Inhibiting MYC binding to the E-box DNA motif by ME47 decreases tumour xenograft growth.

Developing therapeutics to effectively inhibit the MYC oncoprotein would mark a key advance towards cancer patient care as MYC is deregulated in over 50% of human cancers. MYC deregulation is correlated with aggressive disease and poor patient outcome. Despite strong evidence in mouse models that inhibiting MYC would significantly impact tumour cell growth and patient survival, traditional approaches have not yet yielded the urgently needed therapeutic agents that directly target MYC. MYC functions through its interaction with MAX to regulate gene transcription by binding to E-box DNA response elements of MYC target genes. Here we used a structure-based strategy to design ME47, a small minimalist hybrid protein (MHP) able to disrupt the MAX:E-box interaction/binding and block transcriptional MYC activity. We show that inducing ME47 expression in established tumour xenografts inhibits tumour growth and decreases cellular proliferation. Mechanistically, we show by chromatin immunoprecipitation that ME47 binds to E-box binding sites of MYC target genes. Moreover, ME47 occupancy decreases MYC:DNA interaction at its cognate E-box binding sites. Taken together, ME47 is a prototypic MHP inhibitor that antagonizes tumour cell growth in vitro and in vivo and inhibits the interaction of MYC with DNA E-box elements. These results support ME47's role as a MYC inhibitor and suggest that MHPs provide an alternative therapeutic targeting system that can be used to target transcription factors important in human diseases, including cancer.

Up regulation of nitric oxide synthase-nitric oxide system in the testis of rats undergoing autoimmune orchitis.

BACKGROUND: Male reproductive tract infection and inflammation are important aetiological factors of infertility. Experimental Autoimmune Orchitis (EAO) is a model of chronic inflammation useful to study mechanisms of inflammatory reactions leading to testicular impairment. EAO is characterised by interstitial cell infiltrate of lymphomonocytes, producers of pro-inflammatory cytokines involved in germ cell apoptosis. Nitric oxide (NO), a free radical promoting immune cell activation and apoptosis, is synthesised by conversion of l-arginine to l-citrulline catalysed by NO synthase (NOS). The NOS isoforms are: constitutively endothelial (e) and neuronal (n) NOS and inducible (i) NOS. OBJECTIVES: Although the NO-NOS system was found to be up-regulated by pro-inflammatory mediators in immune and non immune testicular cells, data on its regulation in chronic inflammatory states is lacking. METHODS AND RESULTS: EAO was induced in rats by active immunisation with spermatic antigens and adjuvants; control (C) rats were injected with adjuvants. Untreated normal (N) rats were also studied. We demonstrated that iNOS, eNOS and nNOS was mainly expressed by interstitial cells in N and C rats and that in EAO NOS was up-regulated and also expressed by tubular cells. Constitutive and inducible NOS content (Western blot) as well as NO production and activity increased in the testis of rats with EAO. iNOS content and activity were selectively up-regulated in the testis of rats with orchitis. Flow cytometric analysis of NOS isoforms in testicular macrophages (M) showed that the percentage of ED1(+)ED2(-) and ED1(+)ED2(+) M subsets, expressing constitutive and iNOS isoforms was significantly higher in EAO, but no change in the percentage of ED1(-)ED2(+) resident M was observed compared to C rats. M from EAO rats also released more NO than C and N rats. CONCLUSIONS: In testis of rats with EAO, NO-NOS system was up-regulated and both testicular M and cells from seminiferous tubules contributed to NO increase. NO over production in orchitis was generated mainly by increased iNOS content and activity.

Clinical guidelines for the management of craniofacial fibrous dysplasia.

