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Objective: To quantify discrepancies in the diagnosis of olfactory function that might exist when comparing results obtained from centers using different methods of olfactory testing.Study Design: Prospective study of 50 healthy adult volunteers and 25 adult patients with olfactory complaints.Methods: Two test methods, the Connecticut Chemosensory Clinical Research Center (CCCRC) test widely used in the United States, and the Jet Stream Olfactometer (JSO) test used in Japan, were used to measure and categorize the diagnostic level of olfactory function (normosmia, mild hyposmia, moderate hyposmia, severe hyposmia, anosmia). Olfactory function was measured separately for each nostril.Results: There was a significant correlation (rs = 0.788, P < .01, n = 150 nostrils) between diagnostic categories assigned by the CCCRC and JSO test methods. Diagnostic categories were identical for 66.7% of the nostrils tested, and in only 7.3% of the cases did the results differ by more than one category. For the anosmic and normosmic categories, test results were in agreement 91.7% of the time, whereas for the hyposmic categories (mild, moderate, and severe) results were in agreement only 22.2% of the time.Conclusions: Our results demonstrate that when comparing clinical or research data obtained from centers using different olfactory test methods, subjects with diagnoses of anosmia or normosmia may be more reliably compared than those with different levels of hyposmia. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to review findings from a large prospective national database of chemosensory disturbances associated with coronavirus disease 2019 (COVID-19) infection., Data Sources: The Virginia Commonwealth University Smell and Taste Center national database of COVID-19 chemosensory disturbances., Methods: A series of online surveys, first opened on April 10, 2020, was made accessible nationwide to any adult with sudden chemosensory dysfunction since January 2020. Participants received subsequent follow-up surveys 14 days, 1 month, 3 months, and 6 months after enrollment. An additional survey was sent to all participants on May 28, 2022 to assess long-term outcomes. Information pertaining to demographics, symptoms, comorbidities, treatments, and life impact was collected., Results: Of 363 participants who reported complete smell recovery, 51.2% recovered within 1 month, 70% within 3 months, and 79% within 6 months, while 8.8% took over 1 year to completely recover. Among all participants, 7.5% had no smell recovery. Positive predictors of recovery included age <40, male gender, and the presence of nasal congestion. Negative predictors included difficulty breathing and prior head injury. Many participants reported a decrease in quality of life and the presence of potential safety hazards associated with decreased smell loss., Conclusions: Most subjects with COVID-19-related chemosensory dysfunction recover, with the majority noting complete recovery within weeks of infection. Those aged over 40 years and female gender were associated with lower rates of recovery. A considerable number of participants reported significant impact on quality of life and safety., Competing Interests: The authors declare no conflict of interest., (© 2024 The Authors. World Journal of Otorhinolaryngology ‐ Head and Neck Surgery published by John Wiley & Sons Ltd on behalf of Chinese Medical Association.)

Chemosensory losses have long been considered a cardinal symptom of COVID-19 infection. Recent studies have shown changing symptom profiles with COVID-19, including decreasing incidence of olfactory losses. We accessed the National COVID Cohort Collaborative database to identify patients with and without smell and taste loss within 2 weeks of COVID-19 diagnosis. Peak prevalence time intervals for variants were determined from Covariants.org. Using rates of chemosensory loss during the peak time interval for "Untyped" variants as baseline (4/27/2020-6/18/2020), odds ratios for COVID-19-associated smell or taste disturbance fell for each of the Alpha (0.744), Delta (0.637), Omicron K (0.139), Omicron L (0.079), Omicron C (0.061), and Omicron B (0.070) peak intervals. These data suggest that during the recent Omicron waves and potentially moving forward, the presence or absence of smell and taste disturbances may no longer have predictive value in the diagnosis of COVID-19 infection., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Anecdotal clinical observation suggests that rates of chemosensory dysfunction associated with COVID-19 infection may be decreasing. To investigate, the National COVID Cohort Collaborative database was queried for all patients with and without smell and taste loss within 2 weeks of COVID-19 diagnosis. Six-week periods of peak variant prevalence were selected by using CoVariants.org for analysis. Of 3,678,214 patients with COVID-19 in the database, 616,318 met inclusion criteria during the time intervals of interest, with 3431 having an associated smell or taste disturbance diagnosis. With the initial/untyped variant set as the baseline, the odds ratios for alpha, delta, and omicron (December 27, 2021-February 7, 2022) were 0.50 (95% CI, 0.45-0.55; P < .0001), 0.44 (95% CI, 0.41-0.48; P < .0001), and 0.17 (95% CI, 0.15-0.18; P < .0001), respectively. These data strongly support the clinical observation that patients infected with more recent variants are at a significantly lower risk of developing associated chemosensory loss., (© 2022 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Objective: To report long-term patterns of recovery and non-recovery in a large nationwide cohort of subjects with COVID-19 associated smell loss., Study Design: Prospectively, longitudinal questionnaires., Setting: Web-based national survey., Methods: A longitudinal survey of adults with COVID-19 and/or sudden change in smell or taste since January 1, 2020 was launched April 10, 2020. Participants were queried again in late May 2022 regarding recovery. Data from respondents with >2 years since loss were analyzed and compared to recovery status of those more recently effected., Results: 1103 responded to the survey of whom 946 met inclusion criteria. Among the 267 respondents for whom at least 2 years of follow up was available, 38.2 % reported full recovery, 54.3 % partial, and 7.5 % no recovery. For the entire cohort (all with ≥3 months since smell loss), 38.7 % reported complete recovery, 51.0 % reported partial recovery (ranging from mild complaints to severe phantosmia or dysosmia), and 10.3 % reported no improvement at all. Complete recovery of smell function was significantly higher in those under 40 years old (45.6 % compared to 32.9 % in those over 40)., Conclusion: Although the vast majority of subjects who do recover do so within the first 3 months, long-term spontaneous recovery can occur. Rates of recovery do not seem to differ depending on when during the pandemic the loss first occurred., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The literature regarding clinical olfaction, olfactory loss, and olfactory dysfunction has expanded rapidly over the past two decades, with an exponential rise in the past year. There is substantial variability in the quality of this literature and a need to consolidate and critically review the evidence. It is with that aim that we have gathered experts from around the world to produce this International Consensus on Allergy and Rhinology: Olfaction (ICAR:O)., Methods: Using previously described methodology, specific topics were developed relating to olfaction. Each topic was assigned a literature review, evidence-based review, or evidence-based review with recommendations format as dictated by available evidence and scope within the ICAR:O document. Following iterative reviews of each topic, the ICAR:O document was integrated and reviewed by all authors for final consensus., Results: The ICAR:O document reviews nearly 100 separate topics within the realm of olfaction, including diagnosis, epidemiology, disease burden, diagnosis, testing, etiology, treatment, and associated pathologies., Conclusion: This critical review of the existing clinical olfaction literature provides much needed insight and clarity into the evaluation, diagnosis, and treatment of patients with olfactory dysfunction, while also clearly delineating gaps in our knowledge and evidence base that we should investigate further., (© 2022 ARS-AAOA, LLC.)

