Utility of Multidetector Computed Tomographic Angiography as an Alternative to Transesophageal Echocardiogram for Preoperative Transcatheter Mitral Valve Repair Planning.

BACKGROUND: Three-dimensional (3D) transesophageal echocardiogram (TEE) is the gold standard for the diagnosis of degenerative mitral regurgitation (dMR) and preoperative planning for transcatheter mitral valve repair (TMVr). TEE is an invasive modality requiring anesthesia and esophageal intubation. The severe acute respiratory syndrome coronavirus 2 pandemic has limited the number of elective invasive procedures. Multi-detector computed tomographic angiography (MDCT) provides high-resolution images and 3D reconstructions to assess complex mitral anatomy. We hypothesized that MDCT would reveal similar information to TEE relevant to TMVr, thus deferring the need for a preoperative TEE in certain situations like during a pandemic. METHODS: We retrospectively analyzed data on patients who underwent or were evaluated for TMVr for dMR with preoperative MDCT and TEE between 2017 and 2019. Two TEE and 2 MDCT readers, blinded to patient outcome, analyzed: leaflet pathology (flail, degenerative, mixed), leaflet location, mitral valve area (MVA), flail width/gap, anterior-posterior (AP) and commissural diameters, posterior leaflet length, leaflet thickness, presence of mitral valve cleft and degree of mitral annular calcification (MAC). RESULTS: A total of 22 (out of 87) patients had preoperative MDCT. MDCT correctly identified the leaflet pathology in 77% (17/22), flail leaflet in 91% (10/11), MAC degree in 91% (10/11) and the dysfunctional leaflet location in 95% (21/22) of patients. There were no differences in the measurements for MVA, flail width, commissural or AP diameter, posterior leaflet length, and leaflet thickness. MDCT overestimated the measurements of flail gap. CONCLUSIONS: For preoperative TMVr planning, MDCT provided similar measurements to TEE in our study.

Cellular Metabolomics by a Universal Redox-Reactive Nanosensors Array: From the Cell Level to Tumor-on-a-Chip Analysis.

Although biosensors based on nanowires-field effect transistor were proved extraordinarily efficient in fundamental applications, screening of charges due to the high-ionic strength of most physiological solutions imposes severe limitations in the design of smart, "real-time" sensors, as the biosample solution has to be previously desalted. This work describes the development of a novel nanowire biosensor that performs extracellular real-time multiplex sensing of small molecular metabolites, the true indicators of the body's chemistry machinery, without any preprocessing of the biosample. Unlike other nanoFET devices that follow direct binding of analytes to their surfaces, our nanodevice acts by sensing the oxidation state of redox-reactive chemical species bound to its surface. The device's surface array is chemically modified with a reversible redox molecular system that is sensitive to H2O2 down to 100 nM, coupled with a suite of corresponding oxidase enzymes that convert target metabolites to H2O2, enabling the direct prompt analysis of complex biosamples. This modality was successfully demonstrated for the real-time monitoring of cancer cell samples' metabolic activity and evaluating chemotherapeutic treatment options for cancer. This distinctive system displays ultrasensitive, selective, noninvasive, multiplex, real-time, label-free, and low-cost sensing of small molecular metabolites in ultrasmall volumes of complex biosamples, in the single-microliter scale, placing our technology at the forefront of this cutting-edge field.

Early management of atrial fibrillation to prevent cardiovascular complications.

