Metallothionein immunohistochemistry has high sensitivity and specificity for detection of Wilson disease.

Diagnosis of Wilson disease (WD) can be difficult because of its protean clinical presentations, but early diagnosis is important because effective treatment is available and can prevent disease progression. Similarly, diagnosis of WD on liver biopsy specimens is difficult due to the wide range of histologic appearances. A stain that could help identify WD patients would be of great value. The goal of this study was to use mass spectrometry-based proteomics to identify potential proteins that are differentially expressed in WD compared to controls, and could serve as potential immunohistochemical markers for screening. Several proteins were differentially expressed in WD and immunohistochemical stains for two (metallothionein (MT) and cytochrome C oxidase copper chaperone (COX17)) were tested and compared to other methods of diagnosis in WD including copper staining and quantitative copper assays. We found diffuse metallothionein immunoreactivity in all liver specimens from patients with WD (n = 20); the intensity of the staining was moderate to strong. This staining pattern was distinct from that seen in specimens from the control groups (none of which showed strong, diffuse staining), which included diseases that may be in the clinical or histologic differential of WD (steatohepatitis (n = 51), chronic viral hepatitis (n = 40), autoimmune hepatitis (n = 50), chronic biliary tract disease (n = 42), and normal liver (n = 20)). COX17 immunostain showed no significant difference in expression between the WD and control groups. MT had higher sensitivity than rhodanine for diagnosis of WD. While the quantitative liver copper assays also had high sensitivity, they require more tissue, have a higher cost, longer turnaround time, and are less widely available than an immunohistochemical stain. We conclude that MT IHC is a sensitive immunohistochemical stain for the diagnosis of WD that could be widely deployed as a screening tool for liver biopsies in which WD is in the clinical or histologic differential diagnosis.

Diagnostic challenges of focal nodular hyperplasia: interobserver variability, accuracy, and the utility of glutamine synthetase immunohistochemistry.

AIMS: The diagnosis of focal nodular hyperplasia (FNH) and the interpretation of glutamine synthetase (GS) staining can be challenging on biopsies. We aimed to evaluate the reproducibility of needle biopsy diagnosis of FNH, the effect of GS immunohistochemistry on FNH diagnosis, and which histological features are most useful for the diagnosis of FNH. METHODS AND RESULTS: The study included virtual needle biopsies generated from 75 resection specimens (30 FNHs, 15 hepatocellular adenomas, 15 hepatocellular carcinomas, and 15 non-lesional liver specimens). Pathologists were reasonably accurate (83.1%) in the diagnosis of FNH with haematoxylin and eosin alone. Ductular reaction and nodularity had the highest sensitivity for a diagnosis of FNH (88.1% and 82.2%, respectively), whereas central scar was the most specific feature (90.6%). The presence of two or more of the classic histological features had 89.6% sensitivity and 86.2% specificity for a diagnosis of FNH. Diagnostic accuracy was significantly higher with the addition of a GS stain. A map-like GS staining pattern was highly specific (99.3%) for FNH. However, GS staining was interpreted as non-map-like in 14.4% of reviews of true FNH cases, and overall interobserver agreement for interpretation of the GS staining pattern was only moderate (kappa = 0.42). CONCLUSIONS: Pathologists are reasonably accurate in the diagnosis of FNH on virtual biopsies, and GS staining improves accuracy. However, a subset of FNH cases remain challenging. Steatosis and a pseudo-map-like GS staining pattern were associated with increased difficulty. Therefore, although a map-like GS staining pattern is useful for confirmation of a diagnosis, the lack of a map-like GS staining pattern on needle biopsy does not necessarily exclude a diagnosis of FNH.

Liver Stiffness Measured by Either Magnetic Resonance or Transient Elastography Is Associated With Liver Fibrosis and Is an Independent Predictor of Outcomes Among Patients With Primary Biliary Cholangitis.