Objective: To determine which factors (demographic, symptoms, comorbidities, and treatments) are associated with recovery of smell in patients with COVID-19 associated olfactory loss., Study Design: Prospective, longitudinal questionnaires., Setting: National survey., Methods: A longitudinal web-based nationwide survey of adults with COVID-19 associated smell and taste loss was launched April 10, 2020. After completing an initial entry survey, participants received detailed follow-up questionnaires 14 days, and 1, 3 and 6 months later., Results: As of June 25, 2021, 798 participants met study inclusion criteria and completed 6-month questionnaires. Of demographic characteristics only age <40 years was positively associated with smell recovery (p < .003). Of symptoms, difficulty breathing was negatively associated with smell recovery (p < .004), and nasal congestion positively associated with smell recovery (p < .03). Of pre-existing comorbidities only previous head injury (p < .017) was negatively associated with smell recovery. None of the queried medications used to treat COVID were associated with better rates of smell recovery., Conclusions: Age <40 and presence of nasal congestion at time of COVID-19 infection were predictive of improved rates of smell recovery, while difficulty breathing at time of COVID-19 infection, and prior head trauma predicted worsened rates of recovery. Further study will be required to identify potential mechanisms for the other observed associations. Such information can be used by clinicians to counsel patients suffering COVID-19 associated smell loss as to prognosis for recovery., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: The association between COVID-19 and chemosensory loss has garnered substantial attention, however to date little is known about the real-life consequences of impairment in this unique patient population. The aim of this study is to evaluate the quality of life (QOL) and personal safety deficits experienced by patients with COVID-19 infection., Study Design: Prospective, longitudinal questionnaires., Setting: National survey., Methods: A longitudinal web-based nationwide survey of adults with COVID-19 and/or a sudden change in smell and taste was launched April 10, 2020. Previously published questions on chemosensory-related QOL and safety events were asked at the 6-month follow-up survey., Results: As of February 10, 2021, 480 eligible respondents took the 6-month questionnaire, of whom 322 were COVID-19 positive. Impact on QOL was substantial with 96% of subjects reporting at least one of the defined deficits, and over 75% reporting at least 3 of these. "Reduced enjoyment of food" was the most common complaint (87%), while 43% of subjects self-reported depression. The prevalence of safety-related issues was common in this population, with over 57% reporting at least one, and 36% reporting 2 or more events. Of the events asked, the inability to smell smoke that others could perceive was the most common at 45%., Conclusions: COVID-19 associated chemosensory losses have a real and substantial impact on both quality of life and safety, beyond mere inconvenience. The high prevalence of these issues despite a relatively short period of olfactory deficit should alert clinicians to the serious risks to an already vulnerable patient population., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Spag6 encodes an axoneme central apparatus protein that is required for normal flagellar and cilia motility. Recent findings suggest that Spag6 also plays a role in ciliogenesis, orientation of cilia basal feet, and planar polarity. Sensory cells of the inner ear display unique structural features that underlie their mechanosensitivity. They represent a distinctive form of cellular polarity, known as planar cell polarity (PCP). However, a role for Spag6 in the inner ear has not yet been explored. In the present study, the function of Spag6 in the inner ear was examined using Spag6 -deficient mice. Our results demonstrate hearing loss in the Spag6 mutants, associated with abnormalities in cellular patterning, cell shape, stereocilia bundles, and basal bodies, as well as abnormally distributed Frizzled class receptor 6 (FZD6), suggesting that Spag6 participates in PCP regulation. Moreover, we found that the subapical microtubule meshwork was disrupted. Our observations suggest new functions for Spag6 in hearing and PCP in the inner ear.

Since the COVID-19 pandemic began, many individuals have reported acute loss of smell and taste. In order to better characterize all patients with these symptoms, a longitudinal national survey was created. Since April 10, 2020, 549 completed the initial survey, with 295 completing 14-day, and 202 completing 1-month follow up surveys. At 1-month follow-up, 71.8% reported a return to "very good" or "good" smell, and 84.2% reported a return to "very good" or "good" taste. Chemosensory changes are a cardinal sign of COVID-19. Fortunately, our data, representing a large longitudinal study of patients experiencing smell and taste losses during the COVID-19 pandemic, indicates that the majority appear to recover within a month., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Since the COVID-19 pandemic began, many individuals have noted acute loss of smell and/or taste, although not all patients with these symptoms are tested for COVID-19. To better characterize all patients with these rare symptoms, a national survey was created. Over 13 days in April 2020, a total of 220 people completed the survey in its entirety, representing a wide geographic distribution across the United States. Of the 220 respondents, 93 (42%) were diagnosed with COVID-19, and 127 (58%) were not. A total of 37.7% of respondents reported changes in smell/taste as the initial or sole presentation of their condition. Most but not all patients had other symptoms suggestive of COVID-19 at the time of chemosensory loss. Despite its inclusion as a major symptom of COVID-19 by the CDC (Centers for Disease Control and Prevention), respondents with additional CDC-defined symptoms associated with COVID-19 were statistically more likely to be tested/diagnosed than those without.

