"Coexistence of Multiple Peptides and Classic Transmitters in Airway Neurons: Functional and Pathophysiologic Aspects." American Review of Respiratory Disease, 136(6_pt_2), pp. S16–S22

BACKGROUND:Chronic noninfectious, nonallergic rhinitis (NINAR) is a complex syndrome with a principally unknown pathophysiology. New technology has made it possible to examine differentially expressed genes and according to network theory, genes connected by their function that might have key roles in the disease.METHODS:Connectivity analysis was used to identify NINAR key genes. mRNA was extracted from nasal biopsies from 12 NINAR patients and 12 healthy volunteers. Microarrays were performed using Affymetrix chips with 54 613 genes. Data were analysed with the Ingenuity Pathway System for organization of genes into annotated biological functions and, thereafter, linking genes into networks due to their connectivity. The regulation of key genes was confirmed with reverse transcription-polymerase chain reaction (RT-PCR).RESULTS:In all, 43 genes were differentially expressed. The functional analysis showed that these genes were primarily involved in cellular movement, haematological system development and immune response. Merging these functions, 10 genes were found to be shared. Network analysis generated three networks and two of these 'shared genes' in key positions, c-fos and cell division cycle 42 (Cdc42). These genes were upregulated in both the array and the RT-PCR analysis.CONCLUSION:Ten genes were found to be of pathophysiological interest for NINAR and of these, c-fos and Cdc42 seemed to be of specific interest due to their ability to interact with other genes of interest within this context. Although the role of c-fos and Cdc42 in upper airway inflammation remains unknown, they might be used as potential disease markers.

Background: Given the key role of interleukin‐5 (IL‐5) in eosinophil function, we investigated the regulated expression of the membrane‐anchored (TM‐IL‐5Rα) isoform, or a secreted (SOL IL‐5Rα) isoform, on both protein and transcript level in vitro and in vivo . Methods: A real‐time PCR, FACS and ELISA were established to determine IL‐5Rα isoform expression in peripheral blood and nasal tissue from control subjects and nasal polyp (NP) patients with or without asthma. Human peripheral blood eosinophils were incubated with IL‐5 and were analyzed for SOL‐IL‐5Rα and TM‐IL‐5Rα mRNA and protein levels in comparison with CD‐69 expression. Results: SOL‐IL‐5Rα and TM‐IL‐5Rα mRNA and protein expression was significantly increased in NP vs controls. In polyp tissue, SOL‐IL‐5Rα expression correlated to disease severity and eosinophils counts, whereas TM‐IL‐5Rα levels were inversely correlated to eosinophils counts and SOL‐IL‐5Rα expression. FACS analysis revealed increased CD‐69 and decreased TM‐IL‐5Rα expression in NP tissue eosinophils vs blood eosinophils. Incubation of blood eosinophils with IL‐5 caused up‐regulation of CD‐69 and down‐regulation of TM‐IL‐5Rα after 2 and 24 h. Conclusion: The expression of SOL‐IL‐5Rα and TM‐IL‐5Rα differs according to the eosinophil activation state and localization in the body (blood vs tissue) and may therefore be involved in the fine‐tuning of the eosinophil homeostasis. Exposure of eosinophils to IL‐5 reduces their responsiveness to IL‐5 by regulated expression of the IL‐5Rα isoforms. Since, TM‐IL‐5Rα is down‐regulated and SOL‐IL‐5Rα (antagonistic) is upregulated in NP tissue, our findings are important to understand the clinical trials with anti‐IL‐5 in humans.

