Pegylated peptides. V. Carboxy-terminal PEGylated analogs of growth hormone-releasing factor (GRF) display enhanced duration of biological activity in vivo

In the present study, human growth hormone-releasing factor (hGRF) and analogs were successfully pegylated at the carboxy-terminus using a novel solid- and solution-phase strategy. Following synthesis, these pegylated hGRF analogs were evaluated for in vitro and in vivo biological activity. Specifically, hGRF (1-29)-NH2, [Ala15]-hGRF (1-29)-NH2, [desNH2Tyr1, D-Ala2, Ala15]-hGRF(1-29)-NH2 and [His1, Val2, Gln8, Ala15, Leu27]-hGRF(1-32)-OH were each C-terminally extended using a Gly-Gly-Cys-NH2 spacer (previously demonstrated not to alter intrinsic biological activity), and then monopegylated via coupling to an activated dithiopyridyl-PEG reagent. PEG moieties of 750, 2000, 5000 or 10,000 molecular weight (MW) were examined to determine the effect of polymer weight on activity. Initial biological evaluations in vitro revealed that all C-terminally pegylated hGRF analogs retained high growth hormone (GH)-releasing potencies, regardless of the MW of PEG polymer employed. Two of these pegylated hGRF analogs, [desNH2Tyr1, D-Ala2, Ala15]-hGRF (1-29)-Gly-Gly-Cys(NH2)-S-Nle-PEG5000 and [His1, Val2, Gln8, Ala15, Leu27]-hGRF(1-32)-Gly-Cys(NH2)-S-Nle-PEG5000, were subsequently evaluated in both pig and mouse models and found to be highly potent (in vivo potency range = 12-55-fold that of native hGRF). Relative to their non-pegylated counterparts, these two pegylated hGRF analogs exhibited enhanced duration of activity.     

Mechanical and fracture behavior of an artificially ultraviolet‐irradiated poly(ethylene‐carbon monoxide) copolymer

In this work, 1 wt % carbon monoxide (CO) poly(ethylene‐carbon monoxide) (ECO) copolymer sheets were artificially exposed to ultraviolet (UV) light with a power density of 3 mW/cm² for up to 130 h. A thorough mechanical characterization of the irradiated material was conducted, in which both the stress–strain data and the values of the quasistatic crack initiation and growth toughness were measured and correlated with companion uniaxial tensile tests and single‐edge‐notched fracture tests. Average values of the elastic modulus, failure strain, and failure stress were determined from the tensile tests. The full‐field optical technique of digital image correlation was used to quantify in‐plane deformation (displacements and displacement gradients) during the fracture experiments and to extract values of the crack initiation and growth fracture toughness. The elastic modulus increased monotonically with UV irradiation for the exposure times used in this investigation. In addition, for low irradiation times of less than 5 h, both the failure strain and failure stress of ECO decreased, and this caused a corresponding decrease in the crack initiation and growth toughness. However, for longer irradiation times, the failure strain remained almost invariable, whereas the failure stress increased by about 25% over that of unirradiated ECO. As a result, for longer irradiation times (>5 h), 1 wt % CO ECO became not only stiffer but also stronger and tougher, as quantified by companion fracture experiments. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 92: 139–148, 2004     

Effects of bombardment on optical properties during the deposition of silicon nitride by reactive ion-beam sputtering

Thin silicon nitride (Si(1_x)N(x)) films were synthesized without substrate heating by means of reactive argon-ion sputtering of either silicon or a silicon nitride target in the 1000-1500-eV energy range at a nitrogen partial pressure of 1.3 × 10(-2) Pa and with simultaneous nitrogen ion-assisted bombardment in the 300-500-eV low energy range. The extinction coefficient and refractive index of the films were directly dependent on the N(+) ion-to-atom arrival ratio, assisted ion energy, film growth rate, and indicated a correlation with film stoichiometry and disorder. Si(3)N(4) films were obtained for N(+) ion/Si atom arrival ratios from 0.6 to 1.7 and for different Si:N atom arrival rates and had a refractive index as high as 2.04 (633 nm) and a low hydrogen content as indicated by IR spectra.     

A process model of cyberbullying in adolescence

Cyberbullying is an emerging form of aggression that utilizes information and communication technologies (ICTs). While cyberbullying incidents attract considerable attention, research on the causes and psychosocial predictors of cyberbullying is still limited. The present study used an integrated theoretical model incorporating empathy, moral disengagement, and social cognitions related to cyberbullying. Structured questionnaires were administered to 355 randomly selected adolescents (M = 14.7, SD = 1.20). Linear regression analysis showed that social norms, prototype similarity and situational self-efficacy directly predicted cyberbullying expectations. Multiple mediation modelling indicated that normative influences mediated the effects of moral disengagement and affective empathy on cyberbullying expectations. These findings provide valuable information regarding the effect of both distal and proximal risk factors for cyberbullying in adolescence, highlight the relationship between normative processes and moral self-regulation, and set the basis for related educational and preventive interventions.     

Predicting Greek adolescents’ intentions to smoke: A focus on normative processes.

