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Aims: To compare early and late mortality of acute isolated tricuspid valve infective endocarditis (TVIE) treated with valve repair or replacement., Methods: Patients who were surgically treated for TVIE from 1983 to 2018 were retrieved from the Italian Registry for Surgical Treatment of Valve and Prosthesis Infective Endocarditis. All the patients were followed up by means of phone interview or calling patient referral physicians or cardiologists. Kaplan-Meier method was used to assess late survival and survival free from TVIE recurrence with log-rank test for univariate comparison. The primary end points were early mortality (30 days after surgery) and long-term survival free from TVIE recurrence., Results: A total of 4084 patients were included in the registry. Among them, 149 patients were included in the study. Overall, 77 (51.7%) underwent TV repair and 72 (48.3%) TV replacement. Early mortality was 9% (13 patients). Expected early mortality according to EndoSCORE was 12%. The TV repair showed lower mortality and major complication rate (7% and 16%), compared with TV replacement (11% and 25%), but statistical significance was not reached. Median follow-up was 19.1 years (14.3-23.8). Late deaths were 30 and IE recurrences were 5. No difference in cardiac survival free from IE was found between the two groups after 20 years (80 ± 6% Repair Group vs 59 ± 13% Replacement Group, P = 0.3)., Conclusions: Overall results indicate that once surgically addressed, TVIE has a low recurrence rate and excellent survival, apparently regardless of the type of surgery used to treat it., (Copyright © 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.)

Objectives: Endocarditis after the Bentall procedure is a severe disease often complicated by a pseudoaneurysm or mediastinitis. Reoperation is challenging but conservative therapy is not effective. The aim of this study was to assess short- and midterm outcomes of patients reoperated on for Bentall-related endocarditis., Methods: Seventy-three patients with Bentall procedure-related endocarditis were recorded in the Italian registry. The mean age was 57 ± 14 years and 92% were men; preoperative comorbidities included hypertension (45%), diabetes (12%) and renal failure (11%). The logistic EuroSCORE was 25%; the EuroSCORE II was 8%., Results: Preoperatively, 12% of the patients were in septic shock; left ventricular-aortic discontinuity was present in 63% and mitral valve involvement occurred in 12%. The most common pathogens were Staphylococcus aureus (22%) and Streptococci (14%). Reoperations after a median interval of 30 months (1-221 months) included a repeat Bentall with a bioconduit (41%), a composite mechanical (33%) or biological valved conduit (19%) and a homograft (6%). In 1 patient, a heart transplant was required (1%); in 12%, a mitral valve procedure was needed. The hospital mortality rate was 15%. The postoperative course was complicated by renal failure (19%), major bleeding (14%), pulmonary failure (14%), sepsis (11%) and multiorgan failure (8%). At multivariate analysis, urgent surgery was a risk factor for early death [hazard ratio 20.5 (1.9-219)]. Survival at 5 and 8 years was 75 ± 6% and 71 ± 7%, with 3 cases of endocarditis relapse., Conclusions: Surgery is effective in treating endocarditis following the Bentall procedure although it is associated with high perioperative mortality and morbidity rates. Endocarditis relapse seems to be uncommon., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Background: Infective endocarditis (IE) is associated with high rates of mortality. Prolonged treatments with high-dose intravenous antibiotics often fail to eradicate the infection, frequently leading to high-risk surgical intervention. By providing a mechanism of antibiotic tolerance, which escapes conventional antibiotic susceptibility profiling, microbial biofilm represents a key diagnostic and therapeutic challenge for clinicians. This study aims at assessing a rapid biofilm identification assay and a targeted antimicrobial susceptibility profile of biofilm-growing bacteria in patients with IE, which were unresponsive to antibiotic therapy., Results: Staphylococcus aureus was the most common isolate (50%), followed by Enterococcus faecalis (25%) and Streptococcus gallolyticus (25%). All microbial isolates were found to be capable of producing large, structured biofilms in vitro. As expected, antibiotic treatment either administered on the basis of antibiogram or chosen empirically among those considered first-line antibiotics for IE, including ceftriaxone, daptomycin, tigecycline and vancomycin, was not effective at eradicating biofilm-growing bacteria. Conversely, antimicrobial susceptibility profile of biofilm-growing bacteria indicated that teicoplanin, oxacillin and fusidic acid were most effective against S. aureus biofilm, while ampicillin was the most active against S. gallolyticus and E. faecalis biofilm, respectively., Conclusions: This study indicates that biofilm-producing bacteria, from surgically treated IE, display a high tolerance to antibiotics, which is undetected by conventional antibiograms. The rapid identification and antimicrobial tolerance profiling of biofilm-growing bacteria in IE can provide key information for both antimicrobial therapy and prevention strategies.

