FEV1 Is a Better Predictor of Mortality than FVC: The PLATINO Cohort Study

Objective

To determine whether the presence of chronic obstructive lung disease (COPD) and reduction of lung function parameters were predictors of mortality in a cohort.

Materials/Patients and Methods

Population based cohorts were followed in Montevideo, Santiago and Sao Paulo during 5, 6 and 9 years, respectively. Outcomes included all-cause, cardiovascular, respiratory and cancer mortality; exposures were COPD, forced expiratory volume in one second (FEV₁) and forced vital capacity (FVC). Cox regression was used for analyses. Sensitivity, specificity, positive and negative predictive values, receiver operator characteristics curves and Youden''s index were calculated.

Results

Main causes of death were cardiovascular, respiratory and cancer. Baseline COPD was associated with overall mortality (HR = 1.43 for FEV₁/FVC<LLN; 2.01 for GOLD 2-4; 1.46 for GOLD 1-4; 1.50 for FEV₁/FEV₆ <LLN). For cardiovascular mortality, significant associations were found with GOLD 2-4 (HR = 2.68) and with GOLD 1-4 (HR = 1.78) for both genders together (not among women). Low FEV₁ was risk for overall and respiratory mortality (both genders combined). FVC was not associated with overall mortality. For most COPD criteria sensitivity was low and specificity high. The area under the curve for FEV₁ was greater than for FVC for overall and cardiovascular mortality.

Answer to the Question

COPD and low FEV₁ are important predictors for overall and cardiovascular mortality in Latin America.     

A Pathogenic Mosaic TP53 Mutation in Two Germ Layers Detected by Next Generation Sequencing

Background

Li-Fraumeni syndrome is caused by germline TP53 mutations and is clinically characterized by a predisposition to a range of cancers, most commonly sarcoma, brain tumours and leukemia. Pathogenic mosaic TP53 mutations have only rarely been described.

Methods and Findings

We describe a 2 years old child presenting with three separate cancers over a 6 month period; two soft tissue mesenchymal tumors and an aggressive metastatic neuroblastoma. As conventional testing of blood DNA by Sanger sequencing for mutations in TP53, ALK, and SDH was negative, whole exome sequencing of the blood DNA of the patient and both parents was performed to screen more widely for cancer predisposing mutations. In the patient''s but not the parents'' DNA we found a c.743 G>A, p.Arg248Gln (CCDS11118.1) TP53 mutation in 3–20% of sequencing reads, a level that would not generally be detectable by Sanger sequencing. Homozygosity for this mutation was detected in all tumor samples analyzed, and germline mosaicism was demonstrated by analysis of the child''s newborn blood spot DNA. The occurrence of separate tumors derived from different germ layers suggests that this de novo mutation occurred early in embryogenesis, prior to gastrulation.

Conclusion

The case demonstrates pathogenic mosaicim, detected by next generation deep sequencing, that arose in the early stages of embryogenesis.     

Toxocara canis: Potential activity of natural products against second-stage larvae in vitro and in vivo

The anthelmintic activity of extracts from Chenopodiumambrosioides, Pycnanthusangolensis and Nutridesintox® was in vitro and in vivo investigated, against Toxocaracanis larvae. The in vitro assays results showed that the aqueous extract of Nutridesintox® was the most effective, followed by C. ambrosioides extracts, hexane, dichloromethane and the infusion. P. angolensis extracts showed a lower anthelmintic activity compared to the other natural products. For the in vivo assays, Nutridesintox®, the hexane extract and the infusion of C. ambrosioides were administered orally to T. canis-infected mice, in single doses, during three consecutive days. The efficacy was evaluated on the 17th day post-infection, not only by counting T. canis larvae in the tissues but also by ELISA detection of IgM and IgG antibodies and histological analysis of liver and lungs. The different treatments did not reduce the larvae burden and had no influence on the antibodies dynamic. Interestingly, a reduction on the inflammatory infiltrates was observed in the liver and lung sections of the group treated with the hexane extract of C. ambrosioides. In conclusion, the hexane extract of C. ambrosioides is of further research interest, as it showed an anthelmintic activity in vitro and a reduction on the inflammatory reaction produced by the infection of T. canis larvae in vivo.     

