Perioperative dental screening and treatment in patients undergoing cardiothoracic surgery and interventional cardiovascular procedures. A consensus report based on RAND/UCLA methodology.

AIM: To reach a consensus on a consistent strategy to adopt when screening patients for dental/periodontal infections and on the feasibility of providing dental treatment before cardiothoracic surgery, cardiovascular surgery or other cardiovascular invasive procedures. METHODOLOGY: A panel of experts from six Italian scientific societies was created. The deliberations of the panel were based on the RAND method. From an initial systematic literature review, it became clear that a consensually validated protocol for the reproducible dental screening of patients awaiting cardiac interventions was considered mandatory by professionals with expertise in the dental, cardiologic and cardiac surgery areas. However, a systematic review also concluded that the treatment options to be provided, their prognosis and timing in relation to the physical condition of patients, had never been defined. Following the systematic review, several fundamental questions were generated. The panel was divided into two working groups each of which produced documents that addressed the topic and which were subsequently used to generate a questionnaire. Each member of the panel completed the questionnaire independently, and then, a panel discussion was held to reach a consensus on how best to manage patients with dental/periodontal infections who were awaiting invasive cardiac procedures. RESULTS: A high level of agreement was reached regarding all the items on the questionnaire, and each of the clinical questions formulated were answered. Three tables were created which can be used to generate a useful tool to provide standardized dental/periodontal screening of patients undergoing elective cardiovascular interventions and to summarize both the possible oral and cardiovascular conditions of the patient and the timing available for the procedures considered. CONCLUSIONS: Upon publication of this consensus document, the dissemination of the information to a wide dental and cardiac audience should commence. The authors hope that this consensus will become a model for the development of a dedicated protocol, ideally usable by heart and dental teams in the pre-interventional preparation phase.

Early Aspirin Nonresponders Identification by Routine Use of Aggregometry Test in Patients With Left Ventricle Assist Devices Reduces the Risk of Pump Thrombosis.

Left ventricular assist device (LVAD) management is very challenging since many adverse events can occur in ongoing patients. Inadequate anticoagulation treatment can lead to life-threatening situations like ischemic stroke or pump thrombosis. The main intention of our study was to investigate if early identification of aspirin nonresponders by using aggregometry can improve anticoagulation management, reducing the risk of pump thrombosis. METHODS: From December 2010 to May 2018, 24 patients were implanted with a HeartMate II (HMII), 6 received a HeartWare HVAD system--full support VAD (HVAD), and 22 received a HeartMate III (HMIII). All patients were maintained with a target INR of 2.0 to 3.0. When the aggregometry test revealed a normal platelet function, 100 mg of aspirin were initiated. Only aspirin nonresponders were early identified by repeating the aggregometry after 7 days of aspirin administration. In acetylsalicylic acid nonresponder patients, 75 mg of clopidogrel was used, and the patients were tested again. Ticlopidine (250 mg) was used when clopidogrel was unsuccessful. RESULTS: Four patients required modification in antiplatelet therapy. Three patients (5%), 2 HVAD and 1 HMII, suffered from pump thrombosis. One patient died as a consequence of a large intracranial hemorrhagic event following thrombolytic treatment. One patient required a pump exchange; in 1 patient, thrombolytic infusion was conducted successfully. CONCLUSION: Reported rates of pump thrombosis at 12 months for patients implanted with commonly used LVADs were 6% to 12% for axial-flow pumps and 8% with centrifugal-flow devices. In our series, the reported 5% overall incidence of pump thrombosis encourages the routine use of an aggregometry test for early identification of aspirin nonresponders.

Perioperative dental screening and treatment in patients undergoing cardio-thoracic surgery and interventional cardiovascular procedures. A consensus report based on RAND/UCLA methodology.

