Search

Purpose: The difference between rest and peak stress end-systolic pressure-volume relation (ΔESPVR) is an afterload-independent index of left ventricular (LV) contractility. We assessed the independent prognostic value of ΔESPVR index by dipyridamole stress-cardiovascular magnetic resonance (CMR) in patients with known/suspected coronary artery disease (CAD). Methods: We considered 196 consecutive patients (62.74 ± 10.66 years, 49 females). Wall motion and perfusion abnormalities at rest and peak stress were analysed. Replacement myocardial fibrosis was detected by late gadolinium enhancement (LGE) technique. The ESPVR was evaluated at rest and peak stress from raw measurement of systolic arterial pressure and end-systolic volume by biplane Simpson's method. Results: A reduced ΔESPVR index (≤ 0.02 mmHg/mL/m2) was found in 88 (44.9%) patients and it was associated with a lower LV ejection fraction (EF) and with a higher frequency of abnormal stress CMR and myocardial fibrosis. During a mean follow-up of 53.17 ± 28.21 months, 50 (25.5%) cardiac events were recorded: 5 cardiac deaths, 17 revascularizations, one myocardial infarction, 23 hospitalisations for heart failure or unstable angina, and 4 ventricular arrhythmias. According to Cox regression analysis, diabetes, family history, LVEF, abnormal stress CMR, myocardial fibrosis, and reduced ΔESPVR were significant univariate prognosticators. In the multivariate analysis the independent predictors were ΔESPVR index ≤ 0.02 mmHg/mL/m2 (hazard ratio-HR = 2.58, P = 0.007), myocardial fibrosis (HR = 2.13, P = 0.036), and diabetes (HR = 2.33, P = 0.012). Conclusion: ΔESPVR index by stress-CMR was independently associated with cardiac outcomes in patients with known/suspected CAD, in addition to replacement myocardial fibrosis and diabetes. Thus, the assessment of ΔESPVR index may be included into the standard stress-CMR exam to further stratify the patients. [ABSTRACT FROM AUTHOR]

Objectives: The prognostic role of left ventricular (LV) papillary muscle abnormalities in patients with preserved LV systolic ejection fraction (LVEF) is unknown. We sought to evaluate the prognosis role of LV papillary muscle abnormalities by CMR in patients with ventricular arrhythmias, preserved LVEF with no cardiac disease. Methods: A total of 391 patients with > 500/24 h premature ventricular complexes and/or with non-sustained ventricular tachycardia (NSVT), preserved LVEF, and no cardiac disease were enrolled. Different features of LV papillary muscles were considered: supernumerary muscles, papillary thickness, the attachment, late gadolinium enhancement (LGE). Dark-Paps was defined as end-systolic signal hypointensity of both papillary muscles in early post-contrast cine CMR images. Mitral valve prolapse, mitral annular disjunction (MAD), and myocardial LGE were considered. Results: Dark-Paps was found in 79 (20%) patients and was more frequent in females. It was associated with higher prevalence of mitral valve prolapse and MAD. During a median follow-up of 2534 days, 22 hard cardiac events occurred. At Kaplan-Meier curve analysis, patients with Dark-Paps were at higher risk of events than those without (p < 0.0001). Dark-Paps was significantly associated with hard cardiac events in all the multivariate models. Dark-Paps improved prognostic estimation when added to NSVT (p = 0.0006), to LGE (p = 0.005) and to a model including NSVT+LGE (p = 0.014). Dark-Paps allowed a significant net reclassification when added to NSVT (NRI 0.30, p = 0.03), to LGE (NRI 0.25, p = 0.04), and to NSVT + LGE (NRI 0.32, p = 0.02). Conclusions: In LV papillary muscles, Dark-Paps is a novel prognostic marker in patients with ventricular arrhythmias and preserved ejection fraction. Key Points: • Papillary muscle abnormalities are seen in patients with ventricular arrhythmias and preserved left ventricular ejection fraction. • Early post-contrast hypointensity of papillary muscles in end-systolic cine images (Dark-Paps) is a novel prognostic marker in patients with ventricular arrhythmias and preserved ejection fraction. • Dark-Paps had an additive prognostic role over late gadolinium enhancement and non-sustained ventricular tachycardia. [ABSTRACT FROM AUTHOR]

