Budesonide/formoterol effects on metalloproteolytic balance in TGFβ-activated human lung fibroblasts

SummaryIn the airways of asthmatic patients, activated fibroblasts account for an excessive matrix production including proteoglycans (PGs). Transforming growth factor-β (TGFβ), metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play key roles in matrix turnover. It is unclear whether asthma therapy with combination of inhaled glucocorticoids and long-acting β2-agonists affects metalloproteolytic equilibrium and by that counteracts airway fibrosis.The effects of the glucocorticoid, budesonide, and the long-acting β2-agonist, formoterol, on the PG production and the activity of PGs' main regulators: MMP-3, MMP-9, MMP-2 and TIMP-1 were investigated in human lung fibroblasts (HFL-1) treated for 24h with TGFβ1 (10ng/ml) without/with budesonide (10−9 to 10−6M) and/or formoterol (10−11 to 10−6M).TGFβ1 significantly increased production of PGs and TIMP-1, and the activity of MMP-3, MMP-9 and MMP-2. Concurrent budesonide/formoterol combination counteracted the enhanced: PG and TIMP-1 production, MMP-9 activity and MMP-9/TIMP-1 ratio, whereas MMP-2 and MMP-3 were not affected and so their ratios to TIMP-1 were significantly increased. Budesonide or formoterol alone achieved equal effects as budesonide/formoterol on MMP-9 and MMP-9/TIMP-1 ratio but had no effects on TIMP-1, MMP-2 or MMP-3. In the formoterol absence, higher budesonide concentrations were required to reduce the PG production, whereas formoterol alone had no effects.These results suggest that the budesonide/formoterol combination enhanced metalloproteolytic activity of human lung fibroblasts via a synergistic decrease of TIMP-1, and that this mechanism may be involved in the synergistic inhibition of the TGFβ1-induced PG production. This implies that budesonide/formoterol combination therapy can counteract excessive matrix production and thus pathological airway fibrotic remodeling in asthma

Ozon uygulamasının devital ağartma yapılan dentinde rezin simanın shear bağlanma dayanımına etkisi

Amaç: Ozon uygulanan ve uygulanmayan devital ağartma yapılmış dentine iki rezin simanın bağlanma dayanımının incelenmesi Gereç ve Yöntemler: : Seksen yeni çekilmiş sağlam insan maksiller kesici kuronları sekiz gruba ayrıldı (n=10): (G1, G2). Ağartmayı takiben ozon uygulanmayan (10% carbamide peroxide, Opalescence Boost %38 Hydrogen peroxide) veya uygulanan gruplar (G3, G4) (40%, 50 second, CR probe, Biozonix; High-Frequency Ozone Generator, Germany), ozonun ağartma yapılmadan uygulandığı gruplar (G5, G6) ve herhangi bir işlem uygulanmayan kontrol grupları (G7, G8). Kuronlar akrilik rezin içine dentin yüzeyleri açıkta kalacak şekilde yerleştirildi. Örneklerde iki rezin simandan biri kullanıldı: Secure Cement (Sun Medical) (G1, G3, G5, G7); Clearfil Esthetic Cement (Kuraray) (G2, G4, G6, G8). 3 x 3 boyutunda rezin siman oluturulan gruplar setleşme süresinden (37ºC, 100% nemli, 24 saat) sonra shear bağlanma dayanımı ile test edildi ( 0.5 mm/minute). Veriler MPa olarak hesaplandı ve Kruskal-Wallis testi ile analizler yapıldı (P < 0.05). Bulgular: Ağartma işleminin ozon uygulaması ile kombine kullanımı hem Secure siman (G3) hem de Clearfil Esthetic simanın (G4) bağlanma dayanımını artırdı (p > 0.05). Ozon uygulanan Secure siman örnekleri (G5), G1, G3, ve G7 gruplarından anlamlı derecede daha düşük bağlanma dayanımı gösterdi (P < 0.05). Clearfil Esthetic siman grubu (G4) kontrol grubundan (G8) anlamlı derecede daha yüksek bağlanma dayanımı gösterdi. Sonuç: Bonding işlemleri öncesinde ozon uygulaması ağartma sonrası geride kalan peroksitin etkisini azaltabilir. Devital ağartma sonrası ozon uygulaması rezin simanın dentin yüzeyine bağlantısını artırabilir

The frequency of Duchenne muscular dystrophy/Becker muscular dystrophy and Pompe disease in children with isolated transaminase elevation: results from the observational VICTORIA study