AIM: To reach a consensus on a consistent strategy to adopt when screening patients for dental/periodontal infections, and on the feasibility of providing dental treatment before cardiothoracic surgery, cardiovascular surgery or other cardiovascular invasive procedures. METHODOLOGY: A panel of experts from six Italian scientific societies was created. The deliberations of the panel were based on the RAND method. From an initial systematic literature review, it became clear that a consensually validated protocol for the reproducible dental screening of patients awaiting cardiac interventions was considered mandatory by professionals with expertise in the dental, cardiologic and cardiac surgery areas. However, systematic review also concluded that the treatment options to be provided, their prognosis and timing in relation to the physical condition of patients had never been defined. Following the systematic review several fundamental questions were generated. The panel was divided into two working groups each of which produced documents that addressed the topic and which were subsequently used to generate a questionnaire. Each member of the panel completed the questionnaire independently and then a panel discussion was held to reach a consensus on how best to manage patients with dental/periodontal infections who were awaiting invasive cardiac procedures. RESULTS: A high level of agreement was reached regarding all the items on the questionnaire, and each of the clinical questions formulated were answered. Three tables were created which can be used to generate a useful tool to provide standardized dental/periodontal screening of patients undergoing elective cardiovascular interventions, and to summarize both the possible oral and cardiovascular conditions of the patient and the timing available for the procedures considered. CONCLUSIONS: Upon publication of this consensus document, the dissemination of the information to a wide dental and cardiac audience should commence. The authors hope that this consensus can become a model for the development of a dedicated protocol, ideally usable by heart and dental teams in the pre-interventional preparation phase.

Pulse Oximeter Usefulness for Blood Pressure Monitoring in Patients Implanted With Latest-Generation Continuous-Flow Device HeartMate 3.

INTRODUCTION: The measurement of blood pressure (BP) and the management of hypertension in patients with continuous-flow ventricular assist devices (CF-VADs) can present unique challenges. Patients with CF-VADs often do not have a palpable pulse, and therefore traditional blood pressure measurement by auscultation or automated cuff is less reliable. We tested the efficacy of blood pressure estimation using sphygmomanometry combined with finger pulse oximetry only after a hemodynamic optimization was effected to make the values estimated approximately similar to mean arterial pressure. METHODS: Fifteen consecutive patients with a mean age of 57.8 ± 11.2 years were implanted with HeartMate 3 between November 2015 and March 2017. All patients underwent pump speed optimization by conducting a ramp test during right heart catheterization. The patients were prospectively studied during the follow-up period and mean arterial pressure was estimated using 3 different methodologies: Doppler ultrasound, pulse oximeter, and automated blood pressure cuff. For each method 3 consecutive evaluations were conducted during 3 follow-up visits. RESULTS: For each patient, 9 different evaluations were obtained (3 for each method). The overall success rate was 100% for blood pressure assessment conducted with Doppler ultrasound and pulse oximeter and 80%-87% for automated monitor evaluations. The first 2 methodologies were 100% successful, while the third was 60% successful. Pearson's correlation analyses for the Doppler ultrasound and pulse oximeter measurements showed a good correlation when evaluations conducted with the same method were compared. A high variability emerged between estimations obtained by using an automated monitor and a poor correlation was found when this method was compared to the Doppler ultrasound and pulse oximeter measurements. CONCLUSION: According to our results, the pulse oximeter method showed a high success rate and a good correlation level with the standard procedure. Our data encourage the use of oximeters for domiciliary blood pressure assessment in patients implanted with a continuous flow device.

Pump Speed Optimization in Patients Implanted With the HeartMate 3 Device.

