Chem. Senses 27: 623-628,
2002
© Oxford University Press 2002
Biopsies of Human Olfactory Epithelium
Rocky Mountain Taste and Smell Center, Denver, CO, USA
Correspondence to be sent to: Bruce W. Jafek, Department of Otolaryngology—Head and Neck Surgery, UCHSC (B-205), 4200 East Ninth Avenue, Denver, CO 80262, USA. e-mail: bruce.jafek{at}uchsc.edu
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Abstract |
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 Top Abstract IntroductionMethodOlfactory epitheliumOutlookReferences |
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It has been shown that olfactory epithelium can be safely biopsied from the living, intact human being. Observations of the ultrastructure of this epithelium shows changes that can then be correlated with the etiology and degree of olfactory loss, allowing a greater understanding of both normal transduction and of the pathology of dysfunction. Examples of the common forms of olfactory dysfunction are presented and discussed. Additionally, the technique will allow additional immuno-histochemical and molecular study of the tissue, will increase the understanding of both normal and pathological function and should translate to new therapeutic regimens.
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Introduction |
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TopAbstractIntroductionMethodOlfactory epitheliumOutlookReferences |
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Biopsy of olfactory epithelium in the intact human being is essential in understanding human disease and dysfunction, as well as in obtaining `normal' epithelium for research. In 1982 we developed an instrument and technique for the safe biopsy of the olfactory epithelium in the living, intact human being (Lovell et al., 1982
). Since that time, the technique has been in continuous use
in our laboratory and disseminated to a number of centers in the USA, as well
as abroad. Major complications have not occurred and the biopsy technique has
continued to safely and reliably provide tissue for study. Preliminary evaluation
Prior to biopsy, the patient with a chemosensory complaint undergoes
detailed historical and physical evaluation. This evaluation usually focuses
attention upon one of the >200 conditions and an equal number of putative
medical reactions or toxicities that have been linked to olfactory loss
(Schiffman, 1983;
Hastings and Miller, 1997). We
use a standardized historical review, followed by a detailed otolaryngological
examination and neurological and general examination as indicated by the
initial evaluation. Our psychophysical testing includes a butyl alcohol
threshold test (Linschoten et
al., 2001), a seven item smell identification test
(Cain et al., 1988),
the University of Pennsylvania Smell Identification Test (UPSIT)
(Doty et al., 1984)
and taste testing as indicated. The details of the testing have been published
previously (Hill and Jafek,
1989). Radiological evaluation of the olfactory system is limited
to coronally oriented computerized tomography of the ethmoid region. For
additional evaluation, high resolution coronal MRI images, with and without
contrast material and with fat suppression techniques, offer the best
opportunity to study the olfactory bulbs and tracts
(Truit and Kelly, 1993). Other
routine tests (e.g. CBC and blood chemistries) rarely produce diagnostic
results in olfactory dysfunction and are not obtained routinely. Additional
considerations and an algorithm for the evaluation of patients with loss of
smell have recently been presented (Jafek
et al., 2000).
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Method |
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TopAbstractIntroductionMethodOlfactory epitheliumOutlookReferences |
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The patient is placed in the supine position and the operating microscope is used to evaluate the internal nose. Alternatively, the endoscope might be used, but the operating microscope, with a self-retaining speculum, stabilized in the non-dominant hand, offers maximal exposure and three-dimensional visualization with variable magnification and is preferred by the authors (Lovell et al., 1982
).
A 4% cocaine nasal spray is used for vasoconstriction and anesthesia.
Alternatively, a combination of 1% lidocaine and 0.05% oxymetazoline might be
used. Following an initial nasal spray, a cotton pledget soaked in the mixture
is inserted superiorly into the olfactory cleft until resistance is
encountered to maximize vasoconstriction and anesthesia. The biopsy is
obtained from the anterior septum, as high as possible, just anterior and
superior to the insertion of the middle turbinate. The olfactory biopsy
instrument is a hook-shaped open tool that is designed to obtain the biopsy as
free of crush artifact as is possible. The instrument (SP7-31609) is
commercially available by custom order through the Bausch & Lomb
Surgical/Chiron Vision/Storz Instrument Co. (Manchester, MO). Following
placement in the superior nasal vestibule, the cutting edge of the biopsy
instrument is rotated 90° and gently pressed against the septal mucosa.
