Identifying Treatments for Taste and Smell Disorders: Gaps and Opportunities.

The chemical senses of taste and smell play a vital role in conveying information about ourselves and our environment. Tastes and smells can warn against danger and also contribute to the daily enjoyment of food, friends and family, and our surroundings. Over 12% of the US population is estimated to experience taste and smell (chemosensory) dysfunction. Yet, despite this high prevalence, long-term, effective treatments for these disorders have been largely elusive. Clinical successes in other sensory systems, including hearing and vision, have led to new hope for developments in the treatment of chemosensory disorders. To accelerate cures, we convened the "Identifying Treatments for Taste and Smell Disorders" conference, bringing together basic and translational sensory scientists, health care professionals, and patients to identify gaps in our current understanding of chemosensory dysfunction and next steps in a broad-based research strategy. Their suggestions for high-yield next steps were focused in 3 areas: increasing awareness and research capacity (e.g., patient advocacy), developing and enhancing clinical measures of taste and smell, and supporting new avenues of research into cellular and therapeutic approaches (e.g., developing human chemosensory cell lines, stem cells, and gene therapy approaches). These long-term strategies led to specific suggestions for immediate research priorities that focus on expanding our understanding of specific responses of chemosensory cells and developing valuable assays to identify and document cell development, regeneration, and function. Addressing these high-priority areas should accelerate the development of novel and effective treatments for taste and smell disorders.

Nasal Structural and Aerodynamic Features That May Benefit Normal Olfactory Sensitivity.

Nasal airflow that effectively transports ambient odors to the olfactory receptors is important for human olfaction. Yet, the impact of nasal anatomical variations on airflow pattern and olfactory function is not fully understood. In this study, 22 healthy volunteers were recruited and underwent computed tomographic scans for computational simulations of nasal airflow patterns. Unilateral odor detection thresholds (ODT) to l-carvone, phenylethyl alcohol (PEA) and d-limonene were also obtained for all participants. Significant normative variations in both nasal anatomy and aerodynamics were found. The most prominent was the formation of an anterior dorsal airflow vortex in some but not all subjects, with the vortex size being significantly correlated with ODT of l-carvone (r = 0.31, P < 0.05). The formation of the vortex is likely the result of anterior nasal morphology, with the vortex size varying significantly with the nasal index (ratio of the width and height of external nose, r = -0.59, P < 0.001) and nasal vestibule "notch" index (r = 0.76, P < 0.001). The "notch" is a narrowing of the upper nasal vestibule cartilage region. The degree of the notch also significantly correlates with ODT for PEA (r = 0.32, P < 0.05) and l-carvone (r = 0.33, P < 0.05). ODT of d-limonene, a low mucosal soluble odor, does not correlate with any of the anatomical or aerodynamic variables. The current study revealed that nasal anatomy and aerodynamics might have a significant impact on normal olfactory sensitivity, with greater airflow vortex and a narrower vestibule region likely intensifying the airflow vortex toward the olfactory region and resulting in greater olfactory sensitivity to high mucosal soluble odors.

Endoscopic ultrasonic dacryocystorhinostomy for recurrent dacryocystitis following rhinoplasty.

UNLABELLED: The lacrimal sac is the structure most vulnerable to injury when performing rhinoplastic osteotomies. When performed in a low lateral position or along the frontal process of the frontal-maxillary suture, osteotomies can potentially tear the medial canthal tendon and injure the underlying lacrimal sac, possibly resulting in dacryocystitis. In this case report, the authors discuss a case of dacryocystitis following primary rhinoplasty; this injury was repaired with endoscopic dacryocystorhinostomy (DCR) using a Sonopet ultrasonic bone aspirator (Stryker, Kalamazoo, Michigan) at a single institution. This method achieved nasolacrimal duct patency, and the patient continued to be symptom-free at an 18-month follow-up. This is the first reported case of recurrent dacryocystitis following rhinoplasty as treated by endoscopic DCR. LEVEL OF EVIDENCE: 5.

