Changes of TNF-α, PDGF and HA in nasal secretions and olfactory function of patients with chronic sinusitis before and after endoscopic sinus surgery

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1 EXPERIMENTAL AND THERAPEUTIC MEDICINE 16: , 2018 Chnges of TNF-α, PDGF nd HA in nsl secretions nd olfctory function of ptients with chronic sinusitis before nd fter endoscopic sinus surgery LINQI WEI *, YONGHONG ZHANG * nd HUAZHANG TAN Deprtment of Otolryngology-Hed nd Neck Surgery, Xingyng No.1 People's Hospitl, Hubei University of Medicine, Xingyng, Hubei , P.R. Chin Received Jnury 25, 2018; Accepted August 2, 2018 DOI: /etm Abstrct. This study imed to investigte the chnges of tumor necrosis fctor-α (TNF-α), pltelet-derived fctor (PDGF), hyluronic cid (HA) in nsl secretions nd olfctory function in ptients with chronic sinusitis before nd fter endoscopic sinus surgery. A totl of 94 ptients with chronic sinusitis treted t Xingyng No.1 People's Hospitl, Hubei University of Medicine (Xingyng, Chin) from My 2016 to April 2017 were rndomly divided into the control nd observtion groups, with 47 ptients in ech group. The observtion underwent endoscopic sinus surgery, while the control group were treted with trditionl extrnsl surgery. The tretment efficcy of the two groups were compred 3 months fter the tretment. A self-designed symptom questionnire ws used to evlute the symptom scores. Enzyme-linked immunosorbent ssy (ELISA) ws used to detect the TNF-α, PDGF nd HA levels in nsl secretions. The olfctory function of the ptients ws evluted by the stndrd T&T olfctometry test. The life qulity before nd fter the tretment ws compred by using the SNOT-20 questionnire. The tretment efficcy of the observtion group ws significntly higher thn tht of the control group (P<0.05). Both groups showed improved symptom scores fter the tretment, while improvement in the observtion group ws more obvious (P<0.05). The observtion showed significntly lower TNF-α level thn the control group (P<0.05). One, four nd eight weeks fter tretment, the levels of PDGF nd HA were significntly higher in the observtion group thn in the control group Correspondence to: Dr Huzhng Tn, Deprtment of Otolryngology-Hed nd Neck Surgery, Xingyng No.1 People's Hospitl, Hubei University of Medicine, 15 Jiefng Rod, Xingyng, Hubei , P.R. Chin E-mil: tzu46m@163.com * Contributed eqully Key words: chronic sinusitis, nsl endoscopic surgery, TNF-α, pltelet-derived fctor, hyluronic cid, olfctory function (P<0.05). Both groups exhibited significntly improved olfctory function scores fter tretment, nd improvement in the observtion group ws more thn tht in the control group (P<0.05). After tretment, decresed scores of SNOT-20 in the observtion group ws more significnt (P<0.05). Compred with trditionl surgery, endoscopic surgery resulted in lighter postopertive inflmmtory responses, better nsl mucos repir, nd more improved postopertive olfctory function. Introduction Chronic sinusitis is common clinicl otorhinolryngology disese with high incidence nd recurrence rte in the generl popultion. It is often ccompnied by nsl polyps. The min clinicl mnifesttions include hedche, stuffy nose, snoring, loss of the sense of smell nd runny nose (1). Chronic sinusitis is usully cused by chronic purulent inflmmtion of the sinus mucos, cusing eyesight chnges nd otitis medi in ptients when it is getting more severe (2). Cliniclly, the tretment of chronic sinusitis includes conservtive nd surgicl tretment. The former often results in indequte tretment nd repeted recurrence. Although surgicl tretment hs better tretment