Cancer cell dependence on activated oncogenes is therapeutically targeted, but acquired resistance is virtually unavoidable. Here we show that the treatment of addicted melanoma cells with BRAF inhibitors, and of breast cancer cells with HER2-targeted drugs, led to an adaptive rise in neuropilin-1 (NRP1) expression, which is crucial for the onset of acquired resistance to therapy. Moreover, NRP1 levels dictated the efficacy of MET oncogene inhibitors in addicted stomach and lung carcinoma cells. Mechanistically, NRP1 induced a JNK-dependent signaling cascade leading to the upregulation of alternative effector kinases EGFR or IGF1R, which in turn sustained cancer cell growth and mediated acquired resistance to BRAF, HER2, or MET inhibitors. Notably, the combination with NRP1-interfering molecules improved the efficacy of oncogene-targeted drugs and prevented or even reversed the onset of resistance in cancer cells and tumor models. Our study provides the rationale for targeting the NRP1-dependent upregulation of tyrosine kinases, which are responsible for loss of responsiveness to oncogene-targeted therapies.

Vascular normalizing strategies, aimed at ameliorating blood vessel perfusion and lessening tissue hypoxia, are treatments that may improve the outcome of cancer patients. Secreted class 3 semaphorins (SEMA3), which are thought to directly bind neuropilin (NRP) co-receptors that, in turn, associate with and elicit plexin (PLXN) receptor signaling, are effective normalizing agents of the cancer vasculature. Yet, SEMA3A was also reported to trigger adverse side effects via NRP1. We rationally designed and generated a safe, parenterally deliverable, and NRP1-independent SEMA3A point mutant isoform that, unlike its wild-type counterpart, binds PLXNA4 with nanomolar affinity and has much greater biochemical and biological activities in cultured endothelial cells. In vivo, when parenterally administered in mouse models of pancreatic cancer, the NRP1-independent SEMA3A point mutant successfully normalized the vasculature, inhibited tumor growth, curbed metastatic dissemination, and effectively improved the supply and anticancer activity of chemotherapy. Mutant SEMA3A also inhibited retinal neovascularization in a mouse model of age-related macular degeneration. In summary, mutant SEMA3A is a vascular normalizing agent that can be exploited to treat cancer and, potentially, other diseases characterized by pathological angiogenesis., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Neuropilins are a class of cell surface proteins implicated in cell migration and angiogenesis, with aberrant expression in human tumors. Here, we show that the expression of Neuropilin-2 (NRP2) controls EGFR protein levels, thereby impinging on intracellular signaling, viability, and response to targeted therapies of oncogene-addicted cells. Notably, increased NRP2 expression in EGFR-addicted tumor cells led to downregulation of EGFR protein and tumor cell growth inhibition. NRP2 also blunted upregulation of an EGFR "rescue" pathway induced by targeted therapy in Met-addicted carcinoma cells. Cancer cells acquiring resistance to MET oncogene-targeted drugs invariably underwent NRP2 loss, a step required for EGFR upregulation. Mechanistic investigations revealed that NRP2 loss activated NFkB and upregulated the EGFR-associated protein KIAA1199/CEMIP, which is known to oppose the degradation of activated EGFR kinase. Notably, KIAA1199 silencing in oncogene-addicted tumor cells improved therapeutic responses and counteracted acquired drug resistance. Our findings define NRP2 as the pivotal switch of a novel broad-acting and actionable pathway controlling EGFR signaling, and driving resistance to therapies targeting oncogene-addiction. Significance: These important findings identify the cell surface molecule Nrp2 as the pivotal switch of a novel, actionable pathway driving EGFR upregulation and resistance to oncogene- targeted therapies. Cancer Res; 78(4); 1058-68. ©2017 AACR ., (©2017 American Association for Cancer Research.)

