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.     

Functional implications of short‐term retinal detachment in porcine eyes: study by multifocal electroretinography

Purpose: The aim of the study was to determine the type and magnitude of detectable changes in pig multifocal electroretinography (mfERG) induced by the vitreoretinal surgical procedures necessary to gain access to the subretinal space. Methods: Twenty pigs underwent posterior segment surgery. Six animals had a vitrectomy (V), six had in addition a retinal bleb detachment (V + B); five had in addition a retinal diathermia on the bleb (V + B + D) and three received a retinotomy in the diathermized retinal area (V + B + D + R). mfERG evaluation was performed at baseline and 1 and 6 weeks postoperatively. Selected eyes were enucleated for histological evaluation. Results: The retinal detachments blebs all reattached spontaneously. All four surgical sequences resulted in slight, non‐significant changes in the mfERG peaks. A trend towards an amplitude reduction of the mfERG peaks N1, P1 and N2 were observed within the first postoperative week. After 6 weeks, all amplitudes had normalized. Of the implicit times only that of peak N1 (after retinal diathermia) was prolonged significantly at 1 week (P = 0.037). However, it returned to the preoperative level after 6 weeks. Histologically, the retinal detachment bleb was characterized by transient double layering of the retinal pigment epithelium (RPE) and loss photoreceptor outer segments. Conclusion: Access to the subretinal space in pigs can be gained without permanent detectable changes in the mfERG. A short‐term retinal detachment was found to cause only reversible electrophysiological and histological changes in the outer retina, which suggests that this procedure is tolerated well in the porcine retina. The size of the known destructive lesion (retinotomy) was too small to be detected, given the spatial resolution of the mfERG method applied. In the future, the presented protocol can be used to assess the functional outcome of surgery and transplantation in the subretinal space in pigs.     

Non-Invasive Fetal K Status Prediction: 7 Years of Experience

IntroductionIn the Kell blood group system, the K and k antigens are the clinically most important ones. Maternal anti-K IgG antibodies can lead to the demise of a K-positive fetus in early pregnancy. Intervention can save the fetus. Prenatal K status prediction of the fetus in early pregnancy is desirable and gives a good basis for pregnancy risk management. We present the results from 7 years of clinical experience in predicting fetal K status as well as some theoretical considerations relevant for design of the assay and evaluation of results.MethodsBlood was collected from 43 women, all immunized against K, at a mean gestational age of 18 weeks (range 10–38). A total of 56 consecutive samples were tested. The KEL *01.01 /KEL *02 single nucleotide variant that determines K status was amplified from maternal plasma DNA by PCR without allele specificity. The PCR product was sequenced by NGS technology, and the number of sequenced KEL *01.01 and KEL *02 reads were counted. Prediction of the fetal K status was based on this count and was compared with the serologically determined K status of the newborns.ResultsAll fetal K predictions were in accordance with postnatal serology where available (n = 34), using our current data analysis.ConclusionWe have developed an NGS-based method for the non-invasive prediction of fetal K status. This approach requires special considerations in terms of primer design, stringent preanalytical sample handling, and careful analytical procedures. We analyzed samples starting at GA 10 weeks and demonstrated the correct prediction of fetal K status. This assay enables timely clinical intervention in pregnancies at risk of hemolytic disease of the fetus and newborn caused by maternal anti-K IgG antibodies.     

Prognostic value of neurofilament light in blood in patients with polyneuropathy: A systematic review

Neurofilament light protein (NfL) is a part of the neuronal skeleton, primarily expressed in axons, and is released when nerves are damaged. NfL has been found to be a potential diagnostic biomarker in different types of polyneuropathies. However, whether NfL levels can be used as a predictor for the risk of disease progression is currently less understood. We searched MEDLINE (PubMed), Embase, Cochrane Library, and Web of Science Searches and included longitudinal studies with a baseline and follow-up examination of adult patients with polyneuropathy and NfL measured in blood. Twenty studies investigating NfL as a predictor of disease progression were identified, examining eight polyneuropathy subtypes. The results from studies in Chronic Inflammatory Demyelinating Polyneuropathy (CIDP) patients were divergent, with two out of five studies finding a significant association between NfL levels and clinical outcomes. Meta-analysis of the three Guillian-Barré Syndrome (GBS) studies found higher odds for the inability to run after 1 year in patients with high levels of NfL (odds ratio 2.18, 95% confidence interval 1.04–4.56). Results from studies examining other subacute or chronic polyneuropathies like Charcot–Marie–Tooth (CMT) varied in study design and results. Our findings suggest NfL can be used as a predictor of disease progression, particularly in polyneuropathies such as CIDP and GBS. However, NfL may not serve as a reliable and cost-effective biomarker for slowly progressive polyneuropathies like CMT. Future standardized studies considering NfL as a prognostic blood biomarker in patients with different types of polyneuropathies are warranted.     

