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To test the hypotheses that, after the delivery of manual wheelchairs following the WHO 8-step service-delivery process, wheelchair-related health and quality of life, wheelchair skills, wheelchair use, and poverty probability would improve; and that the number of wheelchair repairs required, adverse events, caregiver burden, and the level of assistance provided would decrease. This was a longitudinal, prospective within-subject study including 247 manual wheelchair users, and 119 caregivers, in El Salvador who received a wheelchair following the WHO 8-step process as well as maintenance reminders. Outcome measurements were performed via structured questionnaires and dataloggers at the initial assessment, at wheelchair delivery, and at 3- and 6-month follow-up. Significant improvements in wheelchair-related health indicators (all with p < 0.004) and quality of life (p = 0.001), and a significant reduction in national and "extreme" poverty probability (p = 0.004 and p = 0.012) were observed by six months. Wheelchair use significantly decreased (p = 0.011 and p = 0.035) and wheelchair skills increased (p = 0.009). Caregiver burden did not change (p = 0.226) but the number of activities of daily living (ADLs) that required no assistance significantly increased (p = 0.001) by three months and those who required complete assistance decreased (p = 0.001). No changes were observed in wheelchair repairs (p = 0.967) and breakdowns over time with new wheelchairs. Wheelchair service delivery using the WHO 8-step process on manual wheelchair users in El Salvador has positive effects on health and quality of life, wheelchair skills, caregiver assistance levels, and poverty. Further research is needed to determine the relative contributions of the intervention components. Providing manual wheelchairs using the 8-step process of the WHO has benefits on health and quality of life, wheelchair skills, caregiver assistance levels, and poverty. The WHO 8-steps service delivery process for manual wheelchairs can be used in less-resourced settings. [ABSTRACT FROM AUTHOR]

It is documented that wheelchair failures occur frequently, repair times are lengthy, and users often experience adverse consequences. This study aims to gather evidence on efficiency of current wheelchair repair processes from the perspective of complex rehabilitation technology (CRT) suppliers who perform repairs within the United States. A 20 statement survey was developed to identify barriers and facilitators related to wheelchair repairs across the domains of administrative and operational factors as well as to identify future opportunities for improvement. Key statements in these areas included time to perform a repair, documentation requirements, tracking repair progress, reimbursement, technician competency, emerging strategies and preventative maintenance. The online survey was broadly disseminated to a nationwide network of CRT suppliers for data collection. A total of 127 responses were received. Results showed that administrative statements received the lowest scores while those statements dealing with future opportunities received the highest scores. Areas of the industry that suppliers were in most disagreement with included wait time for insurance approval, reimbursement for parts, reimbursement for technician travel time and lack of coverage for preventative maintenance. Telehealth system usage, preventative maintenance coverage, tracking repairs and repair scheduling were future opportunities that suppliers were in most agreement with. Administrative issues exist in the CRT industry due to restrictive insurance policies associated with repairs and maintenance. Future opportunities to improve the process exist including payment models and the application of telehealth, device monitoring and service-based performance incentives to reduce adverse consequences to the user. Highlights the direct importance and barriers faced within the wheelchair repair industry by CRT suppliers. In a sample of CRT suppliers, there is agreement there exists many administrative and operational issues related to wheelchair repairs. There is agreement among survey respondents of opportunities to investigate further telehealth and remote strategies, preventative maintenance coverage and online tracking for wheelchair repairs. [ABSTRACT FROM AUTHOR]

Wheeled mobility and seating (WMS) devices allow users to achieve greater mobility independence. Previous studies determined that 53% of wheelchair users required one or more repairs over a 6-month period; however, there are a limited number of studies that have evaluated types of repairs. The purpose of this study was to describe the types of manual wheelchair, power wheelchair, and scooter repairs within the Wheelchair Repair Registry (WRR) and examine the association between WMS devices and the frequency of repairs. A dataset of 4,645 devices distributed in the United States was collected from equipment suppliers who performed and logged community-based wheelchair repair services. The results demonstrated common repairs found across devices were within the wheels/tires/forks and batteries/ cables categories. Device type was the most significant predictor of variance in the number of repairs. Customizable manual wheelchairs, tilt-in-space, Groups 2 & 3 power wheelchairs, and scooters were associated with higher number of repairs compared to non-customizable manual wheelchairs, pediatric, heavy-duty manual wheelchairs, and Group 4 power wheelchairs. The higher failure rate found in specific devices may be associated with a population of more active users, environment/conditions where equipment is used, time spent in equipment, additional features on device, or lower durability. [ABSTRACT FROM AUTHOR]