The secreted semaphorin Sema3E controls cell migration and invasiveness in cancer cells. Sema3E-receptor, PlexinD1, is frequently upregulated in melanoma, breast, colon, ovarian and prostate cancers; however, the mechanisms underlying PlexinD1 upregulation and the downstream events elicited in tumor cells are still unclear. Here we show that the canonical RBPjk-dependent Notch signaling cascade controls PlexinD1 expression in primary endothelial and cancer cells. Transcriptional activation was studied by quantitative PCR and promoter activity reporter assays. We found that Notch ligands and constitutively activated intracellular forms of Notch receptors upregulated PlexinD1 expression; conversely RNAi-based knock-down, or pharmacological inhibition of Notch signaling by gamma-secretase inhibitors, downregulated PlexinD1 levels. Notably, both Notch1 and Notch3 expression positively correlates with PlexinD1 levels in prostate cancer, as well as in other tumor types. In prostate cancer cells, Sema3E-PlexinD1 axis was previously reported to regulate migration; however, implicated mechanisms were not elucidated. Here we show that in these cells PlexinD1 activity induces the expression of the transcription factor Slug, downregulates E-cadherin levels and enhances cell migration. Moreover, our mechanistic data identify PlexinD1 as a pivotal mediator of this signaling axis downstream of Notch in prostate cancer cells. In fact, on one hand, PlexinD1 is required to mediate cell migration and E-cadherin regulation elicited by Notch. On the other hand, PlexinD1 upregulation is sufficient to induce prostate cancer cell migration and metastatic potential in mice, leading to functional rescue in the absence of Notch. In sum, our work identifies PlexinD1 as a novel transcriptional target induced by Notch signaling, and reveals its role promoting prostate cancer cell migration and downregulating E-cadherin levels in Slug-dependent manner. Collectively, these findings suggest that Notch-PlexinD1 signaling axis may be targeted to impair prostate cancer cell invasiveness and metastasis., Competing Interests: The authors have declared that no competing interests exist.

Background: In 2015 a new device for the collection of mediastinal fluid from patients with deep sternal wound infection (DSWI) in the presence of negative-pressure wound therapy (NPWT) became available. The present study was designed to evaluate whether changing sample collection devices increased micro-organism detection in patients undergoing NPWT., Methods: During 2013-2014, 207 samples were collected and cultured from NPWT patients (n = 23) to demonstrate the presence of DSWI using reticulated polyurethane sponge culture, a swab, and blood culture. In 2015, a new collection device was introduced for specimen collection. A total of 357 samples (n = 17) were collected using the ESwab(™) (Copan, Murrieta, CA) for deep and superficial wound sample collection. In addition, blood culture devices were used for collecting mediastinal fluid aspirated directly from the wound and biologic fluid obtained from the NPWT device. Fisher exact test was performed to test the rate of independence rate of micro-organism identification using the NPWT sponge device and taking blood culture results as a reference for micro-organism identification., Results: After the introduction of the new collection device in our hospital, an overall increase in the detection of micro-organisms (46.7%) was reported. During 2013-2014 our traditional microbiologic collection method did not detect a pathogen in 30.4% of patients. During 2015, the new sample collection approach, direct from the NPWT device, improved micro-organism detection by 10.4% and reduced DSWIs with undetected pathogens to 17.6% (p < 0.01)., Conclusions: As a result of proficiency gained in the last year, the most representative specimen in wound infection was represented by mediastinal fluid collected directly from the wound and the NPWT device. Given the correlation between the blood culture of micro-organisms detected using the ESwab device from the wound, mediastinal drainage, and drainage from the NPWT device, we can assume that the NPWT device may replace the other biologic sampling devices.

This is the first reported case of 2 biofilm-producing bacteria, Staphylococcus aureus and Proteus mirabilis, identified from an aortic valve using an innovative device with dithiothreitol solution, able to dislodge bacterial biofilm. The method is usable in the operating theatre and recommended in infective endocarditis nonresponders to empiric therapy., (Copyright © 2016 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Neuropilin-1 (Nrp1) guides the development of the nervous and vascular systems, but its role in the mature brain remains to be explored. Here we report that the expression of the 65 kDa isoform of Sema3A, the ligand of Nrp1, by adult vascular endothelial cells, is regulated during the ovarian cycle and promotes axonal sprouting in hypothalamic neurons secreting gonadotropin-releasing hormone (GnRH), the neuropeptide controlling reproduction. Both the inhibition of Sema3A/Nrp1 signaling and the conditional deletion of Nrp1 in GnRH neurons counteract Sema3A-induced axonal sprouting. Furthermore, the localized intracerebral infusion of Nrp1- or Sema3A-neutralizing antibodies in vivo disrupts the ovarian cycle. Finally, the selective neutralization of endothelial-cell Sema3A signaling in adult Sema3aloxP/loxP mice by the intravenous injection of the recombinant TAT-Cre protein alters the amplitude of the preovulatory luteinizing hormone surge, likely by perturbing GnRH release into the hypothalamo-hypophyseal portal system. Our results identify a previously unknown function for 65 kDa Sema3A-Nrp1 signaling in the induction of axonal growth, and raise the possibility that endothelial cells actively participate in synaptic plasticity in specific functional domains of the adult central nervous system, thus controlling key physiological functions such as reproduction., Competing Interests: The authors have declared that no competing interests exist.

