Insulin regulates Nedd4-2 via a PKB-dependent mechanism in HEI-OC1 auditory cells-crosstalks with sphingolipid and cAMP signaling.

BACKGROUND: The mechanisms of association between diabetes and inner ear dysfunction are unknown, although endolymphatic hydrops may be involved. We have previously shown that insulin signaling components are expressed in human saccule and that insulin signaling takes place in HEI-OC1 auditory cells. AIM: To explore Nedd4-2 as a target for insulin signaling. MATERIALS AND METHODS: Effects of insulin were analyzed using western blot and confocal microscopy in HEI-OC1 auditory cells. RESULTS: Insulin induced phosphorylation of Nedd4-2 and increased the amount of ENaC at the plasma membrane. Also, protein kinase B (PKB) and NDRG1, a substrate for SGK1 (serum and glucocorticoid stimulated kinase), were phosphorylated in response to insulin. The SGK1 inhibitor GSK650394 prevented insulin-induced phosphorylation of NRDG1, but not of PKB and Nedd4-2, whereas the phosphatidylinositol 3-kinase (PI3K) inhibitor wortmannin and the PKB inhibitor MK2206 inhibited phosphorylation of all components. Ceramides prevented insulin-induced phosphorylation of PKB and NDRG1, but not of Nedd4-2. The ceramide metabolite sphingosine 1-phosphate induced phosphorylation of Nedd4-2. CONCLUSIONS: Insulin induces phosphorylation of Nedd4-2, most likely involving PI3K/PKB signaling. Sphingosine 1-phosphate might protect Nedd4-2 against ceramide-induced insulin resistance. SIGNIFICANCE: Insulin-mediated regulation of Nedd4-2 might impact on inner ear sodium homeostasis with implications for diabetes-induced inner ear damage.

Vision-Based Tracking of Surgical Motion During Live Open-Heart Surgery.

BACKGROUND: Motion tracking during live surgeries may be used to assess surgeons' intra-operative performance, provide feedback, and predict outcome. Current assessment protocols rely on human observations, controlled laboratory settings, or tracking technologies not suitable for live operating theatres. In this study, a novel method for motion tracking of live open-heart surgery was developed, and evaluated. MATERIALS AND METHODS: Three-D-printed 'tracking die' with miniature markers were fitted to DeBakey forceps. The surgical field was recorded with a video camera mounted above the operating table. Software was developed for tracking the die from the recordings. The system was tested on five open-heart procedures. Surgeons were asked to report subjective system related concerns during live surgery and assess the weight of the die on blind test. The accuracy of the system was evaluated against ground truth generated by a robot. RESULTS: The 3D-printed die weighed 6 g and tolerated sterilization with hydrogen peroxide, which added approximately 13% to the mass of the forceps. Surgeons sensed a shift in the balance of the instrument but could on blind test not correctly verify changes in weight. When two or more markers were detected, the 3D position estimate was on average within 2-3 mm, and 1.1-2.6 degrees from ground truth. Computational time was 30-50 ms per frame on a standard laptop. CONCLUSIONS: The vision-based motion tracking system was applicable for live surgeries with negligible inconvenience to the surgeons. Motion data was extracted with acceptable accuracy and speed at low computational cost.

Robotized Testing of Camera Positions to Determine Ideal Configuration for Stereo 3D Visualization of Open-Heart Surgery.

Stereo 3D video from surgical procedures can be highly valuable for medical education and improve clinical communication. But access to the operating room and the surgical field is restricted. It is a sterile environment, and the physical space is crowded with surgical staff and technical equipment. In this setting, unobscured capture and realistic reproduction of the surgical procedures are difficult. This paper presents a method for rapid and reliable data collection of stereoscopic 3D videos at different camera baseline distances and distances of convergence. To collect test data with minimum interference during surgery, with high precision and repeatability, the cameras were attached to each hand of a dual-arm robot. The robot was ceiling-mounted in the operating room. It was programmed to perform a timed sequence of synchronized camera movements stepping through a range of test positions with baseline distance between 50-240 mm at incremental steps of 10 mm, and at two convergence distances of 1100 mm and 1400 mm. Surgery was paused to allow 40 consecutive 5-s video samples. A total of 10 surgical scenarios were recorded.