Fibrous dysplasia (FD) is a non-malignant condition caused by post-zygotic, activating mutations of the GNAS gene that results in inhibition of the differentiation and proliferation of bone-forming stromal cells and leads to the replacement of normal bone and marrow by fibrous tissue and woven bone. The phenotype is variable and may be isolated to a single skeletal site or multiple sites and sometimes is associated with extraskeletal manifestations in the skin and/or endocrine organs (McCune-Albright syndrome). The clinical behavior and progression of FD may also vary, thereby making the management of this condition difficult with few established clinical guidelines. This paper provides a clinically-focused comprehensive description of craniofacial FD, its natural progression, the components of the diagnostic evaluation and the multi-disciplinary management, and considerations for future research.

Expression of cell adhesion molecules, chemokines and chemokine receptors involved in leukocyte traffic in rats undergoing autoimmune orchitis.

The testis is considered an immunologically privileged site where germ cell antigens are protected from autoimmune attack. Yet in response to infections, inflammatory diseases, or trauma, there is an influx of leukocytes to testicular interstitium. Interactions between endothelial cells (EC) and circulating leukocytes are implicated in the initiation and evolution of inflammatory processes. Chemokines are a family of chemoattractant cytokines characterized by their ability to both recruit and activate cells. Thus, we investigated the expression of CCL3, its receptors, and adhesion molecules CD31 and CD106 in an in vivo model of experimental autoimmune orchitis (EAO). In EAO, the highest content of CCL3 in testicular fluid coincides with onset of the disease. However, CCL3 released in vitro by testicular macrophages is higher during the immunization period. The specific chemokine receptors, CCR1 and CCR5, were expressed by testicular monocytes/macrophages and an increased number of CCR5+ cells was associated with the degree of testicular lesion. EC also play an essential role by facilitating leukocyte recruitment via their ability to express cell surface adhesion molecules that mediate interactions with leukocytes in the bloodstream. Rats with EAO showed a significant increase in the percentage of CD31+ EC that upregulate the expression of CD106. The percentage of leukocytes isolated from peripheral blood and lymph nodes expressing CD49d (CD106 ligand) also increases during orchitis. These data suggest that cell adhesion molecules, in conjunction with chemokines, contribute to the formation of a chemotactic gradient within the testis, causing the leukocyte infiltration characteristic of EAO histopathology.

α-Synuclein deficiency and efferent nerve degeneration in the mouse cochlea: a possible cause of early-onset presbycusis.

OBJECTIVES/HYPOTHESIS: Efferent nerves under the outer hair cells (OHCs) play a role in the protection of these cells from loud stimuli. Previously, we showed that cochlear α-synuclein expression is localized to efferent auditory synapses at the base of the OHCs. To prove our hypothesis that α-synuclein deficiency and efferent auditory deficit might be a cause of hearing loss, we compared the morphology of efferent nerve endings and α-synuclein expression within the cochleae of two mouse models of presbycusis. STUDY DESIGN: Comparative animal study of presbycusis. METHODS: The C57BL/6J(C57) mouse strain, a well-known model of early-onset hearing loss, and the CBA mouse strain, a model of relatively late-onset hearing loss, were examined. Auditory brainstem responses and distortion product otoacoustic emissions were recorded, and cochlear morphology with efferent nerve ending was compared. Western blotting was used to examine α-synuclein expression in the cochlea. RESULTS: Compared with CBA mice, C57 mice showed earlier onset high-frequency hearing loss and decreased function in OHCs, especially within high-frequency regions. C57 mice demonstrated more severe pathologic changes within the cochlea, particularly within the basal turn, than CBA mice of the same age. Weaker α-synuclein and synaptophysin expression in the efferent nerve endings and cochlear homogenates in C57 mice was observed. CONCLUSIONS: Our results support the hypothesis that efferent nerve degeneration, possibly due to differential α-synuclein expression, is a potential cause of early-onset presbycusis. Further studies at the cellular level are necessary to verify our results.

Impaired expression and distribution of adherens and gap junction proteins in the seminiferous tubules of rats undergoing autoimmune orchitis.

