Iron deficiency in heart failure patients

A anemia é uma comorbidade frequente nos pacientes com insuficiência cardíaca (IC) e sua presença parece estar associada à pior evolução, sendo descrita em alguns estudos como fator de prognóstico independente tanto na IC sistólica quanto na diastólica. Entretanto, ainda não sabemos se a anemia causa pior evolução ou se é apenas um marcador do maior comprometimento cardíaco nos portadores de IC. A etiologia da anemia na IC é multifatorial e parece variar conforme a população estudada. Os fatores como a deficiência nutricional de ferro, presença de insuficiência renal, intensa atividade inflamatória sistêmica, uso de medicações que inibem a produção de eritropoetina ou que causam perda sanguínea são os mais frequentes causadores de anemia na IC. A prevalência de anemia citada nos estudos de IC é muito variável (de 9% a 79,1%) e isto é dependente da população estudada, da fase da cardiopatia, do método e referências hematimétricas utilizadas para diagnóstico. A deficiência de ferro é um importante fator etiológico e está presente em um número significativo de pacientes com anemia e IC associada. Em estudo realizado em nosso grupo, a incidência de deficiência de ferro nos pacientes com anemia foi de 61,8%. Portanto, a anemia é um achado frequente, sua presença acentua as manifestações clínicas da IC e está associada a piora do prognóstico. Conhecer a causa da anemia facilita o seu tratamento e, apesar da sua correção ainda não ser consenso, os pacientes sem anemia têm melhor evolução.Anemia is common in heart failure (HF) patients with its presence apparently associated to a worse prognosis, and as such is described in some studies as an independent predictor of death and hospitalization of patients suffering from systolic and diastolic dysfunction. It remains unknown whether anemia causes the worse evolution of HF patients or whether it is only one marker of a worse heart disease stage. The etiology of anemia is multifactorial and seems to change dependent on the studied population. Factors such as nutritional iron deficiency, presence of kidney failure, intense systematic inflammatory activity, medication use that inhibits the production of erythropoietin or that results in blood loss are the most frequent causes of anemia in heart disease. The prevalence of anemia reported in studies of HF is very variable (from 9 to 79.1%) and is dependent of the studied population, stage of heart disease and method and references used for diagnosis. Iron deficiency is an important etiologic factor which is present in a significant number of patients with the association of anemia and HF. In a study carried out by our group, the incidence of iron deficiency in anemic patients was 61.8%. Hence, anemia is a frequent finding; its presence accentuates the clinical manifestations of HF and is associated to a worse prognosis. An understanding of the cause of anemia makes treatment easier and although there is no consensus on its correction, patients without anemia have a better evolution