Atrial fibrillation (AF) is generally considered a progressive disease, typically evolving from paroxysmal through persistent to 'permanent' forms, a process attributed to electrical and structural remodelling related to both the underlying disease and AF itself. Medical treatment has yet to demonstrate clinical efficacy in preventing progression. Large clinical trials performed to date have failed to show benefit of rhythm control compared with rate control, but these trials primarily included patients at late stages in the disease process. One possible explanation is that intervention at only an early stage of progression may improve prognosis. Evolving observations about the progressive nature of AF, along with the occurrences of major complications such as strokes upon AF presentation, led to the notion that earlier and more active approaches to AF detection, rhythm-reversion, and maintenance of sinus rhythm may be a useful strategy in AF management. Approaches to early and sustained rhythm control include measures that prevent development of the AF substrate, earlier catheter ablation, and novel antiarrhythmic drugs. Improved classifications of AF mechanism, pathogenesis, and remodelling may be helpful to enable patient-specific pathophysiological diagnosis and therapy. Potential novel therapeutic options under development include microRNA-modulation, heatshock protein inducers, agents that influence Ca(2+) handling, vagal stimulators, and more aggressive mechanism-based ablation strategies. In this review, of research into the basis and management of AF in acute and early settings, it is proposed that progression from paroxysmal to persistent AF can be interrupted, with potentially favourable prognostic impact.

Autophagy induction by silver nanowires: a new aspect in the biocompatibility assessment of nanocomposite thin films.

Nanomaterials and their enabled products have increasingly been attracting global attention due to their unique physicochemical properties. Among these emerging products, silver nanowire (AgNW)-based thin films are being developed for their promising applications in next generation nanoelectronics and nanodevices. However, serious concerns remain about possible health and safety risks they may pose. Here, we employed a multi-modal systematic biocompatibility assessment of thin films incorporating AgNW. To represent the possible routes of nanomaterial entry during occupational or environmental exposure, we employed four different cell lines of epithelial, endothelial, gastric, and phagocytic origin. Utilizing a cell-based automated image acquisition and analysis procedure in combination with real-time impedance sensing, we observed a low level of cytotoxicity of AgNW, which was dependent on cell type, nanowire lengths, doses and incubation times. Similarly, no major cytotoxic effects were induced by AgNW-containing thin films, as detected by conventional cell viability and imaging assays. However, transmission electron microscopy and Western immunoblotting analysis revealed AgNW-induced autophasosome accumulation together with an upregulation of the autophagy marker protein LC3. Autophagy represents a crucial mechanism in maintaining cellular homeostasis, and our data for the first time demonstrate triggering of such mechanism by AgNW in human phagocytic cells. Finally, atomic force microscopy revealed significant changes in the topology of cells attaching and growing on these films as substrates. Our findings thus emphasize the necessity of comprehensive biohazard assessment of nanomaterials in modern applications and devices and a thorough analysis of risks associated with their possible contact with humans through occupational or environmental exposure.

Imaging of the right ventricle.

For many years, the right ventricle (RV) was considered less relevant in cardiac disease than its left counterpart, partly because of limited ability to noninvasively evaluate the RV with accuracy. From an earlier period when chest x-ray and invasive contrast ventriculography were the only available imaging modalities, the development of ultrasound and nuclear techniques represented important steps forward for noninvasive RV assessment. Advances in echocardiography, computed tomography, and magnetic resonance imaging provide new insights into the anatomy and function of the RV, and its importance in health and disease. In this article, we review the current state of RV imaging.

Impaired clearance and enhanced pulmonary inflammatory/fibrotic response to carbon nanotubes in myeloperoxidase-deficient mice.

Advancement of biomedical applications of carbonaceous nanomaterials is hampered by their biopersistence and pro-inflammatory action in vivo. Here, we used myeloperoxidase knockout B6.129X1-MPO (MPO k/o) mice and showed that oxidation and clearance of single walled carbon nanotubes (SWCNT) from the lungs of these animals after pharyngeal aspiration was markedly less effective whereas the inflammatory response was more robust than in wild-type C57Bl/6 mice. Our results provide direct evidence for the participation of MPO - one of the key-orchestrators of inflammatory response - in the in vivo pulmonary oxidative biodegradation of SWCNT and suggest new ways to control the biopersistence of nanomaterials through genetic or pharmacological manipulations.

Future Perspectives on Percutaneous Coronary Interventions in Women.

