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Aims: Osteochondral lesions of the talus (OLT) are a common cause of disability and chronic ankle pain. Many operative treatment strategies have been introduced; however, they have their own disadvantages. Recently lesion repair using autologous cartilage chip has emerged therefore we investigated the efficacy of particulated autologous cartilage transplantation (PACT) in OLT. Methods: We retrospectively analyzed 32 consecutive symptomatic patients with OLT who underwent PACT with minimum one-year follow-up. Standard preoperative radiography and MRI were performed for all patients. Follow-up second-look arthroscopy or MRI was performed with patient consent approximately one-year postoperatively. Magnetic resonance Observation of Cartilage Repair Tissue (MOCART) score and International Cartilage Repair Society (ICRS) grades were used to evaluate the quality of the regenerated cartilage. Clinical outcomes were assessed using the pain visual analogue scale (VAS), Foot Function Index (FFI), and Foot Ankle Outcome Scale (FAOS). Results: All patients had ICRS grade IV cartilage lesions, except for one (ICRS grade III). The paired MOCART scores significantly improved from 42.5 (SD 1.53) to 63.5 (SD 22.60) (p = 0.025) in ten patients. Seven patients agreed to undergo second-look arthroscopy; 5 patients had grade I (normal) ICRS scores and two patients had grade II (nearly normal) ICRS scores. VAS, FFI, and all subscales of FAOS were significantly improved postoperatively (p ≤ 0.003). Conclusion: PACT significantly improved the clinical, radiological, and morphological outcomes of OLT. We consider this to be a safe and effective surgical method based on the short-term clinical results of this study. Cite this article: Bone Jt Open 2023;4(12):942–947.

Managing chronic inflammatory immune-mediated eye diseases currently involves the non-specific suppression of the immune system. Oral corticosteroids are still the chief component of this therapy, but additional immunosuppressive agents are often indicated to control the disease as well as to avoid the side effects of long-term therapy with high doses of corticosteroids. Many different drugs are available including cyclosporine, azathioprine and occasionally cyclophosphamide, chlorambucil, or more recently mycophenolate mofetil and tacrolimus (FK-506). Pulsed low-dose oral methotrexate (MTX) is now widely used in rheumatological disease and has been introduced in the management of sight-threatening uveitis. Some reports using low doses advocate its use as an alternative when multiple drug therapy is necessary or to help lower the dose of other drugs. In our group of 11 patients with long-standing disease, adding MTX to the treatment regimen allowed control of the inflammation with a reduction of the corticosteroid dose in more than 50% of the cases and decreased the number of disease relapses in 45%. These results indicate that MTX is useful as an alternative option when a second/third agent is needed, achieving a better control of the disease in some cases. [ABSTRACT FROM AUTHOR]

Assessing sustainability is extremely necessary and appears as an industrial need and requirement in order to facilitate decision making and to evaluate the impacts of existing strategies, products and technologies. Thus, the main goal of this research was to develop a sustainability calculator based on the opinion of experts that work in the different branches of the cosmetic industry, in order to cover the entire life cycle of a cosmetic product. A detailed survey in which all the steps of a cosmetic product life cycle were addressed, was designed and applied to cosmetic professionals. The data obtained with the survey was statistically analysed for the positive and negative impacts of each parameter on sustainability. The analysed data allowed the creation of a Microsoft Excel tool that mirrors the experts' opinion. A proof of concept was also designed in order to prove the usefulness of the tool. The results show that there are no raw materials and/or packaging materials and practices, that can be considered 100% sustainable. However, with the appropriate strategies, it is possible to drastically decrease the impacts of any type of cosmetic product on sustainability. This is a promising tool that includes the three dimensions of sustainability in a simple, fast, objective and interactive way for the user. Its application will facilitate the work of the formulators and reduce the time of analysis and decision. [ABSTRACT FROM AUTHOR]

