Sirtuin1 (SIRT1) regulates central metabolic functions such as lipogenesis, protein synthesis, gluconeogenesis, and bile acid (BA) homeostasis through deacetylation. Here we describe that SIRT1 ...tightly controls the regenerative response of the liver. We performed partial hepatectomy (PH) to transgenic mice that overexpress SIRT1 (SIRT). SIRT mice showed increased mortality, impaired hepatocyte proliferation, BA accumulation, and profuse liver injury after surgery. The damaging phenotype in SIRT mice correlated with impaired farnesoid X receptor (FXR) activity due to persistent deacetylation and lower protein expression that led to decreased FXR‐target gene expression; small heterodimer partner (SHP), bile salt export pump (BSEP), and increased Cyp7A1. Next, we show that 24‐norUrsodeoxycholic acid (NorUDCA) attenuates SIRT protein expression, increases the acetylation of FXR and neighboring histones, restores trimethylation of H3K4 and H3K9, and increases miR34a expression, thus reestablishing BA homeostasis. Consequently, NorUDCA restored liver regeneration in SIRT mice, which showed increased survival and hepatocyte proliferation. Furthermore, a leucine‐enriched diet restored mammalian target of rapamycin (mTOR) activation, acetylation of FXR and histones, leading to an overall lower BA production through SHP‐inhibition of Cyp7A1 and higher transport (BSEP) and detoxification (Sult2a1) leading to an improved liver regeneration. Finally, we found that human hepatocellular carcinoma (HCC) samples have increased presence of SIRT1, which correlated with the absence of FXR, suggesting its oncogenic potential. Conclusion: We define SIRT1 as a key regulator of the regenerative response in the liver through posttranscriptional modifications that regulate the activity of FXR, histones, and mTOR. Moreover, our data suggest that SIRT1 contributes to liver tumorigenesis through dysregulation of BA homeostasis by persistent FXR deacetylation. (Hepatology 2014;59:1972–1983)
Metabolic genes have been associated with the function of metabolizing and detoxifying environmental carcinogens. Polymorphisms present in these genes could lead to changes in their metabolizing and ...detoxifying ability and thus may contribute to individual susceptibility to different types of cancer. We investigated if the individual and/or combined modifying effects of the CYP1A1 MspI T6235C, GSTM1 present/null, GSTT1 present/null and GSTP1 Ile105Val polymorphisms are related to the risk of developing lung cancer in relation to tobacco consumption and occupation in Asturias, Northern Spain.
A hospital-based case-control study (CAPUA Study) was designed including 789 lung cancer patients and 789 control subjects matched in ethnicity, age, sex, and hospital. Genotypes were determined by PCR or PCR-RFLP. Individual and combination effects were analysed using an unconditional logistic regression adjusting for age, pack-years, family history of any cancer and occupation.
No statistically significant main effects were observed for the carcinogen metabolism genes in relation to lung cancer risk. In addition, the analysis did not reveal any significant gene-gene, gene-tobacco smoking or gene-occupational exposure interactions relative to lung cancer susceptibility. Lastly, no significant gene-gene combination effects were observed.
These results suggest that genetic polymorphisms in the CYP1A1, GSTM1, GSTT1 and GSTP1 metabolic genes were not significantly associated with lung cancer risk in the current study. The results of the analysis of gene-gene interactions of CYP1A1 MspI T6235C, GSTM1 present/null, GSTT1 present/null and GSTP1 Ile105Val polymorphisms in lung cancer risk indicate that these genes do not interact in lung cancer development.
Glycine N‐methyltransferase (GNMT) catabolizes S‐adenosylmethionine (SAMe), the main methyl donor of the body. Patients with cirrhosis show attenuated GNMT expression, which is absent in ...hepatocellular carcinoma (HCC) samples. GNMT−/− mice develop spontaneous steatosis that progresses to steatohepatitis, cirrhosis, and HCC. The liver is highly enriched with innate immune cells and plays a key role in the body's host defense and in the regulation of inflammation. Chronic inflammation is the major hallmark of nonalcoholic steatohepatitis (NASH) progression. The aim of our study was to uncover the molecular mechanisms leading to liver chronic inflammation in the absence of GNMT, focusing on the implication of natural killer (NK) / natural killer T (NKT) cells. We found increased expression of T helper (Th)1‐ over Th2‐related cytokines, tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL)‐R2/DR5, and several ligands of NK cells in GNMT−/− livers. Interestingly, NK cells from GNMT−/− mice were spontaneously activated, expressed more TRAIL, and had strong cytotoxic activity, suggesting their contribution to the proinflammatory environment in the liver. Accordingly, NK cells mediated hypersensitivity to concanavalin A (ConA)‐mediated hepatitis in GNMT−/− mice. Moreover, GNMT−/− mice were hypersensitive to endotoxin‐mediated liver injury. NK cell depletion and adoptive transfer of TRAIL−/− liver‐NK cells protected the liver against lipopolysaccharide (LPS) liver damage. Conclusion: Our data allow us to conclude that TRAIL‐producing NK cells actively contribute to promote a proinflammatory environment at early stages of fatty liver disease, suggesting that this cell compartment may contribute to the progression of NASH. (HEPATOLOGY 2012)
Objective
To report clinical and ancillary findings in a kindred with spinocerebellar ataxia 38 (SCA38).
