279 research outputs found
A biosequence of soils formed from loess and volcanic ash in the Western Kenai Peninsula, Alaska
In the western Kenai Peninsula, Alaska, the well drained Cohoe and Island soils have formed in a mixture of volcanic ash and loess. The Cohoe soils have some properties of Spodosols and support a climax spruce forest. The Island soils are classified as Inceptisols and occupy broad, shallow grass-covered depressions that occur as openings within areas of the forested Cohoe soils, Field evidence indicates that in western Alaska the forest is advancing at the expense of the grasslands. In soils high in volcanic ash or other pyroclastic materials that yield high amounts of amorphous materials, it is sometimes difficult to distinguish between a spodic and a cambic horizon by the kinds of measurements commonly made in the laboratory. Several lines of evidence indicate that Andepts are converted to Spodosols in a relatively short time following their occupation by spruce forest in western Alaska. The main objective of this study was to apply some of the physical and chemical studies which are commonly used to distinguish between spodic and cambic horizons high in amorphous materials. A second objective was to relate the soil forming factor of vegetation to the morphology of these soils. Two transects extending from the grass-covered Island soils to the forested Cohoe soils were chosen near Ninilchik on the southwestern. Kenai Peninsula. Samples from horizons were taken from representative pedons of an Island, a Cohoe, and a transitional soil on the forest grass border. Some of the chemical studies included: (1) cation exchange capacity, (2) exchangeable bases, (3) percent organic carbon, (4) percent nitrogen, (5) extractable acidity, (6) percent free iron, and (7) pH values determined in water paste, N KCl paste, and .0.1M CaCl2. In addition, pH values were determined in 1N NaF. X-ray, DTA, bulk density, and pyrophosphate dithionite extractable C, Fe, and A1 studies were made on the horizons of the sola. Percentage water retention at 15-bars was determined on air-dry, field-moist, and oven-dry samples. Particle size distribution was determined by the standard method of dispersion using hexametaphosphate preceding overnight shaking. In addition, results were compared on air-dry and field-moist samples. On selected horizons, ultrasonic sound was employed as an additional dispersant. The difficulty of wetting and differences in percentage water retention at 15-bars on field-moist and air-dry samples showed that these soils dry irreversibly. Particle size distribution suggested incomplete dispersion by all methods used. X-ray, DTA, and NaF pH values indicated a high content of amorphous material, but not a high content of allophane. The organic fraction was almost as important a part of the active fraction as was the clay in the chemical properties that were measured. Pyrophosphate dithionite extractable C, Fe, and A1 were similar at comparable depths in the three soils studied. The forested Cohoe and Transitional soils have thin albic hori-zons over reddish B horizons that have some properties of spodic horizons; the grass-covered Island soils have thick, dark umbric epipedons. The laboratory studies, however, revealed that the difference in measured properties were small
CHD associated with syndromic diagnoses: peri-operative risk factors and early outcomes
CHD is frequently associated with a genetic syndrome. These syndromes often present specific cardiovascular and non-cardiovascular co-morbidities that confer significant peri-operative risks affecting multiple organ systems. Although surgical outcomes have improved over time, these co-morbidities continue to contribute substantially to poor peri-operative mortality and morbidity outcomes. Peri-operative morbidity may have long-standing ramifications on neurodevelopment and overall health. Recognising the cardiovascular and non-cardiovascular risks associated with specific syndromic diagnoses will facilitate expectant management, early detection of clinical problems, and improved outcomes--for example, the development of syndrome-based protocols for peri-operative evaluation and prophylactic actions may improve outcomes for the more frequently encountered syndromes such as 22q11 deletion syndrome
Molecular Characterization of Pediatric Restrictive Cardiomyopathy from Integrative Genomics
Pediatric restrictive cardiomyopathy (RCM) is a genetically heterogeneous heart disease with limited therapeutic options. RCM cases are largely idiopathic; however, even within families with a known genetic cause for cardiomyopathy, there is striking variability in disease severity. Although accumulating evidence implicates both gene expression and alternative splicing in development of dilated cardiomyopathy (DCM), there have been no detailed molecular characterizations of underlying pathways dysregulated in RCM. RNA-Seq on a cohort of pediatric RCM patients compared to other forms of adult cardiomyopathy and controls identified transcriptional differences highly common to the cardiomyopathies, as well as those unique to RCM. Transcripts selectively induced in RCM include many known and novel G-protein coupled receptors linked to calcium handling and contractile regulation. In-depth comparisons of alternative splicing revealed splicing events shared among cardiomyopathy subtypes, as well as those linked solely to RCM. Genes identified with altered alternative splicing implicate RBM20, a DCM splicing factor, as a potential mediator of alternative splicing in RCM. We present the first comprehensive report on molecular pathways dysregulated in pediatric RCM including unique/shared pathways identified compared to other cardiomyopathy subtypes and demonstrate that disruption of alternative splicing patterns in pediatric RCM occurs in the inverse direction as DCM
