Edmund A. Pribitkin

Amyloidosis of the upper aerodigestive tract

Objectives/Hypothesis To delineate the clinical and pathologic characteristics of upper aerodigestive tract amyloidosis with particular attention to laryngeal amyloidosis.

Sour Ageusia in Two Individuals Implicates Ion Channels of the ASIC and PKD Families in Human Sour Taste Perception at the Anterior Tongue

Background The perception of sour taste in humans is incompletely understood at the receptor cell level. We report here on two patients with an acquired sour ageusia. Each patient was unresponsive to sour stimuli, but both showed normal responses to bitter, sweet, and salty stimuli. Methods and Findings Lingual fungiform papillae, containing taste cells, were obtained by biopsy from the two patients, and from three sour-normal individuals, and analyzed by RT-PCR. The following transcripts were undetectable in the patients, even after 50 cycles of amplification, but readily detectable in the sour-normal subjects: acid sensing ion channels (ASICs) 1a, 1β, 2a, 2b, and 3; and polycystic kidney disease (PKD) channels PKD1L3 and PKD2L1. Patients and sour-normals expressed the taste-related phospholipase C-β2, the δ-subunit of epithelial sodium channel (ENaC) and the bitter receptor T2R14, as well as β-actin. Genomic analysis of one patient, using buccal tissue, did not show absence of the genes for ASIC1a and PKD2L1. Immunohistochemistry of fungiform papillae from sour-normal subjects revealed labeling of taste bud cells by antibodies to ASICs 1a and 1β, PKD2L1, phospholipase C-β2, and δ-ENaC. An antibody to PKD1L3 labeled tissue outside taste bud cells. Conclusions These data suggest a role for ASICs and PKDs in human sour perception. This is the first report of sour ageusia in humans, and the very existence of such individuals (“natural knockouts”) suggests a cell lineage for sour that is independent of the other taste modalities.

Numerical modeling of nasal obstruction and endoscopic surgical intervention: Outcome to airflow and olfaction

Background Mechanical obstruction of odorant flow to the olfactory neuroepithelium may be a primary cause of olfactory loss in nasal-sinus disease patients. Surgical removal of nasal obstruction may facilitate the recovery of olfactory ability. Unfortunately, quantifying the functional impact of nasal obstruction and subsequent surgical outcomes using acoustic rhinometry, rhinomanometry, or CT scans is inadequate. Methods Using computational fluid dynamics (CFD) techniques, we can convert patient CT scans into anatomically accurate 3D numerical nasal models that can be used to predict nasal airflow and odorant delivery rates. These models also can be rapidly modified to reflect anatomic changes, e.g., surgical removal of polyps. Results CFD modeling of one patients nose pre- and postsurgery showed significant improvement in postsurgical ortho- and retronasal airflow and odorant delivery rate to olfactory neuroepithelium (<1000 times), which correlated well with olfactory recovery. Conclusion This study has introduced a novel technique (CFD) to calculate nasal airflow dynamics and its effects on olfaction, nasal obstruction, and sinus disease. In the future, such techniques may provide a quantitative evaluation of surgical outcome and an important preoperative guide to optimize nasal airflow and odorant delivery.

Prevalence and Causes of Severe Taste Loss in a Chemosensory Clinic Population

Although complete or near-complete olfactory loss has been extensively documented and described, few published reports have documented severe generalized gustatory loss (across qualities and neural fields) with rigorous psychophysical testing, and none have explored the prevalence or causes of such losses in a large clinical population. This study retrospectively reviews our chemosensory clinics experience of 1,176 patients evaluated for complaints of chemosensory dysfunction in order to address these issues. Our series confirms that despite the complex, bilateral innervation and regenerative capacity of the gustatory system, severe generalized taste loss does occur as a clinical entity, albeit rarely: only 0.85% (n = 10) of our patients evidenced such a deficit, as compared to 32% (n = 371) who were found to have a profound olfactory deficit. Combinations of systemic and/or acute events may underlie many cases of severe taste loss, and in half of our cases, these patients evidenced moderate to complete smell loss as well.

Neuropathology of the olfactory mucosa in chronic rhinosinusitis.

Background Chronic rhinosinusitis (CRS) is a complex heterogeneous inflammatory disease that affects the nasal cavity, but the pathological examination of the olfactory mucosa (OM) in this disease has been limited. Methods Nasal biopsy specimens were obtained from 20 control subjects and 50 CRS patients in conjunction with clinical assessments. Histopathology of these nasal biopsy specimens was performed and immunohistochemistry was used to characterize nonneuronal, neuronal, and inflammatory cells in the OM. These OM characteristics were then evaluated to determine the degree to which pathological features may be related to smell loss in CRS. Results Histopathological examination of control and CRS OM revealed changes in the normal pseudostratified olfactory epithelium (OE): intermixing of goblet cells, metaplasia to squamous-like cells, and erosion of the OE. Lower percentages of normal epithelium and olfactory sensory neurons were found in CRS OE compared with controls. Relative to other CRS patients, those with anosmia had the greatest amount of OE erosion, the highest density of eosinophils infiltrating the OE, and exhibited the most extensive abnormalities on CT and endoscopic examination, including being significantly more likely to exhibit nasal polyposis. Conclusion Our results suggest that OM pathology observed in nasal biopsy specimens can assist in understanding the degree of epithelial change and sensorineural damage in CRS and the potential for olfactory loss.

