A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial.

BACKGROUND Fragile X syndrome (FXS) is an inherited neurodevelopmental condition characterised by behavioural, learning disabilities, physical and neurological symptoms. In addition, an important degree of comorbidity with autism is also present. Considered a rare disorder affecting both genders, it first becomes apparent during childhood with displays of language delay and behavioural symptoms.Main aim: To show whether the combination of 10 mg/kg/day of ascorbic acid (vitamin C) and 10 mg/kg/day of α-tocopherol (vitamin E) reduces FXS symptoms among male patients ages 6 to 18 years compared to placebo treatment, as measured on the standardized rating scales at baseline, and after 12 and 24 weeks of treatment.Secondary aims: To assess the safety of the treatment. To describe behavioural and cognitive changes revealed by the Developmental Behaviour Checklist Short Form (DBC-P24) and the Wechsler Intelligence Scale for Children-Revised. To describe metabolic changes revealed by blood analysis. To measure treatment impact at home and in an academic environment. METHODS/DESIGN A phase II randomized, double-blind pilot clinical trial. SCOPE male children and adolescents diagnosed with FXS, in accordance with a standardized molecular biology test, who met all the inclusion criteria and none of the exclusion criteria. INSTRUMENTATION clinical data, blood analysis, Wechsler Intelligence Scale for Children-Revised, Conners parent and teacher rating scale scores and the DBC-P24 results will be obtained at the baseline (t0). Follow up examinations will take place at 12 weeks (t1) and 24 weeks (t2) of treatment. DISCUSSION A limited number of clinical trials have been carried out on children with FXS, but more are necessary as current treatment possibilities are insufficient and often provoke side effects. In the present study, we sought to overcome possible methodological problems by conducting a phase II pilot study in order to calculate the relevant statistical parameters and determine the safety of the proposed treatment. The results will provide evidence to improve hyperactivity control and reduce behavioural and learning problems using ascorbic acid (vitamin C) and α-tocopherol (vitamin E). The study protocol was approved by the Regional Government Committee for Clinical Trials in Andalusia and the Spanish agency for drugs and health products. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT01329770 (29 March 2011).

The rationale of retinal endovascular fibrinolysis in the treatment of retinal vein occlusion : from experimental data to clinical application.

PURPOSE: : We describe a retinal endovascular fibrinolysis technique to directly reperfuse experimentally occluded retinal veins using a simple micropipette. METHODS: : Retinal vein occlusion was photochemically induced in 12 eyes of 12 minipigs: after intravenous injection of 10% fluorescein (1-mL bolus), the targeted retinal vein segment was exposed to thrombin (50 units) and to Argon laser (100-200 mW) through a pars plana approach. A beveled micropipette with a 30-μm-diameter sharp edge was used for micropuncture of the occluded vein and endovascular microinjection of tissue plasminogen activator (50 μg/mL) in 11 eyes. In one control eye, balanced salt solution was injected. The lesion site was examined histologically. RESULTS: : Retinal vein occlusion was achieved in all cases. Endovascular microinjection of tissue plasminogen activator or balanced salt solution led to reperfusion of the occluded retinal vein in all cases. Indicative of successful reperfusion were the following: continuous endovascular flow, unaffected collateral circulation, no optic disk ischemia, and no venous wall bleeding. However, balanced salt solution injection was accompanied by thrombus formation at the punctured site, whereas no thrombus was observed with tissue plasminogen activator injection. CONCLUSION: : Retinal endovascular fibrinolysis constitutes an efficient method of micropuncture and reperfusion of an experimentally occluded retinal vein. Thrombus formation at the punctured site can be prevented by injection of tissue plasminogen activator.

