Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine

This article has been made available through the Brunel Open Access Publishing Fund.Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 μg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (HTPCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the HTPC range, whereas no effects were observed at plasma concentrations below the HTPCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation

Auditory presentation and synchronization in Adobe Flash and HTML5/JavaScript Web experiments

Substantial recent research has examined the accuracy of presentation durations and response time measurements for visually presented stimuli in Web-based experiments, with a general conclusion that accuracy is acceptable for most kinds of experiments. However, many areas of behavioral research use auditory stimuli instead of, or in addition to, visual stimuli. Much less is known about auditory accuracy using standard Web-based testing procedures. We used a millisecond-accurate Black Box Toolkit to measure the actual durations of auditory stimuli and the synchronization of auditory and visual presentation onsets. We examined the distribution of timings for 100 presentations of auditory and visual stimuli across two computers with difference specs, three commonly used browsers, and code written in either Adobe Flash or JavaScript. We also examined different coding options for attempting to synchronize the auditory and visual onsets. Overall, we found that auditory durations were very consistent, but that the lags between visual and auditory onsets varied substantially across browsers and computer systems

Prior Mating Experience Modulates the Dispersal of Drosophila in Males More Than in Females

Cues from both an animal’s internal physiological state and its local environment may influence its decision to disperse. However, identifying and quantifying the causative factors underlying the initiation of dispersal is difficult in uncontrolled natural settings. In this study, we automatically monitored the movement of fruit flies and examined the influence of food availability, sex, and reproductive status on their dispersal between laboratory environments. In general, flies with mating experience behave as if they are hungrier than virgin flies, leaving at a greater rate when food is unavailable and staying longer when it is available. Males dispersed at a higher rate and were more active than females when food was unavailable, but tended to stay longer in environments containing food than did females. We found no significant relationship between weight and activity, suggesting the behavioral differences between males and females are caused by an intrinsic factor relating to the sex of a fly and not simply its body size. Finally, we observed a significant difference between the dispersal of the natural isolate used throughout this study and the widely-used laboratory strain, Canton-S, and show that the difference cannot be explained by allelic differences in the foraging gene

Carbon stable isotope analysis of cereal remains as a way to reconstruct water availability: preliminary results

Reconstructing past water availability, both as rainfall and irrigation, is important to answer questions about the way society reacts to climate and its changes and the role of irrigation in the development of social complexity. Carbon stable isotope analysis of archaeobotanical remains is a potentially valuable method for reconstructing water availability. To further define the relationship between water availability and plant carbon isotope composition and to set up baseline values for the Southern Levant, grains of experimentally grown barley and sorghum were studied. The cereal crops were grown at three stations under five different irrigation regimes in Jordan. Results indicate that a positive but weak relationship exists between irrigation regime and total water input of barley grains, but no relationship was found for sorghum. The relationship for barley is site-specific and inter-annual variation was present at Deir ‘Alla, but not at Ramtha and Khirbet as-Samra

Characteristic Evolution and Matching

I review the development of numerical evolution codes for general relativity based upon the characteristic initial value problem. Progress in characteristic evolution is traced from the early stage of 1D feasibility studies to 2D axisymmetric codes that accurately simulate the oscillations and gravitational collapse of relativistic stars and to current 3D codes that provide pieces of a binary black hole spacetime. Cauchy codes have now been successful at simulating all aspects of the binary black hole problem inside an artificially constructed outer boundary. A prime application of characteristic evolution is to extend such simulations to null infinity where the waveform from the binary inspiral and merger can be unambiguously computed. This has now been accomplished by Cauchy-characteristic extraction, where data for the characteristic evolution is supplied by Cauchy data on an extraction worldtube inside the artificial outer boundary. The ultimate application of characteristic evolution is to eliminate the role of this outer boundary by constructing a global solution via Cauchy-characteristic matching. Progress in this direction is discussed.Comment: New version to appear in Living Reviews 2012. arXiv admin note: updated version of arXiv:gr-qc/050809

Depression symptomatology and diagnosis: discordance between patients and physicians in primary care settings

<p>Abstract</p> <p>Background</p> <p>To examine the agreement between depression symptoms using an assessment tool (PHQ-9), and physician documentation of the same symptoms during a clinic visit, and then to examine how the presence of these symptoms affects depression diagnosis in primary care settings.</p> <p>Methods</p> <p>Interviewer administered surveys and medical record reviews. A total of 304 participants were recruited from 2321 participants screened for depression at two large urban primary care community settings.</p> <p>Results</p> <p>Of the 2321 participants screened for depression 304 were positive for depression and of these 75.3% (n = 229) were significantly depressed (PHQ-9 score ≥ 10). Of these, 31.0% were diagnosed by a physician with a depressive disorder. A total of 57.6% (n = 175) of study participants had both significant depression symptoms and functional impairment. Of these 37.7% were diagnosed by physicians as depressed. Cohen's Kappa analysis, used to determine the agreement between depression symptoms elicited using the PHQ-9 and physician documentation of these symptoms showed only slight agreement (0.001–0.101) for all depression symptoms using standard agreement rating scales. Further analysis showed that only suicidal ideation and hypersomnia or insomnia were associated with an increased likelihood of physician depression diagnosis (OR 5.41 P sig < .01 and (OR 2.02 P sig < .05 respectively). Other depression symptoms and chronic medical conditions had no affect on physician depression diagnosis.</p> <p>Conclusion</p> <p>Two-thirds of individuals with depression are undiagnosed in primary care settings. While functional impairment increases the rate of physician diagnosis of depression, the agreement between a structured assessment and physician elicited and or documented symptoms during a clinical encounter is very low. Suicidality, hypersomnia and insomnia are associated with an increase in the rate of depression diagnosis even when physician and self report of the symptom differ. Interventions that emphasize the use of routine structured screening of primary care patients might also improve the rate of diagnosis of depression in these settings. Further studies are needed to explore depression symptom assessment during physician patient encounter in primary care settings.</p

