Validation of Visual Analogue Scale for loss of smell as a quick test in chronic rhinosinusitis with nasal polyps.

BACKGROUND AND OBJECTIVE: Diagnostic criteria of chronic rhinosinusitis with nasal polyps (CRSwNP) include, among others, olfactory dysfunction (OD). We hypothesize that patients suffering with CRSwNP are good at self-assessing their sense of smell through visual analogue scale (VAS) compared to smell tests. METHODS: A controlled cross-sectional study was planned. Adults diagnosed with severe CRSwNP waiting for endoscopic sinus surgery were included. A cohort of healthy controls was also studied. All participants performed Barcelona smell test (BAST-24), sinonasal outcomes test 22 (SNOT-22), and VAS for loss of smell. CRSwNP underwent blood test (eosinophils count, total serum IgE), CT scan (Lund-Mackay Score), and nasal endoscopy. RESULTS: 138 severe CRSwNP and 40 controls subjects were included. The BAST-24 identification score was strongly correlated with the VAS score in the CRSwNP group (rho=-0.79, p<0.001) but not in the control group (rho=-0.14; p=0.39), this difference between groups being statistically significant (p<0.001). A significant correlation of SNOT-22 item 21 (loss of smell) was also found with BAST-24 identification (rho=-0.65, p<0.001), this difference being statistically significant (Z=-2.43; p=0.015). In the ROC curve, the area under the curve (AUC) was 0.85 with 72.5% sensitivity and 93.1% specificity. CONCLUSION: This study demonstrates a potential role of the VAS score for the screening of OD in severe CRSwNP in daily clinical practice.

Septoplasty and/or inferior turbinoplasty produce significant improvements of the sense of smell.

BACKGROUND: Patients with septal deviation and/or turbinal hypertrophy may experience olfactory disfunction (OD). The aim of this study was to analyse the effect of septoplasty and/or turbinoplasty on both lateralized and bilateral olfactory function. METHODOLOGY: Prospective study of 47 patients with nasal obstruction secondary to septal deviation and/or turbinal hypertrophy and 20 healthy controls. The Barcelona Olfactory test (BOT-8), a new supraliminal orthonasal subjective olfactometry, was applied 3 times in a row (in each nostril separately and in both simultaneously). The 8 items were applied randomly to minimize the possible risk of learning. The test has not established the minimal clinically important difference (MCID). Anterior rhinomanometry and acoustic rhinometry were performed. All participants self-assessed smell loss and nasal obstruction using a visual analogue scale (VAS) and completed questionnaires for nasal obstruction (Nasal Obstruction Symptom Evaluation, NOSE) and for quality of life (QoL), using disease-specific (SinoNasal Outcome Test-22, SNOT-22) and generic (Short Form-12 Health Survey, SF-12) questionnaires. Nasal measurements and questionnaires were performed preoperatively and 12 months after surgery. RESULTS: Before surgery, patients reported worse VAS on smell loss and on nasal obstruction compared to controls. Patients scored lower BOT-8 than controls. Lateralized preoperative olfactory function showed that all BOT-8 characteristics were lower at the narrow side than the wider one. Smell function and QoL improved significantly one year after surgery. CONCLUSIONS: Nasal septal deviation and turbinal hypertrophy lead to an olfactory impairment on the obstructed nostril. Nasal surgery provides a positive outcome on olfactory function, as well as on subjective and objective outcomes.

Sinonasal mucosal melanomas: defining profiles for better survival outcomes.

