Hypotheses Electrocochleography (ECoG) to acoustic stimuli can differentiate relative degrees of cochlear responsiveness across the population of cochlear implant recipients. The magnitude of the ongoing portion of the ECoG, which includes both hair cell and neural contributions, will correlate with speech outcomes as measured by results on CNC word score tests. Background Postoperative speech outcomes with cochlear implants vary from almost no benefit to near normal comprehension. A factor expected to have a high predictive value is the degree of neural survival. However, speech performance with the implant does not correlate with the number and distribution of surviving ganglion cells when measured post-mortem. We will investigate whether ECoG can provide an estimate of cochlear function that helps predict postoperative speech outcomes. Methods An electrode was placed at the ipsilateral round window of the ear about to be implanted during implant surgery. Tone bursts were delivered through an insert earphone. Subjects included children (N=52, 1–18 years) and postlingually hearing impaired adults (N=32). Word scores at six months were available from 21 adult subjects. Results Significant responses to sound were recorded from almost all subjects (80/84 or 95%). The ECoG magnitudes spanned more than 50 dB in both children and adults. The distributions of ECoG magnitudes and frequencies were similar between children and adults. The correlation between the ECoG magnitude and word score accounted for 47% of the variance. Conclusions ECoGs with high signal to noise ratios can be recorded from almost all implant candidates, including both adult and pediatric populations. In post-lingual adults, the ECoG magnitude is more predictive of implant outcomes than other non-surgical variables such as duration of deafness or degree of residual hearing.

Hypothesis Acoustically evoked neural and hair cell potentials can be measured from the round window (RW) intraoperatively in the general population of cochlear implant recipients. Background Cochlear implant performance varies greatly among patients. Improved methods to assess and monitor functional hair cell and neural substrate prior to and during implantation could potentially aid in enhanced non-traumatic intracochlear electrode placement and subsequent improved outcomes. Methods Subjects (1–80 years) undergoing cochlear implantation were included. A monopolar probe was placed at the RW after surgical access was obtained. The cochlear microphonic (CM), summating potential (SP), compound action potential (CAP), and auditory nerve neurophonic (ANN) were recorded in response to tone bursts at frequencies of 0.25 – 4 kHz at various levels. Results Measurable hair cell/neural potentials were detected to one or more frequencies in 23 of 25 subjects. The greatest proportion and magnitude of cochlear responses were to low frequencies (<1000 Hz). At these low frequencies the ANN, when present, contributed to the ongoing response at the stimulus frequency. In many subjects the ANN was small or absent while hair cell responses remained. Conclusions In cochlear implant recipients, acoustically evoked cochlear potentials are detectable even if hearing is extremely limited. Sensitive measures of cochlear and neural status can characterize the state of hair cell and neural function prior to implantation. Whether this information correlates with speech performance outcomes, or can help in tailoring electrode type, placement or audiometric fitting, can be determined in future studies.

Objective/Hypothesis Previous reports have documented the feasibility to utilize electrocochleography (ECochG) to acoustic signals to assess trauma caused during cochlear implantation. The hypothesis is that intraoperative round window ECochG before and after electrode insertion will help predict postoperative hearing preservation outcomes in cochlear implant recipients. Study Design Prospective cohort study Methods Intraoperative round window ECochG responses were collected from thirty-one cochlear implant recipients (14 children and 17 adults) immediately prior to and just after electrode insertion. Hearing preservation was determined by postoperative changes in behavioral thresholds. Results On average, the post-insertion response was smaller than the pre-insertion by an average of 4 dB across frequency. However, in some cases (12/31) the response increased after insertion.. The subsequent hearing loss was greater than the acute loss in the ECochG, averaging 22 dB across the same frequency range (250–1000 Hz). There was no correlation between the change in the ECochG response and the corresponding change in audiometric threshold. Conclusion Intraoperative ECochG is a sensitive method for detecting electrophysiologic changes during implantation but had limited prognostic value regarding hearing preservation in the current conventional cochlear implant patient population where hearing preservation was not intended.

