Safety and efficacy of the sulfydryl ACE-inhibitor zofenopril in the management of cardiovascular disease

In the 1970s, pharmacological therapy interrupting the renin-angiotensin system was considered beneficial for patients with high-renin hypertension. Angiotensin-converting enzyme (ACE) inhibitors proved to be effective not only in patients with high renin and elevated blood pressure, but also in many hypertensive patients with normal levels of plasma renin activity. ACE inhibitors are used in a wide range of chronic illnesses such as atherosclerosis, hypertension, myocardial infarction, heart failure, diabetic complications, and stroke. To date, more than ninety controlled clinical trials evaluating the beneficial effects of 14 different ACE inhibitors were conducted. Moreover, data from experimental studies showed that ACE inhibitors can attenuate the development of atherosclerosis, oxidative stress, and vascular inflammation in a wide range of species indicating that ACE inhibition also favourably affects the vasculature. More than fifteen years ago, the bi-sulfydryl ACE-inhibitor zofenopril has shown an excellent clinical safety and efficacy in patients with hypertension and in those with myocardial infarction. More recently, this compound exhibited a potent antioxidant and antiatherosclerotic effect indicating a clinical useful vasoprotective action

La caduta del khanato siberiano nella cronachistica russa della prima metà del XVII secolo: correlazione concettuale dei testi ed ipotesi genealogiche

Il presente lavoro è dedicato alla concezione della caduta del khanato siberiano di Kučum nella cronachistica uralico-siberiana della prima metà del XVII secolo e ad un esame della genealogia dei testi appartenenti al corpus in questione. Le fonti utilizzate nel nostro esame sono alcune cronache russo-europee e uralico-siberiane, dove è stato affrontato il motivo dell'annessione del khanato siberiano alla Moscovia Nel nostro lavoro affrontiamo un argomento (la cronachistica uralico-siberiana della prima metà del XVII secolo) poco considerato dalla slavistica europea. Riteniamo inoltre che il nostro contributo sia particolarmente utile a migliorare le conoscenze della tarda cronachistica russa, di cui il ramo uralico-siberiano è un interessantissimo esito, dal momento che non costituisce un fenomeno puramente regionale, ma è fisiologicamente innervato nel processo evolutivo che il genere cronachistico antico-russo si trova complessivamente a sostenere nel corso del XVII secolo. Relativamente ai soli studi di letteratura russo-siberiana, abbiamo riconsiderato i rapporti genealogico-concettuali delle cronache uralico-siberiane tramite un'estensione delle fonti e la determinazione di afferenze ed influssi sino ad ora poco notati. I risultati della tesi sono validi per una maggiore conoscenza della cronachistica uralico-siberiana da un punto di vista storico, concettuale e testologico. ABSTRACT Our work has been focused on the conception of the fall of Kuchum's siberian Khanate in the uralic-siberian Chronicles of the first half of XVII century as well as on the genealogic relationships between such writings. In the work we directed our attention to some european-russian and uralic-siberian sources, where has been depicted the conquer of siberian Khanate by Ermak's cossacks. We deal with such an issue (uralic-siberian chronicles of the first half of XVII century), which has been payd no attention by western slavistics. In consequence, we believe that our work would be extremely useful to enhance knowledge of late russian Chronicles, of which the uralic-siberian branch is an interesting outcome: indeed, this branch does nor represent a merely regional phenomenon, since it is functionally bound up with the developmental stages early russian historic genres have undergone during XVII century. The conclusions, achieved in our work, could support a deeper knowledge of uralic-siberian Chronicles by a historic, conceptual and textologic point of view

Geomechanical characterization of an Italian complex formation with a block-in-matrix fabric

Melanges are chaotic and heterogeneous geological mixtures of strong rock blocks embedded in a weaker finer-grained matrix. These complex formations, often referred to as “bimrocks” (block-in-matrix rocks) and “bimsoils” (block-in-matrix soils), are characterized by a high spatial, dimensional and lithological variability. Such a variability, together with the presence of rock inclusions of different lithologies and dimensions, makes the collection of representative high-quality specimens for laboratory tests very challenging. As a consequence, the determination of the geomechanical properties of such geomaterials is extraordinarily problematic. In this paper a preliminary characterization of an Italian sedimentary chaotic melange is performed by means of several laboratory tests. In dry conditions it looks like a bimrock but it is very sensitive to water and will transform into a bimsoil if it comes into contact with water. Since conventional drilling methods could not be employed to collect the pecimens, a manual coring had to be used. The irregular lumps obtained were then cut with a specially made cutting machine. Point load tests and uniaxial compression tests were performed on the melange specimens. Atterberg limits, grading curves and mineralogical analyses were further carried out on the matrix material, in order to characterize it. The paper comments on both the procedure of these tests and the results obtained

