Evaluation of Limited Sampling Methods for Oral Busulfan Pharmacokinetic Monitoring in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation.

BACKGROUND: Monitoring busulfan area under the plasma concentration-time curve (AUC) to establish the dose regimen for stem cell transplantation desirable to achieve efficacy while avoiding toxicity. OBJECTIVE: Our objective was to compare AUCs calculated by 18 limited sampling methods (LSMs) from 2 to 5 samples to reference AUCs determined from 10 samples in a retrospective study of 103 adult patients receiving oral busulfan. LSMs using 2 or 3 samples were ineffective. METHODS: Four LSMs using 4 or 5 blood samples that accurately characterized busulfan AUC were identified. The best 2 methods were obtained with sampling at 0.5, 1, 2, 4, and 6 hours and after 1, 1.5, 2, 4, and 6 hours postdose. For these LSMs, the incidence of 20% difference between AUCs from LSMs and reference AUCs was less than 1.3%. CONCLUSIONS: Effective and safe determination of AUC for oral busulfan can be made with strategies using only 4 or 5 concentration timepoints.

Electrophysiological evidence for an early processing of human voices.

BACKGROUND: Previous electrophysiological studies have identified a "voice specific response" (VSR) peaking around 320 ms after stimulus onset, a latency markedly longer than the 70 ms needed to discriminate living from non-living sound sources and the 150 ms to 200 ms needed for the processing of voice paralinguistic qualities. In the present study, we investigated whether an early electrophysiological difference between voice and non-voice stimuli could be observed. RESULTS: ERPs were recorded from 32 healthy volunteers who listened to 200 ms long stimuli from three sound categories - voices, bird songs and environmental sounds - whilst performing a pure-tone detection task. ERP analyses revealed voice/non-voice amplitude differences emerging as early as 164 ms post stimulus onset and peaking around 200 ms on fronto-temporal (positivity) and occipital (negativity) electrodes. CONCLUSION: Our electrophysiological results suggest a rapid brain discrimination of sounds of voice, termed the "fronto-temporal positivity to voices" (FTPV), at latencies comparable to the well-known face-preferential N170.

Impact of GSTA1 Polymorphisms on Busulfan Oral Clearance in Adult Patients Undergoing Hematopoietic Stem Cell Transplantation.

BACKGROUND: Busulfan pharmacokinetics exhibit large inter-subject variability. Our objective was to evaluate the influence of glutathione S-transferase A1 (GSTA1) gene variants on busulfan oral clearance (CLo) in a population of patients undergoing hematopoietic stem cell transplantation. METHODS: This is a quasi-experimental retrospective study in adult patients (n = 87 included in the final analyses) receiving oral busulfan. Pharmacokinetics data (area under the plasma concentration-time curve (AUC) determined from 10 blood samples) were retrieved from patients' files and GSTA1 *A and *B allele polymorphisms determined from banked DNA samples. Three different limited sampling methods (LSM) using four blood samples were also compared. RESULTS: Carriers of GSTA1*B exhibited lower busulfan CLo than patients with an *A/*A genotype (p < 0.002): Busulfan CLo was 166 ± 31, 187 ± 37 vs. 207 ± 47 mL/min for GSTA1*B/*B, *A/*B and *A/*A genotypes, respectively. Similar results were obtained with the tested LSMs. Using the standard AUC method, distribution of patients above the therapeutic range after the first dose was 29% for GSTA1*A/*A, 50% for *A/*B, and 65% for *B/*B. The LSMs correctly identified ≥91% of patients with an AUC above the therapeutic range. The misclassified patients had a mean difference less than 5% in their AUCs. CONCLUSION: Patients carrying GSTA1 loss of function *B allele were at increased risk of overdosing on their initial busulfan oral dose. Genetic polymorphisms associated with GSTA1 explain a significant part of busulfan CLo variability which could be captured by LSM strategies.

Brain response to birdsongs in bird experts.