GOALS: We aimed to describe the diagnostic and prognostic performance of transient elastography (TE) and magnetic resonance elastography (MRE) in patients with primary biliary cholangitis (PBC). BACKGROUND: The diagnostic performance of TE and MRE in detecting advanced fibrosis in PBC and in predicting outcomes independent of existing serologic prognostic markers is incompletely understood. MATERIALS AND METHODS: Five hundred thirty-eight consecutive patients with PBC at 3 centers with liver stiffness (LS) measurements by TE (n=286) or MRE (n=332) were reviewed. LS cutoffs for predicting fibrosis stages were determined by receiver operating characteristic curves among those with a liver biopsy (TE, n=63; MRE, n=98). Cox proportional hazard regression modeling was used to identify associations between covariates and hepatic decompensation. RESULTS: The optimal LS thresholds for predicting histologic stage F4 were 14.40 kPa (area under the curve=0.94) for TE and 4.60 kPa (area under the curve=0.82) for MRE. Both TE and MRE outperformed biochemical markers for the prediction of histologic advanced fibrosis. Optimal LS thresholds to predict hepatic decompensation were 10.20 kPa on TE and 4.30 kPa on MRE. LS by TE and MRE (respectively) remained predictors of hepatic decompensation after adjusting for ursodeoxycholic acid responsiveness [hazard ratio (HR), 1.14; 95% confidence interval (CI), 1.05-1.24 and HR, 1.68; 95% CI, 1.28-2.19] and the GLOBE score (HR, 1.13; 95% CI, 1.07-1.19 and HR, 2.09; 95% CI, 1.57-2.78). CONCLUSION: LS measurement with either TE or MRE can accurately detect advanced fibrosis and offers additional prognostic value beyond existing serologic predictive tools.

Gross tumor size using the AJCC 8th ed. T staging criteria does not provide prognostic stratification for neoadjuvant treated pancreatic ductal adenocarcinoma.

The 8th edition AJCC T stage criteria for pancreatic ductal adenocarcinoma (PDAC) are now size based. These criteria provide better prognostic stratification in patients without neoadjuvant therapy. Our aim was to determine if gross tumor size is prognostically significant using the 8th ed. staging criteria for neoadjuvant treated PDAC. The study included 289 patients who underwent resection for PDAC following neoadjuvant therapy. By AJCC 7th ed., there were 12 (4.2%) ypT0, 32 (11.1%) ypT1, 64 (22.1%) ypT2, and 181 (62.6%) ypT3 patients. By AJCC 8th ed., there were 12 (4.2%) ypT0, 74 (25.6%) ypT1 (6 ypT1a, 1 ypT1b, 67 ypT1c), 161 (55.7%) ypT2, and 42 (14.5%) ypT3 patients. 182 patients had negative lymph nodes and 107 had positive lymph nodes. 77 patients were ypN1 and 30 were ypN2 by 8th ed. criteria. 7th ed. T stage significantly correlated with OS (p = 0.048), while 8th ed. T stage did not correlate with OS (p = 0.13). In ypN0 patients, neither the 7th ed. or 8th ed. T stages significantly correlated with patient OS (p = 0.065 and 0.26, respectively). Higher 7th ed. T stage correlated with lymph node status (p ≤ 0.001) more strongly than 8th ed. T stage (p = 0.04). 7th ed. and 8th ed. N stage correlated with OS (p = 0.004 and p = 0.0002, respectively). By 8th ed. AJCC staging criteria, gross tumor size does not provide good prognostic stratification in neoadjuvant therapy PDAC. Mapped grossing techniques combining gross and microscopic examination to determine tumor size may provide more accurate staging of neoadjuvant treated tumors.

Coexisting pancreatic serous cystadenoma and pancreatic ductal adenocarcinoma: A cytological-pathologic correlation with literature review.

