Neurological Insights of COVID-19 Pandemic.

The novel coronavirus SARS-CoV-2, which was identified after a recent outbreak in Wuhan, China, in December 2019, has kept the whole world in tenterhooks due to its severe life-threatening nature of the infection. The virus is unlike its previous counterparts, SARS-CoV and MERS-CoV, or anything the world has encountered before both in terms of virulence and severity of the infection. If scientific reports relevant to the SARS-CoV-2 virus are noted, it can be seen that the virus owes much of its killer properties to its unique structure that has a stronger binding affinity with the human angiotensin-converting enzyme 2 (hACE2) protein, which the viruses utilize as an entry point to gain accesses to its hosts. Recent reports suggest that it is not just the lung that the virus may be targeting; the human brain may soon emerge as the new abode of the virus. Already instances of patients with COVID-19 have been reported with mild (anosmia and ageusia) to severe (encephalopathy) neurological manifestations, and if that is so, then it gives us more reasons to be frightened of this killer virus. Keeping in mind that the situation does not worsen from here, immediate awareness and more thorough research regarding the neuroinvasive nature of the virus is the immediate need of the hour. Scientists globally also need to up their game to design more specific therapeutic strategies with the available information to counteract the pandemic. In this Viewpoint, we provide a brief outline of the currently known neurological manifestations of COVID-19 and discuss some probable ways to design therapeutic strategies to overcome the present global crisis.

[Experimental study on the effect of olfactory training on olfactory function in mice with olfactory dysfunction].

Objective: To observe the effect of olfactory training on mice with olfactory dysfunction induced by 3-methylindole (3-MI). Methods: Thirty-one male BALB/c mice were randomly divided into 3 groups by random digits table: control group (group A, n=10), olfactory dysfunction group (group B, n=10) and olfactory dysfunction+olfactory training group (group C, n=11). Mice in group B and group C were intraperitoneally injected with 150 mg/kg 3-MI to induce olfactory dysfunction model, while mice in group A were intraperitoneally injected with corn oil of the same volume. From the first day after injection, mice in group C were treated with 4 kinds of odors by inhalation, while mice in group B were treated with distilled water by inhalation, with 2 times/d, 30 min/time/kind of odor, and continuous training for 28 d. Group A was not treated. Buried food pellet tests were conducted before injection and at 7, 14, 21 and 28 days after injection, respectively. The olfactory epithelium was harvested for observation of the number of olfactory marker protein (OMP) and the thickness of olfactory epithelium on the 28th day after injection. SPSS 23.0 software was used for statistical analysis. Results: Before injection, all mice in each group had no olfactory dysfunction. At the 7th, 14th, 21st and 28th days after injection, the food finding time of mice in group C was shorter than that in group B, and the difference was statistically significant ((175.88±100.50) s vs (266.73±46.83) s, (132.00±84.62) s vs (264.10±48.50) s, (103.57±77.43) s vs (197.43±69.78) s, (67.79±32.54) s vs (176.63±61.06) s, all P<0.05), but food finding time of mice in group B and C was longer than that in group A (the food finding time of group A at the 7th, 14th, 21st and 28th days after injection was (27.13±5.36) s, (25.83±7.28) s, (23.13±2.72) s, (26.63±7.60) s, respectively, all P<0.05). At the 28th day after olfactory training, the number of OMP positive cells in group B and C were fewer than that in group A, and the difference was statistically significant ((108.00±28.19)/HP vs (288.22±84.06)/HP, (199.33±58.55)/HP vs (288.22±84.06)/HP, all P<0.05). The number of OMP positive cells in group C were higher than that in group B (P<0.05). The number of OMP positive cells had negative correlation with food finding time (r=-0.886, P<0.01). As for the thickness of the olfactory epithelium, the thickness of group B was thinner than that in group A and C, and the difference was statistically significant ((59.57±31.27) µm vs (114.55±40.70)µm vs (90.54±37.72) µm, all P<0.05). Conclusion: Olfactory training can accelerate the recovery of olfactory function in 3-MI-induced olfactory impaired mice.