High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.

Skeletal ciliopathies are a heterogenous group of disorders with overlapping clinical and radiographic features including bone dysplasia and internal abnormalities. To date, pathogenic variants in at least 30 genes, coding for different structural cilia proteins, are reported to cause skeletal ciliopathies. Here, we summarize genetic and phenotypic features of 34 affected individuals from 29 families with skeletal ciliopathies. Molecular diagnostic testing was performed using massively parallel sequencing (MPS) in combination with copy number variant (CNV) analyses and in silico filtering for variants in known skeletal ciliopathy genes. We identified biallelic disease-causing variants in seven genes: DYNC2H1, KIAA0753, WDR19, C2CD3, TTC21B, EVC, and EVC2. Four variants located in non-canonical splice sites of DYNC2H1, EVC, and KIAA0753 led to aberrant splicing that was shown by sequencing of cDNA. Furthermore, CNV analyses showed an intragenic deletion of DYNC2H1 in one individual and a 6.7 Mb de novo deletion on chromosome 1q24q25 in another. In five unsolved cases, MPS was performed in family setting. In one proband we identified a de novo variant in PRKACA and in another we found a homozygous intragenic deletion of IFT74, removing the first coding exon and leading to expression of a shorter message predicted to result in loss of 40 amino acids at the N-terminus. These findings establish IFT74 as a new skeletal ciliopathy gene. In conclusion, combined single nucleotide variant, CNV and cDNA analyses lead to a high yield of genetic diagnoses (90%) in a cohort of patients with skeletal ciliopathies.

Integration of whole genome sequencing into a healthcare setting: high diagnostic rates across multiple clinical entities in 3219 rare disease patients.

BACKGROUND: We report the findings from 4437 individuals (3219 patients and 1218 relatives) who have been analyzed by whole genome sequencing (WGS) at the Genomic Medicine Center Karolinska-Rare Diseases (GMCK-RD) since mid-2015. GMCK-RD represents a long-term collaborative initiative between Karolinska University Hospital and Science for Life Laboratory to establish advanced, genomics-based diagnostics in the Stockholm healthcare setting. METHODS: Our analysis covers detection and interpretation of SNVs, INDELs, uniparental disomy, CNVs, balanced structural variants, and short tandem repeat expansions. Visualization of results for clinical interpretation is carried out in Scout-a custom-developed decision support system. Results from both singleton (84%) and trio/family (16%) analyses are reported. Variant interpretation is done by 15 expert teams at the hospital involving staff from three clinics. For patients with complex phenotypes, data is shared between the teams. RESULTS: Overall, 40% of the patients received a molecular diagnosis ranging from 19 to 54% for specific disease groups. There was heterogeneity regarding causative genes (n = 754) with some of the most common ones being COL2A1 (n = 12; skeletal dysplasia), SCN1A (n = 8; epilepsy), and TNFRSF13B (n = 4; inborn errors of immunity). Some causative variants were recurrent, including previously known founder mutations, some novel mutations, and recurrent de novo mutations. Overall, GMCK-RD has resulted in a large number of patients receiving specific molecular diagnoses. Furthermore, negative cases have been included in research studies that have resulted in the discovery of 17 published, novel disease-causing genes. To facilitate the discovery of new disease genes, GMCK-RD has joined international data sharing initiatives, including ClinVar, UDNI, Beacon, and MatchMaker Exchange. CONCLUSIONS: Clinical WGS at GMCK-RD has provided molecular diagnoses to over 1200 individuals with a broad range of rare diseases. Consolidation and spread of this clinical-academic partnership will enable large-scale national collaboration.

Different Visual Weighting due to Fast or Slow Vestibular Deafferentation: Before and after Schwannoma Surgery.