BACKGROUND: Sinonasal mucosal melanoma is an aggressive malignancy with a 5-year survival rate ranging from 20% to 39%. Despite the evolving surgical and radiotherapy techniques, and introduction of immune-checkpoint inhibitor therapy, overall survival rates remain poor. METHODOLOGY: A retrospective cohort study was conducted at the Hospital Clinic de Barcelona and the Hospital de la Santa Creu i Sant Pau between 1984 and 2020; primary outcome measures were 3 and 5-year melanoma-specific survival (MSS). Kaplan-Meier survival analysis and Cox proportional hazards model were performed to identify predictors of survival. RESULTS: Fifty patients were included, the mean age was 70.4, MSS at 3 and 5 years was 51.2%, and 29.5%, respectively. The median follow-up was 39.6 months during which 46% presented locoregional recurrence and 36%, metastasis. The univariate and multivariate analyses found as survival predictors the N category, the treatment received, the surgical margins and the mitotic index. CONCLUSIONS: We found an overall 5-year MSS of 29.5%. Those patients with intention-to-cure (stages III and IVa) treated by surgery that were N0 at diagnosis, with < 10 mitoses per HPF showed a 5-year MSS rate of 74.1%. More studies will be needed to adequately define the patients' profiles that will benefit from a better survival outcome.

Twelve-year long-term postoperative outcomes in patients with chronic rhinosinusitis with nasal polyps.

BACKGROUND: Evidence regarding long-term postoperative follow-up of chronic rhinosinusitis with nasal polyps (CRSwNP) patients is scarce in the literature. The objective of the present study was to report long-term 12-year postoperative outcomes for CRSwNP patients. METHODS: CRSwNP patients were prospectively followed after endoscopic sinus surgery. Sinonasal symptoms, nasal polyp score (NPS), Barcelona Smell Test 24 (BAST-24), Lund-Mackay Score (LMS), and Medical Outcome Study Short Form-36 (SF-36) questionnaire were assessed before and 12 years after surgery. RESULTS: At long-term follow-up (median, 12 years), a strong improvement was noted for all patients (N=76) in nasal symptoms score, NPS, BAST-24, and LMS scores compared with baseline. No long-term improvement in SF-36 was found. CONCLUSION: Patients with CRSwNP have a long-term 12-year postoperative improvement in nasal symptoms, polyp size, computed tomography, and olfaction.

Twelve-year long-term postoperative outcomes in patients with chronic rhinosinusitis with nasal polyps.

BACKGROUND: Evidence regarding long-term postoperative follow-up of chronic rhinosinusitis with nasal polyps (CRSwNP) patients is scarce in the literature. The objective of the present study was to report long-term 12-year postoperative outcomes for CRSwNP patients. METHODS: CRSwNP patients were prospectively followed after endoscopic sinus surgery. Sinonasal symptoms, nasal polyp score (NPS), Barcelona Smell Test 24 (BAST-24), Lund-Mackay Score (LMS), and Medical Outcome Study Short Form-36 (SF-36) questionnaire were assessed before and 12 years after surgery. RESULTS: At long-term follow-up (median, 12 years), a strong improvement was noted for all patients (N=76) in nasal symptoms score, NPS, BAST-24, and LMS scores compared with baseline. No long-term improvement in SF-36 was found. CONCLUSION: Patients with CRSwNP have a long-term 12-year postoperative improvement in nasal symptoms, polyp size, computed tomography, and olfaction.

Endoscopic endonasal surgery to treat intrinsic brainstem lesions: correlation between anatomy and surgery.

OBJECTIVE: The endoscopic endonasal approach (EEA) has been proposed as an alternative in the surgical removal of ventral brainstem lesions. However, the feasibility and limitations of this approach to treat such pathologies are still poorly understood. This study aimed to report our experience in five consecutive cases of intrinsic brainstem lesions that were managed via an EEA, as well as the specific anatomy of each case. METHODS: All patients were treated in a single center by a multidisciplinary surgical team between 2015 and 2019. Before surgery, a dedicated anatomical analysis of the brainstem safe entry zone was performed, and proper surgical planning was carried out. Neurophysiological monitoring was used in all cases. Anatomical dissections were performed in three human cadaveric heads using 0° and 30° endoscopes, and specific 3D reconstructions were executed using Amira 3D software. RESULTS: All lesions were located at the level of the ventral brainstem. Specifically, one mesencephalic cavernoma, two pontine ca- vernomas, one pontine gliomas, and one medullary diffuse midline glioma were reported. Cerebrospinal fluid leak was the major complication that occurred in one case (medullary diffuse midline glioma). From an anatomical standpoint, three main safe entry zones were used, namely the anterior mesencephalic zone (AMZ), the peritrigeminal zone (PTZ, used in two cases), and the olivar zone (OZ). Reviewing the literature, 17 cases of various brainstem lesions treated using an EEA were found. CONCLUSIONS: To our knowledge, this was the first preliminary clinical series of intrinsic brainstem lesions treated via an EEA presented in the literature. The EEA can be considered a valid surgical alternative to traditional transcranial approaches to treat selected intra-axial brainstem lesions located at the level of the ventral brainstem. To achieve good results, surgery must involve comprehensive anatomical knowledge, meticulous preoperative surgical planning, and intraoperative neurophysiological moni- toring.