Capitalism in the classroom : the impact of self-enhancement values and normative assessment on student motivation, goals and attitudes towards cheating

Abstract The neo-liberal capitalist ideology has come under heavy fire with anecdotal evidence indicating a link between these same values and unethical behavior. Academic institutions reflect social values and act as socializing agents for the young. Can this explain the high and increasing rates of cheating that currently prevail in education? Our first chapter examines the question of whether self-enhancement values of power and açhievement, the individual level equivalent of neo-liberal capitalist values, predict positive attitudes towards cheating. Furthermore, we explore the mediating role of motivational factors. Results of four studies reveal that self-enhancement value endorsement predicts the adoption of performance-approach goals, a relationship mediated by introjected regulation, namely desire for social approval and that self-enhancement value endorsement also predicts the condoning of cheating, a relationship mediated by performance-approach goal adoption. However, self-transcendence values prescribed by a normatively salient source have the potential to reduce the link between self-enhancement value endorsément and attitudes towards cheating. Normative assessment constitutes a key tool used by academic institutions to socialize young people to accept the competitive, meritocratic nature of a sociéty driven by a neo-liberal capitalist ideology. As such, the manifest function of grades is to motivate students to work hard and to buy into the competing ethos. Does normative assessment fulfill these functions? Our second chapter explores the reward-intrinsic motivation question in the context of grading, arguably a high-stakes reward. In two experiments, the relative capacity of graded high performance as compared to the task autonomy experienced in an ungraded task to predict post-task intrinsic motivation is assessed. Results show that whilst the graded task performance predicts post-task appreciation, it fails to predict ongoing motivation. However, perceived autonomy experienced in non-graded condition, predicts both post-task appreciation and ongoing motivation. Our third chapter asks whether normative assessment inspires the spirit of competition in students. Results of three experimental studies reveal that expectation of a grade for a task, compared to no grade, induces greater adoption of performance-avoidance, but not performance-approach, goals. Experiment 3 provides an explanatory mechanism for this, showing that reduced autonomous motivation experienced in previous graded tasks mediates the relationship between grading and adoption of performance avoidance goals in a subsequent task. The above results, when combined, provide evidence as to the deleterious effects of self enhancement values and the associated practice of normative assessment in school on student motivation, goals and ethics. We conclude by using value and motivation theory to explore solutions to this problem.

Homemade thermometry instruments in the field.

OBJECTIVE: Esophageal temperature is the gold standard for in-the-field temperature monitoring in hypothermic victims with cardiac arrest. For practical reasons, some mountain rescue teams use homemade esophageal thermometers to measure esophageal temperature; these consist of nonmedical inside/outside temperature monitoring instruments that have been modified to allow for esophageal insertion. We planned a study to determine the accuracy of such thermometers. METHODS: Two of the same model of digital cabled indoor/outdoor thermometer were modified and tested in comparison with a reference thermometer. The thermometers were tested in a water bath at different temperatures between 10°C and 35.2°C. Three hundred measurements were taken with each thermometer. RESULTS: Our experimental study showed that both homemade thermometers provided a good correlation and a clinically acceptable agreement in comparison with the reference thermometer. Measurements were within 0.5°C in comparison with the reference thermometer 97.5% of the time. CONCLUSIONS: The homemade thermometers performed well in vitro, in comparison with a reference thermometer. However, because these devices in their original form are not designed for clinical use, their use should be restricted to situations when the use of a conventional esophageal thermometer is impossible.

Large fluctuations in the disassembly rate of microtubules revealed by atomic force microscopy.

Atomic force microscopy (AFM) in situ has been used to observe the cold disassembly dynamics of microtubules at a previously unrealised spatial resolution. Microtubules either electrostatically or covalently bound to aminosilane surfaces disassembled at room temperature under buffer solutions with no free tubulin present. This process was followed by taking sequential tapping-mode AFM images and measuring the change in the microtubule end position as a function of time, with an spatial accuracy down to +/-20nm and a temporal accuracy of +/-1s. As well as giving average disassembly rates on the order of 1-10 tubulin monomers per second, large fluctuations in the disassembly rate were revealed, indicating that the process is far from smooth and linear under these experimental conditions. The surface bound rates measured here are comparable to the rates for GMPCPP-tubulin microtubules free in solution, suggesting that inhibition of tubulin curvature through steric hindrance controls the average, relatively low disassembly rate. The large fluctuations in this rate are thought to be due to multiple pathways in the kinetics of disassembly with differing rate constants and/or stalling due to defects in the microtubule lattice. Microtubules that were covalently bound to the surface left behind the protofilaments covalently cross-linked to the aminosilane via glutaraldehyde during the disassembly process. Further work is needed to quantitatively assess the effects of surface binding on protofibril disassembly rates, reveal any differences in disassembly rates between the plus and minus ends and to enable assembly as well as disassembly to be imaged in the microscope fluid cell in real-time.

