The formation of intracellular glyceraldehyde-derived advanced glycation end-products and cytotoxicity

Background  

Nonalcoholic steatohepatitis (NASH) is a feature of metabolic syndrome. Advanced glycation end-products (AGEs) are formed by the Maillard reaction, which contributes to aging and to certain pathological complications of diabetes. A recent study has suggested that glyceraldehyde-derived AGEs (Glycer-AGEs) are elevated in the sera of patients with NASH. Furthermore, immunohistochemistry of Glycer-AGEs showed intense staining in the livers of patients with NASH. The present study aimed to examine the effect of intracellular Glycer-AGEs on hepatocellular carcinoma (Hep3B) cells.     

Interferon-gamma production by human cord blood monocyte-derived dendritic cells

Interferon (IFN)-gamma is produced by T cells and natural killer cells and activates monocytes and dendritic cells (DCs). Recently, IFN-gamma has been shown to be produced by mouse DCs following stimulation with interleukin (IL)-12, which is markedly augmented by the addition of IL-18. We here analyzed whether human DCs secrete IFN-gamma in response to IL-12 and/or IL-18. Human immature DCs, generated from cord blood CD14(+) monocytes by treating with granulocyte-macrophage colony-stimulating factor and IL-4, were incubated with IL-12 and/or IL-18 and assayed for IFN-gamma production. IL-12, but not IL-18, weakly induced IFN-gamma production, while IL-12 together with IL-18 induced high levels of IFN-gamma production. Similar results were obtained with mature DCs, although levels of IFN-gamma production were less than those in immature DCs. Also with mature and immature DCs, IL-12 upregulated the expression of IL-18 receptor alpha (Ralpha), and costimulation with IL-12 and IL-18 upregulated CD40 expression. Anti-IL-18Ralpha antibody abrogated both the IFN-gamma induction and the CD40 upregulation by IL-12 plus IL-18. These findings suggest that IL-12 upregulates IL-18Ralpha expression on human DCs and acts synergistically with IL-18 to induce high levels of IFN-gamma, which subsequently enhances CD40 expression on DCs in an autocrine manner.     

Pitavastatin, an HMG-CoA reductase inhibitor, exerts eNOS-independent protective actions against angiotensin II induced cardiovascular remodeling and renal insufficiency

Angiotensin II (Ang II) plays a pivotal role in cardiovascular remodeling leading to hypertension, myocardial infarction, and stroke. Pitavastatin, an HMG-CoA reductase inihibitor, is known to have pleiotropic actions against the development of cardiovascular remodeling. The objectives of this study were to clarify the beneficial effects as well as the mechanism of action of pitavastatin against Ang II-induced organ damage. C57BL6/J mice at 10 weeks of age were infused with Ang II for 2 weeks and were simultaneously administered pitavastatin or a vehicle. Pitavastatin treatment improved Ang II-induced left ventricular hypertrophy and diastolic dysfunction and attenuated enhancement of cardiac fibrosis, cardiomyocyte hypertrophy, coronary perivascular fibrosis, and medial thickening. Ang II-induced oxidative stress, cardiac TGFbeta-1 expression, and Smad 2/3 phosphorylation were all attenuated by pitavastatin treatment. Pitavastatin also reduced Ang II-induced cardiac remodeling and diastolic dysfunction in eNOS-/- mice as in wild-type mice. In eNOS-/- mice, the Ang II-induced cardiac oxidative stress and TGF-beta-Smad 2/3 signaling pathway were enhanced, and pitavastatin treatment attenuated the enhanced oxidative stress and the signaling pathway. Moreover, pitavastatin treatment reduced the high mortality rate and improved renal insufficiency in Ang II-treated eNOS-/- mice, with suppression of glomerular oxidative stress and TGF-beta-Smad 2/3 signaling pathway. In conclusion, pitavastatin exerts eNOS-independent protective actions against Ang II-induced cardiovascular remodeling and renal insufficiency through inhibition of the TGF-beta-Smad 2/3 signaling pathway by suppression of oxidative stress.     

Differential effects of central fructose and glucose on hypothalamic malonyl-CoA and food intake

The American diet, especially that of adolescents, contains highly palatable foods of high-energy content and large amounts of high-fructose sweeteners. These factors are believed to contribute to the obesity epidemic and insulin resistance. Previous investigations revealed that the central metabolism of glucose suppresses food intake mediated by the hypothalamic AMP-kinase/malonyl–CoA signaling system. Unlike glucose, centrally administered fructose increases food intake. Evidence presented herein indicates that the more rapid initial steps of central fructose metabolism deplete hypothalamic ATP level, whereas the slower regulated steps of glucose metabolism elevate hypothalamic ATP level. Consistent with effects on the [ATP]/[AMP] ratio, fructose increases phosphorylation/activation of hypothalamic AMP kinase causing phosphorylation/inactivation of acetyl–CoA carboxylase, whereas glucose has the inverse effects. The changes provoked by central fructose administration reduce hypothalamic malonyl–CoA level and thereby increase food intake. These findings explain the paradoxical fructose effect on food intake and lend credence to the malonyl–CoA hypothesis.     

