This study investigates the osseointegration of poly(propylene fumarate) (PPF) with beta-tricalcium phosphate (beta-TCP) scaffolds in a critical-size (diameter, 1.6 cm), cranial defect in 4-month-old ...rabbits (n = 51), killed at 6 or 12 weeks. Two molecular weights of PPF were used to produce bilayer scaffolds with 0.5-mm solid external and 2.0-mm porous internal layers. The porous layer was infused with bone marrow aspirate, with half the animals receiving 0.8 microg of transforming growth factor beta2 (TGF-beta2). No foreign body or inflammatory response was observed externally or on histological examination of explants. Statistical analysis of histological areal and linear measures of new bone formation found significantly more bone at the later sacrifice time, followed by implants receiving TGF-beta2, followed by low molecular weight PPF implants. Approximately 40% of the explants were tested for incorporation strength with a one-point "push-in" test. Because no permanent fixation was used, implant strength (28.37-129.03 N; range, 6.4 to 29.0 lb of resistance) was due entirely to new bone formation. The strongest bone was seen in implants receiving TGF-beta2-infused marrow in animals killed at 12 weeks. These results support the use of PPF as an osteogenic substrate and future research into preoperative fabrication of critical size and supercritical-size cranial prosthetic implants.
The results of a study show that in some pediatric patients with pulmonary hypertension, infusion of atrial natriuretic peptide reduced mean pulmonary artery pressure and the pulmonary vascular ...resistance index more than 20% without significantly lowering systemic vascular resistance.
Success rates for genomic analyses of highly heterogeneous disorders can be greatly improved if a large cohort of patient data is assembled to enhance collective capabilities for accurate sequence ...variant annotation, analysis, and interpretation. Indeed, molecular diagnostics requires the establishment of robust data resources to enable data sharing that informs accurate understanding of genes, variants, and phenotypes. The “Mitochondrial Disease Sequence Data Resource (MSeqDR) Consortium” is a grass-roots effort facilitated by the United Mitochondrial Disease Foundation to identify and prioritize specific genomic data analysis needs of the global mitochondrial disease clinical and research community. A central Web portal (https://mseqdr.org) facilitates the coherent compilation, organization, annotation, and analysis of sequence data from both nuclear and mitochondrial genomes of individuals and families with suspected mitochondrial disease. This Web portal provides users with a flexible and expandable suite of resources to enable variant-, gene-, and exome-level sequence analysis in a secure, Web-based, and user-friendly fashion. Users can also elect to share data with other MSeqDR Consortium members, or even the general public, either by custom annotation tracks or through the use of a convenient distributed annotation system (DAS) mechanism. A range of data visualization and analysis tools are provided to facilitate user interrogation and understanding of genomic, and ultimately phenotypic, data of relevance to mitochondrial biology and disease. Currently available tools for nuclear and mitochondrial gene analyses include an MSeqDR GBrowse instance that hosts optimized mitochondrial disease and mitochondrial DNA (mtDNA) specific annotation tracks, as well as an MSeqDR locus-specific database (LSDB) that curates variant data on more than 1300 genes that have been implicated in mitochondrial disease and/or encode mitochondria-localized proteins. MSeqDR is integrated with a diverse array of mtDNA data analysis tools that are both freestanding and incorporated into an online exome-level dataset curation and analysis resource (GEM.app) that is being optimized to support needs of the MSeqDR community. In addition, MSeqDR supports mitochondrial disease phenotyping and ontology tools, and provides variant pathogenicity assessment features that enable community review, feedback, and integration with the public ClinVar variant annotation resource. A centralized Web-based informed consent process is being developed, with implementation of a Global Unique Identifier (GUID) system to integrate data deposited on a given individual from different sources. Community-based data deposition into MSeqDR has already begun. Future efforts will enhance capabilities to incorporate phenotypic data that enhance genomic data analyses. MSeqDR will fill the existing void in bioinformatics tools and centralized knowledge that are necessary to enable efficient nuclear and mtDNA genomic data interpretation by a range of shareholders across both clinical diagnostic and research settings. Ultimately, MSeqDR is focused on empowering the global mitochondrial disease community to better define and explore mitochondrial diseases.
•MSeqDR is a genomic data repository and analysis resource for mitochondrial disease.•MSeqDR GBrowse enhances the interrogation of both genomes with custom annotation tracks.•MSeqDR LSDB curates variation in >1300 genes relevant to mitochondrial biology.•MSeqDR GEM.app enables Web-based exome or genome dataset curation and analysis.•MSeqDR hosts bioinformatics & phenotyping tools for mitochondrial disease analyses.
Abstract
The exchange of carbon between the Earth’s atmosphere and biosphere influences the atmospheric abundances of carbon dioxide (CO
2
) and methane (CH
4
). Airborne eddy covariance (EC) can ...quantify surface-atmosphere exchange from landscape-to-regional scales, offering a unique perspective on carbon cycle dynamics. We use extensive airborne measurements to quantify fluxes of sensible heat, latent heat, CO
2
, and CH
4
across multiple ecosystems in the Mid-Atlantic region during September 2016 and May 2017. In conjunction with footprint analysis and land cover information, we use the airborne dataset to explore the effects of landscape heterogeneity on measured fluxes. Our results demonstrate large variability in CO
2
uptake over mixed agricultural and forested sites, with fluxes ranging from −3.4 ± 0.7 to −11.5 ± 1.6
μ
mol m
−2
s
−1
for croplands and −9.1 ± 1.5 to −22.7 ± 3.2
μ
mol m
−2
s
−1
for forests. We also report substantial CH
4
emissions of 32.3 ± 17.0 to 76.1 ± 29.4 nmol m
−2
s
−1
from a brackish herbaceous wetland and 58.4 ± 12.0 to 181.2 ± 36.8 nmol m
−2
s
−1
from a freshwater forested wetland. Comparison of ecosystem-specific aircraft observations with measurements from EC flux towers along the flight path demonstrate that towers capture ∼30%–75% of the regional variability in ecosystem fluxes. Diel patterns measured at the tower sites suggest that peak, midday flux measurements from aircraft accurately predict net daily CO
2
exchange. We discuss next steps in applying airborne observations to evaluate bottom-up flux models and improve understanding of the biophysical processes that drive carbon exchange from landscape-to-regional scales.
