Results of a phase IIa clinical trial of an anti-inflammatory molecule, chaperonin 10, in multiple sclerosis

Background Chaperonin 10 (Cpn10) is a mitochondrial molecule involved in protein folding. The aim of this study was to determine the safety profile of Cpn10 in patients with multiple sclerosis (MS). Methods A total of 50 patients with relapse-remitting or secondary progressive MS were intravenously administered 5 mg or 10 mg of Cpn10 weekly for 12 weeks in a double-blind, randomized, placebo controlled, phase II trial. Clinical reviews, including Expanded Disability Status Scale and magnetic resonance imaging (MRI) with Gadolinium, were undertaken every 4 weeks. Stimulation of patient peripheral blood mononuclear cells with lipopolysaccharide ex vivo was used to measure the in vivo activity of Cpn10. Results No significant differences in the frequency of adverse events were seen between treatment and placebo arms. Leukocytes from both groups of Cpn10-treated patients produced significantly lower levels of critical proinflammatory cytokines. A trend toward improvement in new Gadolinium enhancing lesions on MRI was observed, but this difference was not statistically significant. No differences in clinical outcome measures were seen. Conclusions Cpn10 is safe and well tolerated when administered to patients with MS for 3 months, however, a further extended phase II study primarily focused on efficacy is warranted.

Current status of pharmacogenomics testing for anti-tumor drug therapies : approaches to non-melanoma skin cancer

Skin cancer is one of the most commonly occurring cancer types, with substantial social, physical, and financial burdens on both individuals and societies. Although the role of UV light in initiating skin cancer development has been well characterized, genetic studies continue to show that predisposing factors can influence an individual's susceptibility to skin cancer and response to treatment. In the future, it is hoped that genetic profiles, comprising a number of genetic markers collectively involved in skin cancer susceptibility and response to treatment or prognosis, will aid in more accurately informing practitioners' choices of treatment. Individualized treatment based on these profiles has the potential to increase the efficacy of treatments, saving both time and money for the patient by avoiding the need for extensive or repeated treatment. Increased treatment responses may in turn prevent recurrence of skin cancers, reducing the burden of this disease on society. Currently existing pharmacogenomic tests, such as those that assess variation in the metabolism of the anticancer drug fluorouracil, have the potential to reduce the toxic effects of anti-tumor drugs used in the treatment of non-melanoma skin cancer (NMSC) by determining individualized appropriate dosage. If the savings generated by reducing adverse events negate the costs of developing these tests, pharmacogenomic testing may increasingly inform personalized NMSC treatment.

Analysis of androgen and anti-androgen regulation of KLK-related peptidase 2, 3, and 4 alternative transcripts in prostate cancer

We assessed whether alternative transcripts (using KLK2, KLK3 and KLK4 as models) are differentially regulated by androgens and anti-androgens as an indicator of prostate cancers as they acquire treatment resistance. Using RNAseq of LNCaP cells treated with dihydrotestosterone, bicalutamide and enzalutamide, we show that the expression of variant KLK transcripts is markedly different to other variant transcripts at those loci. We also reveal that KLK variants are also over 2-fold more highly expressed in prostate cancers compared to their corresponding normal prostate. We propose that androgens and anti-androgens can activate specific variant transcripts of critical prostate cancer genes during treatment resistance

Does activity in computer game play have an impact on creative behavior?

This paper describes a behaviour analysis designed to measure the creative potential of computer game activities. The research approach applies a behavioural and verbal protocol to analyze the factors that influence the creative processes used by people as they play computer games from the puzzle genre. Creative components are measured by examining task motivation as well as domain-relevant and creativity-relevant skills factors. This paper focuses on how three puzzle games embody activity that might facilitate creative processes. The findings show that game playing activities significantly impact upon creative potential of computer games.