Makerspaces can engage people with disabilities in the design and development of assistive technology (AT) that can enhance their capabilities to perform new activities and function. However, the adoption of makerspaces in the environments and institutions serving people with disabilities remains challenging. The authors modeled a makerspace training program, an environmental intervention, based on the capability approach framework. This mixed methods study investigates the feasibility of an 8-week program to train adults (n = 5) with intellectual and developmental disabilities (IDD) and staff members (n = 5) at a community services center. Study outcomes were measured using knowledge tests, surveys, QUEST 2.0 and interviews. Results indicate a significant increase in staff's knowledge (p = 0.035) and familiarity with program topics (p < 0.05). Participants with IDD were highly satisfied with the ease of use, weight and effectiveness of the AT devices they created. Five themes emerged from the thematic analysis of interviews: (1) inclusive environment, (2) freedom and improved Capability for building technology for self or client, (3) multidisciplinary collaboration, (4) interactive program elements, (5) makerspace challenges. Overall, the makerspace training program is a valuable program that empowers people with disabilities and ensures the realization of their right of autonomy to create their own AT. [ABSTRACT FROM AUTHOR]

Background: Wheelchair part failures have doubled over the past decade. Preventative wheelchair maintenance reduces wheelchair failures and prevents user consequences. We are developing a smartphone app called WheelTrak, which alerts users when maintenance is required, to encourage maintenance practices and compliance. Objective: This mixed methods study aimed to develop a wheelchair maintenance app using broad stakeholder advice and investigate older adults' interaction experience with the app and their perceived barriers to and facilitators of maintenance. Methods: Interviews were conducted with stakeholders, including mobility device users, to generate needs statements and app specifications. The app was designed in 2 stages. Stage 1 involved the development of the app according to the specifications and evaluation of the app interface by lead users. Stage 2 included the revision of the app screens and manual functionality testing. Usability testing and semistructured interviews were conducted with older wheelchair and scooter users. The System Usability Scale was used to measure app usability. Results: Interviews with power and manual wheelchair users (37/57, 65%), wheelchair service providers (15/57, 26%), manufacturers (2/57, 4%), seating and mobility researchers (1/57, 2%), and insurance plan providers (2/57, 4%) informed the needs and specifications of the app technology. The 2-stage development process delivered a fully functional app that met the design specifications. In total, 12 older adults (mean age 74.2, SD 9.1 years; n=10, 83% women; and n=2, 17% men) participated in the usability testing study. Of the 12 participants, 9 (75%) agreed to use WheelTrak for preventative maintenance. WheelTrak scored an average System Usability Scale score of 60.25 (SD 16). Four overarching themes were identified: WheelTrak app improvements, barriers to maintenance, consequences related to mobility device failure, and smart technology use and acceptance. Older adults preferred the simplicity, readability, personalization, and availability of educational resources in the app. Barriers to maintenance pertained to health issues and lack of maintenance knowledge among older adults. Facilitators of maintenance included notification for maintenance, app connectivity with the service provider, reporting of device failure, and the presence of a caregiver for maintenance. Conclusions: This study highlighted age-friendly design improvements to the app, making it easy to be used and adopted by older wheelchair users. The WheelTrak app has close to average system usability. Additional usability testing will be conducted following app revision in the future. [ABSTRACT FROM AUTHOR]