We evaluated histologic results for surgical left maze with an high-intensity focused ultrasound (HIFU) energy source. Two patients came to our attention 6 and 48 months, respectively, after ablation concomitant to a valve procedure. Tissue specimens, obtained from the lesion site on the mitral isthmus and from the "box lesion" around the pulmonary veins were analyzed histologically. A complete transmural lesion was found in all specimens. Chronic lesions exhibited replacement of the muscular band with connective tissue. The atrial wall maintained normal thickness and vascularization. HIFU ablation represents an acceptable energy source to create transmural lesions on the beating human left atrium., (Copyright © 2012 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Mycotic ascending aortic pseudoaneurysm (AAP) is an uncommon but surgically challenging problem with high morbidity and mortality rates. We describe endovascular repair of an acute mycotic AAP in a high-risk patient. A 45-year old man, HIV serum positive, chronic hepatitis HBV and HCV related, presented, after two sternotomies, with a fast growing 11 6 cm AAP that was sealed with two Gore Exluder aortic cuffs, inserted from the left axillary artery. Nine months control CT continued to show no endoleak with shrinking of the AAP.

Reproduction in mammals is dependent on the function of specific neurons that secrete gonadotropin-releasing hormone-1 (GnRH-1). These neurons originate prenatally in the nasal placode and migrate into the forebrain along the olfactory-vomeronasal nerves. Alterations in this migratory process lead to defective GnRH-1 secretion, resulting in heterogeneous genetic disorders such as idiopathic hypogonadotropic hypogonadism (IHH), and other reproductive diseases characterized by the reduction or failure of sexual competence. Combining mouse genetics with in vitro models, we demonstrate that Semaphorin 7A (Sema7A) is essential for the development of the GnRH-1 neuronal system. Loss of Sema7A signaling alters the migration of GnRH-1 neurons, resulting in significantly reduced numbers of these neurons in the adult brain as well as in reduced gonadal size and subfertility. We also show that GnRH-1 cells differentially express the Sema7 receptors β1-integrin and Plexin C1 as a function of their migratory stage, whereas the ligand is robustly expressed along developing olfactory/vomeronasal fibers. Disruption of Sema7A function in vitro inhibits β1-integrin-mediated migration. Analysis of Plexin C1(-/-) mice did not reveal any difference in the migratory process of GnRH-1 neurons, indicating that Sema7A mainly signals through β1-integrin to regulate GnRH-1 cell motility. In conclusion, we have identified Sema7A as a gene implicated in the normal development of the GnRH-1 system in mice and as a genetic marker for the elucidation of some forms of GnRH-1 deficiency in humans.

The aim of this study was to examine perioperative mortality and morbidity and midterm results in patients undergoing coronary bypass graft and mitral valve annuloplasty with advanced dilated cardiomyopathy. Sixty-one patients with ischemic dilated cardiomyopathy underwent coronary artery bypass grafting and mitral valve annuloplasty between January 1998 and December 2003. Patients eligible for revascularization that presented a mild or more severe mitral valve regurgitation at echocardiography (effective regurgitant orifice > 0.2 cm(2)) were considered for annuloplasty with a Cosgrove ring. New York Heart Association class (NYHA) III/IV was present in 40 patients (66%) and Canadian Cardiovascular Society class III-IV in 19 (31%). A previous acute myocardial infarction was reported in 48 patients (79%). The mean number of graft anastomoses was 2.5 +/- 0.7 and the left internal mammary artery was used in 49 patients (80%). In-hospital mortality was 4.9% (3 patients), due to unsuccessful weaning from cardiopulmonary bypass, multiple organ failure, and stroke, respectively. Left ventricle ejection fraction improved from 28.9% +/- 5.2% preoperatively to 35.4% +/- 8.1% at follow-up (P = 0.0001) and a significant reduction in NYHA III/IV was detected: from 40 patients preoperatively (66%) to 14 (31%) at follow-up (P = 0.031). Midterm cardiac-related mortality rate was 3.4%. In our experience combined coronary artery bypass grafting and ring annuloplasty for ischemic dilated cardiomyopathy can be performed with acceptable risks for in-hospital mortality and morbidity. Midterm results show a good survival rate and a durable functional improvement in this subset of patients.