Physical activity, sedentary behavior and total wellness changes among sedentary adults : a 4-week randomized controlled trial

Background The construct of total wellness includes a holistic approach to the body, mind and spirit components of life. While the health benefits of reducing sedentary behavior and increasing physical activity are well documented, little is known about the influence on total wellness of an internet-based physical activity monitor designed to help people to achieve higher physical activity levels. Purpose The purpose of this four-week, personal activity monitor-based intervention program was to reduce sedentary behavior and increase physical activity levels in daily living for sedentary adults and to determine if these changes would also be associated with improvement in total wellness. Methods Twenty-two men and 11 women (27 years ± 4.0) were randomly assigned to either an intervention (n = 18) or control group (n = 15). The intervention group interacted with an online personal activity monitor (Gruve Solution™) designed to reduce sedentary time and increase physical activity during activities of daily living. The control group did not interact with the monitor, as they were asked to follow their normal daily physical activities and sedentary behavior routines. The Wellness Evaluation of Lifestyle (WEL) inventory was used to assess total wellness. Sedentary time, light, walking, moderate and vigorous intensity physical activities were assessed for both intervention and control groups at baseline and at week-4 by the 7-day Sedentary and Light Intensity Physical Activity Log (7-day SLIPA Log) and the International Physical Activity Questionnaire (IPAQ). Results Significant increases in pre-post total wellness scores (from 64% ± 5.7 to 75% ± 8.5) (t (17) = -6.5, p < 0.001) were observed in the intervention group by the end of week four. Intervention participants decreased their sedentary time (21%, 2.3 hours/day) and increased their light (36.7%, 2.5 hours/day), walking (65%, 1057 MET-min/week), moderate (67%, 455 MET-min/week) and vigorous intensity (60%, 442 MET-min/week) physical activity (all p < 0.001). No significant differences for total wellness were observed between the groups at baseline and no pre-post significant differences were observed for any outcome variable in the control group. Conclusion Total wellness is improved when sedentary, but sufficiently physically active adults, reduce sedentary time and increase physical activity levels (i.e. light, walking, moderate and vigorous).

Mice selectively bred for High and Low fear behavior show differences in the number of pMAPK (p44/42 ERK) expressing neurons in lateral amygdala following Pavlovian fear conditioning

Individual variability in the acquisition, consolidation and extinction of conditioned fear potentially contributes to the development of fear pathology including posttraumatic stress disorder (PTSD). Pavlovian fear conditioning is a key tool for the study of fundamental aspects of fear learning. Here, we used a selected mouse line of High and Low Pavlovian conditioned fear created from an advanced intercrossed line (AIL) in order to begin to identify the cellular basis of phenotypic divergence in Pavlovian fear conditioning. We investigated whether phosphorylated MAPK (p44/42 ERK/MAPK), a protein kinase required in the amygdala for the acquisition and consolidation of Pavlovian fear memory, is differentially expressed following Pavlovian fear learning in the High and Low fear lines. We found that following Pavlovian auditory fear conditioning, High and Low line mice differ in the number of pMAPK-expressing neurons in the dorsal sub nucleus of the lateral amygdala (LAd). In contrast, this difference was not detected in the ventral medial (LAvm) or ventral lateral (LAvl) amygdala sub nuclei or in control animals. We propose that this apparent increase in plasticity at a known locus of fear memory acquisition and consolidation relates to intrinsic differences between the two fear phenotypes. These data provide important insights into the micronetwork mechanisms encoding phenotypic differences in fear. Understanding the circuit level cellular and molecular mechanisms that underlie individual variability in fear learning is critical for the development of effective treatment of fear-related illnesses such as PTSD.

Examining gender differences in drivers' thoughts and feelings about different outcomes of speeding: Implications for future anti-speeding messages

Speeding remains a pervasive road safety problem, increasing both crash frequency and severity. Advertising countermeasures which aim to change individuals’ attitudes and behaviours are a key component in the array of countermeasures aimed at reducing this risky behaviour. Enhancing individuals’ perceptions of the personal relevance of such messages is important for increasing persuasiveness. This study examined what males and females reported as the most concerning aspects associated with (i) receiving a speeding fine, (ii) losing one’s license, and (iii) being involved in a crash. For each of these outcomes, a range of specific and appropriate aspects were assessed. For instance, in relation to receiving a fine, individuals reported the extent to which they would, for example, feel concerned about losing demerit points and paying more in insurance premiums. An online survey of 751 drivers (579 males; 16-79 years) was administered. When controlling for age, overall significant gender differences were found in relation to two of the three outcomes; receiving a fine and being in a crash. Follow-up tests of univariate effects revealed that females consistently reported being significantly more concerned than males on all aspects. Thus, for being fined, females were significantly more concerned with, for example, being caught and receiving a ticket in the mail; while, for being in a crash, specific aspects included, for example, injuring/killing oneself and seeing oneself as not a good/safe driver. The findings are discussed in terms of their implications for developing well-targeted messages aimed at discouraging drivers from speeding.