Background: Taste complaints are commonly encountered in clinical practice. Although changes in taste function may arise from varied etiologies, numerous other factors may impact patients' taste perceptions, the most common of which is olfactory dysfunction. Thus, patients with taste complaints may or may not have measurable deficits in taste function. This poses a challenge to providers faced with evaluation of patients with taste disorders, and may delay diagnosis and management., Methods: We retrospectively examined records of 1108 patients evaluated at the Virginia Commonwealth University Health System Smell and Taste Clinic and compared patients' subjective taste complaints with results of objective testing of the senses of taste and smell., Results: A total of 358 patients had a subjective taste complaint and results from both gustatory and olfactory function tests. Patients were grouped by subjective complaint as "taste only" (n = 63) or "taste and smell" (n = 295). Of patients reporting a "taste-only" complaint, 25.4% had abnormal gustatory function, whereas 44.4% had abnormal olfactory function. For those reporting taste-and-smell complaints, only 9.5% had abnormal gustatory function, whereas 86.8% had abnormal olfactory function., Conclusion: This study supports the hypothesis that patients who present with a taste complaint are more likely to have an underlying olfactory than gustatory impairment. However, those with a taste-only complaint are more likely to have objective gustatory deficits than those with a taste-and-smell complaint. These findings may prove useful to healthcare providers who evaluate patients presenting with complaints of taste loss., (© 2018 ARS-AAOA, LLC.)

Objective: All successful endonasal surgery, including functional endoscopic sinus surgery (FESS), depends on knowledge of both anatomy and the specific variations that can occur between and within patients. Familiarity with these structures is a critical component in preventing complications from these procedures, and failure to understand subtle variation can have disastrous results. The aim of this study was to characterize the anatomical variations (if any) of the cribriform plate using a large cadaveric sample set. Better understanding of the disparities within and between patients may have important implications for surgical planning., Methods: Whole human skull specimens (31 specimens, 62 sides) were examined to obtain dimensional measurements of the cribriform plate on the right and left sides., Results: The average length of the cribriform plate was 21.28mm (range 15.25-27.73mm, SD 3.30mm). The average width of the cribriform plate (including the crista galli) was 4.53mm (range 1.75-8.03mm, SD 1.20mm). When comparing side differences in individual specimens, there was more variability between widths, relative standard deviation 26.4%, than between lengths, relative standard deviation 15.5%., Conclusion: There is a range of both length and width of the cribriform plate, between and within individuals. This is particularly true for width. In practice, this emphasizes the importance of pre-operative imaging and recognition of anatomic variability for sinus or anterior skull base procedure., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Recent wearable devices offer portable monitoring of biopotentials, heart rate, or physical activity, allowing for active management of human health and wellness. Such systems can be inserted in the oral cavity for measuring food intake in regard to controlling eating behavior, directly related to diseases such as hypertension, diabetes, and obesity. However, existing devices using plastic circuit boards and rigid sensors are not ideal for oral insertion. A user-comfortable system for the oral cavity requires an ultrathin, low-profile, and soft electronic platform along with miniaturized sensors. Here, we introduce a stretchable hybrid electronic system that has an exceptionally small form factor, enabling a long-range wireless monitoring of sodium intake. Computational study of flexible mechanics and soft materials provides fundamental aspects of key design factors for a tissue-friendly configuration, incorporating a stretchable circuit and sensor. Analytical calculation and experimental study enables reliable wireless circuitry that accommodates dynamic mechanical stress. Systematic in vitro modeling characterizes the functionality of a sodium sensor in the electronics. In vivo demonstration with human subjects captures the device feasibility for real-time quantification of sodium intake, which can be used to manage hypertension., Competing Interests: Conflict of interest statement: R.M.C. and W.-H.Y. are inventors on Patent Application US 2017/0087363A1 that covers “Wireless implantable taste system.” The other authors declare that they have no competing financial interests.

Background: The aim of this study was to demonstrate how direct electrical stimulation can activate the olfactory bulb after denervation of the olfactory nerve input., Methods: Sprague-Dawley rats (n = 5) were anesthetized and olfactory bulbs exposed. Olfactory nerves were transected by passing a Teflon blade between the cribriform plate and ventral surface of the bulb. A cochlear implant electrode array was used to stimulate 6 different positions along the ventral surface of the olfactory bulb. Biphasic constant-current pulses were used (50-1000 μA, 50-1000 μs) to stimulate the bulb, and a 16-electrode paddle array was used to record localized negative field potential responses at the dorsal surface of the bulb., Results: Localized negative field potentials were reliably obtained using biphasic, 500-μA, 200-μs pulses. A shift in stimulating position by 1 mm resulted in a significant change in the dorsal field potential., Conclusion: Direct stimulation of the deafferented olfactory bulb was effective in generating localized field potential responses. These findings support the potential use of direct electrical stimulation for the treatment of anosmia., (© 2018 ARS-AAOA, LLC.)

Olfactory impairment is a well-established sequela of head injury. The presence and degree of olfactory dysfunction is dependent on severity of head trauma, duration of posttraumatic amnesia, injuries obtained, and as more recently established, age. Deficits in smell can be conductive or neurosensory, contingent on location of injury. The former may be amenable to medical or surgical treatment, whereas the majority of patients with neurosensory deficits will not recover. Many patients will not seek treatment for such deficits until days, weeks, or even months after the traumatic event due to focus on more pressing injuries. Evaluation should start with a comprehensive history and physical exam. Determination of the site of injury can be aided by CT and MRI scanning. Verification of the presence of olfactory deficit, and assessment of its severity requires objective olfactory testing, which can be accomplished with a number of methods. The prognosis of posttraumatic olfactory dysfunction is unfortunate, with approximately only one third improving. Emphasis must be placed on identification of reversible causes, such as nasal bone fractures, septal deviation, or mucosal edema/hematoma. Olfactory loss is often discounted as an annoyance, rather than a major health concern by both patients and many healthcare providers. Patients with olfactory impairment have diminished quality of life, decreased satisfaction with life, and increased risk for personal injury. Paramount to the management of these patients is counseling with regard to adoption of compensatory strategies to avoid safety risks and maximize quality of life. Practicing otolaryngologists should have a thorough understanding of the mechanisms of traumatic olfactory dysfunction in order to effectively diagnose, manage, and counsel affected patients.