BACKGROUND: Pump speed optimization in patients implanted with a ventricular assist device represents a major challenge during the follow-up period. We present our findings on whether combined invasive hemodynamic ramp tests and cardiopulmonary exercise testing (CPX) can help optimize patient management. METHODS: Eighteen patients implanted with a HeartMate 3 (HM3) device underwent ramp tests with right heart catheterization (including central venous pressure [CVP], pulmonary artery pressure, pulmonary capillary wedge pressure [PCWP], and blood pressure) and echocardiography. Data were recorded at up to 4 speed settings. Speed changes were in steps of 200 revolutions/min (rpm). Evaluation of functional capacity by CPX was conducted according to the modified Bruce protocol. RESULTS: Only 30% of patients had normal PCWPs at their original rpm settings. In going from lowest to highest speeds, cardiac output improved by 0.25 ± 0.35 L/min/step (total change, 1.28 ± 0.3 L/min), and PCWP decreased by 1.9 ± 0.73 mm Hg/step (total change, 6 ± 1.6 mm Hg). CVP and systolic blood pressure did not change significantly with rpm. The rpm assessment was adjusted based on test results to achieve CVPs and PCWPs as close to normal limits as possible, which was feasible in all patients. On CPX, all patients demonstrated good performance (peak VO2, 16.8 ± 3.5 mL/kg/min). CONCLUSION: Hemodynamic ramp testing provides an objective means of optimizing rpm, and has the potential to provide good exercise tolerance.

Posterior wall as atypical localization of left atrial myxoma : Diagnosis and management.

Atrial myxomas are the most common benign cardiac neoplasms. Although the majority occur in the left atrium (LA) and are attached to the interatrial septum (75-80 % of cases), they can arise from any part of the LA and the cardiac chambers. We report the case of a 65-year-old woman who presented with features of worsening dyspnea and persistent headache. During transthoracic echocardiography, a suspected cardiac myxoma was found arising from the posterior wall of the LA.

Delayed luminescence induced by complex domains in water and in TEOS aqueous solutions.

Many recent studies on water have conjectured a complex structure composed of hydrogen bonded low- and high-density domains. In this work the structure of pure water and aqueous solutions of silica gel (TEOS) has been investigated by using delayed luminescence, which has previously shown a significant increase in aqueous salt solutions where low-density domain formation is expected. Photon emission shows an Arrhenius trend with an activation energy in water-TEOS solutions larger than in pure water and salt-water solutions. Moreover, delayed photon emission decay shows an intrinsic lifetime of about 5 µs both in solutions and in pure water that, along with secondary lifetimes induced by the presence of TEOS, could be related to the formation of different domains.

Click chemistry, a potent tool in medicinal sciences.

This review focuses on the application of click chemistry in medicinal sciences, and particularly on its role in drug discovery. Because of its high modularity, click chemistry helps to accelerate the current drug discovery process, which relies on massive screening of chemical libraries. This article describes examples of click chemistry applications that are aimed at finding new lead candidates against pathologies such as cancer, AIDS and Alzheimer's disease, and explores the impact that the technique could have in therapy and prevention in the near future, through application in drug delivery systems, bioconjugation and diagnostic. An introduction, addressed to researchers who intend to use this methodology, examines the opportunities to perform click reactions according to the most common and best studied techniques, such as synthesis in water, on solid phase, and under microwave or ultrasound irradiation. Every topic is furnished with examples which have appeared in the literature in the last five years and is clarified by schemes and figures.

Spectrometer for cluster ion beam induced luminescence.

A spectrometer to detect the ultra-weak luminescence originated by the collision of cluster ions on the surfaces of solid materials was constructed. This spectrometer consists of 11 photomultipliers with band-pass interference filters that can detect the luminescence within the wavelength ranging from 300 to 700 nm and of a photomultiplier without filter. The calibration of the detection system was performed using the photons emitted from a strontium aluminate fluorescent tape and from a high temperature tungsten filament. Preliminary measurements show the ability of this spectrometer to detect the cluster ion beam induced luminescence.

Hck inhibitors as potential therapeutic agents in cancer and HIV infection.

