A Steady-State Head-to-Head Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF): An Open-Label, Prospective, Randomized, Two-Arm, Three-Period Crossover Study.

This two-sequence, three-period crossover study is the first pharmacokinetic (PK) study to compare all three innovator formulations of tacrolimus (twice-daily immediate-release tacrolimus capsules [IR-Tac]; once-daily extended-release tacrolimus capsules [ER-Tac]; novel once-daily tacrolimus tablets [LCPT]). Stable renal transplant patients were dosed with each drug for 7 days, and blood samples were obtained over 24 h. Thirty subjects were included in the PK analysis set. A conversion factor of 1:1:0.80 for IR-Tac:ER-Tac:LCPT was used; no dose adjustments were permitted during the study. The median (interquartile range) total daily dose was 6.0 (4.0-8.0) mg for IR-Tac and ER-Tac and 4.8 (3.3-6.3) for LCPT. Significantly higher exposure on a per milligram basis, lower intraday fluctuation and prolonged time (Tmax ) to peak concentration (Cmax ) were found for LCPT versus IR-Tac or ER-Tac. ER-Tac showed no differences versus IR-Tac in exposure, Cmax , Tmax or fluctuation. The observed exposure of IR-Tac was used to normalize exposure for LCPT and ER-Tac, resulting in the following recommended total daily dose conversion rates: IR-Tac:ER-Tac, +8%; IR-Tac:LCPT, -30%; ER-Tac:LCPT, -36%. After exposure normalization, Cmax was ~17% lower for LCPT than for IR-Tac or ER-Tac; Cmin was ~6% lower for LCPT compared with IR-Tac and 3% higher compared with ER-Tac.

[Upgrading a pediatric pharmaceutical care service in Quebec]. / Mise à niveau d'un secteur pédiatrique de soins pharmaceutiques au Québec.

INTRODUCTION: Clinical pharmacy has developed since the 1960s in North America, with large disparities in the presence of decentralized pharmacists in hospital units between healthcare programs. Decentralized pharmacists have been present in pediatrics since the 1970s. The main objective of this study was to describe the steps used to upgrade the pediatrics department's pharmaceutical care. METHODS: A descriptive study was conducted to upgrade the pharmaceutical care provided by two full-time equivalents in two pediatric sectors including 81 beds of a tertiary mother-child hospital. The upgrade includes three steps: a structured literature review, a description of the department, and a description of the practice upgrades proposed by the research team, in consensus with the clinical pharmacy team. RESULTS: Out of the 236 articles initially identified, 13 relevant articles were found on the role and impact of pharmacists in pediatrics. Nine pharmaceutical activities were supported by high-quality data. Following the literature review and concerted reflection, 15 improvements were identified as feasible without increasing the staff. CONCLUSION: There are data on the impact of pharmacists in pediatrics. This descriptive study illustrates a method that was used to upgrade the pediatrics sector in a university mother-child health center.

Reliability of a food menu to measure energy and macronutrient intake in adolescents.

BACKGROUND/OBJECTIVES: The aim of this study was to evaluate the reliability of a food menu to measure energy and macronutrient intake within the laboratory and under real-life conditions in adolescents. SUBJECTS/METHODS: A total of 12 boys and 8 girls (age 14.3 (s.d. 2.4) years, body mass index (BMI) 20.8 (s.d. 4.0) kg/m(2)) completed two identical in-laboratory sessions (ILS) and two out-of-laboratory sessions (OLS). During the ILS, participants had ad libitum access to a variety of foods (74 items in total), which they chose from a menu every hour, for 5 h (0800-1300 h). For the OLS (1300 h until bedtime), the foods were chosen from the same menu at 1300 h and packed into containers to bring home with them. RESULTS: Test-retest analysis of energy and macronutrient intake revealed no significant differences (ILS and OLS). Intra-class correlations ranged between 0.69 and 0.83 (ILS) and between 0.48 and 0.73 (OLS) for energy and macronutrient intake (all P<0.01). Within-subject coefficients of variation ranged between 12.9% and 23.5% for the ILS and between 24.0% and 37.7% for the OLS. Bland-Altman plots showed acceptable agreement. Finally, the food menu was well appreciated by the participants with a 75% appreciation rate on a visual analog scale. CONCLUSIONS: This food menu provides a reasonably reliable measure of energy and macronutrient intake in adolescents, irrespective of sex and BMI, especially inside the laboratory setting. Despite the difficulties in capturing a stable measure of energy intake in research, this tool could be a useful addition to the methods currently used to assess ad libitum food intake in youth.