Three-dimensional (3D) printing is an innovative manufacturing method with the potential to revolutionize topical and transdermal dosage forms. Nowadays, it is established that Vat-based photopolymerization (VP) 3D printing technologies offer superior printing efficiency and versatility compared to other 3D printing technologies available on the market. However, there are some limitations that impair their full application in pharmaceutical contexts, such as the lack of a range of biocompatible materials for topical and transdermal applications. This review article explores all types of VP-based 3D printing and discusses the relevance of implementing this kind of technology. We start with a detailed description of the printing process, focusing on the commercial materials available and lab-made resins proposed by different authors. We also review recent studies in this field, which mainly focus on the fabrication of transdermal devices based on microneedle arrays. In the future, it is expected that the manufacturers of 3D printers invest in modifications to the printing apparatus to allow the simultaneous printing of different resins and/or compound types, which will open frontiers to the personalization of treatment approaches., Competing Interests: All the authors declare no conflict of interest., (© 2024 Shenyang Pharmaceutical University. Published by Elsevier B.V.)

Immunotherapy has revolutionized the treatment of cancers. Reinvigorating lymphocytes with checkpoint blockade has become a cornerstone of immunotherapy for multiple tumor types, but the treatment of glioblastoma has not yet shown clinical efficacy. A major hurdle to treat GBM with checkpoint blockade is the high degree of myeloid-mediated immunosuppression in brain tumors that limits CD8 T-cell activity. A potential strategy to improve anti-tumor efficacy against glioma is to use myeloid-modulating agents to target immunosuppressive cells, such as myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment. We found that the co-inhibition of the chemokine receptors CCR2 and CCR5 in murine model of glioma improves the survival and synergizes robustly with anti-PD-1 therapy. Moreover, the treatment specifically reduced the infiltration of monocytic-MDSCs (M-MDSCs) into brain tumors and increased lymphocyte abundance and cytokine secretion by tumor-infiltrating CD8 T cells. The depletion of T-cell subsets and myeloid cells abrogated the effects of CCR2 and CCR5 blockade, indicating that while broad depletion of myeloid cells does not improve survival, specific reduction in the infiltration of immunosuppressive myeloid cells, such as M-MDSCs, can boost the anti-tumor immune response of lymphocytes. Our study highlights the potential of CCR2/CCR5 co-inhibition in reducing myeloid-mediated immunosuppression in GBM patients., Competing Interests: M.L. has received research support from Arbor, BMS, Accuray, Tocagen, Biohaven, Kyrin-Kyowa and Biohaven, has been a consultant to Tocagen, VBI, InCephalo Therapeutics, Pyramid Bio, Merck, BMS, Insightec, Biohaven, Sanianoia, Hemispherian, Black Diamond Therapeutics, Novocure, is a shareholder of Egret Therapeutics and has patents for Focused radiation + checkpoint inhibitors, Local chemotherapy + checkpoint inhibitors and Checkpoint agonists for Neuro-Inflammation., (© 2024 The Author(s). Published with license by Taylor & Francis Group, LLC.)

The semiconductor industry is one of the most technology-evolving and capital-intensive market sectors. Effective inspection and metrology are necessary to improve product yield, increase product quality and reduce costs. In recent years, many types of semiconductor manufacturing equipments have been equipped with sensors to facilitate real-time monitoring of the production processes. These production-state and equipment-state sensor data provide an opportunity to practice machine-learning technologies in various domains, such as anomaly/fault detection, maintenance scheduling, quality prediction, etc. In this work, we focus on the soft-sensing regression problem in metrology systems, which uses sensor data collected during wafer processing steps to predict impending inspection measurements that used to be measured in wafer inspection and metrology systems. We proposed a regressor based on Long Short-term Memory network and devised two distinct loss functions for the purpose of the training model. Although the assessment of our prediction errors by engineers is subjective, a novel piece-wise evaluation metric was introduced to evaluate model accuracy in a mathematical way. Our experimental results showcased that the proposed model is capable of achieving both accurate and early prediction across various types of inspections in complicated manufacturing processes.