Aumento de Óbitos Domiciliares devido a Parada Cardiorrespiratória em Tempos de Pandemia de COVID-19

BackgroundCardiovascular diseases constitute an important group of causes of death in the country. Ischemic heart diseases that are the main causes of cardiopulmonary arrest, leading to an impact on the mortality of the cardiovascular diseases in the health system.ObjectiveAssess the number of home deaths by cardiopulmonary arrest notified by the Mobile Emergency Medical Service (SAMU) in March 2018, 2019 and 2020.MethodsObservational study carried out from the analysis of cardiopulmonary arrest mortality data of citizens assisted by SAMU in Belo Horizonte, Minas Gerais, Brazil. Social and clinical characteristics and occurrence information of the patients were analyzed. The mortality rate due to cardiopulmonary arrest in relation to the total number of attendances was assessed. A significance level of 95% was considered.ResultsThere was increase of home deaths due to cardiopulmonary arrest in March 2020 compared to March 2018 (p<0.001) and March 2019 (p=0.050). Of the deaths reported in 2020, 63.8% of the patients were aged 60 years or older, 63.7% of the occurrences were performed in the afternoon and approximately 87% of the cardiopulmonary arrest notified had associated clinical comorbidities, with systemic arterial hypertension and heart failure represented by 22.87% and 13.03% of the reported cases, respectively. The majority of the evaluated sample of this study did not have any medical care follow-up (88.7%).ConclusionConsidering the increase in the number of the deaths, we suggest reflections and readjustments regarding the monitoring of chronic non-transmissible diseases during a pandemic, as well as improvements in death surveillance. (Arq Bras Cardiol. 2021; 116(2):266-271)     

Positron emission tomography-positive squalene-induced lipoid pneumonia confirmed by gas chromatography-mass spectrometry of bronchoalveolar lavage fluid

Squalene is a type of oil obtained from shark liver. We describe a 76-year-old man diagnosed with chronic exogenous lipoid pneumonia due to squalene. A chest CT scan revealed pulmonary consolidation with ground-glass opacities in the right upper lobe. Positron emission tomography (PET) revealed significant uptake of 2-deoxy-2-F-fluoro-d-glucose (FDG) and 3'-deoxy-3'-F-fluorothymidine (FLT). Bronchoalveolar lavage (BAL) fluid contained many lipid-laden macrophages, and a transbronchial lung biopsy specimen showed clusters of foamy macrophages in alveolar spaces and granulomatous lesions. In addition, the presence of squalene in the BAL fluid was confirmed by gas chromatography-mass spectrometry, leading to a diagnosis of squalene-induced lipoid pneumonia. To the best of our knowledge, this is the first report of squalene-induced lipoid pneumonia in which squalene itself was successfully detected. This case also suggests the possibility that lipoid pneumonia shows significant uptake in FDG-PET and FLT-PET.     

Acute myeloid leukemia with t(8;21)(q22;q22) manifesting as granulocytic sarcomas in the rhinopharynx and external acoustic meatus at relapse after high-dose cytarabine: case report and review of the literature

We report a 31-year-old female with t(8;21)(q22;q22) acute myeloid leukemia (AML), M2 in the FAB classification. Complete remission was achieved with daunorubicin and cytarabine induction therapy followed by three courses of high-dose cytarabine consolidation. Only 3 months later, the patient relapsed with granulocytic sarcomas (GSs) in her rhinopharynx, external acoustic meatus, and bone marrow. She received focal radiation for the GSs and successfully underwent reinduction chemotherapy. Subsequently, she received a matched related donor peripheral blood stem cell transplantation followed by high-dose chemotherapy and is now in a second remission. We summarized 79 reported cases of t(8;21) AML with GS and reviewed the literature to identify differences in the characteristics of t(8;21) AML with GS between adults and children. To our knowledge, this is the first report of pharyngeal GS in t(8;21) AML, and focal irradiation plus more intensive postinduction therapy during first remission, such as allogeneic-SCT, may be effective in adult t(8;21) AML patients with GS.     

Oral vancomycin versus metronidazole for the treatment of Clostridioides difficile infection: Meta-analysis of randomized controlled trials

At present, vancomycin (VCM) and metronidazole (MNZ) are used for the first-line standard treatment of Clostridioides difficile infection (CDI). However, their differential use has not been sufficiently investigated. In this study, a meta-analysis on differences in the efficacy for CDI between VCM and MNZ was performed. Reports of randomized controlled studies using VCM or MNZ to treat CDI were surveyed. Meta-analysis was performed using the Mantel-Haenszel method and random-effects model, and the risk ratio and 95% confidence interval were calculated. Excluding overlapping reports, 1043 reports were extracted and 5 randomized controlled studies were extracted. There was no difference in therapeutic effects for CDI between VCM and MNZ (RR = 1.08, 95% CI (0.99–1.17), p = 0.09, I² = 37%). On subgroup analysis by the severity, there was no difference in the clinical effects for CDI between VCM and MNZ in non-severe cases (risk ratio: 1.09, 95% confidence interval: 1.00–1.19, p = 0.06), but the clinical effects of VCM were significantly higher than those of MNZ in severe cases (risk ratio: 1.19, 95% confidence interval: 1.02–1.39, p = 0.03). No significant difference was noted in the recurrence rate, incidence of adverse event, time to exhibit therapeutic effects, or judgment of the bacteriological effects. As the therapeutic effects of VCM were superior in severe CDI cases, VCM should be considered first in severe cases.     

Impact of mucosal barrier injury laboratory-confirmed bloodstream infection (MBI-LCBI) on central line-associated bloodstream infections (CLABSIs) in department of hematology at single university hospital in Japan

Background

Central line-associated bloodstream infections (CLABSIs) are among the most serious complications especially in blood cancer patients. In January 2013, Centers for Disease and Prevention (CDC) introduced a new surveillance definition of mucosal barrier injury-associated laboratory-confirmed bloodstream infection (MBI-LCBI). This study was to determine the impact of MBI-LCBI on CLABSIs and compare the clinical characteristics of MBI versus non-MBI-LCBI cases.