A randomised controlled trial of a novel tramadol chewable tablet: pharmacokinetics and tolerability in children.

Tramadol is a bitter atypical opioid analgesic drug and is prescribed to treat postoperative pain in children. However, in many countries there is no licensed paediatric tramadol formulation available. We have formulated a novel chewable chocolate-based drug delivery system for the administration of tramadol to children. This pilot, single-centre, open-label, randomised clinical study assessed the taste tolerability and comparative population pharmacokinetics of the novel tramadol chewable tablet against a compounded tramadol hydrochloride oral liquid, at a dose of 1 mg.kg-1 . A 5-point facial hedonic scale was used by the children, parents and nurses to assess tolerability. One hundred and forty-one children aged 3-16 years were given tramadol 30 min before general anaesthesia. Blood samples were taken following the induction of anaesthesia and for up to 5 h following tramadol administration. Tramadol and its active metabolite O-desmethyltramadol were analysed using reversed-phase high-performance liquid chromatography. A population pharmacokinetic model was built using non-linear mixed effects modelling. The relative bioavailability for the tablet was 1.25 times higher (95%CI 1.16-1.35) than for tramadol hydrochloride oral liquid, while the absorption rate constant for the tablet was significantly lower (1.97 h-1 vs. 3.34 h-1 , p < 0.001). Larger inter-individual variability in absorption rates were observed with the liquid tramadol. The tramadol chewable tablet was more acceptable in taste to children when assessed by the children, parents and nurses (all p < 0.001). We conclude that the novel tramadol chewable tablet has favourable acceptability and more reliable relative bioavailability in children compared with tramadol hydrochloride oral liquid.

A novel, palatable paediatric oral formulation of midazolam: pharmacokinetics, tolerability, efficacy and safety.

Midazolam is one of many bitter drugs where provision of a suitable oral paediatric formulation, particularly in the pre-anaesthetic setting, remains a challenge. To overcome this problem, a novel chocolate-based tablet formulation has been developed with positive pre-clinical results. To further investigate the potential of this formulation, 150 children aged 3-16 years who were prescribed midazolam as a premedication were randomly assigned to receive 0.5 mg.kg-1 either as the novel formulation or an intravenous solution given orally, which is the current standard at our institution. Tolerability was assessed by each child, parent and nurse using a 5-point facial hedonic scale and efficacy was determined as the time to onset of sedation. Blood samples for midazolam and 1-hydroxymidazolam levels were analysed using high-performance liquid chromatography. Population pharmacokinetics were evaluated using non-linear mixed effects modelling. The novel formulation had significantly improved tolerability scores from children, parents and nurses (all p < 0.001). Time to effect was not different between the groups (p = 0.140). The pharmacokinetics of midazolam and 1-hydroxymidazolam were able to be modelled simultaneously. The novel formulation was subject to a higher estimated first-pass metabolism compared with the intravenous solution (8.6% vs. 5.0%) and a significantly lower relative bioavailability of 82.1% (p = 0.013), with no other significant differences. Exposure relative to dose was in the range previously reported for midazolam syrup. We conclude that the novel chocolate-based formulation of midazolam provides improved tolerability while remaining efficacious with suitable pharmacokinetics when used as a premedicant for children.

The enhanced recovery after surgery (ERAS) Greenie Board: a Navy-inspired quality improvement tool.

The United States Navy uses a visual feedback system for pilots, named 'the Greenie Board', to improve flight manoeuvres on aircraft carriers. Given that increased compliance with enhanced recovery after surgery protocols reduces postoperative complications, we decided to apply a similar feedback system to our institutional enhanced recovery programme. We undertook a prospective 12-month audit of 194 patients assigned to our enhanced recovery programme and evaluated adherence to the anaesthesia-related components of our protocol, before and after implementing a Greenie Board. A compliance score was calculated by summing points for adherence to: intra-operative antibiotic prophylaxis; temperature management; goal-directed intravenous fluid therapy; postoperative nausea and vomiting prophylaxis; and postoperative fluid restriction. The score for each patient was then colour-coded and anonymously displayed for each anaesthetist on a Greenie Board within the operating theatre suite. Protocol adherence improved significantly following introduction, with 'Green' scores (acceptable compliance) increasing from 33% to 72% of patients (p < 0.0001). The greatest improvement was seen with anti-emetic prophylaxis (49% to 70%, p = 0.004) with a consequent reduction in postoperative nausea and vomiting (OR 0.42, 95% CI 0.19-0.88, p = 0.021). We did not observe a decrease in other postoperative complications nor hospital length of stay. We conclude that this US Navy-inspired feedback system is an easily implemented, low-cost quality improvement tool that significantly improved adherence to intra-operative components of our enhanced recovery protocol. The system lends itself to global scaling to drive quality improvement in healthcare delivery and would be suited to institutions without electronic medical records, including low-resource countries.