Background: Olfactory dysfunction is an increasingly recognised condition, associated with reduced quality of life and major health outcomes such as neurodegeneration and death. However, translational research in this field is limited by heterogeneity in methodological approach, including definitions of impairment, improvement and appropriate assessment techniques. Accordingly, effective treatments for smell loss are limited. In an effort to encourage high quality and comparable work in this field, among others, we propose the following ideas and recommendations. Whilst the full set of recommendations are outlined in the main document, points include the following: • Patients with suspected olfactory loss should undergo a full examination of the head and neck, including rigid nasal endoscopy with small diameter endoscopes. • Subjective olfactory assessment should not be undertaken in isolation, given its poor reliability. • Psychophysical assessment tools used in clinical and research settings should include reliable and validated tests of odour threshold, and/or one of odour identification or discrimination. • Comprehensive chemosensory assessment should include gustatory screening. • Smell training can be helpful in patients with olfactory loss of several aetiologies., Conclusions: We hope the current manuscript will encourage clinicians and researchers to adopt a common language, and in so doing, increase the methodological quality, consistency and generalisability of work in this field.

Objectives: To directly measure the spatial mapping in the olfactory bulb by odor presentation and by direct electrical stimulation., Study Design: Experimental (animal)., Setting: University research laboratory., Subjects and Methods: Odor (n = 8) and electrical stimulation (n = 4) of the olfactory bulb in rats were used to demonstrate the spatial mapping of neural responses in the olfactory bulb. Both multiunit responses to odor stimulation and evoked potential responses to localized electrical stimulation were measured in different regions of the olfactory bulb., Results: Responses that were recorded simultaneously from an array of 32 electrodes positioned at different locations within the olfactory bulb were mapped. Results show different spatial patterns of neural activity for different odors (odor maps). Direct stimulation of the olfactory bulb with electrical current pulses from electrodes positioned at different locations was also effective in generating spatial patterns of neural activity., Conclusion: These data suggest that by programming an array of stimulating electrodes, it should be possible to selectively activate different regions of the olfactory bulb, generating unique patterns of neural activity as seen in normal smell., (© American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.)

Impairment of smell may occur following injury to any portion of the olfactory tract, from nasal cavity to brain. A thorough understanding of the anatomy and pathophysiology combined with comprehensively obtained history, physical exam, olfactory testing, and neuroimaging may help to identify the mechanism of dysfunction and suggest possible treatments. Although most olfactory deficits are neuronal mediated and therefore currently unable to be corrected, promising technology may provide novel treatment options for those most affected. Until that day, patient counseling with compensatory strategies and reassurance is essential for the maintenance of safety and QoL in this unique and challenging patient population., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Height is the result of many growth and development processes. Most of the genes associated with height are known to play a role in skeletal development. Single-nucleotide polymorphisms in the SPAG17 gene have been associated with human height. However, it is not clear how this gene influences linear growth. Here we show that a targeted mutation in Spag17 leads to skeletal malformations. Hind limb length in mutants was significantly shorter than in wild-type mice. Studies revealed differences in maturation of femur and tibia suggesting alterations in limb patterning. Morphometric studies showed increased bone formation evidenced by increased trabecular bone area and the ratio of bone area to total area, leading to reductions in the ratio of marrow area/total area in the femur. Micro-CTs and von Kossa staining demonstrated increased mineral in the femur. Moreover, osteocalcin and osterix were more highly expressed in mutant mice than in wild-type mice femurs. These data suggest that femur bone shortening may be due to premature ossification. On the other hand, tibias appear to be shorter due to a delay in cartilage and bone development. Morphometric studies showed reduction in growth plate and bone formation. These defects did not affect bone mineralization, although the volume of primary bone and levels of osteocalcin and osterix were higher. Other skeletal malformations were observed including fused sternebrae, reduced mineralization in the skull, medial and metacarpal phalanges. Primary cilia from chondrocytes, osteoblasts, and embryonic fibroblasts (MEFs) isolated from knockout mice were shorter and fewer cells had primary cilia in comparison to cells from wild-type mice. In addition, Spag17 knockdown in wild-type MEFs by Spag17 siRNA duplex reproduced the shorter primary cilia phenotype. Our findings disclosed unexpected functions for Spag17 in the regulation of skeletal growth and mineralization, perhaps because of its role in primary cilia of chondrocytes and osteoblasts.

Background: Oxyntomodulin (OXM1-37) is an anorectic gut-secreting peptide with a promise to treat obesity, but its needle-free delivery has yet to be successful., Results: Pulmonary delivery of OXM1-37, but not its C-terminal octapeptides, caused dose-related, transient 4-6 h food intake suppression in rats. At 0.5 mg/kg, its 30-38% food intake suppression led to 46% reduction in body weight gain by day 8. Its lung absorption was fast, elevating the systemic level rapidly, yet the bioavailability was low at 13%. In the brain, twofold neuronal c-fos activation was seen in the hypothalamus arcuate nucleus and brainstem area postrema., Conclusion: Pulmonary delivery is a promising needle-free systemic delivery option for OXM1-37 to treat obesity, as enabling effective lung absorption and brain interaction.

SPAG6, an axoneme central apparatus protein, is essential for function of ependymal cell cilia and sperm flagella. A significant number of Spag6-deficient mice die with hydrocephalus, and surviving males are sterile because of sperm motility defects. In further exploring the ciliary dysfunction in Spag6-null mice, we discovered that cilia beat frequency was significantly reduced in tracheal epithelial cells, and that the beat was not synchronized. There was also a significant reduction in cilia density in both brain ependymal and trachea epithelial cells, and cilia arrays were disorganized. The orientation of basal feet, which determines the direction of axoneme orientation, was apparently random in Spag6-deficient mice, and there were reduced numbers of basal feet, consistent with reduced cilia density. The polarized epithelial cell morphology and distribution of intracellular mucin, α-tubulin, and the planar cell polarity protein, Vangl2, were lost in Spag6-deficient tracheal epithelial cells. Polarized epithelial cell morphology and polarized distribution of α-tubulin in tracheal epithelial cells was observed in one-week old wild-type mice, but not in the Spag6-deficient mice of the same age. Thus, the cilia and polarity defects appear prior to 7 days post-partum. These findings suggest that SPAG6 not only regulates cilia/flagellar motility, but that in its absence, ciliogenesis, axoneme orientation, and tracheal epithelial cell polarity are altered.

