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Öğe Asetilsalisilik Asit ve Vitamin C Kombinasyonunun Sığır Nötrofil Fonksiyonlarına Etkilerinin İn Vitro Şartlarda İncelenmesi(Selçuk Üniversitesi, 1998) Baş, Ahmet Levent; Başpınar, Nuri; Elmas, Muammer; Haliloğlu, Seyfullah; Yazar, EnverIn Ihis study, the effects ol combination of acetylsalicylic acid (ASA) and vitamin C at dilferenl doses on lunctions of bovine neuırophils (polymorphonuclear leucocytelPMNl), and the elfacts of dillerent ASA concenırations on accumulation of vitamin C in neutrophils were investigated. Neutrophils were obtained from six heatthy Holstein· heifers in University Dairy Herd. Phagocytic and microbicidal activity of PMNl were measured with fluorescent mic· roscopic technlque and intracellular vitamin C levels were detenııined by spectrophotometer. Inlracellular vitamin C le· vels were incerased by combination of ASA and vitamin C al different corıcentrations, bul this increase was not sta· tistically significanl. Furthenııore, phagocytic and microbicidal activity of PMNl were not statistically changed by these combinations.Öğe Chitosan film containing fucoidan as a wound dressing for dermal burn healing: Preparation and in Vitro/In vivo evaluation(SPRINGER, 2007) Sezer, Ali Demir; Hatipoğlu, Fatih; Cevher, Erdal; Oğurtan, Zeki; Baş, Ahmet Levent; Akbuğa, JulideThe aim of this study was to develop chitosan film containing fucoidan and to investigate its suitability for the treatment of dermal burns on rabbits. Porous films, thickness between 29.7 and 269.0 mu m, were obtained by the solvent dropping method. Water vapor permeability (3.3-16.6/0.1 g), the swelling (0.67-1.77 g/g), tensile strength (7.1-45.8 N), and bioadhesion (0.076-1.771 mJ/cm(2)) of the films were determined. The thinnest films were obtained with the lowest chitosan concentration (P < .05). The water absorption capacity of the films sharply increased with the freeze-drying technique. The film having the thickness of 29.7 mu m showed the highest amount of moisture permeability (16.6 g/0.1 g). Higher chitosan concentration significantly increased tensile strength of the films (P < .05). Using higher concentration of lactic acid made films more elastic and applicable, and these films were selected for in vivo studies. Seven adult male New Zealand white rabbits were used for the evaluation of the films on superficial dermal burns. Biopsy samples were taken at 7, 14, and 21 days after wounding, and each wound site was examined macroscopically and histopathologically. After 7 days treatment, fibroplasia and scar were observed on wounds treated with fucoidan-chitosan film. The best regenerated dermal papillary formation, best reepithelization, and the fastest closure of wounds were found in the fucoidan-chitosan film treatment group after 14 days compared with other treatment and control groups. It can be concluded that fucoidan-chitosan films might be a potential treatment system for dermal burns and that changing formulation variables can modulate the characterizations of the films.Öğe Cytologic-enzymologic diagnosis of experimental pneumonia induced by klebsiella pneumoniae serotype II in rats and its treatment with free and liposomal enrofloxacin(KAFKAS UNIV, VETERINER FAKULTESI DERGISI, 2013) Baş, Ahmet Levent; Üney, Kamil; Hadimli, Hasan Hüseyin; Sezer, Ali Demir; Hatipoğlu, Fatih; Maden, Mehmet; Akbuğa, JulideEnrofloxacin (ENR) rapidly localizes in eukaryotic cells in vitro but does not remain for prolonged periods, thereby reducing the ENR efficacy of defense against intracellular pathogens. Delivery of ENR in a liposome-encapsulated form may enhance its intracellular residence time. In this study, experimental pneumonia was induced in healthy and dexamethasone-treated rats using Klebsiella pneumoniae serotype II. Free and liposome-encapsulated