1,442 research outputs found
Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia
BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients.
METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations.
RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries.
CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension
Saddle point localization of molecular wavefunctions
The quantum mechanical description of isomerization is based on bound eigenstates of the molecular potential energy surface. For the near-minimum regions there is a textbook-based relationship between the potential and eigenenergies. Here we show how the saddle point region that connects the two minima is encoded in the eigenstates of the model quartic potential and in the energy levels of the [H, C, N] potential energy surface. We model the spacing of the eigenenergies with the energy dependent classical oscillation frequency decreasing to zero at the saddle point. The eigenstates with the smallest spacing are localized at the saddle point. The analysis of the HCN???HNC isomerization states shows that the eigenstates with small energy spacing relative to the effective (v1, v3, l) bending potentials are highly localized in the bending coordinate at the transition state. These spectroscopically detectable states represent a chemical marker of the transition state in the eigenenergy spectrum. The method developed here provides a basis for modeling characteristic patterns in the eigenenergy spectrum of bound states
The effects of laryngeal mask airway passage simulation training on the acquisition of undergraduate clinical skills: a randomised controlled trial
Background\ud
Effective use of the laryngeal mask airway (LMA) requires learning proper insertion technique in normal patients undergoing routine surgical procedures. However, there is a move towards simulation training for learning practical clinical skills, such as LMA placement. The evidence linking different amounts of mannequin simulation training to the undergraduate clinical skill of LMA placement in real patients is limited. The purpose of this study was to compare the effectiveness in vivo of two LMA placement simulation courses of different durations. \ud
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Methods\ud
Medical students (n = 126) enrolled in a randomised controlled trial. Seventy-eight of these students completed the trial. The control group (n = 38) received brief mannequin training while the intervention group (n = 40) received additional more intensive mannequin training as part of which they repeated LMA insertion until they were proficient. The anaesthetists supervising LMA placements in real patients rated the participants' performance on assessment forms. Participants completed a self-assessment questionnaire. \ud
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Results\ud
Additional mannequin training was not associated with improved performance (37% of intervention participants received an overall placement rating of > 3/5 on their first patient compared to 48% of the control group, = 0.81, p = 0.37). The agreement between the participants and their instructors in terms of LMA placement success rates was poor to fair. Participants reported that mannequins were poor at mimicking reality. \ud
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Conclusions\ud
The results suggest that the value of extended mannequin simulation training in the case of LMA placement is limited. Educators considering simulation for the training of practical skills should reflect on the extent to which the in vitro simulation mimics the skill required and the degree of difficulty of the procedure. \ud
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Dissolution dominating calcification process in polar pteropods close to the point of aragonite undersaturation
Thecosome pteropods are abundant upper-ocean zooplankton that build aragonite shells. Ocean acidification results in the lowering of aragonite saturation levels in the surface layers, and several incubation studies have shown that rates of calcification in these organisms decrease as a result. This study provides a weight-specific net calcification rate function for thecosome pteropods that includes both rates of dissolution and calcification over a range of plausible future aragonite saturation states (Omega_Ar). We measured gross dissolution in the pteropod Limacina helicina antarctica in the Scotia Sea (Southern Ocean) by incubating living specimens across a range of aragonite saturation states for a maximum of 14 days. Specimens started dissolving almost immediately upon exposure to undersaturated conditions (Omega_Ar,0.8), losing 1.4% of shell mass per day. The observed rate of gross dissolution was different from that predicted by rate law kinetics of aragonite dissolution, in being higher at Var levels slightly above 1 and lower at Omega_Ar levels of between 1 and 0.8. This indicates that shell mass is affected by even transitional levels of saturation, but there is, nevertheless, some partial means of protection for shells when in undersaturated conditions. A function for gross dissolution against Var derived from the present observations was compared to a function for gross calcification derived by a different study, and showed that dissolution became the dominating process even at Omega_Ar levels close to 1, with net shell growth ceasing at an Omega_Ar of 1.03. Gross dissolution increasingly dominated net change in shell mass as saturation levels decreased below 1. As well as influencing their viability, such dissolution of pteropod shells in the surface layers will result in slower sinking velocities and decreased carbon and carbonate fluxes to the deep ocean
Enhancing surface heat transfer by carbon nanofins: towards an alternative to nanofluids?