With a light downward pull, the biopsy is obtained and the instrument
withdrawn (Figure 1). Patients
are advised not to blow their nose for 24 h and to avoid heavy lifting or
straining after the biopsy. Biopsies are obtained from the flat nasal septum,
rather than the more convoluted lateral superior turbinate. Olfaction is not
adversely affected by biopsy (Lanza et
al., 1994).
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Alternatively, Lanza and Trojanowski have described the use of cupped
forceps to obtain olfactory tissue
(Trojanowski et al.,
1991; Lanza et al.,
1993). The advantage of the forceps, regardless of the design, is
that it minimizes the occasional loss of the specimen and can obtain a larger
specimen. The disadvantage is that it induces additional trauma and a `crush
artifact' to the specimen. Monti-Bloch et al.
(Monti-Bloch et al.,
1998) recommended the use of a bristle brush to obtain nasal
chemosensory tissue, but this has not worked well in our hands. Hasegawa
et al. (Hasegawa et al.,
1986) also devised their own biopsy instrument.
Specimens may be processed for routine electron microscopic evaluation of
the epithelial fine structure (Jafek
et al., 1997), for immunohistochemical study
(Jafek et al., 1997)
or for single cell study or recording
(Murrow et al.,
2000).
Microscopic structure of the human nasal mucosa
Six types of epithelium line the nasal passages in humans. Anteriorly, in
direct contact with the environment, there is a keratinized, stratified
squamous epithelium. Anteriolaterally, the sinus cavities are lined by low
pseudostratified respiratory epithelium. Postero-laterally, there is an abrupt
transition to a moist, non-keratinized stratified epithelium. Superiorly,
there is a pseudostratified columnar respiratory epithelium which
interdigitates with and, more superiorly, transitions to the ciliated columnar
olfactory epithelium (Jafek,
1983). About 1 cm posterior to the anterior columella and 0.3-0.4
cm above the floor of the nose lies the organ of Jacobson (VNO) with its
unique ciliated epithelium (Moran et
al., 1991; Jafek et
al., 1997; Knecht et
al., 2001). This organ processes pheromones in lower
vertebrates and is thought by some to function similarly in humans
(Jafek et al., 1997).
Others are less confident that the human VNO is functional
(Meredith, 2001).
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Olfactory epithelium |
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TopAbstractIntroductionMethodOlfactory epitheliumOutlookReferences |
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The human olfactory epithelium is a pseudostratified columnar epithelium that rests on a highly cellular lamina propria that contains the Bowman's glands and extends
150 µm down to the underlying bone or cartilage. It
contains four major cell types, ciliated bipolar olfactory receptors,
microvillar cells, sustentacular cells and basal cells. All except the basal
cells project to the surface. In addition, occasional degenerating cells and
inflammatory cells, primarily lymphocytes, are seen
(Meredith, 2001). Pathology
The histopathology of the dysfunctional olfactory epithelium confirms the
hypothesis that olfactory dysfunction is usually accompanied by
ultrastructural change that can be correlated with the nature and degree of
dysfunction (Jafek et al.,
1997). Over 200 conditions and an equal number of medications and
toxins have been associated with olfactory loss, although many of these
reports are anecdotal and poorly documented. Schiffman
(Schiffman, 1983) and Amoore
(Amoore, 1986) produced
comprehensive early reviews, which were subsequently updated and reorganized
by Hastings and Miller (Hastings and
Miller, 1997), focusing primarily on the `toxic' exposures. Others
(Doty et al., 1991;
Yamagishi and Nakano, 1992;
Seiden,
1997a,b)
offer more recent reviews.
Four etiologies of olfactory loss (post-traumatic, postviral, nasal/sinus
disease and idiopathic) constitute 70-85% of reported cases (Seiden,
1997a,b).
The histopathology, as elucidated by olfactory biopsy, is as follows.
Post-traumatic, or `post-concussive', olfactory disorder (PTOD) is found in
5% of head injury patients (Jafek
et al., 1989). Occipital trauma is most common with
injury or laceration of the `tethered' fila olfactoria. Frontal impacts
produced less dysfunction than back or side impacts
(Doty et al., 1997).
