A comparison of macroscopic lipid content within porcine pulmonary and aortic valves: Implications for bioprosthetic valves

AbstractLipid droplets have been demonstrated within both explanted porcine bioprostheses and normal porcine aortic valves. Because of the increasing interest in pulmonary valves as an allograft or xenograft aortic valve substitute, we examined the incidence and distribution of such lipid deposits in 50 porcine aortic valves and 50 matched porcine pulmonary valves. All 300 cusps were removed with surgical scissors and, under a dissecting microscope, the ventricularis layer was removed to expose the spongiosal layer. Macroscopic extracellular lipid droplets were exposed. The position and amount of the visible unstained droplets were analyzed by means of a dissecting microscope with an eyepiece grid and stereology point-counting techniques to provide an area-density average spatial probability map for each cusp. Only 8% of porcine aortic valves were free of lipid, with the distribution of the lipids being 52% ± 14% right coronary cusp, 90% ± 8% left coronary cusp, and 68% ± 13% noncoronary cusp. Of the pulmonary valves, 60% were free of lipid, with the incidence of lipids being 26% ± 12% left cusp, 6% ± 7% right cusp, and 12% ± 9% anterior cusp. Subsequently, lipid cluster samples underwent thin-layer chromatography, which showed them to be phospholipids, oleic acid (fatty acid), triglycerides, and unesterified cholesterol. One primary mode of bioprosthetic valve failure is leaflet calcification. The similarity of distribution within the spongiosal layer between leaflet calcification and intrinsic cusp lipids suggests that the observed lipids might act as a nucleation site for calcification. The substantially lower incidence of lipid in pulmonary valves therefore may represent a potential benefit when these valves are considered for use as aortic valve replacements. (J THORAC CARDIOVASC SURG 1995;110:1756-61

Study of wavelength-shifting chemicals for use in large-scale water Cherenkov detectors

Cherenkov detectors employ various methods to maximize light collection at the photomultiplier tubes (PMTs). These generally involve the use of highly reflective materials lining the interior of the detector, reflective materials around the PMTs, or wavelength-shifting sheets around the PMTs. Recently, the use of water-soluble wavelength-shifters has been explored to increase the measurable light yield of Cherenkov radiation in water. These wave-shifting chemicals are capable of absorbing light in the ultravoilet and re-emitting the light in a range detectable by PMTs. Using a 250 L water Cherenkov detector, we have characterized the increase in light yield from three compounds in water: 4-Methylumbelliferone, Carbostyril-124, and Amino-G Salt. We report the gain in PMT response at a concentration of 1 ppm as: 1.88 $\pm$ 0.02 for 4-Methylumbelliferone, stable to within 0.5% over 50 days, 1.37 $\pm$ 0.03 for Carbostyril-124, and 1.20 $\pm$ 0.02 for Amino-G Salt. The response of 4-Methylumbelliferone was modeled, resulting in a simulated gain within 9% of the experimental gain at 1 ppm concentration. Finally, we report an increase in neutron detection performance of a large-scale (3.5 kL) gadolinium-doped water Cherenkov detector at a 4-Methylumbelliferone concentration of 1 ppm.Comment: 7 pages, 9 figures, Submitted to Nuclear Instruments and Methods

Polymer assembly encapsulation of lanthanide nanoparticles as contrast agents for in vivo micro-CT

Despite recent technological advancements in microcomputed tomography (micro-CT) and contrast agent development, pre-clinical contrast agents are still predominantly iodine-based. Higher contrast can be achieved when using elements with higher atomic numbers, such as lanthanides; lanthanides also have x-ray attenuation properties that are ideal for spectral CT. However, the formulation of lanthanide-based contrast agents at the high concentrations required for vascular imaging presents a significant challenge. In this work, we developed an erbium-based contrast agent that meets micro-CT imaging requirements, which include colloidal stability upon redispersion at high concentrations, evasion of rapid renal clearance, and circulation times of tens of minutes in small animals. Through systematic studies with poly(ethylene glycol) (PEG)-poly(propylene glycol), PEG-polycaprolactone, and PEG-poly(l-lactide) (PLA) block copolymers, the amphiphilic block copolymer PEG114-PLA53 was identified to be ideal for encapsulating oleate-coated lanthanide-based nanoparticles for in vivo intravenous administration. We were able to synthesize a contrast agent containing 100 mg/mL of erbium that could be redispersed into colloidally stable nanoparticles in saline after lyophilization. Contrast enhancement of over 250 HU was achieved in the blood pool for up to an hour, thereby meeting the requirements of live animal micro-CT

The lysosomal inhibitor, chloroquine, increases cell surface BMPR-II levels and restores BMP9 signalling in endothelial cells harbouring BMPR-II mutations.

