Metabolism of low-density lipoproteins by cultured hepatocytes from normal and homozygous familial hypercholesterolemic subjects

The profoundly elevated concentrations of low-density lipoproteins (LDL) present in homozygous familial hypercholesterolemia lead to symptomatic cardiovascular disease and death by early adulthood. Studies conducted in nonhepatic tissues demonstrated defective cellular recognition and metabolism of LDL in these patients. Since mammalian liver removes at least half of the LDL in the circulation, the metabolism of LDL by cultured hepatocytes isolated from familial hypercholesterolemic homozygotes was compared to hepatcytes from normal individuals. Fibroblast studies demonstrated that the familial hypercholesterolemic subjects studied were LDL receptor-negative (less than 1% normal receptor activity) and LDL receptor-de fective (18% normal receptor activity). Cholesterol-depleted hepatocytes from normal subjects bound and internalized 125I-labeled LDL (Bmax = 2.2 μg LDL/mg cell protein). Preincubation of normal hepatocytes with 200 μg/ml LDL reduced binding and internalization by approx. 40%. In contrast, 125I-labeled LDL binding and internalization by receptor-negative familial hypercholesterolemic hepatocytes was unaffected by cholesterol loading and considerably lower than normal. This residual LDL uptake could not be ascribed to fluid phase endocytosis as determined by [14C]sucrose uptake. The residual LDL binding by familial hypercholesterolemia hepatocytes led to a small increase in hepatocyte cholesterol content which was relatively ineffective in reducing hepatocyte 3-hydroxy-3-methylglutaryl-CoA reductase activity. Receptordefective familial hypercholesterolemia hepatocytes retained some degree of regulatable 125I-labeled LDL uptake, but LDL uptake did not lead to normal hepatocyte cholesterol content or 3-hydroxy-3-methylglutaryl-CoA reductase activity. These combined results indicate that the LDL receptor abnormality present in familial hypercholesterolemia fibroblasts reflects deranged hepatocyte LDL recognition and metabolism. In addition, a low-affinity, nonsaturable uptake process for LDL is present in human liver which does not efficiently modulate hepatocyte cholesterol content or synthesis. © 1986

Independent predictors of failure up to 7.5 years after 35 386 single-brand cementless total hip replacements: a retrospective cohort study using National Joint Registry data

The popularity of cementless total hip replacement (THR) has surpassed cemented THR in England and Wales. This retrospective cohort study records survival time to revision following primary cementless THR with the most common combination (accounting for almost a third of all cementless THRs), and explores risk factors independently associated with failure, using data from the National Joint Registry for England and Wales. Patients with osteoarthritis who had a DePuy Corail/Pinnacle THR implanted between the establishment of the registry in 2003 and 31 December 2010 were included within analyses. There were 35 386 procedures. Cox proportional hazard models were used to analyse the extent to which the risk of revision was related to patient, surgeon and implant covariates. The overall rate of revision at five years was 2.4% (99% confidence interval 2.02 to 2.79). In the final adjusted model, we found that the risk of revision was significantly higher in patients receiving metal-on-metal (MoM: hazard ratio (HR) 1.93, p < 0.001) and ceramic-on-ceramic bearings (CoC: HR 1.55, p = 0.003) compared with the best performing bearing (metal-on-polyethylene). The risk of revision was also greater for smaller femoral stems (sizes 8 to 10: HR 1.82, p < 0.001) compared with mid-range sizes. In a secondary analysis of only patients where body mass index (BMI) data were available (n = 17 166), BMI ≥ 30 kg/m2 significantly increased the risk of revision (HR 1.55, p = 0.002). The influence of the bearing on the risk of revision remained significant (MoM: HR 2.19, p < 0.001; CoC: HR 2.09, p = 0.001). The risk of revision was independent of age, gender, head size and offset, shell, liner and stem type, and surgeon characteristics. We found significant differences in failure between bearing surfaces and femoral stem size after adjustment for a range of covariates in a large cohort of single-brand cementless THRs. In this study of procedures performed since 2003, hard bearings had significantly higher rates of revision, but we found no evidence that head size had an effect. Patient characteristics, such as BMI and American Society of Anesthesiologists grade, also influence the survival of cementless components

Symptom and Quality of Life Improvement in LUX-Lung 8, an Open-Label Phase III Study of Second-Line Afatinib Versus Erlotinib in Patients With Advanced Squamous Cell Carcinoma of the Lung After First-Line Platinum-Based Chemotherapy

