The beneficial effects of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) on coronary events have generally been attributed to their hypocholesterolemic properties. ...Mevalonate and other intermediates of cholesterol synthesis (isoprenoids) are necessary for cell proliferation and other important cell functions; thus effects other than cholesterol reduction may help to explain the antiatherosclerotic properties of statins. Recently we provided in vitro and in vivo evidence of decreased smooth-muscle cell (SMC) proliferation and migration by fluvastatin and simvastatin, but not by pravastatin, independent of plasma cholesterol reduction. The ability of fluvastatin to interfere with arterial SMC proliferation at therapeutic concentrations (0.1-1 μM) prompted us to investigate the pharmacologic activity of sera from 10 patients treated with fluvastatin, 40 mg once daily, on the proliferation of cultured human arterial myocytes. Pravastatin, 40 mg once daily, displays a lipid-lowering activity similar to that of fluvastatin without affecting SMC proliferation and was investigated as a control for assessing this non-lipid-related effect of fluvastatin. Fluvastatin and pravastatin, given for 6 days to patients with type IIa hypercholesterolemia, resulted in a similar decrease in low-density-lipoprotein (LDL) cholesterol. However, the addition of 15% whole-blood sera from patients treated with fluvastatin to the culture medium resulted in a 43% inhibition of cholesterol synthesis in SMCs (p < 0.01) that mirrored the pharmacokinetic profile of fluvastatin. When SMC proliferation was investigated, a significant inhibition of cell growth (−30%; p < 0.01) was detected with sera obtained 6 h after the last dose. No effect on SMC proliferation or cholesterol biosynthesis was observed when sera from patients treated with pravastatin were evaluated. These results suggest that statins exert a direct antiproliferative effect on the arterial wall, beyond their effects on plasma lipids, which could prevent significant cardiovascular disease.
At the beginning of the COVID-19 pandemic, fears grew that making vaccination a political (instead of public health) issue may impact the efficacy of this life-saving intervention, spurring the ...spread of vaccine-hesitant content. In this study, we examine whether there is a relationship between the political interest of social media users and their exposure to vaccine-hesitant content on Twitter. We focus on 17 European countries using a multilingual, longitudinal dataset of tweets spanning the period before COVID, up to the vaccine roll-out. We find that, in most countries, users' endorsement of vaccine-hesitant content is the highest in the early months of the pandemic, around the time of greatest scientific uncertainty. Further, users who follow politicians from right-wing parties, and those associated with authoritarian or anti-EU stances are more likely to endorse vaccine-hesitant content, whereas those following left-wing politicians, more pro-EU or liberal parties, are less likely. Somewhat surprisingly, politicians did not play an outsized role in the vaccine debates of their countries, receiving a similar number of retweets as other similarly popular users. This systematic, multi-country, longitudinal investigation of the connection of politics with vaccine hesitancy has important implications for public health policy and communication.
We evaluated the pharmacological activity of whole-blood serum from atorvastatin-
vs. simvastatin- (both 40
mg/day) treated hypercholesterolemic patients (
n
=
10) on cultured smooth muscle cell ...(SMC) proliferation and cholesterol biosynthesis, as related to lipid-lowering effect. Patients received either single or 2-weeks repeated doses of both simvastatin and atorvastatin, following a randomised, double-blind, cross-over design. Blood samples were collected before drug administration and at the scheduled intervals after administration, and the obtained serum was separated by centrifugation, sterilized and frozen until assayed. Cultured SMC were supplemented with medium plus 15% of separate serum sampled from the patients, and grown for 72
h. Proliferation was assayed by a Coulter Counter, while cholesterol biosynthesis was measured by the incorporation of
14C-acetate into cholesterol, under the same experimental conditions. Atorvastatin was more active
vs. simvastatin in reducing total- (−28.3%
vs. −20.7%;
p
=
0.045) and LDL-cholesterol (−39.8%
vs. −30.1%;
p
=
0.011) after a 2-weeks regimen. Serum from atorvastatin-treated patients inhibited SMC proliferation
vs.
t
=
0 after both single (AUC −21.6%) and repeated (AUC −26.9%) doses, while serum from simvastatin-treated patients inhibited SMC proliferation only after repeated doses (AUC −24.5%). Interestingly, in the same experimental conditions, the serum concentrations of both statins (and of their active metabolites) were constantly below the detection limits, as shown from the lack of inhibition of cholesterol biosynthesis. The absence of any significant association between the lipid-lowering effects and the inhibition of SMC proliferation, together with no detectable active statin in the serum, suggests that these effects are elicited through independent mechanisms.