Free nasal floor mucosal grafting after endoscopic total ethmoidectomy for severe nasal polyposis: a pilot study.

BACKGROUND: We report a novel surgical technique based on an endonasal free mucosal graft (mucoplasty) for improving clinical results and local healing in chronic rhinosinusitis with nasal polyps (CRSwNP). METHODS: Patients diagnosed with bilateral CRSwNP scheduled for endoscopic sinus surgery were included. They underwent complete removal of anterior and posterior ethmoid cells, in addition to bilateral type III frontal sinusotomy. An endoscopic mucoplasty was performed in the left nasal cavity, whereas the right nasal cavity served as control. Patients were evaluated before surgery and 6 months after operation, including Sino-Nasal Outcome Test (SNOT-22), Visual Analogue Scale (VAS) for olfaction, endoscopic evaluation using the Modified und-Kennedy (MLK) scoring system and healing evaluation. RESULTS: Ten patients (mean age 53.6 years) were included. A significa t decrease of SNOT-22 score from 57.0 (21.1) to 20.3 (20.6) (P = 0.024) and a non-significa t decrease of VAS for olfaction score from 9.3 (0.5) to 4.6 (3.9) were found. Preoperative mean MLK score was 4.9 (0.7) in the right nostril and 4.8 (1.0) in the left one. After operation, there was a greater decrease of MLK score in the left nostril than in the right (1.9 [1.0] vs. 1.3 [0.8], P = 0.034). Better healing was proved in the nostril with the mucoplasty. CONCLUSION: Endonasal mucoplasty could be an effective, safe and feasible complementary surgical procedure in the treatment of CRSwNP. The reduced local edema associated with lower amount of secretions may confer a better control in the frontal recess, orbital wall and nasal roof.

Modified nasal floor and inferior meatus flap for septal perforation repair. Extension and limits.

BACKGROUND: The nasal floor and inferior meatus (NFIM) flap represents an available option for the reconstruction of a septal perforation (SP). This study explores the feasibility of repairing SPs using a modified simple and extended (including inferior turbinate) NFIM flap. METHODS: An anatomic study was achieved in fresh frozen cadaveric specimens to measure the area and lengths of NFIM flap. The repair of SP with simple and extended NIFM flaps was performed in some of these cadaveric specimens. Preoperative radiological evaluation of CT scans allowed studying the reconstruction limits of the simple or extended NFIM flap. A cohort of patients with SP who underwent reconstruction with an NFIM flap was also included. RESULTS: Complete SP repair with NFIM was achieved in all specimens (n=10). In 38 fresh cadaveric specimens, coronal and sagittal lengths and area of simple NFIM flaps were smaller than in extended NFIM flaps. The radiological analysis of 75 CT scans revealed that the septal height could be reconstructed with a simple and extended NFIM flap. Complete SP repair wasachieved in 5 patients (4 male, mean age 57.4 years) using modified NFIM flaps. CONCLUSION: The simple or expanded NFIM flap represents a feasible option to repair small or medium-sized perforations located at the lower 1/3 or 3/4 of the nasal septum.

Expanded endoscopic endonasal surgery for advanced stage juvenile angiofibromas: a retrospective multi-center study.

