José Manuel Nascimento Costa

Oxidative stress levels are correlated with P15 and P16 gene promoter methylation in myelodysplastic syndrome patients

Oxidative stress and abnormal DNA methylation have been implicated in some types of cancer, namely in myelodysplastic syndromes (MDS). Since both mechanisms are observed in MDS patients, we analyzed the correlation of intracellular levels of peroxides, superoxide anion, and glutathione (GSH), as well as ratios of peroxides/GSH and superoxide/GSH, with the methylation status of P15 and P16 gene promoters in bone marrow leukocytes from MDS patients. Compared to controls, these patients had lower GSH content, higher peroxide levels, peroxides/GSH and superoxide/GSH ratios, as well as higher methylation frequency of P15 and P16 gene promoters. Moreover, patients with methylated P15 gene had higher oxidative stress levels than patients without methylation (peroxides: 460xa0±xa042 MIF vs 229xa0±xa025 MIF, pxa0=xa00.001; superoxide: 383xa0±xa048 MIF vs 243xa0±xa017 MIF, pxa0=xa00.022; peroxides/GSH: 2.50xa0±xa00.08 vs 1.04xa0±xa00.34, pxa0<xa00.001; superoxide/GSH: 1.76xa0±xa00.21 vs 1.31xa0±xa00.10, pxa0=xa00.007). Patients with methylated P16 and at least one methylated gene had higher peroxide levels as well as peroxides/GSH ratio than patients without methylation. Interestingly, oxidative stress levels allow the discrimination of patients without methylation from ones with methylated P15, methylated P16, or at least one methylated (P15 or P16) promoter. Taken together, these findings support the hypothesis that oxidative stress is correlated with P15 and P16 hypermethylation.

Glycogen Storage Disease type 1a – a secondary cause for hyperlipidemia: report of five cases

Background and aimsGlycogen storage disease type Ia (GSD Ia) is a rare metabolic disorder, caused by deficient activity of glucose-6-phosphatase-α. It produces fasting induced hypoglycemia and hepatomegaly, usually manifested in the first semester of life. Besides, it is also associated with growth delay, anemia, platelet dysfunction, osteopenia and sometimes osteoporosis. Hyperlipidemia and hyperuricemia are almost always present and hepatocellular adenomas and renal dysfunction frequent late complications.MethodsThe authors present a report of five adult patients with GSD Ia followed in internal medicine appointments and subspecialties.ResultsFour out of five patients were diagnosed in the first 6 months of life, while the other one was diagnosed in adult life after the discovery of hepatocellular adenomas. In two cases genetic tests were performed, being identified the missense mutation R83C in one, and the mutation IVS4-3Cu2009>u2009G in the intron 4 of glucose-6-phosphatase gene, not previously described, in the other. Growth retardation was present in 3 patients, and all of them had anemia, increased bleeding tendency and hepatocellular adenomas; osteopenia/osteoporosis was present in three cases. All but one patient had marked hyperlipidemia and hyperuricemia, with evidence of endothelial dysfunction in one case and of brain damage with refractory epilepsy in another case. Proteinuria was present in two cases and end-stage renal disease in another case. There was a great variability in the dietary measures; in one case, liver transplantation was performed, with correction of the metabolic derangements.ConclusionsHyperlipidemia is almost always present and only partially responds to dietary and drug therapy; liver transplantation is the only definitive solution. Although its association with premature atherosclerosis is rare, there have been reports of endothelial dysfunction, raising the possibility for increased cardiovascular risk in this group of patients. Being a rare disease, no single metabolic center has experience with large numbers of patients and the recommendations are based on clinical experience more than large scale studies.

Genetic variants involved in oxidative stress, base excision repair, DNA methylation, and folate metabolism pathways influence myeloid neoplasias susceptibility and prognosis.

Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) share common features: elevated oxidative stress, DNA repair deficiency, and aberrant DNA methylation. We performed a hospital‐based case‐control study to evaluate the association in variants of genes involved in oxidative stress, folate metabolism, DNA repair, and DNA methylation with susceptibility and prognosis of these malignancies. To that end, 16 SNPs (one per gene: CAT, CYBA, DNMT1, DNMT3A, DNMT3B, GPX1, KEAP1, MPO, MTRR, NEIL1, NFE2F2, OGG1, SLC19A1, SOD1, SOD2, and XRCC1) were genotyped in 191 patients (101 MDS and 90 AML) and 261 controls. We also measured oxidative stress (reactive oxygen species/total antioxidant status ratio), DNA damage (8‐hydroxy‐2′‐deoxyguanosine), and DNA methylation (5‐methylcytosine) in 50 subjects (40 MDS and 10 controls). Results showed that five genes (GPX1, NEIL1, NFE2L2, OGG1, and SOD2) were associated with MDS, two (DNMT3B and SLC19A1) with AML, and two (CYBA and DNMT1) with both diseases. We observed a correlation of CYBA TT, GPX1 TT, and SOD2 CC genotypes with increased oxidative stress levels, as well as NEIL1 TT and OGG1 GG genotypes with higher DNA damage. The 5‐methylcytosine levels were negatively associated with DNMT1 CC, DNMT3A CC, and MTRR AA genotypes, and positively with DNMT3B CC genotype. Furthermore, DNMT3A, MTRR, NEIL1, and OGG1 variants modulated AML transformation in MDS patients. Additionally, DNMT3A, OGG1, GPX1, and KEAP1 variants influenced survival of MDS and AML patients. Altogether, data suggest that genetic variability influence predisposition and prognosis of MDS and AML patients, as well AML transformation rate in MDS patients.

Disfunção tiróidea e amiodarona

Although most patients remain clinically euthyroid, some develop amiodarone-induced hyperthyroidism (HPEAI) or hypothyroidism (HPOAI). The authors present a retrospective analysis of ten patients with amiodarone-induced thyroid dysfunction. Six patients were female and mean amiodarone intake was 17.7 months. HPOIA was more common (six patients). From all the patients with HPEAI, two had type 2, one had type 1, and one had type 3 hyperthyroidism. Symptoms suggestive of thyroid dysfunction occurred in five patients, most of them with HPOAI. In HPEAI, the most frequent symptom was exacerbation of arrhythmia (three patients). Discontinuation of amiodarone and treatment with levothyroxine was chosen in 83.3% of the HPOAI cases, while thyonamide treatment with corticosteroids and without amiodarone was the option in 75% of the HPEAI cases. There were three deaths, all in patients with HPEAI. HPEAI is potentially fatal. The clinical picture may be vague, so the thyroid monitoring is mandatory.

Species activity promote the stability of fruit-frugivore interactions across a five-year multilayer network

Although biological communities are intrinsically dynamic, with both, species and interactions changing over time, interaction networks analyses to date are still largely static. We implemented a temporal multilayer network approach to explore the changes on species roles and on the emergent structure of a seed-dispersal network over five years. Network topology was relatively constant, with four well defined interaction modules spanning across all years. Importantly, species that were present on more years, were also disproportionally important on each year, thus forming a core of temporally reliable species that are critical to the cohesiveness of the multilayer network structure. We propose a new descriptor termed species activity that reflects the number of temporal, spatial or functional layers (e.g., different years, habitats, or functions) that each species integrates, providing a simple and powerful index of species importance for multilayer network cohesion.

Pollination networks from natural and anthropogenic-novel communities show high structural similarity

The Anthropocene is marked by an unprecedented homogenisation of the world’s biota, confronting species that never co-occurred during their evolutionary histories. Interactions established in these novel communities may affect ecosystem functioning; however, most research has focused on the impacts of a minority of aggressive invasive species, while changes inflicted by a less conspicuous majority of non-invasive alien species on community structure are still poorly understood. This information is critical to guide conservation strategies, and instrumental to advance ecological theory, particularly to understand how non-native species integrate in recipient communities and affect the interactions of native species. We evaluated how the structure of 50 published pollination networks changes with the proportion of alien plant species and found that network structure is largely unaffected. Although some communities were heavily invaded, the proportion of alien plant species was relatively low (meanu2009=u200910%; max.u2009=u200938%). We further characterized the pollination network in a botanic garden with a plant community dominated by non-invasive alien species (85%). We show that the structure of this novel community is also not markedly different from native-dominated communities. Plant–pollinator interactions revealed no obvious differences regarding plant origin (native vs. alien) or the native bioregion of the introduced plants. This overall similarity between native and alien plants is likely driven by the contrasting patterns of invasive plants (promoting generalism), and non-invasive aliens, suggested here to promote specialization.