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BackgroundIrradiation, which affects cytokine secretion, is used to treat cancer patients. Cytokine levels have correlations to disease parameters, serving as biomarkers for patients. We aim to explore the effect of irradiation on cytokine production both in vitro (using lymphocytes from healthy donors) and in vivo (using serum levels of head and neck cancer patients following irradiation) and correlating them to mucositis severity/need for percutaneous endoscopic gastroscopy (PEG) tube installation.MethodsCytokine production by cultured lymphocytes from healthy donors, in vitro, following irradiation of 5 or 10 Gy. In addition, blood from 23 patients with head and neck cancers, irradiated by 60–72G in vivo, were assessed for inflammatory cytokines (tumor necrosis factor (TNF)α, interleukin (IL)-6, IL-8, IL-18), the anti-inflammatory cytokine IL-10, and the general marker sIL-2R. Following radiation, selected patients who were developing mucositis were treated by PEG tube installation. Changes in cytokine levels were studied as predictive biomarkers of response to therapy/PEG tube installation. Cytokine production levels were measured using ELISAs kits.ResultsIrradiation decreased the levels of all tested cytokines, most notably IL-6 and IL-8, proportional to irradiation dose. In patients, increases in cytokine levels, correlated with mucositis severity and potentially the need for PEG tube installation.ConclusionsIrradiation decreased the levels of all cytokines of healthy lymphocytes in a dose-dependent manner, especially those of IL-6 and IL-8. This study shows a correlation between high and increasing levels of inflammatory cytokines, sIL-2R, plus radiation toxicity and the need for PEG. The reduction of cytokine levels after radiotherapy predicts that PEG will not be required. Thus, our study shows that cytokine changes are predictive biomarkers in head and neck cancer patients.

Item does not contain fulltext PURPOSE: This study aimed to investigate the clinical and genetic aspects of solute carrier (SLC) genes in inherited retinal diseases (IRDs). METHODS: Exome sequencing data were filtered to identify pathogenic variants in SLC genes. Analysis of transcript and protein expression was performed on fibroblast cell lines and retinal sections. RESULTS: Comprehensive analysis of 433 SLC genes in 913 exome sequencing IRD samples revealed homozygous pathogenic variants in 6 SLC genes, including 2 candidate novel genes, which were 2 variants in SLC66A1, causing autosomal recessive retinitis pigmentosa (ARRP), and a variant in SLC39A12, causing autosomal recessive mild widespread retinal degeneration with marked macular involvement. In addition, we present 4 families with ARRP and homozygous null variants in SLC37A3 that were previously suggested to cause retinitis pigmentosa, 2 of which cause exon skipping. The recently reported SLC4A7- c.2007dup variant was found in 2 patients with ARRP resulting in the absence of protein. Finally, variants in SLC24A1 were found in 4 individuals with either ARRP or congenital stationary night blindness. CONCLUSION: We report on SLC66A1 and SLC39A12 as candidate novel IRD genes, establish SLC37A3 pathogenicity, and provide further evidence of SLC4A7 as IRD genes. We extend the phenotypic spectrum of SLC24A1 and suggest that its ARRP phenotype may be more common than previously reported.

The aim of the study was to develop a sustained-release varnish (SRV) containing chlorhexidine (CHX) for sinonasal stents (SNS) to reduce bacterial growth and biofilm formation in the sinonasal cavity. Segments of SNS were coated with SRV-CHX or SRV-placebo and exposed daily to bacterial cultures of Staphylococcus aureus subsp. aureus ATCC 25923 or Pseudomonas aeruginosa ATCC HER-1018 (PAO1). Anti-bacterial effects were assessed by disc diffusion assay and planktonic-based activity assay. Biofilm formation on the coated stents was visualized by confocal laser scanning microscopy (CLSM) and high-resolution scanning electron microscopy (HR-SEM). The metabolic activity of the biofilms was determined using the 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) method. Disc diffusion assay showed that SRV-CHX-coated SNS segments inhibited bacterial growth of S. aureussubsp. aureus ATCC 25923 for 26 days and P. aeruginosa ATCC HER-1018 for 19 days. CHX was released from coated SNS segments in a pH 6 medium up to 30 days, resulting in growth inhibition of S. aureussubsp. aureus ATCC 25923 for 22 days and P. aeruginosa ATCC HER-1018 for 24 days. The MTT assay showed a reduction of biofilm growth on the coated SNS by 69% for S. aureussubsp. aureus ATCC 25923 and 40% for P. aeruginosa ATCC HER-1018 compared to the placebo stent after repeated exposure to planktonic growing bacteria. CLSM and HR-SEM showed a significant reduction of biofilm formation on the SRV-CHX-coated SNS segments. Coating of SNS with SRV-CHX maintains a sustained delivery of CHX, providing an inhibitory effect on the bacterial growth of S. aureussubsp. aureus ATCC 25923 and P. aeruginosa ATCC HER-1018 for approximately 3 weeks.

Vertigo is a complex symptom which imposes diagnostic and treatment challenges. Laboratory evaluation of vertigo includes video-nystagmography (VNG) and computerized dynamic posturography (CDP) for the evaluation of different aspects of this complaint. There are vague indications for each test and potential disagreements between them. The aim of this study is to examine the association between the test results of the VNG and sensory organization test (SOT) of CDP in patients referred for both vestibular tests. Retrospective data regarding 56 patients age 17–82 years were collected. Patients suffered vestibular complaints and were referred for VNG and CDP evaluation on the same day. The level of agreement between VNG (including caloric test) and the vestibular input of the SOT for each patient was calculated. Among the study group, 10 showed abnormal caloric test results, of which 3 (5.4%) had normal vestibular input in the SOT, and 7 (12.5%) had impaired input (p = 0.724). Spontaneous nystagmus was recorded in 13 patients by VNG, of which 2(3.6%) had normal vestibular input and 11(19.6%) had impaired vestibular input (p = 0.056). This study shows no statistically significant association between the VNG test and SOT test results. Our results emphasize the difference between the tested aspects in each laboratory test, and the need to define specific indications for each of them. There is a marginally significant association between impaired vestibular input and spontaneous nystagmus, demonstrating the non-localizing nature of this sign.