Experimental autoimmune orchitis (EAO) is characterized by an interstitial lymphomononuclear cell infiltration and a severe lesion of seminiferous tubules (ST) with germ cells that undergo apoptosis and sloughing. The aim of this study was to analyse the expression and localization of adherens junction (AJ) proteins: N-cadherin, α-, ß- and p120 catenins and gap junction protein, connexin 43 (Cx43), to explore some aspects of germ-cell sloughing during the development of orchitis. EAO was induced in Sprague-Dawley adult rats by active immunization with testicular homogenate and adjuvants. Control rats (C) were injected with saline solution and adjuvants. Concomitant with early signs of germ-cell sloughing, we observed by immunofluorescence and Western blot, a delocalization and a significant increase in N-cadherin and α-catenin expression in the ST of EAO compared with C rats. In spite of this increased AJ protein expression, a severe germ-cell sloughing occurred. This is probably due to the impairment of the AJ complex function, as shown by the loss of N-cadherin/ß-catenin colocalization (confocal microscopy) and increased pY654 ß-catenin expression, suggesting lower affinity of these two proteins and increased pERK1/2 expression in the testis of EAO rats. The significant decrease in Cx43 expression detected in EAO rats suggests a gap junction function impairment also contributing to germ-cell sloughing.

Characterization of dendritic cells in testicular draining lymph nodes in a rat model of experimental autoimmune orchitis.

The maturation state of dendritic cells (DC) is regarded as a control point for the induction of peripheral tolerance or autoimmunity. Experimental autoimmune orchitis (EAO) serves as a model to investigate inflammatory-based testicular impairment, which ranks as a significant cause of male infertility. This work aimed to determine whether DC enrichment occurs organotypically in testicular draining lymph nodes (TLN) compared with LN draining the site of immunization (ILN) and thus contributes to the pathogenesis of autoimmune orchitis. In this regard, we quantified and characterized the DC from TLN and ILN in rats with EAO. Flow cytometric analysis showed a significant increase in the percentage of DC (OX62+) only in TLN from EAO rats compared with normal (N) and adjuvant control (C) groups. The number of DC from ILN and TLN expressing CD80, CD86 and major histocompatibility complex (MHC) II was comparable among N, C and experimental (E) groups at 30 and 50 days after the first immunization. However, TLN DC from EAO rats (50 days) showed an increase in mean fluorescence intensity for MHC II compared with N, C and E groups (30 days). The mRNA expression level of IL-10 and IL-12p35 was significantly upregulated in enriched DC fraction from TLN in EAO rats with no significant changes observed in ILN DC. The expression of IL-23p19 mRNA remained unchanged. Functional data, using proliferation assays showed that EAO-DC from TLN, but not from ILN, significantly enhanced the proliferation of naïve T cells compared with C-DC. In summary, our data suggest that the DC in TLN from orchitis rats are mature, present antigens to T cells and stimulate an autoimmune response against testicular antigens, thus causing immunological infertility.

Adenosine regulates Sertoli cell function by activating AMPK.

This work evaluates adenosine effects on Sertoli cell functions, which are different to those resulting from occupancy of purinergic receptors. The effects of adenosine and N(6)-cyclohexyladenosine (CHA) - an A(1) receptor agonist resistant to cellular uptake - on Sertoli cell physiology were compared. Adenosine but not CHA increased lactate production, glucose uptake, GLUT1, LDHA and MCT4 mRNA levels, and stabilized ZO-1 protein at the cell membrane. These differential effects suggested a mechanism of action of adenosine that cannot be solely explained by occupancy of type A(1) purinergic receptors. Activation by adenosine but not by CHA of AMPK was observed. AMPK participation in lactate production and ZO-1 stabilization was confirmed by utilizing specific inhibitors. Altogether, these results suggest that activation of AMPK by adenosine promotes lactate offer to germ cells and cooperates in the maintenance of junctional complex integrity, thus contributing to the preservation of an optimum microenvironment for a successful spermatogenesis.

