Novel use of fused cardiac computed tomography and transesophageal echocardiography for left atrial appendage closure

The use of the Watchman left atrial appendage occlusion device (Boston Scientific Inc.) is becoming increasingly frequent in patients with atrial fibrillation. Cardiac computed tomography (CT) for device sizing pre-procedure can help facilitate more accurate device selection compared with transesophageal echo (TEE) alone. CT can also help identify minor lobes and trabeculations that may not be apparent on TEE. We report a series of three cases to highlight the utility of a novel application of CT-TEE fusion imaging to provide procedural guidance during Watchman implant and to assess for peri-device leak post-implant.     

Inappropriate renin secretion and abnormal cardiovascular reflexes in coarctation of the aorta.

The response of the renin-angiotensin system to high and low sodium diets, to standing, and to saralasin infusion was assessed before and after surgical correction of aortic coarctation in a 27-year-old man. The cardiovascular responses to tests of autonomic function were measured. The heart rate responses to the Valsalva manoeuvre and standing were abnormal before operation, and plasma renin levels were high and renin secretion responded poorly to changes in dietary sodium, to standing, and to saralasin. Renin responsiveness and cardiovascular reflexes returned to normal after operation. The results are consistent with the hypothesis that there is a high level of sympathetic efferent activity in coarctation of the aorta and that factors other than increased activity of the renin-angiotensin system may cause high blood pressure.     

Greater late lumen loss after successful coronary balloon angioplasty in the proximal left anterior descending coronary artery is not explained by extent of vessel wall damage or plaque burden

OBJECTIVES: We investigated whether the greater late lumen loss after coronary balloon angioplasty in the proximal left anterior descending artery (P-LAD) compared with that in other segments might be related to differences in vascular dimensions or morphology as determined by angiography and intravascular ultrasound imaging. BACKGROUND: The greater late lumen loss after angioplasty in the P-LAD that has been observed in several studies has not been explained. METHODS: We studied 178 patients and 194 coronary artery lesions by quantitative angiography and 30 MHz intravascular ultrasound imaging after successful balloon angioplasty. Vessel wall morphology was compared among three proximal and three nonproximal segments. Follow-up quantitative angiography for late lumen loss calculation was performed in 168 lesions. Multivariate analysis was used to determine predictors of late lumen loss. RESULTS: Absolute and relative late loss were significantly greater at the P-LAD compared with the pooled group of other segments (0.42 +/- 0.60 mm vs. 0.10 +/- 0.48 mm, p = 0.0008 and 0.14 +/- 0.24 vs. 0.03 +/- 0.17, p < 0.001). Also, a greater percentage of calcific lesions (65% vs. 44%, p = 0.034), a lower incidence of rupture (51% vs. 74%, p = 0.009) and a larger reference segment plaque area (5.4 +/- 2.2 mm2 vs. 4.7 +/- 1.9 mm2, p = 0.05) were found in the P-LAD. In multivariate analysis however, these variables were not predictive of late loss. CONCLUSIONS: Greater late lumen loss after coronary balloon angioplasty of the P-LAD is not explained by differences in atherosclerotic plaque burden or in vessel wall damage.     

Detection and quantitation of coronary artery stenoses from digital subtraction angiograms compared with 35-millimeter film cineangiograms

To assess the ability to detect coronary artery narrowings from computer-acquired angiograms, a panel of 4 observers independently identified and measured focal coronary narrowings from digital subtraction angiograms and compared the results to those obtained from standard 35-mm cine film angiograms. Both cine and digital angiograms were obtained sequentially using selective intracoronary artery injection of standard amounts of iodinated contrast media. Digital images were obtained at 8 frames/s with a 512 × 512 × 8-bit pixel matrix. Modifications in the imaging chain for computer acquisition included a slower pulsed radiographic mode, a progressive scan camera, and initial storage of the images on an 80-megabyte digital hard disk. Postprocessing computer algorithms were used to enhance the unsubtracted digital images; these included single-frame, mask-mode subtraction, vessel boundary edge enhancement, and 4-fold pixel magnification. In 19 patient studies, 32 arteries were reduced more than 25 % in diameter according to at least 1 of 4 observers on either the digital or cine film angiograms. There was no significant difference in the mean percent diameter narrowing for all the narrowings between the digital angiograms (53 ± 31 %) and the cineangiograms (52 ± 31 %). In addition, a 2-way analysis of variance yielded no significant difference between the amount of variability in the measurements between the cine film and the digital technique. This similar variability persisted when subsets of patients based on the degrees of stenosis were considered (e.g., only narrowings from 50 to 90% diameter reduction). Because digital acquisition permits immediate playback with image enhancement and greater ease of coronary artery quantification, digital angiography may have widespread clinical use for the detection and quantitation of coronary artery disease.     