A Study of the Therapeutic Potential of AF4 Mimetic Peptides

Mixed lineage leukemias (MLL) are a group of acute and aggressive leukemias. They account for over 70% of infant leukemias, and 10% of acute adult leukemias. Pediatric ALL and therapy related MLL leukemias carry poor prognosis in spite of several advancement in the field of leukemia research. Therefore, new therapies for MLL leukemias are needed. Majority of MLL leukemias arise due to the balanced translocations of the MLL gene. As a result of these translocations, chimeric MLL fusion proteins are expressed. The most frequently occurring MLL fusion proteins are known to aberrantly recruit the super elongation complex (SEC) resulting in constitutive transcription of genes that promote the development of leukemia. Hence, our strategy is to target the SEC as a means of inhibiting MLL leukemia. AF4 and AF9 proteins co-purify with components of the SEC and directly interact with each other. Our laboratory has previously identified the domain of AF4 which is required for AF9 interaction and demonstrated that inhibition of this interaction using an AF4 mimetic peptide results in decreased viability of leukemia cell lines expressing MLL fusion genes. The AF4 mimetic peptide was modified to improve its in vivo stability and the newly designed peptide was designated SPK111. Here, we demonstrate that SPK111 peptide inhibits the AF4-AF9 interaction and reduces the activity of the SEC using luciferase reporter assays. Further, we show that SPK111 selectively reduces the viability of MLL leukemic cells in vitro. It induces membrane permeability and necrotic cell death. In order to test the in vivo efficacy of SPK111, we generated mice xenografts of MOLM13 and KOPN8 MLL leukemia cells. We observed a trend toward prolonged survival of xenografted mice following SPK111 treatment. However, the increased survival of treated mice did not reach statistical significance. A larger dose or dosing at an earlier point in time during disease progression had little effect on survival. Although it was difficult to achieve efficacy in vivo, pretreatment of leukemic cells with SPK111 prior to tail vein injection effectively inhibited xenograft establishment. This suggests that SPK111 is effective on leukemia initiating cells and may be developed as an effective bone marrow purging agent. We also developed an ELISA for detection of serum SPK111 which can be used for future kinetic studies. PFWT is an AF4 mimetic peptide similar to SPK111. Previous studies suggest that PFWT perturbs the actin cytoskeleton which is likely to induce cell death. However our investigations show that PFWT does not adversely affect the filamentous actin content of leukemic cells. Moreover, pretreatment with actin stabilizing drugs does not protect against PFWT induced cell death. An apparent 10 kDa increase in the molecular weight of the AF9 protein was identified on exposure to PFWT. Our analysis of probable post-translational modifications shows the absence of O-glycosylation and monoubiqutination. Interestingly, multiple phosphorylation sites and an acetylation site of AF9 were identified using mass spectroscopy. Our studies on the AF4 mimetic peptide, suggest that inhibition of the AF4-AF9 protein-protein interaction serves as an effective therapy for MLL leukemias

Land use change in a pericolonial society: intensification and diversification in Ifugao, Philippines between 1570 and 1800 CE

Land use modelling is increasingly used by archaeologists and palaeoecologists seeking to quantify and compare the changing influence of humans on the environment. In Southeast Asia, the intensification of rice agriculture and the arrival of European colonizers have both been seen as major catalysts for deforestation, soil erosion, and biodiversity change. Here we consider the Tuwali-Ifugao people of the Cordillera Central (Luzon, Philippines), who resisted Spanish colonial subjugation from the 16th to the mid-nineteenth century, in part through the development of a world-renowned system of intensive wet-rice terrace agriculture. To quantify changes in how the Tuwali-Ifugao used their environment, we model land use in Old Kiyyangan Village, a long-inhabited settlement, at two timepoints: circa 1570 CE, prior to the Spanish arrival in Luzon, and circa 1800 CE, before the village was sacked by Spanish military expeditions. Our model demonstrates that between 1570 and 1800 the adoption of rice as a staple and the corresponding expansion in terrace agriculture, along with a general diversification of diet and land use, enabled the village’s population to double without increasing total land use area. Further, this major intensification led to the solidification of social hierarchies and occurred without a proportional increase in deforestation.Introduction Methodology - Models in Ifugao: The History and Socio-Ecology of the Region - The Historical Land Use Model - Model Calculations for OKV - Population and Boble (Settled Area) at OKV - Payo (Terraces) - Uma (Swidden Fields) - Muyong (Private Forests) - Domesticated Animals - Hunting, Foraging, and Fishing - Fuel and Resource Extraction - Commerce - Agricultural Productivity and Nutritional Value - Dietary Proportions Results - 1800 - 1570 - Exploring Social Difference: Kadangyan and Nawotwot Land Use in 1800 Discussio

Short-term add-on therapy with angiotensin receptor blocker for end-stage inotrope-dependent heart failure patients: B-type natriuretic peptide reduction in a randomized clinical trial

OBJECTIVE: We aimed to evaluate angiotensin receptor blocker add-on therapy in patients with low cardiac output during decompensated heart failure. METHODS: We selected patients with decompensated heart failure, low cardiac output, dobutamine dependence, and an ejection fractio

Influência do El niño e La niña nos Campos de Precipitação e Temperatura na Reserva de Caxiuanã , PA - Amazônia Oriental

