Aberrant interleukin-1 signalling does not increase susceptibility of mice to NOD2-dependent uveitis.

BACKGROUND: NOD2 is the genetic cause of Blau syndrome, an autoinflammatory disease that manifests as coincident uveitis and arthritis. Since dysregulation of IL-1 signalling is considered a pathogenic mechanism in a number of related autoinflammatory conditions, we examined the extent to which unimpeded interleukin (IL)-1 signalling influences NOD2-dependent inflammation of the eye versus the joint. METHODS: Mice deficient for IL-1R antagonist (IL-1Ra) were administered the NOD2 agonist muramyl dipeptide (MDP) by systemic (intraperitoneal) or local (intraocular and/or intra-articular) injections. NOD2-deficient mice received an intraocular injection of recombinant IL-1ß. Uveitis was evaluated by intravital videomicroscopy and histopathology, and arthritis was assessed by near-infrared imaging and histopathology. Ocular levels of IL-1α, IL-1ß and IL-1Ra were quantified by enzyme-linked immunosorbent assay. RESULTS: IL-1Ra deficiency did not render mice more responsive to systemic exposure of MDP. Despite the increased production of IL-1R agonists IL-1α and IL-1ß in response to intraocular injection of MDP, deficiency in IL-1Ra did not predispose mice to MDP-triggered uveitis, albeit intravascular cell rolling and adherence were exacerbated. NOD2 expression was dispensable for the potential of IL-1 to elicit uveitis. However, we find that IL-1Ra does play an important protective role in arthritis induced locally by MDP injection in the joint. CONCLUSIONS: Our findings highlight the complexity of NOD2 activation and IL-1 signalling effects that can be compounded by local environmental factors of the target organ. These observations may impact how we understand the molecular mechanisms by which NOD2 influences inflammation of the eye versus joint, and consequently, treatment options for uveitis versus arthritis.

Use of the Diet History Questionnaire III to determine the impact of dysosmia on dietary quality.

BACKGROUND: Dysosmia could alter dietary quality through mechanisms including changes in appetite, food choice, and subsequent nutritional intake. However, there are few studies that directly assess olfactory performance and dietary quality. In this pilot study, we aimed to measure dietary quality in patients with dysosmia compared with controls with normosmia. METHODS: Community-dwelling adults prospectively underwent olfactory testing using the Sniffin' Sticks test from which composite threshold, discrimination, and identification (TDI) scores were used to identify patients with dysosmia (TDI <31) and controls with normosmia (TDI ≥31). Participants completed the Diet History Questionnaire III (DHQ III), a standardized and validated tool for nutritional assessment developed by the National Institutes of Health. The Healthy Eating Index (HEI) was calculated to determine compliance with the US Dietary Guidelines for Americans. RESULTS: Sixty patients were enrolled, including 29 patients with dysosmia and 31 controls with normosmia with no difference in age or sex among groups. A significant correlation between TDI score and HEI component score was seen for protein (r = 0.256; p = 0.048), dairy (r = 0.285; p = 0.027), and saturated fat (r = -0.262; p = 0.043) scores. Compared with controls with normosmia, patients with dysosmia were found to have less total protein and total dairy intake, as well as less total saturated fat intake. CONCLUSIONS: This study found significantly altered nutritional quality in patients with reduced olfactory function, including decreased intake of protein, dairy, and saturated fats. These findings are relevant given the high prevalence of dysosmia in the aging population and previous studies showing associations with mortality.

Endocrine mucin-producing sweat gland carcinoma: a systematic review and meta-analysis.

BACKGROUND: Endocrine mucin-producing sweat gland carcinoma is a rare, under-reported cutaneous adnexal tumor that is often misdiagnosed and has an unknown incidence of metastasis. OBJECTIVE: To determine the incidence of metastasis and tumor recurrence, as well as diagnostic accuracy and current trends in treatment modality. METHODS: A search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Tumor pathology and clinical data concerning demographics, presentation, diagnosis, treatment and follow-up were assessed. RESULTS: A total of 36 publications with 110 cases were identified. Initial pathological diagnosis was incorrect in 45.5% of cases. One case of metastatic disease was reported. The incidence of locoregional recurrence was 10.6% over a mean follow-up period of 21.3 months. Of cases with known methods of resection, 34.6% were resected by excisional biopsy, 42.8% were resected by wide surgical excision, and 31.3% were cleared by Mohs micrographic surgery. LIMITATIONS: The low reported incidence and level of evidence was suboptimal with only case reports and retrospective case studies being reported. CONCLUSION: Reported cases of this pathology demonstrate poor diagnostic accuracy. High rates of misdiagnosis and inadequate definitive treatment suggest the need for more comprehensive work-up and management of lesions suspicious for this pathology.

