ESC Guidelines for the diagnosis and management of syncopeThe Task Force for the diagnosis and management of syncope of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA)

Although gastrointestinal cancers are frequently associated with chronic inflammation, the underlying molecular links have not been comprehensively deciphered. Using loss- and gain-of-function mice in a colitis-associated cancer model, we establish here a link comprising the gp130/Stat3 transcription factor signaling axis. Mutagen-induced tumor growth and multiplicity are reduced following intestinal epithelial cell (IEC)-specific Stat3 ablation, while its hyperactivation promotes tumor incidence and growth. Conversely, IEC-specific Stat3 deficiency enhances susceptibility to chemically induced epithelial damage and subsequent mucosal inflammation, while excessive Stat3 activation confers resistance to colitis. Stat3 has the capacity to mediate IL-6- and IL-11-dependent IEC survival and to promote proliferation through G1 and G2/M cell-cycle progression as the common tumor cell-autonomous mechanism that bridges chronic inflammation to tumor promotion.

The CX3C chemokine fractalkine (CX3CL1) exists as a membrane-expressed protein promoting cell-cell adhesion and as a soluble molecule inducing chemotaxis. Transmembrane CX3CL1 is converted into its soluble form by defined proteolytic cleavage (shedding), which can be enhanced by stimulation with phorbol-12-myristate-13-acetate (PMA). PMA-induced CX3CL1 shedding has been shown to involve the tumor necrosis factor-␣-converting enzyme (TACE), whereas the constitutive cleavage in unstimulated cells remains elusive. Here we demonstrate a role of the closely related disintegrin-like metalloproteinase 10 (ADAM10) in the constitutive CX3CL1 cleavage. The hydroxamate GW280264X, capable of blocking TACE as well as ADAM10, proved to be an effective inhibitor of the constitutive and the PMA-inducible CX3CL1 cleavage in CX3CL1-expressing ECV-304 cells (CX3CL1-ECV-304), whereas GI254023X, preferentially blocking ADAM10 but not TACE, reduced the constitutive cleavage only. Overexpression of ADAM10 in COS-7 cells enhanced constitutive cleavage of CX3CL1 and, more importantly, in murine fibroblasts deficient of ADAM10 constitutive CX3CL1 cleavage was markedly reduced. Thus, ADAM10 contributes to the constitutive shedding of CX3CL1 in un- IntroductionLeukocyte recruitment to inflammatory sites involves a sequence of adhesive events that are mediated by different classes of adhesion molecules expressed on the endothelium and the leukocytes. 1 Whereas adhesion molecules of the selectin family usually contribute to the rolling of leukocytes under flow, members of the integrin family are involved in establishing a stable shear-resistant cell adhesion. Chemokines are thought to play a role in modulating cell adhesion by inducing shedding of L-selectin and by increasing functional integrins on the leukocyte surface. Thus, besides acting as chemoattractants in the tissue, chemokines can promote the transition from an early to a late adhesion type in the course of leukocyte recruitment.Within the chemokine family a transmembrane molecule termed CX3C chemokine ligand 1 (CX3CL1), or fractalkine, has been identified that by itself induces adhesion. 2 CX3CL1 is encoded as a 95-kDa multidomain molecule consisting of a chemokine domain linked to a transmembrane domain via a mucin-rich stalk. The chemokine is expressed on endothelial cells, 2 epithelial cells, 3,4 smooth muscle cells, 5,6 dendritic cells, 7,8 neurons, 9,10 and macrophages. 11 In vitro, CX3CL1 induces cell adhesion by interaction with its receptor CX3CR1 expressed on monocytes, T cells, mast cells, and natural killer cells. 2,[12][13][14] This adhesion does not require signaling of the receptor, is resistant to physiologic shear flow, and is independent of extracellular calcium. 2,15,16 Besides its activity as an adhesion molecule, CX3CL1 can be cleaved from the cell membrane to produce a soluble 80-kDa molecule that induces chemotaxis of CX3CR1-expressing leukocytes. 2 In vivo, upregulation of CX3CL1 has been found in atherosclerotic blood vessels, 6,11 rejected transplants, 1...

Aims/hypothesis Brain-derived neurotrophic factor (BDNF) is produced in skeletal muscle, but its functional significance is unknown. We aimed to determine the signalling processes and metabolic actions of BDNF. Methods We first examined whether exercise induced BDNF expression in humans. Next, C2C12 skeletal muscle cells were electrically stimulated to mimic contraction. L6 myotubes and isolated rat extensor digitorum longus muscles were treated with BDNF and phosphorylation of the proteins AMP-activated protein kinase (AMPK) (Thr 172 ) and acetyl coenzyme A carboxylase β (ACCβ) (Ser 79 ) were analysed, as was fatty acid oxidation (FAO).Finally, we electroporated a Bdnf vector into the tibialis cranialis muscle of mice. Results BDNF mRNA and protein expression were increased in human skeletal muscle after exercise, but muscle-derived BDNF appeared not to be released into the circulation. Bdnf mRNA and protein expression was increased in muscle cells that were electrically stimulated. BDNF increased phosphorylation of AMPK and ACCβ and enhanced FAO both in vitro and ex vivo. The effect of BDNF on FAO was AMPK-dependent, since the increase in FAO was abrogated in cells infected with an AMPK dominant negative adenovirus or treated with Compound C, an inhibitor of AMPK. Electroporation of a Bdnf expression

