Inhibition of phosphoinositide 3-kinase/protein kinase B signaling hampers the vasopressin-dependent stimulation of myogenic differentiation

Arginine-vasopressin (AVP) promotes muscle differentiation, hypertrophy, and regeneration through the combined activation of the calcineurin and Calcium/Calmodulin-dependent Protein Kinase (CaMK) pathways. The AVP system is impaired in several neuromuscular diseases, suggesting that AVP may act as a physiological factor in skeletal muscle. Since the Phosphoinositide 3-kinases/Protein Kinase B/mammalian Target Of Rapamycin (PI3K/Akt/mTOR) signaling plays a significant role in regulating muscle mass, we evaluated its role in the AVP myogenic effect. In L6 cells AKT1 expression was knocked down, and the AVP-dependent expression of mTOR and Forkhead box O3 (FoxO) was analyzed by Western blotting. The effect of the PI3K inhibitor LY294002 was evaluated by cellular and molecular techniques. Akt knockdown hampered the AVP-dependent mTOR expression while increased the levels of FoxO transcription factor. LY294002 treatment inhibited the AVP-dependent expression of Myocyte Enhancer Factor-2 (MEF2) and myogenin and prevented the nuclear translocation of MEF2. LY294002 also repressed the AVP-dependent nuclear export of histone deacetylase 4 (HDAC4) interfering with the formation of multifactorial complexes on the myogenin promoter. We demonstrate that the PI3K/Akt pathway is essential for the full myogenic effect of AVP and that, by targeting this pathway, one may highlight novel strategies to counteract muscle wasting in aging or neuromuscular disorders

O formoterol e uma dose média/ elevada de corticosteróides inalados são mais eficazes do que uma dose elevada de corticosteróides na asma moderada e grave