Type 2/Th2-driven inflammation impairs olfactory sensory neurogenesis in mouse chronic rhinosinusitis model.

BACKGROUND: Chronic rhinosinusitis (CRS) with nasal polyps (CRSwNP) is a chronic inflammatory disease often accompanied by impairment of sense of smell. This symptom has been somewhat overlooked, and its relationship to inflammatory cytokines, tissue compression, neuronal loss, and neurogenesis is still unclear. METHODS: In order to elucidate potential mechanisms leading to CRS in humans, we have established a type 2/T helper type 2 cell (Th2)-mediated allergic CRS mouse model, based on house dust mite (HDM) and Staphylococcus aureus enterotoxin B (SEB) sensitization. The inflammatory status of the olfactory epithelium (OE) was assessed using histology, biochemistry, and transcriptomics. The sense of smell was evaluated by studying olfactory behavior and recording electro-olfactograms (EOGs). RESULTS: After 22 weeks, a typical type 2/Th2-mediated inflammatory profile was obtained, as demonstrated by increased interleukin (IL)-4, IL-5, and IL-13 in the OE. The number of mast cells and eosinophils was increased, and infiltration of these cells into the olfactory mucosa was also observed. In parallel, transcriptomic and histology analyses indicated a decreased number of immature olfactory neurons, possibly due to decreased renewal. However, the number of mature sensory neurons was not affected and neither the EOG nor olfactory behavior was impaired. CONCLUSION: Our mouse model of CRS displayed an allergic response to HDM + SEB administration, including the type 2/Th2 inflammatory profile characteristic of human eosinophilic CRSwNP. Although the sense of smell did not appear to be altered in these conditions, the data reveal the influence of chronic inflammation on olfactory neurogenesis, suggesting that factors unique to humans may be involved in CRSwNP-associated anosmia.

Olfactory cleft evaluation: a predictor for olfactory function in smell-impaired patients?

OBJECTIVE: In this study, we introduce an extension of previous work by Soler et al. (Int Forum Allergy Rhinol 6(3):293-298, 2016) on a modified endoscopic scoring system of the Lund-Kennedy Score (focusing on the olfactory cleft) to evaluate its correlation with the olfactory function in patients with various smell disorders. STUDY DESIGN: A prospective cohort study. METHODS: Two-hundred and eighty-eight participants were included and categorized in five groups according to the cause of their olfactory disorder: (0) control, (1) idiopathic, (2) sino-nasal, (3) postinfectious and (4) post traumatic olfactory loss. Olfaction was evaluated using the "Sniffin' Sticks" test. The classical Lund-Kennedy scoring and a new olfactory cleft specific Lund-Kennedy scoring (OC-LK) were performed to evaluate mucosal changes. RESULTS: Significantly higher OC-LK scores on both sides were found in smell-impaired patients as compared to normosmic controls. When comparing the 4 groups, a significant difference of the OC-LK score were present between the sino-nasal and all other groups. Most importantly, significant negative correlations with strong effects were shown in the sino-nasal group between the OC-LK score and odor discrimination and odor identification. However, no such correlation emerged between the classical LK score and smell function. CONCLUSION: Olfactory cleft evaluation using the OC-LK score correlates with the olfactory function in patients with sino-nasal smell disorder. This diagnostic tool may reflect the underlying pathophysiological mechanism of sino-nasal smell loss, and therefore, should complement olfactory diagnostics in patients with sino-nasal smell disorder.

Periodic olfactory assessment in patients undergoing skull base surgery with preservation of the olfactory strip.