The neuroergonomic evaluation of human machine interface design in air traffic control using behavioral and EGG/ERP measures.

The Air Traffic Control (ATC) environment is complex and safety-critical. Whilst exchanging information with pilots, controllers must also be alert to visual notifications displayed on the radar screen (e.g., warning which indicates a loss of minimum separation between aircraft). Under the assumption that attentional resources are shared between vision and hearing, the visual interface design may also impact the ability to process these auditory stimuli. Using a simulated ATC task, we compared the behavioral and neural responses to two different visual notification designs--the operational alarm that involves blinking colored "ALRT" displayed around the label of the notified plane ("Color-Blink"), and the more salient alarm involving the same blinking text plus four moving yellow chevrons ("Box-Animation"). Participants performed a concurrent auditory task with the requirement to react to rare pitch tones. P300 from the occurrence of the tones was taken as an indicator of remaining attentional resources. Participants who were presented with the more salient visual design showed better accuracy than the group with the suboptimal operational design. On a physiological level, auditory P300 amplitude in the former group was greater than that observed in the latter group. One potential explanation is that the enhanced visual design freed up attentional resources which, in turn, improved the cerebral processing of the auditory stimuli. These results suggest that P300 amplitude can be used as a valid estimation of the efficiency of interface designs, and of cognitive load more generally.

Using near infrared spectroscopy and heart rate variability to detect mental overload.

Mental workload is a key factor influencing the occurrence of human error, especially during piloting and remotely operated vehicle (ROV) operations, where safety depends on the ability of pilots to act appropriately. In particular, excessively high or low mental workload can lead operators to neglect critical information. The objective of the present study is to investigate the potential of functional near infrared spectroscopy (fNIRS) - a non-invasive method of measuring prefrontal cortex activity - in combination with measurements of heart rate variability (HRV), to predict mental workload during a simulated piloting task, with particular regard to task engagement and disengagement. Twelve volunteers performed a computer-based piloting task in which they were asked to follow a dynamic target with their aircraft, a task designed to replicate key cognitive demands associated with real life ROV operating tasks. In order to cover a wide range of mental workload levels, task difficulty was manipulated in terms of processing load and difficulty of control - two critical sources of workload associated with piloting and remotely operating a vehicle. Results show that both fNIRS and HRV are sensitive to different levels of mental workload; notably, lower prefrontal activation as well as a lower LF/HF ratio at the highest level of difficulty, suggest that these measures are suitable for mental overload detection. Moreover, these latter measurements point toward the existence of a quadratic model of mental workload.

Identification and characterization of a novel HIV-1 nucleotide-competing reverse transcriptase inhibitor series.

Several groups have recently reported on the identification of nucleotide-competing reverse transcriptase inhibitors (NcRTIs), a new class of RT inhibitors. NcRTIs reversibly inhibit binding of the incoming nucleotide to the RT active site but do not act as chain terminators, unlike the nucleos(t)ide reverse transcriptase inhibitor (NRTI) class. We identified a novel benzo[4,5]furo[3,2,d]pyrimidin-2-one NcRTI chemical series. Structure-activity relationship evaluation of this series with both RT and viral replication assays led to the identification of compound A, a new NcRTI. Compound A inhibited HIV-1 RT in a primer extension assay (50% inhibitory concentration, 2.6 nM) but had no measurable activity against human DNA polymerase γ at 10 µM. It potently inhibited HIV-1 replication in vitro (50% effective concentration, 1.5 nM). The antiviral potency of compound A was unaffected by the presence of nonnucleotide RT inhibitor (NNRTI) mutations tested (L100I, K103N/Y181C, V106A, or Y188L). Notably, viruses encoding K65R were hypersusceptible to inhibition by compound A. Compound A also retained full activity against viruses encoding M184V. In vitro selection for resistant virus to compound A led to the selection of a single substitution within RT: W153L. A recombinant virus encoding the RT W153L was highly resistant to compound A (fold change, 160). W153 is a highly conserved residue in HIV RT and has not been previously associated with drug resistance. In summary, a novel NcRTI series with optimized antiviral activity, minimal cross-resistance to existing RT inhibitor classes, and a distinct resistance profile has been discovered. These results further establish NcRTIs as an emerging class of antiretroviral agents.

