Pharmacokinetics of nebulized and oral procaterol in asthmatic and non‐asthmatic subjects in relation to doping analysis

The purpose of the present study was to investigate pharmacokinetics of procaterol in asthmatics and non‐asthmatics after nebulized and oral administration in relation to doping. Ten asthmatic and ten non‐asthmatic subjects underwent two pharmacokinetic trials. At first trial, 4 µg procaterol was administered as nebulization. At second trial, 100 µg procaterol was administered orally. Serum and urine samples were collected before and after administration of procaterol. Samples were analyzed by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). Serum and urine concentrations of procaterol were markedly higher after oral administration compared to nebulized administration. After oral administration, serum procaterol concentration‐time area under the curve (AUC) was higher (P ≤ 0.05) for asthmatics than non‐asthmatics. Likewise, urine concentrations were higher (P ≤ 0.01) for asthmatics than non‐asthmatics 4 (47 ± 12 vs. 28 ± 9 ng/mL) and 8 h (39 ± 9 vs. 15 ± 5 ng/mL) after oral administration. Detection of serum procaterol was difficult after nebulized administration with 38 samples (27%) below limit of quantification (LOQ) and only trends were observed. No differences were observed between asthmatics and non‐asthmatics in the urine concentrations of procaterol after nebulized administration. In summary, our data showed that asthmatics had higher urine concentrations of procaterol than non‐asthmatics after oral administration of 100 µg, whereas no difference was observed between the groups after nebulized administration. For doping control purposes, our observations indicate that it is possible to differentiate therapeutic nebulized administration of procaterol from prohibited use of oral procaterol. Copyright © 2016 John Wiley & Sons, Ltd.     

A cerebral glioma model for experimental therapy andin vivo invasion studies in syngeneic BD IX rats

Anin vivo glioma model was developed in syngeneic BD IX rats. The BT₄An tumor was derived from serialin vivo passages of the BT₄A tumor, originally induced from transformed fetal rat brain cells after transplacental exposure to ethylnitrosourea. The cell line was characterized for the presence of neuroglial differentiation markers, chromosome content and cell cycle distribution as determined by flowcytometry. A standardized method for i.c. tumor induction was developed, and the tumors were investigated by light and electron microscopy and for evidence of blood-brain barrier disruption. Tumor cell ability for phagocytosis was studied, as this property may be important for the invasion pattern of the tumors. We conclude that the model seems suitable for bothin vivo therapy and invasion studies. The tumor had 100% tumor take, yielded a predictable symptom-free life span after inoculation, had a characteristic histological picture of an aggressive glioma, and the blood-brain barrier within the tumor was in part disrupted. Compared to the parent cell line, there was loss of neuroglial differentiation markers, the chromosomal distribution was changed, and the ability for phagocytosis was practically lost.     

The prevalence and prognostic value of concomitant eosinophilia in chronic graft-versus-host disease after allogeneic stem cell transplantation

The prognostic significance of eosinophilia after myeloablative allogeneic stem cell transplantation (ASCT) remains to be established. Patients, whom developed chronic graft-versus-host disease (cGVHD) after ASCT, were included (n = 142). Eosinophil count was analyzed at cGVHD onset. We observed no significant association between EO and the grade of cGVHD, thrombocytopenia, nor extensive skin involvement. Importantly, we observed no significant association between cGVHD with concomitant eosinophilia and long-term clinical outcomes, and subgroup analyses revealed a considerable confounding effect of ongoing steroid treatment. In conclusion, we advocate that prognostic conclusions regarding cGVHD with concomitant eosinophilia after ASCT should be interpreted with caution.     

Induction of labor or serial antenatal fetal monitoring in postterm pregnancy: a randomized controlled trial

OBJECTIVE: To compare induction of labor at gestational age 41 weeks with expectant management in regard to neonatal morbidity. Secondary aims were to assess the effect of these managements on mode of delivery and maternal complications. METHODS: Between September 2002 and July 2004, postterm women with singleton cephalic presentation and no prelabor rupture of membranes were randomly assigned to induction of labor at 289 days or antenatal fetal surveillance every third day until spontaneous labor. Main outcome measures were neonatal morbidity, operative delivery rates, and maternal complications. RESULTS: Five hundred eight women were randomly assigned, 254 in each group. No differences of clinical importance were observed in women in whom labor was induced compared with women who were expectantly managed with regard to the following outcomes: neonates whose 5-minute Apgar score was less than 7 (three neonates in the induction group compared with four in the monitoring group, P=.72); neonates whose umbilical cord pH was less than 7 (three compared with two, P=.69); prevalence of cesarean delivery (28 compared with 33, P=.50); or prevalence of operative vaginal delivery (32 compared with 27, P=.49). In the induction group more women had precipitate labors (33 compared with 12, P<.01; number needed to treat was 13), and the duration of second stage of labor was more often less than 15 minutes (94 compared with 56, P<.01; number needed to treat was 7). CONCLUSION: No differences were found between the induced and monitored groups regarding neonatal morbidity or mode of delivery, and the outcomes were generally good. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00385229. LEVEL OF EVIDENCE: I.     