The genomics of ecological flexibility,large brains,and long lives in capuchin monkeys revealed with fecalFACS

Ecological flexibility, extended lifespans, and large brains have long intrigued evolutionary biologists, and comparative genomics offers an efficient and effective tool for generating new insights into the evolution of such traits. Studies of capuchin monkeys are particularly well situated to shed light on the selective pressures and genetic underpinnings of local adaptation to diverse habitats, longevity, and brain development. Distributed widely across Central and South America, they are inventive and extractive foragers, known for their sensorimotor intelligence. Capuchins have among the largest relative brain size of any monkey and a lifespan that exceeds 50 y, despite their small (3 to 5 kg) body size. We assemble and annotate a de novo reference genome for Cebus imitator. Through high-depth sequencing of DNA derived from blood, various tissues, and feces via fluorescence-activated cell sorting (fecalFACS) to isolate monkey epithelial cells, we compared genomes of capuchin populations from tropical dry forests and lowland rainforests and identified population divergence in genes involved in water balance, kidney function, and metabolism. Through a comparative genomics approach spanning a wide diversity of mammals, we identified genes under positive selection associated with longevity and brain development. Additionally, we provide a technological advancement in the use of noninvasive genomics for studies of free-ranging mammals. Our intra- and interspecific comparative study of capuchin genomics provides insights into processes underlying local adaptation to diverse and physiologically challenging environments, as well as the molecular basis of brain evolution and longevity.