OBJECTIVES: Endoscopic resection has become an established surgical option for most juvenile nasopharyngeal angiofibromas (JNA). However, surgical management of JNA with intracranial extension remains challenging. This retrospective multicenter study reviews a series of patients with advanced stage JNA treated via endonasal/endoscopic approach. METHODS: The experience of five academic tertiary or quaternary care ORL-HNS Departments were included. Medical records of all patients operated for JNA staged as Radkowski stage IIIA or IIIB were reviewed. Main outcome measures included intraoperative blood loss, length of hospital stay, complication rate, and rate of persistence or recurrence. RESULTS: A total of 74 male patients with stages IIIA and IIIB were included. The mean age was 16.4 years and preoperative embolization was performed in 71 patients. The mean blood loss in 45 patients for whom the data was available was 1279.7 ml. The more anatomic subsites were involved, the higher the risk was of intraoperative bleeding. The mean follow-up for 54 out of 73 patients was 37.9 months. Patients with residual disease are significantly linked to involvement of combined (anterior-lateral and posterior) anatomic subsites and to a higher number of affected subsites. At last follow-up, all patients were asymptomatic and those with residual tissue displayed no imaging signs of growth. CONCLUSIONS: This retrospective multicenter study supports the notion that expanded endonasal endoscopic approaches for advance staged JNA are a feasible option associated with good long-term results.

A clinical audit of the nutritional status and need for nutrition support amongst head and neck cancer patients treated with radiotherapy.

BACKGROUND: Radiotherapy is an effective treatment for head and neck cancers but patients often experience side effects which lead to weight loss. Nutrition intervention in the form of counselling or oral nutrition support (ONS) is frequently needed for these patients. For some patients, tube feeding is required to minimise weight loss during treatment. METHOD: Data was collected on 48 patients who received radiotherapy to the head and neck region over a nine-month period (June 2009-March 2010). Retrospective data collection was commenced in July 2010. Each patient's Diet Therapy Department record was reviewed. Main outcome measures were: 1) type of nutrition support; 2) percentage weight change during treatment; and 3) Patient-Generated Subjective Global Assessment Global (PG-SGA) rating. RESULTS: On initial assessment 28 (77.8%) patients were classified as well nourished using the PG-SGA. Mean weight loss during radiotherapy was 5.74%. Risk factors for the need for ONS and enteral nutrition support (ENS) were older age, presence of nutrition impact symptoms, high-risk tumour sites, advanced disease and chemotherapy. No significant difference was shown in weight loss between ONS and ENS groups. CONCLUSION: This study identified the need for early dietetic intervention for high nutritional risk groups of head and neck cancer patients to prevent significant weight loss. Pre-treatment nutritional status did not influence weight loss during treatment. ONS alone cannot prevent significant weight loss in patients with multiple nutrition impact symptoms. Early enteral feeding should be considered in this group of patients.

Oral and intranasal steroid treatments improve nasal patency and paradoxically increase nasal nitric oxide in patients with severe nasal polyposis.

INTRODUCTION: Recently, we demonstrated that acoustic rhinometry (AR) measurements correlated with nasal cavity volumes in patients with nasal polyposis (NP). The aim of the present study was to evaluate whether AR and nasal nitric oxide (nNO) are useful methods in monitoring and follow-up of medical treatment of NP. MATERIAL AND METHODS: Patients with severe nasal polyps were randomized into two groups after a 4-week steroid washout period (w0): a treatment group received oral prednisone for 2 weeks (w2) and intranasal budesonide for 12 weeks (w12) while the control group received no steroid treatment. Nasal volume (Vol 0-6), minimum cross-sectional area (mCSA), nNO, peak nasal inspiratory flow (PNIF), nasal obstruction, and smell loss were evaluated. RESULTS: At w2, the treatment group showed a significant increase of vol 0-6 compared to w0 and the control group. The mCSA area also increased compared to w0 and the control group. At w12, the improvement in vol 0-6 and mCSA was maintained after intranasal steroids compared to w0. At w2, the treatment group showed a paradoxical increase of nNO compared to w0 and the control group. At w12, this increase was maintained by intranasal steroids. CONCLUSION: Both oral and intranasal steroid treatments improve nasal patency and paradoxically increase nNO, by opening the ostiomeatal complex. This suggests that AR and nNO are useful methods in the monitoring and follow-up of patients with NP.

Modulation of extracellular matrix using adenovirus vectors.