2,3,7,8-Tetrachlorodibenzo-p-dioxin in breast milk increases autistic traits of 3-year-old children in Vietnam.

Dioxin levels in the breast milk of mothers residing near a contaminated former airbase in Vietnam remain much higher than in unsprayed areas, suggesting high perinatal dioxin exposure for their infants. The present study investigated the association of perinatal dioxin exposure with autistic traits in 153 3-year-old children living in a contaminated area in Vietnam. The children were followed up from birth using the neurodevelopmental battery Bayley-III. The high-2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) exposed groups (⩾3.5 pg per g fat) showed significantly higher Autism Spectrum Rating Scale (ASRS) scores for both boys and girls than the mild-TCDD exposed groups, without differences in neurodevelopmental scores. In contrast, the high total dioxin-exposed group, indicated by polychlorinated dibenzo-p-dioxins/furans (PCDDs/Fs)--the toxic equivalents (TEQ) levels⩾17.9 pg-TEQ per g fat, had significantly lower neurodevelopmental scores than the mild-exposed group in boys, but there was no difference in the ASRS scores. The present study demonstrates a specific impact of perinatal TCDD on autistic traits in childhood, which is different from the neurotoxicity of total dioxins (PCDDs/Fs).

CLICK--topology-independent comparison of biomolecular 3D structures.

Our server, CLICK: http://mspc.bii.a-star.edu.sg/click, is capable of superimposing the 3D structures of any pair of biomolecules (proteins, DNA, RNA, etc.). The server makes use of the Cartesian coordinates of the molecules with the option of using other structural features such as secondary structure, solvent accessible surface area and residue depth to guide the alignment. CLICK first looks for cliques of points (3-7 residues) that are structurally similar in the pair of structures to be aligned. Using these local similarities, a one-to-one equivalence is charted between the residues of the two structures. A least square fit then superimposes the two structures. Our method is especially powerful in establishing protein relationships by detecting similarities in structural subdomains, domains and topological variants. CLICK has been extensively benchmarked and compared with other popular methods for protein and RNA structural alignments. In most cases, CLICK alignments were statistically significantly better in terms of structure overlap. The method also recognizes conformational changes that may have occurred in structural domains or subdomains in one structure with respect to the other. For this purpose, the server produces complementary alignments to maximize the extent of detectable similarity. Various examples showcase the utility of our web server.

[Comparison of incident reporting and learning systems for radiation oncology in France and abroad]. / Comparaison des systèmes de déclaration d'incidents en radiothérapie en France et à l'étranger.

Reporting and learning are key components of quality and safety in radiotherapy. Each event must be reported to national authorities if considered significant according to national criteria. Lessons learnt from analysis of causal factors are primordial to decrease the risk of reoccurrence or the severity of further events. Thanks to national or international, mandatory or voluntary incidents reporting systems, and experience feedbacks, various sources of learning are available to improve risk management. This article aims to compare the regulations about mandatory declarations of significant events and describe national or international incident reporting and learning systems available.

High basal NF-κB activity in nonpigmented melanoma cells is associated with an enhanced sensitivity to vitamin D3 derivatives.