OBJECTIVES/HYPOTHESIS: Others have reported olfactory disturbances following endoscopic approaches to the skull base. However, there is a lack of consensus on the extent and duration of dysfunction. This study aimed to compare our results with previously published work and to validate the olfactory strip-sparing approach. STUDY DESIGN: Prospective study to assess olfaction in 50 patients scheduled to undergo resection of skull base tumors via extended endoscopic approaches. METHODS: Patients were divided into two groups. Group I had a nasoseptal flap (NSF), and group II included patients in whom rescue flaps were performed bilaterally. Olfactory outcomes were assessed using repeated University of Pennsylvania Smell Identification Test at baseline, 6 weeks, 3 months, and 6 months following surgery. RESULTS: Ultimately, 42 patients (seven group I and 35 group II) were available for assessment. Scores for group I were lower than at baseline at 6 weeks postoperatively (30.71 ± 5.5 vs. 24.5 ± 5.4; P = .05). However, by the third postoperative month the scores had improved to a level that was not significantly different from baseline (29.0 ± 3.7; P = .5). At 6 months, the score was 30.0 ± 3.9. Patients in group II showed no difference between their baseline and 6-week scores (31.5 ± 5.3 vs. 29.7 ± 5.9; P = .16). Six months postoperatively, the score was significantly higher (33.78 ± 3.6; P = .04). CONCLUSIONS: Expanded endoscopic approaches to skull base tumors involving reconstruction with an NSF are associated with a short-term negative impact on olfaction. Olfaction does not seem to be affected by the surgical resection of pituitary adenomas associated with rescue flaps. Identification of the olfactory epithelium and meticulous harvesting of the NSF are critical to preserve olfaction. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1970-1975, 2017.

Cigarette Smoke Delays Regeneration of the Olfactory Epithelium in Mice.

The olfactory system is a unique part of the mammalian nervous system due to its capacity for neurogenesis and the replacement of degenerating receptor neurons. Cigarette smoking is a major cause of olfactory dysfunction. However, the mechanisms by which cigarette smoke impairs the regenerative olfactory receptor neurons (ORNs) remain unclear. Here, we investigated the influence of cigarette smoke on ORN regeneration following methimazole-induced ORN injury. Administration of methimazole caused detachment of the olfactory epithelium from the basement membrane and induced olfactory dysfunction, thus enabling us to analyze the process of ORN regeneration. We found that intranasal administration of cigarette smoke solution (CSS) suppressed the recovery of ORNs and olfaction following ORN injury. Defective ORN recovery in CSS-treated mice was not associated with any change in the number of SOX2(+) ORN progenitor cells in the basal layer of the OE, but was associated with impaired recovery of GAP43(+) immature ORNs. In the nasal mucosa, mRNA expression levels of neurotrophic factors such as brain-derived neurotrophic factor, neurotrophin-3, neurotrophin-5, glial cell-derived neurotrophic factor, and insulin-like growth factor-1 (IGF-1) were increased following OE injury, whereas CSS administration decreased the ORN injury-induced IGF-1 expression. Administration of recombinant human IGF-1 prevented the CSS-induced suppression of ORN recovery following injury. These results suggest that CSS impairs regeneration of ORNs by suppressing the development of immature ORNs from ORN progenitors, at least partly by reducing IGF-1 in the nasal mucosa.

Damage to Olfactory Progenitor Cells Is Involved in Cigarette Smoke-Induced Olfactory Dysfunction in Mice.

Exposure to cigarette smoke is a major cause of olfactory dysfunction. However, the underlying mechanisms by which cigarette smoke interferes with the highly regenerative olfactory nerve system remain unclear. To investigate whether cigarette smoke induces olfactory dysfunction by disrupting cell proliferation and cell survival in the olfactory epithelium (OE), we developed a mouse model of smoking that involved intranasal administration of a cigarette smoke solution (CSS). Immunohistological analyses and behavioral testing showed that CSS administration during a period of 24 days reduced the number of olfactory marker protein-positive mature olfactory receptor neurons (ORNs) in the OE and induced olfactory dysfunction. These changes coincided with a reduction in the number of SOX2(+) ORN progenitors and Ki-67(+) proliferating cells in the basal layer of the OE, an increase in the number of caspase-3(+) apoptotic cells, and an increase in the expression of mRNA for the inflammatory cytokines IL-1ß and IL-6. Notably, the proliferating ORN progenitor population recovered after cessation of treatment with CSS, resulting in the subsequent restoration of mature ORN numbers and olfaction. These results suggest that SOX2(+) ORN progenitors are targets of CSS-induced impairment of the OE, and that by damaging the ORN progenitor population and increasing ORN death, CSS exposure eventually overwhelms the regenerative capacity of the epithelium, resulting in reduced numbers of mature ORNs and olfactory dysfunction.