Mcl-1 mediates intrinsic resistance to RAF inhibitors in mutant BRAF papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most frequent form of thyroid cancer. PTC commonly presents with mutations of the serine/threonine kinase BRAF (BRAFV600E), which drive ERK1/2 pathway activation to support growth and suppress apoptosis. PTC patients often undergo surgical resection; however, since the average age of PTC patients is under 50, adverse effects associated with prolonged maintenance therapy following total thyroidectomy are a concern. The development of mutant-selective BRAF inhibitors (BRAFi), like vemurafenib, has been efficacious in patients with metastatic melanoma, but the response rate is low for mutant BRAF PTC patients. Here, we assay the therapeutic response of BRAFi in a panel of human PTC cell lines and freshly biopsied patient samples. We observed heterogeneous responses to BRAFi, and multi-omic comparisons between susceptible and resistant mutant BRAF PTC revealed overrepresented stress response pathways and the absence of compensatory RTK activation - features that may underpin innate resistance. Importantly, resistant cell lines and patient samples had increased hallmarks of failed apoptosis; a cellular state defined by sublethal caspase activation and DNA damage. Further analysis suggests that the failed apoptotic phenotypes may have features of "minority mitochondrial outer membrane permeabilization (MOMP)" - a stress-related response characterized by fragmented and porous mitochondria known to contribute to cancer aggressiveness. We found that cells presenting with minority MOMP-like phenotypes are dependent on the apoptotic regulator, Mcl-1, as treatment with the Mcl-1 inhibitor, AZD5991, potently induced cell death in resistant cells. Furthermore, PI3K/AKT inhibitors sensitized resistant cells to BRAFi; an effect that was at least in part associated with reduced Mcl-1 levels. Together, these data implicate minority MOMP as a mechanism associated with intrinsic drug resistance and underscore the benefits of targeting Mcl-1 in mutant BRAF PTC.

The ultrasonic bone aspirator in transnasal endoscopic dacryocystorhinostomy.

PURPOSE: To evaluate the outcomes of endoscopic dacryocystorhinostomy (eDCR) with and without the use of ultrasonic bone aspirator (UBA; Sonopet). METHODS: A retrospective, institutional review board approved chart review of all eDCRs over 49 months. Data included demographics, indication/etiologic factors of nasolacrimal duct obstruction, comorbidities, intraoperative findings, epiphora symptoms pre- and postoperatively, and complications. Patients were grouped in eDCR with or without UBA. RESULTS: One hundred and twenty-three primary eDCRs in 99 patients were included, 59 with UBA and 64 without UBA. Most patients were Caucasians (80.8%) and women (72.0%), with a mean age of 55.9 years (range, 9-89). There were no significant differences in the demographics of the 2 subgroups. Complete resolution of symptoms was obtained in 81.3% of procedures without UBA and in 79.7% with UBA. Most patients (72.7%) were deemed idiopathic preoperatively. Lacrimal sac biopsy demonstrated significant pathologic factors in 9 (7.3%) cases, with 7 (5.7%) of these resulting in a new diagnosis for the patient. There were no cases of cerebrospinal fluid leakage, visual loss, diplopia, infection, or uncontrolled epistaxis in either group. CONCLUSIONS: Early results of eDCR with UBA appear to show reasonable efficacy. The overall success and failure rates of eDCR with and without UBA are similar. Neither group had any complications in this study, although any conclusion on the overall safety of the procedure is limited by the power of this study.

Air reflux and other sequelae following endoscopic dacryocystorhinostomy.