Pancreatic serous cystadenoma (SCA) is a benign neoplastic lesion with a distinctive gross and microscopic appearance consisting of numerous thin-walled cysts lined by uniform epithelial cells with clear cytoplasm and small nuclei. The vast majority of serous cystadenomas are benign. Pancreatic SCA has rarely been reported in association with other pancreatic lesions. We present a challenging case in which a cystic and solid pancreatic mass was identified on imaging studies. FNA was performed and showed clusters of atypical cells with significant nuclear pleomorphism (>4:1), disorganized, overlapping nuclei, and prominent nucleoli. The FNA diagnosis was positive for malignancy, consistent with adenocarcinoma. The patient underwent neoadjuvant therapy and pancreaticoduodenectomy. Final pathology showed a serous cystadenoma associated with small foci of high-grade PanIN. The lack of invasive adenocarcinoma in the resection specimen was most likely due to complete response of the tumor to neoadjuvant chemoradiation therapy, but it is also possible that only high-grade PanIN was present initially. To our knowledge, this is the first reported case of SCA and high grade PanIN/PDAC that was assessed by FNA. We discuss the cytologic differential diagnosis and how to avoid potential pitfalls highlighted by this case.

Colonic graft-vs.-host disease in autologous versus allogeneic transplant patients: earlier onset, more apoptosis, and lack of regulatory T-cell attenuation.

Histologic characterization of graft-vs.-host disease in autologous stem cell transplant patients has been limited. The aims of this study were to characterize colonic graft-vs.-host disease in autologous stem cell transplant patients and compare to a control group of allogeneic stem cell transplant patients, to determine whether graft-vs.-host disease can be diagnosed < 21 days post transplantation in autologous stem cell transplant recipients, and to quantify colonic T-cell populations in autologous stem cell transplant patients. Colonic biopsies taken to evaluate for graft-vs.-host disease in both allogenic and autologous stem cell transplant patients were reviewed for the maximum number of apoptotic bodies per 10 contiguous crypts. Immunohistochemical stains for CD4, CD8, and FoxP3 were performed. Clinical information was collected from chart review. The study group consisted of 122 colonic biopsies from 84 patients. Sixteen patients underwent autologous stem cell transplant and 68 allogeneic stem cell transplant. Autologous stem cell transplant patients underwent biopsy significantly earlier compared with allogeneic stem cell transplant patients (median 20 vs. 87 days, p = 0.0002), had significantly higher apoptotic counts compared with matched-related donor patients (7.5 vs. 3.9, p = 0.03), and had higher FoxP3-positive lamina propria lymphocytes counts compared to allogeneic stem cell transplant patients (9.2 vs. 5.3, p = 0.03). In patients undergoing biopsy < 21 days post transplantation, allogeneic stem cell transplant patients showed less CD8-positive lamina propria lymphocytes and a trend of less FoxP3- and CD4-positive lamina propria lymphocytes compared with autologous stem cell transplant patients. Autologous stem cell transplant patients have more prominent crypt apoptosis compared with allogenic stem cell transplant patients and do not have numerically decreased FoxP3-positive lamina propria lymphocytes. Presence of robust T-cell populations in the early period following transplantation suggest that the 21-day cutoff for diagnosis of graft-vs.-host disease is not applicable to autologous stem cell transplant patients.

Development and evaluation of the British English coordinate response measure speech-in-noise test as an occupational hearing assessment tool.

OBJECTIVE: The studies described in this article outline the design and development of a British English version of the coordinate response measure (CRM) speech-in-noise (SiN) test. Our interest in the CRM is as a SiN test with high face validity for occupational auditory fitness for duty (AFFD) assessment. DESIGN: Study 1 used the method of constant stimuli to measure and adjust the psychometric functions of each target word, producing a speech corpus with equal intelligibility. After ensuring all the target words had similar intelligibility, for Studies 2 and 3, the CRM was presented in an adaptive procedure in stationary speech-spectrum noise to measure speech reception thresholds and evaluate the test-retest reliability of the CRM SiN test. STUDY SAMPLE: Studies 1 (n = 20) and 2 (n = 30) were completed by normal-hearing civilians. Study 3 (n = 22) was completed by hearing impaired military personnel. RESULTS: The results display good test-retest reliability (95% confidence interval (CI) < 2.1 dB) and concurrent validity when compared to the triple-digit test (r ≤ 0.65), and the CRM is sensitive to hearing impairment. CONCLUSION: The British English CRM using stationary speech-spectrum noise is a "ready to use" SiN test, suitable for investigation as an AFFD assessment tool for military personnel.