Patients and methods
Five family members spanning two generations developed gait ataxia and ...intermittent diplopia. On examination, a cerebellar syndrome accompanied by downbeat nystagmus and a saccadic head impulse test (HIT) were found.
Results
Whole-exome sequencing demonstrated a heterozygous variant in
ELOVL5
, c.779A > G (p.Tyr260Cys), in four tested patients. Intermittent concomitant esotropia and hypertropia caused transient diplopia in one individual each. Saccadic HIT responses were found in four subjects. Sensorineural hypoacusis was present in every case. Electrophysiological studies demonstrated a sensory neuronopathy in patients from the first generation, with prolonged disease duration. Baseline serum docosahexaenoic acid (DHA) percent was diminished in four individuals. Oral 26-week dietary DHA supplementation, 650 mg/day, raised serum DHA percent and induced a statistically significant reduction in Scale for the Assessment and Rating of Ataxia (SARA) total scores, and in stance and heel–shin slide item scores.
Conclusion
The mentioned
ELOVL5
variant segregated with disease in this kindred. Downbeat nystagmus, intermittent heterotropia causing transient diplopia, vestibular impairment demonstrated by abnormal HIT, and sensory neuronopathy were part of the clinical picture in this series. DHA supplementation raised serum DHA percent in cases with diminished levels, and induced a clinical amelioration and a statistically significant reduction in SARA scores in the study group. Further studies are needed to investigate the role of these findings in SCA38, and to determine the response to prolonged DHA supplementation.
With population aging and the subsequent accumulation of cardiovascular risk factors, a growing proportion of patients presenting with acute coronary syndrome (ACS) are octogenarian (aged between 80 ...and 89). The marked heterogeneity of this population is due to several factors like age, comorbidities, frailty, and other geriatric conditions. All these variables have a strong impact on outcomes. In addition, a high prevalence of multivessel disease, complex coronary anatomies, and peripheral arterial disease, increases the risk of invasive procedures in these patients. In advanced age, the type and duration of antithrombotic therapy need to be individualized according to bleeding risk. Although an invasive strategy for non-ST-segment elevation acute myocardial infarction (NSTEMI) is recommended for the general population, its need is not so clear in octogenarians. For instance, although frail patients could benefit from revascularization, their higher risk of complications might change the risk/benefit ratio. Age alone should not be the main factor to consider when deciding the type of strategy. The risk of futility needs to be taken into account and identification of risk factors for adverse outcomes, such as renal impairment, could help in the decision-making process. Finally, an initially selected conservative strategy should be open to a change to invasive management depending on the clinical course (recurrent angina, ventricular arrhythmias, heart failure). Further evidence, ideally from prospective randomized clinical trials is urgent, as the population keeps growing.With population aging and the subsequent accumulation of cardiovascular risk factors, a growing proportion of patients presenting with acute coronary syndrome (ACS) are octogenarian (aged between 80 and 89). The marked heterogeneity of this population is due to several factors like age, comorbidities, frailty, and other geriatric conditions. All these variables have a strong impact on outcomes. In addition, a high prevalence of multivessel disease, complex coronary anatomies, and peripheral arterial disease, increases the risk of invasive procedures in these patients. In advanced age, the type and duration of antithrombotic therapy need to be individualized according to bleeding risk. Although an invasive strategy for non-ST-segment elevation acute myocardial infarction (NSTEMI) is recommended for the general population, its need is not so clear in octogenarians. For instance, although frail patients could benefit from revascularization, their higher risk of complications might change the risk/benefit ratio. Age alone should not be the main factor to consider when deciding the type of strategy. The risk of futility needs to be taken into account and identification of risk factors for adverse outcomes, such as renal impairment, could help in the decision-making process. Finally, an initially selected conservative strategy should be open to a change to invasive management depending on the clinical course (recurrent angina, ventricular arrhythmias, heart failure). Further evidence, ideally from prospective randomized clinical trials is urgent, as the population keeps growing.
Mitochondria contribute to macrophage immune function through the generation of reactive oxygen species, a byproduct of the mitochondrial respiratory chain. MCJ (also known as DnaJC15) is a ...mitochondrial inner membrane protein identified as an endogenous inhibitor of respiratory chain complex I. Here we show that MCJ is essential for the production of tumor necrosis factor by macrophages in response to a variety of Tolllike receptor ligands and bacteria, without affecting their phagocytic activity. Loss of MCJ in macrophages results in increased mitochondrial respiration and elevated basal levels of reactive oxygen species that cause activation of the JNK/c-Jun pathway, lead to the upregulation of the TACE (also known as ADAM 17) inhibitor TIMP-3, and lead to the inhibition of tumor necrosis factor shedding from the plasma membrane. Consequently, MCJ-deficient mice are resistant to the development of fulminant liver injury upon lipopolysaccharide administration. Thus, attenuation of the mitochondrial respiratory chain by MCJ in macrophages exquisitely regulates the response of macrophages to infectious insults.
