Comorbidità nell’asma grave pediatrico

Asthma comorbidities frequently cause adverse outcomes, such as poor asthma control, frequent asthma attacks, reduced quality of life, and higher healthcare costs. Comorbidities are well-known treatable traits whose proper management can help achieve optimal asthma control. Although multimorbidity is frequent among asthmatics, comorbidities are still a potential cause of misdiagnosis and under or overtreatments, and little is known about their impact on severe pediatric asthma. Over the years, growing scientific evidence has pointed to the existence of a clear epidemiological correlation between asthma and its comorbidities and of possible common pathogenetic mechanisms responsible for a mutual bi-directional influence between the diseases, with sometimes the possibility of describing distinct asthma phenotypes. In this light, the appropriate management of asthma comorbidities could be crucial to propose personalized or adjunctive therapies of apparent efficacy in patients with severe asthma

In vitro epigenetic reprogramming of human cardiac mesenchymal stromal cells into functionally competent cardiovascular precursors

Adult human cardiac mesenchymal-like stromal cells (CStC) represent a relatively accessible cell type useful for therapy. In this light, their conversion into cardiovascular precursors represents a potential successful strategy for cardiac repair. The aim of the present work was to reprogram CStC into functionally competent cardiovascular precursors using epigenetically active small molecules. CStC were exposed to low serum (5% FBS) in the presence of 5 \ub5M all-trans Retinoic Acid (ATRA), 5 \ub5M Phenyl Butyrate (PB), and 200 \ub5M diethylenetriamine/nitric oxide (DETA/NO), to create a novel epigenetically active cocktail (EpiC). Upon treatment the expression of markers typical of cardiac resident stem cells such as c-Kit and MDR-1 were up-regulated, together with the expression of a number of cardiovascular-associated genes including KDR, GATA6, Nkx2.5, GATA4, HCN4, NaV1.5, and \u3b1-MHC. In addition, profiling analysis revealed that a significant number of microRNA involved in cardiomyocyte biology and cell differentiation/proliferation, including miR 133a, 210 and 34a, were up-regulated. Remarkably, almost 45% of EpiC-treated cells exhibited a TTX-sensitive sodium current and, to a lower extent in a few cells, also the pacemaker I(f) current. Mechanistically, the exposure to EpiC treatment introduced global histone modifications, characterized by increased levels of H3K4Me3 and H4K16Ac, as well as reduced H4K20Me3 and H3s10P, a pattern compatible with reduced proliferation and chromatin relaxation. Consistently, ChIP experiments performed with H3K4me3 or H3s10P histone modifications revealed the presence of a specific EpiC-dependent pattern in c-Kit, MDR-1, and Nkx2.5 promoter regions, possibly contributing to their modified expression. Taken together, these data indicate that CStC may be epigenetically reprogrammed to acquire molecular and biological properties associated with competent cardiovascular precursors

Controversies in the treatment of mild asthma. What novelties and practical implications?

Mild asthma is prevalent in childhood and causes as many as 30%-40% asthma exacerbations requiring emergency visits. The management of "intermittent" and "mild persistent" asthma phenotypes is still a matter of debate, even if the role of inhaled corticosteroids, both continuous and intermittent, is a cornerstone in this field. Recent updates of the guidelines on the strategies to manage these patients are coming, since the role of inflammation in these asthma phenotypes is crucial, as well as the potential side effect and risks of short-acting beta 2 agonists overuse, prescribed as the only "as-needed" treatments. In this paper, we overview the new (r)evolution regarding intermittent and mild persistent asthma management

the outcome ofpregnancy in type1 and type2 diabetic women

37TH ANNUAL MEETING OF DIABETIC PREGNANCY STUDY GROUP DPSG of EUROPEAN ASSOCIATION of DIABETES, MYCONOS, GREEC

Efficacy and Safety Profile of Diclofenac/Cyclodextrin and Progesterone/Cyclodextrin Formulations: A Review of the Literature Data