Pulmonary arterial hypertension (PAH) is characterized by dysregulated pulmonary artery endothelial cell (PAEC) proliferation, apoptosis and permeability. Loss-of-function mutations in the bone morphogenetic protein receptor type-II (BMPR-II) are the most common cause of heritable PAH, usually resulting in haploinsufficiency. We previously showed that BMPR-II expression is regulated via a lysosomal degradative pathway. Here, we show that the antimalarial drug, chloroquine, markedly increased cell surface expression of BMPR-II protein independent of transcription in PAECs. Inhibition of protein synthesis experiments revealed a rapid turnover of cell surface BMPR-II, which was inhibited by chloroquine treatment. Chloroquine enhanced PAEC expression of BMPR-II following siRNA knockdown of the BMPR-II transcript. Using blood outgrowth endothelial cells (BOECs), we confirmed that signalling in response to the endothelial BMPR-II ligand, BMP9, is compromised in BOECs from patients harbouring BMPR-II mutations, and in BMPR-II mutant PAECs. Chloroquine significantly increased gene expression of BMP9-BMPR-II signalling targets Id1, miR21 and miR27a in both mutant BMPR-II PAECs and BOECs. These findings provide support for the restoration of cell surface BMPR-II with agents such as chloroquine as a potential therapeutic approach for heritable PAH

Technical note: Use of an atmospheric simulation chamber to investigate the effect of different engine conditions on unregulated VOC-IVOC diesel exhaust emissions

Diesel exhaust emissions were introduced into an atmospheric simulation chamber and measured using thermal desorption (TD) comprehensive two-dimensional gas chromatography coupled to a flame ionisation detector (GC × GC-FID). An extensive set of measurements were performed to investigate the effect of different engine conditions (i.e. load, speed, driving scenarios) and emission control devices (with or without diesel oxidative catalyst, DOC) on the composition and abundance of unregulated exhaust gas emissions from a light-duty diesel engine, fuelled with ultra-low sulfur diesel (ULSD). A range of exhaust dilution ratios were investigated (range = 1:60 to 1:1158), simulating the chemical and physical transformations of the exhaust gas from near to downwind of an emission source. In total, 16 individual and 8 groups of compounds (aliphatics and single-ring aromatics) were measured in the exhaust gas ranging from volatile to intermediate volatility (VOC-IVOC), providing both detailed chemical speciation and groupings of compounds based on their structure and functionality. Measured VOC-IVOC emission rates displayed excellent reproducibility from replicate experiments using similar exhaust dilution ratios. However, at the extremes of the investigated exhaust dilution ratios (comparison of 1:60 and 1:1158), measured VOC-IVOC emission rates displayed some disagreement owing to poor reproducibility and highlighted the importance of replicate sample measurements. The investigated DOC was found to remove 43±10% (arithmetic mean±experimental uncertainty) of the total speciated VOC-IVOC ( ∑ SpVOC-IVOC) emissions. The compound class-dependant removal efficiencies for the investigated DOC were 39±12% and 83±3% for the aliphatics and single-ring aromatics, respectively. The DOC aliphatic removal efficiency generally decreased with increasing carbon chain length. The  ∑ SpVOC-IVOC emission rates varied significantly with different engine conditions, ranging from 70 to 9268mgkg−1 (milligrams of mass emitted per kilogram of fuel burnt).  ∑ SpVOC-IVOC emission rates generally decreased with increasing engine load and temperature, and to a lesser degree, engine speed. The exhaust gas composition changed considerably as a result of two influencing factors: engine combustion and DOC hydrocarbon (HC) removal efficiency. Increased engine combustion efficiency resulted in a greater percentage contribution of the C7 to C12 n-alkanes to the  ∑ SpVOC-IVOC emission rate. Conversely, increased DOC HC removal efficiency resulted in a greater percentage contribution of the C7 to C12 branched aliphatics to the  ∑ SpVOC-IVOC emission rate. At low engine temperatures ( < 150°C, below the working temperature of the DOC), the contribution of n-alkanes in the exhaust gas increased with increasing combustion efficiency and may be important in urban environments, as n-alkanes are more efficient at producing secondary organic aerosol (SOA) than their branched counterparts. At very high engine temperatures (maximum applied engine speed and load, engine temperature = 700°C), the n-alkane contribution increased by a factor of 1.6 times greater than that observed in the cold-start experiment (most similar to unburnt fuel) and may suggest liquid-fuel-based estimates of SOA yields may be inconsistent with exhaust SOA yields, particularly at high engine speeds and loads (i.e. high engine temperatures). Emission rates were found to be 65 times greater from a cold-start experiment than at maximum applied engine speed and load. To our knowledge, this is the first study which uses an atmospheric simulation chamber to separate the effects of the DOC and combustion efficiency on the exhaust gas composition