In the United States alone, more than 1 million cardiac catheterizations are performed each year, with approximately 600,000 patients undergoing percutaneous coronary intervention (PCI). A meaningful perspective on the future of PCI in women requires not only reflection on some of the major developments in interventional cardiology but also a look back more generally at the changing patterns in the burden of coronary disease in the population and at the gains accrued in understanding and combating cardiovascular disease in women.

Hepatitis C virus targets the T cell secretory machinery as a mechanism of immune evasion.

UNLABELLED: T cell activation and the resultant production of interleukin (IL-2) is a central response of the adaptive immune system to pathogens, such as hepatitis C virus (HCV). HCV uses several mechanisms to evade both the innate and adaptive arms of the immune response. Here we demonstrate that liver biopsy specimens from individuals infected with HCV had significantly lower levels of IL-2 compared with those with other inflammatory liver diseases. Cell culture-grown HCV particles inhibited the production of IL-2 by normal peripheral blood mononuclear cells, as did serum from HCV-infected patients. This process was mediated by the interaction of HCV envelope protein E2 with tetraspanin CD81 coreceptor. HCV E2 attenuated IL-2 production at the level of secretion and not transcription by targeting the translocation of protein kinase C beta (PKCß), which is essential for IL-2 secretion, to lipid raft microdomains. The lipid raft disruptor methyl-ß-cyclodextrin reversed HCV E2-mediated inhibition of IL-2 secretion, but not in the presence of a PKCß-selective inhibitor. HCV E2 further inhibited the secretion of other cytokines, including interferon-γ. CONCLUSION: These data suggest that HCV E2-mediated disruption of the association of PKCß with the cellular secretory machinery represents a novel mechanism for HCV to evade the human immune response and to establish persistent infection.

Porphyrin-magnetite nanoconjugates for biological imaging.

BACKGROUND: The use of silica coated magnetic nanoparticles as contrast agents has resulted in the production of highly stable, non-toxic solutions that can be manipulated via an external magnetic field. As a result, the interaction of these nanocomposites with cells is of vital importance in understanding their behaviour and biocompatibility. Here we report the preparation, characterisation and potential application of new "two-in-one" magnetic fluorescent nanocomposites composed of silica-coated magnetite nanoparticles covalently linked to a porphyrin moiety. METHOD: The experiments were performed by administering porphyrin functionalised silica-coated magnetite nanoparticles to THP-1 cells, a human acute monocytic leukaemia cell line. Cells were cultured in RPMI 1640 medium with 25 mM HEPES supplemented with heat-inactivated foetal bovine serum (FBS). RESULTS: We have synthesised, characterised and analysed in vitro, a new multimodal (magnetic and fluorescent) porphyrin magnetic nanoparticle composite (PMNC). Initial co-incubation experiments performed with THP-1 macrophage cells were promising; however the PMNC photobleached under confocal microscopy study. ß-mercaptoethanol (ß-ME) was employed to counteract this problem and resulted not only in enhanced fluorescence emission, but also allowed for elongated imaging and increased exposure times of the PMNC in a cellular environment. CONCLUSION: Our experiments have demonstrated that ß-ME visibly enhances the emission intensity. No deleterious effects to the cells were witnessed upon co-incubation with ß-ME alone and no increases in background fluorescence were recorded. These results should present an interest for further development of in vitro biological imaging techniques.

Carbon nanotubes degraded by neutrophil myeloperoxidase induce less pulmonary inflammation.

We have shown previously that single-walled carbon nanotubes can be catalytically biodegraded over several weeks by the plant-derived enzyme, horseradish peroxidase. However, whether peroxidase intermediates generated inside human cells or biofluids are involved in the biodegradation of carbon nanotubes has not been explored. Here, we show that hypochlorite and reactive radical intermediates of the human neutrophil enzyme myeloperoxidase catalyse the biodegradation of single-walled carbon nanotubes in vitro, in neutrophils and to a lesser degree in macrophages. Molecular modelling suggests that interactions of basic amino acids of the enzyme with the carboxyls on the carbon nanotubes position the nanotubes near the catalytic site. Importantly, the biodegraded nanotubes do not generate an inflammatory response when aspirated into the lungs of mice. Our findings suggest that the extent to which carbon nanotubes are biodegraded may be a major determinant of the scale and severity of the associated inflammatory responses in exposed individuals.