Resume Objectifs Preciser chez les patients porteurs d’un surdite brusque idiopathique neurosensorielle, la relation entre cette surdite et la presence d’anticorps IgG seriques anti-prestine, la specificite diagnostique de ces anticorps et leur eventuel impact sur le pronostic. Methode Les serums de 63 patients porteurs d’une surdite brusque idiopathique ont fait l’objet d’une recherche d’auto-anticorps anti-prestine en utilisantla technique immuno-enzymatique Elisa (enzyme-linked immunosorbent assay). Chaque serum a ete teste pour les anticorps IgG anti-prestine en utilisant de la prestine humaine recombinante (SLC26 A5). Les variables demographiques, cliniques et audiometriques ont ete analysees. Resultats Chez deux patients (3,17 %) on a pu demontrer la presence d’anticorps anti-prestine dans le serum (intervalle de confiance (IC) 95 % : −1,16 % a 7,5 %). Aucune correlation statistiquement significative n’a ete trouvee entre la presence d’auto-anticorps anti-prestine et les parametres demographiques ou audiologiques. Conclusions Cette etude preliminaire inedite n’est pas en faveur de la presence d’une reaction immunitaire humorale active anti-prestine dans la genese des surdites brusques idiopathiques.

Objectives Idiopathic sudden sensorineural hearing loss (SSNHL) represents a frequently encountered otological entity, of various types and severity, with an array of associated symptoms including vertigo. This is a devastating life-changing condition with a blurry prognosis. The objective of this study was to determine the clinical association of vestibular impairment by electronystagmography (ENG) and caloric tests, and their ability to predict prognosis. Methods An observational, crossectional study was carried out amongst patients admitted with SSNHL. Each consenting patient had an audiometry test performed on admission as well as ENG and caloric tests. Treatment included oral steroids and carbogen with intratympanic steroids used only as salvage treatment. Follow-up was completed after 6 months when hearing gains were evaluated. Finally, an association was sought between the rate of recovery and ENG and caloric test results. Results Of 35 patients included, marked recovery was seen in patients without vertigo when compared to those with vertigo (p=0.003). A statistically significant association was found between the presence of vertigo and hearing deterioration (p=0.008). More so, normal electronystagmography results were associated with marked recovery (p=0.04). Conclusions The vestibular end organs are both subjectively and objectively affected in SSNHL as demonstrated by the abnormal ENG and caloric tests in our study despite the small sample size. Concomitant vestibular involvement carries poorer prognosis and routine identification may help foresee the recovery of patients with SSNHL and as such, aid in patient counseling. ENG and caloric tests are easily available and may be recommended for all patients with SSNHL.

This study aimed to find out the frequency of sleep-related breathing disorders (SRBD) in young orthodontic patients in Israel. SRBD is characterized by prolonged upper airway obstruction during sleep.The study group consisted of 309 children aged 6-17 years who attended the Orthodontic Clinic at Hadassah Medical Center. Parents were asked to complete a translated validated Pediatric Sleep Questionnaire.Of the examined children, 10% were at high risk for SRBD. Boys were at higher risk for SRBD and were at high risk at a younger age than girls. Girls had a low risk of SRBD after adenotonsillectomy, whereas 50% of the boys that underwent adenotonsillectomy were at high risk for SRBD.Our findings propose that 10% of the children aged 6-17 years, who were seeking orthodontic consultation at our medical center, were at high risk for SRBD. Boys were significantly at a higher risk for SRBD than girls and were at high risk at a younger age. It is important to screen young orthodontic patients for SRBD and to refer high-risk patients to their physicians for further evaluation and treatment.

In this study, we aimed to develop a novel, sustained release varnish (SRV) for voice prostheses (VP) releasing chlorhexidine (CHX), for the prevention of biofilm formation caused by the common oral bacteria Streptococcus mutans on VP surfaces. This study was performed in an in vitro model as a step towards future in vivo trials. VPs were coated with a SRV containing CHX (SRV-CHX) or SRV alone (placebo-SRV) that were daily exposed to S. mutans. The polymeric materials of SRV were composed of ethylcellulose and PEG-400. Biofilm formation was assessed by DNA quantification (qPCR), crystal violet staining, confocal laser scanning microscopy (CLSM), scanning electron microscopy (SEM), and kinetics experiments. The amount of DNA in the biofilms formed by S. mutans on VP surfaces coated once with SRV-CHX (1.024 ± 0.218 ng DNA/piece) was 58.5 ± 8.8% lower than that of placebo-SRV-coated VPs (2.465 ± 0.198 ng DNA/piece) after a 48-h exposure to S. mutans (p = 0.038). Reduced biofilm mass on SRV-CHX-coated VPs was visually confirmed by CLSM and SEM. CV staining of SRV-CHX single-coated VPs that have been exposed to S. mutans nine times showed a 98.1 ± 0.2% reduction in biofilm mass compared to placebo-SRV-coated VPs (p = 0.003). Kinetic experiments revealed that SRV-CHX triple-coated VPs could delay bacterial growth for 23 days. Coating VPs with SRV-CHX has an inhibitory effect on biofilm formation and prevents bacterial growth in their vicinities. This study is a proof-of-principle that paves the way for developing new clinical means for reducing both VPs’ bacterial biofilm formation and device failure.

Smell loss is important for coronavirus disease-2019 (COVID-19) screening and diagnosis. Particular attention should be paid to individuals with pre-COVID-19 chronic hyposmia or anosmia. We report a case of reversible taste impairment in a COVID-19 patient with chronically impaired sense of smell. This case emphasizes the importance of COVID-19-related taste assessment.

Background/aim Prognostic factors serve as a vital tool in the treatment of patients with head and neck cancer (HNC). The aim of this study was to evaluate the clinical potential of Thymidine-kinase-1 (TK1) marker in the prognosis of HNC patients. Patients and methods We evaluated 366 blood samples from 278 HNC patients and 88 healthy controls, using an ELISA assay. Correlations of TK1 levels with disease stage, lymph node involvement and response to radiation therapy, were determined. Results In HNC patients, TK1 levels were significantly higher compared to healthy controls. Significantly higher TK1 levels were demonstrated in node positive cases and in advanced disease stages compared to node negative and early disease stages. Levels were higher prior to radiation and decreased significantly thereafter, in patients responding to treatment. Increasing levels of TK1 post-radiation were indicative of recurrence or of non-response to treatment, while decreasing levels indicated a positive response. Conclusion TK1 is a tumor marker in HNC patients with the ability to assess response to therapy. High or increasing levels correlated to a poor prognosis, whereas low levels correlated to an overall increased survival.

