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Biomedical subjects

R C Kern

Publications and source records attributed to R C Kern.

At least 19 recordsLinked to original sources
PubMed2004

Pathology of the olfactory mucosa: implications for the treatment of olfactory dysfunction.

OBJECTIVE: The pathology of the olfactory mucosa is poorly understood; however, most cases of hyposmia and anosmia appear to be associated with a decline in the number of functioning mature olfactory sensory neurons (OSNs). Under normal conditions, OSNs undergo apoptotic cell death at a baseline rate likely secondary to their exposed location in the nose. Regeneration of mature OSNs from precursors in the epithelium allows the animal to maintain an adequate number of neurons necessary for olfactory sensation. In many cases of olfactory dysfunction, this balance is apparently disturbed, with a net loss of OSNs. The current study will examine normal and diseased olfactory tissue for the presence of data demonstrating that the preferred mechanism of OSN cell death is apoptotic in both health and disease. The potential therapeutic implications will be discussed. STUDY DESIGN: Histologic analysis of human and animal olfactory tissue. METHODS: Normal and diseased human and animal olfactory mucosa were assessed for immunohistochemical evidence of apoptosis. RESULTS: Increased activity of the apoptotic effector enzyme caspase-3 was demonstrated in diseased olfactory mucosa in comparison with normal controls. CONCLUSION: These results indicate that a common pathway may mediate OSN cell death from a diverse set of pathologic insults including aging, trauma, and sinusitis. Interference with this pathway of cell death is currently the subject of intense pharmacotherapeutic research for the management of stroke and meningitis. These drugs may ultimately prove useful in the treatment of clinical olfactory dysfunction.

Aging↗
PubMed2004

Pathology of the olfactory epithelium: smoking and ethanol exposure.

OBJECTIVE: To investigate the effects of tobacco smoke on the olfactory epithelium. Cigarette smoking has been associated with hyposmia; however, the pathophysiology is poorly understood. The sense of smell is mediated by olfactory sensory neurons (OSNs) exposed to the nasal airway, rendering them vulnerable to environmental injury and death. As a consequence, a baseline level of apoptotic OSN death has been demonstrated even in the absence of obvious disease. Dead OSNs are replaced by the mitosis and maturation of progenitors to maintain sufficient numbers of neurons into adult life. Disruption of this balance has been suggested as a common cause for clinical smell loss. This current study will evaluate the effects of tobacco smoke on the olfactory mucosa, with emphasis on changes in the degree of OSN apoptosis. STUDY DESIGN: A rat model was used to assess the olfactory epithelium after exposure to tobacco smoke. METHODS: Rats were exposed to tobacco smoke alone (for 12 weeks), smoke plus dietary ethanol (for the final 5 weeks), or to neither (control). Immunohistochemical analysis of the olfactory epithelium was performed using an antibody to the active form of caspase-3. Positive staining for this form of the caspase-3 enzyme indicates a cell undergoing apoptotic proteolysis. RESULTS: Control rats demonstrated a low baseline level of caspase-3 activity in the olfactory epithelium. In contrast, tobacco smoke exposure triggered a dramatic increase in the degree of OSN apoptosis that affected all stages of the neuronal lineage. CONCLUSIONS: These results support the following hypothesis: smell loss in smokers is triggered by increased OSN death, which eventually overwhelms the regenerative capacity of the epithelium.

Animals↗
PubMed2004

Treatment of olfactory dysfunction, II: studies with minocycline.

OBJECTIVES/HYPOTHESIS: The treatment of anosmia has changed minimally since the early 1970s, despite dramatic advances in the understanding of the molecular biology of olfaction. Recent studies from the authors' laboratory have suggested that most common causes of clinical olfactory dysfunction, including rhinosinusitis, appear to be associated with increased apoptotic death of olfactory sensory neurons. This appears to result in a decline in the number of functioning mature olfactory sensory neurons, despite the capacity of the olfactory epithelium for regeneration. The current study evaluated the ability of the antibiotic minocycline to inhibit olfactory sensory neuron apoptosis. This drug is known to inhibit apoptosis separate from its anti-infective properties. Olfactory sensory neuron apoptosis was triggered by surgical deafferentation ("bulbectomy"), the standard experimental model. Earlier studies have indicated that bulbectomy and sinusitis invoke similar proteolytic enzyme cascades in olfactory sensory neurons. STUDY DESIGN: Histological analysis of animal olfactory tissue. METHODS: Mice underwent unilateral olfactory bulbectomy to induce apoptotic olfactory sensory neuron death, with and without 45 mg/kg intraperitoneal minocycline given 12 hours before surgery and every 12 hours until death. Mice were killed at 2 and 4 days after bulbectomy and assessed for activation of capsase-3 and olfactory sensory neuron survival by immunohistochemical analysis. RESULTS: Minocycline resulted in partial suppression of cell death at 2 days after surgery when compared with untreated animals. CONCLUSION: Minocycline inhibits olfactory sensory neuron death in the face of a potent pro-apoptotic stimulus. This drug is well tolerated and is currently undergoing human trials for the management of a variety of neurological disorders associated with apoptosis. The current results suggest that minocycline may be efficacious in the management of peripheral olfactory loss as well.