The World Health Organization (WHO) estimates that only 17–37% of the approximately 77 million people who need a wheelchair have access to one. Many organizations are trying to address this need through varying service delivery approaches. For instance, some adhere to WHO's recommended 8-steps service approach while others provide wheelchairs with little to no service. There is limited and sometimes conflicting evidence of the impact of the WHO's recommendations on the outcomes of wheelchair provision. To help build this evidence, we \explored outcomes of two groups of users who received their wheelchairs through two service models over time. The 8-Steps group (n = 118) received a wheelchair selected from a range of models from service providers trained using the WHO process, and the standard of care (SOC) group (n = 24) received hospital-style wheelchairs and without clinical service. Interviews were conducted at baseline and at follow-up 3 to 6 months after provision, to collect data about wheelchair usage, satisfaction, skills, maintenance and repairs, and life satisfaction. Across-group statistical comparisons were not appropriate due to significant differences between groups. In general, participants used their wheelchairs every day but reported very low mobility levels (<500 meters for the 8-steps group, and <100 meters for the SOC group.) The 8-steps group used their wheelchair for either between 1–3 hours per day, or more than 8 hours per day. The SOC used it between 1 and 3 hours per day. Overall, wheelchair usage and wheelchair skills decreased over the 3- to 6-month data collection timeline. Wheelchair breakdowns were common in both groups emphasizing the need for maintenance, occurring more frequently in the 8-Steps (28.8%) compared to the SOC group (8%), and emphasizing the need for maintenance services. No significant differences were found when comparing device satisfaction across wheelchairs types. Our results emphasize the need for routine maintenance to address frequent wheelchair breakdowns. Our results also demonstrate a large disparity in several outcome variables across groups which motivates future studies where across-group comparisons are possible. [ABSTRACT FROM AUTHOR]

Introduction: Wheelchair casters fail frequently in the field causing multiple user consequences and wheelchair breakdowns. To inform caster design improvement, there exists no validated tools that can collect caster failures. This need motivated the development of a user-reported, caster failure inspection tool (C-FIT). Methods: To develop C-FIT, a multistep design and testing approach was used which included face validity testing, test-retest reliability testing and expert review. Reliability testing was conducted with two independent cohorts of wheelchair professionals who inspected caster failures physically and online through pictures. The tool was revised based on testing outcomes and expert feedback. For preliminary data collection and evaluating usability, C-FIT was piloted at wheelchair service centers in Scotland, Indonesia and Mexico. Results: Caster failure items reported in the literature were screened to develop the initial list of C-FIT items. Face validity testing conducted through surveys with wheelchair experts (n = 6) provided 14 items for C-FIT inclusion. The test-retest reliability was found to be high for 10 items with physical failure inspections (n = 12). For each of these items, 75% or more participants had substantial to almost perfect agreement scores (κ = 0.6–1.0). Lower reliability scores were found with online failure inspections (n = 11). C-FIT received positive usability feedback from study participants and data collectors in the field. Pilot field data (n = 31) included comprehensive details about failures useful for manufacturers, designers and researchers to improve caster designs. Conclusions: The C-FIT tool developed in this study has substantial reliability and can be used for documenting caster failures at wheelchair service centers. Collecting data on caster failures is an important first step to inform design improvements and caster quality testing methods. The caster failure inspection tool is a reliable tool that can be used during wheelchair repair and servicing to collect caster failures in a standardized way. The failure data can be used by wheelchair manufacturers, designers, technicians and researchers to develop reliable caster designs. Wheelchair providers can select caster designs based on context of use. [ABSTRACT FROM AUTHOR]

Wheelchair castors fail frequently causing physical, social and economic consequences for wheelchair users. These failures occur in spite of established wheelchair test methods and regulations, suggesting that the existing tests may not be sufficient to screen poorly designed castors. An expert stakeholder group, convened by the International Society of Wheelchair Professionals (ISWP), noted castor failures as a high priority and recommended that a new castor testing system should be developed. In a previous study, the effect of shock exposure on castor durability was studied. The current paper extends the previous work and focuses on the development of a castor testing protocol based on shock, corrosion and abrasion exposure data collected in the community. The testing protocol was applied to 8 different castor models tested under four conditions: shock, corrosion + shock, abrasion + shock and abrasion + corrosion + shock. For each model, a total of n = 8 samples were evaluated across the four conditions. Results demonstrate that corrosion and abrasion reduced castor durability between 13% to 100% depending on the model. Importantly, the inclusion of corrosion and abrasion resulted in changes in the failure modes for 75% of the tested models and two-thirds of the altered failure modes are associated with increased risk of injury for wheelchair users. These results suggest that corrosion and abrasion present in the community reduce castor durability, thus supporting their inclusion in the castor testing protocol and potentially other wheelchair standards. [ABSTRACT FROM AUTHOR]

