Mechanical ventilation and volutrauma: study in vivo of a healthy pig model

Mechanical ventilation is essential in intensive care units. However, it may itself induce lung injury. Current studies are based on rodents, using exceptionally large tidal volumes for very short periods, often after a "priming" pulmonary insult. Our study deepens a clinically relevant large animal model, closely resembling human physiology and the ventilator setting used in clinic settings. Our aim was to evaluate the pathophysiological mechanisms involved in alveolo/capillary barrier damage due to mechanical stress in healthy subjects. We randomly divided 18 pigs (sedated with medetomidine/tiletamine-zolazepam and anesthetised with thiopental sodium) into three groups (n=6): two were mechanically ventilated (tidal volume of 8 or 20 ml/kg), the third breathed spontaneously for 4 hours, then animals were sacrifi ced (thiopental overdose). We analyzed every 30' hemogasanalysis and the main circulatory and respiratory parameters. Matrix gelatinase expression was evaluated on bronchoalveolar lavage fl uid after surgery and before euthanasia. On autoptic samples we performed zymographic analysis of lung, kidney and liver tissues and histological examination of lung. Results evidenced that high V T evoked profound alterations of lung mechanics and structure, although low V T strategy was not devoid of side effects, too. Unexpectedly, also animals that were spontaneously breathing showed a worsening of the respiratory functions

Effects of Hyaluronan on Breast Cancer Aggressiveness

Simple summary: Breast cancer is the most common neoplasm in women. Although the primary tumor does not appear in a vital organ, lethality is due to the ability of tumor cells to invade and seed distant organs, causing metastases. Approaches to reduce breast cancer cell aggressiveness target hormone receptors that sustain cell growth and motility. However, other factors contribute to aberrant cell behaviors in cancer cells, and nowadays, the role of the environment surrounding cancer cells is evident. The extracellular matrix polysaccharide hyaluronan is a ubiquitous component of the tumor microenvironment that not only modulates cell growth and movement but also plays a critical role in modulating the inflammatory response. In this review, we discuss the role of hyaluronan in relation to the expression of critical hormone receptors. The expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) in breast cancer cells is critical for determining tumor aggressiveness and targeting therapies. The presence of such receptors allows for the use of antagonists that effectively reduce breast cancer growth and dissemination. However, the absence of such receptors in triple-negative breast cancer (TNBC) reduces the possibility of targeted therapy, making these tumors very aggressive with a poor outcome. Cancers are not solely composed of tumor cells, but also include several types of infiltrating cells, such as fibroblasts, macrophages, and other immune cells that have critical functions in regulating cancer cell behaviors. In addition to these cells, the extracellular matrix (ECM) has become an important player in many aspects of breast cancer biology, including cell growth, motility, metabolism, and chemoresistance. Hyaluronan (HA) is a key ECM component that promotes cell proliferation and migration in several malignancies. Notably, HA accumulation in the tumor stroma is a negative prognostic factor in breast cancer. HA metabolism depends on the fine balance between HA synthesis by HA synthases and degradation yielded by hyaluronidases. All the different cell types present in the tumor can release HA in the ECM, and in this review, we will describe the role of HA and HA metabolism in different breast cancer subtypes

Neurochemical characterization of myenteric neurons in the juvenile gilthead sea bream (Sparus aurata) intestine

We evaluated the chemical coding of the myenteric plexus in the proximal and distal intestine of gilthead sea bream (Sparus aurata), which represents one of the most farmed fish in the Mediterranean area. The presence of nitric oxide (NO), acetylcholine (ACh), serotonin (5-HT), calcitonin-gene-related peptide (CGRP), substance P (SP) and vasoactive intestinal peptide (VIP) containing neurons, was investigated in intestinal whole mount preparations of the longitudinal muscle with attached the myenteric plexus (LMMP) by means of immunohistochemical fluorescence staining. The main excitatory and inhibitory neurochemicals identified in intestinal smooth muscle were ACh, SP, 5HT, and NO, VIP, CGRP. Some neurons displayed morphological features of ascending and descending interneurons and of putative sensory neurons. The expression of these pathways in the two intestinal regions is largely superimposable, although some differences emerged, which may be relevant to the morphological properties of each region. The most important variances are the higher neuronal density and soma size in the proximal intestine, which may depend on the volume of the target tissue. Since in the fish gut the submucosal plexus is less developed, myenteric neurons substantially innervate also the submucosal and epithelial layers, which display a major thickness and surface in the proximal intestine. In addition, myenteric neurons containing ACh and SP, which mainly represent excitatory motor neurons and interneurons innervating the smooth muscle were more numerous in the distal intestine, possibly to sustain motility in the thicker smooth muscle coat. Overall, this study expands our knowledge of the intrinsic innervation that regulates intestinal secretion, absorption and motility in gilthead sea bream and provides useful background information for rational design of functional feeds aimed at improving fish gut health

Hyaluronan in the Cancer Cells Microenvironment

The presence of the glycosaminoglycan hyaluronan in the extracellular matrix of tissues is the result of the cooperative synthesis of several resident cells, that is, macrophages and tumor and stromal cells. Any change in hyaluronan concentration or dimension leads to a modification in stiffness and cellular response through receptors on the plasma membrane. Hyaluronan has an effect on all cancer cell behaviors, such as evasion of apoptosis, limitless replicative potential, sustained angiogenesis, and metastasis. It is noteworthy that hyaluronan metabolism can be dramatically altered by growth factors and matrikines during inflammation, as well as by the metabolic homeostasis of cells. The regulation of HA deposition and its dimensions are pivotal for tumor progression and cancer patient prognosis. Nevertheless, because of all the factors involved, modulating hyaluronan metabolism could be tough. Several commercial drugs have already been described as potential or effective modulators; however, deeper investigations are needed to study their possible side effects. Moreover, other matrix molecules could be identified and targeted as upstream regulators of synthetic or degrading enzymes. Finally, co-cultures of cancer, fibroblasts, and immune cells could reveal potential new targets among secreted factors