PURPOSE: To assess postoperative sequelae of endoscopic dacryocystorhinostomy (endoDCR), including rates of air reflux and other otolaryngologic sequelae. METHODS: Patients who underwent endoDCR over a 5-year period were included in a follow-up questionnaire regarding side effects after surgery. The questionnaire included questions regarding tearing, air reflux, and nasal symptoms. RESULTS: Results were obtained on 82 patients (101 endoDCRs). Most patients were women (70.7%) and white (85.4%). The mean postoperative period was 39.7 months (range 8-66 months). The most common sequela was air reflux from the puncta (46 cases, 45.5%). Of the 82 patients, 58.7% experienced symptoms only "rarely," while 18.5% had symptoms daily. Air reflux was most commonly associated with nose blowing (73.9%). Success of endoDCR correlated with presence of air reflux (p = 0.0044). All patients with air reflux preferred having air reflux to epiphora. Epistaxis was present in 8 cases (7.9%) and nasal congestion in 21.8% of the cases. CONCLUSIONS: Treatment for epiphora with endoDCR results in air reflux in almost half of patients, which is minimally bothersome to patients. The presence of air reflux highly correlates with resolution of epiphora and has a similar incidence in external and endoDCRs.

Orbital resection by intranasal technique (ORBIT): A new classification system for reporting endoscopically resectable primary benign orbital tumors.

BACKGROUND: The Cavernous Hemangioma Exclusively Endonasal Resection (CHEER) staging system has become the gold standard for outcomes reporting in endoscopic orbital surgery for orbital cavernous hemangiomas (OCHs). A recent systematic review demonstrated similar outcomes between OCHs and other primary benign orbital tumors (PBOTs). Therefore, we hypothesized that a simplified and more comprehensive classification system could be developed to predict surgical outcomes of other PBOTs. METHODS: Patient and tumor characteristics as well as surgical outcomes from 11 international centers were recorded. All tumors were retrospectively assigned an Orbital Resection by Intranasal Technique (ORBIT) class and stratified based on surgical approach as either exclusively endoscopic or combined (endoscopic and open). Outcomes based on approach were compared using chi-squared or Fisher's exact tests. The Cochrane-Armitage test for trend was used to analyze outcomes by class. RESULTS: Findings from 110 PBOTs from 110 patients (age 49.0 ± 15.0 years, 51.9% female) were included in the analysis. Higher ORBIT class was associated with a lower likelihood of gross total resection (GTR). GTR was more likely to be achieved when an exclusively endoscopic approach was utilized (p < 0.05). Tumors resected using a combined approach tended to be larger, to present with diplopia, and to have an immediate postoperative cranial nerve palsy (p < 0.05). CONCLUSION: Endoscopic treatment of PBOTs is an effective approach, with favorable short-term and long-term postoperative outcomes as well as low rate of adverse events. The ORBIT classification system is an anatomic-based framework that effectively facilitates high-quality outcomes reporting for all PBOTs.

Lizard bites of the head and neck.

BACKGROUND: As the ownership of lizards becomes more prevalent in the United States, injuries from these exotic pets will increase. Emergency and primary care physicians must be familiar with the proper management of lizard bites to the head and neck. OBJECTIVES: The aim of this case report is to discuss the potential complications and proper management of lizard bites to the head and neck. CASE REPORT: A 47-year-old man presented to the emergency department 3 h after his 5-foot iguana bit his face. The wounds were irrigated and primarily closed. Tetanus prophylaxis was administered. He was given oral amoxicillin/clavulanate potassium for 7 days. Sutures were removed 1 week after the repair. CONCLUSIONS: Topical antiseptic care, verification of tetanus status, primary wound closure, and careful monitoring of non-venomous lizard bites is recommended for lizard bites to the head and neck. Wounds at risk for infection should be treated with a quinolone or other antibiotics covering Salmonella as well as human skin flora. Venomous lizard (e.g., Gila monster and Mexican Beaded Lizard) bites require prompt attention due to potentially significant morbidities including anaphylaxis, disseminated intravascular coagulation, and acute myocardial infarction.

The minimally-invasive thyroidectomy incision: a histological analysis.