The effect of rat bone marrow derived mesenchymal stem cells transplantation for restoration of olfactory disorder.

The purpose of the study was to investigate the effect of bone marrow-derived mesenchymal stem cells (BMSCs) transplantation on olfactory epithelium (OE) of morphologic and functional restoration following neural Sensorineural Disorder in rats. Except the Normal group, twenty-one rats underwent Triton X-100 (TX-100) irrigation to induce degeneration of OE, and then BMSCs and PBS were treated from the both medial canthus to the rear part of the both nasal cavity into the experimental group and then were observed for restoration according to time point. At two and four weeks after transplantation with BMSCs, restoration of OE was observed with olfactory marker protein (OMP) and behavioral test. And we observed the expression of OMP, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF). After TX-100 irrigation, the OE almost disappeared in 3 days. At four weeks after transplantation with BMSCs, the thickness and cellular composition of OE was considerably restored to normal group and expression of OMP was markedly increased when compared with PBS group and reduced the searching time in the behavioral test. Furthermore at two weeks after treatment with BMSCs, expression of NGF and BDNF was greatly increased when compared with PBS group. However at four weeks after treatment with BMSCs, expression of NGF and BDNF was slightly decreased. Our results suggest the BMSCs transplantation affect restoration of OE and olfaction, most likely via regulation of the neurotrophic factor expression, especially the expression of NGF and BDNF and has a possibility of a new therapeutic strategy for the treatment of olfactory disorder caused by the degeneration of OE.

Postoperative changes in olfactory function after transcanalicular diode laser dacryocystorhinostomy.

PURPOSE: Transcanalicular diode laser dacryocystorhinostomy (TCL-DCR) is used much in recent years for the surgery of nasolacrimal duct obstruction (NLDO). Although TCL-DCR is accepted to be minimally invasive, safe, and effective, there is no report focusing on postoperative changes in olfactory function after this procedure. Hence, the aim of this current study was to investigate the changes in olfactory function after TCL-DCR procedure. MATERIALS AND METHODS: This study was carried out in 42 volunteers (16 men and 26 women) between the ages of 20 and 81 years. All participants received detailed lateralized olfactory tests preoperatively and at the postoperative first week, first month, third month, and sixth month. After lateralized olfactory tests were performed, the results were grouped according to the side of the nasal passage where the operation was performed for NLDO: the nonoperated side served as the control. RESULTS: The current investigation produced 2 major findings: (1) olfactory function decreased significantly after TCL-DCR procedure at the operated side of the nose compared with the nonoperated side; (2) olfactory abilities of the patients returned to normal within 3 months. CONCLUSION: The results of this study showed that transcanalicular diode laser could be used safely in terms of olfactory function for dacryocystorhinostomy. Temporary decrease of olfactory function on the side having TCL-DCR should be taken into account when obtaining informed patient consent.

Olfactory neuroepithelium in the superior and middle turbinates: which is the optimal biopsy site?

INTRODUCTION: Olfactory neuroepithelium (ON) biopsy has several therapeutic applications for both disorders of olfaction and neurodegenerative diseases. Successful collection of ON is still anything but routine due to a dearth of studies on the distribution of ON in the superior and middle turbinates. AIM: To determine the location in which ON is most likely to be present in endoscopically removed cadaver superior and middle turbinates as well as the influences of gender, age, and naris side on the presence of ON and the extent to which it is present. METHODS: We conducted a prospective anatomical study. The superior and middle turbinates on both sides endoscopically removed from 25 fresh cadavers (less than 12 h post-mortem). The turbinates were halved into anterior and posterior segments for a total of 200 specimens, which were analyzed after hematoxylin and eosin and immunohistochemical staining. Hematoxylin and eosin-stained slides were subjected to blind examination by 3 independent pathologists, and the presence of ON was graded on a 5-point scale from 0 to 4. Kappa measurement was used to determine the agreement between pairs of observers. RESULTS: ON was present in 82.9% of superior turbinate samples and in 17.1% of middle turbinate samples. Immunohistochemistry detected ON in superior turbinates only by S-100 staining and only in 15 fragments. Gender, age, and naris side had no statistically significant effects on the presence of ON. CONCLUSION: When biopsying ON, the posterior portion of the superior turbinate should be targeted whenever possible because it has the highest concentration of ON among the nasal structures.