Hematopoietic cell kinase (Hck) is a member of the Src-family of non-receptor tyrosine kinases, which plays many roles in signalling pathways involved in the regulation of cell processes. Hck is expressed in cells of hematopoietic origin, specifically myelomonocytic cells and B lymphocytes. It participates in phagocytosis, adhesion, migration, regulation of protrusion formation on cell membrane, lysosome exocytosis, podosome formation and actin polymerization. More importantly from a medicinal chemistry point of view, high levels of Hck are involved in chronic myeloid leukemia and other hematologic tumors. Furthermore, Hck activity has been associated with virus infections including HIV-1. In particular, Hck is activated by the HIV-1 accessory protein Nef, a multifunctional HIV-1 protein that accelerates progression to AIDS and enhances the infectivity of progeny viruses. Nef binding to Hck leads to kinase activation which is important in AIDS pathogenesis. For these reasons, Hck represents a potentially good therapeutic target for the treatment of both specific cancers and HIV infection. This article summarizes Hck biological activities connected with malignancies and HIV infection, many of which have been only recently reported, and presents an overview of the compounds endowed with Hck inhibitory activity, especially focusing on the medicinal chemistry aspect.

Mechanical circulatory support in advanced heart failure: single-center experience.

BACKGROUND: Currently, ventricular assist device (VAD) or total artificial heart (TAH) mechanical support provides an effective treatment of unstable patients with advanced heart failure. We report our single-center experience with mechanical circulatory support therapy. METHODS: From March 2002 to December 2012, 107 adult patients (mean age, 56.8 ± 9.9 y; range, 31-76 y) were primarly supported on temporary or long-term VAD or TAH support as treatment for refractory heart failure at our institution. Temporary extracorporeal radial VAD support (group A) was established in 49 patients (45.7%), and long-term paracorporeal and intracorporeal VAD or TAH (group B) in 58 patients (54.2%). Left ventricular (LVAD) support was established in 55 patients (51.4%; n = 33, Heartmate II; n = 6, Heartmate I XVE; n = 4, Heartware HVAD; and n = 12, Centrimag) and biventricular (BVAD/TAH) support (group B) in 28 patients (26.1%; n = 10, Thoratec paracorporeal; n = 2, Heartware HVAD, n = 1, Thoratec implantable; n = 1, Syncardia TAH; and n = 14, Centrimag). The temporary Centrimag was the only device adopted as isolated right ventricular (RVAD) support, and it was inserted in 24 patients (22.4%). RESULTS: In group A, overall mean support time was 10.2 ± 6.6 days (range, 3-43 d). In group B, LVAD mean support time was 357 ± 352.3 days (range, 1-902 d) and BVAD/TAH support time was 98 ± 82.6 days (range, 8-832 d). In group A, the overall success rate was 55.1% (27 patients). In group B, LVAD overall success rate was 74.4% (32 patients) and BVAD/TAH success rate was 50% (7 patients). Overall heart transplantation rate for both groups was 27.1% (n = 2, group A; n = 27, group B). Overall 1-year and 5-year survivals after heart transplantation were 72.4% (n = 21) and 58.6% (n = 17), respectively. CONCLUSIONS: Mechanical circulatory support is an effective strategy even in cases of end-stage heart failure according to our experience. Further improvement of VAD and TAH technologies may support their adoption as an encouraging alternative to heart transplantation in the near future.

Equipment to detect luminescence induced by cluster ion collision.

The possibility to analyze on-line the surface region of solid materials using the cluster ion beam luminescence spectroscopy has been examined. At this aim, the cluster ion beam apparatus for the processing of solid materials was modified. The neutral clusters were ionized by the electron impact ionization to obtain an intense cluster ion beam. The tungsten filament used in this ionization method was replaced with an oxide one to reduce the emission of the background light by decreasing the operating temperature of the filament. To further suppress this light, antireflection materials were used to cover the parts inside the vacuum chamber, such as walls and inner surfaces of the einzel lens. The signal to noise ratio was improved more than one order of magnitude. The emission of photons induced by the irradiation of cluster ion beams was detected.