Diagnostic phrasing is independently correlated with the decision to treat for graft-versus-host disease: retrospective review of colon biopsies with rare apoptosis.

AIMS: The risks of immunosuppression and the non-specific nature of rare crypt apoptosis has led to debate over the lower threshold for histological diagnosis of colonic graft-versus-host disease (GVHD). A recent study proposed the diagnostic category of indeterminate for GVHD (iGVHD) for cases with six or fewer apoptotic bodies per 10 crypts. Our aim was to assess colon biopsies with iGVHD histology to determine whether the diagnosis was retrospectively predictive of the decision to treat, and to correlate these findings with endoscopic and clinical findings. METHODS AND RESULTS: A retrospective search was performed for colonic biopsies taken to evaluate for GVHD from 2008 to 2014. Biopsies were blindly reviewed for the maximum number of apoptotic bodies per 10 contiguous crypts, evidence of crypt dropout, and ulceration. Clinical information was collected through chart review. One hundred and twenty-two biopsies from 84 transplant patients were included. Forty-seven cases met the histological criteria for iGVHD. Patients with an original diagnosis of iGVHD were more likely to be managed conservatively than those with a diagnosis of grade 1 GVHD (25% versus 0%). Eight symptomatic patients reclassified as iGVHD had resolution of symptoms without increased immunosuppression. A clinicopathologically similar group of 10 patients with iGVHD histology, normal or subtle endoscopic findings and no evidence of GVHD at other organ sites were treated with increased immunosuppression. On multivariate analysis, the original diagnostic category was the most significant predictor of the decision to treat. CONCLUSION: The use of the diagnostic category iGVHD alerts clinicians to the presence of minimal crypt apoptosis, and allows treatment based on clinical judgement.

Fit for the frontline? identification of mission-critical auditory tasks (MCATs) carried out by infantry and combat-support personnel.

The ability to listen to commands in noisy environments and understand acoustic signals, while maintaining situational awareness, is an important skill for military personnel and can be critical for mission success. Seventeen auditory tasks carried out by British infantry and combat-support personnel were identified through a series of focus groups conducted by Bevis et al. For military personnel, these auditory tasks are termed mission-critical auditory tasks (MCATs) if they are carried in out in a military-specific environment and have a negative consequence when performed below a specified level. A questionnaire study was conducted to find out which of the auditory tasks identified by Bevis et al. satisfy the characteristics of an MCAT. Seventy-nine British infantry and combat-support personnel from four regiments across the South of England participated. For each auditory task participants indicated: 1) the consequences of poor performance on the task, 2) who performs the task, and 3) how frequently the task is carried out. The data were analysed to determine which tasks are carried out by which personnel, which have the most negative consequences when performed poorly, and which are performed the most frequently. This resulted in a list of 9 MCATs (7 speech communication tasks, 1 sound localization task, and 1 sound detection task) that should be prioritised for representation in a measure of auditory fitness for duty (AFFD) for these personnel. Incorporating MCATs in AFFD measures will help to ensure that personnel have the necessary auditory skills for safe and effective deployment on operational duties.

Morquio A syndrome: diagnosis and current and future therapies.

Morquio A syndrome is an autosomal recessive disorder, one of 50 lysosomal storage diseases (LSDs), and is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Deficiency of this enzyme causes specific glycosaminoglycan (GAG) accumulation: keratan sulfate (KS) and chondroitin-6-sulfate (C6S). The majority of KS is produced in the cartilage, therefore, the undegraded substrates accumulate mainly in cartilage and in its extracelluar matrix (ECM), causing direct leads to direct impact on cartilage and bone development and leading to the resultant systemic skeletal spondyloepiphyseal dysplasia. Chondrogenesis ,the earliest phase of skeletal formation that leads to cartilage and bone formation is controlled by cellular interactions with the ECM, growth and differentiation factors and other molecules that affect signaling pathways and transcription factors in a temporal-spatial manner. In Morquio A patients, in early childhood or even at birth, the cartilage is disrupted presumably as a result of abnormal chondrogenesis and/ or endochondral ossification. The unique clinical features are characterized by a marked short stature, odontoid hypoplasia, protrusion of the chest, kyphoscoliosis, platyspondyly, coxa valga, abnormal gait, and laxity of joints. In spite of many descriptions of the unique clinical manifestations, diagnosis delay still occurs. The pathogenesis of systemic skeletal dysplasia in Morquio A syndrome remains an enigmatic challenge. In this review article, screening, diagnosis, pathogenesis and current and future therapies of Morquio A are discussed.