The initial events of viral infection at the primary mucosal entry site following horizontal person-to-person transmission have remained ill defined. Our limited understanding is further underscored by the absence of animal models in the case of human-restricted viruses, such as human cytomegalovirus (HCMV), a leading cause of congenital infection and a major pathogen in immunocompromised individuals. Here, we established a novel ex vivo model of HCMV infection in native human nasal turbinate tissues. Nasal turbinate tissue viability and physiological functionality were preserved for at least 7 days in culture. We found that nasal mucosal tissues were susceptible to HCMV infection, with predominant infection of ciliated respiratory epithelial cells. A limited viral spread was demonstrated, involving mainly stromal and vascular endothelial cells within the tissue. Importantly, functional antiviral and proleukocyte chemotactic signaling pathways were significantly upregulated in the nasal mucosa in response to infection. Conversely, HCMV downregulated the expression of nasal epithelial cell-related genes. We further revealed tissue-specific innate immune response patterns to HCMV, comparing infected human nasal mucosal and placental tissues, representing the viral entry and the maternal-to-fetal transmission sites, respectively. Taken together, our studies provide insights into the earliest stages of HCMV infection. Studies in this model could help evaluate new interventions against the horizontal transmission of HCMV. IMPORTANCE HCMV is a ubiquitous human pathogen causing neurodevelopmental disabilities in congenitally infected children and severe disease in immunocompromised patients. The earliest stages of HCMV infection in the human host have remained elusive in the absence of a model for the viral entry site. Here, we describe the establishment and use of a novel nasal turbinate organ culture to study the initial steps of viral infection and the consequent innate immune responses within the natural complexity and the full cellular repertoire of human nasal mucosal tissues. This model can be applied to examine new antiviral interventions against the horizontal transmission of HCMV and potentially that of other viruses.

Objectives To define the clinical association of serum prestin autoantibodies and their impact on prognosis, as specific serum diagnostic markers in patients with idiopathic sudden sensorineural hearing loss (ISSNHL). Design Sera from 63 patients with ISSNHL were screened prospectively for the presence of prestin autoantibodies by an enzyme-linked immunosorbent assay (Elisa) test. Serum was assayed for anti-prestin IgG antibodies using recombinant human prestin (SLC26 A5). Demographic, clinical, and audiometric variables were analyzed. Results Two patients (3.17%) had demonstrable anti-prestin antibodies in serum (exact 95% CI: −1.16% to 7.5%). No statistically significant association was found between prestin autoantibodies and demographic or audiologic parameters. Conclusions This preliminary and novel study does not support the presence of an active humoral immune reaction against prestin in ISSNHL.

The objective of this study was to describe the occurrence, clinical manifestations, audiometric findings, pathogenesis and approach to sensorineural hearing loss (SNHL) among patients diagnosed with vitiligo with a review of the literature. We present a systematic review of the literature on cases of SNHL in patients diagnosed with vitiligo and studies conducted to investigate audiometric changes in such patients. Data on presentation, diagnosis and medical approach were reviewed. A total of 21 studies and case reports revealed at least 102 cases of SNHL in patients diagnosed with vitiligo. Arguments for a common causative etiology related to melanocyte function were mentioned in most of the literature. Evaluation of hearing function among all patients diagnosed with vitiligo seems to be an accepted approach; it should include audiometry, otoacoustic emissions (OAE) and ABR measurements. Extra precaution to prevent ototoxic or noise-induced hearing loss is strongly recommended. Further research is needed to better understand its pathogenesis.

Objects: Dizziness makes up a diagnostic and treatment challenge. The diagnostic accuracy of the medical history and vestibular physical examination in cases of vestibular symptoms is not clear. The aim of this study is to determine the association between vestibular physical examination, vestibular questionnaires, and electronystagmography (ENG) test in patients with vestibular symptoms. Methods: This is a prospective study of 135 adults with vestibular symptoms. The subjects underwent targeted physical examination and filled vestibular questionnaires, including the Dizziness Handicap Inventory (DHI), before ENG testing. The results of the physical examination and questionnaires were compared with the final ENG findings. Results: Of patients who had normal ENG results, 32.1% (17/52) showed abnormal physical examination, and 48.8% (40/82) of the patient who had normal physical examination showed abnormal ENG results ( P = .46). Among patients with severe disability by DHI, 46.4% (13/28) had an abnormal ENG, and 42.9% (12/28) had a normal ENG ( P = .39). Conclusions: This study did not demonstrate association between vestibular physical examination, vestibular questionnaires, and ENG results. Although history (augmented by questionnaires) and physical examination are the initial steps in the evaluation of vertigo, the current study suggests that they should be complemented by objective testing for evaluation of inner ear origin of vertigo.

Objective: Hearing abnormalities frequently occur in Human Immunodeficiency Virus (HIV) infected individuals. Both conductive and uni- or bilateral sensorineural hearing loss (SNHL) have been described along with other audiological and vestibular symptoms such as tinnitus, vertigo and balance disturbances. While frequent middle ear infections may explain impairment of peripheral hearing abilities, the exact etiology of cochlear, and central auditory processing deficits still remains unclear. Direct effects of HIV, opportunistic infections, ototoxic side effects of antiretroviral therapy (ART), and immunologic responses to the central nervous system involving the auditory pathway have been proposed. We aim to review the audiological profile in HIV infected adults related to the effects of HIV and HAART on the inner ear structures. Methods: We present a review of the literature on cases of HIV related SNHL in adult patients and studies conducted to investigate audiometric changes in such patients. Data on presentation, diagnosis and pathophysiology were reviewed. Results: Sensorineural hearing loss in the higher frequencies is a common form of hearing loss in HIV infected individuals throughout disease progression, along with decreased otoacoustic emission (OAE) responses, increased PTA hearing thresholds and prolonged latencies for auditory brainstem responses (ABR). Conclusion: HIV affects all stages of auditory perception in a way similar to accelerated aging of the auditory system. And we postulate that synaptic loss may be the first step, followed by cochlear damage and central pathology as the virus remains present in all the structures of the auditory pathway causing local inflammation and degeneration. Evaluation of hearing function among all patients diagnosed with HIV infection seems to be an accepted approach; it should include OAE testing, pure tone and speech audiometry, speech-in-noise tests and ABR measurements.

