Role of β3-adrenergic receptors in the action of a tumour lipid mobilizing factor

Induction of lipolysis in murine white adipocytes, and stimulation of adenylate cyclase in adipocyte plasma membranes, by a tumour-produced lipid mobilizing factor, was attenuated by low concentrations (10-7-10-5M) of the specific β3-adrenoceptor antagonist SR59230A. Lipid mobilizing factor (250 nM) produced comparable increases in intracellular cyclic AMP in CHOKI cells transfected with the human β3-adrenoceptor to that obtained with isoprenaline (1 nM). In both cases cyclic AMP production was attenuated by SR59230A confirming that the effect is mediated through a β3-adrenoceptor. A non-linear regression analysis of binding of lipid mobilizing factor to the β3-adrenoceptor showed a high affinity binding site with a Kd value 78±45 nM and a Bmax value (282±1 fmole mg protein-1) comparable with that of other β3-adrenoceptor agonists. These results suggest that lipid mobilizing factor induces lipolysis through binding to a β3-adrenoceptor. © 2002 The Cancer Research Campaign.

Entry modes and performance of foreign direct investment in China

How does a firm choose a proper model of foreign direct investment (FDI) for entering a foreign market? Which mode of entry performs better? What are the performance implications of joint venture (JV) ownership structure? These important questions face a multinational enterprise (MNE) that decides to enter a foreign market. However, few studies have been conducted on such issues, and no consistent or conclusive findings are generated, especially with respect to China. It’s composed of five chapters, providing corresponding answers to the questions given above. Specifically, Chapter One is an overall introductory chapter. Chapter Two is about the choice of entry mode of FDI in China. Chapter Three examines the relationship between four main entry modes and performance. Chapter Four explores the performance implications of JV ownership structure. Chapter Five is an overall concluding chapter. These empirical studies are based on the most recent and richest data that has never been explored in previous studies. It contains information on 11,765 foreign-invested enterprises in China in seven manufacturing industries in 2000, 10,757 in 1999, and 10,666 in 1998. The four FDI entry modes examined include wholly-owned enterprises (WOEs), equity joint ventures (EJVs), contractual joint ventures (CJVs), and joint stock companies (JSCs). In Chapter Two, a multinominal logit model is established, and techniques of multiple linear regression analysis are employed in Chapter Three and Four. It was found that MNEs, under the conditions of a good investment environment, large capital commitment and small cultural distance, prefer the WOE strategy. If these conditions are not met, the EJV mode would be of greater use. The relative propensity to pursue the CJV mode increases with a good investment environment, small capital commitment, and small cultural distance. JSCs are not favoured by MNEs when the investment environment improves and when affiliates are located in the coastal areas. MNEs have been found to have a greater preference for an EJV as a mode of entry into the Chinese market in all industries. It is also found that in terms of return on assets (ROA) and asset turnover, WOEs perform the best, followed by EJVs, CJVs, and JSCs. Finally, minority-owned EJVs or JSCs are found to outperform their majority-owned counterparts in terms of ROA and asset turnover.

Formulation of topical non-steroidal anti-inflammatory agents

Reversed-pahse high-performance liquid chromatographic (HPLC) methods were developed for the assay of indomethacin, its decomposition products, ibuprofen and its (tetrahydro-2-furanyl)methyl-, (tetrahydro-2-(2H)pyranyl)methyl- and cyclohexylmethyl esters. The development and application of these HPLC systems were studied. A number of physico-chemical parameters that affect percutaneous absorption were investigated. The pKa values of indomethacin and ibuprofen were determined using the solubility method. Potentiometric titration and the Taft equation were also used for ibuprofen. The incorporation of ethanol or propylene glycol in the solvent resulted in an improvement in the aqueous solubility of these compounds. The partition coefficients were evaluated in order to establish the affinity of these drugs towards the stratum corneum. The stability of indomethacin and of ibuprofen esters were investigated and the effect of temperature and pH on the decomposition rates were studied. The effect of cetyltrimethylammonium bromide on the alkaline degradation of indomethacin was also followed. In the presence of alcohol, indomethacin alcoholysis was observed and the kinetics of decomposition were subjected to non-linear regression analysis and the rate constants for the various pathways were quantified. The non-isothermal, sufactant non-isoconcentration and non-isopH degradation of indomethacin were investigated. The analysis of the data was undertaken using NONISO, a BASIC computer program. The degradation profiles obtained from both non-iso and iso-kinetic studies show that there is close concordance in the results. The metabolic biotransformation of ibuprofen esters was followed using esterases from hog liver and rat skin homogenates. The results showed that the esters were very labile under these conditions. The presence of propylene glycol affected the rates of enzymic hydrolysis of the ester. The hydrolysis is modelled using an equation involving the dielectric constant of the medium. The percutaneous absorption of indomethacin and of ibuprofen and its esters was followed from solutions using an in vitro excised human skin model. The absorption profiles followed first order kinetics. The diffusion process was related to their solubility and to the human skin/solvent partition coefficient. The percutaneous absorption of two ibuprofen esters from suspensions in 20% propylene glycol-water were also followed through rat skin with only ibuprofen being detected in the receiver phase. The sensitivity of ibuprofen esters to enzymic hydrolysis compared to the chemical hydrolysis may prove valuable in the formulation of topical delivery systems.