Induction of multiple reinstatements of ethanol- and sucrose-seeking behavior in Long–Evans rats by the α-2 adrenoreceptor antagonist yohimbine

Rationale Developing models to efficiently explore the mechanisms by which stress can mediate reinstatement of drug-seeking behavior is crucial to the development of new pharmacotherapies for alcohol use disorders. Objectives We examined the effects of multiple reinstatement sessions using the pharmacological stressor, yohimbine, in ethanol- and sucrose-seeking rats in order to develop a more efficient model of stress-induced reinstatement. Methods Long–Evans rats were trained to self-administer 10% ethanol with a sucrose-fading procedure, 20% ethanol without a sucrose-fading procedure, or 5% sucrose in 30-min operant self-administration sessions, followed by extinction training. After reaching extinction criteria, the animals were tested once per week with yohimbine vehicle and yohimbine (2 mg/kg), respectively, 30 min prior to the reinstatement sessions or blood collection. Levels of reinstatement and plasma corticosterone (CORT) were determined each week for four consecutive weeks. Results Yohimbine induced reinstatement of ethanol- and sucrose-seeking in each of the 4 weeks. Interestingly, the magnitude of the reinstatement decreased for the 10% ethanol group after the first reinstatement session but remained stable for the 20% ethanol group trained without sucrose. Plasma CORT levels in response to injection of both vehicle and yohimbine were significantly higher in the ethanol-trained animals compared to sucrose controls. Conclusions The stable reinstatement in the 20% ethanol group supports the use of this training procedure in studies using within-subject designs with multiple yohimbine reinstatement test sessions. Additionally, these results indicate that the hormonal response to stressors can be altered following extinction from self-administration of relatively modest amounts of ethanol.

Discounts and consumer search behavior : the role of framing

This paper studies the pure framing effect of price discounts, focusing on its impact on consumer search behavior. In a simple two-shop search experiment, we compare search behavior in base treatments (where both shops post net prices without discounts) to discount treatments (where either the first shop or the second shop posts gross prices with separate discount offers, keeping the net prices constant). Although the objective search problems are identical across treatments, subjects search less in discount frames, irrespective where the discount is offered. There is evidence showing that subjects only base their decisions on salient characteristics of the situation rather than on the objective price information.

Computer-assisted measurements of coronal knee joint laxity in vitro are related to low-stress behavior rather than structural properties of the collateral ligaments

The relationship between coronal knee laxity and the restraining properties of the collateral ligaments remains unknown. This study investigated correlations between the structural properties of the collateral ligaments and stress angles used in computer-assisted total knee arthroplasty (TKA), measured with an optically based navigation system. Ten fresh-frozen cadaveric knees (mean age: 81 ± 11 years) were dissected to leave the menisci, cruciate ligaments, posterior joint capsule and collateral ligaments. The resected femur and tibia were rigidly secured within a test system which permitted kinematic registration of the knee using a commercially available image-free navigation system. Frontal plane knee alignment and varus-valgus stress angles were acquired. The force applied during varus-valgus testing was quantified. Medial and lateral bone-collateral ligament-bone specimens were then prepared, mounted within a uni-axial materials testing machine, and extended to failure. Force and displacement data were used to calculate the principal structural properties of the ligaments. The mean varus laxity was 4 ± 1° and the mean valgus laxity was 4 ± 2°. The corresponding mean manual force applied was 10 ± 3 N and 11 ± 4 N, respectively. While measures of knee laxity were independent of the ultimate tensile strength and stiffness of the collateral ligaments, there was a significant correlation between the force applied during stress testing and the instantaneous stiffness of the medial (r = 0.91, p = 0.001) and lateral (r = 0.68, p = 0.04) collateral ligaments. These findings suggest that clinicians may perceive a rate of change of ligament stiffness as the end-point during assessment of collateral knee laxity.

Testing an extended theory of planned behavior to predict young people's intentions to join a bone marrow donor registry

An extended theory of planned behavior (TPB) was used to understand the factors, particularly control perceptions and affective reactions, given conflicting findings in previous research, informing younger people's intentions to join a bone marrow registry. Participants (N  = 174) completed attitude, subjective norm, perceived behavioral control (PBC), moral norm, anticipated regret, self-identity, and intention items for registering. The extended TPB (except PBC) explained 67.2% of variance in intention. Further testing is needed as to the volitional nature of registering. Moral norm, anticipated regret, and self-identity are likely intervention targets for increasing younger people's bone marrow registry participation.