COVID-19 has been the talk of the year 2020, taking many lives and leaving others in critical conditions. It has clearly and severally been reported that the SARSCoV-2 uses the Angiotensin Converting Enzyme-2 receptors to penetrate and infect cells. Reports have also stated that the nasal and olfactory mucosa are overloaded with these receptors. We emphasize that anosmia in COVID-19 is secondary to the binding of the SARSCoV-2 to Angiotensin Converting Enzyme-2 receptors on the olfactory mucosa. A hypotheses pertaining to the presentation, diagnosis, management and possible prevention of SARS-CoV-2 is proposed. Given the high false negative rates of the polymerase chain reaction (PCR) tests, we suggest that COVID-19 negative patients with anosmia without any other nasal symptom should raise a high index of suspicion and should be further evaluated. We propose the formulation and use of Angiotensin Converting Enzyme-2 receptors agonist or angiotensin receptor blockers (ARBs) as nasal lavage, to reduce the viral load of confirmed positive patients, and as a mode of prevention, especially in high risk patients, until a vaccine is developed. These medications are readily available and testing this theory involves determination of the correct dosage of angiotensin receptor blockers or ACE inhibitors (via dilution in water) that can be used as nasal lavage and performing efficacy trials. Potential side effects to be monitored for include low blood pressure or changes in heart rate. Administration of a medicated nasal lavage may be easier and rapidly disseminated on the nasal mucosa.

Kaposiform Hemangioendothelioma (KHE) is a rare vascular locally aggressive tumor. The primary treatment is surgical resection, which may be challenging depending on its location and vascularity. Pharmacological treatment includes steroids, vincristine, and recently, Sirolimus (immunosuppressant with anti-proliferative activity). We describe a rare case of refractory KHE located in the middle ear. In addition to its unusual and inoperable anatomical location, this pediatric patient was a non-responder to first line Sirolimus monotherapy. After two months of dual therapy adding Vincristine to the treatment schedule, significant tumor reduction was seen on MRI, with no relapse during the two-year follow-up after completion of treatment.

Purpose: We aimed to identify the cause of disease in patients suffering from a distinctive, atypical form of Usher syndrome. Methods: Whole-exome and genome sequencing were performed in five patients from three families of Yemenite Jewish origin, suffering from distinctive retinal degeneration phenotype and sensorineural hearing loss. Functional analysis of the wild-type and mutant proteins was performed in human fibrosarcoma cells. Results: We identified a homozygous founder missense variant, c. 133G> T (p. D45Y) in arylsulfatase G (ARSG). All patients shared a distinctive retinal phenotype with ring-shaped atrophy along the arcades engirdling the fovea, resulting in ring scotoma. In addition, patients developed moderate to severe sensorineural hearing loss. Both vision and hearing loss appeared around the age of 40 years. The identified variant affected a fully conserved amino acid that is part of the catalytic site of the enzyme. Functional analysis of the wild-type and mutant proteins showed no basal activity of p.D45Y. Conclusion: Homozygosity for ARSG-p.D45Y in humans leads to protein dysfunction, causing an atypical combination of late-onset Usher syndrome. Although there is no evidence for generalized clinical manifestations of lysosomal storage diseases in this set of patients, we cannot rule out the possibility that mild and late-onset symptoms may appear.

Dizziness makes up a diagnostic and treatment challenge. The diagnostic accuracy of the medical history and vestibular physical examination in cases of vestibular symptoms is not clear. The aim of this study is to determine the association between vestibular physical examination, vestibular questionnaires, and electronystagmography (ENG) test in patients with vestibular symptoms.This is a prospective study of 135 adults with vestibular symptoms. The subjects underwent targeted physical examination and filled vestibular questionnaires, including the Dizziness Handicap Inventory (DHI), before ENG testing. The results of the physical examination and questionnaires were compared with the final ENG findings.Of patients who had normal ENG results, 32.1% (17/52) showed abnormal physical examination, and 48.8% (40/82) of the patient who had normal physical examination showed abnormal ENG results ( P = .46). Among patients with severe disability by DHI, 46.4% (13/28) had an abnormal ENG, and 42.9% (12/28) had a normal ENG ( P = .39).This study did not demonstrate association between vestibular physical examination, vestibular questionnaires, and ENG results. Although history (augmented by questionnaires) and physical examination are the initial steps in the evaluation of vertigo, the current study suggests that they should be complemented by objective testing for evaluation of inner ear origin of vertigo.

Background Complications associated with long-term tracheotomy are obstruction of the distal end of the tube by granulation tissue and tracheomalacia. These complications have traditionally been surgically treated. Methods Prospective study in a chronic ventilator-dependent division, including 234 consecutive patients with tracheotomy and mechanical ventilation. Endoscopic evaluation was performed in patients in whom there was respiratory distress with difficulty in passing a suction catheter through the tube, and/or increased inspiratory resistance and increased peak inspiratory pressure. Results Nineteen patients were diagnosed with granulation or tracheomalacia. Two patients were treated by surgical removal of the obstructing tissue. Nonsurgical patients were conservatively managed with symptoms' resolution by bypassing the pathology with a longer tube than the previous one or by an adjustable flange tube under endoscopic visualization, with a median symptom-free period of 433 days (range, 55–1230 days). Conclusion In nonsurgical candidates, insertion of a longer tube is a conservative and feasible long-term treatment. © 2014 Wiley Periodicals, Inc. Head Neck 37: 716–721, 2015

PMF of infancy is a recently described autosomal recessive disorder presenting with severe bone marrow failure, accelerated neutrophil apoptosis, and significant platelet dysfunction, caused by a mutation in the VPS45 gene. In this study, we update our group of patients with PMF, highlighting different aspects of this disease, and evaluating the effectiveness of HSCT for the treatment of this disorder. Update of clinical data, hematological features, molecular studies, treatment and final outcome of four children diagnosed with VPS 45-associated PMF of infancy. The patients described had clinical and hematological findings consistent with MF. Molecular studies showed that all patients were homozygous for the Thr224Asn mutation in the VPS 45 gene. HSCT was carried out in three patients and was successful in two. VPS 45-associated MF is a novel primary immune deficiency that can be successfully corrected by HSCT if applied early in the course of disease using appropriate conditioning. The diagnosis of VPS 45-associated PMF should be considered in all children presenting with SCN with subsequent development of pancytopenia. Long-term follow-up of these patients is necessary to identify extra-hematological manifestations of VPS45 deficiency.

Retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by photoreceptor death, which results in visual failure. Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66). In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101−1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified. In another family, a homozygous c.134T>G (p.Met45Arg) mutation was identified. In the mouse retina, ARL2BP localized to the basal body and cilium-associated centriole of photoreceptors and the periciliary extension of the inner segment. Depletion of ARL2BP caused cilia shortening. Moreover, depletion of ARL2, but not ARL3, caused displacement of ARL2BP from the basal body, suggesting that ARL2 is vital for recruiting or anchoring ARL2BP at the base of the cilium. This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells. These data demonstrate a role for ARL2BP and ARL2 in primary cilia function and that this role is essential for normal photoreceptor maintenance and function.

Inherited retinal diseases (IRDs) are a diverse group of genetically and clinically heterogeneous retinal abnormalities. The present study was designed to identify genetic defects in individuals with an uncommon combination of autosomal recessive progressive cone-rod degeneration accompanied by sensorineural hearing loss (arCRD-SNHL). Homozygosity mapping followed by whole-exome sequencing (WES) and founder mutation screening revealed two truncating rare variants (c.893-1G>A and c.534delT) in CEP78 , which encodes centrosomal protein 78, in six individuals of Jewish ancestry with CRD and SNHL. RT-PCR analysis of CEP78 in blood leukocytes of affected individuals revealed that the c.893-1G>A mutation causes exon 7 skipping leading to deletion of 65bp, predicted to result in a frameshift and therefore a truncated protein (p.Asp298Valfs ∗ 17). RT-PCR analysis of 17 human tissues demonstrated ubiquitous expression of different CEP78 transcripts. RNA-seq analysis revealed three transcripts in the human retina and relatively higher expression in S-cone-like photoreceptors of Nrl -knockout retina compared to rods. Immunohistochemistry studies in the human retina showed intense labeling of cone inner segments compared to rods. CEP78 was reported previously to interact with c-nap1, encoded by CEP250 that we reported earlier to cause atypical Usher syndrome. We conclude that truncating mutations in CEP78 result in a phenotype involving both the visual and auditory systems but different from typical Usher syndrome.

Head and neck cancer (HNC) patients are usually diagnosed with advanced disease and multimodality therapies are required, as well as prognostic biomarkers to predict their response and assess survival. In this study, we aimed to evaluate the ability and clinical significance of the immune biomarker sIL-2R in HNC patients, to assess therapy response and prognosis.We evaluated 328 blood samples from 145 head and neck cancer patients (HNC) from several subgroups: 84 larynx carcinomas pre- and 39 post-therapy, 46 oral cavity carcinomas pre- and 29 post-therapy, 12 nasopharynx carcinomas, 16 parotid and other salivary gland carcinoma patients. The control group included 45 healthy subjects. Serum sIL-2R levels were evaluated by ELISA assays and correlated to disease stage, lymph nodes, response to therapy, survival and cancer differentiation.Significantly higher sIL-2R levels were recorded in all HNC patients, as opposed to controls, in advanced versus early-stage disease that decreased following therapy. sIL-2R distinguished best, in comparison to other tumor markers, between HNC patients and controls. Survival was strongly associated to lower sIL-2R levels in patients entering the study.sIL-2R is a sensitive immune marker for HNC patients. Its levels correlate to disease stage, assess response to therapy and are predictive of recurrence or better survival. We suggest, therefore, using sIL-2R as a reliable prognostic marker in HNC patients as a single marker, or in a combined panel of biomarkers.

Background: Endoscopic anterior skull-base surgery has been previously suggested to cause a significant deterioration in olfactory function. Given the impact on quality of life, the objective of this study was to determine the ef fect of a unilateral middle-turbinate–sacrificing approach on olfactory function and sinonasal outcome. Methods: Prospective cohort study comparing olfactory and sinonasal outcomes pre- and post-transsphenoidal skull-base surgery. Olfaction was the primary outcome and was measured prospectively using the University of Pennsylvania Smell Identification Test (SIT). Sinonasal symptoms were assessed subjectively via sinonasal-specific questions from the 22-item Sino-Nasal Outcome Test (SNOT-22), and objectively via the Lund-Kennedy Endoscopic Scoring system (LKES). Results: Twenty-two patients met study inclusion criteria and completed all data acquisition. The mean preoperative SIT score was 34.8 and the mean postoperative SIT value was 35.1 (p = 0.37). The average change in score (delta) was an increase of 0.3, with changes ranging from − 3t o+4. When examined categorically, 91% of patients maintained their preoperative olfactory function classification. There was no significant difference in mean pre- and postoperative symptom scores. A small increase in the LKES was noted, from a mean of 0.6 to 2.5 (p = 0.001) in the early postoperative period. Conclusion: Olfactory function, as measured by the SIT test, was preserved with a middle-turbinate–sacrificing skull-base approach. Subjective sinonasal symptom scores were unaffected, but a slight worsening of objective endoscopic appearance was noted. C � 2012 ARS-AAOA, LLC.