ENR were injected intravenously into the infected animals at a dose of 7.5 mg/kg/day for 5 days. Samples of tissue, plasma and bronchoalveolar lavage (BAL) fluid were obtained at 1, 2, 3 and 4 days and 1, 2, 3 and 4 weeks after the first antibiotic treatment. All of the samples were evaluated cytologically, enzymologically, microbiologically and pathologically. It was determined that cytologic and enzymologic diagnoses of BAL fluid are not meaningful for evaluating the treatment of the experimental pneumonia in rats. However, it was established that the use of ENR in liposomal form at a dose of 7.5 mg/kg for 5 days is more effective than the free form both in the treatment of K. pneumoniae infections and in the prevention of recurrent infections. Liposome-encapsulated antimicrobial agents should provide another choice for antimicrobial therapy in the future, but further investigation must be completed before clinical use.Öğe Determination of Intracellular (Neutrophil and Monocyte) Concentrations of Free and Liposome Encapsulated Ampicillin in Sheep(Czech Academy Agricultural Sciences, 2006) Yazar, Enver; Baş, Ahmet Levent; Birdane, Yavuz Osman; Yapar, Kürşad; Elmas, Muammer; Traş, BünyaminIn the current study, intracellular ( neutrophil and monocyte) concentrations of free and liposome encapsulated ampicillin in sheep were investigated. Free ampicillin ( 5 mg/kg b.w.) and liposome encapsulated ampicillin ( 5 mg/kg b.w.) were administered as a bolus intravenous injection to sheep. After the injections, blood samples ( 5 ml) were collected into tubes from v. jugularis at 10, 30, 60 minutes and 2, 4 and 8 hours. Neutrophils and monocytes were isolated, and lysed in distilled water. Ampicillin concentrations were measured by high performance liquid chromatography. The results indicate that liposome encapsulated ampicillin caused the higher intracellular concentrations within neutrophil ( ratio of liposome encapsulated ampicillin/free ampicillin; from 1.393 to 5.416) and monocyte ( ratio of liposome encapsulated ampicillin/free ampicillin; from 0.973 to 2.906) cells than free ampicillin, and liposome encapsulated ampicillin existed a longer length of time within neutrophil ( 4 hours) and monocyte ( 4 hours) cells than free ampicillin ( 60 minutes), as well. This formulation may be beneficial, in that the treatment of intracellular infections are caused by sensitive bacteria.Öğe Determination of Intracellular Concentrations of Free and Two Types of Liposome-Encapsulated Enrofloxacin in Anatolian Shepherd Dog Monocytes(Blackwell Verlag Gmbh, 2002) Baş, Ahmet Levent; Şimşek, Atilla; Çorlu, M.; Yazar, Enver; Elmas, Muammer; Değim, Zeliha GülIn this study, it was evaluated the accumulation of free and two types of liposome-encapsulated enrofloxacin (LEE) at the doses of 0.25, 0.5 and 1 mu g/ml, which were clinically relevant concentrations into monocytes of healthy Anatolian shepherd dogs. Enrofloxacin was encapsulated with two different types of liposome in multilamellar large vesicles (MLV). Type A MLV composed of 15 mg egg phosphatidylcholine and 35 mg cholesterol, Type B MLV composed of phosphatidylcholine (PC), cholesterol and enrofloxacin, in a molar ratio of 1 : 1 : 1. The mean sizes of Type A and Type B liposome were found to be 7.65 and 4.27 mu m, respectively. However, the mean encapsulation rate determined of Type A (13 +/- 2%) was found lower than Type B liposome (44 +/- 3%). The amounts of intracellular enrofloxacin concentrations were determined by high performance liquid chromatography. Type B LEE accumulated significantly higher level into monocytes when compared to free drug or Type A liposome. This study showed that Type B LEE markedly concentrated within monocytes and may improve the antibacterial efficacy of the antibiotic.