INTRODUCTION: In the phase III LUX-Lung 8 trial, afatinib significantly improved progression-free survival (PFS) and overall survival (OS) versus erlotinib in patients with squamous cell carcinoma (SCC) of the lung progressing during or after platinum-based chemotherapy. Patient-reported outcomes (PROs) and health-related quality of life (QoL) in these patients are presented. PATIENTS AND METHODS: Patients (n = 795) were randomized 1:1 to oral afatinib (40 mg/d) or erlotinib (150 mg/d). PROs were collected (baseline, every 28 days until progression, 28 days after discontinuation) using the European Organization for Research and Treatment of Cancer QoL questionnaire and lung cancer-specific module. The percentage of patients improved during therapy, time to deterioration (TTD), and changes over time were analyzed for prespecified lung cancer-related symptoms and global health status (GHS)/QoL. RESULTS: Questionnaire compliance was 77.3% to 99.0% and 68.7% to 99.0% with afatinib and erlotinib, respectively. Significantly more patients who received afatinib versus erlotinib experienced improved scores for GHS/QoL (36% vs. 28%; P = .041) and cough (43% vs. 35%; P = .029). Afatinib significantly delayed TTD in dyspnea (P = .008) versus erlotinib, but not cough (P = .256) or pain (P = .869). Changes in mean scores favored afatinib for cough (P = .0022), dyspnea (P = .0007), pain (P = .0224), GHS/QoL (P = .0320), and all functional scales. Differences in adverse events between afatinib and erlotinib, specifically diarrhea, did not affect GHS/QoL. CONCLUSION: In patients with SCC of the lung, second-line afatinib was associated with improved prespecified disease-related symptoms and GHS/QoL versus erlotinib, complementing PFS and OS benefits with afatinib

Extraction of Knowledge Rules for the Retrieval of Mesoscale Oceanic Structures in Ocean Satellite Images

The processing of ocean satellite images has as goal the detection of phenomena related with ocean dynamics. In this context, Mesoscale Oceanic Structures (MOS) play an essential role. In this chapter we will present the tool developed in our group in order to extract knowledge rules for the retrieval of MOS in ocean satellite images. We will describe the implementation of the tool: the workflow associated with the tool, the user interface, the class structure, and the database of the tool. Additionally, the experimental results obtained with the tool in terms of fuzzy knowledge rules as well as labeled structures with these rules are shown. These results have been obtained with the tool analyzing chlorophyll and temperature images of the Canary Islands and North West African coast captured by the SeaWiFS and MODIS-Aqua sensors

Decadal changes of the Western Arabian sea ecosystem

Historical data from oceanographic expeditions and remotely sensed data on outgoing longwave radiation, temperature, wind speed and ocean color in the western Arabian Sea (1950–2010) were used to investigate decadal trends in the physical and biochemical properties of the upper 300 m. 72 % of the 29,043 vertical profiles retrieved originated from USA and UK expeditions. Increasing outgoing longwave radiation, surface air temperatures and sea surface temperature were identified on decadal timescales. These were well correlated with decreasing wind speeds associated with a reduced Siberian High atmospheric anomaly. Shoaling of the oxycline and nitracline was observed as well as acidification of the upper 300 m. These physical and chemical changes were accompanied by declining chlorophyll-a concentrations, vertical macrofaunal habitat compression, declining sardine landings and an increase of fish kill incidents along the Omani coast

The use of happiness research for public policy

Research on happiness tends to follow a "benevolent dictator" approach where politicians pursue people's happiness. This paper takes an antithetic approach based on the insights of public choice theory. First, we inquire how the results of happiness research may be used to improve the choice of institutions. Second, we show that the policy approach matters for the choice of research questions and the kind of knowledge happiness research aims to provide. Third, we emphasize that there is no shortcut to an optimal policy maximizing some happiness indicator or social welfare function since governments have an incentive to manipulate this indicator

Topological Analysis of Small Leucine-Rich Repeat Proteoglycan Nyctalopin

Nyctalopin is a small leucine rich repeat proteoglycan (SLRP) whose function is critical for normal vision. The absence of nyctalopin results in the complete form of congenital stationary night blindness. Normally, glutamate released by photoreceptors binds to the metabotropic glutamate receptor type 6 (GRM6), which through a G-protein cascade closes the non-specific cation channel, TRPM1, on the dendritic tips of depolarizing bipolar cells (DBCs) in the retina. Nyctalopin has been shown to interact with TRPM1 and expression of TRPM1 on the dendritic tips of the DBCs is dependent on nyctalopin expression. In the current study, we used yeast two hybrid and biochemical approaches to investigate whether murine nyctalopin was membrane bound, and if so by what mechanism, and also whether the functional form was as a homodimer. Our results show that murine nyctalopin is anchored to the plasma membrane by a single transmembrane domain, such that the LRR domain is located in the extracellular space