The early adolescent brain on music: Analysis of functional dynamics reveals engagement of orbitofrontal cortex reward system

Music listening plays a pivotal role for children and adolescents, yet it remains unclear how music modulates brain activity at the level of functional networks in this young population. Analysing the dynamics of brain networks occurring and dissolving over time in response to music can provide a better understanding of the neural underpinning of music listening. We collected functional magnetic resonance imaging (fMRI) data from 17 preadolescents aged 10–11 years while listening to two similar music pieces separated by periods without music. We subsequently tracked the occurrence of functional brain networks over the recording time using a recent method that detects recurrent patterns of phase‐locking in the fMRI signals: the leading eigenvector dynamics analysis (LEiDA). The probabilities of occurrence and switching profiles of different functional networks were compared between periods of music and no music. Our results showed significantly increased occurrence of a specific functional network during the two music pieces compared to no music, involving the medial orbitofrontal and ventromedial prefrontal cortices—a brain subsystem associated to reward processing. Moreover, the higher the musical reward sensitivity of the preadolescents, the more this network was preceded by a pattern involving the insula. Our findings highlight the involvement of a brain subsystem associated with hedonic and emotional processing during music listening in the early adolescent brain. These results offer novel insight into the neural underpinnings of musical reward in early adolescence, improving our understanding of the important role and the potential benefits of music at this delicate age.     

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.     

A non‐fatal case of invasive zygomycete (Lichtheimia corymbifera) infection in an allogeneic haematopoietic cell transplant recipient

Post‐transplant infections in allogeneic haematopoietic cell transplant (allo‐HCT) recipients often have severe consequences. This is especially the case when dealing with zygomycete infections where the result is often fatal. A major problem when dealing with zygomycete infections is the need for an accurate and fast diagnosis as the phylum is highly resistant towards the conventional antifungals. We herein describe a non‐fatal case of Lichtheimia corymbifera infection in an allo‐HCT recipient.     

Individualized 6‐mercaptopurine increments in consolidation treatment of childhood acute lymphoblastic leukemia: A NOPHO randomized controlled trial

Objectives

This randomized controlled trial tested the hypothesis that children with non‐high‐risk acute lymphoblastic leukemia could benefit from individualized 6‐mercaptopurine increments during consolidation therapy (NCT00816049). Primary and secondary end points were end of consolidation minimal residual disease (MRD) positivity and event‐free survival.

Methods

392 patients were randomized to experimental and 396 to standard therapy. Patients allocated to standard therapy received oral 6‐mercaptopurine (25 mg/m²/day) from days 30 to 85, while the experimental arm received stepwise increments of additional 25 mg/m²/day beginning on days 50 and/or 71 unless dose‐limiting myelosuppression had occurred.

Results

In the experimental arm, 166 patients (42%) received one dose increment, and 62 (16%) received two. Fifty‐seven of 387 (15%) patients in the experimental arm were MRD positive at end of consolidation vs 77 of 389 (20%) in the control arm (P = .08). Five‐year probability of event‐free survival was 0.89 (95% CI: 0.85‐0.93) in the experimental arm vs 0.93 (0.90‐0.96) in the control arm (P = .13). The median accumulated length of 6‐mercaptopurine treatment interruptions was 7 (IQR 2‐12) in the experimental arm vs 4 (IQR 0‐10) in the control arm (P = .002).

Conclusion

This study found no benefit from individualized 6‐mercaptopurine increments compared to standard therapy.