Objectives: Myocardial extracellular volume (ECV) by cardiovascular magnetic resonance (CMR) is a surrogate marker of diffuse fibrosis. We evaluated the association between ECV and demographics, CMR findings, and cardiac involvement in patients with thalassemia major (TM). Methods: A total of 108 β-TM patients (62 females, 40.16 ± 8.83 years), consecutively enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network, and 16 healthy subjects (6 females, 37.12 ± 16.13 years) underwent CMR. The protocol included assessment of T2*, native T1, and T2 values in all 16 myocardial segments for myocardial iron overload (MIO) quantification, cine images for left ventricular (LV) function quantification, post-contrast T1 mapping for ECV calculation, and late gadolinium enhancement (LGE) technique for replacement myocardial fibrosis detection. Results: Global ECV values were significantly higher in females than in males. Global ECV values were significantly higher in patients with significant MIO (global heart T2* < 20 ms) than in patients without significant MIO, and both groups exhibited higher global ECV values than healthy subjects. No association was detected between native T1 and ECV values, while patients with reduced global heart T2 values showed significantly higher global ECV values than patients with normal and increased global heart T2. Global ECV values were not correlated with LV function/size and were comparable between patients with and without LGE. Compared to patients without heart failure, patients with a history of heart failure (N = 10) showed significantly higher global heart ECV values. Conclusion: In TM, increased myocardial ECV, potentially reflecting diffuse interstitial fibrosis, is associated with MIO and heart failure. Key Points: • CMR-derived myocardial extracellular volume is increased in thalassemia major patients, irrespective of the presence of late gadolinium enhancement. • In thalassemia major, myocardial iron overload contributes to the increase in myocardial ECV, which potentially reflects diffuse interstitial fibrosis and is significantly associated with a history of heart failure. [ABSTRACT FROM AUTHOR]

Dielectric singularities (DSs) constitute one of the most exotic features occurring in the effective permittivity of artificial multilayers called hyperbolic metamaterials (HMMs). Associated to DSs, a rich phenomenology arises that justifies the ever-increasing interest profuse by the photonic community in achieving an active control of their properties. As an example, the possibility to "canalize" light down to the nanoscale as well as the capability of HMMs to interact with quantum emitters, placed in their proximity, enhancing their emission rate (Purcell effect), are worth mentioning. HMMs, however, suffer of an intrinsic lack of tunability of its DSs. Several architectures have been proposed to overcome this limit and, among them, the use of graphene outstands. Graphene-based HMMs recently shown outstanding canalization capabilities achieving λ/1660 light collimation. Despite the exceptional performances promised by these structures, stacking graphene/oxide multilayers is still an experimental challenge, especially envisioning electrical gating of all the graphene layers. In this paper, we propose a valid alternative in which indium-tin-oxide (ITO) is used as an electrically tunable metal. Here we have numerically designed and analyzed an ITO/SiO2 based HMM with a tunable canalization wavelength within the range between 1.57 and 2.74 μm. The structure feature light confinement of λ/8.8 (resolution of about 178 nm), self-focusing of the light down to 0.26 μm and Purcell factor of approximately 700. The proposed HMM nanoarchitecture could be potentially used in many applications, such as ultra-fast signal processing, high harmonic generation, lab-on-a-chip nanodevices, bulk plasmonic waveguides in integrated photonic circuits and laser diode collimators. [ABSTRACT FROM AUTHOR]