Despite the efforts that have been made at an international level to identify and control cardiovascular risk factors, cardiopathies and, in particular, coronary artery disease (CAD), remain the principal cause of death in Europe and the United States. These data confirm the importance and necessity of noninvasive, reliable diagnostic imaging of early CAD. Coronary angiography is still the hinge, around which all instrumental and laboratory investigations turn, for cardiac ischaemia today. Indeed, it still holds the role of "gold standard" for the study of the coronary arterial lumina, particularly the smaller vessels due to their complex spatial geometry and because of cardiac motion. At present, with the exception of the study of the coronary arterial lumen, MR is a non-invasive examination, already capable of supplying precise global and regional function, the evaluation of the intra-cardiac flow, myocardial perfusion and the overall viability of the heart.

Coronary artery bypass grafting (CABG) still plays a fundamental role in the management of acute coronary syndromes. The aim of this study is to report the experience of our center in the treatment of patients with acute coronary sindromes without persistent ST elevation urgently operated on with CABG, and to discuss surgical problems related. Two-hundred and six patients were urgently operated on for CABG for acute coronary syndromes without persistent ST-segment elevation from January 2001 to February 2003. The majority of them had three vessel coronary disease (72%) and left main stem disease occurred in 20% of the patients. Mean LVEF (left ventricular ejection fraction) was 54 +/- 12% whereas 9% of the patients had a LVEF < 40%. Twenty-one patients (10%) received glycoprotein IIb/IIIa receptor inhibitors and 35 (17%) received intravenous heparin therapy before surgery. Mean interval time between the onset of symptoms and surgery was 16 +/- 10 days (range 4-50). In-hospital mortality was 2% (4 patients). Perioperative AMI (acute myocardial infarction) occurred in 4% (8 patients) and a transient low cardiac output syndrome in 27 patients (13%). Bleeding requiring surgery occurred in 1% of the patients. Transient respiratory insufficiency was present in 12 patients (6%) and acute renal failure in 8 patients (4%). Mean I.C.U. time was 2.4 days (1-17). Urgent CABG for acute coronary syndromes shows a low risk for in-hospital mortality and morbidity. In acute patients arterial grafts are not detrimental for the outcome, but are recommended in the absence of contraindications to improve long-term results. In spite of recent developments in cardioplegic cardiac arrest, optimal myocardial protection against perioperative myocardial infarction still remains a challenge.

Background: The authors present their personal experience of 3715 cases of head injury in pediatric patients, occurring during the last three years (1997-1999), admitted to the Emergency ward at the "Anna Meyer" children's hospital in Florence., Methods: A prospective study was made, starting from the evaluation made by the paediatric surgeon and following the subsequent diagnostic and clinical course. Depending on the severity of injury, this took the form of immediate discharge with a written sheet of instructions, "short observation" (up to 12 hours) in an Emergency ward and/or admission to neurosurgery or general medicine or to intensive care. The authors also analyse the diagnostic and instrumental tests carried out at the various stages (cranial X-ray, direct cranial CT, EEG) and the specialist consultations required (neurosurgery, neurology, paediatrics, resuscitation). Data for injured children transferred from other hospitals for neurosurgery were excluded from the study which only included patients examined primarily at our hospital. If admitted for more than 48 hours, a neurosurgical outpatient check-up was programmed one week later. In more severe cases, patients were admitted to day hospital between six months and one year later., Results: Injuries were minor in 91% of cases and the age of patients ranged between 5 days and 14 years; moreover, 60% of the patients observed were male. Only 1.5% of cases seen in Emergency were admitted to hospital and 8.4% of all head injuries, with a total stay of between 1 and 6 days. There were 4 deaths in severely polytraumatised patients. There was only one case of firearm injury which was not fatal. Head X-rays were performed in 13.4% of patients showing evidence of fracture in 19.1% of cases. Direct cranial CT was performed in 10.2% of cases with pathological findings in 23.9% of cases. Neurosurgery was performed in one of the 5.9% patients admitted to hospital. The late sequelae to head injury included one case of epilepsy that occurred 7 months after injury., Conclusions: Anamnesis showed that the most frequent reason leading to head injury was lack of adult supervision and that the majority of severe injuries were caused by road accidents, both as pedestrians and as passengers. Lastly, the authors emphasise the importance of recognising and correctly treating so-called secondary cerebral damage, which has a non-immediate onset but is potentially severe, and identifying the risk factors for head injury in order to reduce the incidence and severity.