Slope stability in heterogeneous rock masses with a block-in-matrix fabric

Heterogeneous rock masses composed of strong rock blocks embedded in a weaker matrix belong to complex formations and are often referred as BIMRocks (Block-In-Matrix-Rocks). The high variability of such rock bodies (spatial, dimensional and lithological) and the extraordinary problematic determination of their geomechanical properties make both the planning and the modelling of engineering works in and on these geomaterials ex-tremely challenging. The aim of this study is to investigate the stability of theoretical slopes in bimrocks. In or-der to determine how rock inclusions may influence the overall behaviour of these rock units, different block orientations and several Volumetric Block Proportions (VBP) are considered. To take the inherent spatial and dimensional variability of the blocks into ac-count, many heterogeneous slope models are generated for each block orientation and VBP examined. In order to do this, a stochastic approach is used, which provides for an acceptable statistical validity of the results

Effects of block shape and inclination on the stability of melange bimrocks

A wide range of heterogeneous geological units composed of strong rock blocks enclosed in a bonded matrix of fine texture exists worldwide. Such geomaterials belong to geotechnically complex formations and are often referred to as bimrocks (block-in-matrix rocks) or bimsoils (block-in-matrix soils), as a function of their matrix characteristics and the interface strength between the matrix and blocks. Stability problems occurring in such complex geomaterials have been analysed almost exclusively by means of deterministic approaches and with the aim of investigating the effects of variable block contents on their mechanical behaviour. However, bimrocks and bimsoils can present very different internal block-in-matrix arrangements and properties according to their forming process and, consequently, significantly dissimilar mechanical behaviours. Therefore, the aim of this paper was to statistically investigate and compare the stability of theoretical slopes in the most widespread bimrock formations, i.e. sedimentary and tectonic melanges. These formations are characterised by substantial differences in their rock inclusion geometry. To this aim, a great number of 2D slope models were generated to enclose blocks with variable shapes, dimensions, arrangements, inclinations and contents. To obtain statistically based results, fifteen configurations were analysed for each block content and geometrical configuration considered. The results obtained indicate that block shapes and orientations significantly affect the stability of slopes in bimrocks only when the block contents are greater than 40%. Moreover, it is demonstrated that blocks inclined 0° to the horizontal provide the most tortuous and irregular failure surfaces and, consequently, the highest safety factors

CXCR4 inhibitors: tumor vasculature and therapeutic challenges

CXCL12, also known as SDF-1, is the single natural ligand for chemokine receptors CXCR4 and CXCR7. CXCL12 has angiogenic properties in normal endothelial tissue and is involved in the outgrowth and metastasis of CXCR4 expressing tumors. Recent investigations have indicated that CXCL12 levels increase after chemo- and anti- VEGF therapy, favouring recurrences. The blockade of CXCL12/CXCR4 axis has emerged as a potential additional or alternative target for neo-adjuvant treatments. We have reviewed recent patent applications between 2008 and 2011 in tumor angiogenesis and the most clinical data supporting the potential use of anti-CXCR4 agents in this field. Among these, AMD3100, also known as Plerixaform (Mozobil® by Genzyme), is approved for stem cell mobilisation in patients with leukaemia, while BKT140 (Emory University), POL6326 (Polyphor Ag) and TG-0054 (ChemoCentryx) are currently in clinical trials in combination with chemotherapy for multiple myeloma and leukaemia. The aptamer Nox-A12 (Noxxon) is in trials for chronic lymphatic leukaemia treatment. MSX-122 (Metastatix) is in Phase I trials for solid tumor treatment, while CXCR7-specific inhibitor CCX2066 (ChemoCentryx) is still in preclinical studies. We have also considered other strategies, such RNA interference and miRNA, which could be tested for solid tumor adjuvant therapy

Preliminary Characterisation of an Italian Soft Rock with a Block-in-Matrix Fabric