Background: Nanofluids are suspensions of nanoparticles and fibers which have recently attracted much attention because of their superior thermal properties. Nevertheless, it was proven that, due to modest dispersion of nanoparticles, such high expectations often remain unmet. In this article, by introducing the notion of nanofin, a possible solution is envisioned, where nanostructures with high aspect-ratio are sparsely attached to a solid surface (to avoid a significant disturbance on the fluid dynamic structures), and act as efficient thermal bridges within the boundary layer. As a result, particles are only needed in a small region of the fluid, while dispersion can be controlled in advance through design and manufacturing processes. Results: Toward the end of implementing the above idea, we focus on single carbon nanotubes to enhance heat transfer between a surface and a fluid in contact with it. First, we investigate the thermal conductivity of the latter nanostructures by means of classical non-equilibrium molecular dynamics simulations. Next, thermal conductance at the interface between a single wall carbon nanotube (nanofin) and water molecules is assessed by means of both steady-state and transient numerical experiments. Conclusions: Numerical evidences suggest a pretty favorable thermal boundary conductance (order of 107 W·m-2·K-1) which makes carbon nanotubes potential candidates for constructing nanofinned surface
The Cost of Simplifying Air Travel When Modeling Disease Spread
BACKGROUND: Air travel plays a key role in the spread of many pathogens. Modeling the long distance spread of infectious disease in these cases requires an air travel model. Highly detailed air transportation models can be over determined and computationally problematic. We compared the predictions of a simplified air transport model with those of a model of all routes and assessed the impact of differences on models of infectious disease. METHODOLOGY/PRINCIPAL FINDINGS: Using U.S. ticket data from 2007, we compared a simplified "pipe" model, in which individuals flow in and out of the air transport system based on the number of arrivals and departures from a given airport, to a fully saturated model where all routes are modeled individually. We also compared the pipe model to a "gravity" model where the probability of travel is scaled by physical distance; the gravity model did not differ significantly from the pipe model. The pipe model roughly approximated actual air travel, but tended to overestimate the number of trips between small airports and underestimate travel between major east and west coast airports. For most routes, the maximum number of false (or missed) introductions of disease is small (<1 per day) but for a few routes this rate is greatly underestimated by the pipe model. CONCLUSIONS/SIGNIFICANCE: If our interest is in large scale regional and national effects of disease, the simplified pipe model may be adequate. If we are interested in specific effects of interventions on particular air routes or the time for the disease to reach a particular location, a more complex point-to-point model will be more accurate. For many problems a hybrid model that independently models some frequently traveled routes may be the best choice. Regardless of the model used, the effect of simplifications and sensitivity to errors in parameter estimation should be analyzed
Results and harmonization guidelines from two large-scale international Elispot proficiency panels conducted by the Cancer Vaccine Consortium (CVC/SVI)
The Cancer Vaccine Consortium of the Sabin Vaccine Institute (CVC/SVI) is conducting an ongoing large-scale immune monitoring harmonization program through its members and affiliated associations. This effort was brought to life as an external validation program by conducting an international Elispot proficiency panel with 36 laboratories in 2005, and was followed by a second panel with 29 participating laboratories in 2006 allowing for application of learnings from the first panel. Critical protocol choices, as well as standardization and validation practices among laboratories were assessed through detailed surveys. Although panel participants had to follow general guidelines in order to allow comparison of results, each laboratory was able to use its own protocols, materials and reagents. The second panel recorded an overall significantly improved performance, as measured by the ability to detect all predefined responses correctly. Protocol choices and laboratory practices, which can have a dramatic effect on the overall assay outcome, were identified and lead to the following recommendations: (A) Establish a laboratory SOP for Elispot testing procedures including (A1) a counting method for apoptotic cells for determining adequate cell dilution for plating, and (A2) overnight rest of cells prior to plating and incubation, (B) Use only pre-tested serum optimized for low background: high signal ratio, (C) Establish a laboratory SOP for plate reading including (C1) human auditing during the reading process and (C2) adequate adjustments for technical artifacts, and (D) Only allow trained personnel, which is certified per laboratory SOPs to conduct assays. Recommendations described under (A) were found to make a statistically significant difference in assay performance, while the remaining recommendations are based on practical experiences confirmed by the panel results, which could not be statistically tested. These results provide initial harmonization guidelines to optimize Elispot assay performance to the immunotherapy community. Further optimization is in process with ongoing panels
