Interleukin 6 in hyposmia.

IMPORTANCE: Olfaction is a complex sensory process that has not been fully studied. Elevated plasma levels of interleukin 6 (IL-6) have been found in patients with several acute and chronic diseases but have not been reported in patients with smell loss (hyposmia). OBJECTIVE: To determine IL-6 levels in patients with hyposmia. DESIGN: Retrospective study. All measurements were made without reference to the origin of any collected sample. SETTING An ambulatory private practice at The Taste and Smell Clinic in Washington, DC. PARTICIPANTS: Fifty-nine consecutive patients who presented to the clinic between 2005 and 2008 for evaluation and treatment of various degrees of hyposmia were studied. Nine volunteers with normal sensory function served as controls. MAIN OUTCOMES AND MEASURES: Levels of IL-6 were measured in samples of plasma, urine, saliva, and nasal mucus. RESULTS: All biological fluid samples studied contained IL-6. Mean (SEM) levels in plasma, saliva, and nasal mucus in patients were significantly higher than in controls (0.95 [0.10] vs 0.12 [0.03] pg/mL, 0.57 [0.05] vs 0.30 [0.01] pg/mL, and 29.7 [3.8] vs 11.6 [0.5] pg/mL, respectively; all P < .001). The concentration of IL-6 in nasal mucus in patients was significantly higher than in controls and was more than 30 times higher than in any other biological fluid. Mean (SEM) levels in urine were not significantly different: 0.92 (0.17) pg/mL for patients and 1.26 (0.41) pg/mL for controls (P > .50). CONCLUSIONS AND RELEVANCE: Compared with controls, IL-6 in patients was significantly elevated in plasma, saliva, and nasal mucus. Because IL-6 is a proinflammatory cytokine, these changes can relate to local or systemic inflammatory processes, which can be a cause or a result of pathological processes associated with hyposmia. These results support the concept that hyposmia has a biochemical basis and IL-6 may play a role in biochemical pathological processes underlying hyposmia and its treatment.

Etiological relationships of parotid saliva cyclic nucleotides in patients with taste and smell dysfunction.

OBJECTIVE: We previously demonstrated that parotid saliva cAMP and cGMP were lower in patients with taste and smell dysfunction than in normal subjects. We subsequently demonstrated parotid saliva cAMP and cGMP were inversely correlated with smell loss degree such that as smell loss severity increased parotid saliva cAMP and cGMP decreased proportionately. To learn more about these relationships we studied parotid saliva cAMP and cGMP with respect to aetiology of sensory loss in these patients. DESIGN: Parotid saliva cAMP and cGMP in patients with smell loss (hyposmia) who participated in an open label fixed design controlled clinical trial with treatment with oral theophylline were evaluated with respect to their initial etiological diagnosis. Levels of cyclic nucleotides in each etiological category were compared to each other, to the entire patient group and to normal subjects. RESULTS: Mean cAMP and cGMP in all patients combined were below those in normals, as previously described. However, categorized by aetiology, there was a stratification of levels of both cyclic nucleotides; some levels were below the normal mean and some were at or above the normal mean. CONCLUSIONS: Parotid saliva cyclic nucleotides characterised in hyposmic patients by aetiology indicate (1) there are differential alterations in these nucleotides related to aetiology of sensory dysfunction and (2) these moieties measured prior to treatment indicate which patient groups may benefit from treatment with phosphodiesterase (PDE) inhibitors which increase levels of these moieties and thereby correct their sensory dysfunction.

Aetiological relationships of nasal mucus cyclic nucleotides in patients with taste and smell dysfunction.

