CRISPR-Generated Nrf2a Loss- and Gain-of-Function Mutants Facilitate Mechanistic Analysis of Chemical Oxidative Stress-Mediated Toxicity in Zebrafish.

The transcription factor Nrf2a induces a cellular antioxidant response and provides protection against chemical-induced oxidative stress, as well as playing a critical role in development and disease. Zebrafish are a powerful model to study the role of Nrf2a in these processes but have been limited by reliance on transient gene knockdown techniques or mutants with only partial functional alteration. We developed several lines of zebrafish carrying different null (loss of function, LOF) or hyperactive (gain of function, GOF) mutations to facilitate our understanding of the Nrf2a pathway in protecting against oxidative stress.

Long-term Quality of Life Following Vestibular Schwannoma Excision Via the Translabyrinthine Approach.

Objective: To assess postoperative quality of life (QOL) and other patient-reported outcomes following surgery for vestibular schwannoma.

Study Design: Cross-sectional retrospective case review using postal questionnaires.

Setting: Tertiary referral center.

Dual NRF2 paralogs in Coho salmon and their antioxidant response element targets.

The transcription factor NFE2L2 (Nuclear Factor, Erythroid 2-Like 2, or NRF2) plays a key role in maintaining the redox state within cells. Characterization of this pathway has extended to fish, most notably zebrafish (Danio rerio), in which two paralogs of the transcription factor exist: Nrf2a, an activator, and Nrf2b, a negative regulator during embryogenesis. Only one ARE target has been thoroughly delineated in zebrafish, and this deviated from the canonical sequence derived from studies in mammals.

Auditory Brainstem Implantation in Neurofibromatosis Type 2: Experience From the Manchester Programme.

Objective: To describe the experience of auditory brainstem implantation (ABI) in patients with Neurofibromatosis type 2 (NF2).

Study Design: Retrospective case review.

Setting: Tertiary referral centre.

Subjective outcomes of auditory brainstem implantation.

Aim: To assess the long-term subjective benefits of auditory brainstem implants (ABIs) and investigate the extent to which ABI users perceive it to be a useful device.

Methods: Using the Manchester database, all 31 living patients registered as ABI users were identified and sent the ABI performance questionnaire. Data regarding daily duration of use, auditory fatigue, ability to differentiate between speech and environmental sounds, and subjective usefulness of the ABI in different listening conditions were collected.

Clinical and radiological guidance in managing facial nerve schwannomas.

Objective: To present a review of all patients diagnosed with a facial nerve schwannoma (FNS) managed in our center over almost two decades, and suggest guidelines for their classification and management.

Study Design: Retrospective case review

Setting: Tertiary referral center

Patients: Twenty-eight patients with a facial nerve schwannoma

Intervention: Conservative or surgical management depending on clinical and radiological features

Main Outcome Measure: Patient demographics, site of tumor, and clinical symptoms, including facial nerve function (House-Brackmann score) at baseline and follow-up. In those managed surgically, operative approach and surgical outcomes were also recorded.

Determining protein complex structures based on a Bayesian model of in vivo Förster resonance energy transfer (FRET) data.

The use of in vivo Förster resonance energy transfer (FRET) data to determine the molecular architecture of a protein complex in living cells is challenging due to data sparseness, sample heterogeneity, signal contributions from multiple donors and acceptors, unequal fluorophore brightness, photobleaching, flexibility of the linker connecting the fluorophore to the tagged protein, and spectral cross-talk. We addressed these challenges by using a Bayesian approach that produces the posterior probability of a model, given the input data. The posterior probability is defined as a function of the dependence of our FRET metric FRETR on a structure (forward model), a model of noise in the data, as well as prior information about the structure, relative populations of distinct states in the sample, forward model parameters, and data noise.

Surgical outcomes in cystic vestibular schwannoma versus solid vestibular schwannoma.

Objective: To review the postoperative surgical outcomes of cystic vestibular schwannomas (CVSs), especially facial nerve outcomes, and compare these results with those from matched solid vestibular schwannomas (SVS) resected during the same period at a tertiary referral center.

Study Design: Retrospective case series.

Methods: One hundred thirty-one surgically managed patients with cystic vestibular schwannomas (CVSs) were age, sex, and tumor size matched to 131 surgically managed patients with solid vestibular schwannomas (SVSs).

Cochlear implantation in adolescents: Factors influencing compliance.

Objectives: To quantify rates of non- and partial-use of cochlear implants (CIs) in adolescent patients implanted in adolescence and childhood and identify factors influencing compliance.

Methods: A retrospective case note review undertaken at The Manchester Auditory Implant Centre. Adolescents were defined as young people aged 11-18 years.

History of cochlear implantation.

The evolution of cochlear implantation from early experimentation with electrical stimulation of the ear in the 18th century to the sophisticated multichannel device that we now routinely implant has been remarkable. It is a tribute to the perseverance of a number of dedicated scientists in many disciplines who, in the face of serious, but ultimately unfounded, theoretical objections and ethical challenges, were eventually able to restore useful hearing to that large group of profoundly deaf adults and children, who were hitherto untreatable. The transformation in the lives of prelingually deaf children, who are now able to acquire speech and language and fulfil their full educational potential has been particularly spectacular.

Ipsilateral cochlear implantation after cochlear nerve preserving vestibular schwannoma surgery in patients with neurofibromatosis type 2.

Objective: To investigate the outcomes from ipsilateral simultaneous or sequential cochlear implantation in patients with neurofibromatosis type 2 (NF2) after vestibular schwannoma removal with cochlear nerve preservation.

Study Design: Retrospective case series.

Setting: Single tertiary referral NF2 center.

