O Efeito da Administração Precoce de Solução Salina Hipertônica na Insuficiência Cardíaca Descompensada Aguda / The Effect of Early Administration of Hypertonic Saline Solution İn Acute Decompensated Heart Failure

Resumo Fundamento Não houve evidência científica sobre o tratamento inicial com solução salina hipertônica (SSH) na insuficiência cardíaca agudamente descompensada (ICAD). Objetivos Este estudo avaliou o impacto do uso de SSH junto com um diurético de alça (DA) como o primeiro tratamento diurético para ICAD, com foco na função renal, níveis de eletrólitos e resultados clínicos. Métodos Neste estudo retrospectivo de caso-controle, 171 pacientes adultos (93 mulheres/78 homens) com ICAD foram incluídos entre 1º de janeiro de 2022 e 31 de dezembro de 2022. Os pacientes foram alocados em dois grupos: combinação inicial de SSH+DA e DA padronizada. O desfecho primário foi piora da função renal (PFR). A hospitalização por IC e a mortalidade por todas as causas foram avaliadas durante 6 meses de acompanhamento. O nível de significância adotado na análise estatística foi de 5%. Resultados Os grupos exibiram semelhanças nas características basais. Diurese significativamente maior no 1º dia (3975 [3000-5150] vs. 2583 [2000-3250], p=0,001) e natriurese na 2ª hora (116,00 [82,75-126,00] vs. 131,75-140,00] vs. 94,00-103,25] vs. 99,00 [96,00-103,00], p=0,295), TFG (48,50 [29,75-72,50 vs. 50,00[35,50-63,50, p=0,616) e creatinina (1,20 [0,90-1,70] vs. 1,20 [1,00-1,50], p=0,218) permaneceu estável no grupo SSH combinado inicial quando comparado ao grupo DA padronizado (Cl-: 102,00[99,00-106,00] vs. 98,00[95,00-103,00], p=0,001, TFGe: 56,00 [41,00-71,00] vs. 55,00[35,00-71,00], p=0,050, creatinina: 1,10[0,90-1,40] vs. 1,20 [0,90-1,70], p=0,009). A piora da função renal (16,1% vs. 35,5%, p = 0,007) e o tempo de internação hospitalar (4 dias [3-7] vs. 5 dias [4-7], p = 0,004) foram menores na combinação inicial SSH+DA em comparação com o DA padronizado. A mortalidade hospitalar, a hospitalização por IC e a mortalidade por todas as causas foram semelhantes entre os dois grupos. Conclusão SSH como terapia inicial, quando combinada com DA, pode proporcionar uma diurese segura e eficaz sem prejudicar a função renal na ICAD. Portanto, a SSH pode levar a um menor tempo de internação hospitalar para esses pacientes.

Abstract Background There was no scientific evidence about the initial treatment of hypertonic saline solution (HSS) in acutely decompensated heart failure (ADHF). Objectives This study assessed the impact of using HSS along with a loop diuretic (LD) as the first diuretic treatment for ADHF, focusing on renal function, electrolyte levels, and clinical outcomes. Methods In this retrospective case-control study, 171 adult patients (93 females/78 males) with ADHF were included between January 1, 2022, and December 31, 2022. Patients were allocated into two groups: upfront combo HSS+LD and standardized LD. The primary endpoint was worsening renal function (WRF). Hospitalization for HF and all-cause mortality were evaluated during 6 months of follow-up. The significance level adopted in the statistical analysis was 5%. Results The groups exhibited similarities in baseline characteristics.A significantly higher diuresis on the 1st day (3975 [3000-5150] vs. 2583 [2000-3250], p=0.001) and natriuresis on the 2nd hour (116.00 [82.75-126.00] vs. 68.50 [54.00-89.75], p=0.001) in the initial upfront combo HSS+LD were found in comparison with the standardized LD.When compared to the standardized LD, the utilization of HSS led to an increase in serum Na+ (137.00 [131.75-140.00] vs. 140.00 [136.00-142.25], p=0.001 for upfront combo HSS, 139.00 [137.00-141.00] vs. 139.00 [136.00-140.00], p=.0470 for standardized LD), while chloride (99.00 [94.00-103.25] vs. 99.00[96.00-103.00], p=0.295), GFR (48.50 [29.75-72.50 vs. 50.00 [35.50-63.50, p=0.616), and creatinine (1.20 [0.90-1.70] vs. 1.20 [1.00-1.50], p=0.218) remained stable in the upfront combo HSS group when compared to standardized LD group (Cl-: 102.00 [99.00-106.00] vs. 98.00 [95.00-103.00], p=0.001, eGFR: 56.00 [41.00-71.00] vs. 55.00 [35.00-71.00], p=0.050, creatinine:1.10 [0.90-1.40] vs. 1.20 [0.90-1.70], p=0.009). Worsening renal function (16.1% vs 35.5%, p=0.007), and length of stay in the hospital (4 days [3-7] vs. 5 days [4-7], p=0.004) were lower in the upfront combo HSS+LD in comparison with the standardized LD. In-hospital mortality, hospitalization for HF, and all-cause mortality were similar between the two groups. Conclusion HSS as an initial therapy, when combined with LD, may provide a safe and effective diuresis without impairing renal function in ADHF. Therefore, HSS may lead to a shorter length of stay in the hospital for these patients.