Treatment Outcomes of Bilateral Medialization Thyroplasty for Presbylaryngis.

BACKGROUND: Presbylaryngis is a common cause of dysphonia in elderly patients. Type I thyroplasty serves to improve glottic closure and vocal quality by correcting bowing. Although unilateral and injection-based procedures are well-characterized in the treatment of broadly defined glottic insufficiency, there are insufficient outcomes data for bilateral medialization thyroplasty in the treatment of presbylaryngis. The aim of this study was to review the change in measures of vocal quality before and after bilateral medialization thyroplasty for presbylaryngis. STUDY DESIGN: This is a retrospective case series. METHODS: The records of 21 patients with presbylaryngis undergoing bilateral medialization thyroplasty between 2007 and 2014 were reviewed. Implant materials included silastic (n = 17) and hydroxyapatite (n = 4). Preoperative and postoperative comparison of vocal function was conducted using Voice Handicap Index, maximum phonation time, auditory-perceptual severity ratings, and blinded paired-comparison of Consensus Auditory-Perceptual Evaluation of Voice and Visual-perceptual stroboscopic ratings. Paired sample t tests were used to assess all outcome measures. RESULTS: Significant improvements were found in Voice Handicap Index scores (P < 0.007), maximum phonation time (P < 0.03), Consensus Auditory-Perceptual Evaluation of Voice (P < 0.04), and clinician rating of vocal quality (P < 0.0001). Blinded raters noted a significant improvement in audio (P < 0.05) and videostroboscopic (P < 0.003) samples after surgery. There were no operative complications observed, and median hospital stay was one night. CONCLUSIONS: Patients with presbylaryngis demonstrated significant improvement in both objective and subjective measures of vocal quality following bilateral medialization thyroplasty. These data suggest that medialization thyroplasty is a safe option that warrants consideration in the treatment of presbylaryngis.

Endoscopic repair of spontaneous skull base defects decreases the incidence rate of intracranial complications.

BACKGROUND: Spontaneous skull base defects can result in life-threatening intracranial complications (ICCs), including meningitis and pneumocephalus. Endoscopic skull base reconstruction (ESBR) has traditionally been the treatment of choice, but its impact upon ICCs is not known. In this study, we aimed to describe the incidence rate of preoperative ICCs in patients with spontaneous skull base defects, risk factors associated with ICC development, and the impact of surgical repair on the incidence rate of ICCs. METHODS: A retrospective review was performed of all spontaneous skull base defects undergoing ESBR from 2005 to 2019 at 2 academic tertiary care medical centers. The incidence rate of ICCs and the demographics information and risk factors were collected. RESULTS: In 222 spontaneous skull base defects, preoperative ICCs occurred in 46 subjects (20.7%) with an incidence rate of 22.7 per 100 person-years. Factors significantly associated with preoperative ICCs included symptom duration, reduced body mass index (BMI), resolved cerebrospinal fluid rhinorrhea, and location in the frontal or lateral sphenoid sinuses. Endoscopic repair was successful in 97.2% of subjects and the postoperative ICC incidence rate was significantly reduced at 0.8 per 100 person-years (p < 0.001). CONCLUSION: Spontaneous skull base defects pose significant risk for life-threatening ICCs. Our findings reveal significantly elevated odds of ICC development associated with resolved CSF rhinorrhea, lower BMI, longer duration of symptoms, and defect location. Endoscopic repair is highly successful with low morbidity and significantly reduces the incidence rate of intracranial complications.

Bilateral vocal fold paralysis and dysphagia secondary to diffuse idiopathic skeletal hyperostosis.