Differential changes in CD4+ and CD8+ effector and regulatory T lymphocyte subsets in the testis of rats undergoing autoimmune orchitis.

Experimental autoimmune orchitis (EAO) is a useful model to study organ-specific autoimmunity and chronic testicular inflammation. EAO is characterized by an interstitial lymphomononuclear cell infiltration and damage of the seminiferous tubules showing germ cell sloughing and apoptosis. Using flow cytometry, we analysed the phenotype and number of T lymphocytes present in the testicular interstitium of rats during EAO development. A large increase in the number of testicular CD3+ T lymphocytes was detected. The number of CD4+ and CD8+ effector T lymphocytes (T(effector) cells) dramatically increased in the testis at EAO onset, with the CD4+ cell subset predominating. As the severity of the disease progressed, CD4+ T(effector) cells declined in number while the CD8+ T(effector) cell subset remained unchanged, suggesting their involvement in maintenance of the chronic phase of EAO. As a novel finding, we detected by immunohistochemistry and flow cytometry Foxp3 expressing CD4+ and CD8+ regulatory T lymphocytes (T(regs)) in chronically inflamed testis of EAO rats. The numbers of both T(reg) cell subsets increased in the testis of rats with orchitis, mainly at the onset of EAO; CD4+Foxp3+ T(reg) cells were more abundant than CD8+Foxp3+ T(reg) cells. Unexpectedly, CD25- T lymphocytes were more abundant than CD25+ cells within CD4+Foxp3+ and CD8+Foxp3+ T(reg) cell populations. Although T(reg) subsets are actively accumulated into the testis in EAO rats, these cells are outnumbered by an even more vigorously expanding T(effector) subset. Further, it is possible that factors present in the inflamed testis might limit the ability of T(regs) to abrogate tissue damage.

Localization of synucleins in the mammalian cochlea.

Synucleins are widely expressed synaptic proteins within the central nervous system that have been implicated in such neurodegenerative disorders as Parkinson's disease. In this study, an initial characterization of all three synucleins, alpha-, beta-, and gamma-synuclein, within the cochlea was undertaken. Reverse transcriptase-polymerase chain reaction (PCR) demonstrated all three synuclein mRNA species within microdissected cochlear tissue. Quantitative PCR suggests that beta-synuclein is the most abundantly expressed form, followed by gamma- and then alpha-synuclein. Western blot analysis similarly demonstrates all three synuclein proteins within microdissected cochlear tissue. Immunofluorescence localizes the three synucleins predominantly to the efferent neuronal system at the efferent outer hair cell synapse, with some additional localization within the efferent tunnel-crossing fibers (alpha- and gamma-synuclein), spiral ganglion (beta-synuclein), inner spiral bundle (gamma-synuclein), and stria vascularis (alpha- > beta-synuclein). Developmentally, gamma-synuclein can be seen in the region of the outer hair cells by E19, while alpha- and beta-synuclein do not clearly appear there until approximately P10. Additional studies in a null-mutant gamma-synuclein mouse show no histological changes in the organ of Corti with normal hair cell and spiral ganglion cell counts, and normal ABR and DPOAE thresholds in wild-type vs mutant littermates. Together, these results localize synucleins to the efferent cholinergic neuronal auditory system, pointing to a role in normal auditory function, and raising the potential implications for their role in auditory neurodegenerative disorders. However, gamma-synuclein alone is not required for the development and maintenance of normal hearing through P21. Whether overlapping roles of the other synucleins help compensate for the loss of gamma-synuclein remains to be determined.

Tumour necrosis factor-alpha released by testicular macrophages induces apoptosis of germ cells in autoimmune orchitis.

