Prediction of HLA-DQ3.2 beta ligands: evidence of multiple registers in class II binding peptides

Motivation: While processing of MHC class II antigens for presentation to helper T-cells is essential for normal immune response, it is also implicated in the pathogenesis of autoimmune disorders and hypersensitivity reactions. Sequence-based computational techniques for predicting HLA-DQ binding peptides have encountered limited success, with few prediction techniques developed using three-dimensional models. Methods: We describe a structure-based prediction model for modeling peptide-DQ3.2 beta complexes. We have developed a rapid and accurate protocol for docking candidate peptides into the DQ3.2 beta receptor and a scoring function to discriminate binders from the background. The scoring function was rigorously trained, tested and validated using experimentally verified DQ3.2 beta binding and non-binding peptides obtained from biochemical and functional studies. Results: Our model predicts DQ3.2 beta binding peptides with high accuracy [area under the receiver operating characteristic (ROC) curve A(ROC) > 0.90], compared with experimental data. We investigated the binding patterns of DQ3.2 beta peptides and illustrate that several registers exist within a candidate binding peptide. Further analysis reveals that peptides with multiple registers occur predominantly for high-affinity binders.

SCOTROC 2A: Carboplatin followed by docetaxel or docetaxel gemcitabine as first-line chemotherapy for ovarian cancer

The feasibility of sequential carboplatin followed by docetaxel-based therapy for untreated ovarian cancer was determined. Patients received four q3w cycles of carboplatin AUC 7, then four q3w cycles of either docetaxel 100 mg m(-2) (day 1) (arm A); docetaxel 75 mg m(-2) (day 8) and gemcitabine 1250 mg m(-2) (days 1,8) (arm B) or docetaxel 25 mg m(-2) and gemcitabine 800 mg m(-2) (both given weekly (days 1,8,15)) (arm C). A total of 44 patients were randomised to each treatment arm. None of the arms demonstrated an eight cycle completion rate (70.5/72.7/45.5% in arms A/B/C, respectively), which was statistically greater than 60% (P = 0.102, P = 0.056, P = 0.982) which was our formal feasibility criteria, although only the completion rate in arm C was clearly worse than this level. The overall response rate (ORR) after carboplatin was 65.7% in 70 evaluable patients. In evaluable patients, ORRs after docetaxel-based cycles were: arm A 84.0% (21 out of 25); arm B 77.3% (17 out of 22); arm C 69.6% (16 out of 23). At follow-up (median 30 months), median progression-free survival times were: arm A 15.5 months (95% Cl: 10.5 - 20.6); arm B 18.1 months (95% Cl: 15.9 - 20.3); arm C, 13.7 months (95% Cl: 12.8 - 14.6). Neutropenia was the predominant grade 3 - 4 haematological toxicity: 77.8/85.7/54.4% in arms A/B/C, respectively. Dyspnoea was markedly increased in both gemcitabine-containing arms (P = 0.001) but was worse in arm C. Although just failing to rule out eight cycle completion rates less than 60%, within the statistical limitations of these small cohorts, the overall results for arms A and B are encouraging. Larger phase III studies are required to test these combinations.

Evaluating the properties of a stage-specific self-efficacy scale for physical activity using classical test theory, confirmatory factor analysis and item response modeling

The purpose of this paper was to evaluate the psychometric properties of a stage-specific selfefficacy scale for physical activity with classical test theory (CTT), confirmatory factor analysis (CFA) and item response modeling (IRM). Women who enrolled in the Women On The Move study completed a 20-item stage-specific self-efficacy scale developed for this study [n = 226, 51.1% African-American and 48.9% Hispanic women, mean age = 49.2 (67.0) years, mean body mass index = 29.7 (66.4)]. Three analyses were conducted: (i) a CTT item analysis, (ii) a CFA to validate the factor structure and (iii) an IRM analysis. The CTT item analysis and the CFA results showed that the scale had high internal consistency (ranging from 0.76 to 0.93) and a strong factor structure. Results also showed that the scale could be improved by modifying or eliminating some of the existing items without significantly altering the content of the scale. The IRM results also showed that the scale had few items that targeted high self-efficacy and the stage-specific assumption underlying the scale was rejected. In addition, the IRM analyses found that the five-point response format functioned more like a four-point response format. Overall, employing multiple methods to assess the psychometric properties of the stage-specific self-efficacy scale demonstrated the complimentary nature of these methods and it highlighted the strengths and weaknesses of this scale.

Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral genotype 1

Background: Interferon alpha (IFN-alpha) activated cellular signalling is negatively regulated by inhibitory factors, including the suppressor of cytokine signalling (SOCS) family. The effects of host factors such as obesity on hepatic expression of these inhibitory factors in subjects with chronic hepatitis C virus (HCV) are unknown. Objectives: To assess the independent effects of obesity, insulin resistance, and steatosis on response to IFN-alpha therapy and to determine hepatic expression of factors inhibiting IFN-alpha signalling in obese and nonobese subjects with chronic HCV. Methods: A total of 145 subjects were analysed to determine host factors associated with non-response to antiviral therapy. Treatment comprised IFN-alpha or peginterferon alpha, either alone or in combination with ribavirin. In a separate cohort of 73 patients, real time-polymerase chain reaction was performed to analyse hepatic mRNA expression. Immunohistochemistry for SOCS-3 was performed on liver biopsy samples from 38 patients with viral genotype 1 who had received antiviral treatment. Results: Non-response (NR) to treatment occurred in 55% of patients with HCV genotypes 1 or 4 and 22% with genotypes 2 or 3. Factors independently associated with NR were viral genotype 1/4 (p < 0.001), cirrhosis on pretreatment biopsy (p = 0.025), and body mass index >= 30 kg/m(2) (p = 0.010). Obese subjects with viral genotype 1 had increased hepatic mRNA expression of phosphoenolpyruvate carboxy kinase (p = 0.01) and SOCS-3 (p = 0.047), in comparison with lean subjects. Following multivariate analysis, SOCS-3 mRNA expression remained independently associated with obesity (p = 0.023). SOCS-3 immunoreactivity was significantly increased in obesity (p = 0.013) and in non-responders compared with responders (p = 0.014). Conclusions: In patients with chronic HCV viral genotype 1, increased expression of factors that inhibit interferon signalling may be one mechanism by which obesity reduces the biological response to IFN-alpha.

Searching for cancer deaths in Australia: National Death Index vs Cancer Registries

OBJECTIVE: To compare the accuracy, costs and utility of using the National Death Index (NDI) and state-based cancer registries in determining the mortality status of a cohort of women diagnosed with ovarian cancer in the early 1990s. METHODS: As part of a large prognostic study, identifying information on 822 women diagnosed with ovarian cancer between 1990 and 1993, was simultaneously submitted to the NDI and three state-based cancer registries to identify deceased women as of June 30, 1999. This was compared to the gold standard of "definite deaths". A comparative evaluation was also made of the time and costs associated with the two methods. RESULTS: Of the 450 definite deaths in our cohort the NDI correctly identified 417 and all of the 372 women known to be alive (sensitivity 93%, specificity 100%). Inconsistencies in identifiers recorded in our cohort files, particularly names, were responsible for the majority of known deaths not matching with the NDI, and if eliminated would increase the sensitivity to 98%. The cancer registries correctly identified 431 of the 450 definite deaths (sensitivity 96%). The costs associated with the NDI search were the same as the cancer registry searches, but the cancer registries took two months longer to conduct the searches. CONCLUSIONS AND IMPLICATIONS: This study indicates that the cancer registries are valuable, cost effective agencies for follow-up of mortality outcome in cancer cohorts, particularly where cohort members were residents of those states. For following large national cohorts the NDI provides additional information and flexibility when searching for deaths in Australia. This study also shows that women can be followed up for mortality with a high degree of accuracy using either service. Because each service makes a valuable contribution to the identification of deceased cancer subjects, both should be considered for optimal mortality follow-up in studies of cancer patients.