Conclusions. CT of the sinuses showed long-lasting improvement in the total and CT scores of the osteomeatal complex (OMC) after combined surgical and corticosteroid treatment as compared with medical treatment alone. However, the correlations between the improved CT scores and the patients' symptoms, olfactory thresholds or polyp scores were generally not significant. Objective. To evaluate CT scans as a method for comparing the effect of medical treatment versus combined surgical and medical treatment of nasal polyposis. Patients and methods. Thirty-two patients with nasal polyposis were randomized to unilateral endoscopic sinus surgery after pretreatment with oral prednisolone for 10 days and nasal budesonide bilaterally for 1 month. Postoperatively, they were given nasal steroids (budesonide) bilaterally for 1 year. They were assessed with nasal endoscopy, symptom scores, and olfactory thresholds and followed for 12 months. CT of the sinuses was performed before and 1 year after operation. The CT scans were evaluated using the Lund staging system. Results. From before surgery to 1 year after surgery, we found a significant improvement on the operated side in the CT total scores, and scores of the OMC and the maxillary sinus, but no significant differences on the unoperated side. Significant correlations were also noted between the differences in olfactory thresholds between the operated and unoperated sides.

OBJECT:Cushing disease is a rare disorder. Because of their small size the adrenocorticotropic hormone (ACTH)-producing tumors are often not detectable on neuroimaging studies. To obtain a cure with transsphenoidal surgery (TSS) may therefore be difficult. In this report the authors present 10 years of experience in the treatment of patients with Cushing disease who were followed up with the same protocol and treated by the same surgeon.METHODS:Thirty-four patients, 26 of them female and eight of them male (mean age 40 years, range 13-74 years) were studied. All had obvious clinical signs and symptoms of Cushing syndrome. Magnetic resonance (MR) imaging was performed in all patients, and inferior petrosal sinus (IPS) sampling was done in 14. In 12 patients MR imaging indicated a pituitary tumor; 10 were microadenomas and two were macroadenomas. In six patients with no visible tumor, the results of IPS sampling supported the diagnosis. All patients underwent TSS; the mean follow-up duration was 6 +/- 0.5 years. Selective adenomectomy was performed in 32 and hemihypophysectomy in the other two patients. A cure was obtained in 31 patients (91%) after one TSS and in two more patients after further TSS; one patient was not cured despite two TSSs and one underwent bilateral adrenalectomy. Disease recurrence was seen in two patients after 3 years, and they were successfully treated with stereotactic gamma knife surgery. Half of the patients had an ACTH deficiency postoperatively, whereas one third had other pituitary hormone insufficiencies. There were no serious complications attributable to the surgical intervention.CONCLUSIONS:Transsphenoidal surgery with selective adenomectomy is an effective and safe treatment for Cushing disease. In the patients presented in this study, the surgical outcome seemed to depend on careful preoperative evaluation and the surgeon's experience. For optimal results in this rare disease the authors therefore suggest that the endocrinological, radiological, and surgical procedures be coordinated in a specialized center.

Tumor galanin content was measured in extracts from human pituitary adenomas using a specific RIA method for monitoring human galanin. Twenty-two out of twenty-four tumors contained galanin with notably high levels in corticotroph adenomas, varying levels in clinically inactive tumors, and low levels in GH secreting adenomas. Tumor galanin and ACTH contents were closely correlated in all tumors. In four young patients with microadenomas and highly active Mb Cushing tumor galanin was inversely related to tumor volume. The molecular form of tumor galanin, studied with reverse-phase HPLC, was homogeneous with the majority of tumor galanin coeluting with standard human galanin. In the tumors analysed with in situ hybridization there was a good correlation between galanin peptide levels and galanin mRNA expression. In some tumors galanin mRNA and POMC levels coexisted, in others they were essentially in different cell populations. Levels of plasma galanin-LI were not related to tumor galanin concentration, and galanin levels were in the same range in sinus petrosus close to the pituitary venous drainage as in peripheral blood. Corticotrophin releasing hormone injections in two patients caused ACTH, but no detectable galanin release into sinus petrosus. Our results demonstrate that corticotroph, but not GH adenomas, express high levels of galanin, in addition to ACTH, and that in some tumors both polypeptides are synthesised in the same cell population. However, galanin levels in plasma were not influenced by the tumor galanin content.