AIMS: The authors previously demonstrated that nasal mucus cyclic adenosine 3', 5'-monophosphate (cAMP) and cyclic 3', 5'-guanosine monophosphate (cGMP) were lower in patients with smell and taste dysfunction than in normal individuals. To learn more about these differences this study related levels of nasal mucus cAMP and cGMP in patients with smell and taste dysfunction to the aetiology of their sensory loss and compared these results with those in normal individuals. METHODS: Nasal mucus cAMP and cGMP levels in patients with smell loss (hyposmia) were calculated after assembling data into aetiological groups. Levels were compared with each clinical group, with the entire patient group and with normal individuals. Data were obtained from initial values among patients with hyposmia who participated in a clinical trial of treatment with the phosphodiesterase inhibitor theophylline. RESULTS: Nasal mucus cyclic nucleotides in the entire patient group before treatment were below normal as previously demonstrated. Stratification by aetiology revealed differences not previously apparent. In some groups levels of cAMP and cGMP were below normal, some were similar to normal and some were above the normal mean. CONCLUSIONS: As nasal mucus cyclic nucleotides relate to the growth and development of olfactory epithelial cells these results indicate there are differential alterations in nasal mucus cAMP and cGMP related to the aetiology of smell and taste dysfunction.

Relative resistance to oral theophylline treatment in patients with hyposmia manifested by decreased secretion of nasal mucus cyclic nucleotides.

INTRODUCTION: Oral treatment with the phosphodiesterase inhibitor theophylline in an open-label fixed-design clinical trial in 312 patients with hyposmia improved smell function in >50%. Before treatment, all patients had lower than normal levels of nasal mucus cAMP and cGMP. The purpose of this study was to study relationships among changes in smell function, theophylline levels and nasal mucus cAMP and cGMP among patients whose smell function improved (responders) and those who did not improve (nonresponders) on oral theophylline treatment. METHODS: After all data analysis from the clinical trial was completed, data from each of the 31 of the 312 patients in whom nasal mucus cAMP and cGMP and theophylline levels were available before and after theophylline treatment at several drug doses were evaluated. At initiation and at termination of each treatment, dose smell function, nasal mucus cAMP and cGMP and plasma theophylline were analyzed. RESULTS: On the same theophylline dose, although serum theophylline increased among both responders and nonresponders, serum levels were consistently higher among responders. Nasal mucus cAMP and cGMP were also higher among responders than nonresponders. At higher theophylline doses, cGMP reached normal levels among responders, whereas it did not change significantly among nonresponders. CONCLUSIONS: Some patients with hyposmia with initially low nasal mucus cAMP and cGMP levels may be relatively resistant to oral theophylline treatment. This result may offer a mechanism of response lack among some patients whose smell function did not improve after oral theophylline treatment although other factors may influence their response lack.

Differences between and within human parotid saliva and nasal mucus cAMP and cGMP in normal subjects and in patients with taste and smell dysfunction.

BACKGROUND: We previously described some of the moieties in human saliva and nasal mucus including cyclic nucleotides. However, comparison of levels of these latter moieties in saliva and nasal mucus has not been performed and meaning of differences found has not been discussed. PURPOSE: To compare the levels of cAMP and cGMP in saliva and nasal mucus and to describe the differences in their concentrations and function. METHODS: cAMP and cGMP in saliva and nasal mucus were compared in normal subjects and patients with taste and smell dysfunction by use of a spectrophotometric colorimetric ELISA. RESULTS: Both cAMP and cGMP were present in saliva and nasal mucus of normals and patients with levels of both moieties lower in patients than in normals. In normals, cAMP is 6½ times higher in saliva than in nasal mucus whereas cGMP in nasal mucus is 2½ times higher than in saliva. In patients, these differences persist but are less robust. In normals, within saliva, cAMP is 9½ times higher than cGMP whereas within nasal mucus cAMP is half the level of cGMP. In patients, within saliva, these differences persist but at variable differences. CONCLUSIONS: Both saliva and nasal mucus cAMP and cGMP play roles in taste and smell function, and differences in their concentrations may offer insight into these roles. In nasal mucus, cGMP may be more relevant than cAMP in activity of olfactory epithelial cell function. In saliva, cAMP may be more relevant as a growth factor in taste bud function than cGMP.

Carbonic anhydrase I, II, and VI, blood plasma, erythrocyte and saliva zinc and copper increase after repetitive transcranial magnetic stimulation.