Background: Feedback postural control depends upon information from somatosensation, vision, and the vestibular system that are weighted depending on their relative importance within the central nervous system. Following loss of any sensory component, the weighting changes, e.g., when suffering a vestibular loss, the most common notion is that patients become more dependent on visual cues for maintaining postural control. Dizziness and disequilibrium are common after surgery in schwannoma patients, which could be due to interpretation of the remaining sensory systems involved in feedback-dependent postural control and spatial orientation. Objective: To compare visual dependency in spatial orientation and postural control in patients suffering from unilateral vestibular loss within different time frames. Methods: Patients scheduled for schwannoma surgery: group 1 (n = 27) with no vestibular function prior to surgery (lost through years), group 2 (n = 12) with remaining vestibular function at the time of surgery (fast deafferentation), and group 3 (n = 18) with remaining function that was lost through gentamicin installations in the middle ear (slow deafferentation). All patients performed vibratory posturography and rod and frame investigation before surgery and 6 months after surgery. Results: Postural control improved after surgery in patients that suffered a slow deafferentation (groups 1 and 3) (p < 0.001). Patients that suffered fast loss of remaining vestibular function (group 2) became less visual field dependent after surgery (p ≤ 0.035) and were less able to maintain stability compared with group 1 (p = 0.010) and group 3 (p = 0.010). Conclusions: The nature and time course of vestibular deafferentation influence the weighting of remaining sensory systems in order to maintain postural control and spatial orientation.

PREHAB vs. REHAB - presurgical treatment in vestibular schwannoma surgery enhances recovery of postural control better than postoperative rehabilitation: Retrospective case series.

OBJECT: To evaluate post-surgical postural stability when treating patients with remaining vestibular function with intratympanic gentamicin (PREHAB) prior to schwannoma surgery. METHOD: 44 consecutive patients with some form remaining vestibular function scheduled for vestibular schwannoma surgery. 20 were medically deafferented with intratympanic gentamicin before surgery and 24 were not. Both groups were of the same age, had the same tumor size, same type of surgery, and same perioperative sensory rehabilitation (training exercises), and no surgical complications. Postural stability measured as energy expenditure while standing on a force platform during vibratory stimulation of the calf muscles, performed prior to surgery (or gentamicin treatment) and 6 months after surgery. RESULTS: Patients pretreated with gentamicin had significantly better postural stability at the time for follow-up (p < 0.05) and displayed a better adaptive capacity when faced with a postural challenge (p < 0.01). They were also able to use vision more efficiently to control their stability (p < 0.05). CONCLUSIONS: By separating the sensory loss (through intratympanic gentamicin, that ablates the remaining vestibular function) from the intracranial surgical trauma, the postural control system benefited from a better short-term (adaptation) and long-term (habituation) recovery, when experiencing a postural challenge or resolving a sensory conflict. The benefits could be attributed to; active and continuous motor learning as the vestibular function slowly attenuates; no concomitant central nervous dysfunction due to effects from neurosurgery, thus allowing time for a separate unimpeded recovery process with more limited challenges and objectives; and the initiation and certain progression of sensory reweighting processes allowed prior to surgery. In contrast, worse compensation could be due to; immobilization from nausea after surgery, harmful amount of stress and cognitive dysfunction from the combination of surgical and sensory trauma and an abrupt vestibular deafferentation and its consequences on sensory reweighting.

Elevated visual dependency in young adults after chemotherapy in childhood.

Chemotherapy in childhood can result in long-term neurophysiological side-effects, which could extend to visual processing, specifically the degree to which a person relies on vision to determine vertical and horizontal (visual dependency). We investigated whether adults treated with chemotherapy in childhood experience elevated visual dependency compared to controls and whether any difference is associated with the age at which subjects were treated. Visual dependency was measured in 23 subjects (mean age 25.3 years) treated in childhood with chemotherapy (CTS) for malignant, solid, non-CNS tumors. We also stratified CTS into two groups: those treated before 12 years of age and those treated from 12 years of age and older. Results were compared to 25 healthy, age-matched controls. The subjective visual horizontal (SVH) and vertical (SVV) orientations was recorded by having subjects position an illuminated rod to their perceived horizontal and vertical with and without a surrounding frame tilted clockwise and counter-clockwise 20° from vertical. There was no significant difference in rod accuracy between any CTS groups and controls without a frame. However, when assessing visual dependency using a frame, CTS in general (p = 0.006) and especially CTS treated before 12 years of age (p = 0.001) tilted the rod significantly further in the direction of the frame compared to controls. Our findings suggest that chemotherapy treatment before 12 years of age is associated with elevated visual dependency compared to controls, implying a visual bias during spatial activities. Clinicians should be aware of symptoms such as visual vertigo in adults treated with chemotherapy in childhood.