Genetic parameters and predicted response to selection for lean growth in an Australian commercial nucleus pig herd

Genetic parameters for performance traits in a pig population were estimated using a multi-trait derivative-free REML algorithm. The 2590 total data included 922 restrictively fed male and 1668 ad libitum fed female records. Estimates of heritability (standard error in parentheses) were 0.25 (0.03), 0.15 (0.03), and 0.30 (0.05) for lifetime daily gain, test daily gain, and P2-fat depth in males, respectively; and 0.27 (0.04) and 0.38 (0.05) for average daily gain and P2-fat depth in females, respectively. The genetic correlation between P2-fat depth and test daily gain in males was -0.17 (0.06) and between P2-fat and lifetime average daily gain in females 0.44 (0.09). Genetic correlations between sexes were 0.71 (0.11) for average daily gain and -0.30 (0.10) for P2-fat depth. Genetic response per standard deviation of selection on an index combining all traits was predicted at $AU120 per sow per year. Responses in daily gain and backfat were expected to be higher when using only male selection than when using only female selection. Selection for growth rate in males will improve growth rate and carcass leanness simultaneously.

Prediction of functional capacity in chronic heart failure patients using myocardial tissue Doppler

Background. Exercise therapy improves functional capacity in CHF, but selection and individualization of training would be helped by a simple non-invasive marker of peak VO2. Peak VO2 in these pts is difficult to predict without direct measurement, and LV ejection fraction is a poor predictor. Myocardial tissue velocities are less load-dependent, and may be predictive of the exercise response in CHF pts. We sought to use tissue velocity as a predictor of peak VO2 in CHF pts. Methods. Resting 2D-echocardiography and tissue Doppler imaging were performed in 182 CHF pts (159 male, age 62±10 years) before and after metabolic exercise testing. The majority of these patients (129, 71%) had an ischemic cardiomyopathy, with resting EF of 35±13% and a peak VO2 of 13.5±4.7 ml/kg/min. Results. Neither resting EF (r=0.15) nor peak EF (r=0.18, both p=NS) were correlated with peak VO2. However, peak VO2 correlated with peak systolic velocity in septal (Vss, r=0.31) and lateral walls (Vsl, r=0.26, both p=0.01). In a general linear model (r2 = 0.25), peak VO2 was calculated from the following equation: 9.6 + 0.68*Vss - 0.09*age + 0.06*maximum HR. This model proved to be a superior predictor of peak VO2 (r=0.51, p=0.01) than the standard prediction equations of Wasserman (r= -0.12, p=0.01). Conclusions. Resting tissue Doppler, age and maximum heart rate may be used to predict functional capacity in CHF patients. This may be of use in selecting and following the response to therapy, including for exercise training.

Changes of corneal biomechanics with keratoconus

PURPOSE: To perform advanced analysis of the corneal deformation response to air pressure in keratoconics compared with age- and sex-matched controls. METHODS: The ocular response analyzer was used to measure the air pressure-corneal deformation relationship of 37 patients with keratoconus and 37 age (mean 36 ± 10 years)- and sex-matched controls with healthy corneas. Four repeat air pressure-corneal deformation profiles were averaged, and 42 separate parameters relating to each element of the profiles were extracted. Corneal topography and pachymetry were performed with the Orbscan II. The severity of the keratoconus was graded based on a single metric derived from anterior corneal curvatures, difference in astigmatism in each meridian, anterior best-fit sphere, and posterior best-fit sphere. RESULTS: Most of the biomechanical characteristics of keratoconic eyes were significantly different from normal eyes (P <0.001), especially during the initial corneal applanation. With increasing keratoconus severity, the cornea was thinner (r = -0.407, P <0.001), the speed of corneal concave deformation past applanation was quicker (dive; r = -0.314, P = 0.01), and the tear film index was lower (r = -0.319, P = 0.01). The variance in keratoconus severity could be accounted for by the corneal curvature and central corneal thickness (r = 0.80) with biomechanical characteristics contributing an additional 4% (total r = 0.84). The area under the receiver operating characteristic curve was 0.919 ± 0.025 for keratometry alone, 0.965 ± 0.014 with the addition of pachymetry, and 0.972 ± 0.012 combined with ocular response analyzer biomechanical parameters. CONCLUSIONS: Characteristics of the air pressure-corneal deformation profile are more affected by keratoconus than the traditionally extracted corneal hysteresis and corneal resistance factors. These biomechanical metrics slightly improved the detection and severity prediction of keratoconus above traditional keratometric and pachymetric assessment of corneal shape.

