and that it modulates the enzymatic as well as antiport activities depending on the imposed acidic stress

Effects of physical activity on endothelial progenitor cells (EPCs)

Physical activity has a therapeutic role in cardiovascular disease (CVD), through its beneficial effects on endothelial function and cardiovascular system. Circulating endothelial progenitor cells (EPCs) are bone marrow (BM) derived cells that represent a novel therapeutic target in CVD patients, because of their ability to home to sites of ischemic injury and repair the damaged vessels. Several studies show that physical activity results in a significant increase in circulating EPCs, and, in particular, there are some evidence of the beneficial exercise-induced effects on EPCs activity in CVD settings, including coronary artery disease (CAD), heart failure (HF), and peripheral artery disease (PAD). The aim of this paper is to review the current evidence about the beneficial effects of physical exercise on endothelial function and EPCs levels and activity in both healthy subjects and patients with CVD

Everolimus-associated interstitial pneumonia in a renal transplant patient: a case report

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How to Make the TAVI Pathway More Efficient

Transcatheter aortic valve implantation (TAVI) has been in use for 16 years. As there has been a rapid expansion in its use, there is a need to optimise TAVI programmes to ensure efficiency. In this article, the authors discuss the reasons why clinicians need to make the TAVI pathway more efficient and describe the most important steps to take from screening to early discharge, including procedural optimisation

RET mutation and increased angiogenesis in medullary thyroid carcinomas

Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs. RET mutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors. We examined 45 MTCs with germ-line or somatic RET mutations (RETmut group) and 34 with wild-type RET (RETwt). Taqman Low-Density Arrays were used to assess proangiogenic gene expression. Immunohistochemistry was used to assess intratumoral, peritumoral and nontumoral expression levels of VEGFR1, R2, R3, PDGFRa, PDGFB and NOTCH3. We also assessed microvessel density (MVD) and lymphatic vessel density (LVD) based on CD31-positive and podoplanin-positive vessel counts, respectively, and vascular pericyte density based on staining for a-smooth muscle actin (a-SMA), a pericyte marker. Compared with RETwt tumors, RETmut tumors exhibited upregulated expression of proangiogenic genes (mRNA and protein), especially VEGFR1, PDGFB and NOTCH3. MVDs and LVDs were similar in the two groups. However, microvessels in RETmut tumors were more likely to be a-SMA positive, indicating enhanced coverage by pericytes, which play key roles in vessel sprouting, maturation and stabilization. These data suggest that angiogenesis in RETmut MTCs may be more intense and complete than that found in RETwt tumors, a feature that might increase their susceptibility to antiangiogenic therapy. Given their increased vascular pericyte density, RETmut MTCs might also benefit from combined or preliminary treatment with PDGF inhibitors

Bone Marrow Edema: Overview of Etiology and Treatment Strategies

➤: Bone marrow edema (BME) is a nonspecific but relevant finding, usually indicating the presence of an underlying pathology. ➤: The gold standard technique for detecting BME is magnetic resonance imaging (MRI), as it allows for a correct diagnosis to be made, which is extremely important given the heterogeneity of BME-related diseases. ➤: Depending on the severity of painful symptomatology and the MRI evidence, different treatment strategies can be followed: physical modalities, pharmacological options, and surgical therapy

Sex-Specific Considerations in Degenerative Aortic Stenosis for Female-Tailored Transfemoral Aortic Valve Implantation Management

The impact of sex on pathophysiological processes, clinical presentation, treatment options, as well as outcomes of degenerative aortic stenosis remain poorly understood. Female patients are well represented in transfemoral aortic valve implantation (TAVI) trials and appear to derive favorable outcomes with TAVI. However, higher incidences of major bleeding, vascular complications, and stroke have been reported in women following TAVI. The anatomical characteristics and pathophysiological features of aortic stenosis in women might guide a tailored planning of the percutaneous approach. We highlight whether a sex-based TAVI management strategy might impact on clinical outcomes. This review aimed to evaluate the impact of sex from diagnosis to treatment of degenerative aortic stenosis, discussing the latest evidence on epidemiology, pathophysiology, clinical presentation, therapeutic options, and outcomes. Furthermore, we focused on technical sex-oriented considerations in TAVI including the preprocedural screening, device selection, implantation strategy, and postprocedural management

Adipokines and coronary artery disease

Adipose tissue, besides being an important energetic storage, is also a source of cytokines and hormones which act in a paracrine, autocrine and especially endocrine manner, influencing the cardiometabolic axis. Adipokines are a group of mediators with pleiotropic function, that are involved in many physiological processes, so that a disregulation in their secretion can lead to multiple pathological conditions. In this review our aim was to clarify the role of adipokines in the pathogenesis of atherosclerosis, especially in coronary artery disease, and based on current scientific evidence, to analyze the therapeutic and behavioral strategies that are so far available

KIT/PDGFRA Variant Allele Frequency as Prognostic Factor in Gastrointestinal Stromal Tumors (GISTs): Results From a Multi-Institutional Cohort Study

Background: The patient selection for optimal adjuvant therapy in gastrointestinal stromal tumors (GISTs) is provided by nomogram based on tumor size, mitotic index, tumor location, and tumor rupture. Although mutational status is not currently used to risk assessment, tumor genotype showed a prognostic influence on natural history and tumor relapse. Innovative measures, such as KIT/PDGFRA-mutant-specific variant allele frequency (VAF) levels detection from next-generation sequencing (NGS), may act as a surrogate of tumor burden and correlate with prognosis and overall survival of patients with GIST, helping the choice for adjuvant treatment. Patients and methods: This was a multicenter, hospital-based, retrospective/prospective cohort study to investigate the prognostic role of KIT or PDGFRA-VAF of GIST in patients with radically resected localized disease. In the current manuscript, we present the results from the retrospective phase of the study. Results: Two-hundred (200) patients with GIST between 2015 and 2022 afferent to 6 Italian Oncologic Centers in the EURACAN Network were included in the study. The receiver operating characteristic (ROC) curves analysis was used to classify "low" vs. "high" VAF values, further normalized on neoplastic cellularity (nVAF). When RFS between the low and high nVAF groups were compared, patients with GIST with KIT/PDGFRA nVAF &gt; 50% showed less favorable RFS than patients in the group of nVAF ≤ 50% (2-year RFS, 72.6% vs. 93%, respectively; P = .003). The multivariable Cox regression model confirmed these results. In the homogeneous sub-population of intermediate-risk, patients with KIT-mutated GIST, the presence of nVAF &gt;50% was statistically associated with higher disease recurrence. Conclusion: In our study, we demonstrated that higher nVAF levels were independent predictors of GIST prognosis and survival in localized GIST patients with tumors harboring KIT or PDGFRA mutations. In the cohort of intermediate-risk patients, nVAF could be helpful to improve prognostication and the use of adjuvant imatinib