Donating blood and organs : using an extended theory of planned behavior perspective to identify similarities and differences in individual motivations to donate

Due to the critical shortage and continued need of blood and organ donations (ODs), research exploring similarities and differences in the motivational determinants of these behaviors is needed. In a sample of 258 university students, we used a cross-sectional design to test the utility of an extended theory of planned behavior (TPB) including moral norm, self-identity and in-group altruism (family/close friends and ethnic group), to predict people’s blood and OD intentions. Overall, the extended TPB explained 77.0% and 74.6% of variance in blood and OD intentions, respectively. In regression analyses, common contributors to intentions across donation contexts were attitude, self-efficacy and self-identity. Normative influences varied with subjective norm as a significant predictor related to OD intentions but not blood donation intentions at the final step of regression analyses. Moral norm did not contribute significantly to blood or OD intentions. In-group altruism (family/close friends) was significantly related to OD intentions only in regressions. Future donation strategies should increase confidence to donate, foster a perception of self as the type of person who donates blood and/or organs, and address preferences to donate organs to in-group members only.

Modeling users’ web search behavior and their cognitive styles

Previous studies have shown that users’ cognitive styles play an important role during Web searching. However, only limited studies have showed the relationship between cognitive styles and Web search behavior. Most importantly, it is not clear which components of Web search behavior are influenced by cognitive styles. This paper examines the relationships between users’ cognitive styles and their Web searching and develops a model that portrays the relationship. The study uses qualitative and quantitative analyses to inform the study results based on data gathered from 50 participants. A questionnaire was utilised to collect participants’ demographic information, and Riding’s (1991) Cognitive Style Analysis (CSA) test to assess their cognitive styles. Results show that users’ cognitive styles influenced their information searching strategies, query reformulation behaviour, Web navigational styles and information processing approaches. The user model developed in this study depicts the fundamental relationships between users’ Web search behavior and their cognitive styles. Modeling Web search behavior with a greater understanding of user’s cognitive styles can help information science researchers and information systems designers to bridge the semantic gap between the user and the systems. Implications of the research for theory and practice, and future work are discussed.

Bounded rationality and voting decisions over 160 years : voter behavior and increasing complexity in decision-making

Using a quasi-natural voting experiment encompassing a 160-year period (1848–2009) in Switzerland, we investigate whether a higher level of complexity leads to increased reliance on trusted parliamentary representatives. We find that when more referenda are held on the same day, constituents are more likely to refer to parliamentary recommendations when making their decisions. This finding holds true even when we narrow our focus to referenda with a relatively lower voter turnout on days on which more than one referendum is held. We also demonstrate that when constituents face a higher level of complexity, they follow the parliamentary recommendations rather than those of interest groups. "Viewed as a geometric figure, the ant’s path is irregular, complex, hard to describe. But its complexity is really a complexity in the surface of the beach, not a complexity in the ant." ([1] p. 51)

Hyperelastic constitutive relationship for the strain-rate dependent behavior of shoulder and other joint cartilages

Non-linear finite deformations of articular cartilages under physiological loading conditions can be attributed to hyperelastic behavior. This paper contains experimental results of indentation tests in finite deformation and proposes an empirical based new generalized hyperelastic constitutive model to account for strain-rate dependency for humeral head cartilage tissues. The generalized model is based on existing hyperelastic constitutive relationships that are extensively used to represent biological tissues in biomechanical literature. The experimental results were obtained for three loading velocities, corresponding to low (1x10-3 s-1), moderate and high strain-rates (1x10-1 s-1), which represent physiological loading rates that are experienced in daily activities such as lifting, holding objects and sporting activities. Hyperelastic material parameters were identified by non linear curve fitting procedure. Analysis demonstrated that the material behavior of cartilage can be effectively decoupled into strain-rate independent(elastic) and dependent parts. Further, experiments conducted using different indenters indicated that the parameters obtained are significantly affected by the indenter size, potentially due to structural inhomogeneity of the tissue. The hyperelastic constitutive model developed in this paper opens a new avenue for the exploration of material properties of cartilage tissues.