Hyaluronan Produced by Smooth Muscle Cells Plays a Critical Role in Neointima Formation

Large body of evidence supports the idea that microenvironment plays a critical role in several pathologies including atherosclerosis and cancer. The amount of hyaluronan (HA) is involved in the microenvironment alterations and the concentration of this polymer reflects the progression of the diseases promoting neoangiogenesis, cell migration, and inflammation. The HA synthesis is regulated by several factors: UDP sugar precursors availability and the phosphorylation of synthetic enzyme HAS2 as well as specific drugs reducing the UDP precursors. The HAS2 phosphorylation is done by AMP kinase, a sensor of cell energy. When the cells have low energy, AMP kinase is activated and modifies covalently the regulatory enzymes, blocking all biosynthetic processes and activating the energy producing metabolism. It was recently reported that the hexosamine biosynthetic pathway (HBP) may increase the concentration of HA precursor UDP-N-acetylglucosamine (UDP-GlcNAc) leading to an increase of HA synthesis. We demonstrated that the increase of HA synthesis depends on the HAS2 post translational modification O-GlcNAcylation, which increases HA secretion modifying a residue different from the phosphorylation site of AMP kinase. In this report we highlighted the critical aspects of the post translational HAS2 regulation and its influence on HA synthesis

Cooperazione interistituzionale nelle Pubbliche Amministrazioni: l'Ufficio intercomunale

Nell'ambito dello scenario istituzionale caratterizzato da profonde trasformazioni (si pensi ad esempio alla riforma del titolo V della Costituzione), l'innovazione nella pubblica amministrazione risulta assumere un importanza rilevante. Gli Enti Locali dovranno prepararsi ed adeguarsi a ricevere le funzioni e le responsabilita' derivanti dall'attuazione della riforma. In questo quadro di riferimento si inserisce il presente progetto che individua come idea forza la collaborazione inter-istituzionale come fattore decisivo nella valorizzazione e nell'uso strategico delle risorse turistico culturali del territorio preso in esame. L'area analizzata e' quella dell'alto Casertano, nello specifico i nove Comuni che hanno dimostrato una buona propensione alla collaborazione: Alife, Castello del Matese, Gallo Matese, Letino, Piedimonte Matese, San Gregorio Matese, San Potito Sannitico, Sant'Angelo d'Alife e Valle Agricola. L'idea progetto consiste nella stipulazione di una convenzione tra questi Comuni al fine di istituire un ufficio intercomunale per la gestione associata di diverse funzioni che risultano essere fondamentali per un maggiore coordinamento istituzionale. Il progetto e' strutturato secondo il seguente schema: analisi del cambiamento istituzionale risorse culturali come fattore di sviluppo analisi del quadro di riferimento territoriale analisi swot formulazione della strategia e degli obiettivi idea forza idea progetto aspetti tecnic

Optimal Management of Elective Joint Replacement Surgery in Patients with Hemophilia

Hemophilia is a genetic or acquired disease that leads to spontaneous and recurrent bleedings, which affect the joints and muscles, thus determining chronic damage to the cartilage which will lead to joint disease and hemophilic arthropathy. Even though hemophilic patients were initially thought to have a low incidence of atherothrombotic complications, it is now clear that atherothrombotic events occur. The administration of plasmatic factor VIII has better clinical results in type A hemophilic patients than the transfusion with plasma. We analyzed five patients with hemophilia type A, aged between 35 and 62 years. Two of them had a severe form of hemophilia with factor VIII less than 1%, while the other three had a moderate form with factor VIII ranging between 1 and 5%. The five patients underwent total knee repair interventions and received substitution treatment with clotting factors but also prophylactic anticoagulant treatment. The postsurgical evolution of these patients was favorable, with similar hemostatic profile as the non-hemophilic patients. Moroctocog alfa is an efficient substitutive treatment that manages to normalize the hemostatic profile of patients. Therefore, it is recommended to provide prophylactic antithrombotic therapy after the orthopedic interventions

Correlations between Inflammation and Thrombosis in the Pathogeny of Myocardial Infarction

Atherosclerosis is the main cause of myocardial infarction. This process involves a complex interplay between metabolic pathways governing lipid deposition, inflammatory and immune responses to oxidized lipids, and endothelial dysfunction. Myocardial infarction appears when these processes culminate with a thrombotic event. Markers of inflammation, such as C-reactive protein (CRP), myeloperoxidase (MPO) and leukocyte levels are strong predictors of cardiovascular death, myocardial infarction, and stroke. This process involves a complex interplay between metabolic pathways governing lipid deposition, inflammatory and immune responses to oxidized lipids, and endothelial dysfunction. Myocardial infarction appears when these processes culminate with a thrombotic event. Markers of inflammation, such as C-reactive protein (CRP), myeloperoxidase (MPO) and leukocyte levels are strong predictors of cardiovascular death, myocardial infarction, and stroke. This review will summarize the molecular and cellular links between inflammation and thrombosis in the context of myocardial infarction, which support the concept of a thrombo inflammatory state leading to the vessel obstruction and to the subsequent myocardial necrosis