Regulatory T cells (T reg ) are conventionally viewed as suppressors of endogenous and therapy-induced antitumor immunity; however, their role in modulating responses to immune checkpoint blockade (ICB) is unclear. In this study, we integrated single-cell RNA-seq/T cell receptor sequencing (TCRseq) of >73,000 tumor-infiltrating T reg (TIL-T reg ) from anti-PD-1-treated and treatment-naive non-small cell lung cancers (NSCLC) with single-cell analysis of tumor-associated antigen (TAA)-specific T reg derived from a murine tumor model. We identified 10 subsets of human TIL-T reg , most of which have high concordance with murine TIL-T reg subsets. Only one subset selectively expresses high levels of TNFRSF4 (OX40) and TNFRSF18 (GITR), whose engangement by cognate ligand mediated proliferative programs and NF-κB activation, as well as multiple genes involved in T reg suppression, including LAG3 . Functionally, the OX40 hi GITR hi subset is the most highly suppressive ex vivo, and its higher representation among total TIL-T reg correlated with resistance to PD-1 blockade. Unexpectedly, in the murine tumor model, we found that virtually all TIL-T reg -expressing T cell receptors that are specific for TAA fully develop a distinct T H 1-like signature over a 2-week period after entry into the tumor, down-regulating FoxP3 and up-regulating expression of TBX21 ( Tbet) , IFNG , and certain proinflammatory granzymes. Transfer learning of a gene score from the murine TAA-specific T H 1-like T reg subset to the human single-cell dataset revealed a highly analogous subcluster that was enriched in anti-PD-1-responding tumors. These findings demonstrate that TIL-T reg partition into multiple distinct transcriptionally defined subsets with potentially opposing effects on ICB-induced antitumor immunity and suggest that TAA-specific TIL-T reg may positively contribute to antitumor responses.

Cell-free based therapies, for example, the use of the cell secretome, have emerged as a promising alternative to conventional skin therapies using bioactive and, when combined with 3D printing technologies, allow the development of personalized dosage forms. This research work aimed to develop gelatin-based patches with controlled network topology via extrusion 3D printing, loaded with cell culture medium as a model of the secretome, and applicable as vehicles for topical delivery. Inks were optimized through rheological and printing assays, and the incorporation of medium had minor effects in printability. Regarding network topology, grid infills rendered more defined structures than the triangular layout, depicting clearer pores and pore area consistency. Release studies showed that filament spacing and infill pattern influenced the release of rhodamine B (model bioactive) and bovine serum albumin (model protein). Moreover, the grid patches (G-0.7/1/0.7), despite having around a seven-fold higher mean pore area than 0.7-mm triangular ones (T-0.7), showed a similar release profile, which can be linked to the network topology of the printed structures This work provided insight on employing (bio)printing in the production of carriers with reproducible and controlled pore area, able to incorporate cell-derived secretome and to be quickly tailored to the patient's lesions., (© 2023. The Author(s).)

Development of multifunctional 3D patches with appropriate antibacterial and biocompatible properties is needed to deal with wound care regeneration. Combining gelatin-based hydrogel with a well-known natural antibacterial honey (Manuka honey, MH) in a 3D patch can provide improved printability and at the same time provide favourable biological effects that may be useful in regenerative wound treatment. In this study, an antibacterial Manuka-Gelatin 3D patches was developed by an extrusion-based printing process, with controlled porosity, high shape fidelity, and structural stability. It was demonstrated the antibacterial activity of Manuka-Gelatin 3D patches against both gram-positive bacteria (S. epidermidis and S. aureus) and gram-negative (E. coli), common in wound infection. The 3D Manuka-Gelatin base patches demonstrated antibacterial activity, and moreover enhanced the proliferation of human dermal fibroblasts and human epidermal keratinocytes, and promotion of angiogenesis. Moreover, the ease of printing achieved by the addition of honey, coupled with the interesting biological response obtained, makes this 3D patch a good candidate for wound healing applications., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