Objective-To compare the effect on olfaction of topical glucocorticoid treatment versus placebo given for an extended period in addition to oral short-term glucocorticoids in patients with anosmia/hyposmia.Material and Methods-This was a randomized, double-blind, placebo-controlled study. The criterion for inclusion in the blinded phase was an improvement of at least 2 steps in the butanol odor threshold test following open treatment for 10 days with oral and nasal corticosteroids. Forty patients were included: 20 were randomized to treatment with fluticasone propionate, 10 to placebo and 10 others as controls. The topical treatment was continued for 6 months.Results-The 3 groups showed similar improvements in their sense of smell after the initial 10-day treatment with combined oral and nasal corticosteroids. Patients who continued the local treatment maintained the same level of improvement throughout the study, whether or not they had been given nasal corticosteroids or placebo. We found no significant differences between the treatment groups.Conclusions-In patients with anosmia/hyposmia partly caused by local inflammation, no further improvement in the olfactory threshold is achieved by continuing with a topical intranasal glucocorticoid after an initial combined topical and systemic glucocorticoid treatment.

The clinical impression of the airway as a single entity was recognized by Bostock (1) in the early 19th century. In recent years, an increasing number of articles have been published on this topic. Epidemiological evidence, treatment studies, and documentation of advanced methods in cellular and molecular biology have been covered in reviews (2–6). In a retrospective study in a large number of schoolchildren, Rusconi et al. (7) found that patients with wheezing had a ten-fold greater chance of having allergic rhinitis problems compared to control subjects. The longitudinal study of the Settipane group (8), which had a 23-year follow-up, showed that allergic rhinitis at inclusion resulted in a three-fold risk of developing asthma compared to the group without rhinitis symptoms. In a 12-year follow-up Swedish study by Danielsson and Jessen (9) the number of asthmatics in the group with allergic rhinitis was double that of the group without symptoms at inclusion. An almost ubiquitous presence of allergic rhinitis, in patients with allergic asthma, has been reported by Kapsali and coworkers (10). Further proof of this comes from a recent article by Guerra and colleagues (11). During 2-year follow-up of a large number of patients, rhinitis increased the risk for development of asthma by three times in both allergic and nonallergic patients. They also found a five-fold increase in patients with high IgE levels. The authors conclude that rhinitis is a significant risk factor for developing asthma in both allergic and nonallergic subjects. Consequently there is strong epidemiological evidence in the literature for rhinitis and asthma as a comorbid disease (12, 13). These studies are all in accordance with the article of Linneberg et al. (14) in the present issue of Allergy. The authors present a population-based prospective 8-year follow-up study in which they conclude that allergic rhinitis and allergic asthma are manifestations of the same disease entity. When reading and comparing the many different studies on prevalence of allergic rhinitis and asthma, one of the main difficulties is the variety of definitions of the disease (15, 28). Many studies use different types of questionnaires and inclusion criteria and the outcome can thus be a result of misclassification—a fact which is also commented on by the authors. In the paper by Linneberg et al. (14) the relationship between rhinitis and asthma symptoms was less evident for pollen allergy compared with animal and mite allergy. This is most probably because animal and mite particles are small (2–3 lm) compared with larger pollen grains (10–20 lm). As the nose is able to filter allergen particles sized 10 lm or more, most of the pollen gets stuck in the nasal cavity, leading to an allergy reaction primarily in the nasal mucosa. On the other hand, when pollen allergens are exposed to watery secretion, they can be dissolved, thus reaching the lower airways and inducing asthmatic inflammation (16). The extent of exposition in these cases is also important, as has been shown in thunderstorm-induced asthma (17). Apart from its filtering function, the nose has an important role in warming and humidifying inhaled air before it enters the lower airway. This is possible because of the highly vascularized mucosa, with a large amount of secretory glands. The importance of the conditioning capacity of the nose in patients with asthma and seasonal allergic rhinitis has been studied by Assanasen et al. (18). They found that noses of subjects with asthma were less able to condition inhaled cold dry air compared with controls. Interestingly the group also published a paper showing that hot humid air partially inhibits the nasal response to allergen provocation (19). L. Lundblad Department of Otorhinolaryngology, Karolinska Hospital, Sweden