Animals↗
PubMed2004

Laser-assisted uvulopalatoplasty in the management of snoring and obstructive sleep apnea syndrome.

Laser-assisted uvulopalatoplasty (LAUP) was initially proposed as an alternative method to treat habitual snoring. Throughout the years the indications for LAUP have broadened, however, it has also remained an area of controversy. LAUP is a staged office-based procedure involving removal of excessive uvular mucosa and creation of transpalatal vertical troughs to effectively widen the retropalatal airway. Since postlaser treatment mimics the palatal appearance after uvulopalatopharyngoplasty (UPPP), similar surgical outcomes can be expected in properly selected patients. Although still an area of controversy, the medical literature has supported the cost effectiveness, safety, and comparable efficacy to the standard of UPPP in the treatment of snoring and obstructive sleep apnea syndrome (OSAS). In select patients, LAUP is a viable option for the management of not only snoring, but also OSAS.

Humans↗
PubMed2000

Chronic sinusitis and anosmia: pathologic changes in the olfactory mucosa.

OBJECTIVES: To evaluate histological changes in the olfactory mucosa of patients with chronic rhinosinusitis These results are analyzed in light of current understanding of the pathophysiology of anosmia secondary to nasal and sinus disease. STUDY DESIGN: Prospective study of olfaction on patients undergoing sinus surgery for the management of chronic rhinosinusitis. METHODS: Thirty patients, aged 22 to 39 years, underwent olfactory biopsy at the time of surgery with evaluation by a pathologist. Inflammatory changes were graded as mild (normal), moderate, or severe. Clinical olfactory function was evaluated using the University of Pennsylvania Smell Identification Test (UPSIT). The results correlated with the degree of olfactory dysfunction. RESULTS: Of the 30 patients 19 had unequivocal olfactory mucosa in the biopsy specimen. Eleven had only respiratory or indeterminate mucosa. Nine patients demonstrated normal olfactory mucosa and normal olfactory function (UPSIT > 35). Ten patients demonstrated pathological changes in the olfactory mucosa with an influx of lymphocytes, macrophages, and eosinophils Of these 10 patients, 7 had olfactory deficits as determined by UPSIT. The remaining three patients had normal olfactory function despite moderate chronic inflammation. These studies indicate that the olfactory mucosa is capable of mounting an inflammatory response similar to that seen in the respiratory mucosa of patients with chronic sinusitis These data suggest that the olfactory deficits in these patients may be the result of inflammatory changes within the olfactory mucosa in addition to any alteration in airflow to the olfactory cleft.

Adult↗
PubMed2000

Post-traumatic olfactory dysfunction.

OBJECTIVES: This study demonstrates histopathologic and immunocytochemical changes in the olfactory bulb of a patient with post-traumatic olfactory dysfunction. These results are analyzed in light of current understanding of the pathophysiology of anosmia and dysosmia following head trauma. Emphasis is placed on potential mechanisms of human regeneration and recovery. STUDY DESIGN: The current study documents the history of a patient with the initial complaint of complete anosmia following minor head trauma. Two months after the injury the patient developed persistent, severe dysosmia with debilitating weight loss. Neurosurgical treatment, including removal of the olfactory bulbs and tracts, resulted in permanent resolution of dysosmia. METHODS: Histopathologic and immunocytochemical analysis of the olfactory bulbs was undertaken and compared with age-matched control tissue. RESULTS: Pathological analysis of the olfactory bulb revealed a marked reduction in the number of nerve processes with few intact olfactory glomeruli compared with an age-matched control. Specific immunohistochemical staining for the olfactory neuron-specific protein OMP, however, demonstrated the presence of intact axonal projections between the olfactory mucosa and the bulb. CONCLUSIONS: These results support the hypothesis that post-traumatic anosmia involves, at least in part, damage to peripheral olfactory nerve fibers with histological changes in the olfactory bulb. Potential mechanisms for the development of post-traumatic dysosmia are also discussed.