Objectives/Hypothesis: To determine the effect of mouth breathing during childhood on craniofacial and dentofacial development compared to nasal breathing in malocclusion patients treated in the orthodontic clinic. Study Design: Retrospective study in a tertiary medical center. Methods: Clinical variables and cephalometric parameters of 116 pediatric patients who had undergone orthodontic treatment were reviewed. The study group included 55 pediatric patients who suffered from symptoms and signs of nasal obstruction, and the control group included 61 patients who were normal nasal breathers. Results: Mouth breathers demonstrated considerable backward and downward rotation of the mandible, increased overjet, increase in the mandible plane angle, a higher palatal plane, and narrowing of both upper and lower arches at the level of canines and first molars compared to the nasal breathers group. The prevalence of a posterior cross bite was significantly more frequent in the mouth breathers group (49%) than nose breathers (26%), (P = .006). Abnormal lip-to-tongue anterior oral seal was significantly more frequent in the mouth breathers group (56%) than in the nose breathers group (30%) (P = .05). Conclusions: Naso-respiratory obstruction with mouth breathing during critical growth periods in children has a higher tendency for clockwise rotation of the growing mandible, with a disproportionate increase in anterior lower vertical face height and decreased posterior facial height. Laryngoscope, 2010

Objective To define the criteria for bronchoscopy in children with suspected foreign body (FB) inhalation. Study design Health history, physical examination, and radiologic examination were performed before bronchoscopy in all children referred for suspected FB inhalation between 2003 and 2005. Results A total of 142 children, ranging in age from 3 months to 14 years (median age, 20 months), were referred with a history of suspected FB inhalation. An FB was found in 42 children with abnormal physical and radiologic findings, in 17 children with abnormal physical or radiologic findings, and in 2 children with normal physical and radiologic finding but persistent cough. Bronchoscopy revealed no FB in the children with normal physical and radiologic examinations and no symptoms (n = 16). Conclusion In children with a history of choking, bronchoscopy is mandatory in the presence of persistent symptoms, such as cough, dyspnea, and fever, or any abnormal physical or chest radiography findings. Bronchoscopy is not necessary in asymptomatic children with normal physical and radiographic examinations.

Objectives: The purpose of this study was to define the clinicopathologic features and outcome of the oncocytic variant of papillary thyroid carcinoma (OVPTC) with a review of the literature. Methods: Twenty-three patients with OVPTC over a 10-year period were studied. Demographic, clinical, and histopathologic features and outcome data were analyzed retrospectively. Results: Seventeen women and 6 men, ages ranging from 20 to 76 years (95% confidence interval, 43.0 to 54.48), were studied. Cervical lymph node involvement was found in 43.4% of the patients. Most of the recurrences were associated with thyroid masses greater than 2 cm in diameter. Evaluation of the overall survival data by the Kaplan-Meier method revealed that most recurrences took place earlier than 30 months, and the majority of patients (74%) were well, with no evidence of disease, up to 78 months after the last treatment. All of the OVPTC cases presented as nonencapsulated tumors, and 78.2% demonstrated extrathyroid stromal invasion. Conclusions: OVPTC is a unique variant of papillary thyroid carcinoma that has distinctive clinicopathologic features. Since OVPTC is often associated with local invasion and may involve cervical lymph nodes, it may require more extensive surgery than classic papillary thyroid carcinoma.

It is commonly accepted that aging is associated with a decline in the antioxidant defense of the cell; accordingly, certain redox enzymes are used as markers of biological senescence. To further test and specify this general concept, we studied age-related changes in the enzymes of the methionine-centered redox cycle (MCRC) in four aero-digestive organs of rats. The levels of cytosolic thioredoxin (Trx), thioredoxin reductase (TrxR), and methionine sulfoxide reductase (Msr), all tended to decline with age. The enzymatic activities of MsrA and MsrB were significantly lower in the organs of aged animals. In general, the magnitude of this decline increased in the order: tongue < sternohyoid muscle < larynx < esophagus. The relative stability of MCRC in the old tongues might be part of the well-preserved oxidative metabolism as confirmed by the age-related increase in mitochondrial marker and muscle tissue in these tongues. In total, the results suggest that age-associated oxidative damage is organ-specific and could reflect differences in morphological composition of these tissues, and among them, relative content of striated muscles.

Summary Granular cell tumor (GCT) of the larynx is an uncommon, benign laryngeal neoplasm. Abrikossoff first described the tumor in 1926 as myoblastoma. The origin of this tumor has been debated in the literature. Most of the authors believe that the tumor is of neural origin due to the characteristic immunohistochemical-staining pattern. The authors describe two cases of laryngeal GCTs located in different sites with a review of the histological and clinical features, the differential diagnosis, and the treatment and the prognosis of the tumor.

Sudden sensorineural hearing loss (SSNHL) is frequently classified as ‘idiopathic’ since the causative factor responsible for its onset is not identified in most cases. In the present study, we determined whether SSNHL is clinically associated with serum anti-heat shock protein-70 (anti-HSP70) and antiphospholipids (anti-PLs) autoantibodies and whether these autoantibodies have an impact on the prognosis of SSNHL. Sera from 63 patients with SSNHL were screened prospectively for the presence of anti-HSP70 and anti-PLs autoantibodies by an enzyme-linked immunosorbent assay test. Anti-PLs antibodies in this study consisted of anticardiolipin, and anti-β2-glycoprotein-1 antibodies. Serum was assayed for anti-HSP70 IgG antibodies using recombinant human HSP70. Demographic, clinical, and audiometric variables were analyzed to find the possible role of serum autoantibodies in SSNHL patients. Sixteen patients (25.4%) had demonstrable anti-HSP70 antibodies in serum. Twenty-one patients (33.3%) showed a positive result for at least one isotype (IgM or IgG) of anti-PLs. In 19% of the patients, anti-HSP70 and anti-PLs antibodies were positive in two combinations. A statistically significant association was found between anti-HSP70 antibodies and the Siegel recovery grade subgroup. SSNHL patients who were positive for anti-HSP70 antibodies showed a significantly higher rate of complete recovery and incomplete but partial recovery than SSNHL patients without anti-HSP70 antibodies (p = 0.0496). Statistically significant association was found between total anticardiolipin, total anti-β2-glycoprotein-1, total anti-PLs, and anti-PLs in combination with anti-HSP70 antibodies and age (p = 0.0229). The detection of autoantibodies to HSP70 and PLs offers a pliable explanation for the immune-mediated mechanism of SSNHL. The present study confirms and supports previous studies regarding the association between anti-HSP70 and anti-PLs antibodies with SSNHL, and is the first to identify a positive association between anti-HSP70 antibodies and a positive outcome of SSNHL. Further studies are necessary in order to identify and further clarify the immunologic role of the presence of autoantibodies and their impact on the prognosis of SSNHL.