Brain and systemic glucose metabolism in the healthy elderly following fish oil supplementation.

Cerebral metabolic rate of glucose (CMRg) is lower in individuals affected by cognitive decline and dementia, especially in Alzheimer's disease. However, as yet there is no consensus as to whether CMRg decreases during healthy aging. Epidemiological studies show that weekly consumption of fish abundant in ω3 fatty acids has a protective effect on cognition during aging. Thus, the primary objective of this human study was to use positron emission tomography analysis with (18)F-fluorodeoxyglucose to evaluate whether supplementation with a fish oil rich in ω3 fatty acids increases cerebral glucose metabolism in young or elderly adults. Healthy young (23±5y old; n=5) and elderly (76±3y old; n=6) women and men were included in the study. Semi-quantitative expression of the data as 'standardized uptake values' showed that elderly participants had significantly lower cerebral glucose metabolism compared with the young group. However, when expressed quantitatively a CMRg, there was no effect of age or ω3 supplementation on glucose metabolism in any of the brains regions studied. Higher plasma triglyceride levels and higher plasma insulin levels were associated with lower CMRg in several regions, suggesting that a trend towards the metabolic syndrome may be associated with cerebral hypometabolism. We conclude that under these experimental conditions, ω3 supplementation did not affect brain glucose metabolism in the healthy elderly. Future studies in this area should address whether glucose intolerance or other conditions linked to the metabolic syndrome impact negatively on brain glucose metabolism and cognition.

Rapid determination of uranium isotopes in urine by inductively coupled plasma-mass spectrometry.

Following a radiological or nuclear emergency involving uranium exposure, rapid analytical methods are needed to analyze the concentration of uranium isotopes in human urine samples for early dose assessment. The inductively coupled plasma mass spectrometry (ICP-MS) technique, with its high sample throughput and high sensitivity, has advantages over alpha spectrometry for uranium urinalysis after minimum sample preparation. In this work, a rapid sample preparation method using an anion exchange chromatographic column was developed to separate uranium from the urine matrix. A high-resolution sector field ICP-MS instrument, coupled with a high sensitivity desolvation sample introduction inlet, was used to determine uranium isotopes in the samples. The method can analyze up to 24 urine samples in two hours with the limits of detection of 0.0014, 0.10, and 2.0 pg mL(-1) for (234)U, (235)U, and (238)U, respectively, which meet the requirement for isotopic analysis of uranium in a radiation emergency.

The expression of p53-induced protein with death domain (Pidd) and apoptosis in oral squamous cell carcinoma.

The Pidd (p53-induced protein with death domain) gene was shown to be induced by the tumour suppressor p53 and to mediate p53-dependent apoptosis in mouse and human cells, through interactions with components of both the mitochondrial and the death receptor signalling pathways. To study the role of Pidd in clinical tumours, we measured its expression by quantitative reverse transcription-PCR in microdissected oral squamous cell carcinomas (OSCC) with and without p53 mutation. Tumour cell apoptosis was assessed by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling. Tumour proliferation was assessed by immunohistochemical staining for the Ki-67 antigen. We found a wide range of Pidd expression among OSCC. Statistical analysis revealed an association between Pidd expression and apoptotic index (Mann-Whitney test, P<0.001), consistent with a role of Pidd in apoptosis in this tumour type. Furthermore, we showed a positive correlation between apoptotic index and proliferative index that has not been previously described for OSCC. There was no correlation between Pidd expression and the p53 mutation status of these tumours, suggesting that Pidd expression may be regulated by p53-independent mechanisms. Further characterisation of these molecular defects in the control of proliferation and apoptosis should help in developing treatments that target OSCC according to their biological properties.

Neighbourhood influences on health in Montréal, Canada.