Clinically relevant variants identified in thoracic aortic aneurysm patients by research exome sequencing
Thoracic aortic aneurysm (TAA) is a genetically heterogeneous disease involving subclinical and progressive dilation of the thoracic aorta, which can lead to life-threatening complications such as dissection or rupture. Genetic testing is important for risk stratification and identification of at risk family members, and clinically available genetic testing panels have been expanding rapidly. However, when past testing results are normal, there is little evidence to guide decision-making about the indications and timing to pursue additional clinical genetic testing. Results from research based genetic testing can help inform this process. Here we present 10 TAA patients who have a family history of disease and who enrolled in research-based exome testing. Nine of these ten patients had previous clinical genetic testing that did not identify the cause of disease. We sought to determine the number of rare variants in 23 known TAA associated genes identified by research-based exome testing. In total, we found 10 rare variants in six patients. Likely pathogenic variants included a TGFB2 variant in one patient and a SMAD3 variant in another. These variants have been reported previously in individuals with similar phenotypes. Variants of uncertain significance of particular interest included novel variants in MYLK and MFAP5, which were identified in a third patient. In total, clinically reportable rare variants were found in 6/10 (60%) patients, with at least 2/10 (20%) patients having likely pathogenic variants identified. These data indicate that consideration of re-testing is important in TAA patients with previous negative or inconclusive results
Early aberrant angiogenesis due to elastic fiber fragmentation in aortic valve disease
Elastic fiber fragmentation (EFF) is a hallmark of aortic valve disease (AVD), and neovascularization has been identified as a late finding related to inflammation. We sought to characterize the relationship between early EFF and aberrant angiogenesis. To examine disease progression, regional anatomy and pathology of aortic valve tissue were assessed using histochemistry, immunohistochemistry, and electron microscopy from early-onset (\u3c40 yo) and late-onset (β₯40 yo) non-syndromic AVD specimens. To assess the effects of EFF on early AVD processes, valve tissue from Williams and Marfan syndrome patients was also analyzed. Bicuspid aortic valve was more common in early-onset AVD, and cardiovascular comorbidities were more common in late-onset AVD. Early-onset AVD specimens demonstrated angiogenesis without inflammation or atherosclerosis. A distinct pattern of elastic fiber components surrounded early-onset AVD neovessels, including increased emilin-1 and decreased fibulin-5. Different types of EFF were present in Williams syndrome (WS) and Marfan syndrome (MFS) aortic valves; WS but not MFS aortic valves demonstrated angiogenesis. Aberrant angiogenesis occurs in early-onset AVD in the absence of inflammation, implicating EFF. Elucidation of underlying mechanisms may inform the development of new pharmacologic treatments
Developmental differences in myocyte contractile response after cardioplegic arrest
AbstractAlthough developmental differences in left ventricular function after cardioplegic arrest and rewarming have been postulated, whether differences exist at the level of the myocyte remains unexplored. This project tested the hypothesis that there is a differential effect of hypothermic hyperkalemic cardioplegic arrest with subsequent rewarming on contractile function of immature compared with adult ventricular myocytes. Myocytes were isolated from the left ventricular free wall of five immature and five adult rabbits and incubated for 2 hours in hyperkalemic modified Ringer's solution at 4Β° C (cardioplegia) or for 2 hours in cell culture medium at 37Β° C (normothermia). Myocytes were resuspended (βrewarmedβ) in 37Β° C cell culture medium after the incubation protocol. Normothermic baseline contractile performance was lower in immature, compared with adult, myocytes. Specifically, myocyte shortening velocity was 62 Β± 4 ΞΌm/sec in immature and 112 Β± 6 ΞΌm/sec in adult myocytes (p < 0.01). After cardioplegia and rewarming, immature myocyte contractile function was unchanged, whereas adult myocyte contractile function was significantly diminished. For example, myocyte shortening velocity was 65 Β± 4 ΞΌm/sec in immature and 58 Β± 3 ΞΌm/sec in adult myocytes (p < 0.01 versus normothermic). Myocyte surface area, which reflects myocyte volume, was increased after cardioplegia and rewarming in adults (3582 Β± 55 versus 3316 Β± 46 ΞΌm2, p < 0.01), but remained unchanged in immature myocytes (2212 Β± 27 versus 2285 Β± 28 ΞΌm2, p = not significant). These unique findings demonstrate a preservation of myocyte contractile function and volume regulation in immature myocytes after cardioplegic arrest and rewarming. Thus this study directly demonstrates that developmental differences exist in myocyte responses to hypothermic hyperkalemic cardioplegic arrest with subsequent rewarming. (J THORAC CARDIOVASC SURG 1996;111:1257-66