Project ASPIRE: an Interactive, Multimedia Smoking Prevention and Cessation curriculum for culturally diverse high school students.

A Smoking Prevention Interactive Experience (ASPIRE) is an innovative, computer-based smoking prevention and cessation intervention delivered to a culturally diverse population of high school students. Founded in the Transtheoretical Model of Change, five main and two "booster" sessions comprise the interactive intervention. Here we describe the intervention and the baseline characteristics from our study sample of 1,574 10th graders from 16 high schools in Houston, Texas. Environmental and behavioral smoking risk factors were assessed, and the two intervention groups were comparable with respect to most measured variables. The intervention program holds considerable promise in its ability to reduce smoking among teens.

Impact of A Smoking Prevention Interactive Experience (ASPIRE), an interactive, multimedia smoking prevention and cessation curriculum for culturally diverse high-school students.

Few studies have examined the long-term efficacy of computer-based smoking prevention and cessation programs. We analyzed the long-term impact of A Smoking Prevention Interactive Experience (ASPIRE), a theoretically sound computer-based smoking prevention and cessation curriculum for high school students. Sixteen predominantly minority, inner-city high schools were randomly assigned to receive the ASPIRE curriculum or standard care (receipt of the National Cancer Institute's Clearing the Air self-help booklet). A total of 1160 students, 1098 of whom were nonsmokers and 62 smokers at baseline, were included. At 18-month follow-up, among baseline nonsmokers, smoking initiation rates were significantly lower in the ASPIRE condition (1.9% vs. 5.8%, p < .05). Students receiving ASPIRE also demonstrated significantly higher decisional balance against smoking and decreased temptations to smoke. Differences between groups in self-efficacy and resistance skills were not significant. There was a nonsignificant trend toward improved smoking cessation with ASPIRE, but low recruitment of smokers precluded conclusions with respect to cessation. ASPIRE demonstrated the potential for an interactive multimedia program to promote smoking prevention. Further studies are required to determine ASPIRE's effects on cessation.

CdTe nanoparticles display tropism to core histones and histone-rich cell organelles.

The disclosure of the mechanisms of nanoparticle interaction with specific intracellular targets represents one of the key tasks in nanobiology. Unmodified luminescent semiconductor nanoparticles, or quantum dots (QDs), are capable of a strikingly rapid accumulation in the nuclei and nucleoli of living human cells, driven by processes of yet unknown nature. Here, it is hypothesized that such a strong tropism of QDs could be mediated by charge-related properties of the macromolecules presented in the nuclear compartments. As the complex microenvironment encountered by the QDs in the nuclei and nucleoli of live cells is primarily presented by proteins and other biopolymers, such as DNA and RNA, the model of human phagocytic cell line THP1, nuclear lysates, purified protein, and nucleic acid solutions is utilized to investigate the interactions of the QDs with these most abundant classes of intranuclear macromolecules. Using a combination of advanced technological approaches, including live cell confocal microscopy, fluorescent lifetime imaging (FLIM), spectroscopic methods, and zeta potential measurements, it is demonstrated that unmodified CdTe QDs preferentially bind to the positively charged core histone proteins as opposed to the DNA or RNA, resulting in a dramatic shift off the absorption band, and a red shift and decrease in the pholuminescence (PL) intensity of the QDs. FLIM imaging of the QDs demonstrates an increased formation of QD/protein aggregates in the presence of core histones, with a resulting significant reduction in the PL lifetime. FLIM technology for the first time reveals that the localization of negatively charged QDs to their ultimate nuclear and nucleolar destinations dramatically affects the QDs' photoluminescence lifetimes, and offers thereby a sensitive readout for physical interactions between QDs and their intracellular macromolecular targets. These findings strongly suggest that charge-mediated QD/histone interactions could provide the basis for QD nuclear localization downstream of intracellular transport mechanisms.