Importance: Normal olfaction provides essential cues to allow early detection and avoidance of potentially hazardous situations. Thus, patients with impaired olfaction may be at increased risk of experiencing certain hazardous events such as cooking or house fires, delayed detection of gas leaks, and exposure to or ingestion of toxic substances., Objective: To identify risk factors and potential trends over time in olfactory-related hazardous events in patients with impaired olfactory function., Design, Setting, and Participants: Retrospective cohort study of 1047 patients presenting to a university smell and taste clinic between 1983 and 2013. A total of 704 patients had both clinical olfactory testing and a hazard interview and were studied. On the basis of olfactory function testing results, patients were categorized as normosmic (n = 161), mildly hyposmic (n = 99), moderately hyposmic (n = 93), severely hyposmic (n = 142), and anosmic (n = 209)., Interventions: Patient evaluation including interview, examination, and olfactory testing., Main Outcomes and Measures: Incidence of specific olfaction-related hazardous events (ie, burning pots and/or pans, starting a fire while cooking, inability to detect gas leaks, inability to detect smoke, and ingestion of toxic substances or spoiled foods) by degree of olfactory impairment., Results: The incidence of having experienced any hazardous event progressively increased with degree of impairment: normosmic (18.0%), mildly hyposmic (22.2%), moderately hyposmic (31.2%), severely hyposmic (32.4%), and anosmic (39.2%). Over 3 decades there was no significant change in the overall incidence of hazardous events. Analysis of demographic data (age, sex, race, smoking status, and etiology) revealed significant differences in the incidence of hazardous events based on age (among 397 patients <65 years, 148 [37.3%] with hazardous event, vs 31 of 146 patients ≥65 years [21.3%]; P < .001), sex (among 278 women, 106 [38.1%] with hazardous event, vs 73 of 265 men [27.6%]; P = .009), and race (among 98 African Americans, 41 [41.8%] with hazardous event, vs 134 of 434 whites [30.9%]; P = .04)., Conclusions and Relevance: Increased level of olfactory impairment portends an increased risk of experiencing a hazardous event. Risk is further impacted by individuals' age, sex, and race. These results may assist health care practitioners in counseling patients on the risks associated with olfactory impairment.

Objectives: There is substantial variation in the classification and management of scapula fractures. The first purpose of this study was to analyze the interobserver reliability of the OTA/AO classification and the New International Classification for Scapula Fractures. The second purpose was to assess the proportion of agreement among orthopaedic surgeons on operative or nonoperative treatment., Design: Web-based reliability study., Setting: Independent orthopaedic surgeons from several countries were invited to classify scapular fractures in an online survey., Participants: One hundred three orthopaedic surgeons evaluated 35 movies of three-dimensional computerized tomography reconstruction of selected scapular fractures, representing a full spectrum of fracture patterns., Main Outcome Measurements: Fleiss kappa (κ) was used to assess the reliability of agreement between the surgeons., Results: The overall agreement on the OTA/AO classification was moderate for the types (A, B, and C, κ = 0.54) with a 71% proportion of rater agreement (PA) and for the 9 groups (A1 to C3, κ = 0.47) with a 57% PA. For the New International Classification, the agreement about the intraarticular extension of the fracture (Fossa (F), κ = 0.79) was substantial and the agreement about a fractured body (Body (B), κ = 0.57) or process was moderate (Process (P), κ = 0.53); however, PAs were more than 81%. The agreement on the treatment recommendation was moderate (κ = 0.57) with a 73% PA., Conclusions: The New International Classification was more reliable. Body and process fractures generated more disagreement than intraarticular fractures and need further clear definitions.

Extraskeletal osteosarcoma (ESOS) is a malignant mesenchymal tumor in which neoplastic cells produce bone osteoid in variable amounts. An 81-year-old woman presented with severe abdominal pain, tenesmus, constipation and rectal bleeding. The digital rectal exploration showed a large lesion of hard consistency, occupying the lumen, with the presence of splinters that "pierced" the endoscopist's glove. Endoscopic examination and CTscan revealed an ulcerative exophytic neoplasia of the lower rectum in which multiple calcified areas were found. The lesion showed no bone involvement. An abdominal perineal resection sec Miles was performed. The histological examination revealed a highly cellular mesenchymal lesion, with spindle and epithelioid cells with moderate nuclear pleomorphism. The calcified component consisted of widespread osteoid deposition. The immunohistochemical investigations of neoplastic cells showed strong positivity for vimentin and osteonectin. The definitive histological diagnosis of primary extraskeletal osteosarcoma arising from the colon-rectum was made. To our knowledge, only one previous case of colonic osteosarcoma was published in the literature in 2001, reported by Shimazu and other authors. The extreme rarity of the tumor at this location, also confirmed by morphological and immunohistochemical data, prompted us to present this case report and to review the literature., (Copyright © 2013 Elsevier GmbH. All rights reserved.)

Primary ciliary dyskinesia (PCD), resulting from defects in cilia assembly or motility, is caused by mutations in a number of genes encoding axonemal proteins. PCD phenotypes are variable, and include recurrent respiratory tract infections, bronchiectasis, hydrocephaly, situs inversus, and male infertility. We generated knockout mice for the sperm-associated antigen-17 (Spag17) gene, which encodes a central pair (CP) protein present in the axonemes of cells with "9 + 2" motile cilia or flagella. The targeting of Spag17 resulted in a severe phenotype characterized by immotile nasal and tracheal cilia, reduced clearance of nasal mucus, profound respiratory distress associated with lung fluid accumulation and disruption of the alveolar epithelium, cerebral ventricular expansion consistent with emerging hydrocephalus, failure to suckle, and neonatal demise within 12 hours of birth. Ultrastructural analysis revealed the loss of one CP microtubule in approximately one quarter of tracheal cilia axonemes, an absence of a C1 microtubule projection, and other less frequent CP structural abnormalities. SPAG6 and SPAG16 (CP proteins that interact with SPAG17) were increased in tracheal tissue from SPAG17-deficient mice. We conclude that Spag17 plays a critical role in the function and structure of motile cilia, and that neonatal lethality is likely explained by impaired airway mucociliary clearance.