Metabolism of the extracellular matrix (ECM) is a complex process that becomes disregulated in disease states characterized by chronic inflammation of joints, as is seen in rheumatoid arthritis or fibrosis of the lung. The participation of certain cytokines in this process is generally accepted (transforming growth factor-beta induces fibrosis), while the roles of other cytokines are less clear. Oncostatin M (OSM) is a member of the interleukin-6/leukaemia inhibitory factor (or gp130) cytokine family, and its participation in inflammation and the regulation of ECM metabolism is supported by a number of activities identified in vitro, including regulation of matrix metalloproteinase-1 and tissue inhibitor of metalloproteinases-1. Local overexpression of transforming growth factor-beta has been shown to be fibrogenic in mouse lung, whereas local OSM overexpression via intra-articular administration has been shown to induce a pannus-like inflammatory response in the synovium of mouse knee joints. Here we examine the effects of OSM in the context of those of transforming growth factor-beta using an established adenovirus vector that expresses mOSM (AdmOSM). We administered the virus intra-nasally into Balb/C mice to achieve high expression of OSM in the lung, and examined the effects at various time points. AdmOSM resulted in a vigorous inflammatory response by day 7 which was characterized by an elevation of neutrophil and mononuclear cell numbers and a marked increase in collagen deposition. These data support the use of such systems to study the ECM in vivo, and indicate a potential role for OSM in inflammatory responses that can modulate steady-state ECM deposition in Balb/C mice.

Murine oncostatin M stimulates mouse synovial fibroblasts in vitro and induces inflammation and destruction in mouse joints in vivo.

Oncostatin M (OSM) is a multifunctional cytokine, a member of the interleukin-6/leukemia inhibitory factor (IL-6/LIF) family, that can regulate a number of connective-tissue cell types in vitro including cartilage and synovial tissue-derived fibroblasts, however its role in joint inflammation in vivo is not clear. We have analyzed murine OSM (muOSM) activity in vitro and in vivo in mouse joint tissue, to determine the potential role of this cytokine in local joint inflammation and pathology. The effects of muOSM and other IL-6/LIF cytokines on mouse synovial fibroblast cultures were assessed in vitro and showed induction of monocyte chemotactic protein-1, interleukin-6, and tissue inhibitor metalloproteinase-1, as well as enhancement of colony growth in soft agarose culture. Other IL-6/LIF cytokines including IL-6, LIF, or cardiotrophin-1, did not have such effects when tested at relatively high concentrations (20 ng/ml). To assess effects of muOSM in articular joints in vivo, we used recombinant adenovirus expressing muOSM cDNA (AdmuOSM) and injected purified recombinant virus (10(6) to 10(8) pfu) intra-articularly into the knees of various mouse strains. Histological analysis revealed dramatic alterations in the synovium but not in synovium of knees treated with the control virus Ad-dl70 or knees treated with Adm-IL-6 encoding biologically active murine IL-6. AdmuOSM effects were characterized by increases in the synovial cell proliferation, infiltration of mononuclear cells, and increases in extracellular matrix deposition that were evident at day 4, but much more marked at days 7, 14, and 21 after administration. The synovium took on characteristics similar to pannus and appeared to contact and invade cartilage. Collectively, these results provide good evidence that OSM regulates synovial fibroblast function differently than other IL-6-type cytokines, and can induce a proliferative invasive phenotype of synovium in vivo in mice on overexpression. We suggest that OSM may contribute to pathology in arthritis.

Do earthworms help to sustain the slug predator Pterostichus melanarius (Coleoptera: carabidae) within crops? Investigations using monoclonal antibodies.