Highly refractive index sensitive femtosecond laser inscribed long period gratings

The distinct behaviour of femtosecond laser inscribed long period gratings, with a non-uniform index perturbation within the optical fibre core, has been studied experimentally. The non-uniform laser-induced perturbation results in light coupling from the core mode to a greater number of cladding modes than is the case with their UV laser inscribed counterparts, and this is made evident from the surrounding refractive index (SRI) grating response. Femtosecond inscribed long period gratings are shown to simultaneously couple to multiple sets of cladding modes. A 400μm LPG is shown to result in attenuation peaks that have both blue and red wavelength shifts over a 1250nm to 1700nm wavelength range. This gives rise to SRI sensitivities far greater than anything achievable by monitoring a single attenuation peak. The maximum sensitivity produced by monitoring a single attenuation peak was 1106nm/RIU, whereas monitoring opposing wavelength shifts resulted in a significantly improved sensitivity of 1680nm/RIU. © 2011 Copyright Society of Photo-Optical Instrumentation Engineers (SPIE).

Stock price distributions and news:evidence from index options

We estimate the shape of the distribution of stock prices using data from options on the underlying asset, and test whether this distribution is distorted in a systematic manner each time a particular news event occurs. In particular we look at the response of the FTSE100 index to market wide announcements of key macroeconomic indicators and policy variables. We show that the whole distribution of stock prices can be distorted on an event day. The shift in distributional shape happens whether the event is characterized as an announcement occurrence or as a measured surprise. We find that larger surprises have proportionately greater impact, and that higher moments are more sensitive to events however characterised.

Fast response static var generator for improving the power system performance of an electric arc furnace (EAF)

Cascaded multilevel inverters-based Static Var Generators (SVGs) are FACTS equipment introduced for active and reactive power flow control. They eliminate the need for zigzag transformers and give a fast response. However, with regard to their application for flicker reduction in using Electric Arc Furnace (EAF), the existing multilevel inverter-based SVGs suffer from the following disadvantages. (1) To control the reactive power, an off-line calculation of Modulation Index (MI) is required to adjust the SVG output voltage. This slows down the transient response to the changes of reactive power; and (2) Random active power exchange may cause unbalance to the voltage of the d.c. link (HBI) capacitor when the reactive power control is done by adjusting the power angle d alone. To resolve these problems, a mathematical model of 11-level cascaded SVG, was developed. A new control strategy involving both MI (modulation index) and power angle (d) is proposed. A selected harmonics elimination method (SHEM) is taken for switching pattern calculations. To shorten the response time and simplify the controls system, feed forward neural networks are used for on-line computation of the switching patterns instead of using look-up tables. The proposed controller updates the MI and switching patterns once each line-cycle according to the sampled reactive power Qs. Meanwhile, the remainder reactive power (compensated by the MI) and the reactive power variations during the line-cycle will be continuously compensated by adjusting the power angles, d. The scheme senses both variables MI and d, and takes action through the inverter switching angle, qi. As a result, the proposed SVG is expected to give a faster and more accurate response than present designs allow. In support of the proposal there is a mathematical model for reactive powered distribution and a sensitivity matrix for voltage regulation assessment, MATLAB simulation results are provided to validate the proposed schemes. The performance with non-linear time varying loads is analysed and refers to a general review of flicker, of methods for measuring flickers due to arc furnace and means for mitigation.