Insulin-like growth factor 1 (IGF-1) enhances thymopoiesis but given the broad distribution of IGF-1 receptors (IGF-1Rs), its mechanism of action has remained unclear. To identify points of thymic regulation by IGF-1, we examined its effects on T-cell precursors, thymocytes, and thymic epithelial cells (TECs) in normal and genetically altered mice. In thymusintact but not thymectomized mice, IGF-1 administration increased peripheral naive and recent thymic emigrant (RTE) populations, demonstrating its effect on T-cell production, not peripheral expansion. IGF-1 administration increased bone marrow LSK (lineage ؊ , Sca-1 ؉ , c-kit ؉ ) precursor proliferation and peripheral LSK populations, increased thymocyte populations in a sequential wave of expansion, and proportionately expanded TEC subpopulations and enhanced their chemokine expression. To separate IGF-1's effects on thymocytes and TECs, we generated mice lacking IGF-1R on thymocytes and T cells. Thymocyte and RTE numbers were decreased in these mice, but IGF-1 treatment produced comparable thymocyte numbers to similarly treated wild-type mice. We additionally separated thymic-from LSK-specific effects by demonstrating that IGF-1 increased thymocyte numbers despite impaired early thymic progenitor ( IntroductionThymic function after lymphodepletion as seen in hematopoietic stem cell transplantation (HSCT), HIV infection, and aging is critical for maintaining a broad repertoire of T-cell responses. Impaired thymic function results in not only increased susceptibility to opportunistic infections but also increased risk of tumor relapse due to impaired tumor surveillance. 1 Moreover, given the critical role of the thymus in negative selection and the generation of regulatory T cells, impaired thymic function may be a significant contributory factor in the development of graft-versus-host disease and autoimmunity. 2,3 Strategies to preserve and/or enhance thymic function therefore may overcome these important clinical barriers.Thymic regulation can occur at multiple levels. The thymus requires continuous replenishment of bone marrow-derived progenitors to maintain T-cell production. Thereafter, T-cell development occurs in an ordered temporal-spatial sequence within distinct developmental niches defined by interactions between thymocytes and thymic epithelial cells (TECs). TECs define overall thymic function by modulating thymocyte survival, proliferation, trafficking, and positive and negative selection. 4 Consequently, increasing the number of available T-cell precursors for importation into the thymus, 5,6 expanding developmental niches within the thymus by expanding of TEC populations, 7,8 and manipulating interactions between TECs and thymocytes to increase thymopoietic throughput have all been implicated as potential points of thymic function regulation. Nevertheless, their relative importance in the regulation of overall thymic regulation remains unknown. In this regard, the actions of thymic regulators, which presumably act by one or more of these mech...

To study interleukin-7 (IL-7) in early thymocyte development, we generated mice transgenic (Tg) for the IL-7 gene under control of the lck proximal promoter. Founder line TgA, with the lowest level of IL-7 overexpression, showed enhanced ␣␤ T-cell development. In contrast, in the highest overexpressing founder line, TgB, ␣␤ T-cell development was disturbed with a block at the earliest intrathymic precursor stage. This was due to decreased progenitor proliferation as assessed by Ki-67 staining and in vivo bromodeoxyuridine (BrdU) incorporation. Bcl-2 was upregulated in T-cell-committed progenitors in all Tg lines, and accounted for greater numbers of double positive (DP), CD4 single positive (SP), and CD8SP thymocytes in TgA mice where, in contrast to TgB mice, thymocyte progenitor proliferation was normal. Mixed marrow chimeras using TgB ؉ and congenic mice as donors, and experiments using anti-IL-7 monoclonal antibody (MAb) in vivo, confirmed the role of IL-7 protein in the observed TgB phenotype. In conclusion, at low Tg overexpression, IL-7 enhanced ␣␤ T-cell development by increasing thymocyte progenitor survival, while at high overexpression IL-7 reduces their proliferation, inducing a dramatic block in DP production. These results show for the first time in vivo a dose effect of IL-7 on ␣␤ T-cell development and have implications for IL-7 in the clinical setting. IntroductionInterleukin-7 (IL-7) is a nonredundant cytokine in thymic development. It has been implicated in both proliferation and survival of early T cells. [1][2][3] After the transition from the multipotent to the T-cell-committed stage, thymocyte progenitors become dependent on IL-7 for normal cell cycle progression and cell survival through inhibition of apoptosis via up-regulation of the Bcl-2 expression. 1 Consequently, in several mouse models of IL-7 signal disruption such as IL-7 Ϫ/Ϫ , 2 IL-7 receptor ␣ Ϫ/Ϫ (IL-7R␣ Ϫ/Ϫ ), 3,4 ␥c Ϫ/Ϫ , 5-7 Jak3 Ϫ/Ϫ , [8][9][10] and Jak1 Ϫ/Ϫ , 11 progression beyond double negative-2 (DN2) stage is severely diminished. However, despite its role on proliferation, studies evaluating the need for IL-7 during lymphocyte development led to the conclusion that the primary role of this cytokine was rather in maintaining cell survival. 12 Additionally, IL-7 controls T-cell receptor ␥ (TCR␥) rearrangement by regulating locus accessibility, 13 such that ␥␦ T-cell production is abrogated in the absence of IL-7 signaling, 4,5,9,13-15 demonstrating a complete reliance on IL-7 by this lineage.Many in vitro studies have shown an effect of IL-7 on thymocyte progenitors. [16][17][18][19] However, the effect of IL-7 on ␣␤ T-cell development yielded somewhat conflicting results. Varas et al observed, with rat fetal thymic organ culture (FTOC) grown in the presence of 2000 U/mL IL-7, an enhancement of ␣␤ thymocyte maturation. 19 In contrast, Plum et al's study, which used mouse FTOC treated with different doses of human recombinant IL-7 (rIL-7, 100-5000 U/mL), showed significantly lower numbers of ␣␤ T cells with increasing I...