Mélanges are heterogeneous geological deposits and represent the most widespread bimrock (block-in-matrix) formations. This paper presents the efforts undertaken to characterise an Italian mélange composed of a clayey-marly matrix enclosing strong calcareous blocks. Due to its low uniaxial compressive strength, this geomaterial can be classified as a soft rock. The weak nature of the marly matrix and its water sensitivity, as well as the presence of rock inclusions, made the collection and preparation of intact specimens extremely complex and time-consuming operations. The difficulties encountered during these phases are described in detail; the various non-conventional procedures considered and developed to overcome these problems are also presented. The potential of the solutions proposed lies in the fact that they can be conveniently applied to other soft rocks with a block-in-matrix internal arrangement, such as the Italian mélange. To characterise the Italian mélange, point load and uniaxial compressive tests were carried out. From the results of these tests, a conversion factor equal to 14 is proposed to correct the point load strength index in order to estimate the uniaxial compressive strength of soft rocks, such as the mélange under study. Moreover, to estimate local strains and the deformability of the geomaterial, the non-destructive digital image correlation technique was applied

Evidence for human diabetic cardiomyopathy.

Growing interest has been accumulated in the definition of worsening effects of diabetes in the cardiovascular system. This is associated with epidemiological data regarding the high incidence of heart failure (HF) in diabetic patients. To investigate the detrimental effects both of hyperglycemia and insulin resistance, a lot of preclinical models were developed. However, the evidence of pathogenic and histological alterations of the so-called diabetic cardiomyopathy (DCM) is still poorly understood in humans. Here, we provide a stringent literature analysis to investigate unique data regarding human DCM. This approach established that lipotoxic-related events might play a central role in the initiation and progression of human DCM. The major limitation in the acquisition of human data is due to the fact of heart specimen availability. Postmortem analysis revealed the end stage of the disease; thus, we need to gain knowledge on the pathogenic events from the early stages until cardiac fibrosis underlying the end-stage HF

Immunomodulatory effect of adipose-derived stem cells: the cutting edge of clinical application

Adipose-derived stem cells (ASCs) represent a promising tool for soft tissue engineering as well as for clinical treatment of inflammatory and autoimmune pathologies. The well-characterized multi-differentiation potential and self-renewal properties of ASCs are coupled with their immunomodulatory ability in providing therapeutic efficacy. Yet, their impact in immune or inflammatory disorders might rely both on cell contact-dependent mechanisms and paracrine effects, resulting in the release of various soluble factors that regulate immune cells functions. Despite the widespread use of ASCs in clinical trials addressing several pathologies, the pathophysiological mechanisms at the basis of their clinical use have been not yet fully investigated. In particular, a thorough analysis of ASC immunomodulatory potential is mandatory. Here we explore such molecular mechanisms involved in ASC immunomodulatory properties, emphasizing the relevance of the milieu composition. We review the potential clinical use of ASC secretome as a mediator for immunomodulation, with a focus on in vitro and in vivo environmental conditions affecting clinical outcome. We describe some potential strategies for optimization of ASCs immunomodulatory capacity in clinical settings, which act either on adult stem cells gene expression and local microenvironment. Finally, we discuss the limitations of both allogeneic and autologous ASC use, highlighting the issues to be fixed in order to significantly improve the efficacy of ASC-based cell therapy

Screening for Tuberculosis in Health Care Workers. Experience in an Italian Teaching Hospital

Health care workers (HCW) are particularly at risk of acquiring tuberculosis (TB), even in countries with low TB incidence. Therefore, TB screening in HCW is a useful prevention strategy in countries with both low and high TB incidence. Tuberculin skin test (TST) is widely used although it suffers of low specificity; on the contrary, the in vitro enzyme immunoassay tests (IGRA) show superior specificity and sensitivity but are more expensive. The present study reports the results of a three-year TB surveillance among HCW in a large teaching hospital in Rome, using TST (by standard Mantoux technique) and IGRA (by QuantiFERON-TB) as first- and second-level screening tests, respectively. Out of 2290 HCW enrolled, 141 (6.1%) had a positive TST; among them, 99 (70.2%) underwent the IGRA and 16 tested positive (16.1%). The frequency of HCW tested positive for TB seems not far from other experiences in low incidence countries. Our results confirm the higher specificity of IGRA, but, due to its higher cost, TST can be considered a good first level screening test, whose positive results should be further confirmed by IGRA before the patients undergo X-ray diagnosis and/or chemotherapy