BACKGROUND: Experimental autoimmune orchitis (EAO) is a model of chronic inflammation and infertility useful for studying testicular immune and germ cell (GC) interactions. In this model, EAO was induced in rats by immunization with testicular homogenate and adjuvants; Control (C) rats were injected with adjuvants. EAO was characterized by an interstitial infiltrate of lymphomonocytes and seminiferous tubule damage, moderate 50 days (focal orchitis) and severe 80 days after the first immunization (severe orchitis). Based on the previous results showing that the number of macrophages and apoptotic GC expressing tumour necrosis factor (TNF) receptor 1 increased in EAO, we studied the role of macrophages and TNF-alpha in GC apoptosis. METHODS AND RESULTS: Conditioned media of testicular macrophages (CMTM) obtained from rats killed on Days 50 and 80 decreased the viability (MTS, P < 0.01) and induced apoptosis (terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labelling, TUNEL) of GC obtained from EAO but not from non-immunized, N rats (P < 0.001). TNF-alpha content (enzyme-linked immunosorbent assay) was significantly higher in the CMTM from EAO versus C rats on Day 80 (P < 0.05). The apoptotic effect of CMTM from Day 80 rats was abrogated by a selective TNF-alpha blocker (Etanercept). Moreover, TNF-alpha in vitro induced GC apoptosis. TNF-alpha expression (by immunofluorescence) was observed in testicular (ED2(+)) and non-resident (ED1(+)) macrophages, the percentage of TNF-alpha(+) macrophages being similar in focal and severe orchitis. CONCLUSIONS: Results demonstrated that soluble factors released from testicular EAO macrophages induce apoptosis of GC, biased by the local inflammatory environment, and that TNF-alpha is a relevant cytokine involved in testicular damage during severe orchitis.

Functional and phenotypic characteristics of testicular macrophages in experimental autoimmune orchitis.

Testicular inflammation with compromised fertility can occur despite the fact that the testis is considered an immunoprivileged organ. Testicular macrophages have been described as cells with an immunosuppressor profile, thus contributing to the immunoprivilege of the testis. Experimental autoimmune orchitis (EAO) is a model of organ-specific autoimmunity and testicular inflammation. EAO is characterized by an interstitial inflammatory mononuclear cell infiltration, damage of the seminiferous tubules and germ cell apoptosis. Here we studied the phenotype and functions of testicular macrophages during the development of EAO. By stereological analysis, we detected an increased number of resident (ED2+) and non-resident (ED1+) macrophages in the testicular interstitium of rats with orchitis. We showed that this increase was mainly due to monocyte recruitment. The in vivo administration of liposomes containing clodronate in rats undergoing EAO led to a reduction in the number of testicular macrophages, which correlated with a decreased incidence and severity of the testicular damage and suggests a pathogenic role of macrophages in EAO. By immunohistochemistry and flow cytometry we detected an increased number of testicular macrophages expressing MHC class II, CD80 and CD86 costimulatory molecules in rats with orchitis. Also, testicular macrophages from rats with EAO showed a higher production of IFNgamma (ELISA). We conclude that testicular macrophages participate in EAO development, and the ED1+ macrophage subset is the main pathogenic subpopulation. They stimulate the immune response through the production of pro-inflammatory cytokines and antigen presentation and thus activation of T cells in the target organ.

Chondrosarcomas of the skull base and temporal bone.

OBJECTIVE: To evaluate the clinical presentation and outcomes of treatment for patients with chondrosarcomas involving the skull base and temporal bone. STUDY DESIGN: Retrospective review. SETTING: Tertiary medical centre. PATIENTS: Cases of histologically confirmed chondrosarcoma involving the skull base and temporal bones. INTERVENTION: Surgery. MAIN OUTCOME MEASURES: Demographic features of presenting patients; presenting symptoms and signs; surgical approach employed; use of post-operative radiation therapy; histological grade of tumour; and interval of post-operative follow up. RESULTS: Twelve patients were identified with chondrosarcomas involving the skull base, with post-operative follow up ranging from three to 33 years. The average age at presentation was 42 years. The most common presenting symptoms were diplopia, decreased visual acuity and headaches. Five of the 12 patients required multiple surgical procedures. CONCLUSIONS: Patients with chondrosarcoma involving the skull base and temporal bone may present in a variety of ways. Surgical resection, even subtotal, in combination with radiation therapy, can often provide good tumour control over many years for these rare tumours.