From Francis Alÿs and Ursula Biemann to Vivan Sundaram, Allora & Calzadilla, and the Center for Urban Pedagogy, some of the most compelling artists today are engaging with the politics of land use, ...including the growth of the global economy, climate change, sustainability, Occupy movements, and the privatization of public space. Their work pivots around a set of evolving questions: In what ways is land, formed over the course of geological time, also contemporary and formed by the conditions of the present? How might art contribute to the expansion of spatial and environmental justice? Editors Emily Eliza Scott and Kirsten Swenson bring together a range of international voices and artworks to illuminate this critical mass of practices. One of the first comprehensive treatments of land use in contemporary art,Critical Landscapesskillfully surveys the stakes and concerns of recent land-based practices, outlining the art historical contexts, methodological strategies, and geopolitical phenomena. This cross-disciplinary collection is destined to be an essential reference not only within the fields of art and art history, but also across those of cultural geography, architecture and urban planning, environmental history, and landscape studies.
The fibrosis associated with idiopatic myelofibrosis (IM) is thought to be a reactive process mediated by cytokines released by abnormal megakaryocytes (MKs) in the microenviroment. The biochemical ...details of this process are, however, still not known. GATA-1low mice develop with age myelofibrosis, a syndrome very similar to IM, that manifests itself with thrombocytopenia, anemia and teardrop poikilocytes in the blood and marrow and spleen fibrosis at 12-month of age. From 15-month-on, extramedullary hematopoiesis is observed in the liver. Electron microscopy studies have shown that MKs from GATA-1low mutants are blocked between stage I and II of maturation. The block includes failure to organize the α-granules, abnormal P-selectin localization on the Demarcation Membrane System (DMS), and pathological neutrophil emperipolesis. The neutrophils embedded in the MKs release proteases that are thought to mediate release of TGF-β in the microenviroment through the canaliculi of the DMS. TGF- β is supposed, then, to activate the fibroblasts to produce fibers (Centurione et al, Blood 104:3573, 2004). To clarify the relationship between MKs, neutrophil emperipolesis and fibroblast activation, we present here the ultrastructural analysis of the spleen during the disease progression of GATA-1low mice. The animals were divided into three age groups: 5–8-month (IM-free), 10–12-month (pre-myelofibrotic) and 15-month-on (myelofibrotic). As disease progressed, the number of TGF-β-related immunogold-particles increased from ~30 (IM-free) to 80 (pre-myelofibrotic) and 230 (fibrotic) per field in all of the cells anlyzed (MKs, neutrophils and fibroblasts). TGF-β was found equally localized in the cytoplasm and in nucleus of these cells. In the fibroblasts, the rise of TGF-β content was associated with a dramatic change in morphology. In fact, the fibroblasts from old animals, envolved into larger cells with long protrutions that surrounded the MKs. The link between these protrusions and the MKs were so tight that at times the all structure appeared as a thickening of the cytoplasmic membrane of the MK. Numerous TGF-β particles we found located along these protrutions. Furthermore, some of the fibroblasts from these old animals acquired the morphology of myofibroblasts, with several myosin-like structures in the cytoplasm. These myofibroblasts were localized around the MK nests and isolated these nests from the surrounding fibrotic areas. On the other hand the fibrotic areas were characterized by the presence, in addition to the expected collagen fibers, of muscle fibers intercrossing each other. The presence of high TGF-β content within the cells, the differentiation of fibroblasts into myofibroblasts, the close contact of these cells with MK, as well as the presence of myosin fibers in the connective areas, are all features found also in the process of would healing and in the fibrosis associated with fibrocontractive disease. In summary, these results indicate that abnormal MKs, in addition to pathological interactions with neutrophils, establish pathological interactions with other cell types, including the fibroblasts. We suggest that these interactions may contribute to alter the microenviroment milleu of old GATA-1low mice.