RESUMO: As normas internacionais para o tratamento da asma brônquica recomendam que os doentes com sintomatologia mal controlada com doses baixas/ /intermédias de corticosteróides (CT) inalados sejam submetidos a doses mais elevadas de CT e, se necessário, deverá ser adicionado um β2 agonista de longa duração. No entanto, estudos mais recentes demonstraram que a adição deste fármaco a doses baixas/moderadas de CT inalados permite um melhor controlo da sintomatologia do que a duplicação da dose de CT. O formoterol constitui o β2 agonista de eleição devido ao seu início de acção rápida.O objectivo do presente trabalho foi comparar a eficácia da associação do β2 agonista formoterol a doses médias/elevadas de CT inalados com a duplicação da dose do CT em indivíduos com asma moderada/grave mal controlada.Foram avaliados doentes com idade superior a 18 anos com asma moderada e grave que apresentavam um FEV1â¥50% do previsto e um aumentoâ¥15% do referido parâmetro após inalação de um broncodilatador de curta duração, tendo sido submetido a terapêutica com CT inalados diariamente (dipropionato de beclometasona 1000 μ - budesonida 800 μg) no mês que precedeu o início do estudo em análise. A existência de, pelo menos, dois dos parâmetros seguintes, nos últimos 7 dias do período de run-in, foi imprescindível: sintomatologia interferindo com as actividades de vida diária; interrupção do sono por sintomas nocturnos, necessidade de terapêutica de alívio numa doseâ¥4 puffs salbutamol/dia; variabilidade diária do PEF (Peak Expiratory Flow)â¥15%.Foram critérios de exclusão: doentes cuja dose do CT inalado diária foi alterada no último mês; indivíduos submetidos a CT oral ou β2 agonista de longa duração no mês precedente; doentes com dificuldade de utilizar o aerolizer apesar da instrução adequada.Tratou-se de um estudo randomizado, duplamente cego, envolvendo 203 indivíduos: 102 submetidos a formoterol 12 μg e dipropionato de beclometasona 500 μg duas vezes/dia; 101 sob este corticosteróide na dose de 1000 μg duas vezes/dia e placebo. Ambos os grupos foram tratados com os referidos fármacos durante 12 semanas. Os doentes estudados apresentavam um FEV1 72% do previsto, uma reversibilidade desencadeada pelo (β2 agonista de curta duração de 27%, scores de sintomas moderados e necessidade de terapêutica de alívio na doseâ¥5 puffs de salbutamol/ dia.A diferença do PEF entre os dois grupos foi de 27,78 1/minuto, sendo favorável à associação formoterol/beclometasona (p=0,0002). Foi observada, também, uma diferença estatisticamente significativa na relação cortisol/ creatinina urinário após o tratamento de 12 semanas (p=0,001), indicando supressão do eixo hipotalâmico-hipofisário nos doentes sob 1000 μg de dipropionato de beclometasona duas vezes/ dia. Os scores de sintomas foram significativamente mais baixos nos doentes sob terapêutica combinada, sendo a proporção de doentes livres de sintomas durante o dia duas vezes superior neste grupo e a utilização de terapêutica de alívio inferior. COMENTÃRIO: Este estudo demonstra que, no tratamento de doentes com asma moderada/grave não controlada com dipropionato de beclometasona 1000 μg/dia, a adição de formoterol 12 μg duas vezes/dia é mais eficaz do que a duplicação da dose de beclometasona.A terapêutica combinada melhora significativamente os parâmetros objectivos da obstrução das vias aéreas quando comparada com altas doses de corticosteróides inalados. O efeito benéfico de adição de formoterol na função pulmonar tornou-se evidente após quatro semanas de tratamento e permaneceu inalterada até ao fim do estudo. Este efeito pode dever-se ao antagonismo funcional do formoterol à contracção do músculo liso, à sua capacidade de estabilizar os mastócitos ou de reduzir o edema da parede brônquica.As exacerbações ligeiras e moderadas ocorreram com maior frequência no grupo sob altas doses de CT inalados. Estes resultados foram sobreponíveis aos observados anteriormente em doentes com asma ligeira submetidos à associação formoterol/budesonido (dose baixa/intermédia) ou a doses elevadas deste último fármaco. Também neste estudo se verificou um maior número de exacerbações no segundo grupo.Elevadas doses de CT inalados estão relacionadas com significativos efeitos suprarrenais. Assim, a associação de um β2 agonista de longa acção (formoterol) permite o controlo da doença sem necessidade de doses altas de CT inalados. Neste estudo, o quociente cortisol/creatinina urinário foi significativamente menor no grupo sob corticoterapia em dose elevada do que nos indivíduos submetidos a terapêutica combinada, traduzindo uma maior supressão do risco hipotalâmico-hipofisário no primeiro caso. Estes achados vieram confirmar a observação de que o dipropionato de beclometasona na doseâ¥1500 μg/dia exerce um efeito supressor significativo na libertação de cortisol endógeno.A terapêutica combinada de CT inalados e β2 agonistas de longa acção permitiu um bom controlo da asma brônquica, comparativamente a baixas doses de CT, e conduziu à administração dos fármacos inalados em doses fixas através de um dispositivo único. Ringdal e colaboradores compararam a eficácia do salmeterol 50 μg/ fluticasona 250 μg utilizando Diskus duas vezes/dia com o formoterol 12 μg/ budesonido 500 μg administrados separadamente através do Turbohaler duas vezes/ /dia. A primeira associação foi significativamente superior na redução das exacerbações de asma e dos sintomas nocturnos, apesar da dose mais baixa de fluticasona comparada com a de budesonido. Estes resultados não são, no entanto, inesperados, visto a fluticasona ser mais potente do que o budesonido.Apesar de a administração de fármacos em doses fixas num único dispositivo ter vantagens adicionais em termos de aderência ao tratamento e conveniência, não apresenta grande flexibilidade no ajuste da dose durante as exacerbações. São, assim, necessários novos estudos para avaliar os dispositivos mais apropriados, de forma a obter o maior sinergismo de acção entre β2 agonista de longa duração e os CT inalados. Palavras-chave: Asma moderada/grave, β2 agonista de longa acção, formoterol, corticosteróides inalados, beclometason

The cross-talk between thrombosis and inflammatory storm in acute and long-covid-19: Therapeutic targets and clinical cases