Expression of caveolin-1 in rat Leydig cells

Caveolin-1, the first member of caveolin family reported, is recognized as the structural component of caveola, a plasma membrane invagination or vesicles that are a subcompartment distinct from clathrin-coated pits. This protein is also known to be involved in cholesterol trafficking. The aim of this study was to determine the expression of caveolin-1 in adult rat Leydig cells. Testis sections incubated with an antibody to caveolin-1 showed, by immunohistochemistry, a moderate number of Leydig cells with different degrees of immunoreaction and a strong reaction in endothelial cells and in the lamina propia of seminiferous tubules.Caveolin- 1 was detected in the cell cytoplasm with a granular pattern and on the cell surface of Leydig cells cultured 24 h on uncoated, laminin-1 or type IV collagen coated coverslips. We also observed a milder reaction in 3 h cultures. Immunoreaction was also detected in Leydig cells with an antibody to tyrosine-phosphorylated caveolin-1. By double immunofluorescent technique, we observed co-localization of caveolin- I and 313-hydroxysteroid dehydrogenase. Western blot analysis revealed a band of about 22 kDa molecular weight that was recognized with both caveolin-1 and tyrosine-phosphocaveolin-1 antibodies. Caveolin-l is one of a few proteins with ademonstrated ability to bind cholesterol in vivo. In this context, the presence of caveolin- in Leydig cells may be related to cholesterol traffic--a rate limiting step in steroid biosynthesis.(AU)

Expression of caveolin-1 in rat Leydig cells

Caveolin-1, the first member of caveolin family reported, is recognized as the structural component of caveola, a plasma membrane invagination or vesicles that are a subcompartment distinct from clathrin-coated pits. This protein is also known to be involved in cholesterol trafficking. The aim of this study was to determine the expression of caveolin-1 in adult rat Leydig cells. Testis sections incubated with an antibody to caveolin-1 showed, by immunohistochemistry, a moderate number of Leydig cells with different degrees of immunoreaction and a strong reaction in endothelial cells and in the lamina propia of seminiferous tubules.Caveolin- 1 was detected in the cell cytoplasm with a granular pattern and on the cell surface of Leydig cells cultured 24 h on uncoated, laminin-1 or type IV collagen coated coverslips. We also observed a milder reaction in 3 h cultures. Immunoreaction was also detected in Leydig cells with an antibody to tyrosine-phosphorylated caveolin-1. By double immunofluorescent technique, we observed co-localization of caveolin- I and 313-hydroxysteroid dehydrogenase. Western blot analysis revealed a band of about 22 kDa molecular weight that was recognized with both caveolin-1 and tyrosine-phosphocaveolin-1 antibodies. Caveolin-l is one of a few proteins with ademonstrated ability to bind cholesterol in vivo. In this context, the presence of caveolin- in Leydig cells may be related to cholesterol traffic--a rate limiting step in steroid biosynthesis.

Death receptor and mitochondrial pathways are involved in germ cell apoptosis in an experimental model of autoimmune orchitis.