BACKGROUND: Minimally invasive thyroidectomy (MIT) has gained popularity in the surgical management of benign and malignant pathology of the thyroid. One of the main benefits of utilizing this technique is the use of smaller incisions resulting in increased cosmetic satisfaction. Unfortunately, the retraction required for adequate exposure during MIT may lead to skin damage, impaired wound healing and poor cosmetic outcomes. Some have proposed that excising incision edges prior to closure may improve cosmesis. A review of the literature does not reveal any histologic evidence to support this technique. MATERIAL/METHODS: In this prospective observational study, nine subjects undergoing MIT were identified. Both the superior and inferior skin edges were excised and labeled for orientation. Specimens were sent for hematoxylin and eosin staining and histologic analysis by a staff pathologist. RESULTS: All specimens showed no significant findings such as damage to the architecture of the dermis, acute inflammation, edema or evidence of hemorrhage. Focal blood vessel ectasia within the dermis was identified in three of nine subjects. CONCLUSIONS: Our findings do not yield a histological basis supporting the routine trimming of incisions during MIT. Although no significant findings were noted histologically, further studies are warranted to investigate the long-term cosmetic outcome of MIT incisions.

The T cells in peripheral taste tissue of healthy human adults: predominant memory T cells and Th-1 cells.

A healthy taste system is important to the maintenance of nutrition and overall quality of life, and taste disorders are associated with many inflammatory states. We previously determined the immune cells in normal human gustatory tissue; they are predominantly dendritic cells and CD4 T cells with a few macrophages and B lymphocytes present. There are, however, few reports of the subtypes of resident lymphocytes in or near taste tissues. The present study further characterized the distribution and population of the major subtypes of T cells in situ within biopsies of healthy human fungiform papillae (FP). Immunohistochemical analyses indicated that T-helper (Th)1 cells (CCR5+) were more predominant in FP than Th2 T cells (CCR4+). CD45RO+ memory T cells were the principal T cells in gustatory tissue, whereas CD45RA+ naive T cells were uncommon. Regarding subcompartments of the tissue, most intraepithelial lymphocytes of FPs were gamma/delta T cells, whereas the major subtype of lymphocytes in the lamina propria were alpha/beta T cells. Regulatory T cells that express CTLA-4 (CD152) and interleukin-2 receptors (IL-2R, CD25) were found at low levels in FP. The T cells stand ready to respond to inflammatory and infectious insults and may play a role in the taste alterations observed during acute and chronic inflammatory states.

Preoperative prevalence of methicillin-resistant Staphylococcus aureus (MRSA) colonization in patients undergoing intranasal surgery.

BACKGROUND: The goal of this study was to determine the rates of carriage of methicillin-resistant Staphylococcus aureus among patients undergoing intranasal surgery. MATERIAL/METHODS: One hundred and sixty five patients undergoing inpatient and outpatient rhinologic surgery over a six-month period were enrolled in the study. Patients completed a short questionnaire prior to surgery. Culture swabs of the anterior nares and nasal vestibule were sent to the microbiology lab for evaluation for methicillin-resistant Staphylococcus aureus. Cultures were grown on a MRSA-specific agar plate and were considered final after 48 hours of incubation. The primary endpoint was a positive MRSA culture. RESULTS: Of the one hundred fifty seven patients with nasal cultures taken, two had positive cultures for methicillin-resistant Staphylococcus aureus. Of those with positive cultures, both had a history of prior infection with methicillin-resistant Staphylococcus aureus. CONCLUSIONS: While antibiotic usage among the study group is far higher than the national average, the rates of nasal carriage of methicillin-resistant Staphylococcus aureus mirrors that described in other studies for the general population. The authors conclude that methicillin-resistant Staphylococcus aureus does not represent a significant source of infection among those undergoing intranasal surgery.

Management of auricular hematoma and the cauliflower ear.