BACKGROUND: Diffuse idiopathic skeletal hyperostosis (DISH) is an idiopathic spinal disease common in the elderly and characterized by flowing ossification and osteophyte formation along the spinal column. Cervical hyperostosis is capable of producing dysphagia, stridor, and airway obstruction; however, there are no extant reports of true paralysis of bilateral vocal folds in patients fulfilling the criteria for DISH. METHODS AND RESULTS: We report a case of a 61-year-old man presenting with dysphagia and dyspnea. Flexible laryngoscopy revealed bilateral true vocal fold paralysis. Cervical radiograph showed flowing ossification of the anterior longitudinal ligament with preservation of intervertebral disc height. Tracheotomy and cervical osteophytectomy were performed, after which the patient showed improved swallowing and speaking ability and was decannulated without complication. CONCLUSION: In the case presented, cervical osteophytectomy dramatically reversed bilateral vocal fold paralysis and dysphagia secondary to hyperostosis, thus negating the need for prolonged tracheostomy and feeding tube dependence. © 2016 Wiley Periodicals, Inc. Head Neck 39: E1-E3, 2017.

Secondary free-flap reconstruction following ablation for acute invasive fungal sinusitis.

OBJECTIVE: Acute invasive fungal sinusitis (AIFS) is a frequently fatal infection for which extensive and debilitating surgical debridement is a mainstay of therapy. Resulting defects are often composite in nature, mandating free tissue-transfer reconstruction. Outcomes data for free flap reconstruction are limited. The purpose of this study was to examine surgical outcomes and survival in patients undergoing free flap transfer following invasive fungal sinusitis. STUDY DESIGN: Retrospective case series. METHODS: Between 1995 and 2015, patients undergoing operative debridement for AIFS were identified. Surgical records were used to identify survivors of acute infection who subsequently underwent free flap reconstructive surgery. Patient demographics, cause of immune compromise, defect description, flap type, perioperative complications, indications for revision surgery, functional outcomes, and long-term survival were reviewed. RESULTS: Forty-four patients were treated for AIFS, of those, 30 (68%) survived acute infection. Ten patients underwent maxillectomy, six with orbital exenteration, and were designated candidates for reconstruction. Eight patients underwent reconstruction. Median time from debridement to reconstruction was 67.5 days. Flap types included latissimus dorsi, scapula, anterolateral thigh, rectus, radial forearm, and fibula. Median follow-up was 7.7 months. No perioperative complications were encountered, and all subjects remained disease-free, able to speak and eat normally without prosthetic supplementation. Seven patients (87%) are currently alive. CONCLUSION: Reconstruction of defects left by invasive fungal sinusitis using free-tissue transfer resulted in successful flap survival, with no disease recurrence for all defects and flap types reviewed. Survivors of AIFS are able to tolerate midface reconstruction, with favorable functional outcomes and survival rates. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:815-819, 2017.

High-grade malignant transformation of a radiation-naïve nasopharyngeal angiofibroma.

BACKGROUND: Nasopharyngeal angiofibromas are typically considered benign vascular neoplasms, with descriptions of high-grade sarcomatous change found only in lesions with prior radiotherapy. METHODS AND RESULTS: We describe the first reported case of high-grade malignant change in a nasopharyngeal angiofibroma naive to radiation. A 45-year-old man presented with left-sided nasal congestion and fullness and was found to have a left-sided nasopharyngeal mass with intracranial extension on CT scan. A biopsy of the mass revealed nasopharyngeal angiofibroma. The patient opted for MRI surveillance, which revealed interval growth 3 years later. Decompression surgery revealed only angiofibroma, but resection 9 months later demonstrated high-grade sarcoma and concomitant angiofibroma. The patient had residual disease which progressed through chemoradiation, and is now pursuing clinical trial enrollment. CONCLUSION: Malignant transformation of nasopharyngeal angiofibroma is extremely rare. As highlighted by this report, high-grade undifferentiated lesions may arise in tumors without previous radiation. © 2016 Wiley Periodicals, Inc. Head Neck 38: E2425-E2427, 2016.

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity.