Cardiovascular disease in a cohort exposed to the 1940-45 Channel Islands occupation

BACKGROUND To clarify the nature of the relationship between food deprivation/undernutrition during pre- and postnatal development and cardiovascular disease (CVD) in later life, this study examined the relationship between birth weight (as a marker of prenatal nutrition) and the incidence of hospital admissions for CVD from 1997–2005 amongst 873 Guernsey islanders (born in 1923–1937), 225 of whom had been exposed to food deprivation as children, adolescents or young adults (i.e. postnatal undernutrition) during the 1940–45 German occupation of the Channel Islands, and 648 of whom had left or been evacuated from the islands before the occupation began. METHODS Three sets of Cox regression models were used to investigate (A) the relationship between birth weight and CVD, (B) the relationship between postnatal exposure to the occupation and CVD and (C) any interaction between birth weight, postnatal exposure to the occupation and CVD. These models also tested for any interactions between birth weight and sex, and postnatal exposure to the occupation and parish of residence at birth (as a marker of parish residence during the occupation and related variation in the severity of food deprivation). RESULTS The first set of models (A) found no relationship between birth weight and CVD even after adjustment for potential confounders (hazard ratio (HR) per kg increase in birth weight: 1.12; 95% confidence intervals (CI): 0.70 – 1.78), and there was no significant interaction between birth weight and sex (p = 0.60). The second set of models (B) found a significant relationship between postnatal exposure to the occupation and CVD after adjustment for potential confounders (HR for exposed vs. unexposed group: 2.52; 95% CI: 1.54 – 4.13), as well as a significant interaction between postnatal exposure to the occupation and parish of residence at birth (p = 0.01), such that those born in urban parishes (where food deprivation was worst) had a greater HR for CVD than those born in rural parishes. The third model (C) found no interaction between birth weight and exposure to the occupation (p = 0.43). CONCLUSION These findings suggest that the levels of postnatal undernutrition experienced by children, adolescents and young adults exposed to food deprivation during the 1940–45 occupation of the Channel Islands were a more important determinant of CVD in later life than the levels of prenatal undernutrition experienced in utero prior to the occupatio

Trabecular distribution of distal femur in extant apes and Australopithecus sediba

Knee morphology of fossil hominins is of particular interest to paleoanthropologists due to longstanding debates about relative degrees of arboreality and terrestrial bipedalism in the hominin clade. In addition to external bone shape, the investigation of trabecular bone in the knee joint can provide insights into in vivo locomotor behavior of hominins [1-2]. The nearly complete right distal femur (U.W. 88-63) of Australopithecus sediba (1.98 Ma) shows a unique combination of condyles that resemble other australopith species and Homo-like anatomy of the patellar surface, which has been used to infer a unique locomotor pattern in this species [3]. Here we analyze the trabecular morphology of distal femoral epiphysis of Homo sapiens (N = 15), Gorilla gorilla (N=14), Pan troglodytes verus (N = 15), Pongo sp. (N = 9), and A. sediba (MH2) in order to 1) establish patterns of joint loading in extant taxa of known locomotor behaviour and 2) investigate joint loading in the knee of A. sediba. A canonical holistic morphometric analysis (cHMA), combining holistic morphometric analysis (HMA) and statistical free-form deformation model (SDM), approach was used to analyze the patterns of trabecular bone distribution following published protocols [4]. A principal component (PC) analysis of relative bone volume (rBV/TV) distribution shows clear separation between extant ape taxa. Positive values on PC1, PC2 and PC3 are mostly driven by rBV/TV concentrated on the patellar surface and on the posterior articular surface of the medial condyle separating humans from great apes (PC1, PC2) and chimpanzees (PC3) from humans, gorillas and orangutans. Negative PC1 is mostly driven by rBV/TV concentrated beneath the insertion of posterior cruciate ligament discriminating non-human apes from humans, negative PC2 by loadings on the patellar surface separating gorillas from others, and negative PC3 by loadings on the patellar surface and on the posterior articulation surface of the medial condyle discriminating orangutans from others. Results suggest that differences between humans and apes are primarily in the patellar articular surface. Relative bone volume in humans is concentrated in the posteroinferior region of the lateral condyle and on the lateral patellar surface, which is consistent with loading in an extended knee position during locomotion. In non-human apes relative bone volume is found to extend from the inferior margin of the patellar articulation to the posterior region of both condyles. However, in gorillas it does not extend as posterosuperiorly in the medial condyle as it does in chimpanzees and orangutans. Trabecular bone is concentrated in the lateral condyles in apes, with the greatest values in the posterosuperior and the posteroinferior regions. Unlike humans, ape like a trabecular concentration at the distal regions of both condyles (i.e., those assumed to be loaded in an extended knee), with the lowest values in orangutans. We suggest that this reflects predominant loading in a more flexed knee posture in great apes compared to humans. Finally, among apes, we found the most homogenous distribution of trabecular bone across both condyles in orangutans, which we relate to their more variable knee joint postures during locomotion. A. sediba shows trabecular concentrations on the patellar surface and on the posterior area of the lateral condyle. Values in the posteroinferior and posterosuperior regions of lateral condyle are generally higher than in medial condyle. We interpret these fossil results as reflective of loading the knee joint with a degree of flexion that differs somewhat from modern humans. However, taphonomic erosion of parts of the condyles hinders a complete assessment of trabecular bone distribution in A. sediba