Dihydrotestosterone Ameliorates Degeneration in Muscle, Axons and Motoneurons and Improves Motor Function in Amyotrophic Lateral Sclerosis Model Mice

Amyotrophic lateral sclerosis (ALS) is a lethal disease characterized by a progressive loss of motoneurons. The clinical symptoms include skeletal muscle weakness and atrophy, which impairs motor performance and eventually leads to respiratory failure. We tested whether dihydrotestosterone (DHT), which has both anabolic effects on muscle and neuroprotective effects on axons and motoneurons, can ameliorate clinical symptoms in ALS. A silastic tube containing DHT crystals was implanted subcutaneously in SOD1-G93A mice at early symptomatic age when decreases in body weight and grip-strength were observed as compared to wild-type mice. DHT-treated SOD1-G93A mice demonstrated ameliorated muscle atrophy and increased body weight, which was associated with stronger grip-strength. DHT treatment increased the expression of insulin-like growth factor-1 in muscle, which can exert myotrophic as well as neurotrophic effects through retrograde transport. DHT treatment attenuated neuromuscular junction denervation, and axonal and motoneuron loss. DHT-treated SOD1-G93A mice demonstrated improvement in motor behavior as assessed by rota-rod and gait analyses, and an increased lifespan. Application of DHT is a relatively simple and non-invasive procedure, which may be translated into therapy to improve the quality of life for ALS patients

Effects of a 105 hours psychological training program on attitudes, communication skills and occupational stress in oncology: a randomised study

There is today a wide consensus regarding the need to improve communication skills (CS) of health-care professionals (HCPs) dealing with cancer patients. Psychological training programs (PTPs) may be useful to acquire the needed CS. Testing the efficacy of PTP will allow to define their optimal content. The present study was designed to assess the impact of a PTP on HCP stress, attitudes and CS, and on HCP and patients' satisfaction with HCP communication skills in a randomised study. A total of 115 oncology nurses were randomly assigned to a 105-h PTP or to a waiting list. Stress was assessed with the Nursing Stress Scale, attitudes with a Semantic Differential Questionnaire, CS used during one simulated and one actual patient interview with the Cancer Research Campaign Workshop Evaluation Manual, and satisfaction with the nurses' CS with a questionnaire completed by the patients and the nurses. Trained (TG) and control (CG) groups were compared at baseline, after 3 months (just following training for TG) and after 6 months (3 months after the end of training for TG). Compared to controls, trained nurses reported positive changes on their stress levels (P</=0.05) and on their attitudes (P</=0.05). Positive training effects were found on CS used during the simulated interview: a significant increase in facilitative behaviours (open questions: P</=0.001; evaluative functions: P</=0.05) and a significant decrease in inhibitory behaviours (inappropriate information: P</=0.01; false reassurance: P</=0.05). Less positive training effects were found regarding interviews with a cancer patient: a significant increase in educated guesses (P</=0.001) was noticed. No training effect was observed on nurses' satisfaction levels, but a positive training effect was found on patients' satisfaction levels (P</=0.01). Although results outline PTP efficacy, they indicate the need to design PTP, amplifying the transfer of learned CS to clinical practice.info:eu-repo/semantics/publishe

Health-related physical fitness of adolescents and young adults with myelomeningocele

To assess components of health-related physical fitness in adolescents and young adults with myelomeningocele (MMC), and to study relations between aerobic capacity and other health-related physical fitness components. This cross-sectional study included 50 adolescents and young adults with MMC, aged 16–30 years (25 males). Aerobic capacity was quantified by measuring peak oxygen uptake (peakVO2) during a maximal exercise test on a cycle or arm ergometer depending on the main mode of ambulation. Muscle strength of upper and lower extremity muscles was assessed using a hand-held dynamometer. Regarding flexibility, we assessed mobility of hip, knee and ankle joints. Body composition was assessed by measuring thickness of four skin-folds. Relations were studied using linear regression analyses. Average peakVO2 was 1.48 ± 0.52 l/min, 61% of the participants had subnormal muscle strength, 61% had mobility restrictions in at least one joint and average sum of four skin-folds was 74.8 ± 38.8 mm. PeakVO2 was significantly related to gender, ambulatory status and muscle strength, explaining 55% of its variance. Adolescents and young adults with MMC have poor health-related physical fitness. Gender and ambulatory status are important determinants of peakVO2. In addition, we found a small, but significant relationship between peakVO2 and muscle strength