Applying Information Foraging Theory to understand user interaction with content-based image retrieval

The paper proposes an ISE (Information goal, Search strategy, Evaluation threshold) user classification model based on Information Foraging Theory for understanding user interaction with content-based image retrieval (CBIR). The proposed model is verified by a multiple linear regression analysis based on 50 users' interaction features collected from a task-based user study of interactive CBIR systems. To our best knowledge, this is the first principled user classification model in CBIR verified by a formal and systematic qualitative analysis of extensive user interaction data. Copyright 2010 ACM.

Psychological traits influence autonomic nervous system recovery following esophageal intubation in health and functional chest pain

Background: Esophageal intubation is a widely utilized technique for a diverse array of physiological studies, activating a complex physiological response mediated, in part, by the autonomic nervous system (ANS). In order to determine the optimal time period after intubation when physiological observations should be recorded, it is important to know the duration of, and factors that influence, this ANS response, in both health and disease. Methods: Fifty healthy subjects (27 males, median age 31.9 years, range 20-53 years) and 20 patients with Rome III defined functional chest pain (nine male, median age of 38.7 years, range 28-59 years) had personality traits and anxiety measured. Subjects had heart rate (HR), blood pressure (BP), sympathetic (cardiac sympathetic index, CSI), and parasympathetic nervous system (cardiac vagal tone, CVT) parameters measured at baseline and in response to per nasum intubation with an esophageal catheter. CSI/CVT recovery was measured following esophageal intubation. Key Results: In all subjects, esophageal intubation caused an elevation in HR, BP, CSI, and skin conductance response (SCR; all p < 0.0001) but concomitant CVT and cardiac sensitivity to the baroreflex (CSB) withdrawal (all p < 0.04). Multiple linear regression analysis demonstrated that longer CVT recovery times were independently associated with higher neuroticism (p < 0.001). Patients had prolonged CSI and CVT recovery times in comparison to healthy subjects (112.5 s vs 46.5 s, p = 0.0001 and 549 s vs 223.5 s, p = 0.0001, respectively). Conclusions & Inferences: Esophageal intubation activates a flight/flight ANS response. Future studies should allow for at least 10 min of recovery time. Consideration should be given to psychological traits and disease status as these can influence recovery. The psychological trait of neuroticism retards autonomic recovery following esophageal intubation in health and functional chest pain. © 2013 John Wiley & Sons Ltd.

Regional variation in peripapillary retinal blood flow in primary open angle glaucoma:a follow-up study