Gene finding in the chicken genome

Background: Despite the continuous production of genome sequence for a number of organisms,reliable, comprehensive, and cost effective gene prediction remains problematic. This is particularlytrue for genomes for which there is not a large collection of known gene sequences, such as therecently published chicken genome. We used the chicken sequence to test comparative andhomology-based gene-finding methods followed by experimental validation as an effective genomeannotation method.Results: We performed experimental evaluation by RT-PCR of three different computational genefinders, Ensembl, SGP2 and TWINSCAN, applied to the chicken genome. A Venn diagram wascomputed and each component of it was evaluated. The results showed that de novo comparativemethods can identify up to about 700 chicken genes with no previous evidence of expression, andcan correctly extend about 40% of homology-based predictions at the 5' end.Conclusions: De novo comparative gene prediction followed by experimental verification iseffective at enhancing the annotation of the newly sequenced genomes provided by standardhomology-based methods.

Efficacy of daptomycin in the treatment of experimental endocarditis due to susceptible and multidrug-resistant enterococci.

OBJECTIVES: Daptomycin was tested in vitro and in rats with experimental endocarditis against the ampicillin-susceptible and vancomycin-susceptible Enterococcus faecalis JH2-2, the vancomycin-resistant (VanA type) mutant of strain JH2-2 (strain JH2-2/pIP819), and the ampicillin-resistant and vancomycin-resistant (VanB type) Enterococcus faecium D366. METHODS: Rats with catheter-induced aortic vegetations were treated with doses simulating intravenously kinetics in humans of daptomycin (6 mg/kg every 24 h), amoxicillin (2 g every 6 h), vancomycin (1 g every 12 h) or teicoplanin (12 mg/kg every 12 h). Treatment was started 16 h post-inoculation and continued for 2 days. RESULTS: MICs of daptomycin were 1, 1 and 2 mg/L, respectively, for strains JH2-2, JH2-2/pIP819 and D366. In time-kill studies, daptomycin showed rapid (within 2 h) bactericidal activity against all strains. Daptomycin was highly bound to rat serum proteins (89%). In the presence of 50% rat serum, simulating free concentrations, daptomycin killing was maintained but delayed (6-24 h). In vivo, daptomycin treatment resulted in 10 of 12 (83%), 9 of 11 (82%) and 11 of 12 (91%) culture-negative vegetations in rats infected with strains JH2-2, JH2-2/pIP819 and D366, respectively (P < 0.001 compared to controls). Daptomycin efficacy was comparable to that of amoxicillin and vancomycin for susceptible isolates. Daptomycin, however, was significantly (P < 0.05) more effective than teicoplanin against the glycopeptide-susceptible strain JH2-2 and superior to all comparators against resistant isolates. CONCLUSIONS: These results support the use of the newly proposed daptomycin dose of 6 mg/kg every 24 h for treatment of enterococcal infections in humans.

Importance of genotypic and phenotypic tolerance in the treatment of experimental endocarditis due to Streptococcus gordonii.

Genotypic and phenotypic tolerance was studied in penicillin treatment of experimental endocarditis due to nontolerant and tolerant Streptococcus gordonii and to their backcross transformants. The organisms were matched for in vitro and in vivo growth rates. Rats with aortic endocarditis were treated for 3 or 5 days, starting 12, 24, or 48 h after inoculation. When started at 12 h, during fast intravegetation growth, 3 days of treatment cured 80% of the nontolerant parent compared with &lt;30% of the tolerant derivative (P &lt; .005). When started at 24 or 48 h and if intravegetation growth had reached a plateau, 3 days of treatment failed against both bacteria. However, a significant difference between the 2 organisms was restored when treatment was extended to 5 days. Thus, genotypic tolerance conferred a survival advantage in both fast- and slow-growing bacteria, demonstrating that the in vitro-defined tolerant phenotype also carried the risk of treatment failure in vivo.