Multi-allelic major effect genes interact with minor effect QTLs to control adaptive color pattern variation in Heliconius erato.

Recent studies indicate that relatively few genomic regions are repeatedly involved in the evolution of Heliconius butterfly wing patterns. Although this work demonstrates a number of cases where homologous loci underlie both convergent and divergent wing pattern change among different Heliconius species, it is still unclear exactly how many loci underlie pattern variation across the genus. To address this question for Heliconius erato, we created fifteen independent crosses utilizing the four most distinct color pattern races and analyzed color pattern segregation across a total of 1271 F2 and backcross offspring. Additionally, we used the most variable brood, an F2 cross between H. himera and the east Ecuadorian H. erato notabilis, to perform a quantitative genetic analysis of color pattern variation and produce a detailed map of the loci likely involved in the H. erato color pattern radiation. Using AFLP and gene based markers, we show that fewer major genes than previously envisioned control the color pattern variation in H. erato. We describe for the first time the genetic architecture of H. erato wing color pattern by assessing quantitative variation in addition to traditional linkage mapping. In particular, our data suggest three genomic intervals modulate the bulk of the observed variation in color. Furthermore, we also identify several modifier loci of moderate effect size that contribute to the quantitative wing pattern variation. Our results are consistent with the two-step model for the evolution of mimetic wing patterns in Heliconius and support a growing body of empirical data demonstrating the importance of major effect loci in adaptive change.

Epidemic dynamics revealed in dengue evolution.

Dengue is an emerging tropical disease infecting tens of millions of people annually. A febrile illness with potentially severe hemorrhagic manifestations, dengue is caused by mosquito-borne viruses (DENV-1 to -4) that are maintained in endemic transmission in large urban centers of the tropics with periodic epidemic cycles at 3- to 5-year intervals. Puerto Rico (PR), a major population center in the Caribbean, has experienced increasingly severe epidemics since multiple dengue serotypes were introduced beginning in the late 1970s. We document the phylodynamics of DENV-4 between 1981 and 1998, a period of dramatic ecological expansion during which evolutionary change also occurs. The timescale of viral evolution is sufficiently short that viral transmission dynamics can be elucidated from genetic diversity data. Specifically, by combining virus sequence data with confirmed case counts in PR over these two decades, we show that the pattern of cyclic epidemics is strongly correlated with coalescent estimates of effective population size that have been estimated from sampled virus sequences using Bayesian Markov Chain Monte Carlo methods. Thus, we show that the observed epidemiologic dynamics are correlated with similar fluctuations in diversity, including severe interepidemic reductions in genetic diversity compatible with population bottlenecks that may greatly impact DENV evolutionary dynamics. Mean effective population sizes based on genetic data appear to increase prior to isolation counts, suggesting a potential bias in the latter and justifying more active surveillance of DENV activity. Our analysis explicitly integrates epidemiologic and sequence data in a joint model that could be used to further explore transmission models of infectious disease.

Highly conserved gene order and numerous novel repetitive elements in genomic regions linked to wing pattern variation in Heliconius butterflies.