English consensus protocol evaluating candidacy for auditory brainstem and cochlear implantation in neurofibromatosis type 2.

Objective: Hearing loss resulting from bilateral vestibular schwannomas (VSs) has a significant effect on the quality of life of patients with neurofibromatosis Type 2 (NF2). A national consensus protocol was produced in England as a guide for cochlear implantation (CI) and auditory brainstem implantation (ABI) in these patients.

Study Design: Consensus statement.

Cochlear implantation in children with syndromic deafness.

Objective: To examine the outcome of cochlear implantation in children with syndromic deafness, who are increasingly being considered for cochlear implants and who represent a unique challenge to the cochlear implant team.

Method: In this retrospective case series in a tertiary referral cochlear implant centre, we describe a series of 38 children with a clinical syndrome causing deafness who have undergone cochlear implantation. The outcome measures are Bench-Kowal-Bamford (BKB) speech reception score (range 0-100%) and speech perception ability using the Geers and Moog Speech Reception Score (SRS) (range from 0; no speech perception, to 6; open set recognition of words).

Cochlear implantation in patients deafened by ototoxic drugs.

Objective: To investigate the outcome of cochlear implantation (CI) in patients deafened by ototoxic drugs and to compare this, with the outcome of CI in sudden sensorineural hearing loss (SSNHL) with a similar duration of deafness.

Methods: The Manchester Auditory Implant Centre database was reviewed to identify patients who were implanted to rehabilitate profound sensorineural hearing loss resulting from treatment with ototoxic agents and patients with SSNHL group. A retrospective case note review of selected patients was carried out.

Cochlear implantation in children with Jervell and Lange-Nielsen syndrome - a cautionary tale.

Objective And Importance: Jervell and Lange-Nielsen (JLN) syndrome is a rare cause of congenital profound hearing loss associated with a prolonged QT interval on the electrocardiogram. Children presenting for cochlear implantation with this condition may be asymptomatic but are at risk of sudden death. SCREENING AND SUBSEQUENT: careful management is therefore required to ensure a successful outcome.

Vestibular schwannomas occur in schwannomatosis and should not be considered an exclusion criterion for clinical diagnosis.

Schwannomatosis is a recently delineated inherited condition that has clinical overlap with neurofibromatosis type 2 (NF2). Diagnostic criteria have been developed to distinguish schwannomatosis from NF2, but the existence of mosaic NF2, which may closely mimic schwannomatosis, makes even these criteria problematic. In particular, it is not clear why there is a relative sparing of the cranial nerves from schwannomas in schwannomatosis.

Bilateral cochlear implantation after ethylene glycol intoxication: a case report.

Objective: To report a case of deafness and blindness caused by ethylene glycol poisoning and treated by bilateral simultaneous cochlear implantation.

Study Design: Case report.

Setting: University teaching hospital, tertiary referral center.

Cochlear implantation in children with cerebral palsy.

Objective: Few studies have looked at the outcomes of children with complex needs following cochlear implantation. Increasing evidence supports the case for implantation in these children. To date there is very little evidence available evaluating the role of cochlear implantation in children with cerebral palsy.

Outcome of cochlear implantation in asymptomatic congenital cytomegalovirus deafened children.

Objectives/hypothesis: Congenital cytomegalovirus (cCMV) infection is a common cause of sensorineural hearing loss (SNHL). The incidence of SNHL is higher in symptomatic cCMV infants and is usually identified early. By contrast, the incidence of SNHL is lower in children with asymptomatic cCMV, and the hearing loss can be delayed in onset and progressive.

Cochlear implantation in Donnai-Barrow syndrome.

Objective And Importance: Donnai-Barrow syndrome is a rare autosomal recessive disorder associated with severe sensorineural hearing loss (SNHL). Several ocular abnormalities have also been described in this syndrome, including hypertelorism, down-slanting palpebral fissures, myopia and retinal detachment. The condition is also associated with diaphragmatic hernia, exomphalos, absent corpus callosum and developmental delay.

An intein with genetically selectable markers provides a new approach to internally label proteins with GFP.

Background: Inteins are proteins that catalyze their own removal from within larger precursor proteins. In the process they splice the flanking protein sequences, termed the N-and C-terminal exteins. Large inteins frequently have a homing endonuclease that is involved in maintaining the intein in the host.

Cochlear implantation after bacterial meningitis in children: outcomes in ossified and nonossified cochleas.

Objective: To investigate the outcome of cochlear implantation in children with postmeningitic deafness and to compare the outcomes in ossified and nonossified cochleas.

Study Design: A retrospective case note review of children with postmeningitic deafness requiring cochlear implantation.

Setting: Manchester Auditory Implant Centre--a tertiary referral center.

Empirical development of improved diagnostic criteria for neurofibromatosis 2.

Purpose: Four sets of clinical diagnostic criteria have been proposed for neurofibromatosis 2, but all have low sensitivity at the time of initial clinical assessment for the disease among patients with a negative family history who do not present with bilateral vestibular schwannomas. We have empirically developed and tested an improved set of diagnostic criteria that uses current understanding of the natural history and genetic characteristics of neurofibromatosis 2 to increase sensitivity while maintaining very high specificity.

Methods: We used data from the UK Neurofibromatosis 2 Registry and Kaplan-Meier curves to estimate frequencies of clinical features at various ages among patients with or without unequivocal neurofibromatosis 2.

Neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is an autosomal-dominant inherited tumour predisposition syndrome caused by mutations in the NF2 gene on chromosome 22. Affected individuals develop schwannomas characteristically affecting both vestibular nerves leading to hearing loss and eventual deafness. Rehabilitation with brain stem implants and in some cases cochlear implants is improving this outcome.