Dilated cardiomyopathy (DCM) is a primary heart muscle disease characterized by left or biventricular systolic impairment. Historically, most of the clinical attention has been devoted to the evaluation of left ventricular function and morphology, while right ventricle (RV) has been for many years the forgotten chamber. Recently, progresses in cardiac imaging gave clinicians precious tools for the evaluation of RV, raising the awareness of the importance of biventricular assessment in DCM. Indeed, RV involvement is far from being uncommon in DCM, and the presence of right ventricular dysfunction (RVD) is one of the major negative prognostic determinants in DCM patients. However, some aspects such as the possible role of specific genetic mutations in determining the biventricular phenotype in DCM, or the lack of specific treatments able to primarily counteract RVD, still need research. In this review, we summarized the current knowledge on RV involvement in DCM, giving an overview on the epidemiology and pathogenetic mechanisms implicated in determining RVD. Furthermore, we discussed the imaging techniques to evaluate RV function and the role of RV failure in advanced heart failure. [ABSTRACT FROM AUTHOR]

The variation between rest and peak stress end-systolic pressure–volume relation (ΔESPVR) is an index of myocardial contractility, easily obtained during routine stress echocardiography and never tested during dipyridamole stress-cardiac magnetic resonance (CMR). We assessed the ΔESPVR index in patients with known/suspected coronary artery disease (CAD) who underwent dipyridamole stress-CMR. One-hundred consecutive patients (24 females, 63.76 ± 10.17 years) were considered. ESPVR index was evaluated at rest and stress from raw measurement of systolic arterial pressure and end-systolic volume by biplane Simpson's method. The ΔESPVR index showed a good inter-operator reproducibility. Mean ΔESPVR index was 0.48 ± 1.45 mmHg/mL/m2. ΔESPVR index was significantly lower in males than in females. ΔESPVR index was not correlated to rest left ventricular end-diastolic volume index or ejection fraction. Forty-six of 85 patients had myocardial fibrosis detected by the late gadolinium enhancement technique and they showed significantly lower ΔESPVR values. An abnormal stress CMR was found in 25 patients and they showed significantly lower ΔESPVR values. During a mean follow-up of 56.34 ± 30.04 months, 24 cardiovascular events occurred. At receiver-operating characteristic curve analysis, a ΔESPVR < 0.02 mmHg/mL/m2 predicted the presence of future cardiac events with a sensitivity of 0.79 and a specificity of 0.68. The noninvasive assessment of the ΔESPVR index during a dipyridamole stress-CMR exam is feasible and reproducible. The ΔESPVR index was independent from rest LV dimensions and function and can be used for a comparative assessment of patients with different diseases. ΔESPVR index by CMR can be a useful and simple marker for additional prognostic stratification. [ABSTRACT FROM AUTHOR]

Numerous factors, ranging from genetics, age, lifestyle, and dietary habits to local environments, contribute to the heterogeneity of the microbiota in humans. Understanding the variability of a "healthy microbiota" is a major challenge in scientific research. The gut microbiota profiles of 148 healthy Italian volunteers were examined by 16S rRNA gene sequencing to determine the range and diversity of taxonomic compositions in the gut microbiota of healthy populations. Possible driving factors were evaluated through a detailed anamnestic questionnaire. Microbiota reference intervals were also calculated. A "scaffold" of a healthy Italian gut microbiota composition was identified. Differences in relative quantitative ratios of microbiota composition were detected in two clusters: a bigger cluster (C2), which included 124 subjects, was characterized by more people from the northern Italian regions, who habitually practised more physical activity and with fewer dietary restrictions. Species richness and diversity were significantly higher in this cluster (C2) than in the other one (C1) (C1: 146.67 ± 43.67; C2: 198.17 ± 48.47; F = 23.40; P < 0.001 and C1: 16.88 ± 8.66; C2: 35.01 ± 13.40; F = 40.50; P < 0.001, respectively). The main contribution of the present study was the identification of the existence of a primary healthy microbiological framework that is only marginally affected by variations. Taken together, our data help to contextualize studies on population-specific variations, including marginal aspects, in human microbiota composition. Such variations must be related to the primary framework of a healthy microbiota and providing this perspective could help scientists to better design experimental plans and develop strategies for precision tailored microbiota modulation. [ABSTRACT FROM AUTHOR]