One of the exciting future directions in the 3D printing field is the development of innovative personalized smart constructions for bio-applications, including drug delivery, namely high-throughput drug screening and customized topical/oral administration of pharmaceuticals, as well as tissue engineering. In this context, hydrogels have emerged as a promising material that, when combined with extrusion 3D printing, allow the creation of soft-material structures with defined spatial locations, that can be printed at room temperature and customized by tuning the geometric design and/or the formulation components. Thus, the efficacy and quality of such vehicles is dependent on formulation, design, and printing process parameters. However, hydrogel inks are often designed and characterized using different methods and this lack of uniformity impairs. Characterization techniques are usually arbitrary and differ among research groups, challenging the inference of possible conclusions on hydrogel behaviour and potential applications. Therefore, to properly analyse the potential of a particular hydrogel ink formulation, we review, for the first time, the most frequently employed characterization procedures, from rheological approaches to printing parameters and settings, and discuss their relevance, limitations and drawbacks, and highlight future perspectives. Overall, to accelerate the development of high-quality 3D constructs, comprehensive characterization protocols for both pre-printing and printing assays should be adopted. Furthermore, their transversal adoption could serve as a boost in terms of quality requirements and regulatory aspects., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Spreadability is one of the most important physicochemical properties of cosmetic products, according to the consumer. Thus, it is fundamental to develop strategies with the aim to improve the knowledge and predict the behavior of alternatives to synthetic emollients. The main goal of this research article was to correlate different physicochemical attributes, namely spreading value, apparent viscosity, density, saponification value, iodine value, peroxide value, acid value and melting range, with the spreading behavior of sustainable alternatives for petrolatum and dimethicone. The sensitivity and adequacy of each parameter were statistically analyzed, and the models were built by forward selection. The two adjusted and optimized models include viscosity and density as parameters and, in the petrolatum case, the model further includes the melting range, which was also validated as a significant predictor. Furthermore, it was also possible to compare the data obtained with the consumer's perception of the spreading behavior of the studied raw materials. A strong correlation was observed, suggesting that these tools mirror the consumer opinion. The application of these mathematical models is a valuable tool to assist the entire replacement process, which usually is a time-consuming procedure., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The incorporation of 3D printing technologies in the pharmaceutical industry can revolutionize its R&D, by providing a simple and rapid method to produce tailored one-off batches, each with customized dosages, different compounds, shapes, sizes, and adjusted release rates. Particularly, this type of technology can be advantageous for the development of topical and transdermal drug delivery systems, including patches and microneedles. The use of both systems as drug carriers offers advantages over the oral administration, but the possibility of skin irritation and sensitization, and the high production costs, may hinder the expansion of this market. In this context, 3D printing, a high-resolution technique, allows the design of high quality, personalized, complex and sophisticated structures, thus reducing the production costs and improving the patient compliance. This review covers the 3D printing concept and discusses the relevance of this technology to the pharmaceutical industry, with a special focus on the development of topical and transdermal products - patches and microneedles. The potential of 3D bioprinting for skin applications is also presented, highlighting the development of patch-like skin constructs for wound and burn treatment, and skin equivalents for in vitro research and drug development. Several recent studies were selected to support the relevance of the subjects addressed herein. Additionally, the limitations of these printing technologies are discussed, including regulatory, quality and safety issues., (Copyright © 2021 Elsevier B.V. All rights reserved.)