effects, the trditionl surgicl tretment cn esily led to sinus nd nsl injuries nd intropertive bleeding, resulting in poor recovery of nsl mucosl injury tht interfere with recovery (3,4). With the development of endoscopic technology, endoscopic sinus surgery is widely used cliniclly, nd it cn effectively promote the recovery of sinus function nd improve the ptient's life qulity (5). Postopertive recovery of nsl mucosl injury involves tumor necrosis fctor-α (TNF α), pltelet-derived fctor (PDGF), hyluronic cid (HA) nd other cytokines (6). In the present study, ptients with chronic sinusitis were treted with different surgicl methods, nd the chnges of their TNF-α, PDGF, HA levels were studied to provide bsis for the effective tretment of chronic sinusitis. Mterils nd methods Generl Informtion. A totl of 94 ptients with chronic sinusitis treted t Xingyng No.1 People's Hospitl, Hubei University of Medicine (Xingyng, Chin) from My 2016

2 3414 WEI et l: TNF-α, PDGF AND HA IN CHRONIC SINUSITIS Tble Ⅰ. Generl informtion of the two groups of ptients. Items Control (n=47) Observtion (n=47) t/χ 2 P-vlue Sex (Mle/Femle) 19/28 21/ Age (yers) 45~70 45~75 Averge (yers) 58.56± ± Course of illness (yers) 5.63± ± BMI (kg/m 2 ) 23.63± ± BMI, body mss index. to April 2017 were selected for this study. Inclusion criteri were: i) Meeting the dignostic criteri for chronic sinusitis (7); ii) hving bilterl sinus lesions ssocited with nsl polyps; iii) being ble to communicte properly; nd iv) signing the informed consent. Exclusion criteri were: i) Previous history of sinusitis or nsl polyp surgeries, sthm or llergies; ii) orl dministrtion of hormones or ntibiotics in the pst 1 month; nd iii) topicl nsl mediction in the pst 2 weeks or congenitl bsence of the sense of smell. The ptients were rndomly divided into the observtion nd control groups with 47 cses in ech group. The two groups of ptients hd no sttisticlly differences in their generl informtion (P>0.05) (Tble I). This study ws pproved by the Ethics Committee of Xingyng No.1 People s Hospitl (Xingyng, Chin). Signed written informed consents were obtined from the ptients. Methods Tretment. The control group ws treted by trditionl surgery. Ptients were instructed to tke the supine position. After locl infiltrtion nesthesi, the nsl polyps were removed with nsl polyp snre. After the lesions were clened up, vseline guze ws used to stop the bleeding nd the guze ws removed 2 dys lter. The observtion group ws treted by endoscopic sinus surgery. Antibiotics were given one week before the opertion. After locl infiltrtion nd topicl nesthesi, drenline cotton ptches were used to deflte the nsl mucos so s to fully expose the nsl pssges. The Messerklinger technique ws used to remove the nsl polyps. The mxillry nd ethmoid sinus were opened to remove the lesions. Hemosttic guze ws used to stop the bleeding, nd sodium chloride solution ws used to rinse the wound. Vseline guze ws removed 2 dys lter. Both groups were given ntibiotics for 3 dys postope rtively. Prnsl sinuses nd nsl cvity were clened nd rinsed once week fter the opertion. Detection of TNF-α, PDGF nd HA concentrtions. Before nd 1, 4 nd 8 weeks fter surgery, smll pieces of cotton were put into the ptient's nsl pssges for 10 min to collect the ptient's nsl secretions (before clening). The cotton pieces were then put into 0.9% sodium chloride solution nd the suspension ws collected. After centrifugtion t 4 C t 2,500 x g for 10 min (centrifugtion rdius 15 cm), the superntnt ws collected nd stored in -80 C freezer. The levels of TNF-α, PDGF nd HA were detected by enzyme linked