Adult↗
PubMed1999

Olfactory secretion and sodium, potassium-adenosine triphosphatase: regulation by corticosteroids.

OBJECTIVES: To investigate the cellular distribution and relative intensity of the immunoreactivity associated with the expression of sodium, potassium-adenosine triphosphatase (Na, K-ATPase) in cells of the olfactory mucosa. Second, changes in the activity of this enzyme in the olfactory mucosa are correlated with changes in the circulating corticosteroid aldosterone. METHODS: Combination of immunohistochemical and biochemical techniques were employed to examine the olfactory Na, K-ATPase. RESULTS: Within the olfactory epithelium, the Na, K-ATPase immunoreactivity was greatest at the supranuclear region of sustentacular cells and/or dendrites of olfactory receptor neurons (ORNs). Cell bodies of ORNs demonstrated moderate immunoreactivity, whereas the duct cells of Bowman's gland exhibited moderate to intense immunoreactivity. Acinar cells of the Bowman's gland were the most intensely stained components of the lamina propria, exhibiting strong immunoreactivity at the basolateral plasma membrane domains of the acinar cells and less within the cytoplasm. Binding of ouabain, a specific inhibitor of Na, K-ATPase, was significantly elevated for aldosterone-injected versus sham-injected controls. CONCLUSION: These results suggest that olfactory Na, K-ATPase is regulated by the systemic corticosteroid aldosterone. The results are consistent with the hypothesis that corticosteroids regulate olfactory secretion.

Aldosterone↗
PubMed1999

Mineralocorticoid receptors in the mammalian olfactory mucosa.

Mineralocorticoid hormones regulate secretion and absorption in a wide variety of epithelial tissues, although specific mechanisms in the olfactory mucosa are currently unknown. Utilizing reverse transcription-polymerase chain reaction (RT-PCR) analysis, we have demonstrated the expression of mineralocorticoid (type I) receptor messenger RNA in the rodent olfactory mucosa. Amplification products of predicted size were obtained with nucleotide sequences corresponding to respective mineralocorticoid receptor (MR) kidney transcripts. Immunocytochemistry, using an antibody with known specificity for MRs, was then utilized in order to localize the cellular site(s) of MR protein expression in the olfactory mucosa. The highest levels of MR immunoreactivity were localized to the supranuclear region of sustentacular cells, as well as the acinar cells of the Bowman's glands. The respiratory regions of the nasal cavity were devoid of appreciable MR immunoreactivity. This study demonstrates both MR transcript and protein expression in the olfactory mucosa. We hypothesize that the mineralocorticoid hormones may have a role in modulation of olfactory secretion and/or sensory transduction in the peripheral olfactory system.

Animals↗
PubMed1998

Expression of glucocorticoid receptor mRNA and protein in the olfactory mucosa: physiologic and pathophysiologic implications.

OBJECTIVES: Define the presence and distribution of glucocorticoid receptors (GRs) within the olfactory mucosa in order to assess potential physiologic and pathophysiologic effects of these hormones on olfaction. STUDY DESIGN: The olfactory mucosa was harvested from adult male rats and guinea pigs. Kidney tissue was utilized as a known positive control. METHODS: The techniques of reverse transcriptase-polymerase chain reaction (RT-PCR) and immunocytochemistry were utilized to examine the expression of GR mRNA and protein. To assure the presence of olfactory mucosa in the nasal tissue samples, RT-PCR was utilized to identify the olfactory marker protein (OMP). RESULTS: The presence of GR mRNA was confirmed in both the olfactory mucosa and kidney. GR-like immunoreactivity associated with the olfactory epithelium was greatest at the apical surface, a position corresponding to the dendrites, knobs, and cilia of olfactory receptor neurons, as well as the supranuclear region of sustentacular cells. Weaker GR-like immunoreactivity was associated with the region of the cell bodies of the olfactory receptor neurons. Within the lamina propria, acinar cells of the Bowman's glands and olfactory nerve bundles were intensely immunoreactive. CONCLUSIONS: The presence of GR mRNA and protein within the olfactory mucosa is consistent with a functional role for glucocorticoid hormones in the systemic regulation of olfaction. Furthermore, these studies suggest that corticosteroid medications may have direct effects on the cells of the olfactory mucosa in the pathologic state. The potential mechanisms whereby these hormones may act are discussed.