Development of a primary microglia screening assay and its use to characterize inhibition of system xc- by erastin and its analogs

The inflammatory response in the central nervous system involves activated microglia. Under normal conditions they remove damaged neurons by phagocytosis. On the other hand, neurodegenerative diseases are thought to involve chronic microglia activation resulting in release of excess glutamate, proinflammatory cytokines and reactive oxygen species, leading to neuronal death. System x_C^- cystine/glutamate antiporter (SXC), a sodium independent heterodimeric transporter found in microglia and astrocytes in the CNS, imports cystine into the cell and exports glutamate. SXC has been shown to be upregulated in neurodegenerative diseases including multiple sclerosis, ALS, neuroAIDS Parkinson's disease and Alzheimer's disease. Consequently, SXC inhibitors could be of use in the treatment of diseases characterized by neuroinflammation and glutamate excitotoxicity. We report on the optimization of a primary microglia-based assay to screen for SXC inhibitors. Rat primary microglia were activated using lipopolysaccharides (LPS) and glutamate release and cystine uptake were monitored by fluorescence and radioactivity respectively. LPS-induced glutamate release increased with increasing cell density, time of incubation and LPS concentration. Conditions to screen for SXC inhibitors were optimized in 96-well format and subsequently used to evaluate SXC inhibitors. Known SXC inhibitors sulfasalazine, S-4CPG and erastin blocked glutamate release and cystine uptake while R-4CPG, the inactive enantiomer of S-4CPG, failed to inhibit glutamate release or cystine transport. In addition, several erastin analogs were evaluated using primary microglia and found to have EC₅₀ values in agreement with previous studies using established cell lines.     

Co-Inheritance of alpha-thalassemia and sickle cell disease in a cohort of Angolan pediatric patients

Molecular Biology Reports - The aim of this study was to explore the association between alpha-thalassemia, fetal hemoglobin, hematological indices, and clinical adverse events in Angolan sickle...     

Proteolytic modification of <Emphasis Type="Italic">Leuconostoc mesenteroides</Emphasis> B-512F dextransucrase

Multiple active lower molecular weight forms from Leuconostoc mesenteroides B512F dextransucrase have been reported. It has been suggested that they arise from proteolytic processing of a 170 kDa precursor. In this work, the simultaneous production of proteases and dextransucrase was studied in order to elucidate the dextransucrase proteolytic processing. The effect of the nitrogen source on protease and dextransucrase production was studied. Protease activity reaches a maximum early in the logarithmic phase of dextransucrase synthesis using the basal culture medium but the nitrogen source plays an important effect on growth: the highest protease concentration was obtained when ammonium sulfate, casaminoacids or tryptone were used. Two active forms of 155 and 129 kDa were systematically obtained from dextransucrase precursor by proteolysis. The amino termini of these forms were sequenced and the cleavage site deduced. Both forms of the enzyme obtained had the same cleavage site in the amino terminal region (F209–Y210). From dextransucrase analysis, various putative cleavage sites with the same sequence were found in the variable region and in the glucan binding domain. Although no structural differences were found in dextrans synthesized with both the precursor and the proteolyzed 155 kDa form under the same reaction conditions, their rheological behaviour was modified, with dextran of a lower viscosity yielded by the smaller form.Martha Argüello-Morales and Mónica Sánchez-González equally contributed to this work.     

Conservation implications of genetic structure in the narrowest endemic quillwort from the Eastern Amazon

The quillwort Isoëtes cangae is a critically endangered species occurring in a single lake in Serra dos Carajás, Eastern Amazon. Low genetic diversity and small effective population sizes (N _e) are expected for narrow endemic species (NES). Conservation biology studies centered in a single species show some limitations, but they are still useful considering the limited time and resources available for protection of species at risk of extinction. Here, we evaluated the genetic diversity, population structure, N _e, and minimum viable population (MVP) of I. cangae to provide information for effective conservation programs. Our analyses were based on 55 individuals collected from the Amendoim Lake and 35,638 neutral SNPs. Our results indicated a single panmictic population, moderate levels of genetic diversity, and N _e in the order of thousands, contrasting the expected for NES. Negative F_IS values were also found, suggesting that I. cangae is not under risk of inbreeding depression. Our findings imply that I. cangae contains enough genetic diversity to ensure evolutionary potential and that all individuals should be treated as one demographic unit. These results provide essential information to optimize ex situ conservation efforts and genetic diversity monitoring, which are currently applied to guide I. cangae conservation plans.