Sudden cardiac death (SCD) is a pivotal health problem worldwide. The identification of subjects at increased risk of SCD is crucial for the accurate selection of candidates for implantable cardioverter defibrillator (ICD) therapy. Current strategies for arrhythmic stratification largely rely on left ventricular (LV) ejection fraction (EF), mostly measured by echocardiography, and New York Heart Association functional status for heart failure with reduced EF. For specific diseases, such as hypertrophic and arrhythmogenic cardiomyopathy, some risk scores have been proposed; however, these scores take into account some parameters that are a partial reflection of the global arrhythmic risk and show a suboptimal accuracy. Thanks to a more comprehensive evaluation, cardiac magnetic resonance (CMR) provides insights into the heart muscle (the so-called tissue characterization) identifying cardiac fibrosis as an arrhythmic substrate. Combining sequences before and after administration of contrast media and mapping techniques, CMR is able to characterize the myocardial tissue composition, shedding light on both intracellular and extracellular alterations. Over time, late gadolinium enhancement (LGE) emerged as solid prognostic marker, strongly associated with major arrhythmic events regardless of LVEF, adding incremental value over current strategy in ischemic heart disease and non-ischemic cardiomyopathies. The evidence on a potential prognostic role of mapping imaging is promising. However, mapping techniques require further investigation and standardization. Disclosing the arrhythmic substrate within the myocardium, CMR should be considered as part of a multiparametric approach to personalized arrhythmic stratification. [ABSTRACT FROM AUTHOR]

Ultrafast control of light−matter interactions is fundamental in view of new technological frontiers of information processing. However, conventional optical elements are either static or feature switching speeds that are extremely low with respect to the time scales at which it is possible to control light. Here, we exploit the artificial epsilon-near-zero (ENZ) modes of a metal-insulator-metal nanocavity to tailor the linear photon absorption of our system and realize a nondegenerate all-optical ultrafast modulation of the reflectance at a specific wavelength. Optical pumping of the system at its high energy ENZ mode leads to a strong redshift of the low energy mode because of the transient increase of the local dielectric function, which leads to a sub-3-ps control of the reflectance at a specific wavelength with a relative modulation depth approaching 120%. All-optical switching allows control of one optical signal using another, holding potential to overcome the limitations of electrical switches via ultrafast manipulation of light. In this work, sub-3 ps all-optical switching is achieved in an epsilon-near-zero nanocavity, exhibiting a relative modulation depth of 120% at a specific wavelength. [ABSTRACT FROM AUTHOR]

The presence of myocardial noncompaction (NC), regardless of the criterion used, does not identify cardiomyopathy per se. The distinction between a morphological variant and the presence of an NC cardiomyopathy is challenging. However, thanks to larger cohorts of patients and longer periods of follow-up, better clinical characterization and prognostic evaluation are becoming available. Indeed, the physician is required to integrate the evidence of NC with the clinical history of the patient, which is supplemented by necessary advanced instrumental investigations before a definite diagnosis of NC cardiomyopathy can be made. Therefore, we extensively revised the current literature in order to help the clinicians to identify clinical features which are pivotal supporting diagnostic element for the correct recognition of Left ventricular noncompaction cardiomyopathy and thus highlighting the difference between a form of cardiomyopathy and a mere intraventricular hypertrabeculation. [ABSTRACT FROM AUTHOR]

Nature as a source of inspiration for designing and fabricating nanostructured materials with unconventional properties is an unparalleled driving force of this work leading to low-loss metamaterials. Here, we report about a multipronged approach to create optical metamaterials based on plasmonic nanostructures, hierarchical organization and interplay between plasmon elements and excitonic molecules. This work is focused on strategies and approaches to produce gain to metamaterials across scales with the aim of realizing low-loss optical materials and unlocking their unconvetional electromagnetic properties. Finally, we describe how a biomimetic approach based on gain-functionalized bionanoparticle can be harnessed for diagnostics and theranostics. [ABSTRACT FROM AUTHOR]