Animals↗
PubMed1997

Mineralocorticoid (type I) receptors in the olfactory mucosa of the mammal: studies with [3H]aldosterone and the anti-mineralocorticoid spironolactone.

High-affinity, specific binding sites to mineralocorticoids, with characteristics of mineralocorticoid (type I) receptors, have been found in the mammalian olfactory mucosa. In the presence of RU 28362, which blocks low-affinity binding of the labeled hormone to glucocorticoid (type II) receptors, Scatchard analysis of the specific [3H]aldosterone binding indicates that aldosterone binds to a single class of high-affinity (type I) sites with a dissociation constant, Kd, of 1.2 x 10(-9) M and a maximum number of binding sites, Bmax, of 63 fmol/mg dry tissue. Time course of association of [3H]aldosterone and its binding sites showed maximal binding by 30 min at 25 degrees C which remained unchanged up to 90 min. Competition studies performed with 1 x 10(-7)-1 x 10(-5) M spironolactone, a competitive mineralocorticoid antagonist, showed a dose-response reduction of [3H]aldosterone binding, implying that in the olfactory mucosa this compound behaves as an aldosterone antagonist. These results demonstrate significant [3H]aldosterone binding to receptors of high affinity and mineralocorticoid specificity and suggest that the olfactory mucosa is a target site for mineralocorticoid action.

Aldosterone↗
PubMed1997

Localization of 11 beta-hydroxysteroid dehydrogenase: specific protector of the mineralocorticoid receptor in mammalian olfactory mucosa.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta HSD) plays a major role in the protection of the mineralocorticoid (type I) receptor. The cellular mechanism of aldosterone selectivity relies on the coexpression of mineralocorticoid receptors and 11 beta HSD in the same cells. In the current study, 11 beta HSD activity was localized in the mammalian olfactory mucosa by a histochemical technique which links steroid metabolism with the deposition of formazan. The histochemical reaction results from oxidation of the synthetic substrate 11 beta-hydroxyandrostenedione and is dependent on nicotine-adenine dinucleotide (NAD). This demonstrates the presence of a dehydrogenase activity separate from the nicotineamide-adenine dinucleotide phosphate (NADP)-dependent 11 beta HSD. In the olfactory mucosa, the presence of NAD-dependent 11 beta HSD activity is localized to the sustentacular cells and acinar cells of Bowman's glands. No definite NAD-dependent activity was demonstrated in the olfactory receptor neurons. These data suggest that mineralocorticoid receptors present in acinar cells and sustentacular cells are aldosterone selective.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1995

Cytochemical localization of adenylyl cyclase activity within the sensory epithelium of the trout saccule.

Adenylyl cyclase, the enzyme of synthesis of cAMP, the second messenger molecule mediating signal transduction in response to sensory, neurotransmitter and hormonal stimuli, has been localized in the sensory epithelium of the rainbow trout (Salmo gairdneri R.) saccule by cytochemical detection of enzyme activity. In the sensory receptor cell, or hair cell, reaction product has been visualized in the stereocilia in close association with the outer cell membrane and also at the apical surface of the cuticular plate. A diffuse distribution of precipitate was observed within the cytoplasm of terminal endings of nerve fibers presumed to be efferent on the basis of characteristic synaptic specializations including presynaptic vesicles and a postsynaptic cistern lying within the hair cell. Occasionally, reaction product was observed to be associated with the external cell membrane of these nerve terminals. There appeared to be little or no adenylyl cyclase activity associated with the plasma membrane at the base of the hair cell or in presumptive afferent nerve endings. However, a subpopulation of nerve fiber endings which exhibited both efferent and afferent synaptic specializations contained precipitate. A concentration of adenylyl cyclase activity in hair cell stereocilia and efferent nerve terminals in the sensory epithelium is suggestive of a role for cAMP in second messenger action at these sites, possibly related to mechanosensory transduction and efferent neuromodulation, respectively.

Adenylyl Cyclases↗
PubMed1995

Serum immunoglobulins specific for intracellular proteins of squamous cell carcinoma.