Decreased postural control in adult survivors of childhood cancer treated with chemotherapy.

The objective of cancer treatment is to secure survival. However, as chemotherapeutic agents can affect the central and peripheral nervous systems, patients must undergo a process of central compensation. We explored the effectiveness of this compensation process by measuring postural behaviour in adult survivors of childhood cancer treated with chemotherapy (CTS). We recruited sixteen adults treated with chemotherapy in childhood for malignant solid (non-CNS) tumours and 25 healthy age-matched controls. Subjects performed posturography with eyes open and closed during quiet and perturbed standing. Repeated balance perturbations through calf vibrations were used to study postural adaptation. Subjects were stratified into two groups (treatment before or from 12 years of age) to determine age at treatment effects. Both quiet (p = 0.040) and perturbed standing (p ≤ 0.009) were significantly poorer in CTS compared to controls, particularly with eyes open and among those treated younger. Moreover, CTS had reduced levels of adaptation compared to controls, both with eyes closed and open. Hence, adults treated with chemotherapy for childhood cancer may suffer late effects of poorer postural control manifested as reduced contribution of vision and as reduced adaptation skills. These findings advocate development of chemotherapeutic agents that cause fewer long-term side effects when used for treating children.

Hearing and Vestibular Function After Preoperative Intratympanic Gentamicin Therapy for Vestibular Schwanomma as Part of Vestibular Prehab.

OBJECTIVE: To evaluate auditory and vestibular function after presurgical treatment with gentamicin in schwannoma patients. BACKGROUND: The vestibular PREHAB protocol aims at diminishing the remaining vestibular function before vestibular schwannoma surgery, to ensure less acute symptoms from surgery, and initiate a more efficient vestibular rehabilitation already before surgery. However, the potential cochleotoxicity of gentamicin is a concern, since modern schwannoma surgery strives to preserve hearing. STUDY DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: Seventeen patients diagnosed with vestibular schwannoma between 2004 and 2011, and took part in vestibular PREHAB program. The patients were of age 21 to 66 years (mean 48.8), 9 females and 8 males. INTERVENTION: Intratympanic gentamicin installations before surgery as part of the vestibular PREHAB. MAIN OUTCOME MEASURES: Hearing thresholds, word recognition score, caloric response, subjective visual vertical and horizontal, cVEMP, and vestibular impulse tests. RESULTS: Combined analysis of frequency and hearing threshold showed a significant decrease after gentamicin therapy (p < 0.001). Pure-tone average decreased with 7.1 ± 8.5 dB (p = 0.004), and speech recognition with 10%. The treatment resulted in unilateral vestibular deafferentation with no notable reaction to bithermal caloric irrigation (reduction 64%, p < 0.001), loss of the vestibulo-ocular response measured by the head-impulse test, and deviation of subjective horizontal/vertical to the side of the lesion (+2.2 degrees, p = 0.010). CONCLUSIONS: Intratympanic installations of gentamicin, as part of the vestibular PREHAB, result in unilateral vestibular deafferentation, but constitute a definite risk for high-frequency hearing loss. The hearing results are in line with those reported upon when treating Menière's disease.

A Patient-Assessed Morbidity to Evaluate Outcome in Surgically Treated Vestibular Schwannomas.