Higher education in nursing: the faculty work process in different institutional contexts

Objective To analyze the characteristics of faculty work in nursing higher education. Method An exploratory qualitative study with a theoretical-methodological framework of dialectical and historical materialism. The faculty work process was adopted as the analytical category, grounded on conceptions of work and professionalism. Semi-structured interviews were conducted with 24 faculty members from three higher education institutions in the city of São Paulo, classified according to the typology of institutional contexts. Results The faculty members at these higher education institutions are a heterogeneous group, under different working conditions. Intensification and precarious conditions of the faculty work is common to all three contexts, although there are important distinctions in the practices related to teaching, research and extension. Conclusion Faculty professionalization can be the starting point for analyzing and coping with such a distinct reality of faculty work and practice.


Gentamicin Improves the Activities of Daptomycin and Vancomycin against Enterococcus faecalis In Vitro and in an Experimental Foreign-Body Infection Model.

For enterococcal implant-associated infections, the optimal treatment regimen has not been defined. We investigated the activity of daptomycin, vancomycin, and gentamicin (and their combinations) against Enterococcus faecalis in vitro and in a foreign-body infection model. Antimicrobial activity was investigated by time-kill and growth-related heat production studies (microcalorimetry) as well as with a guinea pig model using subcutaneously implanted cages. Infection was established by percutaneous injection of E. faecalis in the cage. Antibiotic treatment for 4 days was started 3 h after infection. Cages were removed 5 days after end of treatment to determine the cure rate. The MIC, the minimal bactericidal concentration (MBC) in the logarithmic phase, and the MBC in the stationary phase were 1.25, 5, and >20 μg/ml for daptomycin, 1, >64, and >64 μg/ml for vancomycin, and 16, 32, and 4 μg/ml for gentamicin, respectively. In vitro, gentamicin at subinhibitory concentrations improved the activity against E. faecalis when combined with daptomycin or vancomycin in the logarithmic and stationary phases. In the animal model, daptomycin cured 25%, vancomycin 17%, and gentamicin 50% of infected cages. In combination with gentamicin, the cure rate for daptomycin increased to 55% and that of vancomycin increased to 33%. In conclusion, daptomycin was more active than vancomycin against adherent E. faecalis, and its activity was further improved by the addition of gentamicin. Despite a short duration of infection (3 h), the cure rates did not exceed 55%, highlighting the difficulty of eradicating E. faecalis from implants already in the early stage of implant-associated infection.

The implicit theory of historical change in the work of Alan S. Milward

Alan S. Milward was an economic historian who developed an implicit theory ofhistorical change. His interpretation which was neither liberal nor Marxist positedthat social, political, and economic change, for it to be sustainable, had to be agradual process rather than one resulting from a sudden, cataclysmicrevolutionary event occurring in one sector of the economy or society. Benignchange depended much less on natural resource endowment or technologicaldevelopments than on the ability of state institutions to respond to changingpolitical demands from within each society. State bureaucracies were fundamentalto formulating those political demands and advising politicians of ways to meetthem. Since each society was different there was no single model of developmentto be adopted or which could be imposed successfully by one nation-state onothers, either through force or through foreign aid programs. Nor coulddevelopment be promoted simply by copying the model of a more successfuleconomy. Each nation-state had to find its own response to the political demandsarising from within its society. Integration occurred when a number of nation states shared similar political objectives which they could not meet individuallybut could meet collectively. It was not simply the result of their increasinginterdependence. It was how and whether nation-states responded to thesedomestic demands which determined the nature of historical change.

Long-run selection and the work ethic

That individuals contribute in social dilemma interactions even when contributing is costly is a well-established observation in the experimental literature. Since a contributor is always strictly worse off than a non-contributor the question is raised if an intrinsic motivation to contribute can survive in an evolutionary setting. Using recent results on deterministic approximation of stochastic evolutionary dynamics we give conditions for equilibria with a positive number of contributors to be selected in the long run.

Experimental evidence of inbreeding avoidance in the hermaphroditic snail Physa acuta

Inbreeding depression should select for inbreeding avoidance behaviours. Here we test this hypothesis in two populations of the simultaneous hermaphroditic freshwater snail Physa acuta. We recorded the copulatory behaviour of 288 pairs of sib-mates, non-kin mates from the same population, or non-kin mates from two different populations. We find that kin discriminatory behaviours exist in this species, exclusively expressed by individuals playing the female role. We discuss the relevance of our finding in the context of the evolution of recognition systems and the consequences of such a behaviour in natural populations.