OBJECTIVE: To determine an autologous humoral immune response to squamous cell carcinoma (SCC) intracellular proteins in patients with SCC. DESIGN: Intracellular proteins were isolated from 25 different cultured SCC lines. The proteins were used as a source of antigens to measure IgA, IgE, and IgG responses in the serum samples of patients and controls. Antibody response was assessed in both unfractionated and fractionated intracellular proteins. PATIENTS: The serum samples of 65 patients with SCC and of 65 age- and gender-matched controls were tested. RESULTS: Antibodies to SCC intracellular proteins were detected in the serum samples of 40 (62%) of the 65 patients with SCC and in the serum samples of 46 (71%) of 65 controls. Thirty (46%) of the patients with SCC and 40 (62%) of the controls had IgE responses, 18 (28%) of the patients and one (2%) of the controls had IgA responses, and 17 (26%) of the patients and 14 (22%) of the controls had IgG responses. An inverse relation was noted between detectable IgE responses and IgA or IgG responses in the patients and the controls. The analysis of antibody response indicated that 28 molecules were recognized predominantly by the serum samples of patients with SCC, but not by the serum samples of controls. CONCLUSIONS: A substantial proportion of patients with SCC and of controls exhibited an autologous humoral immune response to SCC intracellular proteins. The IgE responses to SCC intracellular proteins were inversely related to IgA or to IgG responses. Different antibody isotypes normally cause markedly different immune functions, and may suggest different roles for the existent immune responses to SCC antigens. We identified many tumor-associated antigens that were selectively recognized by the serum samples of patients with SCC. These antigens could be used to define molecular studies of immune surveillance and selection, and may represent appropriate targets for immunotherapy.

Autoradiography↗
PubMed1995

Direct laryngoscopy with provocation: a useful method to distinguish acute laryngeal edema from nonorganic disease.

BACKGROUND: Acute laryngeal edema is a manifestation of anaphylaxis, is frequently sudden in onset and requires immediate treatment to prevent further airway compromise. Nonorganic disease such as globus hystericus may present with symptoms similar to acute laryngeal edema. Distinguishing life-threatening acute laryngeal edema from non-life-threatening disease may be difficult. OBJECTIVE: We present a patient in which direct laryngoscopy was used to distinguish acute laryngeal edema from nonorganic disease. METHODS: A case report of a woman who had presented to numerous emergency rooms with symptoms of cough, sensation of throat closing, and hoarseness when exposed to odors such as nail polish remover and musk cologne. She was treated repeatedly with subcutaneous epinephrine, oral diphenhydramine and intravenous methylprednisolone. Her history was not classic for IgE-mediated anaphylaxis and we challenged her with nail polish remover while visualizing her vocal cords with direct laryngoscopy. RESULTS: Upon challenge with an offending agent, her symptoms were again suggestive of life-threatening laryngeal edema. Direct laryngoscopy, however, revealed no objective evidence of airway obstruction. CONCLUSION: Direct laryngoscopy with provocation is useful in distinguishing acute laryngeal edema from nonorganic disease.

Bronchial Provocation Tests↗
PubMed1993

Bacterial allergy in nasal polyposis. A new method for quantifying specific IgE.

OBJECTIVES: To determine (1) if bacteria-specific serum IgE levels can be more effectively measured by first absorbing competing IgG antibodies from serum and (2) if patients with chronic paranasal sinus disease exhibit a high positive prevalence of bacteria-specific serum IgE. DESIGN: A modified radioallergosorbent test method was employed wherein each serum sample was absorbed with recProtein A to remove competing non-IgE antibodies, and purified proteins extracted from 16 individual bacteria were used as potential allergens. PARTICIPANTS: Twenty-four patients with nasal polyposis and 14 with chronic sinusitis, all refractory to conventional medical therapy and requiring endoscopic sinusotomies, were tested. Tested as controls were 10 subjects with chronic allergic rhinitis, without a history of chronic sinus disease, and possessing total serum IgE and inhalant-specific IgE levels equal to or higher than the patient group. RESULTS: (1) Pretreatment of serum samples with recProtein A resulted in an increase of bacteria-specific radioallergosorbent test sensitivity. (2) Seventeen of 24 patients with polyps, eight of 14 with chronic sinusitis, and one of 10 with chronic allergic rhinitis were determined to be IgE positive when tested with this assay. CONCLUSIONS: (1) Bacteria-specific serum IgE can be quantified; (2) most patients with nasal polyposis and/or chronic sinusitis possess bacteria-specific IgE in their serum, while subjects with only allergic rhinitis do not; and (3) multiple bacterial species isolated from chronically infected sinuses are capable of inducing IgE-mediated sensitization.

Antibodies, Bacterial↗