The finding of thyroid nodules is a very common occurrence in routine clinical practice. Approximately 5% to 7% of the entire population have thyroid nodules. Vascular lesions are one of the most controversial issues in thyroid pathology. These include benign lesions such as hemangiomas and, rarely, malignant tumors such as angiosarcomas or undifferentiated angiosarcomatoid carcinomas. In particular, angiosarcoma of the thyroid gland is a rare, highly aggressive malignant vascular tumor and in Italy the greatest geographical incidence of this lesion is witnessed near the Alps. Here, a case of thyroid angiosarcoma in a 71-year-old man with a history of goiter for about 20 years is described. The unusual localization of this lesion, the difficulties in reaching a definitive diagnosis for this particular histological type of primary tumor and a history of long-standing multinodular goiter in thyroid of an older man from outside the Alpine region prompted us to report this case of thyroid angiosarcoma mainly to discuss surgical, histopathological and immunohistochemical features.

We previously reported an increase in matrix metalloproteinase-9 (MMP-9) levels in the olfactory bulb immediately after nerve transection; however, its role remains unknown. In this study, we determined the source of MMP-9 by monitoring the infiltration of inflammatory leukocytes in the olfactory bulb after nerve transection. We used myeloperoxidase to identify neutrophils and CD68 to identify macrophages at days 1, 7, and 10. MMP-9 colocalized with neutrophils at all three time points but was not contained in macrophages. This is the first study to demonstrate that MMP-9 is associated with early inflammatory response after olfactory injury, and provides insight into mechanisms underlying olfactory injury and recovery processes.

Aims: Peptide YY (PYY) is an endogenous anorectic gut-secreted peptide that has been shown to suppress appetite in animals and humans, when given by injection. This study tested if needle-free pulmonary delivery of PYY enables food intake suppression and reduced body weight gain in rats. The PYY pharmacokinetics and effects on brain neuropeptide levels were also examined., Methods: Rats received single or once-daily 7-day pulmonary administration of saline or PYYs. Food intake and body weight gain were monitored to study the effects of different doses (0.08-0.90 mg/kg) of PYY3-36, PYY1-36 and PYY13-36. Plasma PYY pharmacokinetics were determined via enzyme-linked immunosorbent assay. Changes in orexigenic neuropeptide Y (NPY) and c-Fos protein levels in the hypothalamus arcuate nucleus (ARC) were measured by immunofluorescence microscopy., Results: PYY3-36 caused dose-dependent and 4- to 6-h food intake suppression following pulmonary delivery. At 0.80 mg/kg, the effect was significant with 35.1 ± 5.7 and 19.7 ± 4.2% suppression at 4 and 6 h, respectively. Repeated administration for 7 days reduced cumulative body weight gain by 39.4 ± 11.0%. PYY1-36, but not PYY13-36, was equipotent to PYY3-36 in food intake suppression. The plasma PYY concentration reached its peak at 10 min following pulmonary delivery with 12-14% of bioavailability. Increased c-Fos and reduced NPY expressions were observed in the hypothalamus ARC, consistent with the magnitude of food intake suppression by each of the PYYs., Conclusions: Pulmonary delivery of PYY enabled significant 4- to 6-h food intake suppression via 12-14% of lung absorption and hypothalamic ARC interaction, leading to reduced body weight gain in rats., (© 2011 Blackwell Publishing Ltd.)

Purpose of Review: To discuss the unique properties of the olfactory epithelium and the potential use of olfactory epithelial grafts to restore olfactory function., Recent Findings: Sensory neurons in the olfactory epithelium undergo continuous regeneration, grow new axons, and reestablish connections with the olfactory bulb throughout life. When transplanted into different regions of the brain, olfactory epithelial graft cells retain their morphological and regenerative properties. Olfactory cells within the grafts grow axons that enter into the surrounding brain tissue. Recent studies have shown that the olfactory epithelium can be grafted directly to the olfactory bulb., Summary: The olfactory epithelium has a remarkable capacity to continuously generate new sensory neurons and survives grafting into different regions of the brain. A review of the literature and the future use of olfactory grafts as a potential method to restore olfactory function is discussed.

Matrix metalloproteinase-9 (MMP-9) and MMP-2 are important for recovery following direct traumatic injury within the central nervous system (CNS). However, most CNS injury models include both direct trauma and neuronal deafferentation. This limits the ability to determine if these MMPs are important to one or both components of injury. To establish if MMPs play a role in the deafferentation processes, we investigated MMP-9 and MMP-2 in the olfactory bulb following methyl bromide gas exposure. This injury model lesions neurons within the olfactory epithelium and thereby leads to deafferentation of the bulb without damaging it directly. We measured the response of MMP-9 and MMP-2 in the olfactory bulb from 1 to 60 days during neuronal deafferentation and recovery. MMP-9 increased rapidly on day 5 and remained elevated for 10 days. MMP-2 expression levels were low compared with MMP-9. Immunohistological staining performed on days 1, 5, and 10 revealed MMP-9 was localized to inflammatory cells within the olfactory nerve and glomerular layers. Our results demonstrate MMP-9 is present in inflammatory cells during deafferentation processes in the olfactory bulb. Although MMP-9 is elevated in other CNS injury models, this is the first report to demonstrate an increase in MMP-9 associated with neuronal deafferentation in the absence of direct trauma.

The ability to identify odors is dependent on the spatial mapping of odorant receptors onto fixed positions within the olfactory bulb. In elderly adults, odor identification and discrimination is often impaired. The objective of this study was to determine if there are age-related changes in odorant receptor mapping. We studied 8 groups of mice ranging in age from 2 weeks to 2.5 years and mapped the projection of P2 odorant receptors onto targeted glomeruli within medial and lateral domains of the olfactory bulb. A total of 60 mice were used to measure the number of P2 glomeruli, bulb length, the position of each glomerulus, and the amount of P2 axons targeting each glomerulus. We found that over 70% of olfactory bulbs contained multiple P2 glomeruli, bulb length increased 42% between the ages of 2 and 13 weeks, and the position of P2 glomeruli shifted with bulb growth. In most cases, targeted glomeruli were either completely or partially filled with P2 axons. In some cases, targeting was diffuse, with glomeruli receiving only a few stray P2-labeled axons. The frequency of diffuse targeting was rare (<4%) in adult mice 3-6 months in age. However, significant increases in diffuse targeting were observed in older mice, reaching 10% at 1 year and 22% at 2 years of age. These findings suggest that odorant receptor mapping becomes more disrupted in old age and could account for impaired olfactory function in elderly adults.