Fit for the frontline? A focus group exploration of auditory tasks carried out by infantry and combat support personnel.

In order to preserve their operational effectiveness and ultimately their survival, military personnel must be able to detect important acoustic signals and maintain situational awareness. The possession of sufficient hearing ability to perform job-specific auditory tasks is defined as auditory fitness for duty (AFFD). Pure tone audiometry (PTA) is used to assess AFFD in the UK military; however, it is unclear whether PTA is able to accurately predict performance on job-specific auditory tasks. The aim of the current study was to gather information about auditory tasks carried out by infantry personnel on the frontline and the environment these tasks are performed in. The study consisted of 16 focus group interviews with an average of five participants per group. Eighty British army personnel were recruited from five infantry regiments. The focus group guideline included seven open-ended questions designed to elicit information about the auditory tasks performed on operational duty. Content analysis of the data resulted in two main themes: (1) the auditory tasks personnel are expected to perform and (2) situations where personnel felt their hearing ability was reduced. Auditory tasks were divided into subthemes of sound detection, speech communication and sound localization. Reasons for reduced performance included background noise, hearing protection and attention difficulties. The current study provided an important and novel insight to the complex auditory environment experienced by British infantry personnel and identified 17 auditory tasks carried out by personnel on operational duties. These auditory tasks will be used to inform the development of a functional AFFD test for infantry personnel.

Reimbursing incarcerated individuals for participation in research: A scoping review.

BACKGROUND: Little is known about global practices regarding the provision of reimbursement for the participation of people who are incarcerated in research. To determine current practices related to the reimbursement of incarcerated populations for research, we aimed to describe international variations in practice across countries and carceral environments to help inform the development of more consistent and equitable practices. METHODS: We conducted a scoping review by searching PubMed, Cochrane library, Medline, and Embase, and conducted a grey literature search for English- and French-language articles published until September 30, 2022. All studies evaluating any carceral-based research were included if recruitment of incarcerated participants occurred inside any non-juvenile carceral setting; we excluded studies if recruitment occurred exclusively following release. Where studies failed to indicate the presence or absence of reimbursement, we assumed none was provided. RESULTS: A total of 4,328 unique articles were identified, 2,765 were eligible for full text review, and 426 were included. Of these, 295 (69%) did not offer reimbursement to incarcerated individuals. A minority (n = 13; 4%) included reasons explaining the absence of reimbursement, primarily government-level policies (n = 7). Among the 131 (31%) studies that provided reimbursement, the most common form was monetary compensation (n = 122; 93%); five studies (4%) offered possible reduced sentencing. Reimbursement ranged between $3-610 USD in total and 14 studies (11%) explained the reason behind the reimbursements, primarily researchers' discretion (n = 9). CONCLUSIONS: The majority of research conducted to date in carceral settings globally has not reimbursed incarcerated participants. Increased transparency regarding reimbursement (or lack thereof) is needed as part of all carceral research and advocacy efforts are required to change policies prohibiting reimbursement of incarcerated individuals. Future work is needed to co-create international standards for the equitable reimbursement of incarcerated populations in research, incorporating the voices of people with lived and living experience of incarceration.

Assessment of bone dysplasia by micro-CT and glycosaminoglycan levels in mouse models for mucopolysaccharidosis type I, IIIA, IVA, and VII.