immunosorbent ssy (ELISA). All kits were provided by Dlin F.T.Z CREDIT Chemicl Technology Development Co., Ltd., (Lioning, Chin). All opertions strictly followed the mnufcturer's instructions. A microplte reder (Elx800; BioTek Instruments, Inc., Winooski, VT, USA) ws used to red the OD vlues t the wvelength of 450 nm nd the concentrtions of TNF-α, PDGF nd HA were clculted. Olfctory function test. Solutions of phenylethyl lcohol, isovleric cid, methylcyclopentenone, serotonin nd undecylenic cid vinegr were mde for the stndrdized T&T olfctometry test. The kit ws provided by Jpn First Phrmceuticl Industry Co., Ltd. (Tokyo, Jpn). Odorless filter pper ws used to smer different odornts in vrious concentrtions (8 concentrtions) sequentilly (t the intervl of 30 sec) nd plced close to the ptient's noses (1 cm) for them to smell from 2 to 3 times. The detection nd recognition thresholds of the ptients were mesured nd the verge olfctory thresholds were clculted. Evlution criteri. Tretment efficcy evlution: i) Cured: disppernce of symptoms such s nsl congestion, hedche nd purulent nsl dischrges; open sinus ostium without stenosis or occlusion; no purulent secretions. ii) Improved: significntly improved symptoms, edem or grnultion in the sinus mucos nd smll mount of purulent secretions. iii) Ineffective: no improvement or worsening of vrious symptoms, sinus stenosis or tresi, obvious swelling, formtion of polyps, lrge mount of purulent secretions (8). A self-designed chronic sinusitis symptom questionnire ws used to obtin the symptom scores of the ptients before nd 1, 4 nd 8 weeks fter tretment. A scle of 0~3 points (0 for no, 3 for severe) were used to evlute ptients' symptoms from severl spects including nsl congestion, purulent nsl dischrge, hedche, decresed sense of smell, nd nsl or throt dryness. The finl score ws positively correlted with the severity of symptoms. ELISA ws used to detect the levels of TNF-α, PDGF nd HA in the nsl secretions of the ptients before nd 1, 4 nd 8 weeks fter tretment. The olfctory function ws evluted before nd 1, 2 nd 3 months fter tretment by the stndrd T&T olfctometry test. The men olfctory threshold of the five olfctory odornts ws used to evlute the olfctory function (9). The SNOT-20 questionnire ws used to evlute life qulity of the ptients before nd fter tretment (10). The scores were evluted from 20 items t scle from 0 to 3 (0,

3 EXPERIMENTAL AND THERAPEUTIC MEDICINE 16: , Tble Ⅱ. Comprison of the tretment efficcy n (%). Groups No. Cured Improved Ineffective Totl effective rte Observtion (68.09) 12 (25.53) 3 (6.38) 44 (93.62) Control (4.04) 20 (42.55) 11 (23.40) 36 (76.60) χ² P-vlue Tble Ⅲ. Chnges of symptom scores of the two groups before nd fter tretment Groups No. Before surgery 1 week 4 weeks 8 weeks F-vlue P-vlue Observtion ± ± ± ± <0.001 Control ± ± ± ± t-test P-vlue <0.001 <0.001 <0.001 Compred with before surgery, P<0.05. Tble Ⅳ. Comprison of the TNF-α levels of the two groups (pg/ml) Groups No. Before surgery 1 week 4 weeks 8 weeks F-vlue P-vlue Observtion ± ± ± ± <0.001 Control ± ± ± ± <0.001 t-test P-vlue <0.001 <0.001 <0.001 Compred with before surgery, P<0.05. TNF-α, tumor necrosis fctor-α. no, nd 3, severe). Afterwrd, the five most importnt items were selected for more further nlysis. Sttisticl nlysis. The dt were processed by using the SPSS 19.0 (SPSS Inc., Chicgo, IL, USA) softwre. The mesurement dt were expressed s men ± stndrd devition (SD). Comprisons between the two groups were tested by t-test. The differences before nd fter tretment were tested by the pired t-test. The count dt were expressed in