Acute auricular hematoma is common after blunt trauma to the side of the head. A network of vessels provides a rich blood supply to the ear, and the ear cartilage receives its nutrients from the overlying perichondrium. Prompt management of hematoma includes drainage and prevention of reaccumulation. If left untreated, an auricular hematoma can result in complications such as perichondritis, infection, and necrosis. Cauliflower ear may result from long-standing loss of blood supply to the ear cartilage and formation of neocartilage from disrupted perichondrium. Management of cauliflower ear involves excision of deformed cartilage and reshaping of the auricle.

Nasal soft tissue trauma and management.

The nose is the most prominent of all facial structures and is susceptible to many types of trauma. All soft tissue injuries of the nose have the potential to distort its appearance and adversely affect the patient's self-image and self-esteem. Once life-threatening injuries are stabilized, a careful history and physical exam should be completed and treatment individualized. The ultimate objective of treatment is to achieve both functional and cosmetic restoration with timely diagnosis and repair. Immediate nasal reconstruction is ideal when medically possible because this decreases long-term sequelae.

Common herbal remedies, adverse reactions, and dermatologic effects.

Herbal remedies (phytomedicines) possess significant biological activity and pharmacologic efficacy. Consequently, they may manifest potential adverse effects and drug interactions. The expansion in sales of herbal remedies has brought products to the marketplace that do not always conform to the standards of safety and efficacy that physicians and patients have come to expect. Relatively few physicians inquire about herbal medicine use, and up to 70% of patients do not reveal their use of herbal medicines to their physicians and pharmacists. All physicians should question patients regarding their use of herbal remedies and document their responses in the medical record. Patients should be aware that potentially limited standardization and quality control, and somewhat circumscribed regulation, may result in variability in content, efficacy, and potential contamination of herbal remedies. Physicians in general, and specifically dermatologists, should be aware of potential adverse reactions related to the use of certain herbal remedies. Specific cautions exist with regard to dermatologic side effects such as contact dermatitis, blisters, urticaria, angioedema, ulceration, photosensitization, and changes in skin pigmentation.

"Sutureless" repair of orbital floor and rim fractures.

PURPOSE: To report on the surgical outcomes of patients undergoing orbital fracture repair without periosteal or conjunctival closure. DESIGN: Retrospective interventional case series. PARTICIPANTS: Eighty-two patients (85 eyes) who underwent transconjunctival repair of isolated floor (n = 38) or complex orbital fracture (n = 47) without conjunctival closure. METHODS: A transconjunctival incision below the tarsus provides preseptal access to the inferior orbital rim, after which the periosteum is incised for exploration and repair of orbital floor fractures. Forced ductions are performed after release of entrapped tissue and placement of an orbital floor implant, and the conjunctiva is reapproximated with forceps and draped into the inferior fornix. MAIN OUTCOME MEASURES: Incidence of postoperative complications, including orbital implant exposure, infection, and migration. RESULTS: Patients were followed for an average of 318 days postoperatively (range 82-978 days). One patient experienced a pyogenic granuloma at the conjunctival incision that resolved with steroid drops. Other complications included lateral canthal dystopia or pyogenic granuloma at the lateral canthotomy site, when used. There were no cases of postoperative implant exposure, infection, or migration. CONCLUSIONS: Forgoing closure of the periorbita and conjunctiva after transconjunctival orbital floor and rim fracture repair is associated with a low incidence of postoperative complications. This technique is applicable in the repair of both isolated floor fractures and complex orbital fractures. FINANCIAL DISCLOSURE(S): The authors have no proprietary or commercial interest in any material discussed in this article.

Smoking-associated squamous metaplasia in olfactory mucosa of patients with chronic rhinosinusitis.

Few studies have examined the induction of squamous metaplasia in human olfactory nasal tissue caused by tobacco use and the implications it may have for olfaction, particularly when there are pre-existing insults, such as chronic rhinosinusitis (CRS). Quantitative histopathological analyses were performed on Alcian blue- and H&E-stained sections of nasal biopsies taken from the upper aspect of the middle turbinate of CRS patients. Chronic rhinosinusitis patients who were current smokers had a predominance of squamous metaplasia in the olfactory sensory epithelium, whereas CRS patients who were nonsmokers and were not exposed to secondhand cigarette smoke had a prevalence of goblet cell hyperplasia. In spite of this difference, the groups did not differ significantly in olfactory threshold sensitivity. The impact of primary cigarette smoke on olfaction and a possible role of squamous metaplasia in preserving olfactory neurogenesis are discussed.