This paper examines neighbourhood effects on health within a large Canadian city--Montréal. Our approach is to consider that individual health outcomes are determined both by individual and neighbourhood characteristics and we consciously take on the problem of neighbourhood definition by developing 'natural' neighbourhoods. Our data come from the Montréal health region sample of the 2000/1 Canadian Community Health Survey, a comprehensive national survey that contains information on health outcomes as well as behavioural and socio-demographic information. Respondents were placed into 'naturally' defined neighbourhoods as opposed to arbitrary geostatistical units, responding to calls in the literature to develop more meaningful units of analysis. We also compare the 'natural' neighbourhood approach with the use of standard census tracts as the unit of analysis. Results show significant between-neighbourhood variation in health status with about 3% of the variance in the Health Utilities Index captured at the neighbourhood level, even after controlling for a variety of socio-demographic and behavioural variables at the individual level. Models using census tracts as the unit of analysis had remarkably similar results to the 'natural' neighbourhood models, suggesting that census tracts are good proxies for natural neighbourhood boundaries in studies of neighbourhood effects on health.

Labour market income inequality and mortality in North American metropolitan areas.

OBJECTIVE: To investigate relations between labour market income inequality and mortality in North American metropolitan areas. METHODS: An ecological cross sectional study of relations between income inequality and working age (25-64 years) mortality in 53 Canadian (1991) and 282 US (1990) metropolitan areas using four measures of income inequality. Two labour market income concepts were used: labour market income for households with non-trivial attachment to the labour market and labour market income for all households, including those with zero and negative incomes. Relations were assessed with weighted and unweighted bivariate and multiple regression analyses. RESULTS: US metropolitan areas were more unequal than their Canadian counterparts, across inequality measures and income concepts. The association between labour market income inequality and working age mortality was robust in the US to both the inequality measure and income concept, but the association was inconsistent in Canada. Three of four inequality measures were significantly related to mortality in Canada when households with zero and negative incomes were included. In North American models, increases in earnings inequality were associated with hypothetical increases in working age mortality rates of between 23 and 33 deaths per 100 000, even after adjustment for median metropolitan incomes. CONCLUSIONS: This analysis of labour market inequality provides more evidence regarding the robust nature of the relation between income inequality and mortality in the US. It also provides a more refined understanding of the nature of the relation in Canada, pointing to the role of unemployment in generating Canadian metropolitan level health inequalities.

The impact of broadband noise on serial memory: changes in band-pass frequency increase disruption.

Irrelevant sound consisting of bursts of broadband noise, in which centre frequency changes with each burst, markedly impaired short-term memory for order. In contrast, a sequence of irrelevant sound in which the same band-pass noise burst was repeated did not produce significant disruption. Serial recall for both visual-verbal (Experiment 1) and visual-spatial items (Experiment 2) was sensitive to the increased disruption produced by changing irrelevant noise. The results provide evidence that sounds that are largely aperiodic can produce marked disruption of serial recall in a similar manner to periodic sounds (e.g., speech, musical streams, and tones), and thus show a changing-state effect.

Hyperbaric oxygen for children with cerebral palsy: a randomised multicentre trial. HBO-CP Research Group.

BACKGROUND: The use of hyperbaric oxygen for children with cerebral palsy has spread worldwide, despite little scientific evidence of efficacy. We did a randomised trial to assess the efficacy and side-effects of this form of therapy in children with cerebral palsy. METHODS: 111 children with cerebral palsy aged 3-12 years were randomly assigned hyperbaric oxygen (n=57) or slightly pressurised room air (n=54). All children received 40 treatments over 2 months. Hyperbaric oxygen treatment was 1 h in 100% oxygen at 1.75 atmospheres absolute (ATA); children on slightly pressurised air received air at 1.3 ATA (the lowest pressure at which pressure can be felt, thereby ensuring the maintenance of masking). The main outcome measure was gross motor function. Secondary outcomes included performance in activities of daily living, attention, working memory, and speech. FINDINGS: For all outcomes, both groups improved over the course of the study, but without any difference between the two treatments. The score on the global gross motor function measure increased by 3.0% in the children on slightly pressurised air and 2.9% in those on hyperbaric oxygen. The mean difference between treatments was -0.40 (95% CI -1.69 to 0.90, p=0.544). Other changes were seen in speech, attention, memory, and functional skills. Ear problems occurred in 27 children treated by hyperbaric oxygen and in 15 treated with hyperbaric air (p=0.004). INTERPRETATION: In this study, hyperbaric oxygen did not improve the condition of children with cerebral palsy compared with slightly pressurised air. The improvement seen in both groups for all dimensions tested deserves further consideration.