The impact of bone mineral density and disc degeneration on shear strength and stiffness of the lumbar spine following laminectomy
Purpose Laminectomy is a standard surgical procedure for elderly patients with symptomatic degenerative lumbar stenosis. The procedure aims at decompression of the affected nerves, but it also causes a reduction of spinal shear strength and shear stiffness. The magnitude of this reduction and the influence of bone mineral density (BMD) and disc degeneration are unknown. We studied the influence of laminectomy, BMD, and disc degeneration on shear force to failure (SFF) and shear stiffness (SS). Methods Ten human cadaveric lumbar spines were obtained (mean age 72.1 years, range 53-89 years). Laminectomy was performed either on L2 or L4, equally divided within the group of ten spines. BMD was assessed by dual X-ray absorptiometry (DXA). Low BMD was defined as a BMD value below the median. Intervertebral discs were assessed for degeneration by MRI (Pfirrmann) and scaled in mild and severe degeneration groups. Motion segments L2-L3 and L4-L5 were isolated from each spine. SFF and SS were measured, while loading simultaneously with 1,600 N axial compression. Results Low BMD had a significant negative effect on SFF. In addition, a significant interaction between low BMD and laminectomy was found. In the high BMD group, SFF was 2,482 N (range 1,678-3,284) and decreased to 1,371 N (range 940-1,886) after laminectomy. In the low BMD group, SFF was 1,339 N (range 909-1,628) and decreased to 761 N (range 561-1,221). Disc degeneration did not affect SFF, nor did it interact with laminectomy. Neither low BMD nor the interaction of low BMD and laminectomy did affect SS. Degeneration and its interaction with laminectomy did not significantly affect SS. Conclusions In conclusion, low BMD significantly decreased SFF before and after lumbar laminectomy. Therefore, DXA assessment may be an important asset to preoperative screening. Lumbar disc degeneration did not affect shear properties of lumbar segments before or after laminectomy. © 2012 Springer-Verlag
Phenethyl isothiocyanate exhibits antileukemic activity in vitro and in vivo by inactivation of Akt and activation of JNK pathways
Effects of phenethyl isothiocyanate (PEITC) have been investigated in human leukemia cells (U937, Jurkat, and HL-60) as well as in primary human acute myeloid leukemia (AML) cells in relation to apoptosis and cell signaling events. Exposure of cells to PEITC resulted in pronounced increase in the activation of caspase-3, -8, -9, cleavage/degradation of PARP, and apoptosis in dose- and time-dependent manners. These events were accompanied by the caspase-independent downregulation of Mcl-1, inactivation of Akt, as well as activation of Jun N-terminal kinase (JNK). Inhibition of PI3K/Akt by LY294002 significantly enhanced PEITC-induced apoptosis. Conversely, enforced activation of Akt by a constitutively active Akt construct markedly abrogated PEITC-mediated JNK activation, Mcl-1 downregulation, caspase activation, and apoptosis, and also interruption of the JNK pathway by pharmacological or genetically (e.g., siRNA) attenuated PEITC-induced apoptosis. Finally, administration of PEITC markedly inhibited tumor growth and induced apoptosis in U937 xenograft model in association with inactivation of Akt, activation of JNK, as well as downregulation of Mcl-1. Taken together, these findings represent a novel mechanism by which agents targeting Akt/JNK/Mcl-1 pathway potentiate PEITC lethality in transformed and primary human leukemia cells and inhibitory activity of tumor growth of U937 xenograft model
Galactic and Extragalactic Samples of Supernova Remnants: How They Are Identified and What They Tell Us
Supernova remnants (SNRs) arise from the interaction between the ejecta of a
supernova (SN) explosion and the surrounding circumstellar and interstellar
medium. Some SNRs, mostly nearby SNRs, can be studied in great detail. However,
to understand SNRs as a whole, large samples of SNRs must be assembled and
studied. Here, we describe the radio, optical, and X-ray techniques which have
been used to identify and characterize almost 300 Galactic SNRs and more than
1200 extragalactic SNRs. We then discuss which types of SNRs are being found
and which are not. We examine the degree to which the luminosity functions,
surface-brightness distributions and multi-wavelength comparisons of the
samples can be interpreted to determine the class properties of SNRs and
describe efforts to establish the type of SN explosion associated with a SNR.
We conclude that in order to better understand the class properties of SNRs, it
is more important to study (and obtain additional data on) the SNRs in galaxies
with extant samples at multiple wavelength bands than it is to obtain samples
of SNRs in other galaxiesComment: Final 2016 draft of a chapter in "Handbook of Supernovae" edited by
Athem W. Alsabti and Paul Murdin. Final version available at
https://doi.org/10.1007/978-3-319-20794-0_90-
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