Sudden sensorineural hearing loss (SSNHL) is frequently classified as ‘idiopathic’ since the causative factor is not identified in most cases. In the present study we determined whether SSNHL is associated with common viral infections, namely enterovirus, cytomegalovirus (CMV) and Epstein-Barr virus (EBV). Between April 2004 and March 2005, we conducted a prospective cohort study on 48 unselected patients with unilateral idiopathic SSNHL. Plasma samples obtained at presentation were analyzed for the presence of enterovirus RNA by reverse-transcription polymerase chain reaction (RT-PCR). Recent occurrence of CMV and EBV infection was determined by serological tests. Among 23 men and 25 women aged 18–84 years (mean age 51.67 years), none presented with clinical symptoms of a viral infection compatible with preceding or concurrent viral infection. One patient (2.08%) had evidence of enterovirus infection by RT-PCR, 3 patients (6.25%) had EBV IgM, and none were positive for CMV IgM. The majority of SSNHL patients (91.67%) did not have evidence of any of the three common viral infections upon presentation. The present study failed to identify recent or concurrent systemic viral infections among SSNHL patients, except for a small proportion who demonstrated recent viral infection. Therefore the theory that viral infection is a factor in SSNHL pathogenesis is not supported by this study. Further studies in larger patient populations and different epidemiological settings are required in order to verify the true role of viral infections in SSNHL.

Establishing prognostic factors is very important in the management of cancer patients. Our aim was to evaluate the clinical significance of a panel of tumor markers, including CEA (Carcino Embryonic Antigen), SCC (Squamous Cell Carcinoma Antigen), TPS (Tissue Polypeptide Specific Antigen) and CYFRA 21-1 in head and neck cancer patients, for assessing treatment response and prognosis of patients.We evaluated 312 blood samples from 143 head and neck cancer patients, from several sub-groups: 82 Larynx Carcinoma pre- and 38 post-therapy, 46 Oral Cavity pre and 29 post-therapy, 12 nasopharynx, 16 parotid and other salivary gland patients. Blood tumor markers levels were evaluated by conventional ELISA assays. Correlations of marker levels to stage of disease, lymph node involvement and therapy, were performed.Serum levels of all four tumor markers were higher before therapy and decreased thereafter in all patients. The decrease in TPS level following therapy was significant (p=0.03). Significantly higher levels of TPS and similarly higher levels of the other tumor markers were demonstrated in advanced disease (stages III and IV) patients, as opposed to early disease (stages I and II) patients (p=0.012). Node positive patients had significantly higher TPS levels as compared to node negative (p=0.02). The same trend was shown by the other markers as well, but did not reach statistical significance. TPS was best correlated to survival of patients; those having low levels had the best clinical outcome and longer survival.CEA, SCC, TPS and CYFRA 21-1 can all serve as useful tumor markers in HNC patients. They assessed response to therapy and were prognostic for recurrence. TPS proved to be the most sensitive predictor of advanced disease and poor prognosis.

OBJECTIVE:: The objective of this study was to analyze the circumstance, demographic features, clinical findings, and complications of caustic ingestion in relation to the type and amount of caustic substance. STUDY DESIGN:: The authors conducted a retrospective cohort study in a tertiary medical center. METHODS:: The authors reviewed medical records from 1988 to 2003 of patients with a history of caustic ingestion and clinical signs of injury to the aerodigestive tract. Parameters examined included age at presentation, gender, demographic status, nature of the caustic substance ingested, amount of substance, circumstance of the event, diagnostic tools, degree of injury, and anatomic distribution of the injury, early and late complications, and requirement for ventilatory support. RESULTS:: A total of 50 cases of caustic ingestion were identified (age range, 5 months-71 years). A biphasic distribution of the patients was noted; half were children under 5 years old and the remainder was adults. The most common caustic agent ingested was alkaline (42%) followed by acidic (32%) and chlorine bleach (26%). The most frequent cause for ingestion was accidental (67%) as opposed to attempt suicide (33%). All cases of attempted suicide occurred in adults. Most of them reported ingestion of large amounts of caustic substance. In the pediatric group, an association between the caustic agent and ethnicity was observed. Among Jewish children, alkaline cleaning agents were the most common cause (82%). Acetic acid was the most common substance ingested by the Arab children (100%). The findings of rigid esophagoscopy in 36 patients were as follows: first-degree esophageal injury in 16 (44%), second-degree in 6 (17%), third-degree in 7 (19%), fourth-degree in 6 (17%), and one (3%) was normal. Mucosal injury to the esophagus was worse in the acidic ingestion group as compared with the alkaline substance ingestion group with marginally statistically significant difference in the median degree of injury between the three types of ingested substances (P = .054). Mucosal injury to the esophagus was worse among patients who attempted suicide as compared with accidental ingestion with a statistically significant difference in the median degree of injury between the two reasons for ingestion (P = .002). CONCLUSION:: Severity of injury from caustic ingestion damages depend on the type of ingested substance, which varies depending on ethnicity. Ingestion of caustic agents by children involves specific substances according to the season, cultural and religious festivals, and ethnicity. The majority of adult cases are intentional with more serious injuries and a higher rate of complications. In our series, ingestion of acidic substances and ingestion associated with suicide attempt had the most severe consequences. Language: en