Background: According to health technology assessment, patients deserve the best medicine. The development of drugs associated with solubility enhancers, such as cyclodextrins, represents a measure taken in order to improve the management of patients. Different drugs, such as estradiol, testosterone, dexamethasone, opioids, non-steroidal anti-inflammatories (NSAIDs; i.e. diclofenac), and progesterone are associated with cyclodextrins. Products containing the association of diclofenac/cyclodextrins are available for subcutaneous, intramuscular, and intravenous administration in doses that range from 25 to 75 mg. Medicinal products containing the association of progesterone/cyclodextrins are indicated for intramuscular and subcutaneous injection at a dose equal to 25 mg. Objectives and Methods: The effects of cyclodextrins have been discussed in the solubility profile and permeability through biological membranes of drug molecules. A literature search was performed in order to give an overview of the pharmacokinetic characteristics, and efficacy and safety profiles of diclofenac/hydroxypropyl-β-cyclodextrin (HPβCD) and progesterone/HPβCD associations. Results: The results of more than 20 clinical studies were reviewed. It was suggested that the new diclofenac/HPβCD formulation gives a rapid and effective response to acute pain and, furthermore, has pharmacokinetic and efficacy/safety profiles comparable to other medicinal products not containing cyclodextrins. One of the principal aspects of these new diclofenac formulations is that in lowering the dose (lower than 50 mg) the drugs could be more tolerable, especially in patients with comorbid conditions. Moreover, results of studies investigating the characteristics of progesterone and cyclodextrins showed that the new formulation (progesterone/HPβCD 25 mg solution) has the same bioavailability as other products containing progesterone. It is more rapidly absorbed and allows the achievement of peak plasma concentrations in a shorter time. Finally, the new formulation of progesterone was shown to be safe and not inferior to other products already on the market, with the exception of progesterone administered vaginally. Conclusions: As shown by the results of clinical studies presented in this review, the newly approved medicines containing cyclodextrins have been found to be as effective and as well-tolerated as other medicinal products that do not contain cyclodextrins. Moreover, the newly approved lower dose of diclofenac associated with cyclodextrins is consistent with the European Medicines Agency recommendations reported in the revision of the Assessment Report for Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) and Cardiovascular Risk. Finally, the use of cyclodextrins led to significant increases in solubility and bioavailability of drugs, such as diclofenac and progesterone, and improvement in the efficacy and safety of these drugs

Mesoangioblasts from ventricular vessels can differentiate in vitro into cardiac myocytes with sinoatrial-like properties

Cardiac mesoangioblasts (MABs) are a class of vessel-associated clonogenic, self-renewing progenitor cells, recently identified in the post-natal murine heart and committed to cardiac differentiation. Cardiomyocytes generated during cardiogenesis from progenitor cells acquire several distinct phenotypes, corresponding to different functional properties in diverse structures of the adult heart. Given the special functional relevance to rhythm generation and rate control of sinoatrial cells, and in view of their prospective use in therapeutical applications, we sought to determine if, and to what extent, cardiac mesoangioblasts could also differentiate into myocytes with properties typical of mature pacemaker myocytes. We report here that a subpopulation of cardiac mesoangioblasts, induced to differentiate in vitro into cardiomyocytes, do acquire a phenotype with specific mature pacemaker myocytes properties. These include expression of the HCN4 isoform of pacemaker ("funny", f-) channels and connexin 45 (Cx45), as well as reduced expression of inwardly-rectifying potassium channels. Furthermore, MAB-derived myocytes form agglomerates of pacing cells displaying stable rhythmic activity, and as in native cardiac pacemaker cells, f-channel modulation by autonomic transmitters contributes to control of spontaneous rate in differentiated mesoangioblasts. These data represent the first evidence for in vitro generation of pacemaker-like myocytes from proliferating non-embryonic stem/progenitor cells