terms of rte nd tested by the χ 2 test. Comprisons of prmeters t different time-points One-wy ANOVA test followed by post hoc test (Lest Significnt Difference). A P<0.05 ws considered to indicte sttisticlly significnt difference. Comprison of the tretment efficcy of the two groups. The observtion hd significntly higher totl effective rte thn the control group (P<0.05) (Tble II). Chnges of symptoms scores of the two groups. One, four nd eight weeks fter tretment, the two groups hd significntly improved symptom scores thn before tretment. The observtion group exhibited more improvement thn the control group (P<0.05) (Tble III). Comprison of the TNF-α levels of the two groups. The TNF-α levels of both groups showed n incresing trend fter surgery, nd reched the pek 1 week fter surgery. Compred with 1 week fter surgery, the TNF-α levels were lower t 4 nd 8 weeks fter surgery. However, they were still higher thn those before surgery. In ddition, the TNF-α levels in the observtion group were less incresed thn in the control group (P<0.05) (Tble IV). Comprison of the PDGF levels of the two groups. The PDGF levels of both groups showed n incresing trend fter surgery, nd reched the pek 1 week fter surgery. Compred with 1 week fter surgery, the PDGF levels were lower t 4 nd 8 weeks fter surgery. However, they were still higher thn those before surgery. In ddition, the PDGF levels in the observtion group were more incresed thn in the control group (Tble V).

4 3416 WEI et l: TNF-α, PDGF AND HA IN CHRONIC SINUSITIS Tble Ⅴ. Comprison of the PDGF levels of the two groups (pg/ml) Groups No. Before surgery 1 week 4 weeks 8 weeks F-vlue P-vlue Observtion ± ± ± ± <0.001 Control ± ± ± ± <0.001 t-test P-vlue <0.001 <0.001 <0.001 Compred with before surgery, P<0.05. PDGF, pltelet-derived fctor. Tble Ⅵ. Comprison of the HA levels of the two groups (ng/l) Groups No. Before surgery 1 week 4 weeks 8 weeks F-vlue P-vlue Observtion ± ± ± ± <0.001 Control ± ± ± ± <0.001 t-test P-vlue <0.001 <0.001 <0.001 Compred with before surgery, P<0.05. HA, hyluronic cid. Tble Ⅶ. Chnges of olfctory function of the two groups of ptients before nd fter tretment. Groups No. Before surgery 1 month 2 months 3 months F-vlue P-vlue Observtion ± ± ± ± <0.001 Control ± ± ± ± <0.001 t-test P-vlue <0.001 <0.001 <0.001 Compred with before surgery, P<0.05. Comprison of HA levels of the two groups. The HA levels of both groups showed n incresing trend fter surgery, nd reched the pek 1 week fter surgery. Compred with 1 week fter surgery, the HA levels were lower t 4 nd 8 weeks fter surgery. However, they were still higher thn those before surgery. In ddition, the HA levels in the observtion group were more incresed thn in the control group (Tble VI). Chnges of olfctory function in the two groups 1, 2 nd 3 months fter tretment. The two groups of ptients hd significntly improved olfctory function when compred with tht before tretment nd the observtion group improved more significntly (P<0.05) (Tble VII). Comprison of life qulity scores of the two groups before nd fter tretment. After tretment, the SNOT-20 scores of both groups were significntly decresed when compred with those before tretment, nd prticulrly those of the observtion group were decresed more thn those of the control group (P<0.05) (Tble VIII). Discussion The cuses of sinusitis re complex nd include trum, disorders in the respirtory ciliry system, gstroesophgel reflux, respirtory llergies nd infections, ntomicl bnormlity of the sinuses nd nsl cvity s well s systemic immunodeficiency (11). The nsl tissues of ptients with chronic sinusitis usully develop edem under the long-term stimultion of inflmmtory cytokines. At the sme time, locl ggregtion of eosinophils occurs nd vriety of cytokines nd toxic proteins re relesed. The increse of the permebility of the nsl blood vessels results in plsm exudtion, epithelil rupture nd continuous proliferte. Extrcellulr mtrix lso prolifertes nd results in the formtion of nsl polyps (12). About two-thirds of ptients with chronic sinusitis lso suffer olfctory dysfunction. The mechnism of olfctory