An efficient management of chronic patients is a key element in the current and future Healthcare context.This paper aims at providing an overview of the PROASSIST 4.0 solution for an healthcare ...assistance territorial model 4.0. The proposed service relies on the integration between the organizational assets and advanced ICT technologies: a dynamic and adaptive system able to respond to the needs of citizens / patients and to support staff healthcare in the management of an ever-increasing number of patients is proposed. This is achieved by optimizing the scheduling of the territorial assistance based on multiple occurrences and actual patients' health status.
Clinical trials have firmly established that 3-hydroxy-3-methylglutaryl-coenzyme-A reductase inhibitors (statins) can induce regression of vascular atherosclerosis as well as reduction of ...cardiovascular-related morbidity and death in patients with and without coronary artery disease. These beneficial effects of statins are usually assumed to result from their ability to reduce cholesterol synthesis. However, because mevalonic acid is the precursor not only of cholesterol but also of many nonsteroidal isoprenoid compounds, inhibition of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase may result in pleiotropic effects. Indeed, statins can interfere with major events involved in the formation and the evolution of atherosclerotic lesions, such as arterial myocyte migration and proliferation and cholesterol accumulation, independent of their hypolipidemic properties. The aim of this article is to focus on clinical and experimental data that show that statins possess effects beyond cholesterol lowering, particularly on arterial smooth muscle cell proliferation. The contribution of these direct vascular effects to the reduction of cardiovascular events observed in clinical trials with statins represents one of the major challenges for future studies to understand the antiatherosclerotic benefits of these agents.
A number of proteins post-translationally modified by the covalent attachment of mevalonate-derived isoprene groups farnesol (FOH) or geranylgeraniol (GGOH), play a role in cell proliferation. For ...this reason, protein farnesyltransferase (PFTase) and protein geranylgeranyltransferases (PGGTases) I and II have gained attention as novel targets for the development of antiproliferative agents. Monoterpenes limonene, perillic acid (PA) and its derivatives have been shown to inhibit cell growth and protein prenylation in cancer cells. In the present study, we evaluated the effect of S(-) PA on diploid rat aorta smooth muscle cell (SMC) proliferation as related to protein prenylation. S(-) PA (1-3.5 mM) decreased, in a concentration-dependent manner, rat SMC proliferation as evaluated by cell counting and DNA synthesis. Morphological criteria and flow cytometry analysis excluded the induction of apoptosis as a potential antiproliferative mechanism of S(-) PA on SMC and confirmed a block of the cell cycle progression in G(0)/G(1) phase. The antiproliferative effect of S(-) PA could not be prevented by the addition of mevalonate, FOH, and GGOH to the culture medium and was independent of cholesterol biosynthesis. Densitometric analysis of fluorographed gels, after sodium dodecyl sulfate-polyacrylamide gel electrophoresis of the cell lysates, further supported that S(-) PA (1-3.5 mM), under the same experimental conditions, concentration-dependently inhibited FOH (up to 70%) and GGOH (up to 70%) incorporation into cellular proteins. We provide evidence that S(-) PA affects protein prenylation, an effect that may contribute to its inhibition of SMC proliferation.
Denoising is a common pre-processing step prior to analysis and interpretation tasks such as classification, unmixing and target detection, typically carried out for hyperspectral images (HSIs). In ...this paper we develop which performs spectralspatial HSI denoising through a convolutional neural network (CNN). Our newly developed method, called single denoising CNN (HSI-SDeCNN), considers HSIs as 3D data cubes, performing the denoising process with only one single model. Experimental results on both synthetic and real data demonstrate that our newly developed HSI-SDeCNN outperforms other stateof-the-art HSI denoising methods.