Oncogenes and inflammation rewire host energy metabolism in the tumor microenvironment: RAS and NFκB target stromal MCT4

Here, we developed a model system to evaluate the metabolic effects of oncogene(s) on the host microenvironment. A matched set of “normal” and oncogenically transformed epithelial cell lines were co-cultured with human fibroblasts, to determine the “bystander” effects of oncogenes on stromal cells. ROS production and glucose uptake were measured by FACS analysis. In addition, expression of a panel of metabolic protein biomarkers (Caveolin-1, MCT1, and MCT4) was analyzed in parallel. Interestingly, oncogene activation in cancer cells was sufficient to induce the metabolic reprogramming of cancer-associated fibroblasts toward glycolysis, via oxidative stress. Evidence for “metabolic symbiosis” between oxidative cancer cells and glycolytic fibroblasts was provided by MCT1/4 immunostaining. As such, oncogenes drive the establishment of a stromal-epithelial “lactate-shuttle”, to fuel the anabolic growth of cancer cells. Similar results were obtained with two divergent oncogenes (RAS and NFκB), indicating that ROS production and inflammation metabolically converge on the tumor stroma, driving glycolysis and upregulation of MCT4. These findings make stromal MCT4 an attractive target for new drug discovery, as MCT4 is a shared endpoint for the metabolic effects of many oncogenic stimuli. Thus, diverse oncogenes stimulate a common metabolic response in the tumor stroma. Conversely, we also show that fibroblasts protect cancer cells against oncogenic stress and senescence by reducing ROS production in tumor cells. Ras-transformed cells were also able to metabolically reprogram normal adjacent epithelia, indicating that cancer cells can use either fibroblasts or epithelial cells as “partners” for metabolic symbiosis. The antioxidant N-acetyl-cysteine (NAC) selectively halted mitochondrial biogenesis in Ras-transformed cells, but not in normal epithelia. NAC also blocked stromal induction of MCT4, indicating that NAC effectively functions as an “MCT4 inhibitor”. Taken together, our data provide new strategies for achieving more effective anticancer therapy. We conclude that oncogenes enable cancer cells to behave as selfish “metabolic parasites”, like foreign organisms (bacteria, fungi, viruses). Thus, we should consider treating cancer like an infectious disease, with new classes of metabolically targeted “antibiotics” to selectively starve cancer cells. Our results provide new support for the “seed and soil” hypothesis, which was first proposed in 1889 by the English surgeon, Stephen Paget.

Superficial Musculoaponeurotic System Elevation and Fat Graft Reconstruction After Superficial Parotidectomy

Objective/Hypothesis: Elevation of the superficial musculoaponeurotic system (SMAS) with or without fat graft interposition during superficial parotidectomy prevents a concave facial deformity and Freys syndrome.

The Evolving Etiology of Bilateral Vocal Fold Immobility

In the past, bilateral vocal fold immobility (BVFI) occurred most commonly after thyroidectomy. However, no large series documenting the etiology of adult BVFI has been published within the past fifteen years. This study reviews the etiologic patterns of BVFI at our institutions. We compare BVFI from before and after 1980. We also review combined studies of unilateral vocal fold immobility (UVFI) to compare and unilateral versus bilateral etiologic trends. In comparison with previously published series, fewer cases of BVFI present today as a complication of thyroid surgery and more as the result of malignancies and nonsurgical trauma. Unfortunately, BVFI caused by malignancy is not usually an initial sign of local disease, but an ominous sign of recurrence or metastases. In comparing UVFI and BVFI we found that thyroidectomy causes a higher percentage of BVFI than of UVFI. Over one-third of UVFI cases were caused by neoplasm which further underscores the potential seriousness of immobile vocal folds and the need for careful investigation.

Functionally mature olfactory neurons from two anosmic patients with Kallmann syndrome.

Patients with Kallmann syndrome (KS) exhibit hypogonadotropic hypogonadism and anosmia [Kallmann et al., Am. J. Mental Def., 48 (1944) 203-236] secondary to failure of gonadotropin-releasing hormone (GnRH)-producing neurons to migrate from the olfactory placode to the brain, and to agenesis of the olfactory bulbs. It has been hypothesized that olfactory neurons (ON) from individuals with KS are immature partly on the basis of studies in animals showing that lack of synaptic connection of ON with the olfactory bulb results in expression of immature ON [Schwob et al., J. Neurosci., 12 (1979) 880-883]. To test this assumption, we obtained olfactory tissue samples from two males diagnosed with KS on the basis of medical history and MRI studies. Both patients were anosmic. The functioning of cells isolated from biopsies taken from the upper middle turbinate and septum was studied by measuring changes in intracellular Ca2+ concentration ([Cai]) using dual excitation fluorescence microscopy. Biopsies from both patients yielded cells that morphologically appeared to be ON. Seven of 16 cells that morphologically resembled ON responded with a change in [Cai] upon stimulation with an odorant mixture. These studies show that at least some ON in KS individuals are functionally mature and suggest that complete development of the olfactory bulbs is not required for differentiation of mature human ON.

Keloid Excision and Recurrence Prophylaxis Via Intradermal Interferon‐Gamma Injections: A Pilot Study

Keloids are an abnormal response to wound healing distinguished by an overproduction of collagen. Thickened bundles of collagen in the reticular dermis oriented haphazardly in relation to the overlying epithelium are found in keloids, in contrast to thinner collagen fibers in a more orderly arrangement that are found in normal scars. Previous clinical trials of intralesional interferon‐gamma (IFN‐G) injections by Larrabee et al. 6 and Granstein et al. 12,14 showed a decrease in lesion size. These findings led to a conclusion that IFN‐G would be a useful adjunct to surgical excision of keloids to aid in preventing recurrence. We performed a double‐blind, placebo‐controlled trial in patients with two or more keloids treated with excision and subsequent local injections of IFN‐G or placebo.