5 EXPERIMENTAL AND THERAPEUTIC MEDICINE 16: , Tble Ⅷ. Comprison of the life qulity scores of the two groups. Twenty items fter surgery (point) Most importnt 5 items (point) Before 12 weeks Before 12 weeks Groups surgery fter surgery t-test P-vlue surgery fter surgery t-test P-vlue Observtion 28.34± ± < ± ± <0.001 Control 28.43± ± < ± ± <0.001 t-test P-vlue < <0.001 dysfunction cused by chronic sinusitis nd nsl polyps is not yet fully understood (13). It is generlly believed tht the nsl mucosl edem nd congestion obstruct olfctory sulcus, nd mke it difficult for odornt molecules to successfully rech the olfctory mucos, resulting in olfctory disorders (14). The nsl nd sinus cvities re nrrow with complex ntomicl structures, with chrcteristics of smll nd deep hole, which mkes the tretment of chronic sinusitis more difficult. The disese hs serious impct on the qulity of life of the ptients. Cliniclly, conservtive tretment nd surgery re two common wys to tret chronic sinusitis. Surgery cn better tret the ptients by improving nd reconstructing sinus nd nsl ventiltion nd dringe (15). The results of our study showed tht fter tretment, the totl tretment effective rte of the observtion group ws significntly higher thn tht of the control group. After tretment, the symptom scores of both groups were significntly improved, nd improvement in the observtion group ws more significnt (P<0.05). This is becuse trditionl sinus surgery cn esily cuse nsl nd sinus dmge s well s serious bleeding, which interferes with the postopertive recovery of the wounds. Endoscopic sinus surgery enbles direct vision under the sinus endoscope. The structure nd function of the prnsl sinuses nd nsl cvity cn be retined s much s possible, which benefits the rpid postopertive recovery of ptients. Ptients with chronic rhinosinusitis usully undergo longer period of recovery fter surgery. During tht time, the lesions will coexist with nsl mucos regenertion, leding to edem nd ductile inflmmtion. Eventully sinus mucos epithelizes nd ptients recover (16). TNF-α is criticl nd one of the erliest inflmmtory meditors tht my initite nd trigger inflmmtory responses. It leds to cscde of rections tht hve significnt impct on the occurrence nd prognosis of post-trumtic inflmmtion. It plys n importnt role in injuries cused by neutrophil ggregtion (17). PDGF is n importnt meditor during the heling of wounds, which my stimulte cell prolifertion, growth nd promote the formtion of grnultion tissues (18). HA is nturl polymeric polyscchride tht is n importnt prt of the tissue mtrix. It hs permebility, pseudoplsticity nd high viscoelstity. Furthermore, it is importnt for wound heling (19). The results of this study showed tht fter tretment, the TNF-α levels in both groups were significntly higher thn those before tretment, but the TNF-α level of the observtion group ws significntly lower thn tht of the control group. The levels of PDGF nd HA in both groups lso incresed significntly when compred with those before tretment, nd the observtion group hd significntly higher PDGF nd HA thn the control group (P<0.05). This is becuse