Preliminary assessment of cardiac short term safety and efficacy of manganese chloride for cardiovascular magnetic resonance in humans

<p>Abstract</p> <p>Background</p> <p>Manganese based agents are intracellular and accumulate inside myocytes allowing for different imaging strategies compared to gadolinium contrasts. While previous agents release manganese very slowly in the circulation, MnCl₂allows for rapid Mn2⁺uptake in myocytes, creating a memory effect that can be potentially explored. Data on animal models are very encouraging but the safety and efficacy of this approach in humans has not yet been investigated. Therefore, our objectives were to study the safety and efficacy of a rapid infusion of manganese chloride (MnCl₂) for cardiovascular magnetic resonance (CMR) in humans.</p> <p>Methods</p> <p>Fifteen healthy volunteers underwent a CMR scan on a 1.5 T scanner. Before the infusion, cardiac function was calculated and images of a short axis mid-ventricular slice were obtained using a 2D and 3D gradient-echo inversion recovery (GRE-IR) sequence, a phase-sensitive IR sequence and a single breath-hold segmented IR prepared steady-state precession acquisition for T₁calculations. MnCl₂was infused over three minutes at a total dose of 5 μMol/kg. Immediately after the infusion, and at 15 and 30 minutes later, new images were obtained and cardiac function re-evaluated.</p> <p>Results</p> <p>There was a significant decrease in T₁values compared to baseline, sustained up to 30 minutes after the MnCl₂infusion (pre,839 ± 281 ms; 0 min, 684 ± 99; 15 min, 714 ± 168; 30 min, 706 ± 172, P = 0.003). The 2D and 3D GRE-IR sequence showed the greatest increase in signal-to-noise ratio compared to the other sequences (baseline 6.6 ± 4.2 and 9.7 ± 5.3; 0 min, 11.3 ± 4.1 and 15.0 ± 8.7; 15 min, 10.8 ± 4.0 and 16.9 ± 10.2; 30 min, 10.6 ± 5.2 and 16.5 ± 8.3, P < 0.001 for both). There was a slight increase in systolic pressure and heart rate after three and four minutes of the infusion with normalization of these parameters thereafter. Patients showed good tolerance to MnCl₂with no major adverse events, despite all reporting transient facial flush.</p> <p>Conclusions</p> <p>In the short term, MnCl₂appears safe for human use. It effectively decreases myocardium T₁, maintaining this effect for a relatively long period of time and allowing for the development of new imaging strategies in CMR, especially in ischemia research.</p

Efeitos da adubação orgânica e da época de colheita na qualidade da matéria-prima e nos rendimentos agrícola e de açúcar mascavo artesanal de duas cultivares de cana-de-açúcar (cana-planta).

Conduziu-se este trabalho com o objetivo de estudar os efeitos de três sistemas de adubação (30 t. ha-1 de esterco de curral, 3,5 t.ha-1 de esterco de galinha e adubação química - 120 kg.ha-1 de P2O5 e de K2O no plantio + 60 kg.ha-1 de N em cobertura) e três épocas de colheita da cana (julho, agosto e setembro de 2003), na qualidade da matéria-prima e nos rendimentos de colmos e de açúcar mascavo de duas cultivares de cana-de-açúcar (SP79-1011 e RB72454). O experimento foi instalado em área do Alambique JM, Perdões, MG. O delineamento experimental foi o de blocos casualizados, em esquema fatorial (2 x 3 x 3), com três repetições. Não houve efeito dos fertilizantes nos rendimentos de colmos e de açúcar mascavo das cultivares estudadas. Verificou-se efeito de épocas de colheita no rendimento de colmos, com destaque para os meses de agosto e setembro. No entanto, para rendimento de açúcar mascavo nenhuma diferença foi observada. Assim, nas condições deste trabalho, é viável a substituição da adubação química pela orgânica (esterco de curral ou de galinha), sem perdas na qualidade da matéria-prima e nos rendimentos de colmos e de açúcar mascavo artesanal, sendo que os meses de agosto e setembro foram os que proporcionaram matéria-prima de melhor qualidade e maiores rendimentos de colmos

Identity by Descent Mapping of Founder Mutations in Cancer Using High-Resolution Tumor SNP Data

Dense genotype data can be used to detect chromosome fragments inherited from a common ancestor in apparently unrelated individuals. A disease-causing mutation inherited from a common founder may thus be detected by searching for a common haplotype signature in a sample population of patients. We present here FounderTracker, a computational method for the genome-wide detection of founder mutations in cancer using dense tumor SNP profiles. Our method is based on two assumptions. First, the wild-type allele frequently undergoes loss of heterozygosity (LOH) in the tumors of germline mutation carriers. Second, the overlap between the ancestral chromosome fragments inherited from a common founder will define a minimal haplotype conserved in each patient carrying the founder mutation. Our approach thus relies on the detection of haplotypes with significant identity by descent (IBD) sharing within recurrent regions of LOH to highlight genomic loci likely to harbor a founder mutation. We validated this approach by analyzing two real cancer data sets in which we successfully identified founder mutations of well-characterized tumor suppressor genes. We then used simulated data to evaluate the ability of our method to detect IBD tracts as a function of their size and frequency. We show that FounderTracker can detect haplotypes of low prevalence with high power and specificity, significantly outperforming existing methods. FounderTracker is thus a powerful tool for discovering unknown founder mutations that may explain part of the “missing” heritability in cancer. This method is freely available and can be used online at the FounderTracker website

The role of environmental filtering, geographic distance and dispersal barriers in shaping the turnover of plant and animal species in Amazonia

To determine the effect of rivers, environmental conditions, and isolation by distance on the distribution of species in Amazonia. Location: Brazilian Amazonia. Time period: Current. Major taxa studied: Birds, fishes, bats, ants, termites, butterflies, ferns + lycophytes, gingers and palms. We compiled a unique dataset of biotic and abiotic information from 822 plots spread over the Brazilian Amazon. We evaluated the effects of environment, geographic distance and dispersal barriers (rivers) on assemblage composition of animal and plant taxa using multivariate techniques and distance- and raw-data-based regression approaches. Environmental variables (soil/water), geographic distance, and rivers were associated with the distribution of most taxa. The wide and relatively old Amazon River tended to determine differences in community composition for most biological groups. Despite this association, environment and geographic distance were generally more important than rivers in explaining the changes in species composition. The results from multi-taxa comparisons suggest that variation in community composition in Amazonia reflects both dispersal limitation (isolation by distance or by large rivers) and the adaptation of species to local environmental conditions. Larger and older river barriers influenced the distribution of species. However, in general this effect is weaker than the effects of environmental gradients or geographical distance at broad scales in Amazonia, but the relative importance of each of these processes varies among biological groups

Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Objective To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. Methods CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. Results In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. Conclusions Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so