Purpose: To investigate whether regional long-term changes in peripapillary retinal flow, measured by scanning laser Doppler flowmetry (SLDF), occur in patients with primary open angle glaucoma (POAG). Methods: 31 healthy volunteers (mean age: 65 8.3 years) and 33 POAG patients (mean age: 71.2 7.6 years) were followed up every 4 months for 16 months. Using SLDF, three images of the superior and inferior optic nerve head were obtained for each subject. A 1010-pixel frame was used to measure blood flow, volume and velocity in the four quadrants of the peripapillary retina. Central 24-2 visual field testing was carried out at each visit. Repeated measures analysis of covariance was used to assess change over time between the normal and POAG groups for the SLDF parameters. Univariate linear regression analysis for mean deviation and glaucoma change probability (GCP) analysis were used to identify visual field progression. Results: Blood volume, flow and velocity measured in the inferior nasal quadrant of the peripapillary retina decreased significantly over time for the POAG group compared to the normal group (p=0.0073, 0.0097, 0.0095 respectively). Overall, 2 glaucoma patients showed a significantly deteriorating MD slope, while 7 patients showed visual field progression with GPA. All of the patients progressing with GPA, showed change in the superior hemifield and, of those, 14% showed change in the inferior hemifield. Conclusion: Glaucoma patients showed a decrease in blood flow, volume and velocity in the inferior nasal peripapillary retina. A regional variation in microvascular retinal capillary blood flow may provide insight into the pathogenesis of glaucomatous optic neuropathy. Keywords: 331 blood supply • 554 retina • 624 visual fields

Characterisation of baseline oscillation in congenital nystagmus eye movement recordings

Congenital nystagmus is an ocular-motor disorder that develops in the first few months of life; its pathogenesis is still unknown. Patients affected by congenital nystagmus show continuous, involuntary, rhythmical oscillations of the eyes. Monitoring eye movements, nystagmus main features such as shape, amplitude and frequency, can be extracted and analysed. Previous studies highlighted, in some cases, a much slower and smaller oscillation, which appears added up to the ordinary nystagmus waveform. This sort of baseline oscillation, or slow nystagmus, hinder precise cycle-to-cycle image placement onto the fovea. Such variability of the position may reduce patient visual acuity. This study aims to analyse more extensively eye movements recording including the baseline oscillation and investigate possible relationships between these slow oscillations and nystagmus. Almost 100 eye movement recordings (either infrared-oculographic or electrooculographic), relative to different gaze positions, belonging to 32 congenital nystagmus patients were analysed. The baseline oscillation was assumed sinusoidal; its amplitude and frequency were computed and compared with those of the nystagmus by means of a linear regression analysis. The results showed that baseline oscillations were characterised by an average frequency of 0.36 Hz (SD 0.11 Hz) and an average amplitude of 2.1° (SD 1.6°). It also resulted in a considerable correlation (R2 scored 0.78) between nystagmus amplitude and baseline oscillation amplitude; the latter, on average, resulted to be about one-half of the correspondent nystagmus amplitude. © 2009 Elsevier Ltd. All rights reserved.

Monocyte subpopulation counts and associations with left ventricular ejection fraction post ST elevation myocardial infarction

Background: Monocytes are implicated in the initiation and progression of the atherosclerotic plaque contributing to plaque instability and rupture. Little is known about the role of the three phenotypically and functionally different monocyte subpopulations in determining ventricular remodelling following ST elevation myocardial infarction (STEMI). Mon1 are the ‘classical’ monocytes with inflammatory action, whilst Mon3 are considered reparative with fibroblast deposition ability. The function of the newly described Mon2 subset is yet to be fully described. Method: STEMI patients (n=196, mean age 62±13 years; 72% male) treated with percutaneous revascularization were recruited within the first 24 h post-infarction. Peripheral blood monocyte subpopulations were enumerated and characterised using flow cytometry after staining for CD14, CD16 and CCR2. Phenotypically, monocyte subpopulations are defined as: CD14++CD16-CCR2+ (Mon1), CD14++CD16+CCR2+ (Mon2) and CD14+CD16++CCR2- (Mon3) cells. Transthoracic 2D echocardiography was performed within 7 days and at 6 months post infarct to assess ventricular volumes, mass, systolic, and diastolic functions as well as strain and strain rate. Results: Using linear regression analysis higher counts for Mon1, and lower counts for Mon2 and Mon3 were significantly associated with the baseline left ventricular ejection fraction (LVEF) within 7 days post infarct (table 1). At 6 months post STEMI lower counts of Mon2 remained positively associated with a decrease in LVEF at completion of remodelling (p=0.002). Conclusion: Peripheral monocytes of all three subsets correlate with LVEF after a myocardial infarction. High counts of the inflammatory Mon1 are associated with the reduced baseline ejection fraction post infarction. After remodelling, the convalescent ejection fraction was independently predicted by monocyte subpopulation 2. As lower counts depicted negative ventricular remodelling, this suggests a possible myofibroblast deposition and angiogenesis role for the newly described intermediate monocyte subpopulation Mon2 as opposed to the previously anticipated inflammatory role.