The prediction of vibration in large electric machines

This thesis reports the development of a reliable method for the prediction of response to electromagnetically induced vibration in large electric machines. The machines of primary interest are DC ship-propulsion motors but much of the work reported has broader significance. The investigation has involved work in five principal areas. (1) The development and use of dynamic substructuring methods. (2) The development of special elements to represent individual machine components. (3) Laboratory scale investigations to establish empirical values for properties which affect machine vibration levels. (4) Experiments on machines on the factory test-bed to provide data for correlation with prediction. (5) Reasoning with regard to the effect of various design features. The limiting factor in producing good models for machines in vibration is the time required for an analysis to take place. Dynamic substructuring methods were adopted early in the project to maximise the efficiency of the analysis. A review of existing substructure- representation and composite-structure assembly methods includes comments on which are most suitable for this application. In three appendices to the main volume methods are presented which were developed by the author to accelerate analyses. Despite significant advances in this area, the limiting factor in machine analyses is still time. The representation of individual machine components was addressed as another means by which the time required for an analysis could be reduced. This has resulted in the development of special elements which are more efficient than their finite-element counterparts. The laboratory scale experiments reported were undertaken to establish empirical values for the properties of three distinct features - lamination stacks, bolted-flange joints in rings and cylinders and the shimmed pole-yoke joint. These are central to the preparation of an accurate machine model. The theoretical methods are tested numerically and correlated with tests on two machines (running and static). A system has been devised with which the general electromagnetic forcing may be split into its most fundamental components. This is used to draw some conclusions about the probable effects of various design features.

Simultaneous measurement of temperature and external refractive index by use of a hybrid grating in D fiber with enhanced sensitivity by HF etching

We propose a dual-parameter optical sensor device achieved by UV inscription of a hybrid long-period grating-fiber Bragg grating structure in D fiber. The hybrid configuration permits the detection of the temperature from the latter's response and measurement of the external refractive index from the former's response. In addition, the host D fiber permits effective modification of the device's sensitivity by cladding etching. The grating sensor has been used to measure the concentrations of aqueous sugar solutions, demonstrating its potential capability to detect concentration changes as small as 0.01%.

Autonomic response in depersonalisation disorder

Background Emotional-processing inhibition has been suggested as a mechanism underlying some of the clinical features of depersonalization and/or derealization. In this study, we tested the prediction that autonomic response to emotional stimuli would be reduced in patients with depersonalization disorder. Methods The skin conductance responses of 15 patients with chronic depersonalization disorder according to DSM-IV, 15 controls, and 11 individuals with anxiety disorders according to DSM-IV, were recorded in response to nonspecific elicitors (an unexpected clap and taking a sigh) and in response to 15 randomized pictures with different emotional valences: 5 unpleasant, 5 pleasant, and 5 neutral. Results The skin conductance response to unpleasant pictures was significantly reduced in patients with depersonalization disorder (magnitude of 0.017 µsiemens in controls and 0.103 µsiemens in patients with anxiety disorders; P = .01). Also, the latency of response to these stimuli was significantly prolonged in the group with depersonalization disorder (3.01 seconds compared with 2.5 and 2.1 seconds in the control and anxiety groups, respectively; P = .02). In contrast, latency to nonspecific stimuli (clap and sigh) was significantly shorter in the depersonalization and anxiety groups (1.6 seconds) than in controls (2.3 seconds) (P = .03). Conclusions In depersonalization disorder, autonomic response to unpleasant stimuli is reduced. The fact that patients with depersonalization disorder respond earlier to a startling noise suggests that they are in a heightened state of alertness and that the reduced response to unpleasant stimuli is caused by a selective inhibitory mechanism on emotional processing.

Fiber laser incorporating an intracavity micro-channel for refractive index and temperature sensing

In this letter, we present a standard linear cavity fiber laser incorporating a microchannel for refractive index (RI) and temperature sensing. The microchannel of ~6µm width created by femtosecond laser aided chemical etching provides an access to the external liquid; therefore, the laser cavity loss changes with the liquids of different RIs. Thus, at a fixed pump power, the output laser power will vary with the change of RI in the microchannel. The results show that the proposed sensing system has a linear response to both the surrounding medium RI and temperature. The RI sensitivity of the laser system is on the order of 10-3, while the temperature sensitivity is about 0.02 C. Both sensitivities could be further enhanced by employing a more sensitive photodetector and using higher pump power.