Intracranial hemorrhage is seen in more severe cases. In our observations, the
pathology of the olfactory epithelium in PTOD consisted of three principal
changes. First, the general epithelial orientation was disorganized. The
epithelium appeared thicker as individual cells were enlarged or appeared
degenerate. The nuclei, which are normally arranged in a band across the
middle of the epithelium, were dispersed throughout the epithelium and even
approached the epithelial surface. Second, axon proliferation was observed,
especially just below the basement membrane, but even throughout the
epithelium. Third, the olfactory receptors were diminished in number. Those
that were present were often found to be `bald', lacking olfactory cilia
projecting from their dendritic vesicles
(Figure 2). Occasionally, basal
bodies were seen within the vesicles, but these were diminished and appeared
unconnected to projecting cilia (Jafek
et al., 1989). These three consistent observations,
olfactory disruption, axon proliferation and absence of ciliogenesis,
supported severance of the fila olfactoria at the cribiform plate as the
mechanism of injury in PTOD. Others confirmed these observations, as Hasegawa
et al. (Hasegawa et al.,
1986) noted that the extent of degeneration varied according to
the degree of damage incurred and the time lapse present from injury. Because
of the probability of bleeding and fibrosis at the cribiform plate, treatment
should be directed at newer (yet to be developed) surgical attempts at lysis
of this scar tissue.
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Post-viral olfactory dysfunction (PVOD) is diagnosed when smell loss
follows an upper respiratory infection. These patients tend to be older, with
a 2:1 female preponderance (the reason for this is unknown)
(Jafek et al.,
1990b). Hyposmia is more common and dysosmia may be seen in up to
two-thirds of patients. Biopsy studies suggest a direct insult to the
olfactory neuroepithelium with a `patchy' regeneration accounting for the high
incidence of dysosmia (Figure
3). Alternatively, patchy degeneration is also possible
(Jafek et al.,
1990b). Looking at the residual olfactory epithelium, we found
that in patients with anosmia the olfactory epithelium was markedly
disorganized. Very few, if any, receptors were seen. Those that were present
usually had dendrites that did not reach the epithelial surface and appeared
somewhat shrunken. In hyposmic patients the individual receptors appeared much
more normal, but reduced in numbers and distributed in `patches'. On biopsy,
frequent junctions of olfactory and respiratory epithelium are seen
(Figure 3), suggesting an
extremely patchy distribution of the olfactory epithelium
(`checkerboard-like') interspersed with respiratory epithelium. The dendrites
of the receptor cells contained large numbers of cytoplasmic inclusions
reminiscent of myelin figures. Although the functional significance of the
presence of these electron-dense bodies is unknown, their presence was
remarkably consistent and limited to receptor cells. Microvillar cells were
observed and appeared normal, as did the support cells, basal cells and
underlying basement membrane. These findings were consistent with subsequent
ones by Yamagishi et al.
(Yamagishi et al.,
1994), who studied biopsies using immunohistochemical staining for
neuron-specific enolase, S-100 protein, cytokeratin and proliferating cell
nuclear antigen (PCNA). Although the recovery of olfactory function in
patients with post-viral olfactory disorders was generally `not very good',
they found that overall a high proportion of Alinamin i.v. injection
test-positive patient's recovered their sense of smell. Immunohistochemical
study of the biopsy specimens revealed a decrease in the number of olfactory
receptor cells and nerve bundles. In a few cases the olfactory neuroepithelium
was replaced by metaplastic squamous epithelium. Sometimes different types of
degeneration were found in the same specimen. No PCNA immunoreactivity was
detected in the olfactory epithelium. They noted that recovery generally
correlated with the initial degree of degeneration of the olfactory mucosa.
Alinamin test-positive patients (generally the hyposmic patients) had more
olfactory receptor cells. They concluded that olfactory mucosal biopsy and the
Alinamin i.v. injection test were useful methods of determining the prognosis
in post-URVI olfactory disorders
(Yamagishi et al.,
1994). While the loss in PVOD does not fluctuate, gradual
improvement in function over a period of years is often seen. Medical or
surgical therapy has not generally been helpful.
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Inflammatory nasal and sinus disease is one of the most common causes of
olfactory loss (Seiden,
1997a,b).
Obstruction of the olfactory cleft, or a `conductive loss', is postulated to
be etiologic, with a recurrent cycle of secretion stagnation, ciliary and
epithelial damage and mucosal change. Histopathologically, the olfactory
epithelium is initially normal in sinusitis
(Jafek et al., 1994;
Seiden,
1997a,b).
However, with recurrent infection and epithelial damage or concurrent viral
infection, irreversible damage of the olfactory receptors with squamous
metaplasia or fibrosis may result, making the olfactory dysfunction permanent
(Jafek et al., 1994;
Seiden,
1997a,b).
This condition is to be differentiated from steroid-dependent anosmia.