BACKGROUND: Melanoma is highly resistant to current modalities of therapy, with the extent of pigmentation playing an important role in therapeutic resistance. Nuclear factor-κB (NF-κB) is constitutively activated in melanoma and can serve as a molecular target for cancer therapy and steroid/secosteroid action. METHODS: Cultured melanoma cells were used for mechanistic studies on NF-κB activity, utilising immunofluorescence, western blotting, EMSA, ELISA, gene reporter, and estimated DNA synthesis assays. Formalin-fixed, paraffin-embedded specimens from melanoma patients were used for immunocytochemical analysis of NF-κB activity in situ. RESULTS: Novel 20-hydroxyvitamin (20(OH)D(3)) and classical 1α,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) secosteroids inhibited melanoma cell proliferation. Active forms of vitamin D were found to inhibit NF-κB activity in nonpigmented cells, while having no effect on pigmented cells. Treatment of nonpigmented cells with vitamin D3 derivatives inhibited NF-κB DNA binding and NF-κB-dependent reporter assays, as well as inhibited the nuclear translocation of the p65 NF-κB subunit and its accumulation in the cytoplasm. Moreover, analysis of biopsies of melanoma patients showed that nonpigmented and slightly pigmented melanomas displayed higher nuclear NF-κB p65 expression than highly pigmented melanomas. CONCLUSION: Classical 1,25(OH)(2)D(3) and novel 20(OH)D(3) hydroxyderivatives of vitamin D3 can target NF-κB and regulate melanoma progression in nonpigmented melanoma cells. Melanin pigmentation is associated with the resistance of melanomas to 20(OH)D(3) and 1,25(OH)(2)D(3) treatment.

HPLC-UV assay of tramadol and O-desmethyltramadol in human plasma containing other drugs potentially co-administered to participants in a paediatric population pharmacokinetic study.

Multimodal analgesia is employed in paediatric pain management to maximise analgesia and minimise side effects. Tramadol is dosed at 1-1.5 mg/kg to treat severe pain in children but the assay for tramadol in plasma samples for pharmacokinetic and toxicology studies does not often consider concurrently administered medications. In this study we developed and validated an HPLC-UV method to quantify tramadol and its main metabolite (O-desmethyltramadol) in human plasma in the presence of seven potentially interfering drugs. Sample preparation method was developed by combining liquid-liquid extraction and protein precipitation. Chromatographic separation was achieved on a BDS-Hypersil-C18 column (5 µm, 250 × 4.6 mm) using a double gradient method. The limit of quantification was 6.7 ng/ml for both tramadol and ODT. The precision and accuracy were in compliance with ICH guidelines. This method was successfully employed to analyse the blood samples of 137 paediatric participants in a tramadol pharmacokinetic trial.

[Reirradiation of brain metastasis: Review of the last five years]. / La réirradiation des métastases cérébrales : revue des cinq dernières années.

No recommandations have been established for reirradiation of brain metastases yet. The purpose of this review is to analyse the data of the five last years about the feasibility, efficacy and tolerance of reirradiation of brain metastases. Reirradiation can be 3D conformal or stereotactic. Whole brain irradiation seems appropriate for multiple brain metastases in order to obtain symptomatic relief, with or without supportive care. Stereotactic reirradiation has shown satisfying results in terms of overall survival, local control, without significant toxicity. Prospective trials are necessary in order to validate consensual recommandations.

exo1-Dependent mutator mutations: model system for studying functional interactions in mismatch repair.

EXO1 interacts with MSH2 and MLH1 and has been proposed to be a redundant exonuclease that functions in mismatch repair (MMR). To better understand the role of EXO1 in mismatch repair, a genetic screen was performed to identify mutations that increase the mutation rates caused by weak mutator mutations such as exo1Delta and pms1-A130V mutations. In a screen starting with an exo1 mutation, exo1-dependent mutator mutations were obtained in MLH1, PMS1, MSH2, MSH3, POL30 (PCNA), POL32, and RNR1, whereas starting with the weak pms1 allele pms1-A130V, pms1-dependent mutator mutations were identified in MLH1, MSH2, MSH3, MSH6, and EXO1. These mutations only cause weak MMR defects as single mutants but cause strong MMR defects when combined with each other. Most of the mutations obtained caused amino acid substitutions in MLH1 or PMS1, and these clustered in either the ATP-binding region or the MLH1-PMS1 interaction regions of these proteins. The mutations showed two other types of interactions: specific pairs of mutations showed unlinked noncomplementation in diploid strains, and the defect caused by pairs of mutations could be suppressed by high-copy-number expression of a third gene, an effect that showed allele and overexpressed gene specificity. These results support a model in which EXO1 plays a structural role in MMR and stabilizes multiprotein complexes containing a number of MMR proteins. A similar role is proposed for PCNA based on the data presented.