Auditory expertise has mostly been studied in relation to musical processing, but expert auditory processing can also involve nonmusical auditory stimuli, such as birdsongs in bird experts. In this study, the neural correlates of bird expertise were investigated by using electroencephalography to measure auditory-evoked potentials in bird experts and novices. Auditory stimuli in three categories (birdsongs, environmental sounds and voices) were presented in a pseudo-random order while participants performed a simple target detection task (pure tone). We observed similar amplitudes and distributions of the N100-component in bird experts and novices. In contrast, the amplitude of the P200 component was significantly smaller in bird experts at the Pz and Cz electrodes, reflecting a more frontal topography of this positivity. Notably, this group difference was observed not only for birdsongs, but also for voices and environmental sounds, suggesting a general processing difference in bird experts, not restricted to the category of expertise.

Cerebral response to 'voiceness': a functional magnetic resonance imaging study.

We evaluated the response of the voice-selective areas of the auditory cortex to sound 'voiceness', that is, the degree to which an auditory stimulus resembles human voice. Normal participants were scanned using event-related functional magnetic resonance imaging while passively listening to stimuli drawn from a 'voiceness' continuum generated via auditory morphing between sounds of voice and sounds of musical instruments. The voice-selective areas of the left and right superior temporal sulcus did not show the expected relation between 'voiceness' and size effect. Instead, superior temporal sulcus activity seemed mostly driven by sound naturalness, with largest activity differences observed for the intermediate, voice-instrument hybrid stimuli.

Human PDCD2L Is an Export Substrate of CRM1 That Associates with 40S Ribosomal Subunit Precursors.

Protein arginine methyltransferase 3 (PRMT3) forms a stable complex with 40S ribosomal protein S2 (RPS2) and contributes to ribosome biogenesis. However, the molecular mechanism by which PRMT3 influences ribosome biogenesis and/or function still remains unclear. Using quantitative proteomics, we identified human programmed cell death 2-like (PDCD2L) as a novel PRMT3-associated protein. Our data suggest that RPS2 promotes the formation of a conserved extraribosomal complex with PRMT3 and PDCD2L. We also show that PDCD2L associates with 40S subunit precursors that contain a 3'-extended form of the 18S rRNA (18S-E pre-rRNA) and several pre-40S maturation factors. PDCD2L shuttles between the nucleus and the cytoplasm in a CRM1-dependent manner using a leucine-rich nuclear export signal that is sufficient to direct the export of a reporter protein. Although PDCD2L is not required for the biogenesis and export of 40S ribosomal subunits, we found that PDCD2L-null cells accumulate free 60S ribosomal subunits, which is indicative of a deficiency in 40S subunit availability. Our data also indicate that PDCD2L and its paralog, PDCD2, function redundantly in 40S ribosomal subunit production. Our findings uncover the existence of an extraribosomal complex consisting of PDCD2L, RPS2, and PRMT3 and support a role for PDCD2L in the late maturation of 40S ribosomal subunits.

The Montreal Affective Voices: a validated set of nonverbal affect bursts for research on auditory affective processing.

The Montreal Affective Voices consist of 90 nonverbal affect bursts corresponding to the emotions of anger, disgust, fear, pain, sadness, surprise, happiness, and pleasure (plus a neutral expression), recorded by 10 different actors (5 of them male and 5 female). Ratings of valence, arousal, and intensity for eight emotions were collected for each vocalization from 30 participants. Analyses revealed high recognition accuracies for most of the emotional categories (mean of 68%). They also revealed significant effects of both the actors' and the participants' gender: The highest hit rates (75%) were obtained for female participants rating female vocalizations, and the lowest hit rates (60%) for male participants rating male vocalizations. Interestingly, the mixed situations--that is, male participants rating female vocalizations or female participants rating male vocalizations--yielded similar, intermediate ratings. The Montreal Affective Voices are available for download at vnl.psy.gla.ac.uk/ (Resources section).