Chronic myelomonocytic leukemia (CMML) has recently been associated with a high incidence of diverse mutations in genes such as TET2 or EZH2 that are implicated in epigenetic mechanisms. We have ...performed genome-wide DNA methylation arrays and mutational analysis of TET2, IDH1, IDH2, EZH2 and JAK2 in a group of 24 patients with CMML. 249 genes were differentially methylated between CMML patients and controls. Using Ingenuity pathway analysis, we identified enrichment in a gene network centered around PLC, JNK and ERK suggesting that these pathways, whose deregulation has been recently described in CMML, are affected by epigenetic mechanisms. Mutations of TET2, JAK2 and EZH2 were found in 15 patients (65%), 4 patients (17%) and 1 patient (4%) respectively while no mutations in the IDH1 and IDH2 genes were identified. Interestingly, patients with wild type TET2 clustered separately from patients with TET2 mutations, showed a higher degree of hypermethylation and were associated with higher risk karyotypes. Our results demonstrate the presence of aberrant DNA methylation in CMML and identifies TET2 mutant CMML as a biologically distinct disease subtype with a different epigenetic profile.
The electrocardiogram (ECG) represents an essential tool to determine cardiac electrical abnormalities in COVID-19 patients, the effects of anti-SARS-CoV-2 drugs, and potential drug interactions. ...Smartphone-based heart monitors have increased the spectrum of ECG monitoring however, we are not aware of its reliability in critically ill COVID-19 patients. We aim to evaluate the feasibility and reliability of nurse-performed smartphone electrocardiography for QT interval monitoring in critically ill COVID-19 patients using KardiaMobile-6L compared with the standard 12-lead ECG. An observational comparative study was conducted comparing consecutive KardiaMobile-6L and 12-lead ECG recordings obtained from 20 patients admitted to the intensive care unit with SARS-CoV-2 infection and on invasive mechanical ventilation. The heart rate-corrected QT (QTc) intervals measured by KardiaMobile-6L and 12-lead ECG were compared. In 60 percent of the recordings, QTc intervals measured by KardiaMobile-6L matched those by 12-lead ECG. The QTc intervals measured by KardiaMobile-6 and 12-lead ECG were 428 ± 45 ms and 425 ± 35 ms (p = 0.82), respectively. The former demonstrated good agreement (bias = 2.9 ms; standard deviation of bias = 29.6 ms) with the latter, using the Bland-Altman method of measurement agreement. In all but one recording, KardiaMobile-6L demonstrated QTc prolongation. QTc interval monitoring with KardiaMobile-6L in critically ill COVID-19 patients was feasible and demonstrated reliability comparable to the standard 12-lead ECG.
Respiratory viruses are part of the normal microbiota of the respiratory tract, which sometimes cause infection with/without respiratory insufficiency and the need for hospital or ICU admission. The ...aim of this study is to determine the prevalence of respiratory viruses in nontransplanted postoperative septic patients as well as lymphocyte count influence in their presence and its relationship to mortality. 223 nontransplanted postsurgical septic patients were recruited on the Intensive Care Unit (ICU) at Hospital Clínico Universitario de Valladolid prior to the SARS-COV-2 pandemic. Patients were split into 2 groups according to the presence/absence of respiratory viruses. Multivariate logistic regression analysis was used to identify independent factors related to positive respiratory virus PCR test. Respiratory viruses were isolated in 28.7% of patients. 28-day mortality was not significantly different between virus-positive and virus-negative groups. Logistic regression analysis revealed that lymphocyte count ≤ 928/µl is independently associated with a positive PCR result OR 3.76, 95% CI (1.71-8.26), P = .001 adjusted by platelet count over 128,500/µL OR 4.27, 95% CI (1.92-9.50) P < .001 and the presence of hypertension OR 2.69, 95% CI (1.13-6.36) P = .025 as confounding variables. Respiratory viruses' detection by using PCR in respiratory samples of nontransplanted postoperative septic patients is frequent. These preliminary results revealed that the presence of lymphopenia on sepsis diagnosis is independently associated to a positive virus result, which is not related to a higher 28-day mortality.
Automatic prediction of the aesthetic value of images has received increasing attention in recent years. This is due, on the one hand, to the potential impact that predicting the aesthetic value has ...on practical applications. Even so, it remains a difficult task given the subjectivity and complexity of the problem. An image aesthetics assessment system was developed in recent years by our research group. In this work, its potential to be applied in commercial tasks is tested. With this objective, a set of three portals and three real estate agencies in Spain were taken as case studies. Images of their websites were taken to build the experimental dataset and a validation method was developed to test their original order with another proposed one according to their aesthetic value. So, in this new order, the images that have the high aesthetic score by the AI system will occupy the first positions of the portal. Relevant results were obtained, with an average increase of 52.54% in the number of clicks on the ads, in the experiment with Real Estate portals. A statistical analysis prove that there is a significant difference in the number of clicks after selecting the images with the AI system.
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