A new microtubule-targeting compound PBOX-15 inhibits T-cell migration via post-translational modifications of tubulin.

The ordered, directional migration of T-lymphocytes is a key process during immune surveillance, immune response, and development. A novel series of pyrrolo-1,5-benzoxazepines have been shown to potently induce apoptosis in variety of human chemotherapy resistant cancer cell lines, indicating their potential in the treatment of both solid tumors and tumors derived from the hemopoietic system. Pyrrolobenzoxazepine 4-acetoxy-5-(1-naphtyl)naphtho[2,3-b]pyrrolo[1,2-d][1,4]-oxazepine (PBOX-15) has been shown to depolymerize tubulin in vitro and in the MCF7 breast cancer cell line. We hypothesized that this may suggest a role for this compound in modulating integrin-induced T-cell migration, which is largely dependent on the microtubule dynamics. Experiments were performed using human T lymphoma cell line Hut78 and peripheral blood T-lymphocytes isolated from healthy donors. We observed that human T-lymphocytes exposed to PBOX-15 have severely impaired ability to polarize and migrate in response to the triggering stimulus generated via cross-linking of integrin lymphocyte function associated antigen-1 receptor. Here, we show that PBOX-15 can dramatically impair microtubule network via destabilization of tubulin resulting in complete loss of the motile phenotype of T-cells. We demonstrate that PBOX-15 inhibitory mechanisms involve decreased tubulin polymerization and its post-translational modifications. Novel microtubule-targeting effects of PBOX-15 can possibly open new horizons in the treatment of overactive inflammatory conditions as well as cancer and cancer metastatic spreading.

Nonfunctionalized nanocrystals can exploit a cell's active transport machinery delivering them to specific nuclear and cytoplasmic compartments.

We use high content cell analysis, live cell fluorescent imaging, and transmission electron microscopy approaches combined with inhibitors of cellular transport and nuclear import to conduct a systematic study of the mechanism of interaction of nonfunctionalized quantum dots (QDs) with live human blood monocyte-derived primary macrophages and cell lines of phagocytic, epithelial, and endothelial nature. Live human macrophages are shown to be able to rapidly uptake and accumulate QDs in distinct cellular compartment specifically to QDs size and charge. We show that the smallest QDs specifically target histones in cell nuclei and nucleoli by a multistep process involving endocytosis, active cytoplasmic transport, and entering the nucleus via nuclear pore complexes. Treatment of the cells with an anti-microtubule agent nocodazole precludes QDs cytoplasmic transport whereas a nuclear import inhibitor thapsigargin blocks QD import into the nucleus. These results demonstrate that the nonfunctionalized QDs exploit the cell's active transport machineries for delivery to specific intranuclear destinations.

Molecular and functional analysis of glutamine uptake in human hepatoma and liver-derived cells.

Human hepatoma cells take up glutamine at rates severalfold faster than the system N-mediated transport rates observed in normal human hepatocytes. Amino acid inhibition, kinetic, Northern blotting, RT-PCR, and restriction enzyme analyses collectively identified the transporter responsible in six human hepatoma cell lines as amino acid transporter B(0) (ATB(0)), the human ortholog of rodent ASCT2. The majority of glutamine uptake in liver fibroblasts and an immortalized human liver epithelial cell line (THLE-5B) was also mediated by ATB(0). The 2.9-kb ATB(0) mRNA was equally expressed in all cell lines, whereas expression of the system A transporters ATA2 and ATA3 was variable. In contrast, the system N isoforms (SN1 and SN2) were expressed only in well-differentiated hepatomas. ATB(0) mRNA was also expressed in cirrhotic liver and adult and pediatric liver cancer biopsies but was not detectable in isolated human hepatocytes or fetal liver. Although the growth of all hepatomas was glutamine dependent, competitive inhibition of ATB(0)-mediated glutamine uptake blocked proliferation only in poorly differentiated cells lacking SN1 or SN2 expression and exhibiting low glutamine synthetase mRNA levels.