Ophthalmic injuries in patients with zygomaticomaxillary complex fractures requiring surgical repair.

PURPOSE: Injuries to the middle third of the face commonly destroy the integrity of the orbital skeleton, and are frequently complicated by injury to the eye, ranging between 2.7% and 90.6% in reported series. This article is a retrospecitve, descriptive case study assessing the spectrum and incidence of ophthalmic involvement in patients presenting with zygomaticomaxillary complex (ZMC) fractures. PATIENTS AND METHODS: Ninety-six patients with ZMC fractures who were surgically treated in 1 academic institution between 1996 and 2006 were assessed pre- and postoperatively by the same oculoplastic surgeon and were included in the study. All patients had a thorough ophthalmologic examination that included assessment of visual acuity, pupillary reactivity, anterior and posterior segment examination, and extraocular motility. In cases of optic neuropathy, automated perimetry was also performed. The variables reviewed included patients' age, gender, mechanism of injury, visual acuity, pupillary reactivity, extraocular motility, presence or absence of diplopia, ocular and orbital findings, and intraorbital hypoesthesia. RESULTS: Gender distribution of the patients was 88% male, with a mean age of 36 years. The most common etiology of trauma was assult (56%), followed by falls (21%). Most patients (66.6%) sustained minor ocular injuries such as subconjuctival hemorrhage, iris sphincter tear, and corneal abrasion. Subconjunctival hemorrhage was the most common minor injury, accounting for 55% of the cases. Major injuries such as ruptured globe and retinal hemorrhage occurred in 10% of the patients. Orbital findings such as restriction of extraocular movement occurred in 15% of cases. Symptomatic diplopia was noted in 16% of the patients and traumatic optic neuropathy occurred in 6%. Diplopia significantly improved in the first 3 postoperative months, dropping from a preoperative incidence of 16% to 2%. CONCLUSION: Comminuted ZMC fractures had been reported to be associated with a signficantly higher incidence of visual sequelae than other forms of midfacial injury. A 10% incidence of major or blinding injuries and a 6% incidence of traumatic optic neuropathy are significant, and warrants a prompt ophthalmologic examination of all patients with ZMC fractures as quickly as possible, and always preoperatively in injuries necessitating surgical repair.

Thyroid lymphosonography: a novel method for evaluating lymphatic drainage.

OBJECTIVES: We evaluated lymphosonography, or contrast-enhanced, ultrasonography (US)-guided sentinel lymph node (SLN) detection, as a technique for demonstrating the lymphatic drainage of the thyroid gland. METHODS: In this prospective animal study, four 50-kg Yorkshire swine underwent transcutaneous injection of a US contrast agent and methylene blue dye into the thyroid gland. Contrast-enhanced US was used to identify draining lymphatic channels and SLNs. Sentinel node biopsy was conducted. Subsequently, bilateral neck and upper mediastinal dissection was carried out. RESULTS: In 3 of 4 cases, a blue dye-positive and US contrast-positive SLN was identified. We identified SLNs in level IV in 2 cases. One case revealed 2 adjacent nodes in the superior mediastinum. In 1 case, a lymphatic channel was identified traveling into the mediastinum, but exposure of the SLN could not be obtained. No residual blue dye-positive or US contrast-positive nodes were identified on subsequent dissection. CONCLUSIONS: Lymphosonography of the thyroid gland in a porcine model correlates well with blue dye-guided sentinel node biopsy and is technically feasible, although in some cases access to the SLN may be difficult. This technique could potentially enable a detailed analysis of thyroidal lymphatic drainage if applied to humans.