Earthworms provide a major potential source of alternative food for polyphagous predators, such as carabid beetles, that are natural enemies of slugs, aphids and other agricultural pests. Non-pest prey may foster larger numbers of natural enemies, which then help to control pests, or alternatively may help to divert the predators away from pest control. An earthworm-specific monoclonal antibody was developed to study carabid-earthworm interactions in the field and assess the role of earthworms as alternative prey. The antibody could identify as little at 7 ng of earthworm protein in an ELISA, and could detect earthworm remains in the foregut of the carabid beetle Pterostichus melanarius for 64 h after consumption. Thirty-six per cent of field-collected beetles contained earthworm remains. Quantities of earthworm proteins in the beetle foreguts were negatively related to total foregut biomass, suggesting that earthworm consumption increased as total prey availability declined. There was also a negative relationship between foregut biomass and beetle numbers, but both quantities and concentrations of earthworm proteins in beetle foreguts were positively related to beetle numbers. This suggests that as beetle activity-density increased, total prey availability declined, or, as prey availability declined, beetles spent more time searching. In these circumstances, beetles fed to a greater extent on earthworms, an acceptable but nonpreferred food item. Earthworms may, therefore, provide an ideal alternative prey for P. melanarius, helping to sustain it when pest numbers are low but allowing it to perform a 'lying-in-wait' strategy, ready to switch back to feeding on pests when they become available.

Stimulation of osteoclast differentiation in vitro by mouse oncostatin M, leukaemia inhibitory factor, cardiotrophin-1 and interleukin 6: synergy with dexamethasone.

The role of oncostatin M in bone metabolism is not clearly defined, and the actions of mouse oncostatin M (mOSM) on osteoclast development has not been previously determined. We therefore examined the ability of recombinant mOSM to stimulate osteoclast formation and activity using cocultures of murine calvaria and bone marrow cells, and compared the responses to other members of the interleukin 6 family of cytokines including mouse leukaemia inhibitory factor (LIF), cardiotrophin-1 (CT-1) and IL-6. Mouse OSM, LIF and CT-1 strongly induced the formation of tartrate resistant acid phosphatase positive (TRAP(+)) multinucleated cells (MNC) in a dose-dependent fashion. OSM, LIF or CT-1 also elevated the number and size of resorptive pits when cocultures were added to smooth cortical bone slices, indicating enhancement of osteoclast activity. The activity of OSM was reduced by indomethacin (10(-8)-10(-6) M), whereas addition of dexamethasone (DEX) at 10(-7)-10(-5) M synergistically enhanced OSM-induced numbers of TRAP(+)MNC. DEX (10(-7) M) costimulation also synergistically enhanced TRAP(+)cell numbers of LIF, and CT-1 treated cocultures. IL-6 had no activity alone, but further enhanced TRAP(+)cell formation in mOSM or DEX (10(-7) M) treated cocultures. When added to mouse calvarial osteoblast cultures, mOSM induced secretion of IL-6 protein and elevation of mRNA whereas LIF or CT-1 did not. IL-6 mRNA levels and protein secretion were reduced in osteoblasts by costimulation with DEX. These results show that mouse OSM, LIF and CT-1 induce osteoclast differentiation and activation, that DEX synergizes with each in this activity, and that mouse OSM induces responses in osteoblasts that are not shown by LIF or CT-1. Collectively these data suggest an important role of these cytokines in osteoporosis caused by high levels of corticosteroid.

Treatment of hypertension in patients > or =65 years of age: experience with amlodipine.