An in vitro study comparing a peripherally inserted central catheter to a conventional central venous catheter: no difference in static and dynamic pressure transmission

<p>Abstract</p> <p>Background</p> <p>Early goal directed therapy improves survival in patients with septic shock. Central venous pressure (CVP) monitoring is essential to guide adequate resuscitation. Use of peripherally inserted central catheters (PICC) is increasing, but little data exists comparing a PICC to a conventional CVP catheter. We studied the accuracy of a novel PICC to transmit static and dynamic pressures <it>in vitro</it>.</p> <p>Methods</p> <p>We designed a device to generate controlled pressures via a column of water allowing simultaneous measurements from a PICC and a standard triple lumen catheter. Digital transducers were used to obtain all pressure readings. Measurements of static pressures over a physiologic range were recorded using 5Fr and 6Fr dual lumen PICCs. Additionally, random repetitive pressure pulses were applied to the column of water to simulate physiologic intravascular pressure variations. The resultant PICC and control waveforms were recorded simultaneously.</p> <p>Results</p> <p>Six-hundred thirty measurements were made using the 5 Fr and 6 Fr PICCs. The average bias determined by Bland-Altman plot was 0.043 mmHg for 5 Fr PICC and 0.023 mmHg for 6 Fr PICC with a difference range of 1.0 to -1.0. The correlation coefficient for both catheters was 1.0 (p-value < 0.001). Dynamic pressure waveforms plotted simultaneously between PICC and control revealed equal peaks and troughs.</p> <p>Conclusion</p> <p><it>In vitro</it>, no static or dynamic pressure differences were found between the PICC and a conventional CVP catheter. Clinical studies are required to assess whether the novel PICC has bedside equivalence to conventional catheters when measuring central venous pressures.</p

Formation of unique nanocrystalline Cu-In-Se bulk pn homojunctions for opto-electronic devices

Semiconductor pn junctions, integrated in optoelectronic devices require high quality crystals, made by expensive, technically difficult processes. Bulk heterojunction (BHJ) structures offer practical alternatives to circumvent the cost, flexibility and scale-up challenges of crystalline planar pn junctions. Fabrication methods for the current organic or inorganic BHJ structures invariably create interface mismatch and low doping issues. To overcome such issues, we devised an innovative approach, founded on novel inorganic material system that ensued from single-step electrodeposited copper-indium-selenide compounds. Surface analytical microscopies and spectroscopies reveal unusual phenomena, electro-optical properties and quantum effects. They support the formation of highly-ordered, sharp, abrupt 3-dimensional nanoscale pn BHJs that facilitate efficient charge carrier separation and transport, and essentially perform the same functions as crystalline planar pn junctions. This approach offers a low-cost processing platform to create nanocrystalline films, with the attributes necessary for efficient BHJ operation. It allows roll-to-roll processing of flexible devices in simple thin-film form factor.Partial funding for this work is provided by customers of Xcel Energy through a grant from the Renewable Development Fund. The authors gratefully acknowledge sample preparation, analytical contributions and useful discussions with Sharmila Menezes and Yan Li (InterPhases Solar); Senli Guo (Brucker Nano); Terrence McGuckin (Ephemeron Labs); and Nassim Rahimi (HORIBA Scientific). A. Samantilleke acknowledges Prof. L. M. Peter (Bath University, UK) for introducing EER technique

Sero-survey of rubella IgM antibodies among children in Jos, Nigeria

Sero-survey of rubella IgM antibodies was carried out among children aged 0-10 years in Jos, Nigeria. Blood samples were collected from the subjects and sera extracted. Of the 93(100%) assayed for the rubella IgM antibody, 42(45.2%) were seropositive for rubella IgM antibody while 51(54.8%) were seronegative. A breakdown of the seropositive subjects reveals that 14(15.1%) of the infected children were males while 28(30.1%) were females. Those subjects within the age groups of 1-2, 3-4 and 5-6 years had the highest prevalence of 8(8.6%) followed by those within the age groups of 7-8, 9-10 years with 7(7.5%). Blood transfusion as a risk factor did not show any significant influence on the status of the subjects. The demographic data of the mothers of the subjects were also linked with the seropositivity of the children