Hyperbolic metamaterial (HMM), a sub-wavelength periodic artificial structure with hyperbolic dispersion, can enhance the spontaneous emission of quantum emitters. Here, we demonstrate the large spontaneous emission rate enhancement of an organic dye placed in a grating coupled hyperbolic metamaterial (GCHMM). A two-dimensional (2D) silver diffraction grating coupled with an Ag/Al2O3 HMM shows 18-fold spontaneous emission decay rate enhancement of dye molecules with respect to the same HMM without grating. The experimental results are compared with analytical models and numerical simulations, which confirm that the observed enhancement of GCHMM is due to the outcoupling of non-radiative plasmonic modes as well as strong plasmon-exciton coupling in HMM via diffracting grating. [ABSTRACT FROM AUTHOR]

We report on the effect of gold nanoparticle (Au NP) dispersion in a chiral nematic liquid crystal (LC). Polarized optical microscopy and X-ray diffraction measurements evidence the insurgence of an order change in the LC host. Moreover, a comparative analysis based on dielectric and voltammetric spectroscopies performed on pure LC and on Au NP-doped LC shows that Au NP’s presence besides affecting LC order influences its electric properties: ion conductivity results importantly reduced, and beyond a threshold value of the applied field electrophoresis phenomena are induced. [ABSTRACT FROM AUTHOR]

Hyperbolic metamaterials (HMMs) represent a novel class of fascinating anisotropic plasmonic materials, supporting highly confined bulk plasmon polaritons in addition to the surface plasmon polaritons. However, it is very challenging to tailor and excite those modes at optical frequencies using prism coupling technique because of the intrinsic difficulties to engineer non-traditional optical properties using artificial nanostructures and the unavailability of high refractive index prisms for matching the momentum between the incident light and the guided modes. Here, we experimentally demonstrate the excitation of both surface and bulk plasmon polaritons in aHMMthrough a grating coupling technique of surface plasmon excitation that makes use a hypergrating, which is a combined structure of metallic diffraction grating and HMM. Initially, we propose an optical hyperbolic metamaterial based on Au/TiO2 multilayers and confirm the hyperbolic dispersion, and the presence of high-k modes in the fabricated HMM. Reflection measurements as a function of incident angle and excitation wavelength show the existence of both surface and bulk plasmon polaritons inside the hypergrating. The proposed configuration is expected to find potential applications in bio-chemical sensors, integrated optics and optical sub-wavelength imaging. [ABSTRACT FROM AUTHOR]

The physical properties of anisotropic fluids can be manipulated on very short length scales of 100 nm or less by appropriate treatment of the confining substrate(s). This facilitates the use of ordered fluids in a variety of scientific endeavours and applications. Although future advances will require a complete understanding of their structure at the nanoscale level, high-resolution three-dimensional optical imaging of the fluid’s molecular orientation profile is beyond the reach of extant techniques. Here, we report a powerful imaging approach based on the collection of transmitted light in the far field that is emitted from a light source with a subwavelength aperture. We acquire high-resolution images by raster-scanning, at multiple heights, an optical fibre immersed inside a thin layer of anisotropic fluid, thereby facilitating the visualization of the fluid’s structure with a resolvable volume ∼1/500 of that attainable by current methods. This novel technique offers the intriguing possibility of three-dimensional nanoscale reconstruction of a variety of soft materials, here the first direct visualization and measurement of the liquid-crystal molecular orientation relaxation length. [ABSTRACT FROM AUTHOR]

Notch proteins are a transmembrane receptor family that is structurally and functionally conserved from worms to humans. The mammalian family of Notch proteins consists of several genes encoding Notch receptors and related Notch ligands. Notch signaling is involved in different aspects of the cell-fate decision tree: differentiation, proliferation, and apoptosis. These three processes are finely regulated in human placenta in order to allow a successful pregnancy and correct fetal growth. Notch and its ligands also participate in vascular remodeling and stabilization. Vasculogenesis and blood regulation are of importance in the human placenta for normal fetal development and growth; any disorder of these systems leads to preeclampsia. Drawing on this background, we have investigated the expression of Notch-1, Notch-4, and Jagged-1, together with two members related to the Notch pathway in angiogenesis: VEGF and p21. Normal and preeclamptic human placentas have been evaluated by immunohistochemistry. In preeclamptic samples, a down-regulation of Notch pathway members occurs with a weak/moderate expression of the Notch protein members in all components of placenta compared with physiological placentas that, at term, exhibit the strong expression of Jagged-1 and a moderate expression of both Notch-1 and Notch-4 in all compartments of the placental villi. Moreover, preeclamptic samples also reveal a down-regulation of VEGF expression, together with a moderate nuclear expression of p21Cip1 in the syncytiotrophoblast, cytotrophoblast, and endothelial cells. This down-regulation of VEGF in preeclamptic placentas, in turn, probably decreases Notch protein expression in placental compartments and in endothelial cells and could offer an ethiopathogenetic explanation for the onset of this pathology. [ABSTRACT FROM AUTHOR]