Steroid-dependent anosmia is a special type of sinonasal disease in which
the nose contains a large number of polyps. It is differentiated from
irreversible loss, as described above, by the `burst of steroids test', as
described by Jafek et al. (Jafek
et al., 1987). When this clinical test is positive, a
burst of steroids (60 mg prednisone, decreasing by 5 mg/day, covered by
prophylactic antibiotics) relieves the anosmia, temporarily, while the
steroids are taken. Examination of the olfactory epithelium shows it to be
entirely normal. Failure of the steroid test suggests irreversible extensive
inflammatory disease or olfactory epithelial fibrosis, secondary to recurrent
or chronic sinusitis or post-viral anosmia
(Jafek et al.,
1987).
Olfactory biopsy has been helpful in a few other conditions. In congenital
anosmia (e.g. Kallman's syndrome) we observed an absence or a severe decrease
in the olfactory receptors, but those that were present appeared normal
(Jafek et al.,
1990a). This agreed with Rawson et al.
(Rawson et al.,
1995), who found that at least some olfactory neurons were
functionally mature, by morphology and by calcium imaging, suggesting that
complete development of the olfactory bulbs is not required for
differentiation of mature olfactory receptors. Others have observed that the
neurons that were present lacked cilia (i.e. were morphologically immature),
that the fila olfactoria had fewer than the normal number of axons and a large
proportion of them were apparently undergoing electron-lucent degeneration and
that neuromatous collections of axons were seen superficial to the basement
membrane in the epithelium (Yousem et
al., 1996). They characterized these changes as similar to
those observed in the mucosa of experimentally bulbectomized rodents. This
would be consistent with the absence of olfactory bulbs seen on MRI.
Neurodegenerative disorders (e.g. Wernicke's encephalopathy, Parkinson's
disease, AIDS and dementia) have a variety of non-specific changes in the
olfactory epithelium (Jafek et
al., 1992). In Alzheimer's disease there is severe epithelial
disruption, increased numbers of large mitochondria in the support cells with
electron-dense particles and crystals on the overlying surface on the
epithelium that stain metachromatically with toluidine blue
(Moran et al., 1992).
Radiographic microanalysis of these crystals indicates a high concentration of
silicone in the area of the crystal deposit, while the adjacent respiratory
epithelium exhibits no similar deposit of these crystals. Neurofilament
antibodies and abnormal neuronal structures are also seen in the olfactory
epithelium of patients with Alzheimer's disease, although Trojanowski et
al. (Trojanowski et al.,
1991) observed that dystrophic olfactory neurites occur very
frequently in neurologically normal adults. The relevance of these neuritic
changes to aging or specific disease processes remains speculative, however
(Trojanowski et al.,
1991). Aging produces a decrease in olfactory acuity, probably on
the basis of a decrease in absolute numbers of receptors
(Weiffenbach, 1984).
Toxic causes of olfactory dysfunction probably also produce decreased
numbers of receptors, probably with intervening fibrosis
(Hastings and Miller, 1997).
Hepatic dysfunction, endocrine dysfunction, renal dysfunction and metabolic
and nutritional deficiencies, along with a variety of pharmacological
etiologies, are also described as causing olfactory loss. The exact nature of
the epithelial changes has not yet been elucidated
(Jafek et al.,
1997).
Finally, as many as 29% of patients presenting with chemosensory complaints
have no identifiable taste or smell loss, using standard tests
(Doty et al., 1991).
Here, biopsy would not be indicated, but should show normal epithelium.
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Outlook |
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TopAbstractIntroductionMethodOlfactory epitheliumOutlookReferences |
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Olfactory marker protein (OMP) has been shown to be a robust marker of olfactory receptor neurons (Margolis, 1972
). This will continue to be helpful in evaluating olfactory
biopsies. Immunoelectron microscopy may aid in evaluating the morphology of
OMP-immunoreactive neurons in various conditions
(Johnson et al.,
1989). Immunocytochemical studies using antisera against nerve
growth factors will help to define the importance of nerve growth factor in
various regenerative or developmental conditions. Additional studies of
molecular changes in the components of the receptor cell membrane and
receptors, amplified by PCR, should also help us understand the olfactory
transduction mechanism, along with dysfunctional states
(McClintock, 2000). Additional
studies of ultra-structure, immunocytochemistry, molecular biology and
physiology will continue to provide essential complementary information in
elucidating olfactory pathophysiology. In conclusion, olfactory biopsy of the olfactory epithelium has been shown to be a safe, reliable method to study both normal and pathological olfactory states over the past more than 20 years. Complications related to biopsy have been infrequent and minimal. Pre-biopsy olfactory acuity has been maintained. Additional studies of ultra-structure, complemented by immunocytochemical and molecular function, will continue to provide increased understanding of olfactory function and dysfunction, pointing the way to new therapeutic strategies.