BACKGROUND: Studies on experimental autoimmune orchitis (EAO) have helped to elucidate immunological mechanisms involved in testicular damage. We previously demonstrated that EAO is characterized by lymphomononuclear cell infiltrates and apoptosis of spermatocytes and spermatids expressing Fas and TNFR1. The aim of this work was to characterize the pathways involved in germ cell apoptosis in EAO and to determine the involvement of the Bcl-2 protein family in this process. METHODS AND RESULTS: EAO was induced in rats by immunization with testicular homogenate (TH) and adjuvants, whereas control (C) rats were injected with saline solution and adjuvants. Testis of EAO rats showed procaspase 8 cleavage products (western blot) with high caspase 8 activity. Cytochrome c content increased in the cytosol and decreased in the mitochondrial fraction of testis from EAO rats compared with C, concomitant with increased caspase 9 activity. Bax was mainly expressed in spermatocytes and spermatids and Bcl-2 in basal germ cells (immunohistochemistry). Baxbeta isoform content increased in EAO rat testis compared with C, whereas content of Baxalpha remained unchanged (western blot). However, Baxalpha content decreased in the cytosol and increased in the mitochondrial and endoplasmic reticulum (ER)-enriched fractions of testis from EAO rats compared with C (western blot). Bcl-2 content also increased in the testes of EAO rats. CONCLUSIONS: Our results demonstrated that extrinsic, mitochondrial and possibly ER pathways are inducers of germ cell apoptosis in EAO and that Bax and Bcl-2 proteins modulate this process.

Cochlear implantation in patients with osteogenesis imperfecta.

OBJECTIVE: Hearing loss has been shown to occur in 42% to 58% of patients with osteogenesis imperfecta (OI), with deafness arising in 25% to 60% of the patients. Implantation in patients with OI is relatively rare, with only 4 prior single case reports published in the English-language literature. The goal of this study was to evaluate the feasibility and functional outcome of cochlear implantation in 2 patients with OI tarda type I with profound sensorineural hearing loss. STUDY DESIGN: Case series. SETTING: The implantations were performed in a tertiary academic referral center (Johns Hopkins University). RESULTS: Though promontory vascularity was encountered, full insertion of a normal cochlear implant array could be achieved in both cases. One-year postimplant scores demonstrated 20 to 40 dB hearing thresholds, Consonant-Nucleus-Consonant Test word scores of 54% and 70%, Consonant-Nucleus-Consonant Test phoneme scores of 75% and 83%, Hearing in Noise Test scores of 76% and 99%, and Central Institute of the Deaf Sentence Score sentence scores of 99% and 100%, for patients 1 and 2, respectively. CONCLUSIONS: Cochlear implantation in patients with OI is not only technically possible but the results are similar to implant outcomes for patients with sensorineural hearing loss from a variety of other causes. EBM RATING: C.

Benign positional vertigo after cochlear implantation.

OBJECTIVE: To identify patients who underwent cochlear implantation (CI) and who subsequently developed benign positional vertigo (BPV) after the procedure and to identify any contributing factors. STUDY DESIGN AND SETTING: Academic tertiary referral center. Cochlear implant recipients' medical records were retrospectively reviewed to identify patients with both vertigo and, more specifically, BPV. Preoperative, intraoperative, and postoperative factors were studied vis-a-vis the development of BPV. RESULTS: BPV was newly diagnosed in 12 patients after CI. The etiology of hearing loss included presbycusis (16.6%), autoimmune inner ear disease (16.6%), congenital hearing loss (41.6%), Meniere's disease (8.3%), prematurity (8.3%), and idiopathic factors (8.3%). The onset of BPV varied after the procedure (mean +/- SD, 292 +/- 309 days). BPV symptoms did not affect implant performance. All patients were treated for BPV by Epley's maneuver and vestibular exercises. Symptoms disappeared in 11 patients and persisted in 1. CONCLUSIONS: BPV is an uncommon development after CI, although it occurs more frequently than in the general population. Two theories are proposed: the introduction of bone dust into the labyrinth and the dislodging of otoconia during surgery. The diagnosis, treatment, and prognosis of BPV after CI do not differ from those for non-CI-associated BPV. SIGNIFICANCE: Dizziness after CI usually develops as a result of vestibular hypofunction. BPV, which is a hyperfunctioning form of vestibular dysfunction, should be recognized as a possible sequelae of CI.