The ototoxic aminoglycoside antibiotics are essential to treat severe bacterial infections, particularly in neonatal intensive care units. Using a bacterial lipopolysaccharide (LPS) experimental model of sepsis, we tested whether LPS-mediated inflammation potentiates cochlear uptake of aminoglycosides and permanent hearing loss in mice. Using confocal microscopy and enzyme-linked immunosorbent assays, we found that low-dose LPS (endotoxemia) greatly increased cochlear concentrations of aminoglycosides and resulted in vasodilation of cochlear capillaries without inducing paracellular flux across the blood-labyrinth barrier (BLB) or elevating serum concentrations of the drug. Additionally, endotoxemia increased expression of both serum and cochlear inflammatory markers. These LPS-induced changes, classically mediated by Toll-like receptor 4 (TLR4), were attenuated in TLR4-hyporesponsive mice. Multiday dosing with aminoglycosides during chronic endotoxemia induced greater hearing threshold shifts and sensory cell loss compared to mice without endotoxemia. Thus, endotoxemia-mediated inflammation enhanced aminoglycoside trafficking across the BLB and potentiated aminoglycoside-induced ototoxicity. These data indicate that patients with severe infections are at greater risk of aminoglycoside-induced hearing loss than previously recognized.

Investigation of the peptidoglycan sensing molecule, PGLYRP-2, in murine inflammatory uveitis.

BACKGROUND/AIM: Peptidoglycan (PGN) recognition proteins (PGLYRPs) are innate immune molecules that recognise bacterial cell wall PGN, and participate in several inflammatory diseases such as arthritis. We sought to elucidate the contribution of PGLYRPs in murine uveitis (intraocular inflammatory disease) elicited by PGN, and the extent to which systemically administered PGN alters uveitis compared with arthritis versus locally triggered ocular responses. METHODS: Mice deficient for PGLYRP-2, PGLYRP-3 or PGLYRP-4 were administered PGN by an intraperitoneal or intraocular injection. Arthritis was assessed by near-infrared imaging and histopathology, while uveitis was measured by intravital videomicroscopy and histopathology. RESULTS: Systemic PGN exposure predisposed to arthritis through a PGLYRP-2 dependent mechanism. By contrast, systemic PGN exposure did not predispose to uveitis, and PGLYRP-2 deficiency had no impact on the development the uveitis. When PGN was administered locally, a robust uveitis ensued, which occurred independently of PGLYRP-2. Regardless of whether PGN was administered systemically or locally, neither PGLYRP-3 nor PGLYRP-4 deficiency significantly altered ocular inflammation compared with wild-type control animals. CONCLUSIONS: Our findings highlight the complexity of PGLYRPs and how PGLYRP-2 may use different molecular pathways in the joints versus eyes. Collectively, our results support a non-essential or redundant role for PGLYRPs-2, -3, -4 in uveitis.

Investigation of the differential potentials of TLR agonists to elicit uveitis in mice.

TLRs are critical for host defense and innate immunity. Emerging evidence also supports a role for TLRs in many chronic inflammatory diseases, including inflammatory eye disease, known as uveitis. The activation of TLR4 by endotoxin induces a standard model of murine uveitis. How activation of additional TLRs influences the onset and/or severity of anterior uveitis has not been examined. We sought to elucidate the potential of TLRs (TLR1/2, TLR2/6, TLR3, TLR4, TLR5, TLR7/8, and TLR9) to trigger uveitis in mice. Directly stimulated iris/ciliary body explants demonstrated a marked increase in production of inflammatory cytokines TNF-α, IL-6, IP-10/CXCL10, MCP-1, and KC with relatively little production of IFN-γ, IL-10, IL-12p40, IL-12p70, IL-17, IL-1ß, IL-4, or RANTES. The cytokine-response profiles were comparable amongst the TLR agonists, albeit some differences were noted, such as greater IP-10 production following TLR3 activation. Intra-ocular injection of TLR agonists increased leukocyte interactions with the endothelium of the iris vasculature and resulted in chemotaxis into the iris tissue. Assessment of leukocytic responses by ivt videomicroscopy and histology revealed quantitative differences amongst responses to the TLR agonists with respect to the timing and numbers of rolling, adhering, iris-infiltrating, and aqueous humor-infiltrating cells, along with cytokine levels in vivo. Our data demonstrate the eye's responsiveness to a diverse array of microbial products, which activates TLRs, and reveal differences in relative cellular response among the various TLR agonists in vivo.