Regular weight monitoring is known to help with weight management, which is an important part of maintaining a healthy, active lifestyle. Unfortunately, weight monitoring is challenging for wheelchair users because the few scales that are available are expensive and very large. Consequently, wheelchair users typically learn their weight at infrequent visits to their healthcare providers, which likely contributes to higher prevalence of obesity-related health risks among this population. In this article, we describe the design and development of the Embedded Scale, or E-Scale, which is a bed-integrated bodyweight measuring system that allows a user to measure and track their weight. The E-Scale team followed a standard product development approach to build the E-Scale prototype. Bench testing results indicate that the performance of the prototype is on par with commercially available wheelchair scales (capacity = 1,200 lbs, accuracy = 1.73 lbs, and precision = ± 0.35 lbs over one-fourth rated capacity). Institutional Review Board (IRB)-approved focus groups with 20 Veterans who use wheelchairs for mobility were conducted to gather feedback about the design, which was very positive. Development and testing results suggests the E-Scale technology is feasible and may provide a valuable tool to help wheelchair users manage their weight. [ABSTRACT FROM PUBLISHER]

Abstract: Objective: To assess whether MYH9 mutant alleles linked to hereditary hearing loss induce disruption of cellular functions and associated phenotype following transient expression within cultured human cell lines. Study Design: Dominantly inherited MYH9 mutant alleles, MYH9 R702C and MYH9 R705H , were integrated within eukaryotic expression vector and then transfected into cultured human cell lines for transient expression and analysis. The transfected cells were assessed for transgene-induced alterations of the cellular phenotype, including NMHC-IIA-dependent cell shape, actin cytoskeleton integrity, and inhibition of cytokinesis. Setting: Laboratories of Molecular Otology and Molecular Genetics at the New York University School of Medicine. Subjects and Methods: HeLa and MDA-MB-231 cultured cell lines were transiently transfected with an expression vector carrying a wild type or mutant MYH9 alleles, linked to nonsyndromic and syndromic hearing loss. Expression of exogenous transgene product was detected with antibodies directed toward its N-terminal HA tag, and transfection efficiency was greater than 95 percent. Host cells were characterized for cell shape, integrity of actin-myosin cytoskeleton, and nuclear status before and after transfections via immunofluorescence. Results: MDA-MB-231 cells transfected with MYH9 R705H but not MYH9 R702C were found to have a greater than two-fold increase in cells with filopodia and a ten-fold increase in proportion of cells with multiple nuclei, indicating inhibition of cytokinesis, relative to the control cells transfected with wild type MYH9. Actin cytoskeleton configuration within MDA-MB-231 cells was unaffected by expression of MYH9 R702C or MYH9 R705H . Unlike MDA-MB-231 cells, HeLa cells were refractory to MYH9 R705H and MYH9 R702C . Conclusions: MYH9 R705H -induced altered phenotype of the MDA-MB-231 cell line supports the pathogenicity of the mutation and represents a suitable assay system for identification and characterization of its dysfunction. [Copyright &y& Elsevier]

The endolymphatic hydrops seen in Ménière's disease (MD) results from an inner ear fluid disequilibrium that has a suspected inherited component. Aquaporin-2 and aquaporin-4 (AQP2 and AQP4) water transport proteins may contribute to abnormal fluid homeostasis seen in MD. Our objective was to screen for sequence alterations in AQP2 and AQP4 genes in a northern European population with MD. Amplification for AQP2 (n = 18) and AQP4 (n = 30) was performed for patients with MD. Sequences were screened with denaturing high powered liquid chromatography (DHPLC) and confirmed with sequencing. Allele frequencies were compared with previously reported normal populations. We found that DHPLC failed to identify sequence alterations in any sample. Sequencing identified three intronic and one 3' untranslated region polymorphism in AQP2, and one polymorphism upstream from the start codon in AQP4. Two of the AQP2 intronic allele frequencies showed an A and C allele enrichment, respectively, compared with a reported mixed population (0.389 A vs. 0.00 A; 0.389 C vs. 0.00 C, p<0.001). The remaining polymorphism showed statistical difference from three non-Caucasian populations (0.611 A vs. 0.389 A, 0.375 A, and 0.280 A, p<0.05). The AQP4 allele frequency in the MD population was statistically different from a previously published Japanese population (0.800 G vs. 0.620 G, p = 0.0053) but not from a reported Caucasian population. We concluded that aquaporin polymorphisms may contribute to MD. Additional studies are needed to confirm these findings in well-defined population isolates and to determine if these polymorphisms lead to altered AQP protein function or levels. [ABSTRACT FROM AUTHOR]