In certain materials, the spontaneous spreading of a laser beam (owing to diffraction) can be compensated for by the interplay of optical intensity and material nonlinearity. The resulting non-diffracting beams are called‘spatial solitons’(refs 1-3), and they have been observed in various bulk media. In nematic liquid crystals, solitons can be produced at milliwatt power levels and have been investigated for both practical applications and as a means of exploring fundamental aspects of light interactions with soft matter. Spatial solitons effectively operate as waveguides, and so can be considered as a means of channelling optical information along the self-sustaining filament. But actual steering of these solitons within the medium has proved more problematic, being limited to tilts of just a fraction of a degree. Here we report the results of an experimental and theoretical investigation of voltage-controlled‘walk-off’and steering of self-localized light in nematic liquid crystals. We find not only that the propagation direction of individual spatial solitons can be tuned by several degrees, but also that an array of direction-tunable solitons can be generated by modulation instability. Such control capabilities might find application in reconfigurable optical interconnects, optical tweezers and optical surgical techniques. [ABSTRACT FROM AUTHOR]

Apelin is a novel bioactive peptide that has been isolated from bovine stomach extracts and identified as the endogenous ligand for the APJ receptor. Although the main physiological functions of apelin have not yet been clarified, it is known that apelin is involved in the regulation of blood pressure, central control of body fluid homeostasis and the modulation of immune response. In order to investigate the distribution of apelin in reptiles, we have performed an immunohistochemical analysis on tissues of the lizard Podarcis sicula. The peptide was found to be widely distributed, although its cellular localization differed in the various organs examined. A strong immunopositivity was found in the heart, stomach and intestine. In the spleen, an intense apelin immunopositivity was restricted to a discrete number of cells scattered throughout the red pulp and co-localized with immunoglobulin kappa and lambda chains, suggesting an analogous function of this peptide in immune responses also in reptiles. Intriguingly, apelin immunoreactivity was discretely localized in endothelial cells in the lung and thyroid gland. In the light of these data, we conclude that apelin may have multiple functions in reptiles. [ABSTRACT FROM AUTHOR]

The balance between acetylation and deacetylation of histone and nonhistone proteins controls gene expression in a variety of cellular processes, with transcription being activated by acetyltransferases and silenced by deacetylases. We report here the formation and enzymatic characterization of a complex between the acetyltransferase p300 and histone deacetylases. The C/H3 region of p300 was found to co-purify deacetylase activity from nuclear cell extracts. A prototype of class I histone deacetylases, HDAC1, interacts with p300 C/H3 domain in vitro and in vivo. The p300-binding protein E1A competes with HDAC1 for C/H3 binding; and, like E1A, HDAC1 overexpression interferes with either activation of Gal4p300 fusion protein or p300-dependent co-activation of two C/H3-binding proteins, MyoD and p53. The exposure to deacetylase inhibitors could reverse the dominant-negative effect of a C/H3 fragment insulated from the rest of the molecule, on MyoD- and p53-dependent transcription, whereas inhibition by E1A was resistant to trichostatin A. These data support the hypothesis that association between acetyltransferases and deacetylases can control the expression of genes implicated in cellular growth and differentiation, and suggest that the dominant-negative effect of the p300 C/H3 fragment relies on deacetylase recruitment.Oncogene (2004) 23, 2177-2187. doi:10.1038/sj.onc.1207327 Published online 16 February 2004 [ABSTRACT FROM AUTHOR]

Presents a study which investigated the action of HtrA1 serine protease during human melanoma progression and its impact on the growth of metastatic melanoma cells. Investigation of the immunohistochemical expression of HtrA1 in a tissue array; Examination of the HtrA1 expression in human primary melanomas; Conclusions.