Cholesteryl ester transfer protein (CETP) inhibition with torcetrapib not only increases high-density lipoprotein cholesterol levels but also significantly reduces plasma triglyceride, low-density ...lipoprotein (LDL) cholesterol, and apolipoprotein B (apoB) levels. The goal of the present study was to define the kinetic mechanism(s) by which CETP inhibition reduces levels of apoB-containing lipoproteins.
Nineteen subjects, 9 of whom were pretreated with 20 mg atorvastatin, received placebo for 4 weeks, followed by 120 mg torcetrapib once daily for 4 weeks. Six subjects in the nonatorvastatin group received 120 mg torcetrapib twice daily for an additional 4 weeks. After each phase, subjects underwent a primed-constant infusion of deuterated leucine to endogenously label newly synthesized apoB to determine very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and LDL apoB100 production, and fractional catabolic rates (FCRs). Once-daily 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes by enhancing the FCR of apoB100 within each fraction. On a background of atorvastatin, 120 mg torcetrapib significantly reduced VLDL, IDL, and LDL apoB100 pool sizes. The reduction in VLDL apoB100 was associated with an enhanced apoB100 FCR, whereas the decreases in IDL and LDL apoB100 were associated with reduced apoB100 production.
These data indicate that when used alone, torcetrapib reduces VLDL, IDL, and LDL apoB100 levels primarily by increasing the rate of apoB100 clearance. In contrast, when added to atorvastatin treatment, torcetrapib reduces apoB100 levels mainly by enhancing VLDL apoB100 clearance and reducing production of IDL and LDL apoB100.
ABSTRACT
Introduction
The Cl. NPhys Trial 3 showed that attributes of nerve conduction (NC) were without significant intraobserver differences, although there were significant interobserver ...differences. Methods: Trial 4 tested whether use of written instructions and pretrial agreement on techniques and use of standard reference values, diagnostic percentile values, or broader categorization of abnormality could reduce significant interobserver disagreement and improve agreement among clinical neurophysiologists. Results: The Trial 4 modifications markedly decreased, but did not eliminate, significant interobserver differences of measured attributes of NC. Use of standard reference values and defined percentile values of abnormality decreased interobserver disagreement and improved agreement of judgment of abnormality among evaluators. Therefore, the same clinical neurophysiologist should perform repeat NCs of therapeutic trial patients. Conclusions: Differences in interobserver judgment of abnormality decrease with use of common standard reference values and a defined percentile level of abnormality, providing a rationale for their use in therapeutic trials and medical practice. Muscle Nerve 50: 900–908, 2014
Parents of children with disorders of sex development (DSD) report significant psychological distress, including posttraumatic stress symptoms (PTSS), with mothers consistently reporting higher rates ...of psychological distress than fathers. However, psychological factors contributing to PTSS in both parents are not well understood. The present study sought to fill this gap in knowledge by examining PTSS and illness uncertainty, a known predictor of psychological distress, in parents of children recently diagnosed with DSD. Participants were 52 mothers (
M
age
= 32.55 years,
SD
= 5.08) and 41 fathers (
M
age
= 35.53 years,
SD
= 6.78) of 53 infants (
M
age
= 9.09 months,
SD
= 6.19) with DSD and associated atypical genital development. Participants were recruited as part of a larger, multisite study assessing parents’ psychosocial response to their child’s diagnosis of DSD. Parents completed measures of illness uncertainty and PTSS. Mothers reported significantly greater levels of PTSS, but not illness uncertainty, than fathers, and were more likely than fathers to report clinical levels of PTSS (21.2% compared to 7.3%). Hierarchical regression revealed that parent sex, undiagnosed or unclassified DSD status, and illness uncertainty were each associated with PTSS. The overall model accounted for 23.5% of the variance associated with PTSS. Interventions targeting illness uncertainty may be beneficial for parents of children with newly diagnosed DSD.
When applying genomic medicine to a rare disease patient, the primary goal is to identify one or more genomic variants that may explain the patient's phenotypes. Typically, this is done through ...annotation, filtering, and then prioritization of variants for manual curation. However, prioritization of variants in rare disease patients remains a challenging task due to the high degree of variability in phenotype presentation and molecular source of disease. Thus, methods that can identify and/or prioritize variants to be clinically reported in the presence of such variability are of critical importance. We tested the application of classification algorithms that ingest variant annotations along with phenotype information for predicting whether a variant will ultimately be clinically reported and returned to a patient. To test the classifiers, we performed a retrospective study on variants that were clinically reported to 237 patients in the Undiagnosed Diseases Network. We treated the classifiers as variant prioritization systems and compared them to four variant prioritization algorithms and two single-measure controls. We showed that the trained classifiers outperformed all other tested methods with the best classifiers ranking 72% of all reported variants and 94% of reported pathogenic variants in the top 20. We demonstrated how freely available binary classification algorithms can be used to prioritize variants even in the presence of real-world variability. Furthermore, these classifiers outperformed all other tested methods, suggesting that they may be well suited for working with real rare disease patient datasets.
The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. Here we report the results of an international collaboration to produce and ...make freely available a draft sequence of the human genome. We also present an initial analysis of the data, describing some of the insights that can be gleaned from the sequence.
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