MYH9 encodes a class II nonmuscle myosin heavy chain-A (NMHC-IIA), a widely expressed 1960 amino acid polypeptide, with translated molecular weight of 220 kDa. From studies of type II myosin in invertebrates and analogy with the skeletal and smooth muscle myosin II, NMHC-IIA is considered to be involved in diverse cellular functions, including cell shape, motility and division. The current study assessed the consequences of two separate, naturally occurring MYH9 dominant mutant alleles, MYH9R702C and MYH9R705H linked to syndromic and nonsyndromic hearing loss, respectively, upon diverse NMHC-IIA related functions in two separate cultured cell lines. MYH9-siRNA-induced inhibition of NMHC-IIA in HeLa cells or HEK293 cells resulted in alterations in their shape, actin cytoskeleton and adhesion properties. However, HeLa or HEK293 cells transfected with naturally occurring MYH9 mutant alleles, MYH9R702C or MYH9R705H, as well as in vitro generated deletion derivatives, MYH9ΔN592 or MYH9ΔC570, were unaffected. The effects of MYH9-siRNA-induced suppression underline the critical role of NMHC-IIA in maintenance of cell shape and adhesion. However, the results also indicate that the NMHC-IIA mutants, R702C and R705H do not inactivate or suppress the endogenous wild type NMHC-IIA within the HeLa or HEK293 cell assay system. Cell Motil. Cytoskeleton 2008. © 2008 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

MYH9 encodes a class II nonmuscle myosin heavy chain-A (NMHC-IIA), a widely expressed 1960 amino acid polypeptide, with a translated molecular weight of 220 kDa. The relatively large number of exons (40) that encode NMHC-IIA and the splice variants that have been documented for its two isoforms, MYH10 and MYH14, strongly suggest existence of alternative splicing for MYH9. In the current study, we perform a targeted search for Myh9 splice variants in two separate regions of the heavy chain that encode loop 1 and loop 2 subdomains within which alternative exons in MYH10 and MYH14 splice variants have been identified. The splice variant search was conducted using two strategies: amplification across the suspected exons directly or by amplification of putative splice variants identified through conserved sequence analysis of suspected intronic regions. Within loop 1, two separate insertions of 12 and 41 nucleotides were identified using conserved sequence analysis only. Each of these insertions, located within intron 4, resulted in premature termination of the variant transcript. Within loop 2, a 63-nucleotide-long in-frame insertion was identified using both strategies. The insertion is identical in length and displays 65 sequence identity with its Myh10 counterpart, but differs greatly from the 123-nucleotide-long insertion within Myh14 transcript identified in this study. Both loop 1 and loop 2 variants of Myh9 were detected in the cochlea, with the latter being most abundant in the brain. Expression of loop 1 variants with premature termination codon may reflect an alternate mode of regulating Myh9 expression, while the conserved sequence and selective expression of the loop 2 variant highlight its potential biological importance. [ABSTRACT FROM AUTHOR]

Mutant alleles of MYH9 encoding a class II non-muscle myosin heavy chain-A (NMMHC-IIA) have been linked to hereditary megathrombocytopenia with or without additional clinical features that include sensorineural deafness, cataracts, and nephritis. To assess its biological role in the affected targets, particularly the inner ear, we have generated and characterized mice with Myh9 deficiency. These mice were generated using the XA136 ES cell line (BayGenomics, http://baygenomics.ucsf.edu/) carrying gene trap insertion in Myh9, within the intron flanking exons 4 and 5. Mice heterozygous for the Myh9 null allele, Myh9 +/− were expanded on C57BL/6J background. Intercross of the Myh9 +/− mice did not yield Myh9 −/− pups, indicating embryonic lethality, subsequently determined to occur at or before E7.5, thus precluding a post-natal analysis of the effects of complete Myh9 deficiency. The heterozygous mice were normal for their hearing, parameters of platelet integrity and renal function despite their Myh9 haplo-insufficiency. In addition, the age-dependent auditory threshold of the Myh9 +/− mice and their wild type littermates, spanning from 3 to 12 months of age, were similar indicating that Myh9 haplo-insufficiency does not contribute towards accelerated age-related hearing loss (AHL). The embryonic lethality associated with the complete Myh9 deficiency establishes a critical role for this non-muscle myosin in fetal development. The results of these studies do not support the Myh9 haploinsufficiency as a pathogenic factor in the etiology of auditory dysfunction. [ABSTRACT FROM AUTHOR]