BACKGROUNDRecent studies have reported T cell immunity to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unexposed donors, possibly due to crossrecognition by T cells specific for common cold coronaviruses (CCCs). True T cell crossreactivity, defined as the recognition by a single TCR of more than one distinct peptide-MHC ligand, has never been shown in the context of SARS-CoV-2.METHODSWe used the viral functional expansion of specific T cells (ViraFEST) platform to identify T cell responses crossreactive for the spike (S) glycoproteins of SARS-CoV-2 and CCCs at the T cell receptor (TCR) clonotype level in convalescent COVID-19 patients (CCPs) and SARS-CoV-2-unexposed donors. Confirmation of SARS-CoV-2/CCC crossreactivity and assessments of functional avidity were performed using a TCR cloning and transfection system.RESULTSMemory CD4+ T cell clonotypes that crossrecognized the S proteins of SARS-CoV-2 and at least one other CCC were detected in 65% of CCPs and unexposed donors. Several of these TCRs were shared among multiple donors. Crossreactive T cells demonstrated significantly impaired SARS-CoV-2-specific proliferation in vitro relative to monospecific CD4+ T cells, which was consistent with lower functional avidity of their TCRs for SARS-CoV-2 relative to CCC.CONCLUSIONSOur data confirm, for what we believe is the first time, the existence of unique memory CD4+ T cell clonotypes crossrecognizing SARS-CoV-2 and CCCs. The lower avidity of crossreactive TCRs for SARS-CoV-2 may be the result of antigenic imprinting, such that preexisting CCC-specific memory T cells have reduced expansive capacity upon SARS-CoV-2 infection. Further studies are needed to determine how these crossreactive T cell responses affect clinical outcomes in COVID-19 patients.FUNDINGNIH funding (U54CA260492, P30CA006973, P41EB028239, R01AI153349, R01AI145435-A1, R21AI149760, and U19A1088791) was provided by the National Institute of Allergy and Infectious Diseases, the National Cancer Institute, and the National Institute of Biomedical Imaging and Bioengineering. The Bloomberg~Kimmel Institute for Cancer Immunotherapy, The Johns Hopkins University Provost, and The Bill and Melinda Gates Foundation provided funding for this study.

With the increasing debate on sustainability, there is a strong market trend to formulate more sustainable products for topical application. Several studies emphasize the potential applications of natural, organic, or green chemistry-derived ingredients, but comparative studies between conventional ingredients and sustainable alternatives are lacking. This type of study is considered an excellent baseline and time-saving strategy for future studies. In addition, one of the main challenges of replacing ingredients by sustainable alternatives in topical vehicles is to maintain high-quality products. Thus, the main goal of this research study was to create a well-defined strategy supported by specific experimental data for the development of sustainable topical vehicles with high-quality standards. The study was designed to evaluate the effects of replacing conventional ingredients (e.g., hydrocarbons, silicones, and preservatives) by sustainable ones on the physical, chemical, and microbiological features of topical emulsions. Additionally, in vivo assessment studies were performed to evaluate the safety, biological efficacy, and sensorial aspects of the developed formulations. The results obtained showed that the replacement of ingredients by sustainable alternatives has an effective impact on the physicochemical and structural properties of the emulsions, mainly on their rheological behavior. However, using appropriate strategies for ingredient selection and rheological adjustment, it is possible to overcome some barriers created by the use of natural raw materials, thus developing appealing and high-quality sustainable topical vehicles.

The development of printable hydrogel inks for extrusion-based 3D printing is opening new possibilities to the production of new and/or improved pharmaceutical forms, specifically for topical application. Alginate and starch are natural polysaccharides that have been extensively exploited due to their biocompatibility, biodegradability, viscosity properties, low toxicity, and relatively low cost. This research work aimed to study the physicochemical and release kinetic effects of starch incorporation in alginate-based 3D hydrogel patches for topical delivery using a quality by design approach. The incorporation of a pregelatinized starch is also proposed as a way to improve the properties of the drug delivery system while maintaining the desired quality characteristics. Critical material attributes and process parameters were identified, and the sensitivity and adequacy of each parameter were statistically analyzed. The impact of alginate, starch, and CaCl 2 ·2H 2 O amounts on relevant quality attributes was estimated crosswise. The amount of starch revealed a synergetic impact on porosity ( p = 0.0021). An evident increase in the size and quantity of open pores were detected in the as printed patches as well as after crosslinking (15.6 ± 5.2 µm). In vitro drug release studies from the optimized alginate-starch 3D hydrogel patch, using the probe Rhodamine B, showed an initial high burst release, followed by a controlled release mechanism. The results obtained also showed that the viscoelastic properties, printing accuracy, gelation time, microstructure, and release rates can be modulated by varying the amount of starch added to the system. Furthermore, these results can be considered an excellent baseline for future drug release modulation strategies.