First experimental evidence of one-dimensional plasma modes in superconducting thin wires

We have studied niobium superconducting thin wires deposited onto a SrTiO$_{3}$ substrate. By measuring the reflection coefficient of the wires, resonances are observed in the superconducting state in the 130 MHz to 4 GHz range. They are interpreted as standing wave resonances of one-dimensional plasma modes propagating along the superconducting wire. The experimental dispersion law, $\omega$ versus $q$, presents a linear dependence over the entire wave vector range. The modes are softened as the temperature increases close the superconducting transition temperature. Very good agreement are observed between our data and the dispersion relation predicted by Kulik and Mooij and Sch\"on.Comment: Submitted to Physical review Letter

Ageing is associated with molecular signatures of inflammation and type 2 diabetes in rat pancreatic islets.

AIMS/HYPOTHESIS: Ageing is a major risk factor for development of metabolic diseases such as type 2 diabetes. Identification of the mechanisms underlying this association could help to elucidate the relationship between age-associated progressive loss of metabolic health and development of type 2 diabetes. We aimed to determine molecular signatures during ageing in the endocrine pancreas. METHODS: Global gene transcription was measured in pancreatic islets isolated from young and old rats by Ilumina BeadChip arrays. Promoter DNA methylation was measured by Sequenom MassArray in 46 genes that showed differential expression with age, and correlations with expression were established. Alterations in morphological and cellular processes with age were determined by immunohistochemical methods. RESULTS: Age-related changes in gene expression were found at 623 loci (>1.5-fold, false discovery rate [FDR] <5%), with a significant (FDR < 0.05) enrichment in genes previously implicated in islet-cell function (Enpp1, Abcc8), type 2 diabetes (Tspan8, Kcnq1), inflammatory processes (Cxcl9, Il33) and extracellular matrix organisation (Col3a1, Dpt). Age-associated transcriptional differences negatively correlated with promoter DNA methylation at several loci related to inflammation, glucose homeostasis, cell proliferation and cell-matrix interactions (Il33, Cxcl9, Gpr119, Fbp2, Col3a1, Dpt, Spp1). CONCLUSIONS/INTERPRETATION: Our findings suggest that a significant proportion of pancreatic islets develop a low-grade 'chronic' inflammatory status with ageing and this may trigger altered functional plasticity. Furthermore, we identified changes in expression of genes previously linked to type 2 diabetes and associated changes in DNA methylation that could explain their age-associated dysregulation. These findings provide new insights into key (epi)genetic signatures of the ageing process in islets.Biotechnology and Biological Sciences Research Council (Grant ID: BB/H003312/1), British Heart Foundation, FP6 Epigenome Network of Excellence programme, GlaxoSmithKline, Nuffield Foundation, Royal Society, Medical Research Council (Grant ID: MRC_MC_UU_12012/4)This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00125-015-3837-

Understanding in situ ozone production in the summertime through radical observations and modelling studies during the Clean air for London project (ClearfLo)

Measurements of OH, HO2, RO2i (alkene and aromatic-related RO2) and total RO2 radicals taken during the ClearfLo campaign in central London in the summer of 2012 are presented. A photostationary steady-state calculation of OH which considered measured OH reactivity as the OH sink term and the measured OH sources (of which HO2+ NO reaction and HONO photolysis dominated) compared well with the observed levels of OH. Comparison with calculations from a detailed box model utilising the Master Chemical Mechanism v3.2, however, highlighted a substantial discrepancy between radical observations under lower NOx conditions ([NO] 3 ppbv) the box model increasingly underpredicted total [RO2]. The modelled and observed HO2 were in agreement, however, under elevated NO concentrations ranging from 7 to 15 ppbv. The model uncertainty under low NO conditions leads to more ozone production predicted using modelled peroxy radical concentrations ( ≈ 3 ppbv h-1) versus ozone production from peroxy radicals measured ( ≈ 1 ppbv h-1). Conversely, ozone production derived from the predicted peroxy radicals is up to an order of magnitude lower than from the observed peroxy radicals as [NO] increases beyond 7 ppbv due to the model underprediction of RO2 under these conditions