Although hereditary hearing loss is highly heterogeneous, only a few loci have been implicated with low-frequency hearing loss. Mutations in one single gene, Wolfram syndrome 1 ( WFS1), have been reported to account for most familial cases with this type of hearing impairment. This study was conducted to determine the cause of nonsyndromic low-frequency hereditary hearing impairment in two large families. Two large families from Switzerland and United States with low-frequency hearing loss were identified. Genomewide linkage analysis was performed followed by mutation screening in the candidate gene WFS1 with direct DNA sequencing and restriction fragment analysis. Both families were linked to DFNA6/14/38 with lod scores>3. Two novel heterozygous missense mutations in WFS1 were identified: c.2311G>C leading to p.D771H in the Swiss family and c.2576G>C leading to p.R859P in the US family. The sequence alteration was absent in 100 control chromosomes. Nonsyndromic low-frequency hereditary hearing impairment seems to be predominantly a monogenic disorder due to WFS1. We confirm that most mutations in WFS1 associated with isolated low-frequency hearing loss are clustered in the C-terminal protein domain coded by exon 8. [ABSTRACT FROM AUTHOR]

Background: Pathogenic mutations in the mitochondrial genome are associated with a wide variety of maternally inherited human diseases including sensorineural hearing loss (HL). A specific mutation, m.1555A>G in the mitochondrial 12S rRNA gene, is associated with predisposition to aminoglycoside ototoxicity and HL. Mutation screening in this gene has been recommended before use of aminoglycosides as a preventative strategy to reduce the risk of ototoxicity. Objective: To study the incidence of mutations in the 12S rRNA gene in patients being treated with aminoglycosides and its correlation with ototoxicity. Methods: Patients undergoing treatment with aminoglycosides were prospectively enrolled in this study (n = 27). Total dosage administered and therapeutic levels of the antibiotic were noted. All patients underwent high-frequency pure-tone audiometry pre- and posttherapy and sequencing of the 12S rRNA gene. In addition, 12S rRNA gene was also sequenced in 50 controls to characterize population specific polymorphisms. Results: Five of 27 patients suffered from HL involving the high frequencies: four mild and one moderate. Only one of the five patients with ototoxicity harbored two sequence alterations in 12S rRNA of uncertain pathogenicity. The m.1555A>G and m.961delTInsCn mutations were not detected. Conclusions: High-frequency pure-tone audiometry is critical for detection of aminoglycoside-induced HL. In the Swiss population, screening for mutations in the 12S rRNA gene, before the initiation of aminoglycoside therapy, is not supported by this limited study. A larger multicenter and multicultural study is warranted to more definitively address this critical clinical issue. [ABSTRACT FROM AUTHOR]

Nonsyndromic hereditary hearing impairment (NSHHI) is a highly heterogeneous disorder with more than 90 loci mapped, of which nearly one-half of the responsible genes are identified. In dominant NSSHI hearing loss is typically biased towards the high frequencies while low-frequency hearing loss is unusual. Only two NSHHI loci, DFNA1 and DFNA6/14/38, are associated with predominantly low- frequency loss. We mapped the loci harboring the gene responsible for autosomal dominant low-frequency hearing loss in a multigenerational family. The pedigree of a Swiss family with low-frequency hearing loss was established. Using genomic DNA, DFNA1 and DFNA6/14/38 were excluded by linkage analysis or by direct sequencing of the responsible gene. Genome-wide linkage analysis was performed using commercially available microsatellite markers. Two-point linkage analysis demonstrated linkage to chromosome 5q31, the locus for DFNA15, with a lod score of 6.32 at recombination fraction ?=0 for marker D5S436. Critical recombinations were seen at markers D5S1972 and D5S410. Sequencing of the corresponding genePOU4F3yielded no pathogenic mutation segregating with the affected members. In addition to Wolfram syndrome gene 1 (DFNA6/14/38) and diaphanous (DFNA1) there is evidence for a third gene involved in low-frequency hearing loss located at DFNA15. Because of the differences in auditory phenotype and the absence of pathogenic mutation in the coding region ofPOU4F3it is likely that there is a second gene in 5q31, designated DFNA54, associated with NSHHI. [ABSTRACT FROM AUTHOR]