Objective: To examine the effects of normative influences on adolescent smoking in Greece, a country with weak social norms against smoking and relatively ineffective tobacco control policies. Design: A cross-sectional survey methodology was employed, and a representative sample of Greek high school students was recruited (N = 1,920, M age = 14 years). Main Outcome Measures: Normative beliefs, attitudes, perceived behavioral control, self-esteem, and intentions to smoke. Results: Multiple-regression and mediation analyses were conducted. The effects of public smoking on intentions to smoke were mediated by beliefs of perceived prevalence of smoking among peers, subjective norms, and situational temptations. Self-esteem significantly moderated the effects of subjective norms on intentions to smoke. Conclusions: Prosmoking norms in one’s environment become internalized into biased normative beliefs about smoking, and increase susceptibility to smoke under social pressure. The effect of subjective norms on intentions to smoke was stronger among adolescents with low self-esteem, suggesting that self-esteem may act as a vulnerability factor in the process of smoking initiation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Amplitude Variability in Simulated Incoherent Seismic Ground Motions

This note compares in detail four commonly used schemes for the simulation of spatially variable ground motions. Emphasis is placed not only on the conformity of the simulations with the power and cross spectral density of the random field but, also, on the examination of the consistency of the simulations with the homogeneity condition, and the (Fourier) amplitude variability of the simulations. It is shown that, whereas three techniques that simulate ground motions in parallel satisfy the homogeneity requirement, produce simulations with random amplitudes, and amplitude and phase variability consistent with that of recorded data, one technique that simulates motions in sequence does not.     

Clinical and economic outcome of patients undergoing tracheostomy for prolonged mechanical ventilation in New York state during 1993: analysis of 6,353 cases under diagnosis-related group 483

OBJECTIVE: To examine and describe the relation between age and disposition in patients undergoing tracheostomy. DESIGN: Retrospective analysis of a statewide database. SETTING: All acute care hospitals in New York state. PATIENTS: All patients (n = 6,353) > or = 18 yrs of age who were discharged from the hospital during 1993 with a final diagnosis-related groups code of 483. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The final disposition, according to six disposition codes (other acute care facility, residential healthcare facility, other healthcare facility, home, home healthcare services, and death) was examined for the entire population. Cost per case was assumed to equal the average statewide Medicaid rate. An inverse relation between survival rate and age was observed, which resulted in an age-related increased cost per survivor. Also, survivors in older age groups had an increased rate of discharge to residential healthcare facilities. There was a negative, albeit less marked, effect of older age on the rates of survivors discharged to home and to other healthcare facilities. CONCLUSIONS: Care of patients who undergo tracheostomy for prolonged mechanical ventilation is expensive. The older the patient, the less satisfactory the outcome from an economic, clinical, and possibly social perspective.     

Spectral density estimation of stochastic vector processes

A spectral density matrix estimator for stationary stochastic vector processes is studied. As the duration of the analyzed data tends to infinity, the probability distribution for this estimator at each frequency approaches a complex Wishart distribution with mean equal to an aliased version of the power spectral density at that frequency. It is shown that the spectral density matrix estimators corresponding to different frequencies are asymptotically statistically independent. These properties hold for general stationary vector processes, not only Gaussian processes, and they allow efficient calculation of updated probabilities when formulating a Bayesian model updating problem in the frequency domain using response data. A three-degree-of-freedom Duffing oscillator is used to verify the results.     

Domain Decomposition Method for Calculating the Failure Probability of Linear Dynamic Systems Subjected to Gaussian Stochastic Loads

In this paper the problem of calculating the probability of failure of linear dynamic systems subjected to random vibrations is considered. This is a very important and challenging problem in structural reliability. The failure domain in this case can be described as a union of linear failure domains whose boundaries are hyperplanes. Each linear limit state function can be completely described by its own design point, which can be analytically determined, allowing for an exact analytical calculation of the corresponding failure probability. The difficulty in calculating the overall failure probability arises from the overlapping of the different linear failure domains, the degree of which is unknown and needs to be determined. A novel robust reliability methodology, referred to as the domain decomposition method (DDM), is proposed to calculate the probability that the response of a linear system exceeds specified target thresholds. It exploits the special structure of the failure domain, given by the union of a large number of linear failure regions, to obtain an extremely efficient and highly accurate estimate of the failure probability. The number of dynamic analyses to be performed in order to determine the failure probability is as low as the number of independent random excitations driving the system. Furthermore, calculating the reliability of the same structure under different performance objectives does not require any additional dynamic analyses. Two numerical examples are given demonstrating the proposed method, both of which show that the method offers dramatic improvement over standard Monte Carlo simulations, while a comparison with the ISEE algorithm shows that the DDM is at least as efficient as the ISEE.     

Disposition of aerosolized liposomal amphotericin B

Amphotericin B (AmB) is an important drug for the treatment of fungal infection, but toxicity limits the lung tissue doses which may be achieved through intravenous administration. Although incorporation of AmB in liposomes reduces these effects and increases the therapeutic index for intravenous administration, targeted delivery to lung tissues via inhaled liposomal AmB aerosol may be a more effective approach. Aerosolization of liposomal amphotericin B targets the lungs, the organs first infested by many fungi. Development of optimal aerosolized liposomal AmB therapies requires a better understanding of the effect that liposome surface charge has on lung clearance kinetics. In this work we evaluated the clearance kinetics and organ distribution of inhaled liposomal AmB in male Balb/C mice. Mice were exposed via nose only to AmB-containing liposomal aerosols having positive, negative, or neutral surface charge characteristics. The formulations were aerosolized using a Collison nebulizer. Groups of animals were euthanized at predetermined times and the lungs and other organs were analyzed for AmB. AmB was not detected in serum and other organs such as kidneys, liver, and brain. The disposition of neutral and positive liposomal amphotericin B in lungs followed biexponential kinetics. The alpha and beta phase half-lives for positive liposomes were 1.3 and 15.1 days, respectively, and 2.3 and 22 days for neutral liposomes. AmB delivered via negative liposomes exhibited monoexponential clearance with a half-life of 4.5 days. These results suggest that toxic side effects in nontarget tissues are minimal and may indicate a potential for long term protection against fungal infections.