Öğe The effect of furosemide and acetazolamide induced ion trapping phenomena on renal excretion of chemicals(1998) Traş, Bünyamin; Ok, Mahmut; Elmas, Muammer; Şen, İsmail; Baş, Ahmet Levent; Tanyıldızı, SadettinBu deneysel çalışma, zorunlu diürezis ile vücuttan atılımı artırmak için kimyasalların pKa değerine göre diüretik ilaç seçiminin önemini ortaya koymak üzere gerçekleştirildi. Denemede, ağırlıkları 15-20 kg arasında değişen 15 adet köpek kullanıldı. Köpekler Grup I, II ve III olmak üzere üç gruba ayrıldı ve her gruptaki köpeklere 1 ml'sinde 200 mg sülfadoksin ve 40 mg trimetoprim içeren Animar (Roche)'dan İM yolla yüksek dozda injekte edildi. Grup Il'deki hayvanlara Animar enjeksiyonundan 2 saat sonra İM yolla 5 mg/kg dozunda furosemid uygulandı. Üçüncü gruptaki hayvanlara ise Animar uygulamasını takibeden 1. ve 8. saatlerde toplam 200 mg dozunda asetazolamid ikiye bölünerek oral yolla verildi. Toplanan kan ve idrar numunelerindeki sülfadoksin ve trimetoprim konsantrasyonları HPLC yardımı ile belirlendi. Asetazolamidin sülfadoksinin, furosemidin ise trimetoprimin böbrekten atılımı üzerinde daha etkili olduğu gözlendi. Asetazolamid idrar pH'sını önemli, oranda artırırken, furosemid çok az derecede bir düşüşe neden oldu. Bu çalışmanın sonuçları, kimyasalların böbrekten atılımı üzerine, diüretiklerin potansiyel etkilerinden daha çok diğer faktörlerin etkili olabileceğini ortaya koydu.Öğe Effect of Tilmicosin on Cardiac Muscle and Serum Creatine Kinases Activities and Serum Total Protein Level in Healthy Male Balb/C Mice(ECOLE NATIONALE VETERINAIRE TOULOUSE, 2001) Yazar, Enver; Altunok, Vahdettin; Elmas, Muammer; Traş, Bünyamin; Baş, Ahmet Levent; Özdemir, VuralIn this study, the effect of tilmicosin on cardiac muscle and serum creatine kinases activities and serum total protein level was investigated. Forty male Balb/C mice were used as materials. Ten mice were used as a control group, and thirty mice were injected with tilmicosin (25 mg/kg body weight, SC, single injection) and monitored for 3 days. The results obtained in the present study show that use of tilmicosin caused temporary increases in cardiac muscle creatine kinase activity and serum total protein level in male Balb/C mice.Öğe The Effect of Tilmicosin on Cardiac Superoxide Dismutase and Glutathione Peroxidase Activities(Blackwell Verlag Gmbh, 2002) Yazar, Enver; Altunok, Vahdettin; Elmas, Muammer; Traş, Bünyamin; Baş, Ahmet Levent; Özdemir, V.In this study, the effect of tilmicosin on cardiac superoxide dismutase and glutathione peroxidase activities was investigated. Forty male BALB/c mice were used as material. Ten mice served as a control group, and 30 mice were injected with tilmicosin (25 mg/kg body weight. subcutaneously. with a single injection). After drug administration, they were monitored for 3 days. Tilmicosin caused decreases in cardiac superoxide dismutase and glutathione peroxidase activities.Öğe Effect of Tilmicosin on Serum Creatine Kinase, Creatine Kinase-MB and Troponin I Levels in New Zealand White Rabbits(Eugen Ulmer Gmbh CO, 2002) Yazar, Enver; Birdane, Yavuz Osman; Elmas, Muammer; Traş, Bünyamin; Baş, Ahmet LeventIn this study, the effect of tilmicosin on creatine kinase, creatine kinase-MB and troponin I levels were investigated to determine the possible cardiotoxic effect. Ten male White New Zealand rabbits were used as materials and tilmicosin was injected at a dose of 25 mg/kg body weight, subcutanously, by single injection. Blood samples were taken before the injection (=control) and at 6 hours after injection. Tilmicosin caused increases in creatine kinase, creatine kinase-MB and troponin I levels. However, especially histopathological examinations have to be made for fully determination of tilmicosin cardiotoxicity in rabbits.