Objective The aim of this study was to evaluate the routine use of packing or local hemostatic agents in endoscopic sinus surgery (ESS). Methods Packing and/or hemostatic agents were used only when necessary in 100 consecutive adult ESS patients in a tertiary academic hospital. Necessity for packing the nose after excessive bleeding was analyzed in relation to demographic characteristics, medical history, previous surgeries, current surgical procedure, type of anesthesia, and amount of intraoperative bleeding. Results Three patients who required packing because of other reasons (such as bolstering of mucosa) were excluded from the study. The remaining 97 patients included 61 males and 36 females between the ages of 16 to 86 (mean 44). Forty-nine patients underwent only ESS, 40 ESSs associated with nasal polypectomy, and 8 underwent other endoscopic procedures. Fifty-four underwent the operation under general anesthesia and 43 under local anesthesia. Intraoperative blood loss was less than 30 mL in 82 patients (85%), 30 to 50 mL in 11 (11%), and more than 50 mL in 4 (4%). In 89 patients (92%), packing or a hemostatic agent was not used. No patient had bleeding complications postoperatively. A comparison between patients who required packing to those who did not showed that the only statistically significant associations related to general anesthesia (P = 0.0082) and to the amount of intraoperative bleeding (P Conclusions Most ESS procedures can be managed without packing or any other hemostatic measures. Local anesthesia, use of local vasoconstrictors, and careful operative technique minimize the need for nose packing, thus reducing patient’s discomfort, postoperative complications, and cost of surgery. EBM rating: C-4

UNLABELLED PURPOSE OF VIEW: We review recent developments in the clinical course and imaging modalities for Susac's syndrome, a clinical triad consisting of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss. RECENT FINDINGS Susac's syndrome has variable clinical presentations; recently described presentations include epileptic seizures and transient inverted vision. Advances in neuroradiology suggest that magnetic resonance imaging demonstrates distinctive patterns in the white and grey matter and in the leptomeninges. Reports have verified that Susac's syndrome is under-diagnosed because of its multisystem involvement and confusion with other imitating disorders (such as multiple sclerosis), and because of the fact that neuroradiologists are not acquainted with this syndrome. SUMMARY The precise aetiology of Susac's syndrome is still unknown and many areas have not yet been explored. Magnetic resonance imaging is the neuroimaging study of choice. Findings include multiple small hyperintense foci on T2-weighted images and contrast enhancement in white and grey matter of both supratentorial and infratentorial structures, corpus callosum and, occasionally, leptomeninges. Callosal lesions typically involve the central fibres and are probably pathognomonic for Susac's syndrome. When assessing patients with unexplained encephalopathy involving white and grey matter, leptomeninges and corpus callosum, the findings of sensorinueral hearing loss or visual disturbances may yield important clues regarding the possibility of Susac's syndrome.

This manuscript reports on our experience with purulent chondritis of the laryngeal cartilages (PCLC), an entity that has not yet been described. Three patients had a diagnosis of PCLC. The probable causes were relapsing polychondritis, a previous prolonged intubation, and an idiopathic cause. The patients suffered from hoarseness and inspiratory stridor for 1 to 3 months before diagnosis. None complained of pain in the neck. Laryngoscopy showed supraglottic edema. A computed tomography scan revealed abscess formation between the intact inner and outer perichondria of the thyroid cartilage. The treatment included rigid endoscopy, external incision and drainage, and prolonged medical therapy. The culture results were Staphylococcus aureus in the first 2 cases and Aspergillus fumigatus in the third. The second patient (in whom the cricoid cartilage was also affected) required emergency tracheotomy. The other 2 patients did not require airway intervention. The rarity of PCLC and the relatively mild symptoms require a high index of suspicion for its diagnosis.

The objective of this study was to describe the clinical manifestations; radiographic, audiometric, and retinal fluorescein angiography findings; pathogenesis and treatment of Susac syndrome with review of the literature.We conducted a retrospective case review.This study was conducted at a tertiary referral center.A 50-year-old woman presented with recurrent episodes of neurologic symptoms, bilateral sensorineural hearing loss, and silent retinal artery occlusion.The patient underwent complete evaluation, including magnetic resonance image studies, audiometric tests, and retinal fluorescein angiography. She was treated initially with corticosteroids and later with other immunosuppressive agents.The patient was initially diagnosed with left sudden sensorineural hearing loss. Despite comprehensive clinical and laboratory studies that did not reveal systemic disease, 3 weeks later, the patient developed vertigo, sensorineural hearing loss, and tinnitus in the opposite ear. The neurologic involvement and the bilateral audiologic manifestations raised the possibility of Susac syndrome.Susac syndrome is a rare disorder of unknown origin characterized by the triad of encephalopathy, fluctuating hearing loss, and visual loss resulting from microangiopathy of the brain, cochlea, and retina. The multiple organ involvement seen in Susac syndrome raises a differential diagnosis ranging from autoimmune disease, through systemic vasculitis, to multiple sclerosis. Otolaryngologists should be aware of this syndrome as a result of the vestibulocochlear manifestations and the multidisciplinary evaluation that is required.

Objective: The average age of children undergoing tracheotomy has declined over the years and the indications for tracheotomy have changed from acute airway obstruction due to infection, to treatment of chronically ill children. Tracheotomy-related complication rates are more numerous in younger children and in certain cases have proved to be fatal. A variety of operative techniques have been advocated for reducing the rate of tracheotomy-related morbidity and mortality. This manuscript reports on our experience with a new technique—starplasty tracheotomy (SPT)—and assesses the value of this procedure in preventing tracheotomy-related complications in infants (under 6 months old), in whom complications are more frequent and more dangerous. Methods: Children less than 6 months old who underwent tracheotomy in the Department of Otolaryngology/Head and Neck Surgery, Hadassah University Hospital, Jerusalem, between the years 1999 and 2003 were studied. They were divided into two groups according to the surgical technique preferred and performed by the senior surgeon on call. Children in group 1 underwent tracheotomy by means of a regular technique and children in group 2 underwent SPT. All events related to the tracheotomy were recorded and a comparison was made between the two groups. Results: Eleven of a total of 26 pediatric tracheotomy patients were less than 6 months old. Five underwent regular tracheotomy (RT) and six underwent SPT. Three complications were encountered in the RT group and none in the SPT group. Accidental decannulation and failure to re-insert the cannula resulted in severe hypoxemic brain damage in one patient with RT. No tracheotomy-related deaths occurred. Conclusion: Our experience supports the existing data regarding the superiority of SPT over RT in preventing dangerous tracheotomy-related complications in infants. We, therefore, recommend performing SPT in all infants undergoing tracheotomy, even at the price of having to perform surgical closure of TCF after decannulation in some cases.