BACKGROUND: With over 20 parapatric races differing in their warningly colored wing patterns, the butterfly Heliconius erato provides a fascinating example of an adaptive radiation. Together with matching races of its co-mimic Heliconius melpomene, H. erato also represents a textbook case of Müllerian mimicry, a phenomenon where common warning signals are shared amongst noxious organisms. It is of great interest to identify the specific genes that control the mimetic wing patterns of H. erato and H. melpomene. To this end we have undertaken comparative mapping and targeted genomic sequencing in both species. This paper reports on a comparative analysis of genomic sequences linked to color pattern mimicry genes in Heliconius. RESULTS: Scoring AFLP polymorphisms in H. erato broods allowed us to survey loci at approximately 362 kb intervals across the genome. With this strategy we were able to identify markers tightly linked to two color pattern genes: D and Cr, which were then used to screen H. erato BAC libraries in order to identify clones for sequencing. Gene density across 600 kb of BAC sequences appeared relatively low, although the number of predicted open reading frames was typical for an insect. We focused analyses on the D- and Cr-linked H. erato BAC sequences and on the Yb-linked H. melpomene BAC sequence. A comparative analysis between homologous regions of H. erato (Cr-linked BAC) and H. melpomene (Yb-linked BAC) revealed high levels of sequence conservation and microsynteny between the two species. We found that repeated elements constitute 26% and 20% of BAC sequences from H. erato and H. melpomene respectively. The majority of these repetitive sequences appear to be novel, as they showed no significant similarity to any other available insect sequences. We also observed signs of fine scale conservation of gene order between Heliconius and the moth Bombyx mori, suggesting that lepidopteran genome architecture may be conserved over very long evolutionary time scales. CONCLUSION: Here we have demonstrated the tractability of progressing from a genetic linkage map to genomic sequence data in Heliconius butterflies. We have also shown that fine-scale gene order is highly conserved between distantly related Heliconius species, and also between Heliconius and B. mori. Together, these findings suggest that genome structure in macrolepidoptera might be very conserved, and show that mapping and positional cloning efforts in different lepidopteran species can be reciprocally informative.

First-generation linkage map of the warningly colored butterfly Heliconius erato.

We report the first genetic linkage map of Heliconius erato, a species that shows remarkable variation in its warningly colored wing patterns. We use crosses between H. erato and its sister species, H. himera, to place two major color pattern genes, D and Cr, on a linkage map containing AFLP, allozyme, microsatellite and single-copy nuclear loci. We identified all 21 linkage groups in an initial genetic screen of 22 progeny from an F1 female x male H. himera family. Of the 229 markers, 87 used to identify linkage groups were also informative in 35 progeny from a sibling backcross (H. himera female x F1 male). With these, and an additional 33 markers informative in the second family, we constructed recombinational maps for 19 of the 21 linkage groups. These maps varied in length from 18.1 to 431.1 centimorgans (cM) and yielded an estimated total length of 2400 cM. The average distance between markers was 23 cM, and eight of the 19 linkage groups, including the sex chromosome (Z) and the chromosome containing the Cr locus, contained two or more codominant anchor loci. Of the three potential candidate genes mapped here, Cubitus interruptus (Ci), Decapentaplegic (Dpp) and Wingless (Wg), only Ci was linked, although loosely, to a known Heliconius color pattern locus. This work is an important first step for constructing a denser genetic map of the H. erato color pattern radiation and for a comparative genomic study of the architecture of mimicry in Heliconius butterflies.

Historical demography of Mullerian mimicry in the neotropical Heliconius butterflies.

We compare the historical demographies of two Müllerian comimetic butterfly species: Heliconius erato and Heliconius melpomene. These species show an extensive parallel geographic divergence in their aposematic wing phenotypes. Recent studies suggest that this coincident mosaic results from simultaneous demographic processes shaped by extrinsic forces over Pleistocene climate fluctuations. However, DNA sequence variation at two rapidly evolving unlinked nuclear loci, Mannose phosphate isomerase (Mpi) and Triose phosphate isomerase (Tpi), show that the comimetic species have quite different quaternary demographies. In H. erato, despite ongoing lineage sorting across the Andes, nuclear genealogical estimates showed little geographical structure, suggesting high historical gene flow. Coalescent-based demographic analysis revealed population growth since the Pliocene period. Although these patterns suggest vicariant population subdivision associated with the Andean orogeny, they are not consistent with hypotheses of Pleistocene population fragmentation facilitating allopatric wing phenotype radiation in H. erato. In contrast, nuclear genetic diversity, theta, in H. melpomene was reduced relative to its comimic and revealed three phylogeographical clades. The pattern of coalescent events within regional clades was most consistent with population growth in relatively isolated populations after a recent period of restricted population size. These different demographic histories suggest that the wing-pattern radiations were not coincident in the two species. Instead, larger effective population size (N(e)) in H. erato, together with profound population change in H. melpomene, supports an earlier hypothesis that H. erato diversified first as the model species of this remarkable mimetic association.