Mucopolysaccharidoses (MPS) are a group of lysosomal storage diseases caused by mutations in lysosomal enzymes involved in degradation of glycosaminoglycans (GAGs). Patients with MPS grow poorly and become physically disabled due to systemic bone disease. While many of the major skeletal effects in mouse models for MPS have been described, no detailed analysis that compares GAGs levels and characteristics of bone by micro-CT has been done. The aims of this study were to assess severity of bone dysplasia among four MPS mouse models (MPS I, IIIA, IVA and VII), to determine the relationship between severity of bone dysplasia and serum keratan sulfate (KS) and heparan sulfate (HS) levels in those models, and to explore the mechanism of KS elevation in MPS I, IIIA, and VII mouse models. Clinically, MPS VII mice had the most severe bone pathology; however, MPS I and IVA mice also showed skeletal pathology. MPS I and VII mice showed severe bone dysplasia, higher bone mineral density, narrowed spinal canal, and shorter sclerotic bones by micro-CT and radiographs. Serum KS and HS levels were elevated in MPS I, IIIA, and VII mice. Severity of skeletal disease displayed by micro-CT, radiographs and histopathology correlated with the level of KS elevation. We showed that elevated HS levels in MPS mouse models could inhibit N-acetylgalactosamine-6-sulfate sulfatase enzyme. These studies suggest that KS could be released from chondrocytes affected by accumulation of other GAGs and that KS could be useful as a biomarker for severity of bone dysplasia in MPS disorders.

Simulating the effect of interaural mismatch in the insertion depth of bilateral cochlear implants on speech perception.

A bilateral advantage for diotically presented stimuli has been observed for cochlear implant (CI) users and is suggested to be dependent on symmetrical implant performance. Studies using CI simulations have not shown a true "bilateral" advantage, but a "better ear" effect and have demonstrated that performance decreases with increasing basalward shift in insertion depth. This study aimed to determine whether there is a bilateral advantage for CI simulations with interaurally matched insertions and the extent to which performance is affected by interaural insertion depth mismatch. Speech perception in noise and self-reported ease of listening were measured using matched bilateral, mismatched bilateral and unilateral CI simulations over four insertion depths for seventeen normal hearing listeners. Speech scores and ease of listening reduced with increasing basalward shift in (interaurally matched) insertion depth. A bilateral advantage for speech perception was only observed when the insertion depths were interaurally matched and deep. No advantage was observed for small to moderate interaural insertion-depth mismatches, consistent with a better ear effect. Finally, both measures were poorer than expected for a better ear effect for large mismatches, suggesting that misalignment of the electrode arrays may prevent a bilateral advantage and detrimentally affect perception of diotically presented speech.

Development of an Arabic "Command in Noise" Hearing Test to Assess Fitness for Duty.

Objective: The goal is to implement the developed speech material in a hearing test to assess auditory fitness for duty (AFFD), specifically in areas where the intelligibility of spoken commands is essential. Design: In study 1, a speech corpus with equal intelligibility was constructed using constant stimuli to test each target word's psychometric functions. Study 2 used an adaptive interleaving procedure to maximize equalized terms. Study 3 used Monte Carlo simulations to determine speech test accuracy. Study sample: Study 1 (n = 24) and study 2 (n = 20) were completed by civilians with normal hearing. Study 3 ran 10,000 simulations per condition across various conditions varying in slopes and speech recognition thresholds (SRTs). Results: Studies 1 and 2 produced three 8-word wordlists. The mean, standard deviation in dB SNR is -13.1 1.2 for wordlist 1, -13.7 1.6 for wordlist 2, and -13.7 1.3 for wordlist 3, with word SRTs within 3.4 dB SNR. Study 3 revealed that a 6 dB SNR range is appropriate for equally understandable speech using a closed-set adaptive technique. Conclusion: The developed speech corpus may be used in an AFFD measure. Concerning the homogeneity of the speech in noise test material, care should be taken when generalizing and using ranges and standard deviations from multiple tests.

The audiological rehabilitation of workers with hearing loss in the UK: a qualitative study of workers' perspectives.