Accessing ultrafast photoinduced molecular dynamics on a femtosecond time-scale with vibrational selectivity and at the same time sub-diffraction limited spatial resolution would help to gain important information about ultrafast processes in nanostructures. While nonlinear Raman techniques have been used to obtain highly resolved images in combination with near-field microscopy, the use of femtosecond laser pulses in electronic resonance still constitutes a big challenge. Here, we present our first results on coherent anti-Stokes Raman scattering (fs-CARS) with femtosecond laser pulses detected in the near-field using scanning near-field optical microscopy (SNOM). We demonstrate that highly spatially resolved images can be obtained from poly(3-hexylthiophene) (P3HT) nano-structures where the fs-CARS process was in resonance with the P3HT absorption and with characteristic P3HT vibrational modes without destruction of the samples. Sub-diffraction limited lateral resolution is achieved. Especially the height resolution clearly surpasses that obtained with standard microCARS. These results will be the basis for future investigations of mode-selective dynamics in the near field.

A 51-year-old woman presented with blue sclerae, brittleness of the bones and hearing loss due to osteogenesis imperfecta with ear involvement: Van der Hoeve-De Kleyn syndrome.

DFNA9 is an autosomal dominant genetic inner-ear hearing impairment that starts to show itself in the 3rd and 4th decades of life. This hearing impairment may be of a different degree of severity in each ear. Progression of hearing loss is about 3 dB/year. In about one in three patients severe vestibular symptoms similar to those in Ménière's disease are present as a result of a progressive impairment of the vestibular system. Several mutations were found in the COCH-gene on chromosome 14. There are indications that some of the mutations disrupt the folding of the cochlin protein, an important component of the extracellular matrix in the inner ear. DNA-diagnostics confirming the diagnosis ofDFNA9 are possible.

Non-syndromic low frequency sensorineural hearing loss (LFSNHL) affecting only 2000 Hz and below is an unusual type of hearing loss that worsens over time without progressing to profound deafness. This type of LFSNHL may be associated with mild tinnitus but is not associated with vertigo. We have previously reported two families with autosomal dominant LFSNHL linked to adjacent but non-overlapping loci on 4p16, DFNA6 and DFNA14. However, further study revealed that an individual with LFSNHL in the DFNA6 family who had a recombination event that excluded the DFNA14 candidate region was actually a phenocopy, and consequently, DFNA6 and DFNA14 are allelic. LFSNHL appears to be genetically nearly homogeneous, as only one LFSNHL family is known to map to a different chromosome (DFNA1). The DFNA6/14 critical region includes WFS1, the gene responsible for Wolfram syndrome, an autosomal recessive disorder characterized by diabetes mellitus and optic atrophy, and often, deafness. Herein we report five different heterozygous missense mutations (T699M, A716T, V779M, L829P, G831D) in the WFS1 gene found in six LFSNHL families. Mutations in WFS1 were identified in all LFSNHL families tested, with A716T arising independently in two families. None of the mutations was found in at least 220 control chromosomes with the exception of V779M, which was identified in 1/336 controls. This frequency is consistent with the prevalence of heterozygous carriers for Wolfram syndrome estimated at 0.3-1%. An increased risk of sensorineural hearing loss has been reported in such carriers. Therefore, we conclude that mutations in WFS1 are a common cause of LFSNHL.

Objective: To analyze the relationship between pure-tone hearing threshold and speech recognition performance in DFNA2/KCNQ4 and DFNA9/COCH, 2 types of high-frequency nonsyndromic hearing impairment., Design: Case series with cross-sectional analysis of phoneme recognition scores related to age and hearing level., Setting: University hospital., Patients: Forty-five members of 4 separate families, all carrying 1 of 3 different mutations in the KCNQ4 gene at the DFNA2 locus (1p34); 42 members of 7 separate families, all carrying the same Pro51Ser mutation in the COCH gene at the DFNA9 locus (14q12-q13)., Results: The deterioration of speech recognition dropped to a 90% score at a higher level of hearing impairment (pure-tone-average at 1, 2, and 4 kHz) in DFNA2-affected patients (65 dB) than in DFNA9-affected patients (46 dB)., Conclusion: At similar levels of hearing impairment, DFNA2/KCNQ4-affected patients showed better speech recognition performance than DFNA9/COCH-affected patients.