Although the structural and pharmacological properties of endothelin (ET) receptors have been studied, little is known concerning their physiological significance, even if each subtype is supposed to have a distinct physiological action. Thus, to further elucidate the physiological function of this receptor, we examined the presence and distribution of the endothelin-B receptor (ETB) subtype in tissues of the lizard Podarcis sicula, using immunoblotting and immunohistochemistry. Immunoblotting indicated that, although the ETB receptor appears to be ubiquitous, it is present at different levels in the tissues examined. Furthermore, immunohistochemistry showed that this receptor is very abundant in endothelial cells of all tissues, suggesting that there is an ETB-mediated autocrine system of endothelin, which plays an important role in the regulation of endothelial cell function. On the other hand, the presence of ETB immunoreactivity also in endocrine systems such as adrenal and thyroid glands suggests an involvement also in the paracrine system of these organs. [ABSTRACT FROM AUTHOR]

Presents a study that examined the role of cyclin dependent kinase 9 (cdk9), in association with cyclinT2a, in the activation of the myogenic program. Characteristics of cdk9; Regulatory units of cdk9; Importance of cdk9 complexes in human cells; Effects of the activation of cdk9 on messenger RNA.

The aim of this study was to demonstrate in the adrenocortical and renal tissues of two species of frog, Rana italica and Rana esculenta, the presence and distribution of five neuropeptides: atrial natriuretic peptide (ANP), Leu-enkephalin (Leu-ENK), neuropeptide Y (NPY), substance P (SP) and vasoactive intestinal peptide (VIP). In anurans, the adrenal medulla is the site for the synthesis, storage and secretion of not only catecholamines but also various peptides. These peptides should not be regarded only as neurotransmitters or modulators for the secretion of catecholamines, but also as hormonal substances that induce systemic effects. All the peptides studied (ANP, Leu-ENK, NPY, SP and VIP) are present in both organs. However, different patterns of expression were observed for some of the peptides in two frogs. Immunopositivity to ANP was found in small clusters of chromaffin cells in both frogs whereas a clear strong positivity was present only in Rana esculenta kidney. Large clusters of chromaffin cells were immunoreactive to Leu-ENK in Rana italica but there were approximately 25% fewer compared to the positive cells present in Rana esculenta. Epithelial cells of renal tubules showed strong immunopositivity to Leu-ENK in Rana esculenta but not in Rana italica. A large number of adrenal cells (70–80%) were immunoreactive to NPY in Rana italica, while in Rana esculenta this peptide was localized in small clusters of chromaffin cells. Both frogs showed many NPY-positive cells in kidney. Many chromaffin cells were found positive to SP and VIP. A strong positivity was also observed in kidney in both frogs. These observations suggest a possible role of these peptides in the control of the physiological functions of adrenal glands and kidney of the two species of frogs studied. [ABSTRACT FROM AUTHOR]

The adrenal gland of the lizard Podarcis sicula is formed by a dorsal ribbon of chromaffin cells, generally defined as medullary tissue, arranged along a central part of steroidogenic cells considered as cortical tissue. These two tissues produce catecholamines and steroids as part of the hypothalamo-hypophyseal-adrenal gland axis. Recent studies have demonstrated that Podarcis sicula adrenal gland is not only under hypothalamo-hypophyseal axis control but that several peptides may influence the physiological activity of the gland; among these, vasoactive intestinal peptide is able to enhance strongly both catecholamine and steroid hormone production. The aim of the present study was to verify whether vasoactive intestinal peptide administration could become deleterious. For this reason, we monitored the pattern of expression of two members of the Bcl-2 family, Bcl-2 and Bax, in control and vasoactive intestinal peptide treated specimens. Furthermore, we also tested if peptide treatment induces apoptosis by TUNEL assay. [ABSTRACT FROM AUTHOR]