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References |
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TopAbstractIntroductionMethodOlfactory epitheliumOutlookReferences |
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Amoore, J.E. (1986) Effects of chemical exposure on olfaction in humans. In Barrow, C.S. (ed.), Toxicology of the Nasal Passages. Hemisphere Publishing, Washington, DC.
Cain, W.S., Gent, J.F., Goodspeed, R.B. and Leonard, G. (1988) Evaluation of olfactory dysfunction in the Connecticut Chemosensory Clinical Research Center.Laryngoscope , 98,83 -98.[Web of Science][Medline]
Doty, R.L., Shaman, P. and Dann, M. (1984) Development of the University of Pennsylvania Smell Identification Test: a standardized microencapsulated test of olfactory function. Physiol. Behav., 32,489 -502.[Medline]
Doty R.L., Bartoshuk L. and Snow, J.B. (1991) Causes of olfactory and gustatory disorders. In Getchell, T.V., Doty, R.L., Bartoshuk, L.M. and Snow, J.B. (eds), Smell and Taste in Health and Disease. Raven Press, New York, NY, pp.449 -462.
Doty, R.L., Yousem, D.M., Pham, L.T., Kreshak, A.A., Geckle,
R. and Lee, W.W. (1997) Olfactory dysfunction in
patients with head trauma. Arch. Neurol.,54
, 1131-1140.
Hasegawa, S., Yamagishi, M. and Nakano, Y. (1986) Microscopic studies of human olfactory epithelia following traumatic anosmia. Arch. Otolaryngol.,243 , 112-116.
Hastings, L. and Miller, M.L. (1997) Olfactory loss secondary to toxic exposure. In Seiden, A.M. (ed.),Taste and Smell Disorders . Thieme, New York, NY, pp.88 -106.
Hill, D.P. and Jafek, B.W. (1989) Initial otolaryngologic assessment of patients with taste and smell disorders. Ear Nose Throat J., 68,362 -370.[Medline]
Jafek, B.W. (1983) Ultrastructure of human nasal mucosa. Laryngoscope, 93,1576 -1599.[Web of Science][Medline]
Jafek, B.W, Moran, D.T., Eller, P.M. and Rowley, J.C.
(1987) Steroid dependent anosmia. Arch.
Otol., 113,547
-549.
Jafek, B.W., Eller, P.M., Esses, B.A. and Moran, D.T.
(1989) Post-traumatic anosmia: ultrastructural
correlates. Arch. Neurol., 46,300
-304.
Jafek, B.W., Gordon, A.S.D., Moran, D.T. and Eller, P.M. (1990a) Congenital anosmia. Ear Nose Throat J., 69,331 -337.[Medline]
Jafek, B.W., Hartman, D., Eller, P.M., Johnson, E.W., Strahan, R.C. and Moran, D.T. (1990b) Post-viral olfactory dysfunction. Am. J. Rhinol., 4,91 -100.
Jafek, B.W., Eller, P.M., Johnson, E.W., Chapman, M.M. and Filley, C.M. (1992) Ultrastructural changes in the olfactory epithelium in Alzheimer's disease. Am. J. Rhinol., 6,219 -225.
Jafek, B.W., Murrow, B. and Johnson, E.W. (1994) Olfaction and endoscopic sinus surgery.Ear Nose Throat J. , 73.548 -552.[Medline]
Jafek, B.W., Johnson, E.W., Eller, P. and Murrow, B. (1997) Olfactory mucosal biopsy and related histology. In Seiden, A.M. (ed.), Taste and Smell Disorders. Thieme, New York, NY, pp. 107-127.
Jafek B.W., Linschoten M. and Murrow, B. (2000) Evaluation and treatment of anosmia. Curr. Opin. Otolaryngol. Head Neck Surg., 8,63 -67.
Johnson, E.W., Eller, P.M. and Jafek, B.W. (1989) Immunocytochemical investigation of olfactory neurons and synapses at the light and electron microscopic levels. Chem. Senses, 14,715 .