Using Cost-Effectiveness Analysis to Address Health Equity Concerns

This articles serves as a guide to using cost-effectiveness analysis (CEA) to address health equity concerns. We first introduce the "equity impact plane," a tool for considering trade-offs between improving total health—the objective underpinning conventional CEA—and equity objectives, such as reducing social inequality in health or prioritizing the severely ill. Improving total health may clash with reducing social inequality in health, for example, when effective delivery of services to disadvantaged communities requires additional costs. Who gains and who loses from a cost-increasing health program depends on differences among people in terms of health risks, uptake, quality, adherence, capacity to benefit, and—crucially—who bears the opportunity costs of diverting scarce resources from other uses. We describe two main ways of using CEA to address health equity concerns: 1) equity impact analysis, which quantifies the distribution of costs and effects by equity-relevant variables, such as socioeconomic status, location, ethnicity, sex, and severity of illness; and 2) equity trade-off analysis, which quantifies trade-offs between improving total health and other equity objectives. One way to analyze equity trade-offs is to count the cost of fairer but less cost-effective options in terms of health forgone. Another method is to explore how much concern for equity is required to choose fairer but less cost-effective options using equity weights or parameters. We hope this article will help the health technology assessment community navigate the practical options now available for conducting equity-informative CEA that gives policymakers a better understanding of equity impacts and trade-offs.     

Sleep-Specific Processing of Auditory Stimuli Is Reflected by Alpha and Sigma Oscillations

Recent research revealed a surprisingly large range of cognitive operations to be preserved during sleep in humans. The new challenge is therefore to understand functions and mechanisms of processes, which so far have been mainly investigated in awake subjects. The current study focuses on dynamic changes of brain oscillations and connectivity patterns in response to environmental stimulation during non-REM sleep. Our results indicate that aurally presented names were processed and neuronally differentiated across the wake-sleep spectrum. Simultaneously recorded EEG and MEG signals revealed two distinct clusters of oscillatory power increase in response to the stimuli: (1) vigilance state-independent θ synchronization occurring immediately after stimulus onset, followed by (2) sleep-specific α/σ synchronization peaking after stimulus offset. We discuss the possible role of θ, α, and σ oscillations during non-REM sleep, and work toward a unified theory of brain rhythms and their functions during sleep.SIGNIFICANCE STATEMENT Previous research has revealed (residual) capacity of the sleeping human brain to interact with the environment. How sensory processing is realized by the neural assemblies in different stages of sleep is however unclear. To tackle this question, we examined simultaneously recorded MEG and EEG data. We discuss the possible role of θ, α, and σ oscillations during non-REM sleep. In contrast to versatile θ band response that reflected early stimulus processing step, succeeding α and σ band activity was sensitive to the saliency of the incoming information, and contingent on the sleep stage. Our findings suggest that the specific reorganization of mechanisms involved in later stages of sensory processing takes place upon falling asleep.     

Cardiac arrhythmias six months following traumatic spinal cord injury

ObjectiveTo investigate the incidence of cardiac arrhythmias at six months following traumatic spinal cord injury (SCI) and to compare the prevalence of arrhythmias between participants with cervical and thoracic SCI.DesignA prospective observational study using continuous twenty-four-hour Holter monitoring.SettingInpatient rehabilitation unit of a university research hospital and patient home setting.ParticipantsFifty-five participants with acute traumatic SCI were prospectively included. For each participant, the SCI was characterized according to the International Standards for Neurological Classification of SCI by the neurological level and severity according to the American Spinal Injury Association Impairment Scale.Outcome measuresComparisons between demographic characteristics and arrhythmogenic occurrences as early as possible after SCI (4 ± 2 days) followed by 1, 2, 3, 4 weeks and 6 month time points of Holter monitoring.ResultsBradycardia (heart rate [HR] <50 bpm) was present in 29% and 33% of the participants with cervical (C1–C8) and thoracic (T1–T12) SCI six months after SCI, respectively. The differences in episodes of bradycardia between the two groups were not significant (P < 0.54). The mean maximum HR increased significantly from 4 weeks to 6 months post-SCI (P < 0.001), however mean minimum and maximum HR were not significantly different between the groups at the six-month time point. There were no differences in many arrhythmias between recording periods or between groups at six months.ConclusionsAt the six-month timepoint following traumatic SCI, there were no significant differences in occurrences of arrhythmias between participants with cervical and thoracic SCI compared to the findings observed in the first month following SCI.