Metastatic liposarcoma of the heart. Case series and brief literature review.

Secondary cardiac tumors are 20-40 times more frequent than primary lesions. Primary cardiac lesions are represented by myxomas when related to benign tumors, and by sarcomas in terms of malignant disease. Metastases to the heart from liposarcomas are very rare. We present three cases of secondary liposarcomas involving the left atrium, the right atrium, and the pericardium.

Treatment with daptomycin for Corynebacterium Jeikeium left-sided prosthetic valve endocarditis.

Prosthetic valve endocarditis (PVE) is a serious complication with potential fatal consequences, classified as early or late PVE, depending on whether typical symptoms occur within or later than 12 months from surgery. The incidence of early PVE is under 1%, but it carries high morbidity and mortality rates. There are few reported cases in literature of PVE due to Corynebacterium Jeikeium even though it is present in normal skin flora particularly in hospitalized patients. Corynebacterium species are, in fact, recognized as uncommon agents of endocarditis and little is known regarding species-specific risk factors and the outcome in this kind of endocarditis. Described is an unusual case report of a 57-year-old man who had early aortic PVE due to Corynebacterium Jeikeium infection complicated by dehiscence of the prosthesis, complete atrio-ventricular block, perforation of the interventricular septum and septic shock. Prompt diagnosis, choice of daptomycin as antibiotic therapy although it has only been approved by the European Medicine Agency (EMEA) for right-sided endocarditis and timely open heart surgery, resulted in a successful outcome.

SRC kinase inhibitors: an update on patented compounds.

The cytoplasmatic tyrosine in kinase c-Src is involved in the regulation of several cell functions including adhesion, invasion, proliferation, survival and angiogenesis. Src activity is strictly regulated in healthy cells, whereas its overexpression or hyperactivation plays a critical role during tumor development. Recently it has been suggested that the oncogenic potential of Src is linked to its role in the activation of key signalling molecules involved in several cell pathways, rather than its direct activity. For all these reasons Src represents a promising therapeutic target for the treatment of tumors. In this article a number of examples of c-Src inhibitors appeared in selected patents from 2006 to early 2011 will be reported, focusing on their chemical features and, whenever possible, on structure- activity relationships and mechanism of action. Examples of type I or II ATP-competitive inhibitors or substrate competitive inhibitors will be presented. The research in this field is very active and will probably lead to the discovery of therapeutically useful compounds, both c-Src selective and multitargeted inhibitors, that acting on different cell pathways could be more effective in blocking cancer development. However, only the results of clinical trials will show in the near future the most promising compounds.

ATP-competitive inhibitors of mTOR: an update.

mTOR (mammalian target of rapamycin) is a serine-threonine kinase belonging to the PI3K/Akt/mTOR signalling pathway that is involved in several cell functions, including growth, proliferation, apoptosis and autophagy. mTOR hyperactivation has been detected in several human cancers, thus representing, together with its upstream effectors, an important target for cancer therapy. mTOR exists in two different complexes in cells, mTORC1 and mTORC2 which could both be targeted by potential anticancer agents. Rapamycin, the selective and allosteric inhibitor of mTOR, inhibits the enzyme in mTORC1, but not in mTORC2. In the last few years a number of mTOR ATP-competitive inhibitors has been reported acting on mTOR in both complexes and possessing a more complete anticancer activity in comparison with that of rapamycin and its derivatives. mTOR shares high sequence homology in the hinge-region with PI3K that is a lipid kinase upstream to mTOR in the same signaling pathway; for this reason some compounds originally developed as PI3K inhibitors later showed to also target mTOR. As indicated by preclinical and clinical studies, compounds acting on more than one target could result in a better biological response and in enhanced therapeutic potential and also dual PI3K/mTOR inhibitors result of great interest as potential antitumor agents. This review mainly reports the recently discovered mTOR ATP-competitive inhibitors in terms of medicinal chemistry, classified by their chemical structures, focusing on SAR and modelling studies that led to the discovery of very potent and selective agents, such as AZD-8055, OSI-027 and INK128, already entered clinical trials, or WYE-132, Torin1 and others in preclinical studies. Also some examples of dual PI3K/mTOR inhibitors, including PI-103, GNE477, WJD008 and GSK2126458 are reported together with their biological and clinical data.