IntroductionElevated transaminases and/or creatine phosphokinase can indicate underlying muscle disease. Therefore, this study aims to determine the frequency of Duchenne muscular dystrophy/Becker muscular dystrophy (DMD/BMD) in male children and Pompe disease (PD) in male and female children with isolated hypertransaminasemia.MethodsThis multi-center, prospective study enrolled patients aged 3–216 months with serum alanine transaminase (ALT) and/or aspartate transaminase (AST) levels >2× the upper limit of normal (ULN) for ≥3 months. Patients with a known history of liver or muscle disease or physical examination findings suggestive of liver disease were excluded. Patients were screened for creatinine phosphokinase (CPK) levels, and molecular genetic tests for DMD/BMD in male patients and enzyme analysis for PD in male and female patients with elevated CPK levels were performed. Genetic analyses confirmed PD. Demographic, clinical, and laboratory characteristics of the patients were analyzed.ResultsOverall, 589 patients [66.8% male, mean age of 63.4 months (standard deviation: 60.5)] were included. In total, 251 patients (188 male and 63 female) had CPK levels above the ULN. Of the patients assessed, 47% (85/182) of male patients were diagnosed with DMD/BMD and 1% (3/228) of male and female patients were diagnosed with PD. The median ALT, AST, and CPK levels were statistically significantly higher, and the questioned neurological symptoms and previously unnoticed examination findings were more common in DMD/BMD patients than those without DMD/BMD or PD (p < 0.001).DiscussionQuestioning neurological symptoms, conducting a complete physical examination, and testing for CPK levels in patients with isolated hypertransaminasemia will prevent costly and time-consuming investigations for liver diseases and will lead to the diagnosis of occult neuromuscular diseases. Trial RegistrationClinicaltrials.gov NCT04120168

Lung fibroblast proteoglycan production induced by serum is inhibited by budesonide and formoterol

Copyright (C) 2005 by the American Thoracic Society. 1 Proteoglycans contribute to extracellular matrix remodeling in asthmatic airways. We investigated the effects of budesonide, a glucocorticoid, and formoterol, a long-acting ß2adrenergic agonist, on serum-induced proteoglycan production by human lung fibroblasts. In 10 % serum, total proteoglycan production was increased 1.5-fold (p<0.01) compared to basal production in 0.4 % serum. Budesonide (10-8 M) reduced this increase by 44 % (p<0.01), and while formoterol (10-10 –10-8 M) had no inhibitory effects, the drug combination abolished the increase (p<0.01) without affecting fibroblast proliferation. This synergistic effect required functional glucocorticoid and-adrenergic receptors. The production of the proteoglycans decorin, biglycan, perlecan, and versican, was increased 2.5–5-fold (p<0.01) in 10 % serum. Combination treatment with budesonide (10-8 M) and formoterol (10-10 M) abolished this increase to a significantly greater extent than either drug alone. In 10 % serum, only versican mRNA was increased 1.4-fold (p<0.05), while decorin mRNA was reduced to 39 % (p<0.01) of basal expression. These serum effects were counteracted by the drug combination bu

The effect of lidocaine, bupivacaine and ropivacaine in nasal packs on pain and hemorrhage after septoplasty

We aimed to investigate the effects of local anesthetics soaked in Merocel nasal packs on hemorrhage and pain after septoplasty. The methodology includes a prospective double-blind study that was conducted in patients undergoing septoplasty because of nasal septal deviation. The study included 143 patients. The patients were divided into four groups. Each group received 1% lidocaine + 0.000625% adrenalin, 0.375% ropivacaine, 0.25% bupivacaine as study groups or 0.9% sodium chloride as a control group in their Merocel packs postoperatively. The local anesthetics or sodium chloride were reapplied at the eighth postoperative hour. Each patient was given a questionnaire where verbal analog score and amount of postoperative hemorrhage was noted. The statistical analysis was performed using two sided t test on each patient group at each time point. The results included the patients in the control group needing rescue drug most often. There was no statistically significant difference between bupivacaine and lidocaine plus adrenalin in the patients who requested rescue drug. The patients in the ropivacaine group requested rescue drug more frequently than the bupivacaine and lidocaine plus adrenalin groups. Bupivacaine group had significantly better pain scores versus control group at all intervals except for the first postoperative hour.The bupivacaine group had better pain scores versus ropivacaine and lidocaine plus adrenalin groups in the 4th, 8th and the 24th hours. The bupivacaine group had better pain scores versus lidocaine plus adrenalin in the 12th, 16th and the 20th hours. The ropivacaine group had significantly better pain scores versus control group in the 8th, 12th, 16th, 20th and 24th postoperative hours. The ropivacaine group scored better than lidocaine plus adrenalin group just in the 16th hour. The lidocaine plus adrenalin group had significantly better pain scores versus control group in 4th and 12th hours. There was no statistically significant difference between the study groups in terms of postoperative hemorrhage. We concluded that bupivacaine use in nasal surgery provides better analgesia at least in the first 8 h period and does not cause more bleeding. Topical bupivacaine application to nasal packs should be considered after septoplasty