Faculty Bibliography

OBJECTIVE: To investigate whether children implanted in the first year of life show higher levels of speech perception than later-implanted children, when compared at the same ages and to investigate the time course of sensitive periods for developing speech perception skills. More specifically, to determine whether faster gains in speech perception are made by children implanted before 1 year old relative to those implanted at 2 or 3 years. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary academic referral center. PATIENTS: 117 children with congenital profound bilateral sensorineural hearing loss, with no additional identified disabilities. INTERVENTION: Cochlear implantation in the first, second, or third year of life. MAIN OUTCOME MEASURE: Development curves showing Lexical Neighborhood Test (LNT) word identification scores as a function of age. RESULTS: Children implanted within the first year of life have a mean advantage of 8.2% LNT-easy word scores over those implanted in the second year (p < 0.001) and a 16.8% advantage in LNT-easy word scores over those implanted in the third year of life (p < 0.001). These advantages remained statistically significant after accounting for sex, residual hearing, and bilateral cochlear implant use. When speech perception scores were expressed as a function of 'hearing age' rather than chronological age, however, there were no significant differences among the 3 groups. CONCLUSION: There is a clear speech perception advantage for earlier-implanted children over later-implanted children when compared at the same age but not when compared at the same time after implantation. Thus, the sensitive period for developing word identification seems to extend at least until age 3 years

HYPOTHESIS: When cochlear implant (CI) users are allowed to self-select the 'most intelligible' frequency-to-electrode table, some of them choose one that differs from the default frequency table that is normally used in clinical practice. BACKGROUND: CIs reproduce the tonotopicity of normal cochleas using frequency-to-electrode tables that assign stimulation of more basal electrodes to higher frequencies and more apical electrodes to lower frequency sounds. Current audiologic practice uses a default frequency-to-electrode table for most patients. However, individual differences in cochlear size, neural survival, and electrode positioning may result in different tables sounding most intelligible to different patients. No clinical tools currently exist to facilitate this fitting. METHODS: A software tool was designed that enables CI users to self-select a most intelligible frequency table. Users explore a 2-dimensional space that represents a range of different frequency tables. Unlike existing tools, this software enables users to interactively audition speech processed by different frequency tables and quickly identify a preferred one. Pilot testing was performed in 11 long-term, postlingually deaf CI users. RESULTS: The software tool was designed, developed, tested, and debugged. Patients successfully used the tool to sample frequency tables and to self-select tables deemed most intelligible, which for approximately half of the users differed from the clinical default. CONCLUSION: A software tool allowing CI users to self-select frequency-to-electrode tables may help in fitting postlingually deaf users. This novel approach may transform current methods of CI fitting

Conjugal transfer of chromosomal DNA between strains of Mycobacterium smegmatis occurs by a novel mechanism. In a transposon mutagenesis screen, three transfer-defective insertions were mapped to the lsr2 gene of the donor strain mc(2)155. Because lsr2 encodes a nonspecific DNA-binding protein, mutations of lsr2 give rise to a variety of phenotypes, including an inability to form biofilms. In this study, we show that efficient DNA transfer between strains of M. smegmatis occurs in a mixed biofilm and that the process requires expression of lsr2 in the donor but not in the recipient strain. Testing cells from different strata of standing cultures showed that transfer occurred predominantly at the biofilm air-liquid interface, as other strata containing higher cell densities produced very few transconjugants. These data suggest that the biofilm plays a role beyond mere facilitation of cell-cell contact. Surprisingly, we found that under standard assay conditions the recipient strain does not form a biofilm. Taking these results together, we conclude that for transfer to occur, the recipient strain is actively recruited into the biofilm. In support of this idea, we show that donor and recipient cells are present in almost equal numbers in biofilms that produce transconjugants. Our demonstration of genetic exchange between mycobacteria in a mixed biofilm suggests that conjugation occurs in the environment. Since biofilms are considered to be the predominant natural microhabitat for bacteria, our finding emphasizes the importance of studying biological and physical processes that occur between cells in mixed biofilms.