Telomere shortening impairs regeneration of the olfactory epithelium in response to injury but not under homeostatic conditions.

Atrophy of the olfactory epithelium (OE) associated with impaired olfaction and dry nose represents one of the most common phenotypes of human aging. Impairment in regeneration of a functional olfactory epithelium can also occur in response to injury due to infection or nasal surgery. These complications occur more frequently in aged patients. Although age is the most unifying risk factor for atrophic changes and functional decline of the olfactory epithelium, little is known about molecular mechanisms that could influence maintenance and repair of the olfactory epithelium. Here, we analyzed the influence of telomere shortening (a basic mechanism of cellular aging) on homeostasis and regenerative reserve in response to chemical induced injury of the OE in late generation telomere knockout mice (G3 mTerc(-/-)) with short telomeres compared to wild type mice (mTerc(+/+)) with long telomeres. The study revealed no significant influence of telomere shortening on homeostatic maintenance of the OE during mouse aging. In contrast, the regenerative response to chemical induced injury of the OE was significantly impaired in G3 mTerc(-/-) mice compared to mTerc(+/+) mice. Seven days after chemical induced damage, G3 mTerc(-/-) mice exhibited significantly enlarged areas of persisting atrophy compared to mTerc(+/+) mice (p = 0.031). Telomere dysfunction was associated with impairments in cell proliferation in the regenerating epithelium. Deletion of the cell cycle inhibitor, Cdkn1a (p21) rescued defects in OE regeneration in telomere dysfunctional mice. Together, these data indicate that telomere shortening impairs the regenerative capacity of the OE by impairing cell cycle progression in a p21-dependent manner. These findings could be relevant for the impairment in OE function in elderly people.

The role of TNF-α in inflammatory olfactory loss.

BACKGROUND: Despite the significant health impact of olfactory loss in chronic rhinosinusitis (CRS), the underlying pathophysiology is incompletely understood. A transgenic mouse model of olfactory inflammation induced by tumor necrosis factor-alpha (TNF-α) has provided new insights into the cellular and molecular basis of inflammatory olfactory loss. Here, we utilize systemic corticosteroids to suppress downstream cytokine expression, in order to study the direct role of TNF-α in CRS-associated olfactory dysfunction. METHODS: Transgenic mice were induced to express TNF-α in the olfactory epithelium for 6 weeks. In a subset of mice, 1 mg/kg prednisolone was administered concurrently to inhibit downstream inflammatory responses. The olfactory epithelium (OE) was analyzed by histology and electro-olfactogram (EOG) recordings. RESULTS: Treatment with prednisolone successfully prevented inflammatory infiltration over significant regions of the OE. In areas where significant subepithelial inflammation was present, a corresponding loss of olfactory neurons was observed. In contrast, areas without major inflammatory changes had normal olfactory neuron layers, despite chronic local expression of TNF-α. Prednisolone partially reversed the complete loss of olfaction in the mouse model, preserving odorant responses that were significantly diminished compared to controls, but not absent. CONCLUSIONS: The addition of prednisolone to the transgenic model of olfactory inflammation isolates the direct effects of induced TNF-α expression on the OE. The finding that prednisolone treatment prevents neuronal loss in some regions of the OE suggests that TNF-α does not directly cause neuronal apoptosis--rather, that subepithelial inflammation or other downstream mediators may be responsible. At the same time, EOG results imply that TNF-α directly causes physiologic dysfunction of olfactory neurons, independent of the inflammatory state. An understanding of the role of TNF-α and other inflammatory cytokines may suggest novel therapeutic strategies for CRS-associated olfactory loss.