The El Niño and La Niña influences on air temperature andprecipitation data measured in a meteorological tower at the CaxiuanãNational Reserve –Pará state for August-October period during 2006 to2008 years are investigated in the present paper. In August 2006 startedan El Niño event and in August 2007 begun a La Niña event. However,since June 2008, a neutral period concerning sea surface temperature (SST)was observed in the eastern Pacific Ocean. Comparing the monthlyprecipitation, it was verified a decrease in rainfall during the El Niño,while during La Niña it was observed an increase in rainfall.São estudadas influências dos fenômenos El Niño e La Niñanos campos da temperatura do ar e da precipitação medidos nos trimestresde agosto a outubro dos anos de 2006 a 2008, em torre meteorológicana Floresta Nacional de Caxiuanã-PA. Agosto de 2006 marca o início deum evento de El Niño e Agosto de 2007 marca o início de um evento deLa Niña, sendo que a partir de junho de 2008 iniciou-se um período deneutralidade referente à temperatura da superfície do mar (TSM) do OceanoPacifico. Comparando-se os valores mensais da precipitação observa-se uma diminuição da chuva durante o El Niño, enquanto que durantea La Niña ocorreu o aumento da chuva

The pregnane X receptor drives sexually dimorphic hepatic changes in lipid and xenobiotic metabolism in response to gut microbiota in mice.

The gut microbiota-intestine-liver relationship is emerging as an important factor in multiple hepatic pathologies, but the hepatic sensors and effectors of microbial signals are not well defined. By comparing publicly available liver transcriptomics data from conventional vs. germ-free mice, we identified pregnane X receptor (PXR, NR1I2) transcriptional activity as strongly affected by the absence of gut microbes. Microbiota depletion using antibiotics in Pxr <sup>+/+</sup> vs Pxr <sup>-/-</sup> C57BL/6J littermate mice followed by hepatic transcriptomics revealed that most microbiota-sensitive genes were PXR-dependent in the liver in males, but not in females. Pathway enrichment analysis suggested that microbiota-PXR interaction controlled fatty acid and xenobiotic metabolism. We confirmed that antibiotic treatment reduced liver triglyceride content and hampered xenobiotic metabolism in the liver from Pxr <sup>+/+</sup> but not Pxr <sup>-/-</sup> male mice. These findings identify PXR as a hepatic effector of microbiota-derived signals that regulate the host's sexually dimorphic lipid and xenobiotic metabolisms in the liver. Thus, our results reveal a potential new mechanism for unexpected drug-drug or food-drug interactions. Video abstract

Early detection of left ventricular diastolic dysfunction in Chagas' disease

BACKGROUND: Chagas' disease may cause left ventricular diastolic dysfunction and its early detection in asymptomatic patients would allow to stratify the risk and to optimize medical treatment. The aim of this study is to investigate if transmitral Doppler flow can detect early abnormalities of the diastolic left ventricular function in patients during the indeterminate phase of Chagas' disease, in which the electrocardiogram (ECG), chest x-ray and 2-D echocardiogram (2D-echo) are normal. METHODS: a group of 54 patients with Chagas' disease was studied and compared to a control group of 27 subjects of similar age. All were assessed with an ECG, chest X-ray, 2-D echo, and transmitral Doppler flow. RESULTS: both groups had similar values in the 2D-echo. In patients with Chagas' disease, the transmitral Doppler showed a higher peak A velocity (control group: 0.44 m/sec, Chagas group: 0.55 m/sec, p = 0.001), a lower E/A ratio (control group: 1.45, Chagas group: 1.22, p < 0.05), and a lengthening of the deceleration time of early diastolic filling (control: 138.7 ± 26.8 msec, Chagas group: 167.9 ± 34.6 msec, p = 001), thus revealing an early disorder of the diastolic left ventricular function in patients with Chagas' disease. CONCLUSION: in patients with Chagas' disease who are in the indeterminate phase, transmitral Doppler flow allowed to identify early abnormalities of the left ventricular diastolic function, which provide useful clinical information for prognostic stratification and treatment