OBJECTIVE: Outcome after treatment of vestibular schwannomas can be evaluated by health providers as mortality, recurrence, performance, and morbidity. Because mortality and recurrence are rare events, evaluation has to focus on performance and morbidity. The latter has mostly been reported by health providers. In the present study, we validate 2 new scales for patient-assessed performance and morbidity in comparison with different outcome tools, such as quality of life (QOL) (European Quality of Life-5 dimensions [EQ-5D]), facial nerve score, and work capacity. METHODS: There were 167 total patients in a retrospective (n = 90) and prospective (n = 50) cohort of surgically treated vestibular schwannomas. A new patient-assessed morbidity score (paMS), a patient-assessed Karnofsky score (paKPS), the patient-assessed QOL (EQ-5D) score, work capacity, and the House-Brackmann facial nerve score were used as outcome measures. Analysis of paMS components and their relation to other outcomes was done as uni- and multivariate analysis. RESULTS: All outcome instruments, except EQ-5D and paKPS, showed a significant decrease postoperatively. Only the facial nerve score (House-Brackmann facial nerve score) differed significantly between the retrospective and prospective cohorts. Out of the 16 components of the paMS, hearing dysfunction, tear dysfunction, balance dysfunction, and eye irritation were most often reported. Both paMS and EQ-5D correlated significantly with work capacity. CONCLUSIONS: Standard QOL and performance instruments may not be sufficiently sensitive or specific to measure outcome at the cohort level after surgical treatment of vestibular schwannomas. A morbidity score may yield more detailed information on symptoms that can be relevant for rehabilitation and occupational training after surgery.

Oculomotor Deficits after Chemotherapy in Childhood.

Advances in the diagnosis and treatment of pediatric malignancies have substantially increased the number of childhood cancer survivors. However, reports suggest that some of the chemotherapy agents used for treatment can cross the blood brain barrier which may lead to a host of neurological symptoms including oculomotor dysfunction. Whether chemotherapy at young age causes oculomotor dysfunction later in life is unknown. Oculomotor performance was assessed with traditional and novel methods in 23 adults (mean age 25.3 years, treatment age 10.2 years) treated with chemotherapy for a solid malignant tumor not affecting the central nervous system. Their results were compared to those from 25 healthy, age-matched controls (mean age 25.1 years). Correlation analysis was performed between the subjective symptoms reported by the chemotherapy treated subjects (CTS) and oculomotor performance. In CTS, the temporal control of the smooth pursuit velocity (velocity accuracy) was markedly poorer (p<0.001) and the saccades had disproportionally shorter amplitude than normal for the associated saccade peak velocity (main sequence) (p = 0.004), whereas smooth pursuit and saccade onset times were shorter (p = 0.004) in CTS compared with controls. The CTS treated before 12 years of age manifested more severe oculomotor deficits. CTS frequently reported subjective symptoms of visual disturbances (70%), unsteadiness, light-headedness and that things around them were spinning or moving (87%). Several subjective symptoms were significantly related to deficits in oculomotor performance. To conclude, chemotherapy in childhood or adolescence can result in severe oculomotor dysfunctions in adulthood. The revealed oculomotor dysfunctions were significantly related to the subjects' self-perception of visual disturbances, dizziness, light-headedness and sensing unsteadiness. Assessments of oculomotor function may, thus, offer an objective method to track and rate the level of neurological complications following chemotherapy.

[Diagnostic criteria for Menière's disease. Consensus document of the Bárány Society, the Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society]. / Criterios diagnósticos de enfermedad de Menière. Documento de consenso de la Bárány Society, la Japan Society for Equilibrium Research, la European Academy of Otology and Neurotology (EAONO), la American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) y la Korean Balance Society.

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes 2 categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low-to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 min and 12h. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 min to 24h.

Diagnostic criteria for Menière's disease.

This paper presents diagnostic criteria for Menière's disease jointly formulated by the Classification Committee of the Bárány Society, The Japan Society for Equilibrium Research, the European Academy of Otology and Neurotology (EAONO), the Equilibrium Committee of the American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) and the Korean Balance Society. The classification includes two categories: definite Menière's disease and probable Menière's disease. The diagnosis of definite Menière's disease is based on clinical criteria and requires the observation of an episodic vertigo syndrome associated with low- to medium-frequency sensorineural hearing loss and fluctuating aural symptoms (hearing, tinnitus and/or fullness) in the affected ear. Duration of vertigo episodes is limited to a period between 20 minutes and 12 hours. Probable Menière's disease is a broader concept defined by episodic vestibular symptoms (vertigo or dizziness) associated with fluctuating aural symptoms occurring in a period from 20 minutes to 24 hours.