The p53 protein accumulates rapidly through post-transcriptional mechanisms following cellular exposure to DNA damaging agents and is also activated as a transcription factor leading to growth arrest or apoptosis. Phosphorylation of p53 occurs after DNA damage thereby modulating its activity and impeding the interaction of p53 with its negative regulator oncogene Mdm2. The serines 15 and 37 present in the amino terminal region of p53 are phosphorylated by the DNA-dependent protein kinase (DNA-PK) in response to DNA damage. In order to verify if specific p53 mutations occur in the multi-drug resistance phenotype, we analysed the p53 gene in two T-lymphoblastoid cell lines, CCRF-CEM and its multi-drug-resistant clone CCRF-CEM VLB100, selected for resistance to vinblastine sulfate and cross-resistant to other cytotoxic drugs. Both cell lines showed two heterozygous mutations in the DNA binding domain at codons 175 and 248. The multi-drug resistant cell line, CCRF-CEM VLB100, showed an additional mutation that involves the serine 37 whose phosphorylation is important to modulate the protein activity in response to DNA damage. The effects of these mutations on p53 transactivation capacity were evaluated. The activity of p53 on pro-apoptotic genes expression in response to DNA damage induced by (-irradiation, was affected in the vinblastine (VLB) resistant cell line but not in CCRF-CEM sensitive cell line resulting in a much reduced apoptotic cell death of the multi-drug resistant cells. Oncogene (2000) 19, 5098–5105 [ABSTRACT FROM AUTHOR]

B-Myb is a transcription factor belonging to the myb family, whose activity has been associated with augmented DNA synthesis and cell cycle progression. We showed recently that B-Myb autoregulates its own expression through promoter transactivation. We report in this study that CDK9, the cyclin T associated kinase, which phosphorylates and activates RNA-Polymerase II, suppresses B-Myb autoregulation through direct interaction with the carboxyl-terminus of the B-Myb protein. Down-regulation of the transactivating ability of B-Myb is independent of the kinase activity of CDK9, because a kinase deficient mutant (dn-CDK9) also represses B-myb gene autoregulation. Overexpression of CDK9 did not result in suppression of p53-dependent transactivation or inhibition of the basal activity of the promoters tested so far, demonstrating that CDK9 is a B-Myb-specific repressor. Rather, transfection of the dominant negative dn-CDK9 construct inhibited the basal activity of the reporter genes, confirming an essential role for CDK9 in gene transcription. In addition, Cyclin T1 restores B-Myb transactivating activity when co-transfected along with CDK9, suggesting that the down-regulatory effect observed on B-Myb is specifically due to CDK9 alone. Thus, our data suggest that CDK9 is involved in the negative regulation of activated transcription mediated by certain transcription factors, such as B-Myb. This may indicate the existence of a feedback loop, mediated by the different activities of CDK9, which links basal with activated transcription. Oncogene (2000) 19, 373–379. [ABSTRACT FROM AUTHOR]

Purpose of Review: To analyze the current state of the art of functional mitral regurgitation (FMR) treatment. Recent Findings: The first-line treatment of severe FMR consists of guideline medical therapy (GMT) and resynchronization therapy when indicated; the impact of new medical therapies like sacubitril/valsartan needs further assessment. Valvular intervention may be considered in FMR symptomatic patients despite GMT, and can be performed surgically or percutaneously. MitraClip is a safe percutaneous procedure associated with symptoms improvement. Recently, the COAPT trial showed superior outcomes for MitraClip versus GMT contrasting the MITRA-FR trial which showed no benefit of MitraClip compared with GMT. These results should be interpreted as complementary rather than opposite. Summary: The COAPT trial provided a "proof of concept" that percutaneous treatment of severe FMR in patients without too advanced left ventricular disease translates into a prognostic benefit. Careful patient selection will play a critical role in defining the clinical niche for successful interventions. [ABSTRACT FROM AUTHOR]