This Swedish study group has examined the current knowledge of nasal polyposis with emphasis on different treatment modalities. Polyposis is a multifactorial disease that exists for decades in the majority of cases. Different types of treatment must be considered, focusing on the underlying disease. However, as we only know the specific origin of polyposis in a minority of cases, treatment is usually symptomatic. When making a thorough evaluation of different treatment strategies, it is obvious that there is a real need for more controlled treatment studies which would make the scientific ground more stable when it comes to suggesting medical, surgical or combined treatments.

BACKGROUND Controlled prospective studies are needed to determine whether surgical treatment in fact has an effect additive to that of medical treatment of nasal polyposis. OBJECTIVE We sought to compare the effect of medical treatment versus combined surgical and medical treatment on olfaction, polyp score, and symptoms in nasal polyposis. METHODS Thirty-two patients with nasal polyposis and symmetrical nasal airways were randomized to unilateral endoscopic sinus surgery after pretreatment with oral prednisolone for 10 days and local nasal budesonide bilaterally for 1 month. Postoperatively, patients were given local nasal steroids (budesonide). Patients were evaluated with nasal endoscopy, symptom scores, and olfactory thresholds. They were followed for 12 months. RESULTS The sense of smell was improved by the combination of local and oral steroids. Surgery had no additional effect. Symptom scores improved significantly with medical treatment alone, but surgery had additional beneficial effects on nasal obstruction and secretion. After surgery, the polyp score decreased significantly on the operated side but remained the same on the unoperated side. Twenty-five percent of the patients were willing to undergo an operation also on the unoperated side at the end of the study. CONCLUSIONS Medical treatment seems to be sufficient to treat most symptoms of nasal polyposis. When hyposmia is the primary symptom, no additional benefit seems to be gained from surgical treatment. If nasal obstruction is the main problem after steroid treatment, surgical treatment is indicated. Selection of those who will benefit from surgery should be based on the patient's symptoms and not on the examiner's polyp score.

In order to evaluate the efficacy and safety of mometasone furoate nasal spray (MFNS) in patients with perennial non-allergic rhinitis (PNAR) a phase III, double-blind, randomized, placebo-controlled, Nordic multicenter study was performed at 16 sites (7 in Sweden, 3 in Denmark, 3 in Finland and 3 in Norway). A total of 329 patients (age 18-82 years) with a mean duration of PNAR of 9 years were included in the study. The total duration of the study was 11 weeks: 2 weeks of screening, 6 weeks of treatment and 3 weeks of follow-up. Inclusion criteria were unspecific rhinitis symptoms and exclusion criteria were a positive skin prick test as well as intolerance to aspirin or non-steroidal anti-inflammatory drugs. Endoscopy was performed to exclude patients with structural anomalies and nasal polyps. The primary efficacy variable was the subject's total overall evaluation. In the intention-to-treat (ITT) group of patients (n = 329) the improvement rates were 56% (MFNS) and 49% (placebo). In the per-protocol (PP) group (n = 251) the corresponding figures were 58% and 47%. Stratifying for groups of patients having moderate symptoms, the results were 54% vs 43% in the ITT group and 56% vs 41% in the PP group. The therapeutic response showed greater improvement in total nasal score as recorded by the investigator in the groups treated with MFNS as compared to the placebo group (p = 0.09 [PP], p = 0.14 [ITT]). Adverse events occurred during the study, upper respiratory tract infections and headache being the most frequently reported, but there was no statistically significant difference between MFNS and placebo. The results of this study indicate that MFNS is a safe and effective treatment for patients with PNAR.