Deubiquitylating enzyme, USP9X, regulates proliferation of cells of head and neck cancer lines.

OBJECTIVES: Truncating mutations in USP9X have been identified in oral squamous cell carcinoma patients. The aim of this study was to determine USP9X's functional role, if any, in head and neck cancer cells. MATERIALS AND METHODS: USP9X was depleted/overexpressed in head and neck cancer cell line: SCC15 (tongue), CAL27 (tongue), FaDu (pharynx) and Detroit 562 (pharynx). Cell proliferation was monitored using the CyQUANT assay, and cell cycle distribution was determined by flow cytometry. Immunoblot assays were conducted to assess protein levels. RT-qPCR was performed to determine Notch and Wnt pathway target gene expression. RESULTS: Our data showed a direct correlation between USP9X protein levels and proliferation, as well as Notch pathway activity in head and neck cancer cells. However, at least in FaDu, USP9X did not appear to regulate proliferation through the Notch pathway. Immunoblotting revealed a dramatic reduction in downstream targets of mTOR complex 1, namely total ribosomal protein (S6) and its phosphorylated form (pS6), when USP9X was depleted in FaDu cells. In contrast, in immortalized but non-tumorigenic HaCaT keratinocytes, USP9X depletion led to increase in cell proliferation, maintaining direct regulation of Notch activity. CONCLUSIONS: The functional role of USP9X was found to be context dependent. USP9X possibly promotes head and neck cancer cell proliferation through the mTOR pathway.

Mega-electron-volt ultrafast electron diffraction at SLAC National Accelerator Laboratory.

Ultrafast electron probes are powerful tools, complementary to x-ray free-electron lasers, used to study structural dynamics in material, chemical, and biological sciences. High brightness, relativistic electron beams with femtosecond pulse duration can resolve details of the dynamic processes on atomic time and length scales. SLAC National Accelerator Laboratory recently launched the Ultrafast Electron Diffraction (UED) and microscopy Initiative aiming at developing the next generation ultrafast electron scattering instruments. As the first stage of the Initiative, a mega-electron-volt (MeV) UED system has been constructed and commissioned to serve ultrafast science experiments and instrumentation development. The system operates at 120-Hz repetition rate with outstanding performance. In this paper, we report on the SLAC MeV UED system and its performance, including the reciprocal space resolution, temporal resolution, and machine stability.

An improved GC/MS-based procedure for the quantitation of the isoprostane 15-F2t-IsoP in rat plasma.

This article describes a procedure for the quantitation of the isoprostane 15-F2t-IsoP (9a,11a,15S-trihydroxy-(8b)-prosta-5Z,13E-dien-1-oic acid [CAS#27415-26-5] formerly known as 8-epi-PGF2a or 8-iso-PGF2a, and also as iPF2a-III). We have combined features from several earlier methods for 15-F2t-IsoP and prostaglandins, and identified and modified those steps that may lead to poor recoveries. The resulting protocol is precise and reliable, and was validated by a blind time-course study of plasma levels in rats treated with 120 and 1200 mg CCl4/kg body weight. Plasma levels of 15-F2t-IsoP, as measured according to the procedure described above, are good indicators of acute oxidative stress as induced by CCl4. The precision of the measurements allows detection of elevated plasma 15-F2t-IsoP levels as long as 16 h after an acute exposure of 120 mg CCl4/kg body weight, and 2 h after an exposure of 1 mg CCl4/kg body weight. The results of this low-dose, pilot study suggest that this method has sufficient analytical precision to allow the detection of the small changes in plasma isoprostane levels, which result from chronic and/or lower-level exposures to agents causing oxidative stress.

Influence of attitudes on the intention to use condoms in Quebec sexually active male adolescents.