Clinical epidemiological study of 553 patients with chronic rhinosinusitis in Japan.

BACKGROUND: The relationship between chronic rhinosinusitis (CRS) and asthma has been known for a long time. However, no large studies on the relationship between CRS and lower airway diseases have been reported to date in Japan. Additionally, eosinophilic chronic rhinosinusitis (ECRS) in Japan is considered to be a subgroup of CRS with nasal polyps (CRSwNP) characterized by eosinophil-dominant inflammation. However, the diagnostic criteria of ECRS have not been established. METHODS: To investigate clinical and epidemiological features of patients with CRS from the aspect of their associations with lower airway diseases, 553 patients with CRS who visited one of six local university hospitals were examined and interviewed. Local eosinophilic infiltration was evaluated pathologically by examining NPs. RESULTS: The prevalences of olfactory dysfunction (OD) in the patients with nasal polyps (NPs) and those without NPs were 57.0% and 13.7%, respectively (p < 0.0001). The prevalence of asthma in all patients was 23.1%. Furthermore, the prevalences of NPs and OD in the patients with asthma and those without asthma were 81.0% and 50.1% (p < 0.0001) and 64.2% and 35.7% (p < 0.0001), respectively. 97.4% of the patients with asthma had ≥ 15% mucosal eosinophils, and 87.9% of the patients without asthma had <15% mucosal eosinophils. CONCLUSIONS: Similar to the relationship between nasal allergy and asthma, CRSwNP may be applicable to the concept of "one airway, one disease".

In vivo visualization of olfactory pathophysiology induced by intranasal cadmium instillation in mice.

Intranasal exposure to cadmium has been related to olfactory dysfunction in humans and to nasal epithelial damage and altered odorant-guided behavior in rodent models. The pathophysiology underlying these deficits has not been fully elucidated. Here we use optical imaging techniques to visualize odorant-evoked neurotransmitter release from the olfactory nerve into the brain's olfactory bulbs in vivo in mice. Intranasal cadmium chloride instillations reduced this sensory activity by up to 91% in a dose-dependent manner. In the olfactory bulbs, afferents from the olfactory epithelium could be quantified by their expression of a genetically encoded fluorescent marker for olfactory marker protein. At the highest dose tested, cadmium exposure reduced the density of these projections by 20%. In a behavioral psychophysical task, mice were trained to sample from an odor port and make a response when they detected an odorant against a background of room air. After intranasal cadmium exposure, mice were unable to detect the target odor. These experiments serve as proof of concept for a new approach to the study of the neural effects of inhaled toxicants. The use of in vivo functional imaging of the neuronal populations exposed to the toxicant permits the direct observation of primary pathophysiology. In this study optical imaging revealed significant reductions in odorant-evoked release from the olfactory nerve at a cadmium chloride dose two orders of magnitude less than that required to induce morphological changes in the nerve in the same animals, demonstrating that it is a more sensitive technique for assessing the consequences of intranasal neurotoxicant exposure. This approach is potentially useful in exploring the effects of any putative neurotoxicant that can be delivered intranasally.

Expression and distribution of the intermediate filament protein nestin and other stem cell related molecules in the human olfactory epithelium.

The olfactory epithelium (OE) is unique in regenerating throughout life and thus is an attractive target for examining neurogenesis. The nestin protein was shown to be expressed in the OE of rodents and is suggested to be essentially involved in the process of regeneration. Here we report the expression and distribution of nestin in the human OE at RNA and protein level. Moreover, we analysed the expression profiles in dependence on age and olfactory capacity. After sinus surgery, biopsies were taken from the olfactory epithelium of 16 patients aged 20-80 years with documented differences in their olfactory function. Our studies revealed that nestin is constantly detectable in the apical protuberances of sustentacular cells within the human OE of healthy adults. Its expression is not dependent on age, but rather appears to be related to the olfactory function, as a comparison with specimens obtained from patients suffering either from persistent anosmia or hyposmia suggests. Particularly, in the course of dystrophy, often accompanied with impaired olfaction, nestin expression was occasionally decreased. Contrarily, the expression of the p75-NGFR protein, a marker for human OE basal cells, was not altered, indicating that at least in the tested samples olfactory impairment is not connected with abnormalities at the basal cell level. These observations emphasize an essential role of nestin for the process of regeneration, and also highlight this factor as a candidate marker for sustentacular cells in the human olfactory epithelium.