Objective To determine the prevalence of GJB2 gene mutations in patients undergoing cochlear implantation (CI) and their impact on rehabilitative outcome following implantation. Design Prospective determination of GJB2 mutation by sequence analysis by denaturing high-performance liquid chromatography and its correlation with outcome following CI. Settings Two tertiary academic medical centers. Patients Subjects who have met the audiologic criteria and have undergone CI. Results Of 77 cochlear implant recipients screened, 13 (18%) harbored a detectable sequence alteration in the GJB2 gene. Only 3 of these 13 patients had hearing loss clearly attributable to a biallelic GJB2 mutation. There were 2 patients with homozygous mutations, including a 35delG and a 167delT mutation, and a third with a compound heterozygous mutation. Of the remaining 10 patients, 8 had 1 deafness allele, while 2 had a normal polymorphism that was not believed to be implicated in the hearing loss. Six patients had the common 35delG mutation: 5 patients had heterozygous mutations, which are probably not related to the underlying hearing loss (a second deafness allele cannot be ruled out in these cases because of the screening methodology used), while 1 patient had a homozygous mutation, which was clearly implicated in the patient's deafness. Rehabilitative outcome among those with detectable sequence alterations, as well as the 3 patients with biallelic mutations, varied but were similar on average when compared with outcomes seen in our entire CI population. Conclusions A large percentage of implant candidates harbor mutations or sequence alterations in the GJB2 gene, although only a small number of these changes are biallelic and a clear cause of the hearing loss. These results demonstrate that patients with GJB2-related deafness clearly benefit from CI. [ABSTRACT FROM AUTHOR]

Objectives/Hypothesis Auditory dysfunction following ototoxic insult results from loss of cochlear hair cells. Secondary degeneration of auditory neurons ensues from withdrawal of neurotrophic support from hair cells and can be prevented with administration of neurotrophins. Administration of adeno-associated virus containing the gene for brain-derived neurotrophic factor will promote spiral ganglion neuron survival after the destruction of hair cells. Methods Prevention of aminoglycoside-induced spiral ganglion neuron loss through the expression of brain-derived neurotrophic factor mediated by means of the adeno-associated virus was tested in vitro in cochlear explants and in vivo in mammalian cochlea. Results Neuronal survival was significantly enhanced in adeno-associated virus-brain-derived neurotrophic factor transfected rat cochlear explants compared with control samples (30% vs. 19%, P <.05) following exposure to aminoglycoside. Following deafening with aminoglycoside and loop diuretic and introduction of adeno-associated virus-brain-derived neurotrophic factor through osmotic minipump, the experimental group of animals infused with adeno-associated virus-brain-derived neurotrophic factor displayed enhanced spiral ganglion neuron survival in the basal turn of the cochlea when compared with the control group infused with adeno-associated virus containing green fluorescent protein reporter gene. Conclusions Administration of adeno-associated virus-brain-derived neurotrophic factor enhances spiral ganglion neuron survival following ototoxic exposure in vitro and in vivo. These studies lay the groundwork for further exploration of its application as an adjunct therapy for patients undergoing cochlear implantation because the success of implantation depends directly on the population of neurons available for electrical stimulation. [ABSTRACT FROM AUTHOR]

