SUMMARY Studying 830 pre-B ALL cases from four clinical trials, we found that human ALL can be divided into two fundamentally distinct subtypes based on pre-BCR function. While absent in the majority of ALL cases, tonic pre-BCR signaling was found in 112 cases (13.5%). In these cases, tonic pre-BCR signaling induced activation of BCL6, which in turn increased pre-BCR signaling output at the transcriptional level. Interestingly, inhibition of pre-BCR-related tyrosine kinases reduced constitutive BCL6 expression and selectively killed patient-derived pre-BCR+ ALL cells. These findings identify a genetically and phenotypically distinct subset of human ALL that critically depends on tonic pre-BCR signaling. In vivo treatment studies suggested that pre-BCR tyrosine kinase inhibitors are useful for the treatment of patients with pre-BCR+ ALL.

Three experiments studied auditory streaming using sequences of alternating "ABA" triplets, where "A" and "B" were 50-ms tones differing in frequency by Δf semitones and separated by 75-ms gaps. Experiment 1 showed that detection of a short increase in the gap between a B tone and the preceding A tone, imposed on one ABA triplet, was better when the delay occurred early versus late in the sequence, and for Δf = 4 vs. Δf = 8. The results of this experiment were consistent with those of a subjective streaming judgment task. Experiment 2 showed that the detection of a delay 12.5 s into a 13.5-s sequence could be improved by requiring participants to perform a task on competing stimuli presented to the other ear for the first 10 s of that sequence. Hence, adding an additional task demand could improve performance via its effect on the perceptual organization of a sound sequence. The results demonstrate that attention affects streaming in an objective task and that the effects of build-up are not completely under voluntary control. In particular, even though build-up can impair performance in an objective task, participants are unable to prevent this from happening.

Interaural time difference (ITD) is a critical cue to sound-source localization. Traditional models assume that sounds leading at one ear, and perceived on that side, are processed in the opposite midbrain. Using functional magnetic resonance imaging we demonstrate that as the ITDs of sounds increase, midbrain activity can switch sides, even though perceived location remains on the same side. The data require a new model for human ITD processing.

Humans use differences in the timing of sounds at the two ears to determine the location of a sound source. Various models have been posited for the neural representation of these interaural time differences (ITDs). These models make opposing predictions about the lateralization of ITD processing in the human brain. The weighted-image model predicts that sounds leading in time at one ear activate maximally the opposite brain hemisphere for all values of ITD. In contrast, the π-limit model assumes that ITDs beyond half the period of the stimulus center frequency are not explicitly encoded in the brain and that such “long” ITDs activate maximally the side of the brain to which the sound is heard. A previous neuroimaging study revealed activity in the human inferior colliculus consistent with the π-limit. Here we show that cortical responses to sounds with ITDs within the π-limit are in line with the predictions of both models. However, contrary to the immediate predictions of both models, neural activation is bilateral for “long” ITDs, despite these being perceived as clearly lateralized. Furthermore, processing of long ITDs leads to higher activation in cortex than processing of short ITDs. These data show that coding of ITD in cortex is fundamentally different from coding of ITD in the brain stem. We discuss these results in the context of the two models.

Objective: To determine very late clinical outcomes at up to 20 years followup from a randomized controlled trial of Nissen versus anterior 180-degree partial fundoplication. Summary Background Data: Nissen fundoplication for gastroesophageal reflux can be followed by troublesome side effects. To address this, partial fundoplications have been proposed. Previously reports from a randomized controlled trial of Nissen versus anterior 180-degree partial fundoplication at up to 10 years follow-up showed good outcomes for both procedures. Methods: One hundred seven participants were randomized to Nissen versus anterior 180-degree partial fundoplication. Fifteen to 20 year follow-up data was available for 79 (41 Nissen, 38 anterior). Outcome was assessed using a standardized questionnaire with 0 to 10 analog scores and yes/no questions to determine reflux symptoms, side-effects, and satisfaction with surgery. Results: After anterior fundoplication heartburn (mean score 3.2 vs 1.4, P ¼.001) and proton pump inhibitor use (41.7% vs 17.1%, P ¼.023) were higher, offset by less dysphagia for solids (mean score 1.8 vs 3.3, P ¼.015), and better ability to belch (84.2% vs 65.9%, P ¼.030). Measures of overall outcome were similar for both groups (mean satisfaction score 8.4 vs 8.0, P ¼.444; 86.8% vs 90.2% satisfied with outcome). Six participants underwent revision after anterior fundoplication (Nissen conversion for reflux -6), and 7 underwent revision after Nissen fundoplication (Nissen to partial fundoplication for dysphagia -5; redo Nissen for reflux -1; paraesophageal hernia -1). Conclusions: At 15 to 20 years follow-up Nissen and anterior 180-degree partial fundoplication achieved similar success, but with trade-offs between better reflux control versus more side-effects after Nissen fundoplication.