PURPOSE: Unaddressed hearing loss can adversely affect employment and day-to-day work-life. Efficient and effective audiology support can help optimise hearing in the workplace. This study explores the audiological rehabilitation experiences of workers with hearing loss (WHL). MATERIALS AND METHODS: Twenty-four WHL with experience of a wide range of audiology services across the UK participated in semi-structured interviews. Interviews were analysed using inductive thematic analysis. RESULTS: Three main themes were generated: Theme 1: mixed experiences with audiology services (subdivided into two subthemes and four sub-subthemes). Theme 2: audiology role in work support (subdivided into three subthemes). Theme 3: "I think support could be improved if…" (subdivided into two subthemes). CONCLUSION: The audiological rehabilitation for working-age adults with hearing loss needs improvements to deliver sufficient support and quality care. Some of the barriers to having better-functioning hearing healthcare require fundamental standards in healthcare quality, such as access to services, staff (including audiologists) deaf awareness, information and technology support, and personalised care that considers work-life needs. Further research is required to evaluate the feasibility and cost-effectiveness of improvements, such as support that extends beyond hearing aid care, whether from audiology or non-audiology services.

Workers with hearing loss need audiologists' support to address their work life needs beyond hearing-aids care.Improving audiologists' competencies, audiology departments' efficiency and developing relevant resources may promote better healthcare for workers with hearing loss.Audiologists, employers, workers, and the healthcare system need to collaborate in developing person-centred solutions to sufficiently assist workers with hearing loss.

Long circulating enzyme replacement therapy rescues bone pathology in mucopolysaccharidosis VII murine model.

Mucopolysaccharidosis (MPS) type VII is a lysosomal storage disease caused by deficiency of the lysosomal enzyme ß-glucuronidase (GUS), leading to accumulation of glycosaminoglycans (GAGs). Enzyme replacement therapy (ERT) effectively clears GAG storage in the viscera. Recent studies showed that a chemically modified form of GUS (PerT-GUS), which escaped clearance by mannose 6-phosphate and mannose receptors and showed prolonged circulation, reduced CNS storage more effectively than native GUS. Clearance of storage in bone has been limited due to the avascularity of the growth plate. To evaluate the effectiveness of long-circulating PerT-GUS in reducing the skeletal pathology, we treated MPS VII mice for 12 weeks beginning at 5 weeks of age with PerT-GUS or native GUS and used micro-CT, radiographs, and quantitative histopathological analysis for assessment of bones. Micro-CT findings showed PerT-GUS treated mice had a significantly lower BMD. Histopathological analysis also showed reduced storage material and a more organized growth plate in PerT-GUS treated mice compared with native GUS treated mice. Long term treatment with PerT-GUS from birth up to 57 weeks also significantly improved bone lesions demonstrated by micro-CT, radiographs and quantitative histopathological assay. In conclusion, long-circulating PerT-GUS provides a significant impact to rescue of bone lesions and CNS involvement.

Early detection of non-organic hearing loss using a simple tone-in-noise test.

Early detection of non-organic hearing loss (NOHL) is important in order to ensure appropriate management decisions. One possible audiometric test for achieving this is the tone-in-noise (TIN) test although its current format is not widely applicable and may not optimize accuracy. We sought to investigate a modified TIN test, using narrowband noise, and the influence of different noise levels and alternative approaches to determining the outcome. Seventy-five normal-hearing and 8 hearing-impaired subjects were asked to feign or exaggerate a hearing loss. The shift in genuine or exaggerated/feigned thresholds with the introduction of ipsilateral noise was determined. The TIN test was able to accurately separate between genuine and feigned thresholds when using narrowband noise presented at the effective masking level corresponding to the apparent tone threshold and using a 'fail' criterion of a repeatable threshold shift of ≥ 10 dB at one or more frequencies. It also produced similar shifts in exaggerated thresholds. In conclusion, this modified TIN test is a potentially accurate method to rapidly identify unilateral and bilateral NOHL in a wide range on contexts and could be applied to automated audiometry.