David H. Jung

Unraveling V(D)J Recombination: Insights into Gene Regulation

V(D)J recombination assembles antigen receptor genes from component gene segments. We review findings that have shaped our current understanding of this remarkable mechanism, with a focus on two major reports--the first detailed comparison of germline and rearranged antigen receptor loci and the discovery of the recombination activating gene-1.

A Single DH Gene Segment Creates Its Own Unique CDR-H3 Repertoire and Is Sufficient for B cell Development and Immune Function

To test the contribution of individual D gene segments to B cell development and function, we used gene targeting to create mice that contain only DFL16.1 in the DH locus. We term this D-limited IgH allele ΔD-DFL. Although the absolute number of IgM+IgD− B cells in the bone marrow was decreased, homozygous ΔD-DFL BALB/c mice contained normal numbers of IgM+IgD+ B cells in bone marrow and spleen and normal numbers of B1a, B1b, and B2 cells in the peritoneal cavity. Bone marrow IgM+IgD+ B cells express a CDR-H3 repertoire similar in length and amino acid composition to the DFL16.1 subset of the wild-type BALB/c repertoire but divergent from sequences that do not contain DFL16.1. This similarity in content is the product of both germline bias and somatic selection, especially in the transition to the mature IgM+IgD+ stage of development. Serum Ig concentrations and the humoral immune response to a T-dependent Ag ([4-hydroxy-3-nitrophenyl]acetyl hapten) were nearly identical to wild-type littermate controls. A greater variance in the immune response to the T-independent Ag (α(1→3)-dextran) was observed in ΔD-DFL homozygotes, with half of the mice exhibiting levels below the range exhibited by controls. Although limited to a repertoire specific to DFL16.1, the presence of a single DH gene segment of normal sequence was sufficient for development of normal numbers of mature B cells and for robust humoral immune function.

Association of Hearing Loss with Decreased Employment and Income among Adults in the United States

Objectives: We evaluated the association of hearing loss with employment and income in adults. Methods: Patients with a coded diagnosis of hearing loss were identified from the 2006 and 2008 Medical Expenditure Panel Survey linked household and medical conditions files and compared to patients without hearing loss. Differences in employment, wage income, and Supplemental Security Income were evaluated with multivariate regression models after adjustment for several demographic and Charlson comorbidity variables. Results: An estimated 933,921 ± 88,474 adults were identified with hearing loss (54.7% of whom were male; mean age for all, 51.0 years). Patients with hearing loss were more likely to be unemployed or partly unemployed than those without hearing loss (adjusted odds ratio, 2.2; p < 0.001). Similarly, adults with hearing loss were less likely to have any wage income than those without hearing loss (adjusted odds ratio, 2.5; p < 0.001). The population with hearing loss earned a mean wage of

Dizziness is more prevalent than autophony among patients who have undergone repair of superior canal dehiscence.

23,481 ±

Differential utilization of T cell receptor TCRα/TCRδ locus variable region gene segments is mediated by accessibility

3,366, versus

Histopathology of the Inner Ear in a Case With Recent Onset of Cogan’s Syndrome Evidence for Vasculitis

31,272 ±

Recent advances in therapeutics and drug delivery for the treatment of inner ear diseases: a patent review (2011-2015)

517 for the population without hearing loss (difference in wages,

Intracochlear Drug Delivery Through the Oval Window in Fresh Cadaveric Human Temporal Bones.

7,791; p < 0.001). The association between hearing loss and receiving Supplemental Security Income was not significant (p = 0.109). Conclusions: Adults with hearing loss are more likely to be unemployed and on average earn significantly less wage income than adults without hearing loss. Further work is needed to determine the potential impact of treatment on these differences.

Health Utility Improves After Surgery for Superior Canal Dehiscence Syndrome

Objective Studies have reported high early success rates in rectifying dizziness and autophony after primary repair of superior canal dehiscence (SCD). We sought to identify the prevalence of dizziness and autophony at later time points in patients who had undergone SCD repair. We also assessed any problems with hearing in this population, along with prevalence of headaches and decreases in overall quality of life. Study Quality Design Identification of patients via retrospective chart review, followed by administration of multiple validated surveys. Setting Tertiary, hospital-based neurotology practice. Patients All 62 patients who had undergone primary SCD repair at Massachusetts Eye and Ear Infirmary with follow-up time of at least 3 months were contacted, with 38 responses from 22 women and 16 men. The average follow-up was 34 months (range, 3–155 mo). Interventions Patient surveys. Main Outcome Measures Dizziness Handicap Inventory and Autophony Index. Secondary Outcome Measures Hearing Handicap Survey, MIDAS headache survey, and Short Form-36 Quality of Life Survey. Results Twenty patients reported low DHI scores, whereas 18 patients reported elevated DHI scores corresponding to moderate-to-severe dizziness. Autophony was less prevalent, as 3 patients experienced autophony in the operated ear, whereas 3 patients experienced “unmasking” of autophony in the contralateral ear. HHI scores were not significantly different between the low DHI and high DHI group. There were significantly more female subjects in the high DHI group, which was also characterized by significantly more severe MIDAS grades and significantly worse SF-36 scores. Conclusion Dizziness is more prevalent than autophony among patients who have undergone SCD repair, although the majority of these patients are satisfied with their decision to undergo surgery. Female sex and migraine headaches are associated with dizziness in this patient population. Further work is necessary to determine causal relationships among these associations.

Non-ototoxic local delivery of bisphosphonate to the mammalian cochlea

T cell receptor (TCR) variable region exons are assembled from germline V, (D), and J gene segments, each of which is flanked by recombination signal (RS) sequences that are composed of a conserved heptamer, a spacer of 12 or 23 bp, and a characteristic nonamer. V(D)J recombination only occurs between V, D, and J segments flanked by RS sequences that contain, respectively, 12(12-RS)- and 23(23-RS)-bp spacers (12/23 rule). Additional mechanisms can restrict joining of 12/23 RS matched segments beyond the 12/23 rule (B12/23). The TCRδ locus is contained within the TCRα locus; TCRα variable region exons are encoded by TRAV and TRAJ segments and those of TCRδ by TRDV, TRDD, and TRDJ segments. On the basis of the 12/23 rule, both TRAV and TRDV gene segments are compatible to rearrange with TRDD gene segments; however, TRAV-to-TRDD joins are not observed in vivo. Absence of TRAV-to-TRDD rearrangement might be explained either by B12/23 restriction or by differential accessibility of the TRDV versus TRAV gene segments for rearrangement to TRDD. We used in vitro substrate analysis to reveal that both TRAV and TRDV 23-RSs mediate rearrangements to the 5′TRDD1 12-RS, demonstrating that B12/23 restriction does not explain these rearrangement biases. However, targeted replacement of TRDD1 and its 12-RSs with TRAJ38 and its 12-RS showed that TRDV gene segments rearrange with the ectopic TRAJ38, whereas TRAV segments do not. Our results demonstrate that sorting of TRAV and TRDV gene segments is determined by differential locus accessibility during T cell development.