fter surgery, lrge number of PDGF is ctivted nd its concentrtion continues to rise, promoting the prolifertion nd growth of vriety of cells nd rpid heling of wounds. Compred with trditionl surgicl methods, the endoscopic sinus surgery is minimlly invsive, nd the fster heling of sinus mucos is closely relted to PDGF (18). During the postopertive mucosl epitheli repir process, secondry inflmmtion leds to elevted TNF-α level. Endoscopic sinus surgery cuses less dmge to norml mucos nd the degree of edem is reduced (20). During the erly postopertive mucosl heling process, HA concentrtion rpidly increses nd promotes the prolifertion nd migrtion of fibroblsts. The HA level ws lower in the control group with trditionl surgery thn in the observtion group with endoscopic sinus surgery. This is becuse endoscopic sinus surgery cn clen the lesions within the sinuses nd nsl cvity more thoroughly, nd t the sme time cuse less dmge to the nsl cili. These effects benefit the deposition of collgen fibers nd result in higher HA, promoting postopertive sinus mucos heling (19). The sense of smell is one of the humn sensory functions, nd recovery of the olfctory function fter the tretment of chronic sinusitis ptients directly ffects the tretment efficcy (21). The results of this study showed tht 1, 2 nd 3 months fter tretment, the scores reflecting olfctory function in both groups were significntly improved when compred with those before tretment, nd improvement in the observtion group ws more obvious (P<0.05). This my occur becuse the trditionl surgicl method is less thorough thn the endoscopic sinus surgery in clening lesions. Thus, the suppressive stte of olfctory sulcus cused by inflmmtion is not completely relieved, nd recovery of the impired olfctory cells nd nerve fibers re not idel. In ddition, trditionl surgery my cuse greter dmge to olfctory sulcus nd led to serious postopertive dhesions, disturbing the blnce of the environment round the olfctory sulcus nd incresing the difficulties for the odornt to rech the olfctory mucos, nd thus, resulting in poor olfctory recovery nd decresed life qulity of the ptients. In summry, endoscopic sinus surgery ws more effective in the tretment of chronic sinusitis thn trditionl surgery, which ws reflected by better olfctory function recovery of the ptients. Cliniclly, nsl mucos wound heling could be

6 3418 WEI et l: TNF-α, PDGF AND HA IN CHRONIC SINUSITIS evluted by detecting TNF-α, PDGF nd HA levels in the nsl secretions. Acknowledgements Not pplicble. Funding No funding ws received. Avilbility of dt nd mterils The dtsets used nd/or nlyzed during the present study re vilble from the corresponding uthor on resonble request. Authors' contributions LW nlyzed nd interpreted the ptient dt nd ws mjor contributor in writing the mnuscript. YZ performed the experiment nd prticipted in the design of the study. HT ws lso involved in the conception of the study. All uthors hve red nd pproved the finl mnuscript. Ethics pprovl nd consent to prticipte This study ws pproved by the Ethics Committee of Xingyng No.1 People's Hospitl (Xingyng, Chin). Signed written informed consents were obtined from the ptients. Ptient consent for publiction Not pplicble. Competing interests The uthors declre tht they hve no competing interests. References 1. Smith KA, Orlndi RR nd Rudmik L: Cost of dult chronic rhinosinusitis: A systemtic review. Lryngoscope 125: , Tewfik MA, Ltterich M, DiFlco MR nd Smh M: Proteomics of nsl mucus in chronic rhinosinusitis. Am J Rhinol 21: , Chen FH, Deng J, Hong HY, Xu R, Guo JB, Hou WJ, Sun YQ, Li YY, Li HB nd Shi JB: Authors' Reply: Prognosis nd risk in considering extensive vs functionl endoscopic sinus surgery for chronic rhinosinusitis with nsl polyps nd sthm. Am J Rhinol Allergy 31: 1, Rgb SM, Lund VJ nd Scdding G: Evlution of the medicl nd surgicl tretment of chronic rhinosinusitis: A prospective, rndomised, controlled tril. Lryngoscope 114: , Rudmik L, Soler ZM, Mce JC, Schlosser RJ nd Smith TL: Economic evlution of endoscopic sinus surgery versus continued medicl therpy for refrctory chronic rhinosinusitis. Lryngoscope 125: 25-32, Lin DC, Chndr RK, Tn BK, Zirkle W, Conley DB, Grmmer LC, Kern RC, Schleimer RP nd Peters AT: Assocition between severity of sthm nd degree of chronic rhinosinusitis. Am J Rhinol Allergy 25: , Prince AA, Steiger JD, Khlid AN, Dogrhmji L, Reger C, Eu Clire S, Chiu AG, Kennedy DW, Plmer JN nd Cohen NA: Prevlence of biofilm-forming bcteri in chronic rhinosinusitis. Am J Rhinol 22: , Chen FH, Deng J, Hong HY, Xu R, Guo JB, Hou WJ, Sun YQ, Li YY, Li HB nd Shi JB: Extensive versus functionl endoscopic sinus surgery for chronic rhinosinusitis with nsl polyps nd sthm: A 1-yer study. Am J Rhinol Allergy 30: , Yumoto E, Minod R, Hyodo M nd Ymgt T: Cuses of recurrent lryngel nerve prlysis. Auris Nsus Lrynx 29: 41-45, Xu J, Prk SJ, Prk HS, Hn R, Rh KS nd Kim YM: Effects of trimcinolone-impregnted nsl dressing on subjective nd objective outcomes following endoscopic sinus surgery. Eur Arch Otorhinolryngol 273: , Deroee AF, Nrghi M, Sontou AF, Ebrhimkhni MR nd Dehpour AR: Nitric oxide metbolites s biomrkers for follow-up fter chronic rhinosinusitis surgery. Am J Rhinol Allergy 23: , Ho J, Biley M, Zunders J, Mrd N, Scks R, Sewell W nd Hrvey RJ: Group 2 innte lymphoid cells (ILC2s) re incresed in chronic rhinosinusitis with nsl polyps or eosinophili. Clin Exp Allergy 45: , Kto A: Immunopthology of chronic rhinosinusitis. Allergol Int 64: , Shi JB, Fu QL, Zhng H, Cheng L, Wng YJ, Zhu DD, Lv W, Liu SX, Li PZ, Ou CQ, et l: Epidemiology of chronic rhinosinusitis: Results from cross-sectionl survey in seven Chinese cities. Allergy 70: , Bchert C, Zhng L nd Gevert P: Current nd future tretment options for dult chronic rhinosinusitis: Focus on nsl polyposis. J Allergy Clin Immunol 136: , Ktotomichelkis M, Simopoulos E, Tripsinis G, Zhng N, Dnielides G, Goum P, Bchert C nd Dnielides V: The effects of smoking on qulity of life recovery fter surgery for chronic rhinosinusitis. Rhinology 52: , Tokmdzić VS, Tsuji Y, Bogović T, Lskrin G, Cupurdij K, Strbo N, Koym K, Okmur H, Podck ER nd Rukvin D: IL-18 is present t the mternl-fetl interfce nd enhnces cytotoxic ctivity of decidul lymphocytes. Am J Reprod Immunol 48: , Fischer C, Doll J, Tnner M, Bruckner T, Zimmermnn G, Helbig L, Biglri B, Schmidmier G nd Moghddm A: Quntifiction of TGF-ß1, PDGF nd IGF-1 cytokine expression fter frcture tretment vs. non-union therpy vi msquelet. Injury 47: , Kilincoglu V, Yeter A, Servet E, Kngl M nd Yildirim M: Short term results comprison of intrrticulr pltelet-rich plsm (prp) nd hyluronic cid (h) pplictions in erly stge of knee osteorthritis. Int J Clin Exp Med 8: , Agrwl BB, Nnvti JD, Agrwl N, Shrm N, Agrwl KA, Mnish K, Sluj S nd Agrwl S: Biomoleculr inflmmtory response to surgicl energy usge in lproscopic surgery: Results of rndomized study. Surg Endosc 30: , Jing RS, Lu FJ, Ling KL, Shio JY, Su MC, Hsin CH nd Chen WK: Olfctory function in ptients with chronic rhinosinusitis before nd fter functionl endoscopic sinus surgery. Am J Rhinol 22: , This work is licensed under Cretive Commons Attribution-NonCommercil-NoDerivtives 4.0 Interntionl (CC BY-NC-ND 4.0) License.