Objective: To describe the decline of vestibulocochlear function in a man with vestibulocochlear dysfunction caused by a Pro51Ser mutation within the COCH gene on chromosome 14q12-13 (DFNA9)., Methods: A follow-up of more than 15 years was performed in a single case. Clinical investigations were supplemented by oculomotor, vestibular, and auditory tests., Results: A 50-year-old man had had progressive sensorineural hearing loss and dysequilibrium for 15 years; he had been asymptomatic at the age of 35 years. He suffered from instability in the dark, head movement-dependent oscillopsia, paroxysmal positional vertigo, and vertigo with and without nausea. Hearing impairment started unilaterally, predominantly in the high frequencies. He also reported tinnitus. Disease progressed to severe bilateral high-frequency hearing impairment and vestibular areflexia. Fluctuation of vestibulocochlear function was documented and mentioned by the patient., Conclusions: Our patient proved to suffer from an autosomal dominant vestibulocochlear disorder caused by a COCH gene mutation. The remarkable medical history has some features in common with Meniere disease; however, there are also different clinical and neurophysiological features. In the family, phenotypic variability is present.

Objectives: Analysis of phenotype-genotype correlation., Study Design: Family study., Methods: Auditory and vestibulo-ocular functions were examined in a Dutch family with autosomal dominantly inherited sensorineural hearing impairment caused by a 208C > T mutation in the COCH gene, located in chromosome 14q12-q13 (DFNA9). Linear regression analysis of individual longitudinal hearing threshold data (n = 11) on age was performed., Results: Fifteen of the 16 genetically affected persons could be evaluated. They all developed hearing and vestibular impairment symptoms--and in many cases also cardiovascular disease--in the fourth to fifth decade. At the low frequencies (0.25-2 kHz), hearing loss started at the age of about 40 years and showed an average annual progression of approximately 3 dB, finally resulting in profound hearing losses. In two exceptional cases, annual progression attained levels of up to 24 dB. At the high frequencies (4-8 kHz), the average threshold increased from about 50 dB at the age of 35 years to about 120 dB at the age of 75 years (which amounts to 1.8 dB annual threshold increase). All affected individuals tested showed normal ocular motor functions. The patients older than 46 years generally showed absence of the vestibulo-ocular reflex, but their cervico-ocular reflex was enhanced compared with normal subjects, whereas those aged 40 to 46 years showed either severe vestibular hyporeflexia or unilateral caloric areflexia., Conclusion: These findings suggest a gradual development of cochleovestibular impairment caused by the new mutation found.

We analysed a Dutch family with autosomal dominant non-syndromic progressive sensorineural hearing loss and mapped the underlying gene defect by genetic linkage analysis to a 11.0 cM region overlapping the DFNA9 interval on chromosome 14q12-q13. Clinically, the Dutch family differs from the original DFNA9 family by a later age at onset and a more clearly established vestibular impairment. A gene that is highly and specifically expressed in the human fetal cochlea and vestibule, COCH (previously described as Coch5B2 ), was mapped to the DFNA9 critical region. Sequence analysis revealed a 208C-->T mutation in the COCH gene, resulting in a Pro51Ser substitution in the predicted protein in all affected individuals of the family but not in unaffected family members and 200 control individuals. The same mutation was also identified in three apparently unrelated families with a similar phenotype, suggesting the presence of a Dutch founder mutation. The function of COCH is unknown but several characteristics of the protein point to a structural role in the extracellular matrix. The mutant serine at position 51 is situated between cysteines and possibly interferes with proper COCH protein folding or its interaction with extracellular matrix proteins.