PURPOSE To present the results of orbital decompression in patients with thyroid-associated ophthalmopathy (TAO). METHODS Transantral orbital decompression was performed in 63 patients with TAO. In 40 patients (63%) the operation was made because of progressive ophthalmopathy not responding to medical therapy, and in 23 patients (37%) the operation was made for rehabilitative reasons. The long-term hypesthesia engaging the infraorbital nerve was assessed with a questionnaire using a Visual Analogue Scale (VAS). RESULTS The mean proptosis reduction was 3.2 mm (range 0-8 mm). Twenty-one patients had impaired visual acuity preoperatively, and 20 improved. Altogether 30 patients (40%) had worsened ocular motility postoperatively. Forty-three patients did not have diplopia in the primary position preoperatively, and new diplopia developed in 22 of these (51%). Hypesthesia in the infraorbital nerve area was reported for half of the operated sides, but was a major cause of distress (VAS-scoring >5) to eleven patients. CONCLUSIONS Transantral orbital decompression is indicated in patients with progressive TAO or in patients with prominent exophthalmos, and results in a good proptosis reduction, but the risk of postoperative diplopia is significant. Postoperative hypesthesia is common but often not a major problem.

A common foreign body of the nose in intensive care, the nasotracheal tube, has for 20 years been cited as a cause of bacterial infection of the paranasal sinus. High frequencies of bacterial culture positivity have occurred in several studies. However, the state of critically ill patients has to be evaluated before conclusions about cause of infection can be made. Nosocomial colonization with intensive care unit flora, in combination with use of antibiotics, precludes the use of procedures that are standard in office practice and microbiological diagnostics. New methods of sampling and quantitative culturing for the specific purpose of intensive care antral diagnostics, in combination with endoscopic inspection, have enlarged our knowledge of sinusitis. Among patients ventilator-treated for > or = 1 week, the occurrence of bacterial sinusitis is < 10%. For 80% of the examined antra there were similar inflammatory reactions without clinical signs of infection. Sporadically in these, cultures of antral specimens were positive for bacteria, which, by definition, would represent colonization.

We tested the reliability of visual clinical sinoscopic observations by using video recordings. An edited video tape was made from the video-recorded bilateral antral sinoscopies of nine patients included in a prospective case series of inflammatory maxillary sinus disease in critically ill patients. An expert panel of four consultant ENT surgeons made individual appraisals of the video using a structured form. They had only been informed in general about the study, but had no further case knowledge in order to avoid all biases. Concordance and interobserver variabilities in the expert panel were compared in pairs. The assessments of the expert panel were compared with the observations of the performer, who was biased through individual case knowledge. Nine patients, either nasotracheally intubated or tracheotomized, had ventilator treatment for more than 7 days. One ENT surgeon performed all sinoscopies and made the direct observations. Satisfactory agreement was found on mucosal alterations. The concordance of recognizing bacterial infection was almost perfect. However, the assessment of redness from a video recording displayed only chance agreement. The differences between κ statistic values within the expert panel group compared to the comparisons of performer versus expert panel were not significant. The case knowledge of the sinoscopist did not alter the assessments markedly and thus seemed only to have minor influence. Video recording as a method for second opinion was shown to be a useful technique, but will have to be further developed.

The objective of this study was to investigate maxillary sinus infectious or inflammatory disease in long-term mechanically ventilated patients, using a prospective case series design. The subjects were 33 critically ill patients receiving ventilator treatment for more than 7 days, in the general and neurosurgical intensive care units of a tertiary care hospital. Bilateral antroscopies were performed, and antral secretion and mucosal samples were collected for bacterial culturing. Different stages of inflammatory disease were found in 85% of the antra. Infectious sinusitis was diagnosed in 6%, with a predominance of mixed anaerobic infections. Monoisolates of anaerobic or facultative anaerobic bacteria were found in 5% of the antra without clinical signs of infection. In conclusion, more stringent requirements are needed for the diagnosis of infectious sinusitis in ventilator-treated patients. With improved diagnostic techniques there was a significantly lower frequency of infectious sinusitis than presented in previous reports. The bacteria predominating as infectious agents were different to those in previous reports. Furthermore, reactive inflammatory disease with bacterial colonization occurred.