BACKGROUND: Hypertension is a common finding in patients > or =65 years of age that contributes to cardiovascular morbidity and mortality, but many patients are untreated or their hypertension inadequately controlled. Recent randomized controlled studies have demonstrated the benefits of treating hypertension in the elderly. OBJECTIVE: This study was undertaken to assess the efficacy and tolerability of amlodipine, a long-acting calcium channel blocker, in elderly (> or =65 years of age) patients with mild to moderate hypertension (diastolic blood pressure 95 to 114 mm Hg). METHODS: This was an open-label, multicenter, 10-week, general-practice study involving patients >18 years of age. Patients with malignant or secondary hypertension or unstable angina were excluded, as were those who had experienced an acute myocardial infarction or stroke in the preceding 3 months or had been treated with an alpha-blocker in the preceding 6 months. Patients were assigned to 1 of 4 treatment schedules: amlodipine monotherapy or combination therapy and amlodipine given once daily in the morning or in the evening. Approximately 50% of patients would receive a morning dose, and approximately 80% would receive amlodipine as monotherapy. The paired t test was used to assess the significance of differences from baseline values, with significance set at P < 0.05. RESULTS: A total of 5135 patients received amlodipine and were included in the tolerability analysis. Of these, 3511 of 3628 patients (96.8%) <65 years and 1471 of 1507 patients (97.6%) > or =65 years (including 336 of 349 [96.3%] > or =75 years) were included in the efficacy analysis. Significant reductions (P < 0.05) in blood pressure were noted in all groups after 4 and 8 weeks of treatment. The equivalence of efficacy in all age groups was seen in terms of reduction in blood pressure (reduction of 21/15 mm Hg in patients <65 years of age, 25/16 mm Hg in those > or =65 years of age, and 26/17 mm Hg in those > or =75 years of age) compared with baseline. Therapy was successful in 2878 patients (82.0%) <65 years of age, in 1238 patients (84.2%) > or =65 years of age, and in 284 patients (84.5%) > or =75 years of age. The incidence of adverse events was similar in all age groups (18.0%, <65 years; 22.3%, > or =65 years; and 24.1%, > or =75 years), with no statistically significant differences between groups. Tolerability was rated as good or excellent in all patients, with no significant differences between groups. CONCLUSIONS: Once-daily amlodipine was effective in the treatment of mild to moderate hypertension in this patient population and demonstrated a low frequency of adverse events, a high degree of tolerability, and improved well-being. Morning rather than evening dosing appeared to confer a slight advantage.

Adenovirus vector expressing mouse oncostatin M induces acute-phase proteins and TIMP-1 expression in vivo in mice.

Mouse oncostatin M (MuOSM) regulates the production of acute-phase proteins by hepatocytes as well as tissue inhibitor of metalloproteinases-1 (TIMP-1) production by fibroblasts in vitro. We have generated an adenovirus (Ad) encoding MuOSM and tested the effects of administration of recombinant AdMuOSM to mice in vivo. On intramuscular injection, AdMuOSM (5 X 10(7) plaque-forming units, pfu) induced an increase in serum levels of interleukin-6 (IL-6) as well as the acute-phase proteins serum amyloid A (SAP) and alpha1-acid glycoprotein (AGP) at day 1. SAP and AGP concentrations were elevated to greater levels at day 3 and decreased to near control levels at day 7. Intratracheal treatment with AdMuOSM induced TIMP-1 mRNA levels (as assessed by Northern blots) that corresponded to the presence of transgene MuOSM mRNA levels. TIMP-1 was elevated at day 1 and day 3 and less consistently at day 7 after administration. Intraperitoneal treatment with AdMuOSM also resulted in elevation of TIMP-1 mRNA in lung tissue. These results show that AdMuOSM can induce both local and systemic effects and demonstrate in vivo effects of OSM that are consistent with in vitro studies on acute-phase protein and TIMP-1 expression.

Regulation of tissue inhibitor of metalloproteinase-1 in fibroblasts and acute phase proteins in hepatocytes in vitro by mouse oncostatin M, cardiotrophin-1, and IL-6.

Mouse oncostatin M (mOSM) has been recently cloned; however, its full spectrum of biologic functions has not been defined. To assess its potential role in inflammation, we have tested the activity of mOSM in vitro in regulation of fibroblasts and hepatic cells. At concentrations of 10 and 20 ng/ml, mOSM stimulates tissue inhibitor of metalloproteinase-1 (TIMP-1) mRNA in NIH-3T3 mouse embryonic fibroblasts, rat lung fibroblasts, and rat synovial fibroblasts, whereas mouse cardiotrophin-1 (mCT-1) or human OSM (hOSM) did not. Similarly, only mOSM was able to induce transcription of chloramphenicol acetyl-transferase (CAT) in NIH-3T3 cells transfected with a minimal TIMP-1 promoter/CAT construct. Mouse OSM had strong action inducing primary rat hepatocyte cultures to produce acute phase proteins; however, mOSM was very weak in its ability to stimulate acute phase protein synthesis in rat H35 cells or human HepG2 cells, which was consistent with weak STAT activation in H35 cells and HepG2 cells. Binding studies showed that NIH-3T3 cells possessed high affinity binding sites for mOSM, but rat H35 cells did not. On the other hand, mCT-1 and mouse IL-6 induced strong STAT activation as well as marked increases in acute phase protein production by H35 cells. These results indicate that mOSM does not share a functional receptor with mCT-1 or hOSM in mouse and rat cells and that hOSM does not activate the putatively specific OSM receptor on mouse or rat cells. These results also suggest that mOSM is an important cytokine in inflammation, through modulation of fibroblast function as well as hepatocyte responses.