Esta atualização da Diretriz de Insuficiência Cardíaca Crônica (IC) - 2012 surge para reavaliar as recomendações através de uma avaliação criteriosa das pesquisas (considerando-se a qualidade dos estudos), fundamental para que se atinja esse propósito. Para tanto, foi dada ênfase ao efeito em desfechos de morte, à qualidade "CONSORT" (Consolidated Standards of Reporting Trials), à descrição qualitativa e quantitativa da otimização da medicação, à população realmente incluída, às metanálises somente de estudos qualidade "CONSORT", à custo-efetividade, à existência de efeito de classe, ao número de pacientes incluídos e à análise de subgrupos apenas para gerar hipóteses. Na área da epidemiologia, as recentes abordagens das características da IC com fração de ejeção preservada (ICFEP) e da importância da IC como causa de morte no Brasil foram revisadas. Além disso, este documento contempla a reavaliação do valor dos biomarcadores no diagnóstico e no seguimento da IC, o papel diagnóstico da angiotomografia coronariana nos casos de risco intermediário ou baixo risco de doença coronariana, a não recomendação de rotina do telemonitoramento; o surgimento da avaliação familiar como recomendação importante, e a reavaliação da restrição da adição de sal na dieta. As clínicas de IC e reabilitação física, apesar de alguns resultados negativos ou controversos quanto à mortalidade, continuam com recomendação importante. No campo do tratamento farmacológico, abrange-se a reavaliação da indicação do nebivolol, introduz-se a ivabradina como um novo paradigma no tratamento, os antagonistas da aldosterona não têm efeito de classe reconhecido, o ômega 3 passa a ser recomendado, o ferro administrado por via endovenosa e o sildenafil recebem indicação em casos selecionados. Todas as recomendações para outras etiologias são expandidas para a Doença de Chagas. Na área da anticoagulação, recomenda-se a utilização dos escores CHA2DS2VASC e o HAS-BLED na fibrilação atrial, com introdução de inibidores da trombina e do fator Xa como alternativas na anticoagulação. No tratamento cirúrgico da IC, considerou-se que resultados neutros do estudo STICH influenciaram as recomendações, o transplante cardíaco continua a ser o tratamento indicado nas fases evolutivas tardias de IC, os dispositivos de assistência circulatória mecânica para terapia de destino passam a ter recomendação, a duração do QRS foi fundamental na indicação de TRV-AV, e o CDI continua com recomendação I para miocardiopatia isquêmica. Entretanto, baseada em análise crítica dos estudos considerando-se o custo-efetividade, o CDI não atingiu recomendação I para classes menos graves devido as limitações dos estudos. Também a importância da cardiotoxicidade por drogas para tratamento de neoplasias foi ressaltada, o tratamento da IC na gravidez e da miocardite foi revisado. Novos potenciais métodos de tratamento em fase de pesquisa são apresentados e novos fluxogramas de diagnóstico e tratamento da IC, reformulados, foram incluído

ESC Guidelines for the diagnosis and management of syncopeThe Task Force for the diagnosis and management of syncope of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA)

AimsOrthostatic hypotension (OH) has been linked to increased mortality and incidence of cardiovascular disease in various risk groups, but determinants and consequences of OH in the general population are poorly studied.Methods and resultsProspective data of the Swedish ‘Malmö Preventive Project’ (n = 33 346, 67.3% men, mean age 45.7 ± 7.4 years, mean follow-up 22.7 ± 6.0 years) were analysed. Orthostatic hypotension was found in 6.2% of study participants and was associated with age, female gender, hypertension, antihypertensive treatment, increased heart rate, diabetes, low BMI, and current smoking. In Cox regression analysis, individuals with OH had significantly increased all-cause mortality (in particular those aged less than 42 years) and coronary event (CE) risk. Mortality and CE risk were distinctly higher in those with systolic blood pressure (BP) fall ≥30 mmHg [hazard ratio (HR): 1.6, 95% CI 1.3–1.9, P < 0.0001 and 1.6, 95% CI 1.2–2.1, P = 0.001] and diastolic BP fall ≥15 mmHg (HR: 1.4, 95% CI 1.1–1.9, P = 0.024 and 1.7, 95% CI 1.1–2.5, P = 0.01). In addition, impaired diastolic BP response had relatively greater impact (per mmHg) on CE incidence than systolic reaction.ConclusionOrthostatic hypotension can be detected in ∼6% of middle-aged individuals and is often associated with such comorbidities as hypertension or diabetes. Presence of OH increases mortality and CE risk, independently of traditional risk factors. Although both impaired systolic and diastolic responses predict adverse events, the diastolic impairment shows stronger association with coronary disease.

The protease a disintegrin and metalloprotease (ADAM) 17 cleaves tumor necrosis factor (TNF), L-selectin, and epidermal growth factor receptor (EGF-R) ligands from the plasma membrane. ADAM17 is expressed in most tissues and is up-regulated during inflammation and cancer. ADAM17-deficient mice are not viable. Conditional ADAM17 knockout models demonstrated proinflammatory activities of ADAM17 in septic shock via shedding of TNF. We used a novel gene targeting strategy to generate mice with dramatically reduced ADAM17 levels in all tissues. The resulting mice called ADAM17ex/ex were viable, showed compromised shedding of ADAM17 substrates from the cell surface, and developed eye, heart, and skin defects as a consequence of impaired EGF-R signaling caused by failure of shedding of EGF-R ligands. Unexpectedly, although the intestine of unchallenged homozygous ADAM17ex/ex mice was normal, ADAM17ex/ex mice showed substantially increased susceptibility to inflammation in dextran sulfate sodium colitis. This was a result of impaired shedding of EGF-R ligands resulting in failure to phosphorylate STAT3 via the EGF-R and, consequently, in defective regeneration of epithelial cells and breakdown of the intestinal barrier. Besides regulating the systemic availability of the proinflammatory cytokine TNF, our results demonstrate that ADAM17 is needed for vital regenerative activities during the immune response. Thus, our mouse model will help investigate ADAM17 as a potential drug target.