Lipase inhibition attenuates the acute inhibitory effects of oral fat on food intake in healthy subjects

The lipase inhibitor, orlistat, is used in the treatment of obesity and reduces fat absorption by about 30%. However, the mean weight loss induced by orlistat is less than expected for the degree of fat malabsorption. It was hypothesised that lipase inhibition with orlistat attenuates the suppressive effects of oral fat on subsequent energy intake in normal-weight subjects. Fourteen healthy, lean subjects (nine males, five females; aged 25 +/- 1.3 years) were studied twice, in a double-blind fashion. The subjects received a high-fat yoghurt 'preload' (males 400 g (2562 kJ); females 300 g (1923 kJ)), containing orlistat (120 mg) on one study day (and no orlistat on the other 'control' day), 30 min before ad libitum access to food and drinks; energy intake was assessed during the following 8 h. Blood samples were taken at regular intervals for the measurement of plasma cholecystokinin (CCK). Each subject performed a 3 d faecal fat collection following each study. Energy intake during the day was greater following orlistat (10,220 (SEM 928) kJ) v. control (9405 (SEM 824) kJ) (P=0.02). On both days plasma CCK increased (P<0.05) after the preload. Plasma CCK 20 min following ingestion of the preload was less after orlistat (4.1 (SEM 0.9) pmol/l) v. control (5.3 (SEM 0.9) pmol/l (P=0.028); however there was no difference in the area under the curve 0-510 min between the two study days. Fat excretion was greater following orlistat (1017 (SEM 168) kJ) v. control (484 (SEM 90) kJ) (P=0.004). In conclusion, in healthy, lean subjects the acute inhibitory effect of fat on subsequent energy intake is attenuated by orlistat and the increase in energy intake approximates the energy lost due to fat malabsorption.Deirdre O’Donovan, Christine Feinle-Bisset, Judith Wishart and Michael Horowit

Interactive exploration of population scale pharmacoepidemiology datasets

Population-scale drug prescription data linked with adverse drug reaction (ADR) data supports the fitting of models large enough to detect drug use and ADR patterns that are not detectable using traditional methods on smaller datasets. However, detecting ADR patterns in large datasets requires tools for scalable data processing, machine learning for data analysis, and interactive visualization. To our knowledge no existing pharmacoepidemiology tool supports all three requirements. We have therefore created a tool for interactive exploration of patterns in prescription datasets with millions of samples. We use Spark to preprocess the data for machine learning and for analyses using SQL queries. We have implemented models in Keras and the scikit-learn framework. The model results are visualized and interpreted using live Python coding in Jupyter. We apply our tool to explore a 384 million prescription data set from the Norwegian Prescription Database combined with a 62 million prescriptions for elders that were hospitalized. We preprocess the data in two minutes, train models in seconds, and plot the results in milliseconds. Our results show the power of combining computational power, short computation times, and ease of use for analysis of population scale pharmacoepidemiology datasets. The code is open source and available at: https://github.com/uit-hdl/norpd_prescription_analyse

Label-free proteomics identifies Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers for spinal muscular atrophy

BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disease resulting from mutations in the survival motor neuron 1 (SMN1) gene. Recent breakthroughs in preclinical research have highlighted several potential novel therapies for SMA, increasing the need for robust and sensitive clinical trial platforms for evaluating their effectiveness in human patient cohorts. Given that most clinical trials for SMA are likely to involve young children, there is a need for validated molecular biomarkers to assist with monitoring disease progression and establishing the effectiveness of therapies being tested. Proteomics technologies have recently been highlighted as a potentially powerful tool for such biomarker discovery. METHODS: We utilized label-free proteomics to identify individual proteins in pathologically-affected skeletal muscle from SMA mice that report directly on disease status. Quantitative fluorescent western blotting was then used to assess whether protein biomarkers were robustly changed in muscle, skin and blood from another mouse model of SMA, as well as in a small cohort of human SMA patient muscle biopsies. RESULTS: By comparing the protein composition of skeletal muscle in SMA mice at a pre-symptomatic time-point with the muscle proteome at a late-symptomatic time-point we identified increased expression of both Calreticulin and GRP75/Mortalin as robust indicators of disease progression in SMA mice. We report that these protein biomarkers were consistently modified in different mouse models of SMA, as well as across multiple skeletal muscles, and were also measurable in skin biopsies. Furthermore, Calreticulin and GRP75/Mortalin were measurable in muscle biopsy samples from human SMA patients. CONCLUSIONS: We conclude that label-free proteomics technology provides a powerful platform for biomarker identification in SMA, revealing Calreticulin and GRP75/Mortalin as peripherally accessible protein biomarkers capable of reporting on disease progression in samples of muscle and skin

Ahmed glaucoma valves in refractory glaucoma: A 7-year audit

Purpose: To present the long-term results of Ahmed glaucoma valve (AGV) implantation. Methods: Consecutive case series of 94 eyes with AGV implantation over 7 years. Temporary tube ligation with C3F8 gas fill was used in high-risk eyes (group G&L) and compared with standard implantation in both phakic (group A) and pseudophakic/aphakic eyes (group B). Success was intraocular pressure (IOP) of 6 mm Hg or greater and 21 mm Hg or less and/or IOP reduction of 20% or greater. Results: Average follow-up was 28.9±20.3 months. The mean preoperative IOP changed from 30.8±8.2 to 19.7±7.6 mm Hg and mean preoperative medications changed from 3.3±1.2 to 1.2±1.1 at the final visit. Cumulative probability of survival at 1 and 4 years was 89.1% and 72.9%. There was no statistically significant difference in success between the three groups, but complications due to postoperative hypotony (six eyes) only occurred in group B. Other complications were corneal decompensation (three eyes), tube erosion (six eyes) and aqueous misdirection (four eyes). Conclusions: AGV implantation offered good long-term IOP control with a success rate of 78.7%. The authors recommend C3F8 gas fill and temporary tube ligation in eyes at high risk of postoperative hypotony and the use of donor sclera or human pericardial patch to prevent tube erosion.published_or_final_versio

Random matrix approach in search for weak signals immersed in background noise

We present new, original and alternative method for searching signals coded in noisy data. The method is based on the properties of random matrix eigenvalue spectra. First, we describe general ideas and support them with results of numerical simulations for basic periodic signals immersed in artificial stochastic noise. Then, the main effort is put to examine the strength of a new method in investigation of data content taken from the real astrophysical NAUTILUS detector, searching for the presence of gravitational waves. Our method discovers some previously unknown problems with data aggregation in this experiment. We provide also the results of new method applied to the entire respond signal from ground based detectors in future experimental activities with reduced background noise level. We indicate good performance of our method what makes it a positive predictor for further applications in many areas.Comment: 15 pages, 16 figure