Dominant mutations in GRHL3 cause Van der Woude Syndrome and disrupt oral periderm development.

Mutations in interferon regulatory factor 6 (IRF6) account for ∼70% of cases of Van der Woude syndrome (VWS), the most common syndromic form of cleft lip and palate. In 8 of 45 VWS-affected families lacking a mutation in IRF6, we found coding mutations in grainyhead-like 3 (GRHL3). According to a zebrafish-based assay, the disease-associated GRHL3 mutations abrogated periderm development and were consistent with a dominant-negative effect, in contrast to haploinsufficiency seen in most VWS cases caused by IRF6 mutations. In mouse, all embryos lacking Grhl3 exhibited abnormal oral periderm and 17% developed a cleft palate. Analysis of the oral phenotype of double heterozygote (Irf6(+/-);Grhl3(+/-)) murine embryos failed to detect epistasis between the two genes, suggesting that they function in separate but convergent pathways during palatogenesis. Taken together, our data demonstrated that mutations in two genes, IRF6 and GRHL3, can lead to nearly identical phenotypes of orofacial cleft. They supported the hypotheses that both genes are essential for the presence of a functional oral periderm and that failure of this process contributes to VWS.

Expression of insulin signalling components in the sensory epithelium of the human saccule.

Several studies have demonstrated a link between diabetes and the dysfunction of the inner ear. Few studies, however, have reported the signalling mechanisms involved in metabolic control in human inner ear cells. Knowledge of the expression and role of the insulin receptor and downstream signalling components in the inner ear is sparce. Our immunohistochemistry approach has shown that the insulin receptor, insulin receptor substrate 1 (IRS1), protein kinase B (PKB) and insulin-sensitive glucose transporter (GLUT4) are expressed in the sensory epithelium of the human saccule, which also exhibits expression of a calcium-sensitive cAMP/cGMP phosphodiesterase 1C (PDE1C) and the vasopressin type 2 receptor. IRS1 and PDE1C are selectively expressed in sensory epithelial hair cells, whereas the other components are expressed in sensory epithelial supporting cells or in both cell types, as judged from co-expression or non-co-expression with glial fibrillary acidic protein, a marker for supporting cells. Furthermore, IRS1 appears to be localized in association with sensory nerves, whereas GLUT4 is expressed in the peri-nuclear area of stromal cells, as is the case for aquaporin 2. Thus, the insulin receptor, insulin signalling components and selected cAMP signalling components are expressed in the human saccule. In addition to well-known mechanisms of diabetes complications, such as neuropathy and vascular lesions, the expression of these proteins in the saccule could have a role in the observed link between diabetes and balance/hearing disorders.

'PREHAB': Vestibular prehabilitation to ameliorate the effect of a sudden vestibular loss.

A sudden unilateral loss or impairment of vestibular function causes vertigo, dizziness and impaired postural function. In most occasions, everyday activities supported or not by vestibular rehabilitation programs will promote compensation and the symptoms subside. As the compensatory process requires sensory input, matching performed motor activity, both motor learning of exercises and matching to sensory input are required. If there is a simultaneous cerebellar lesion found during surgery of the posterior cranial fossa, there may be a risk of a combined vestibulo-cerebellar lesion, with reduced compensatory abilities and with prolonged or sometimes permanent disability. On the other hand, a slow gradual loss of unilateral function occurring as the subject continues well everyday activities may go without any prominent symptoms. We therefore implemented a pre treatment plan before planned vestibular lesions (prehab). This was first done in subject undergoing gentamicin treatment for Meniere's disease (MD). Subjects perform vestibular exercises for 14 days before the first gentamicin installation and then continue doing so until free of symptoms. Most subjects would only experience slight dizziness while losing vestibular function. We then expanded the approach to patients with brainstem tumours requiring surgery but with remaining vestibular function to ease postoperative symptoms and reduce risk of combined cerebello-vestibular lesions. This patient group was given gentamicin installations trans-tympanically before tumour sugary and then underwent prehab. In all cases there was a caloric loss, loss of VOR evident in the head impulse tests, impaired subjective vertical and horizontal, and reduced caloric function induced by the pre-surgery gentamicin treatment. The prehab eliminated spontaneous and positional nystagmus, subjective symptoms, and postural function up before surgery and allowed for rapid postoperative recovery.The concept of 'pre-lesion rehabilitation' where training is introduced before a planned lesion and if possible paralleled with a gradual function loss expands the potential of rehabilitation. Here it was used for vestibular lesions but it is possible that similar approaches may be developed for other situations, which include foreseeable loss of function.