Rationale for the Cytogenomics of Cardiovascular Malformations Consortium: A Phenotype Intensive Registry Based Approach
Cardiovascular malformations (CVMs) are the most common birth defect, occurring in 1%-5% of all live births. Although the genetic contribution to CVMs is well recognized, the genetic causes of human CVMs are identified infrequently. In addition, a failure of systematic deep phenotyping of CVMs, resulting from the complexity and heterogeneity of malformations, has obscured genotype-phenotype correlations and contributed to a lack of understanding of disease mechanisms. To address these knowledge gaps, we have developed the Cytogenomics of Cardiovascular Malformations (CCVM) Consortium, a multi-site alliance of geneticists and cardiologists, contributing to a database registry of submicroscopic genetic copy number variants (CNVs) based on clinical chromosome microarray testing in individuals with CVMs using detailed classification schemes. Cardiac classification is performed using a modification to the National Birth Defects Prevention Study approach, and non-cardiac diagnoses are captured through ICD-9 and ICD-10 codes. By combining a comprehensive approach to clinically relevant genetic analyses with precise phenotyping, the Consortium goal is to identify novel genomic regions that cause or increase susceptibility to CVMs and to correlate the findings with clinical phenotype. This registry will provide critical insights into genetic architecture, facilitate genotype-phenotype correlations, and provide a valuable resource for the medical community
Exome Sequencing Identifies Candidate Genetic Modifiers of Syndromic and Familial Thoracic Aortic Aneurysm Severity
Thoracic aortic aneurysm (TAA) is a genetic disease predisposing to aortic dissection. It is important to identify the genetic modifiers controlling penetrance and expressivity to improve clinical prognostication. Exome sequencing was performed in 27 subjects with syndromic or familial TAA presenting with extreme phenotypes (15 with severe TAA; 12 with mild or absent TAA). Family-based analysis of a subset of the cohort identified variants, genes, and pathways segregating with TAA severity among three families. A rare missense variant in ADCK4 (p.Arg63Trp) segregated with mild TAA in each family. Genes and pathways identified in families were further investigated in the entire cohort using the optimal unified sequence kernel association test, finding significance for the gene COL15A1 (p = 0.025) and the retina homeostasis pathway (p = 0.035). Thus, we identified candidate genetic modifiers of TAA severity by exome-based study of extreme phenotypes, which may lead to improved risk stratification and development of new medical therapies
Inhibitory Role of Notch1 in Calcific Aortic Valve Disease
Aortic valve calcification is the most common form of valvular heart disease, but the mechanisms of calcific aortic valve disease (CAVD) are unknown. NOTCH1 mutations are associated with aortic valve malformations and adult-onset calcification in families with inherited disease. The Notch signaling pathway is critical for multiple cell differentiation processes, but its role in the development of CAVD is not well understood. The aim of this study was to investigate the molecular changes that occur with inhibition of Notch signaling in the aortic valve. Notch signaling pathway members are expressed in adult aortic valve cusps, and examination of diseased human aortic valves revealed decreased expression of NOTCH1 in areas of calcium deposition. To identify downstream mediators of Notch1, we examined gene expression changes that occur with chemical inhibition of Notch signaling in rat aortic valve interstitial cells (AVICs). We found significant downregulation of Sox9 along with several cartilage-specific genes that were direct targets of the transcription factor, Sox9. Loss of Sox9 expression has been published to be associated with aortic valve calcification. Utilizing an in vitro porcine aortic valve calcification model system, inhibition of Notch activity resulted in accelerated calcification while stimulation of Notch signaling attenuated the calcific process. Finally, the addition of Sox9 was able to prevent the calcification of porcine AVICs that occurs with Notch inhibition. In conclusion, loss of Notch signaling contributes to aortic valve calcification via a Sox9-dependent mechanism
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