To investigate factors that influence the degree of neural regeneration and recovery, we studied 2 olfactory nerve injury models. Transection of the olfactory nerves along the surface of the olfactory bulb was performed in OMP-tau-lacZ mice using either a flexible Teflon blade (mild injury) or a stainless steel blade (severe injury). Histological assessment of recovery within the olfactory bulb was made at 5, 14, and 42 days after injury. We used X-gal staining to label the degenerating and regenerating olfactory nerve fibers and immunohistochemical staining to detect the presence of reactive astrocytes and macrophages. Areas of injury-associated tissue were significantly smaller in the mild injury model, and at 42 days, the regenerated nerves had reestablished connections to the glomerular layer of the bulb. With severe injury, there were larger areas of injury-associated tissue, more astrocytes and macrophages, and a decrease in regenerated nerve fibers. When dexamethasone (DXM) was injected after severe injury, there was a significant reduction in injury-associated tissue, better nerve recovery, and fewer astrocytes and macrophages. These results demonstrate that recovery in the olfactory system varies with the severity of injury and that DXM treatment may have therapeutic value by reducing injury-associated tissue and improving recovery outcome.

Background: Impaired olfactory function leads to a decrease in the quality of life for many patients. Surgical treatment options are limited, especially for those suffering from hyposmia or anosmia after posttraumatic injury to the olfactory nerves. Stem cells located in the olfactory epithelium (OE) have the capacity to grow new neurons, making the OE an ideal candidate for restorative tissue grafting. This study was performed to determine if strips of OE survive transplantation directly to the olfactory bulb (OB)., Methods: Transgenic mice, expressing a green fluorescent protein (GFP), were used to obtain the donor graft tissue. Strips of OE from GFP donor mice were transplanted directly to sites in the OB and cerebral cortex (CC; control sites) of wild-type mice. Graft survival rates at 30 days were determined for transplant sites in the OB and CC., Results: Strips of OE from transgenic mice survived transplantation to the OB and continued to express the GFP marker protein. The 30-day survival rate in the OB (83%, 5 of 6 grafts) was the same as in the CC (10 of 12 grafts). The morphology of the graft revealed characteristics found in normal OE., Conclusion: We showed that strips of OE can be successfully grafted to both the OB and CC. Grafts of the OE, if strategically positioned on the ventral surface of the bulb and given access to the nasal cavity, could provide the basis for new surgical treatments to restore olfactory function.

Matrix metalloproteineases are associated with extracellular remodeling that occurs in injury and repair processes in the central nervous system (CNS). We examined the role of MMP-2 in a model of olfactory nerve injury and found that MMP-2 levels increased several hours following injury, peaked at day 7 and then decreased rapidly. We previously reported a rapid increase in MMP-9, within 5 h after nerve injury, corresponding to neuronal degeneration and increased glial activity. In this study, we show that MMP-2 peaks later than MMP-9, at the onset of neuronal regeneration and repair. Using MMP-9 knockout mice, we determined that the MMP-2 increase is independent of MMP-9. Our data suggest that MMP-2 and MMP-9 may play different roles in the injury and repair processes.

Matrix metalloproteinases function in the remodeling of the extracellular matrix during growth and development as well as in injury and disease processes. We examined the role of matrix metalloproteinase-9 in a model of olfactory nerve injury in mice. We measured changes in matrix metalloproteinase-9 protein levels for up to 60 days following olfactory nerve transection. Matrix metalloproteinase-9 levels increased within hours after injury, peaked at day 1 and were elevated for approximately 2 weeks before returning to control levels over the 60-day time period. The increase in matrix metalloproteinase-9 was temporally associated with the degeneration of olfactory neurons that follows nerve transection and with increased gliosis. Our results demonstrate a temporal relationship between matrix metalloproteinase-9 elevation, degeneration of olfactory neurons and gliosis.

A new olfactory test, the odor stick identification test for Japanese (OSIT-J), has been developed in Japan. To determine if the OSIT-J would be effective cross-culturally, we administered the test to 52 US and 50 Japanese subjects reporting normal olfactory function. The average composite OSIT-J test score for US subjects was significantly lower (77%) than that for Japanese subjects (94%, P < 0.0001). Both US and Japanese subjects correctly identified eight of the 13 odorants included in the OSIT-J with scores of 80% or higher. However, for five odorants, the US subjects' scores fell below 80% and were consistently lower than Japanese subjects, presumably reflecting cultural differences in odor experience. Most of the US subjects found the OSIT-J to be easy, interesting, pleasant, and short in duration. Although the 13-odorant OSIT-J was found to be suitable for testing US populations, elimination of five test odorants that were unfamiliar to US subjects significantly enhanced the test's effectiveness. Findings from this study emphasize the importance of identifying test odorants that may have a cultural bias, a crucial issue when comparing data obtained from different smell tests used at smell and taste centers around the world.

A large number of substances and disease processes may impact the sense of taste. Toxic substances may cause taste dysfunction from their effects on the gustatory system from the salivary gland, to the taste bud, to the central neural pathways. A number of external toxins, including industrial compounds, tobacco, and alcohol, may adversely affect taste, most commonly through local effects in the oral cavity. Blood-borne toxins, such as medications and those present in autoimmune and other systemic disorders (e.g. renal or liver failure), have access to all parts of the gustatory system, and thus may exhibit varied effects on taste function. An understanding of these potential toxins and their impact on gustation will help physicians better recognize, and potentially limit the impact of such taste alterations on their patients.