INTRODUCTION: Repetitive transcranial magnetic stimulation (rTMS) has been used to treat symptoms from many disorders; biochemical changes occurred with this treatment. Preliminary studies with rTMS in patients with taste and smell dysfunction improved sensory function and increased salivary carbonic anhydrase (CA) VI and erythrocyte CA I, II. To obtain more information about these changes after rTMS, we measured changes in several CA enzymes, proteins, and trace metals in their blood plasma, erythrocytes, and saliva. METHODS: Ninety-three patients with taste and smell dysfunction were studied before and after rTMS in an open clinical trial. Before and after rTMS, we measured erythrocyte CA I, II and salivary CA VI, zinc and copper in parotid saliva, blood plasma, and erythrocytes, and appearance of novel salivary proteins by using mass spectrometry. RESULTS: After rTMS, CA I, II and CA VI activity and zinc and copper in saliva, plasma, and erythrocytes increased with significant sensory benefit. Novel salivary proteins were induced at an m/z value of 21.5K with a repetitive pattern at intervals of 5K m/z. CONCLUSIONS: rTMS induced biochemical changes in specific enzymatic activities, trace metal concentrations, and induction of novel salivary proteins, with sensory improvement in patients with taste and smell dysfunction. Because patients with several neurologic disorders exhibit taste and smell dysfunction, including Parkinson disease, Alzheimer disease, and multiple sclerosis, and because rTMS improved their clinical symptoms, the biochemical changes we observed may be relevant not only in our patients with taste and smell dysfunction but also in patients with neurologic disorders with these sensory abnormalities.

An open-label controlled trial of theophylline for treatment of patients with hyposmia.

BACKGROUND: To test the hypothesis that theophylline is effective in correcting smell loss in patients with hyposmia. METHODS: Three hundred twelve patients with smell loss (hyposmia) were evaluated to determine characteristics of their loss by psychophysical measurements of detection and recognition thresholds, magnitude estimation and hedonic values for 4 odors (pyridine, nitrobenzene, thiophene, and amyl acetate) by use of a forced-choice 3-stimuli staircase design previously documented in a double-blind study. Patients were then treated in a fixed design open-label clinical trial with oral theophylline. Drug was given in equal divided doses from 200 to 800 mg daily for 2- to 8-month periods and subjective and psychophysical measurements of smell function and blood theophylline levels were measured; results were compared with those obtained before treatment. RESULTS: Subjective smell loss improved in 157 (50.3%) patients; smell function was considered normal by 34 (21.7%). Overall, 10.9% of patients in the study considered smell function returned to normal. However, measurements of mean detection and recognition thresholds improved significantly at each drug level; measurements of mean magnitude estimation and hedonic also improved. Improvement was greater at drug doses of 600 and 800 mg than at 200 or 400 mg. Once improvement occurred, as long as treatment was maintained, it persisted for as long as follow-up was measured. CONCLUSION: Theophylline was effective in improving smell function in patients with smell loss. Improvement persisted as long as treatment was continued, which extended from 6 to 72 months.

cAMP and cGMP in human parotid saliva: relationships to taste and smell dysfunction, gender, and age.

Among the chemical moieties present in human parotid saliva, some, such as gustin or carbonic anhydrase VI, have been useful to distinguish patients with taste and smell dysfunction from normal subjects. To continue these studies we compared levels of salivary cAMP and cGMP in patients with taste and smell dysfunction with those in normal subjects. We were also interested in exploring physiological characteristics of salivary cAMP and cGMP including changes with gender and age because previous studies had not clearly defined these issues. To perform these studies parotid saliva was collected from 61 normal volunteers and 253 patients with taste and smell dysfunction. cAMP and cGMP were measured by a spectrophotometric 96 plate ELISA technique; parotid salivary protein and flow rate were also measured. Both cAMP and cGMP were found in saliva of normal subjects and patients in the detection range of the assay used. In patients mean concentrations of both cAMP and cGMP were lower than in normal subjects; for cAMP levels were lower among both men and women patients. cAMP was 7 to 10 times higher than cGMP in both normal subjects and patients. Concentrations of cAMP were consistently higher in normal women than in normal men. cAMP levels were generally lower and cGMP levels were generally higher than in previously reported studies. There was a complex pattern of change for both cAMP and cGMP with age with concentrations increasing to about age 50, then decreasing, then increasing again at age >70 years.