Monocyte subset counts associations with left ventricular systolic function post ST elevation myocardial infarction

Background: Monocytes are implicated in the initiation and progression of theatherosclerotic plaque contributing to plaque instability and rupture. Little is knownof the role played by the 3 phenotypically and functionally different monocytesubpopulations in determining ventricular remodeling following ST elevation my-ocardial infarction (STEMI). Mon1 are "classical" inflammatory monocytes, whilstMon3 are considered reparative with fibroblast deposition ability. The function ofthe newly described Mon2 is yet to be elucidated. Method: STEMI patients (n=196, mean age 62±13 years; 72% male) treatedwith percutaneous revascularization were recruited within the first 24 hours. Pe-ripheral blood monocyte subpopulations were enumerated and characterizedusing flow cytometry after staining for CD14, CD16 and CCR2. Phenotypi-cally, monocyte subpopulations are defined as: CD14+CD16-CCR2+ (Mon1),CD14+CD16+CCR+ (Mon2) and CD14lowCD16+CCR2- (Mon3) cells. Transtho-racic 2D echocardiography was performed within 7 days and 6 months post infarctto assess ventricular volumes, mass, systolic, and diastolic functions. Results: Using linear regression analysis higher counts for Mon1, and lowercounts for Mon2 and Mon3 were significantly associated with the baseline leftventricular ejection fraction (LVEF) within seven days post infarction. At 6 monthspost STEMI lower counts of Mon2 remained positively associated with decreasedLVEF (p value= 0.002).Monocyte subsets correlation with LVEFMonocytes mean florescence Baseline left ventricular Left ventricular ejectionintensity (cells/μl) ejection fraction (%) fraction (%) at 6 months post infarctβ-value P-valueβ-value P-valueTotal Mon0.31 P<0.001 0.360.009Mon 10.019 0.020.070.62Mon 2−0.28 0.001 −0.420.002Mon 3−0.27 0.001 −0.180.21 Conclusion: Peripheral monocytes of all three subsets correlate with LVEF af-ter a myocardial infarction. High counts of the inflammatory Mon1 are associatedwith reduction in the baseline LVEF. Post remodelling, the convalescent EF wasindependently predicted by monocyte subpopulation 2. As lower counts depictednegative ventricular remodeling, this suggests a reparative role for the newly de-scribed Mon2, possibly via myofibroblast deposition and angiogenesis, in contrastto an anticipated inflammatory role.

Statnote 27: Principal components analysis (PCA)

In Statnotes 24 and 25, multiple linear regression, a statistical method that examines the relationship between a single dependent variable (Y) and two or more independent variables (X), was described. The principle objective of such an analysis was to determine which of the X variables had a significant influence on Y and to construct an equation that predicts Y from the X variables. ‘Principal components analysis’ (PCA) and ‘factor analysis’ (FA) are also methods of examining the relationships between different variables but they differ from multiple regression in that no distinction is made between the dependent and independent variables, all variables being essentially treated the same. Originally, PCA and FA were regarded as distinct methods but in recent times they have been combined into a single analysis, PCA often being the first stage of a FA. The basic objective of a PCA/FA is to examine the relationships between the variables or the ‘structure’ of the variables and to determine whether these relationships can be explained by a smaller number of ‘factors’. This statnote describes the use of PCA/FA in the analysis of the differences between the DNA profiles of different MRSA strains introduced in Statnote 26.

Statnote 16: fitting a regression line to data

Fitting a linear regression to data provides much more information about the relationship between two variables than a simple correlation test. A goodness of fit test of the line should always be carried out. Hence, ‘r squared’ estimates the strength of the relationship between Y and X, ANOVA whether a statistically significant line is present, and the ‘t’ test whether the slope of the line is significantly different from zero. In addition, it is important to check whether the data fit the assumptions for regression analysis and, if not, whether a transformation of the Y and/or X variables is necessary.