Oncostatin M stimulates monocyte chemoattractant protein-1- and interleukin-1-induced matrix metalloproteinase-1 production by human synovial fibroblasts in vitro.

OBJECTIVE: To measure levels of oncostatin M (OSM) in the synovial fluid of rheumatoid arthritis (RA) patients and to examine the activities of human OSM in the regulation of human synovial fibroblast (HSF) production of chemokines and matrix metalloproteinases (MMP-1 and MMP-3) in vitro. METHODS: We examined the levels of OSM in the synovial fluids of patients with arthritis by an enzyme-linked immunosorbent assay (ELISA). ELISA of cell culture supernatants and Northern blots were used to assess responses of HSF to interleukin-1alpha (IL-1alpha), OSM, and other members of the IL-6/leukemia inhibitory factor (IL-6/LIF) family of cytokines. RESULTS: We detected variable levels of OSM antigen in 9 of 10 RA patient synovial fluids, but levels were not detectable in 9 of 10 osteoarthritis (OA) patient fluids. Upon examining the responses of HSF in culture, OSM stimulated monocyte chemoattractant protein 1 (MCP-1), whereas RANTES secretion (regulated upon activation, normal T expressed and presumably secreted) was not altered by OSM alone. In IL-1alpha-induced cells, OSM costimulation further enhanced MCP-1 release, but inhibited the release of RANTES and IL-8. Other members of the IL-6/LIF family of cytokines did not show these effects. OSM induced a small elevation of MMP-1 production over 2 and 3 days of stimulation (2-fold), and acted significantly to enhance IL-1alpha-induced production of MMP-1 (to 8-fold and 9-fold at 48 and 72 hours, respectively). No effect of OSM was seen on MMP-3 secretion, either alone or in IL-1alpha-costimulated cells. CONCLUSION: These results suggest that OSM has potentially important functions in the modulation of chemokine and metalloproteinase production by synovial cells of the joint.

Prostaglandin E2 enhances interleukin 8 (IL-8) and IL-6 but inhibits GMCSF production by IL-1 stimulated human synovial fibroblasts in vitro.

OBJECTIVE: To examine in vitro the effect of prostaglandin E2 (PGE2) on synovial cell cytokine production. METHODS: Human synovial fibroblasts were stimulated with PGE2 alone or PGE2 in combination with interleukin 1 alpha (IL-1 alpha) (5 ng/ml) and/or indomethacin (10(6) M) and assessed for the production of IL-8, IL-6, and granulocyte macrophage colony stimulating factor (GMCSF) at the protein and messenger RNA (mRNA) levels. RESULTS: PGE2 alone had little detectable effect on IL-8 or GMCSF; however, a small enhancement of both IL-6 mRNA and protein levels was seen. While all cytokines were markedly stimulated by IL-1 alpha), co-addition of the cyclooxygenase inhibitor indomethacin enhanced IL-8 and GMCSF levels, but caused a reduction in IL-6 expression. The addition of PGE2 to cultures stimulated with IL-1 alpha and indomethacin resulted increases in IL-6 mRNA and protein expression while causing a concomitant reduction in GMCSF protein and mRNA expression. PGE2 and illoprost (PGI2 analog) enhanced IL-8 production in stimulated cells. CONCLUSION: While PGE2 alone has limited effects on synovial cell production of IL-8 and GMCSF, its effects are significant in context of IL-1 alpha stimulation; endogenous PGE2 may alter cytokines secreted by mesenchymally derived cells. PGE2 may be an important modulator of cytokine driven inflammation.