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) commonly complicates with coagulopathy. A syndrome called Long-COVID-19 is emerging recently in COVID-19 survivors, characterized, in addition to the persistence of symptoms typical of the acute phase, by alterations in inflammatory and coagulation parameters due to endothelial damage. The related disseminated intravascular coagulation (DIC) can be associated with high death rates in COVID-19 patients. It is possible to find a prothrombotic state also in Long-COVID-19. Early administration of anticoagulants in COVID-19 was suggested in order to improve patient outcomes, although exact criteria for their application were not well-established. Low-molecular-weight heparin (LMWH) was commonly adopted for counteracting DIC and venous thromboembolism (VTE), due to its pharmacodynamics and anti-inflammatory properties. However, the efficacy of anticoagulant therapy for COVID-19-associated DIC is still a matter of debate. Thrombin and Factor Xa (FXa) are well-known components of the coagulation cascade. The FXa is known to strongly promote inflammation as the consequence of increased cytokine expression. Endothelial cells and mononuclear leucocytes release cytokines, growth factors, and adhesion molecules due to thrombin activation. On the other hand, cytokines can activate coagulation. The cross-talk between coagulation and inflammation is mediated via protease-activated receptors (PARs). These receptors might become potential targets to be considered for counteracting the clinical expressions of COVID-19. SARS-CoV-2 is effectively able to activate local and circulating coagulation factors, thus inducing the generation of disseminated coagula. LMWH may be considered as the new frontier in the treatment of COVID-19 and Long-COVID-19. Indeed, direct oral anticoagulants (DOACs) may be an alternative option for both early and later treatment of COVID-19 patients due to their ability to inhibit PARs. The aim of this report was to evaluate the role of anticoagulants—and DOACs in particular in COVID-19 and Long-COVID-19 patients. We report the case of a COVID-19 patient who, after administration of enoxaparin developed DIC secondary to virosis and positivity for platelet factor 4 (PF4) and a case of Long-COVID with high residual cardiovascular risk and persistence of blood chemistry of inflammation and procoagulative state

Acute Myocarditis After Black Widow Spider Bite: A Case Report

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New evidence of mis 3 relative sea level changes from the messina strait, Calabria (Italy)

none12Investigation of sea-level positions during the highly-dynamic Marine Isotope Stage 3 (MIS 3: 29–61 kyrs BP) proves difficult because: (i) in stable and subsiding areas, coeval coastal sediments are currently submerged at depths of few to several tens of meters below the present sea level; (ii) in uplifting areas, the preservation of geomorphic features and sedimentary records is limited due to the erosion occurred during the Last Glacial Maximum (LGM) with sea level at a depth of −130 m, followed by marine transgression that determined the development of ravinement surfaces. This study discusses previous research in the Mediterranean and elsewhere, and describes new fossiliferous marine deposits overlaying the metamorphic bedrock at Cannitello (Calabria, Italy). Radiocarbon ages of marine shells (about 43 kyrs cal BP) indicate that these deposits, presently between 28 and 30 m above sea level, formed during MIS 3.1. Elevation correction of the Cannitello outcrops (considered in an intermediate-to-far-field position with respect to the ice sheet) with the local vertical tectonic rate and Glacial Isostatic Adjustment (GIA) rate allows the proposal of a revision of the eustatic depth for this highstand. Our results are consistent with recently proposed estimates based on a novel ice sheet modelling technique.openAntonioli F.; Calcagnile L.; Ferranti L.; Mastronuzzi G.; Monaco C.; Orru P.; Quarta G.; Pepe F.; Scardino G.; Scicchitano G.; Stocchi P.; Taviani M.Antonioli, F.; Calcagnile, L.; Ferranti, L.; Mastronuzzi, G.; Monaco, C.; Orru, P.; Quarta, G.; Pepe, F.; Scardino, G.; Scicchitano, G.; Stocchi, P.; Taviani, M

A Systematic Review of the Efficacy and Safety of Direct Oral Anticoagulants in Atrial Fibrillation Patients with Diabetes Using a Risk Index

Diabetes mellitus (DM) represents an independent risk factor for chronic AF and is associated with unfavorable outcomes. We aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) in patients with atrial fibrillation (AF), with and without diabetes mellitus (DM), using a new risk index (RI) defined as: RI = Rate of Events/Rate of Patients at Risk. In particular, an RI lower than 1 suggests a favorable treatment effect. We searched MEDLINE, MEDLINE In-Process, EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials. The risk index (RI) was calculated in terms of efficacy (rate of stroke/systemic embolism (stroke SEE)/rate of patients with and without DM; rate of cardiovascular death/rate of patients with and without DM) and safety (rate of major bleeding/rate of patients with and without DM) outcomes. AF patients with DM (n = 22,057) and 49,596 without DM were considered from pivotal trials. DM doubles the risk index for stroke/SEE, major bleeding (MB), and cardiovascular (CV) death. The RI for stroke/SEE, MB, and CV death was comparable in patients treated with warfarin or DOACs. The lowest RI was in DM patients treated with Rivaroxaban (stroke/SEE, RI = 0.08; CV death, RI = 0.13). The RIs for bleeding were higher in DM patients treated with Dabigatran (RI110 = 0.32; RI150 = 0.40). Our study is the first to use RI to homogenize the efficacy and safety data reported in the DOACs pivotal studies against warfarin in patients with and without DM. Anticoagulation therapy is effective and safe in DM patients. DOACs appear to have a better efficacy and safety profile than warfarin. The use of DOACs is a reasonable alternative to vitamin-K antagonists in AF patients with DM. The RI can be a reasonable tool to help clinicians choose between DOACs or warfarin in the peculiar set of AF patients with DM