Identification of new signaling components in the sensory epithelium of human saccule.

OBJECTIVE: To locate components and target proteins of relevance for the cAMP and cGMP signaling networks including cAMP and cGMP phosphodiesterases (PDEs), salt-inducible kinases (SIKs), subunits of Na+, K+-ATPases, and aquaporins (AQPs) in the human saccule. METHODS: The human saccule was dissected out during the removal of vestibular schwannoma via the translabyrinthine approach and immediately fixed. Immunohistochemistry was performed using PDE, SIK, Na(+), K(+)-ATPase, and AQP antibodies. RESULTS: PDEs selective for cAMP (PDE4A, PDE4D, and PDE8A) and cGMP (PDE9A) as well a dual specificity PDE (PDE10A) were detected in the sensory epithelium of the saccule. Furthermore, AQP2, 4, and 9, SIK1 and the α-1 subunit of the Na(+), K(+)-ATPase were detected. CONCLUSION: cAMP and cGMP are important regulators of ion and water homeostasis in the inner ear. The identification of PDEs and SIK1 in the vestibular system offers new treatment targets for endolymphatic hydrops. Exactly how the PDEs are connected to SIK1 and the SIK1 substrate Na(+), K(+)-ATPase and to AQPs 2, 4, 9 remains to be elucidated. The dissection of the signaling networks utilizing these components and evaluating their roles will add new basic knowledge regarding inner ear physiology.

Severe difficulties with word recognition in noise after platinum chemotherapy in childhood, and improvements with open-fitting hearing-aids.

OBJECTIVE: To investigate word recognition in noise in subjects treated in childhood with chemotherapy, study benefits of open-fitting hearing-aids for word recognition, and investigate whether self-reported hearing-handicap corresponded to subjects' word recognition ability. DESIGN: Subjects diagnosed with cancer and treated with platinum-based chemotherapy in childhood underwent audiometric evaluations. STUDY SAMPLE: Fifteen subjects (eight females and seven males) fulfilled the criteria set for the study, and four of those received customized open-fitting hearing-aids. RESULTS: Subjects with cisplatin-induced ototoxicity had severe difficulties recognizing words in noise, and scored as low as 54% below reference scores standardized for age and degree of hearing loss. Hearing-impaired subjects' self-reported hearing-handicap correlated significantly with word recognition in a quiet environment but not in noise. Word recognition in noise improved markedly (up to 46%) with hearing-aids, and the self-reported hearing-handicap and disability score were reduced by more than 50%. CONCLUSIONS: This study demonstrates the importance of testing word recognition in noise in subjects treated with platinum-based chemotherapy in childhood, and to use specific custom-made questionnaires to evaluate the experienced hearing-handicap. Open-fitting hearing-aids are a good alternative for subjects suffering from poor word recognition in noise.

Challenges and opportunities in managing the dizzy older adult.

Balance disorders are common in elderly people, not only resulting in distressing sensations but also leading to reduced activity levels and quality of life. It has been estimated that 30% of elderly patients experience a balance disorder. Managing these disorders is a substantial challenge for patients and their caregivers and physicians. Moreover, abnormalities in balance are associated with falls, a major cause of morbidity and mortality for elderly people. Management is complicated by the inherent difficulties in assessing the generic complaint of dizziness, as well as the likelihood of multiple, often nonvestibular causes. The authors of this mini-seminar review both vestibular and nonvestibular causes of balance disorders in elderly people, emphasizing practical therapeutic maneuvers that can be used.