Large brains, long lifespans, extended juvenescence, tool use, and problem solving are hallmark characteristics of great apes, and are of enduring interest in studies of human evolution (1–4). Similar suites of traits have arisen in other lineages, including some cetaceans, corvids and, independently, in another radiation of primates, the capuchin monkeys. Like great apes, they have diverse diets, consume and seek out high-energy resources, engage in complex extractive foraging techniques (5, 6) to consume difficult-to-access invertebrates and nuts (6), and have an extended lifespan, presently recorded up to 54 y in captivity (7, 8). While they do not show evidence of some traits linked with large brain size in humans (e.g., human-like social networks and cultural and technological transmission from older to younger groupmates), their propensity for tool use and their ecological flexibility may have contributed to their convergence with the great apes (9), offering opportunities for understanding the evolution of key traits via the comparative method (10–12). Similar approaches have revealed positive selection on genes related to brain size and long lives in great apes and other mammals (13, 14), but our understanding of the genetic underpinnings of these traits remains far from complete.Capuchins also offer excellent opportunities to study local adaptation to challenging seasonal biomes. They occupy diverse habitats, including rainforests and, in the northern extent of their range, tropical dry forests. Particular challenges of the tropical dry forest are staying hydrated during the seasonally prominent droughts, high temperatures in the absence of foliage, and coping metabolically with periods of fruit dearth (Fig. 1). The long-term study of white-faced capuchins (Cebus imitator) occupying these seasonal forests has demonstrated that high infant mortality rates accompany periods of intense drought, illustrating the strength of this selective pressure (15). Furthermore, the seasonally low abundance of fruit is associated with muscular wasting and low circulating levels of urinary creatinine among these capuchins (16). Additionally, the sensory challenges of food search in dry versus humid biomes are also distinct. Odor detection and propagation is affected by temperature and humidity (17), and color vision is hypothesized to be adaptive in the search for ripe fruits and young reddish leaves against a background of thick, mature foliage (18), which is absent for long stretches in dry deciduous forests. The behavioral plasticity of capuchins is widely acknowledged as a source of their ability to adapt to these dramatically different habitats (19–21). However, physiological processes, including water balance and metabolic adaptations to low caloric intake, and sensory adaptations to food search, are also anticipated to be targets of natural selection, as seen in other mammals (22–24). Understanding population-level differences between primates inhabiting different biomes, contextualized by their demographic history, genomic diversity, and historical patterns of migration, will generate new insights.Open in a separate windowFig. 1.SSR during wet (Left) and dry (Center) seasons. (Right) Map of sampling locations in Costa Rica. The two northern sites, SSR and Cañas, have tropical dry-forest biomes, whereas the two southern sites, Quepos and Manuel Antonio, are tropical wet forests. Photos courtesy of A.D.M. Drawing of white-faced capuchin monkey by Alejandra Tejada-Martinez; map courtesy of Eric Gaba–Wikimedia Commons user: Sting.Unfortunately, high-quality biological specimens from wild capuchins are not readily available. As is the case with most of the world’s primates, many of which are rare or threatened (25), this has limited the scope of questions about their biology that can be answered. Although recent advances in noninvasive genomics have allowed for the sequencing of partial genomes by enriching the proportion of endogenous DNA in feces (26–29), it has not yet been feasible to sequence whole genomes from noninvasive samples at high coverage; this has limited the extent to which noninvasive samples can be used to generate genomic resources for nonmodel organisms, such as capuchins.Toward identifying the genetic underpinnings of local adaptation to seasonally harsh environments, large brains, and long lifespans, we assembled and annotated a reference genome of C. imitator (SI Appendix, Table S1). Additionally, we sequenced the genomes of individuals inhabiting two distinct environments in Costa Rica: Lowland evergreen rainforest (southern population) and lowland tropical dry forest (northern population). We conducted high-coverage resequencing (10× to 47×) for 10 of these individuals, and sequenced an additional 13 at low-coverage (0.1× to 4.4×). Importantly, to facilitate the population-wide analyses without the need for potentially harmful invasive sampling of wild primates, we developed a method for minimally biased, whole-genome sequencing of fecal DNA using fluorescence-activated cell sorting (fecalFACS) that we used to generate both high- and low-coverage genomes (Fig. 2). With these genomes, we assess the genetic underpinnings of capuchin-specific biology and adaptation in a comparative framework. First, we scanned the high-coverage genomes (six from the northern dry forest and four from the southern rainforest) for regions exhibiting population specific divergence to assess the extent of local adaptation to dry forest and rainforest environments. We examine how genes related to water balance, metabolism, muscular wasting, and chemosensation have diverged between populations. Second, we conduct an analysis of positive selection on the white-faced capuchin genome through codon-based models of evolution and enrichment tests focusing on genes that may underlie brain development and lifespan. Third, we identify the population structure, genomic diversity, and demographic history of the species using a mixture of traditional and noninvasive fecalFACS genomes (n = 23).Open in a separate windowFig. 2.Mapping percentages of sequencing reads from RNAlater preserved fecal DNA libraries prepared with FACS for (A) all samples (box-plot elements: center line, median; box limits, upper and lower quartiles; whiskers, 1.5× interquartile range; points, outliers), and (B) individual libraries. (C) Increase in mapping rate for RNAlater preserved samples. (D) Relationship between mapped read duplication and number of cells with LOESS smoothing. The duplication rate decreases sharply once a threshold of about 1,000 cells is reached.     

Hematopoietic stem cell transplantation (HSCT) in children with juvenile myelomonocytic leukemia (JMML): results of the EWOG-MDS/EBMT trial

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only proven curative therapy for juvenile myelomonocytic leukemia (JMML). We, the European Working Group on Childhood MDS (EWOG-MDS) and the European Blood and Marrow Transplantation (EBMT) Group, report the outcome of 100 children (67 boys and 33 girls) with JMML given unmanipulated HSCT after a preparative regimen including busulfan, cyclophosphamide, and melphalan. Forty-eight and 52 children received transplants from an HLA-identical relative or an unrelated donor (UD), respectively. The source of hematopoietic stem cells was bone marrow, peripheral blood, and cord blood in 79, 14, and 7 children, respectively. Splenectomy had been performed before HSCT in 24 children. The 5-year cumulative incidence of transplantation-related mortality and leukemia recurrence was 13% and 35%, respectively. Age older than 4 years predicted an increased risk of disease recurrence. The 5-year probability of event-free survival for children given HSCT from either a relative or a UD was 55% and 49%, respectively (P = NS), with median observation time of patients alive being 40 months (range, 6 to 144). In multivariate analysis, age older than 4 years and female sex predicted poorer outcome. Results of this study compare favorably with previously published reports. Disease recurrence remains the major cause of treatment failure. Outcome of UD-HSCT recipients is comparable to that of children receiving transplants from an HLA-identical sibling. (Blood. 2005;105:410-419)