Millstones as indicators of relative sea-level changes in northern Sicily and southern Calabria coast lines, Italy

New data are presented for late Holocene relative sea-level changes in two coastal sites of Sicily and Calabria, southern Italy. Reconstructions are based on precise measurements of submerged archaeological remains that are valuable indicators of past sea-level position. The archaeological remains are millstone quarries carved on sandstone coastal rocks and nowadays partially submerged which, to the authors’ knowledge, are used for the first time as sea-level markers. Millstones of similar typology are located on the coast of Capo d’Orlando (northern Sicily) and Capo dell’Armi (southern Calabria). When the archeologically-based sea-level position is compared with the shoreline elevation provided by geological markers (Holocene beachrock, Late Pleistocene marine terraces), a refined understanding of relative sea-level changes and rates of vertical tectonic movements for these coastline locations is gained

Relative sea-level rise and potential submersion risk for 2100 on 16 coastal plains of the mediterranean sea

The coasts of the Mediterranean Sea are dynamic habitats in which human activities have been conducted for centuries and which feature micro-tidal environments with about 0.40 m of range. For this reason, human settlements are still concentrated along a narrow coastline strip, where any change in the sea level and coastal dynamics may impact anthropic activities. In the frame of the RITMARE and the Copernicus Projects, we analyzed light detection and ranging (LiDAR) and Copernicus Earth Observation data to provide estimates of potential marine submersion for 2100 for 16 small-sized coastal plains located in the Italian peninsula and four Mediterranean countries (France, Spain, Tunisia, Cyprus) all characterized by different geological, tectonic and morphological features. The objective of this multidisciplinary study is to provide the first maps of sea-level rise scenarios for 2100 for the IPCC RCP 8.5 and Rahmstorf (2007) projections for the above affected coastal zones, which are the locations of touristic resorts, railways, airports and heritage sites. On the basis of our model (eustatic projection for 2100, glaciohydrostasy values and tectonic vertical movement), we provide 16 high-definition submersion maps. We estimated a potential loss of land for the above areas of between about 148 km2 (IPCC-RCP8.5 scenario) and 192 km2 (Rahmstorf scenario), along a coastline length of about 400 km

ZNF521 Enhances MLL-AF9-Dependent Hematopoietic Stem Cell Transformation in Acute Myeloid Leukemias by Altering the Gene Expression Landscape

Leukemias derived from the MLL-AF9 rearrangement rely on dysfunctional transcriptional networks. ZNF521, a transcription co-factor implicated in the control of hematopoiesis, has been proposed to sustain leukemic transformation in collaboration with other oncogenes. Here, we demonstrate that ZNF521 mRNA levels correlate with specific genetic aberrations: in particular, the highest expression is observed in AMLs bearing MLL rearrangements, while the lowest is detected in AMLs with FLT3-ITD, NPM1, or CEBPα double mutations. In cord blood-derived CD34(+) cells, enforced expression of ZNF521 provides a significant proliferative advantage and enhances MLL-AF9 effects on the induction of proliferation and the expansion of leukemic progenitor cells. Transcriptome analysis of primary CD34(+) cultures displayed subsets of genes up-regulated by MLL-AF9 or ZNF521 single transgene overexpression as well as in MLL-AF9/ZNF521 combinations, at either the early or late time points of an in vitro leukemogenesis model. The silencing of ZNF521 in the MLL-AF9 + THP-1 cell line coherently results in an impairment of growth and clonogenicity, recapitulating the effects observed in primary cells. Taken together, these results underscore a role for ZNF521 in sustaining the self-renewal of the immature AML compartment, most likely through the perturbation of the gene expression landscape, which ultimately favors the expansion of MLL-AF9-transformed leukemic clones