Data methods in optometry. Part 6: fitting a regression line to data

1. Fitting a linear regression to data provides much more information about the relationship between two variables than a simple correlation test. A goodness of fit test of the line should always be carried out. Hence, r squared estimates the strength of the relationship between Y and X, ANOVA whether a statistically significant line is present, and the ‘t’ test whether the slope of the line is significantly different from zero. 2. Always check whether the data collected fit the assumptions for regression analysis and, if not, whether a transformation of the Y and/or X variables is necessary. 3. If the regression line is to be used for prediction, it is important to determine whether the prediction involves an individual y value or a mean. Care should be taken if predictions are made close to the extremities of the data and are subject to considerable error if x falls beyond the range of the data. Multiple predictions require correction of the P values. 3. If several individual regression lines have been calculated from a number of similar sets of data, consider whether they should be combined to form a single regression line. 4. If the data exhibit a degree of curvature, then fitting a higher-order polynomial curve may provide a better fit than a straight line. In this case, a test of whether the data depart significantly from a linear regression should be carried out.

Statistical analysis in microbiology:statnotes

This book is aimed primarily at microbiologists who are undertaking research and who require a basic knowledge of statistics to analyse their experimental data. Computer software employing a wide range of data analysis methods is widely available to experimental scientists. The availability of this software, however, makes it essential that investigators understand the basic principles of statistics. Statistical analysis of data can be complex with many different methods of approach, each of which applies in a particular experimental circumstance. Hence, it is possible to apply an incorrect statistical method to data and to draw the wrong conclusions from an experiment. The purpose of this book, which has its origin in a series of articles published in the Society for Applied Microbiology journal ‘The Microbiologist’, is an attempt to present the basic logic of statistics as clearly as possible and therefore, to dispel some of the myths that often surround the subject. The 28 ‘Statnotes’ deal with various topics that are likely to be encountered, including the nature of variables, the comparison of means of two or more groups, non-parametric statistics, analysis of variance, correlating variables, and more complex methods such as multiple linear regression and principal components analysis. In each case, the relevant statistical method is illustrated with examples drawn from experiments in microbiological research. The text incorporates a glossary of the most commonly used statistical terms and there are two appendices designed to aid the investigator in the selection of the most appropriate test.

Statnote 24: Multiple regression

In previous statnotes, the application of correlation and regression methods to the analysis of two variables (X,Y) was described. These methods can be used to determine whether there is a linear relationship between the two variables, whether the relationship is positive or negative, to test the degree of significance of the linear relationship, and to obtain an equation relating Y to X. This Statnote extends the methods of linear correlation and regression to situations where there are two or more X variables, i.e., 'multiple linear regression’.

Pronounced reduction of postprandial glucagon by lixisenatide:a meta-analysis of randomized clinical trials

Glucagon-like peptide-1 (GLP-1) receptor agonists improve islet function and delay gastric emptying in patients with type 2 diabetes mellitus (T2DM). This meta-analysis aimed to investigate the effects of the once-daily prandial GLP-1 receptor agonist lixisenatide on postprandial plasma glucose (PPG), glucagon and insulin levels. Methods: Six randomized, placebo-controlled studies of lixisenatide 20μg once daily were included in this analysis: lixisenatide as monotherapy (GetGoal-Mono), as add-on to oral antidiabetic drugs (OADs; GetGoal-M, GetGoal-S) or in combination with basal insulin (GetGoal-L, GetGoal-Duo-1 and GetGoal-L-Asia). Change in 2-h PPG and glucose excursion were evaluated across six studies. Change in 2-h glucagon and postprandial insulin were evaluated across two studies. A meta-analysis was performed on least square (LS) mean estimates obtained from analysis of covariance (ANCOVA)-based linear regression. Results: Lixisenatide significantly reduced 2-h PPG from baseline (LS mean difference vs. placebo: -4.9mmol/l, p<0.001) and glucose excursion (LS mean difference vs. placebo: -4.5mmol/l, p<0.001). As measured in two studies, lixisenatide also reduced postprandial glucagon (LS mean difference vs. placebo: -19.0ng/l, p<0.001) and insulin (LS mean difference vs. placebo: -64.8 pmol/l, p<0.001). There was a stronger correlation between 2-h postprandial glucagon and 2-h PPG with lixisenatide than with placebo. Conclusions: Lixisenatide significantly reduced 2-h PPG and glucose excursion together with a marked reduction in postprandial glucagon and insulin; thus, lixisenatide appears to have biological effects on blood glucose that are independent of increased insulin secretion. These effects may be, in part, attributed to reduced glucagon secretion. © 2014 John Wiley and Sons Ltd.