Knecht, M., Kuhnau, D., Huttenbrink, K.B., Witt, M. and Hummel, T. (2001) Frequency and localization of the putative vomeronasal organ in humans in relation to age and gender.Laryngoscope , 111,448 -452.[Web of Science][Medline]
Lanza, D.C., Moran, D.T., Doty, R.L., Trojanowski, J.Q., Lee, J.H., Rowley, J.C., Crawford, D. and Kennedy, D.W. (1993) Endoscopic human olfactory biopsy technique: a preliminary report. Laryngoscope,103 , 815-819.[Web of Science][Medline]
Lanza, D.C., Deems, D.A., Doty, R.L., Moran, D., Crawford, D., Rowley, J.C., Sajjadian, A. and Kennedy, D.W. (1994) The effect of human olfactory biopsy on olfaction: a preliminary report. Laryngoscope, 104,837 -840.[Web of Science][Medline]
Linschoten, M.R., Harvey, L.O. Jr, Eller, P.M. and Jafek B.W. (2001) Fast and accurate measurement of taste and smell thresholds using a maximum-likelihood adaptive staircase procedure.Percept. Psychophys. , 63,1330 -1347.[Web of Science][Medline]
Lovell, M.A., Jafek, B.W., Moran, D.T. and Rowley,
J.C. (1982) Biopsy of human olfactory mucosa: an
instrument and a technique. Arch. Otol.,108
, 247-249.
Margolis, F.L. (1972) A brain protein
unique to the olfactory bulb. Proc. Natl Acad. Sci. USA,69
, 1221-1224.
McClintock, T.S. (2000) Molecular biology of olfaction. In Finger, T., Silver, W.L. and Restrepo, D. (eds),The Neurobiology of Taste and Smell , 2nd Edn. Wiley-Liss, New York, NY, pp. 179-200.
Meredith, M. (2001) Human vomeronasal organ
function: a critical review of best and worst cases. Chem.
Senses, 26,433
-445.
Monti-Bloch, L., Jennings-White, C. and Berliner, D.L. (1998) The human vomeronasal system. A review.Ann. N.Y. Acad. Sci. , 855,373 -389.[Web of Science][Medline]
Moran, D.T., Jafek, B.W. and Rowley, J.C. (1991) The vomeronasal (Jacobson's) organ in man: ultrastructure and frequency of occurrence. J. Steroid Biochem. Mol. Biol., 39,545 -552.[Web of Science][Medline]
Moran, D.T., Jafek, B.W., Eller, P.M. and Rowley, J.C. (1992) Ultrastructural histopathology of human olfactory dysfunction. Microsc. Res. Tech.,23 , 103-110.[Web of Science][Medline]
Murrow, B.M., Restrepo, D. and Jafek B.W. (2000) A novel isolation system for human olfactory receptor cells. Chem. Senses, 25,5 .
Rawson, N.E., Brand, J.G., Cowart, B.J., Lowry, L.D., Pribitkin, E.A., Rao, V.M. and Restrepo, D. (1995) Functionally mature olfactory neurons from two anosmic patients with Kallmann syndrome. Brain Res., 681,58 -64.[Web of Science][Medline]
Schiffman, S.S. (1983) Taste and smell in disease. N. Engl. J. Med., 308,1337 -1343.[Abstract]
Seiden, A. (ed.) (1997a) Smell and Taste Disorders. Thieme, New York, NY.
Seiden, A. (1997b) Olfactory loss secondary to nasal and sinus pathology. In Seiden, A. (ed.), Smell and Taste Disorders. Thieme, New York, NY, pp.52 -71.
Trojanowski, J.Q., Newman, P.D., Hill, W.D. and Lee, V.M. (1991) Human olfactory epithelium in normal aging, Alzheimer's disease, and other neurodegenerative disorders. J. Comp. Neurol., 310,365 -376.[Web of Science][Medline]
Truit, C.L. and Kelly, W.M. (1993) The olfactory system. Neuroimaging Clin. N. Am.,3 , 47-70.
Weiffenbach, J.M. (1984) Taste and smell perception in aging. Gerodontology,3 , 131-136.[Medline]
Yamagishi, M. and Nakano, Y. (1992) A re-evaluation of the classification of olfactory epithelia in patients with olfactory disorders. Eur. Arch. Otorhinolaryngol.,249 , 393-399.[Medline]
Yamagishi, M., Fujiwara, M. and Nakamura, H. (1994) Olfactory mucosal findings and clinical course in patients with olfactory disorders following upper respiratory viral infection. Rhinology, 32113 -118.[Medline]
Yousem, D.M., Geckle, R.J., Bilker, W., McKeown, D.A. and
Doty, R.L. (1996) MR evaluation of patients with
congenital hyposmia or anosmia. Am. J. Roentgenol.,166
, 439-443.
Accepted May 25, 2002
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