Perceptual skills can be improved even in adulthood, but this learning seldom occurs by stimulus exposure alone. Instead, it requires considerable practice performing a perceptual task with relevant stimuli. It is thought that task performance permits the stimuli to drive learning. A corresponding assumption is that the same stimuli do not contribute to improvement when encountered separately from relevant task performance because of the absence of this permissive signal. However, these ideas are based on only two types of studies, in which the task was either always performed or not performed at all. Here we demonstrate enhanced perceptual learning on an auditory frequency-discrimination task in human listeners when practice on that target task was combined with additional stimulation. Learning was enhanced regardless of whether the periods of additional stimulation were interleaved with or provided exclusively before or after target-task performance, and even though that stimulation occurred during the performance of an irrelevant (auditory or written) task. The additional exposures were only beneficial when they shared the same frequency with, though they did not need to be identical to, those used during target-task performance. Their effectiveness also was diminished when they were presented 15 min after practice on the target task and was eliminated when that separation was increased to 4 h. These data show that exposure to an acoustic stimulus can facilitate learning when encountered outside of the time of practice on a perceptual task. By properly using additional stimulation one may markedly improve the efficiency of perceptual training regimens

The Philadelphia chromosome (Ph)-negative myeloproliferative neoplasms (MPNs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are a group of clonal hematopoietic stem cell disorders with overlapping clinical and cytogenetic features and a variable tendency to evolve into acute leukemia. These diseases not only share overlapping chromosomal abnormalities but also a number of acquired somatic mutations. Recently, mutations in a putative tumor suppressor gene, ten-eleven translocation 2 (TET2) on chromosome 4q24 have been identified in 12% of patients with MPN. Additionally 4q24 chromosomal rearrangements in MPN, including TET2 deletions, have also been observed using conventional cytogenetics. The goal of this study was to investigate the frequency of genomic TET2 rearrangements in MPN using fluorescence in situ hybridization as a more sensitive method for screening and identifying genomic deletions. Among 146 MPN patients, we identified two patients (1.4%) who showed a common 4q24 deletion, including TET2. Our observations also indicated that the frequency of TET2 deletion is increased in patients with an abnormal karyotype (5%).

Monoclonal antibodies are standard therapeutics for several cancers including the anti-CD20 antibody rituximab for B cell non-Hodgkin lymphoma (NHL). Rituximab and other antibodies are not curative and must be combined with cytotoxic chemotherapy for clinical benefit. Here we report the eradication of human NHL solely with a monoclonal antibody therapy combining rituximab with a blocking anti-CD47 antibody. We identified increased expression of CD47 on human NHL cells and determined that higher CD47 expression independently predicted adverse clinical outcomes in multiple NHL subtypes. Blocking anti-CD47 antibodies preferentially enabled phagocytosis of NHL cells and synergized with rituximab. Treatment of human NHL-engrafted mice with anti-CD47 antibody reduced lymphoma burden and improved survival, while combination treatment with rituximab led to elimination of lymphoma and cure. These antibodies synergized through a mechanism combining Fc receptor (FcR)-dependent and FcR-independent stimulation of phagocytosis that might be applicable to many other cancers.

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has shown promise in treating recurrent adult high-grade glioma (HGG). However, there is very little data on recurrent or progressive pediatric HGG treated with bevacizumab. We report the results of a single institution experience using bevacizumab and irinotecan in children who relapsed or progressed following standard therapy. Twelve pediatric patients with recurrent or progressive HGG received bevacizumab at 10 mg/kg every 2 weeks with irinotecan at 125 mg/m(2). Magnetic resonance imaging (MRI) was performed prior to therapy and every 8 weeks subsequently. Ten patients had supratentorial HGG; 2 had DIPG. Radiological responses were defined according to MacDonald's criteria. Progression-free survival (PFS), overall survival (OS), and toxicities were analyzed. Ten (83.3%) patients tolerated bevacizumab without serious toxicity. Therapy was discontinued in 1 patient because of anaphylaxis. Another patient developed grade III delayed wound healing and deep vein thrombosis. Two patients (16.7%) experienced a partial response after the first MRI. No complete radiographic responses were seen. Stable disease was noted in 4 (33.3%) patients. The median PFS and OS were 2.25 and 6.25 months, respectively. A diffuse invasive recurrence pattern was noted in 5 (45.5%) patients. Treatment tolerance, toxicity, and recurrence profiles were comparable to adult HGG patients treated with bevacizumab. However, the radiological response rate, response duration, and survival appeared inferior in pediatric patients. Genetic differences in pediatric gliomas might account for this difference