The effect of ruthenium red, a blocker of transmembrane Ca2+ fluxes, on vasodilation in pig nasal mucosa induced by capsaicin, nicotine, bradykinin or histamine was evaluated in an in vivo preparation. To decrease toxic systemic effects pretreatment with ruthenium red was performed locally, intra-arterially in a nasal artery. Pretreatment with two doses of ruthenium red was evaluated (0.25 and 2.5 mg kg-1). Ruthenium red, in the low dose, resulted in a marked attenuation of the capsaicin-induced nasal vasodilation while the effect on the nicotine-induced vasodilation was not as prominent. Pretreatment with the high dose significantly blocked the vasodilatory effects of capsaicin, nicotine, bradykinin and histamine. Our series indicates that low concentration ruthenium red selectively modulates capsaicin induced vasodilation in pig nasal mucosa in vivo, probably via a direct blocking effect on cation channels opened by capsaicin. A high concentration of ruthenium red may exert a general inhibitory effect on transmembrane Ca2+ transport.

A model was developed using pentobarbital anesthetized pigs to study bilateral blood flow changes in the nasal mucosa by flow-probes on both sphenopalatine arteries. Unilateral mechanical stimulation of the nasal mucosa for 10 s as well as close intra-arterial capsaicin infusion induced bilateral vasodilation. The magnitude of the vasodilator responses were similar on both sides, although the capsaicin effect (maximal increase in arterial blood flow by about 100 ml/min) was larger than that of the mechanical stimulation. Pretreatment with atropine (0.5 mg x kg-1) had no effect on the vascular responses to capsaicin or mechanical stimulation. However, when the pigs were pretreated with the ganglionic nicotinic receptor blocking agent, chlorisondamine (3 mg x kg-1), the vasodilatory responses to mechanical stimulation were abolished and the responses to capsaicin infusion markedly reduced (90-95%). These data indicate that unilateral mechanical stimulation as well as capsaicin infusion evoke bilateral nasal vasodilation which is probably mediated via a central reflex arch with a parasympathetic non-cholinergic final step.

We have studied the effects of acute and long-term treatment of cats and rats with atropine on the levels, release and effects of two peptides, vasoactive intestinal polypeptide (VIP) and peptide histidine isoleucine (PHI), that probably co-exist with acetylcholine in the parasympathetic nerves supplying the submandibular gland. Atropine treatment (progressively increasing doses from 2 to 15 mg kg-1 injected s.c.) for 14 days did not alter the contents of VIP- or PHI-like immunoreactivity (-IR) in the cat submandibular gland or in three other tissues (nasal mucosa, trachea and tongue). Acute as well as long-term atropine treatment decreased the vasodilation following low-, but not high-, frequency parasympathetic nerve stimulation. During prolonged stimulation (60 min) there was a decreased vasodilatation response following both acute and long-term atropine treatment. The overflow of VIP-IR and PHI-IR following parasympathetic nerve stimulation was markedly increased by acute, but not by long-term atropine treatment. The VIP- or PHI-induced stimulation of cyclic AMP (cAMP) accumulation in the cat submandibular gland was not altered after long-term atropine treatment. Similarly, treatment of male Sprague-Dawley rats with atropine (20 mg kg-1) or imipramine (20 mg kg-1) for 14 days did not alter the sensitivity to VIP or to PHI of cAMP accumulation in the submandibular gland, nor was there any change in VIP-IR or PHI-IR content. In conclusion, although atropine treatment causes an acute increase in the overflow of VIP and PHI evoked by parasympathetic nerve stimulation, there is no depletion of peptide stores upon long-term treatment, nor is there any change in the effect of exogenous VIP and PHI on cAMP-accumulation.