Fyn kinase in brain diseases and cancer: the search for inhibitors.

Fyn is a non-receptor tyrosine kinase belonging to the Src family kinases. It has been shown to play important roles in neuronal functions, including myelination and oligodendrocytes formation, and in inflammatory processes. It has also demonstrated its involvement in signaling pathways that lead to severe brain pathologies, such as Alzheimer's and Parkinson's diseases. Moreover, Fyn is upregulated in some malignancies. Experimental studies demonstrated that Fyn inhibition could be useful in the disruption of metabolic processes involved in cancer neurodegenerative diseases. Unfortunately, no specific Fyn inhibitor has been discovered till today, active compounds on other members of Src family or on different tyrosine kinases have also been reported. However, multitargeted inhibitors might be endowed with therapeutic potential. Indeed, as increasingly reported, also a not completely selective inhibitor of a specific protein could be therapeutically useful, affecting a number of cell pathways involved especially in cancer development. In this review, we report some examples of small molecule tyrosine kinase inhibitors for which data on Fyn inhibition, both in enzymatic and in cell assays, have been reported, with the aim of giving information as starting point for the researchers working in this field.

Dual-source CT coronary angiography: prospective versus retrospective acquisition technique.

PURPOSE: The aim of our work was to compare image quality and radiation dose in a group of patients who underwent cardiac dual-source computed tomography (DSCT) with prospective electrocardiographic (ECG) gating with those of a control group studied with retrospective gating. MATERIALS AND METHODS: Sixty patients were randomly assigned to two groups of 30 individuals each. Patients with heart rates >70 bpm and body mass index (BMI) >30 kg/m(2) were excluded. Group A was examined with prospective ECG gating and group B with retrospective gating. The dose-length product (DLP) was recorded to calculate the radiation dose, whereas the effective dose was normalised to a standard 12-cm scan of the heart. RESULTS: Applying the best reconstruction interval, 98.6% of segments in the prospective group and 99.3% in the retrospective group were diagnostic. No significant difference (p>0.05) in image quality was observed between groups. Mean normalised radiation dose was 4.91 ± 0.4 mSv in the prospective-gating group and 14.62 mSv ± 4.36 in the retrospective-gating group (p<0.01). CONCLUSIONS: Coronary CT with prospective ECG gating, a standard feature on new scanners, allows for a significant reduction in radiation dose without causing any significant decrease in image quality or in the number of segments assessed. The prospective technique is thus recommended for patients with heart rates £70 bpm and BMI £30 kg/m(2).

Note: Dead time causes and correction method for single photon avalanche diode devices.

Single photon avalanche diode (SPAD) is the new generation of Geiger-Muller (GM) detectors, developed with semiconductor technology, and able to detect single photons, mainly in visible range. In this work we study the signal generation process and the dead time (DT) mechanisms of the device under a constant light regime. According to our results, it is possible to discriminate low rate signals from afterpulse and noise production and, moreover, to overcome the saturation effect due to the dead time losses. Starting from hybrid DT model [S. H. Lee and R. P. Gardner, Appl. Radiat. Isot. 53, 731 (2000)] we have been able to evaluate the real amount of incident photon rate up to 10(7) cps using a passive quenched device with 0.97 mus total dead time. In this way the passive quenched SPAD achieves the same performance of the active quenched one showing that relatively complex data analysis and complex device implementation are comparable solutions for constant light measurement. We also analyze some effects, lacking in GM counter, which should be introduced in the analysis of semiconductor device, as afterpulse, reduced photon detection efficiency, and noise production.