Theophylline induces changes in the electro-olfactogram of the mouse.

Options for the treatment of hyposmia are limited;available therapies do not provide a long-lasting effect.A recent study suggests that an unspecific phosphodiesterase inhibitor (PDE-I) increases olfactory sensitivity due to interaction with the signal transduction in the olfactory epithelium. The aim of the present study was to investigate whether theophylline, an unspecific PDE-I, evokes changes in the electro-olfactogram (EOG) which would support the hypothesis of a drug-related impact on signal transduction.In addition, the uptake of topically administered theophylline in the olfactory epithelium should be investigated. EOG was obtained in 29 samples of supravital mouse olfactory epithelia. Olfactory stimulation (phenylethyl alcohol, PEA and hydrogen sulfide, H2S) was performed using an air dilution olfactometer. Theophylline concentration in the olfactory epithelium of five samples was measured by means of high pressure liquid chromatography. Administration of theophylline resulted in a tendency towards smaller EOG amplitudes (p = 0.055), being reduced by 13 and 25% in response to stimulation with PEA or H2S,respectively. In comparison to the application of Ringer's solution, theophylline resulted in a significant (p = 0.031)decrease of the EOG amplitude. Latency was not significantly(p = 0.10) influenced by drug administration. The theophylline concentration in the olfactory epithelium ranged from 0.21 to 1.53 microg/mg. Theophylline seems to be taken up into the olfactory epithelium of supravital mice and to interact with the olfactory signal transduction.

Scents and nonsense: olfactory dysfunction in schizophrenia.

Among the sensory modalities, olfaction is most closely associated with the frontal and temporal brain regions that are implicated in schizophrenia and most intimately related to the affective and mnemonic functions that these regions subserve. Olfactory probes may therefore be ideal tools through which to assess the structural and functional integrity of the neural substrates that underlie disease-related cognitive and emotional disturbances. Perhaps more importantly, to the extent that early sensory afferents are also disrupted in schizophrenia, the olfactory system-owing to its strategic anatomic location-may be especially vulnerable to such disruption. Olfactory dysfunction may therefore be a sensitive indicator of schizophrenia pathology and may even serve as an "early warning" sign of disease vulnerability or onset. In this article, we review the evidence supporting a primary olfactory sensory disturbance in schizophrenia. Convergent data indicate that structural and functional abnormalities extend from the cortex to the most peripheral elements of the olfactory system. These reflect, in part, a genetically mediated neurodevelopmental etiology. Gross structural and functional anomalies are mirrored by cellular and molecular abnormalities that suggest decreased or faulty innervation and/or dysregulation of intracellular signaling. A unifying mechanistic hypothesis may be the epigenetic regulation of gene expression. With the opportunity to obtain olfactory neural tissue from live patients through nasal epithelial biopsy, the peripheral olfactory system offers a uniquely accessible window through which the pathophysiological antecedents and sequelae of schizophrenia may be observed. This could help to clarify underlying brain mechanisms and facilitate identification of clinically relevant biomarkers.

The human olfactory mucosa.

Studies of the tissues of the human olfactory mucosa have been performed to investigate olfactory dysfunction and, more recently, olfactory mucosa has attracted a novel interest of investigators because it can be used as an early marker of neurodegenerative conditions of the brain and as a source of multipotent neural stem cells, with applications in regenerative medicine. The olfactory mucosa is readily available to the otolaryngologist, but the harvesting of this tissue must be safe, effective, and reliable, obtaining as little tissue as necessary, while avoiding unnecessary harm to the remaining olfactory tissue and function. The purpose of this review is to summarize the results of the most important studies and knowledge with regard to the human olfactory mucosa and its applications, emphasizing the issue of the distribution of the olfactory mucosa in the nasal cavities.