Head injury is the leading cause of posttraumatic anosmia. Complete or partial loss of olfactory function may occur when the nasal passages are blocked, olfactory nerves are injured or there are contusions or hemorrhages in olfactory centers of the brain. Evaluation of patients with posttraumatic olfactory loss should include a physical examination by the otolaryngologist. Nasal endoscopy and radiological studies should be performed as well as olfactory function tests to determine the degree and type of olfactory impairment. Although treatment options may be limited, physicians should provide information and counseling regarding the risks and hazards associated with loss of olfactory function. For some individuals such as cooks, firefighters, and research scientists, an assessment of vocational activities should be performed prior to reentry into the workplace. Individuals with impaired olfactory function may be unable to detect important warning signs such as gas leaks, volatile chemical fumes and fires and therefore place themselves and coworkers at an increased risk for serious injury or death.

Traumatic events such as motor vehicle accidents, falls, or assaults can lead to dysfunction in olfaction or gustation. Mechanisms of posttraumatic olfactory dysfunction include direct injury to the sinonasal tract or olfactory epithelium, shearing effect on olfactory fibers at the cribriform plate, or brain contusion or intraparenchymal hemorrhage. Posttraumatic gustatory dysfunction is rare, but may occur as a result of direct injury to the tongue, injury to cranial nerves VII or IX, or brain contusion or hemorrhage. Evaluation of head-injured patients presenting with olfactory or gustatory complaints should include a thorough history, including assessment for pre-and posttraumatic chemosensory dysfunction and potential mechanisms of injury, complete head and neck examination including nasal endoscopy and cranial nerve testing, and focused radiographic imaging, usually CT of the sinuses and skull base. Formal olfactory and gustatory testing may be performed using various techniques, although in cases potentially involving litigation, methodologies able to detect malingering should be used. Treatable causes of chemosensory disturbance, most notably conductive olfactory losses caused by chronic rhinosinusitis or nasal obstruction, should be ruled out. In the event of neurosensory deficits, recovery may occur up to 12 to 18 months after the traumatic event. All patients should be counseled regarding the risks of their chemosensory deficits, and given suggestions for appropriate compensatory strategies.

We investigated a model of long-term memory in which the female mouse establishes pheromonal memory of its partner at mating. We examined the reciprocal synapses of the accessory olfactory bulb and found that pheromonal memory was associated with morphological changes in excitatory synapses in the early phase of memory acquisition and by changes in inhibitory synapses in the late phases of memory persistence. After extinction of pheromonal memory, these morphological changes were no longer present. These findings suggest that the persistence of pheromonal memory is associated with continuous and dynamic changes in the morphological plasticity of reciprocal synapses in the accessory olfactory bulb.

Objective: To evaluate the risk of olfactory-related hazardous events in patients with impaired olfactory function., Design: Retrospective cohort study., Setting: A university-based clinic for smell and taste disorders., Patients: A total of 445 patients who underwent olfactory testing between 1983 and 2001., Interventions: Patient interview, olfactory testing., Main Outcome Measures: (1) Frequency of olfactory-related hazardous events including cooking incidents (ie, burning pots or pans), undetected fires, undetected gas leaks, and ingestion of spoiled foods or toxic substances; (2) level of olfactory function (anosmia; severe, moderate, or mild hyposmia; or normosmia) as determined by olfactory testing., Results: Olfactory testing revealed that 76% of patients had some degree of impairment; 30% had complete anosmia. Thirty-seven percent of patients with olfactory impairment but only 19% of patients without impairment experienced at least 1 olfactory-related hazardous event. Of the hazardous events reported by impaired patients, cooking-related incidents were most common, representing 45%, with ingestion of spoiled food (25%), inability to detect a gas leak (23%), and inability to smell a fire (7%) reported less frequently. There was a significant correlation between frequency of hazardous events and degree of olfactory impairment (Cochran-Armitage trend test, P<.001): at least 1 hazardous event was reported by 45.2% of patients with anosmia, 34.1% with severe hyposmia, 32.8% with moderate hyposmia, 24.2% with mild hyposmia, and 19.0% of patients with with normal olfaction by testing., Conclusion: Patients with impaired olfactory function are more likely to experience olfactory-related hazardous events than those with normal olfactory function.

The olfactory epithelium contains neuronal progenitor cells capable of continuous neurogenesis and is a unique model for studying neural degeneration, regeneration, axon outgrowth and recovery from injury. Matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs), have been implicated in cell turnover, development, migration, and metastatic processes. We used Western blot and immunohistochemistry to determine whether MMP-2 and associated proteins TIMP-2 and membrane type 1 matrix metalloproteinase (MT1-MMP) are present in the olfactory epithelium of mice. We found MMP-2 expression localized to the olfactory basal cells and immature neurons. After injury-induced neural degeneration, MMP-2 and MT1-MMP levels decreased while TIMP-2 levels increased. However, following 35 days of neurogenesis and cell replacement TIMP-2 and MT1-MMP returned to control levels. The results show a correlation between MMP and TIMP levels and the stages of neural degeneration, regeneration and recovery of the olfactory epithelium following injury.

Detection thresholds are typically obtained by presenting a subject with serial dilutions of an odorant. Many factors, including the solvent used to dilute the odorant, can influence the measurement of detection thresholds. Differences have been reported in detection thresholds for phenyl ethyl alcohol (PEA) when different solvents are used. In this study we used gas chromatography (GC) to investigate further the effect of solvent on odor detection thresholds. We used a single ascending method and serial dilutions of PEA in four different solvents--liquid paraffin (LP), mineral oil (MO), propylene glycol (PG) and dipropylene glycol (DPG)--to determine the PEA thresholds for 31 adult subjects. For each solvent, we prepared eight serial log base 10 step dilutions (1-8), with corresponding liquid PEA concentrations of 6.3 x 10(1)-6.3 x 10(-6) (% v/v). We found that the threshold concentrations for PEA in LP (step 6.5) and PEA in MO (step 5.5) were significantly lower (P < 0.05) than for PEA in PG (step 4.0) and DPG (step 4.0) We then used GC to measure both the liquid and gas PEA concentrations for the dilution steps prepared with LP and PG. Although there were large threshold differences in the liquid concentrations of PEA in LP and PG, the headspace gas concentrations of PEA were the same. These results demonstrate the importance of determining the gas concentration of odorant stimuli when performing odor threshold measurements, in particular when comparing odor detection thresholds obtained using different solvents.