Hypothesis Fungi have been increasingly recognized as important pathogens in sinusitis. However, detection of fungus with conventional culture techniques is insensitive and unreliable. Polymerase chain reaction (PCR) is an exquisitely sensitive assay that can detect the DNA of 10 or less fungal elements. The aim of this study was to compare the sensitivity of conventional culture techniques using PCR analysis. Methods Nasal swabs and DNA samples were collected from the nasal cavities of control subjects and patients with chronic sinusitis. Fungal-specific PCR analysis and standard cultures were performed on every sample. χ2 analysis was used to test for statistical differences between groups. Results PCR analysis detected fungal DNA in 42% and 40% of control subjects and patients with chronic sinusitis while standard cultures were positive in 7% and 0%, respectively. There was no statistically significant difference in the prevalence of fungi in the normal volunteers and patients with chronic rhinosinusitis. Conclusion PCR is significantly more sensitive than nasal swab cultures in detecting the presence of fungi in nasal mucosa. In addition, our study suggests that the presence of fungi alone is insufficient to implicate it as the pathogen in chronic sinusitis. [ABSTRACT FROM AUTHOR]

Microinjection through the round window membrane has been found to represent a method for vector delivery in intracochlear gene transfer in animal models but breaches the round window membrane, making it necessary to evaluate animals for possible postinjection hearing loss. In the present study healthy guinea pigs were evaluated for their baseline click auditory brainstem response (ABR) thresholds. Each animal was then injected with saline via the round window membrane. After 1 week auditory function was evaluated by click ABR. Animals with increased ABR thresholds were retested at 4 weeks. Animals with 1-week postoperative ABRs similar to baseline were not retested. Results showed that postoperative ABR thresholds in five animals (71%) remained unchanged from baseline, while two animals had increases of 20–¶25 dB in ABRs after 1 week but recovered baseline ABRs after 4 weeks. The mean baseline ABR threshold was ¶25.7 dB and was 27.9 dB after 1 week after injection. The difference between preoperative and 1-week postoperative averages was not significant (P = 0.707). In this preliminary study saline microinjection through the round window membrane did not cause permanent hearing loss in the guinea pigs tested, and any damage caused by microinjection appeared to be reversible. [ABSTRACT FROM AUTHOR]

Type 1 Waardenburg syndrome (WS1) is an autosomal dominant disorder characterized by dystopia canthorum, sensorineural deafness, and pigmentary disturbances. Previous work has linked the disease to PAX3, a transcription factor with two highly conserved DNA binding motifs: a paired box and a homeobox. Several mutations within the paired box of PAX3 have been reported. We have identified the first two mutations within the homeobox in two different families. Herein, we report the phenotypic expression of WS1 in these two families and explore the implications for possible genotype-phenotype correlations. The phenotypic expression was variable within and between the families. Sensorineural hearing loss was present in 71% of affected individuals. Spectrum of hearing loss included unilateral high frequency (>4000 Hz), profound unilateral hearing loss, and bilateral profound hearing loss. The severity of hearing impairment varied significantly within and among families. Phenotypically, these two WS1 families with mutations within the PAX3 homeobox could not be differentiated from those families with paired box mutations. More precise genotype/phenotype correlation may be possible when additional mutations are described throughout the PAX3 gene. [ABSTRACT FROM AUTHOR]

Hypothesis Similar to familial tumors, sporadic head and neck paragangliomas are associated with chromosomal deletions at either 11q13 or 11q22-23. Background Familial paragangliomas are inherited in an autosomal dominant pattern with genomic imprinting of the maternal allele. Genetic studies of familial paragangliomas have localized the causative genetic defect to two separate loci: 11q13.1 and 11q22-23. The molecular pathogenesis of sporadic head and neck paragangliomas has not been studied. Methods Blood and tumor samples from patients with sporadic head and neck paragangliomas were screened for deletions on chromosome 11 using DNA microsatellite markers and polymerase chain reaction. Polymerase chain reaction-amplified alleles from tumor specimens were compared with those from the blood of eight patients. A greater than 50% reduction in band intensity (as determined by densitometric analysis) between blood and tumor sample was indicative of a chromosomal deletion. Results Three of the eight patients were found to have deletions at chromosome 11q: two at chromosome 11q22-23 and one at 11q13. Conclusions Sporadic head and neck paragangliomas are associated with deletions at chromosome 11q13 and 11q22-23. It is thus likely that sporadic and familial paragangliomas share a similar molecular pathogenesis. [ABSTRACT FROM AUTHOR]