PURPOSE: The purpose of this study was to determine the influence of attitudes and other variables on the intention to use condoms in sexually active male adolescents. METHODS: The survey was conducted from April to June 1989 on a sample of 433 sexually active boys aged 12-19 years registered in secondary schools in Laval, Quebec. RESULTS: Information on condoms provided by parents, peers, school, or media had no positive effect on male adolescents' intention to use condoms. Having a favorable attitude towards contraceptive responsibility, however, was significantly associated with the outcome variable. Endorsement of this responsibility seemed short-lived being replaced by the birth control pill in older adolescents. The study also found that in younger adolescents, intention to use condoms was significantly associated with supportive parental attitudes. CONCLUSIONS: The results of this study highlight the importance of developing strategies to encourage sexually active male adolescents to assume greater responsibility for using condoms, and suggest that in order for programs to be effective, STD and acquired immunodeficiency syndrome prevention should be done at younger ages while encouraging parents to take a greater role in sex education.

PIP: The authors surveyed between April and June 1989, 1328 males from six secondary schools in grades 7-11 in Laval, Quebec, to determine the influence of attitudes and other variables on their intentions to use condoms. Findings are based upon survey feedback from the 433 students who reported being sexually active. Although they ranged in age from 12 to 19 years, 91.9% were aged 13-17. Laval is a mainly French-speaking middle-class white suburb immediately north of Montreal and is the second most populous city in the province of Quebec with a population of 314,398. Condom use at first intercourse was greatest among 14 year olds at 72.7%, compared to only 51.2% of 17 year olds. Older adolescents depended more upon their female partners' use of oral contraceptives. In younger adolescents, the intention to use condoms was significantly associated with supportive parental attitudes about sexuality and contraception. Information on condoms provided by parents, peers, schools, and the media had no positive effect upon subjects' intentions to use condoms. The young men seemed instead to be more affected by their personal attitudes about condoms. The authors suggest exposing young men to programs designed to prevent unwanted pregnancy, HIV infection, and other sexually transmitted diseases early in their lives. Parents should also be encouraged to take a greater role in sex education.

Factors influencing the intention to use condoms in Quebec sexually-inactive male adolescents.

PURPOSE: The purpose of this study was to determine whether attitudes and other variables would be associated with intention to use condoms in sexually-inactive male adolescents. METHODS: The survey was conducted from April to June 1989 on a sample of 879 sexually-inactive boys aged 12-19 years registered in secondary schools in Laval, Quebec. RESULTS: The major findings of the study were that: (1) information on condoms provided by peers was significantly associated with the intention to use condoms; (2) information provided by schools, while not significant in the final model, was positively associated with younger adolescents' intention to use condoms; and (3) sexually-inactive male adolescents in a less committed couple relationship had a greater intention to use condoms. CONCLUSIONS: The results of this study highlight the importance of peer instructors as a source of information on condoms, as well as that of teachers and health professionals from the school environment. Other channels of communication, however, need to be developed particularly for older sexually-inactive adolescents who may be impervious to this latter source. The findings also underline the necessity to make sexually-inactive adolescents in stable couple relationships more aware of their potential vulnerability to STDs and AIDS should they commence sexual relations.

Determinants of intention to adopt a low-fat diet in men 30 to 60 years old: implications for heart health promotion.

PURPOSE: The purpose of the study was to identify the determinants of intention to have a low-fat diet in 30- to 60-year-old men. DESIGN: The survey design was cross-sectional and consisted of a self-administered questionnaire. The dependent variable was the intention to have a low-fat diet within the next 4 months, and the independent variables were those suggested by the theory of planned behavior. SETTING: The study population was drawn from three districts representing a modal sample of Laval, the second most populous city (N = 314,398) in the province of Quebec. SUBJECTS: The sample comprised 3200 people. Of the 3200 questionnaires sent out, 2583 were received and 2269 were eligible (i.e., were answered by 30- to 60-year-old men), giving a response rate of 70.9%. Of the 2269 questionnaires, 430 were incomplete, resulted in 1839 being usable for analysis. MEASURES: Multiple regression analysis was conducted to determine the influence of the independent variables on the dependent variable, the intention to have a low-fat diet. The independent variables were (1) direct and indirect determinants of intention as suggested in the theory of planned behavior and (2) sociodemographic and concomitant variables and their interactions. Discriminant analysis was used on the significant variables obtained in the regression to establish the cognitive profile of respondents' intention, strong or weak. RESULTS: In the final model, five variables 51% of the total variance. Respondents who had a stronger intention perceived that their important referents would approve them having a low-fat diet. They scored higher in seeing the advantages of adopting the target behavior and had a more positive attitude toward the behavior. They also perceived themselves as having control over the target behavior, and scored higher in terms of recognizing the perceived power of this control factor. CONCLUSIONS: The results suggests that the theory of planned behavior can be an effective tool in the planning of heart health promotion. They indicate that low-fat diet programs for men should target the work site and peer-group organizations, and place emphasis on adapting usual recipes. Though accenting the health and nutritional benefits of a low-fat diet, messages should appeal to emotion as well as reason.