Auditory distraction and short-term memory: phenomena and practical implications.

Irrelevant sound tends to break through selective attention and impair cognitive performance. This observation has been brought under systematic scrutiny by laboratory studies measuring interference with memory performance during exposure to irrelevant sound. These studies established that the degree of interference depends on the properties of the irrelevant sound as well as those of the cognitive task. The way in which this interference increases or diminishes as characteristics of the sound and of the cognitive task are changed reveals key functional characteristics of auditory distraction. A number of important practical implications that arise from these studies are discussed, including the finding that relatively quiet background sound will have a marked effect on efficiency in performing cognitive tasks.

Upper dental prosthesis instability consecutive to the resection of a cerebral tumor.

A 57-year-old female patient was evaluated for an unstable maxillary dental prosthesis. The patient stated that approximately 2 weeks prior to this consultation the prosthesis was relined four times. Despite this, it often had a tendency to shift during meals. On the other hand, she is very satisfied with a complete fixed prosthesis on implants in the mandibular arch. She has been wearing this latter lower prosthesis for the same length of time as the upper prosthesis. She indicated that a similar problem existed with the former upper prosthesis, resulting in her consulting a prosthodontist.

Interference in memory by process or content? A reply to Neath (2000)

The approach to the irrelevant sound effect by Neath (2000) is discussed in terms of the contrast between content-based and process-based interference. Four themes are highlighted: First, problematic features of the feature model are highlighted; second, results not considered by Neath are presented; third, empirical underpinnings of the feature model not related to the irrelevant-sound effect are questioned; last, the parsimony of the feature model is questioned. The balance of the evidence seems to be in favor of a process-based approach, on the grounds that it provides a comprehensive account of acoustic and task-based factors within the irrelevant sound effect, for both speech and nonspeech sound.

Disruption of comprehension by the meaning of irrelevant sound.

This study investigates the claim that the disruption of comprehension by irrelevant sound is qualitatively different from that of short-term memory for order. Both meaningful and meaningless speech disrupted the comprehensive aspect of the task, but the effect of meaningful speech was significantly greater. Both rehearsal and semantic processing, which are involved in reading comprehension, seem to be susceptible to disruption by irrelevant meaningful speech. The study provides some evidence to suggest that the presence of meaning in the irrelevant sound in creases disruption of performance in cognitive tasks that also call upon processing of meaning.

Inactivated hepatitis A vaccine booster given >/=24 months after the primary dose.

We investigated what happens with the immune response when people come back for their booster dose of inactivated hepatitis A vaccine later than the recommended time of 6-12 months after the primary dose. We recruited a group of 124 travellers who received either the primary doses of Havrix 720 (two doses) or of Havrix 1440 (one dose) >/=24 months before study entry. They received a booster dose of Havrix 1440 and blood was drawn 1 month later. As a control group, we recruited a group of 125 travellers who followed a recommended schedule with a primary dose at month 0 and a booster dose at months 6-12. For both study groups, the GMTs increased dramatically and similarly upon the booster immunisation. Although significantly more late travellers (32%) had lost detectable antibodies than controls (11%) before administration of the booster dose, all these subjects showed an anamnestic response to the booster dose. Delaying the booster dose up to 66 months after primary vaccination did not seem to influence the immunogenicity of the booster dose. However, the recommended 6-12-month interval remains if detectable antibody titers are to be warranted constantly.

Interference from degraded auditory stimuli: linear effects of changing-state in the irrelevant sequence.

Cognitive performance, particularly on a number of tasks involving short-term memory for order, is impaired by the mere presence of irrelevant background sound. The current study examines the features of the irrelevant sound that determine its disruptive potency. Previous research suggests that the amount of variability in an irrelevant stream is related to the degree of disruption of memory. The present experiments used a parametric approach to manipulate degree of change more precisely. Increasing levels of degradation, effected either by low-pass filtering (speech) or by digital manipulation (speech and nonspeech), monotonically decreased the degree of interference. The findings support the following propositions: (i) the degree of physical change within an auditory stream is the primary determinant of the degree of disruption; and, (ii) the effects of irrelevant speech and irrelevant nonspeech sounds are functionally similar.