Is the intention to quit smoking influenced by other heart-healthy lifestyle habits in 30- to 60-year-old men?

The aim of this study was to analyze whether the intention to quit smoking was associated with other lifestyle habits healthy for the heart, namely a low-fat diet and regular exercise, using variables suggested by the theory of planned behavior. Self-administered postal questionnaires were sent to 3,200 men 30 to 60 years of age residing in Laval, Quebec. With a response rate of 70.9%, 671 respondents (29.6%) were smokers. A significant proportion (43%) had all three risk behaviors--smoking, a high-fat diet, and sedentariness, and 42% had two--smoking and one of the other behaviors. The remaining had a single risk behavior, namely smoking. Regression analysis suggested that a healthy diet and exercise had no significant influence on the intention to quit smoking. However, men who had a stronger intention to quit smoking than others had a more favorable attitude toward the behavior, a stronger perception of approval in achieving it on the part of important referents, stronger perceived behavioral control, and were among those who smoked fewer cigarettes per day, but had made more attempts to quit. These results can assist in designing better heart-health intervention programs for this high-risk population.

Vascular endothelial growth factor and platelet derived growth factor modulates the glial response to a cortical stab injury.

Traumatic injury to the brain initiates an increase in astrocyte and microglial infiltration as part of an inflammatory response to injury. Increased astrogliosis around the injury impedes regeneration of axons through the injury, while activated microglia release inflammatory mediators. The persistent inflammatory response can lead to local progressive cell death. Modulating the astrocyte and microglial response to traumatic injury therefore has potential therapeutic benefit in brain repair. We examine the modulatory effect of a single bolus of vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) in combination on astrocytes and microglia to acute cerebral injury. A combination of VEGF and PDGF (20 pg) was injected into the striatum of adult male Sprague-Dawley rats. The effects of treatment were assessed by quantitative immunofluorescence microscopy analyzing astrocytes and microglia across the stab injury over time. Treatment delayed the onset of astrogliosis in the centre and edge of the stab injury up to day 5; however, increased astrogliosis at areas remote to the stab injury up to day 5 was observed. A persistent astrocytic response was observed in the centre and edge of the stab injury up to day 60. Treatment altered microglia cell morphology and numbers across the stab injury, with a decrease in ramified microglia, but an increase in activated and phagocytic microglia up to day 5 after stab injury. The increased microglial response from 10 until day 60 was comprised of the ramified morphology. Thus, VEGF and PDGF applied at the same time as a stab injury to the brain initially delayed the inflammatory response up to day 5 but evoked a persistent astrogliosis and microglial response up to 60 days.

Fuzzy CMAC With incremental Bayesian Ying-Yang learning and dynamic rule construction.

Inspired by the philosophy of ancient Chinese Taoism, Xu's Bayesian ying-yang (BYY) learning technique performs clustering by harmonizing the training data (yang) with the solution (ying). In our previous work, the BYY learning technique was applied to a fuzzy cerebellar model articulation controller (FCMAC) to find the optimal fuzzy sets; however, this is not suitable for time series data analysis. To address this problem, we propose an incremental BYY learning technique in this paper, with the idea of sliding window and rule structure dynamic algorithms. Three contributions are made as a result of this research. First, an online expectation-maximization algorithm incorporated with the sliding window is proposed for the fuzzification phase. Second, the memory requirement is greatly reduced since the entire data set no longer needs to be obtained during the prediction process. Third, the rule structure dynamic algorithm with dynamically initializing, recruiting, and pruning rules relieves the "curse of dimensionality" problem that is inherent in the FCMAC. Because of these features, the experimental results of the benchmark data sets of currency exchange rates and Mackey-Glass show that the proposed model is more suitable for real-time streaming data analysis.