Öğe Effects of Continuous Supplementations of Ascorbic Acid, Aspirin, Vitamin E and Selenium on Some Haematological Parameters and Serum Superoxide Dismutase Level in Broiler Chickens(Carfax Publishing, 2000) Traş, Bünyamin; İnal, Fatma; Baş, Ahmet Levent; Altunok, Vahdettin; Elmas, Muammer; Yazar, Enver1. This study was conducted using male broiler chickens to determine the effects of ascorbic acid, aspirin, ascorbic acid+aspirin, vitamin E+selenium and ascorbic acid+aspirin+vitamin E+selenium supplementations on haematological parameters and serum superoxide dismutase concentration. 2. One hundred and twenty day-old male Hubbunt broiler chicks were randomly divided into 6 experimental groups of 20 chicks each and placed in different pens. Groups 2, 3, 4, 5 and 6 were given a diet supplemented with ascorbic acid, aspirin (in water), ascorbic acid+aspirin, vitamin E+selenium and ascorbic acid+aspirin+vitamin E+selenium, respectively for 45 d while group 1 was given a commercial broiler diet. 3. There was no significant effect of ascorbic acid, aspirin, ascorbic acid+aspirin, vitamin E+selenium supplementations on any of the haematological parameters (red blood cell, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin concentration, mean corpuscular haemoglobin) in broilers but ascorbic acid+aspirin+vitamin E+selenium supplementation significantly decreased the white blood cell counts. 4. In addition to this, ascorbic acid, aspirin, ascorbic acid+aspirin and ascorbic acid+aspirin+vitamin E+selenium supplementations had no significant effect on the serum superoxide dismutase level, but vitamin E+selenium supplementation increased the serum superoxide dismutase level.Öğe Effects of Continuous Supplementations of Ascorbic Acid, Aspirin, Vitamin E, and Selenium on Performance, Immune Response, and Some Biochemical Parameters Under Normal Environmental and Management Conditions in Broilers(EUGEN ULMER GMBH CO, 2001) Traş, Bünyamin; İnal, Fatma; Baş, Ahmet Levent; Altunok, Vahdettin; Elmas, Muammer; Yazar, EnverMale broiler chickens were used to determine the effects of ascorbic acid, aspirin, ascorbic acid + aspirin, vitamin E + selenium, and ascorbic acid + aspirin + vitamin E + selenium supplementation on performance, IgG levels, and some biochemical parameters in blood. Three hundred and ninety six 1-day-old male. Hubbunt broilers were randomly divided into six groups. Each group was placed in different pens and feed and water were provided ad libitum. Performance parameters (body weight, feed intake and feed conversion), IgG levels, vitamins A and E, and some biochemical parameters in blood (Na, K, Cl, total protein and albumin) were measured on days 15, 30, and 45 in all groups. The results revealed at the end of the study showed that aspirin, vitamin C, vitamin E + selenium administrations exhibited no effects on levels of vitamin A, vitamin E, total protein, albumin, Na, Cl and K in blood, while aspirin administration decreased IgG level. Vitamin C administration increased IgG level in serum, aspirin + vitamin C administration increased albumin and K in serum, aspirin + vitamin C + vitamin E + selenium administration increased vitamin E and Na level in serum. Also, there was no significant difference in performance between the control and the experimental groups. It was suggested that vitamin C administration to diets may be useful for broiler breeds due to the observed increased IgG level.Öğe Efficacies of Free and Liposome-Encapsulated Enrofloxacin (Baytril®) Against Staphylococcus Aureus Infection in Turkish Shepherd Dog Neutrophils in Vitro(2000) Baş, Ahmet Levent; Elmas, Muammer; Şimşek, Atilla; Traş, Bünyamin; Yazar, E.; Hadimli, H. H.The influence of free and liposome-encapsulated enrofloxacin at concentrations of 1, 2 and 4 ?g/ml was studied on phagocytic and intracellular killing of Staphylococcus aureus, in cultured neutrophils of six healthy Turkish Shepherd Dogs. Enrofloxacin was encapsulated by using reverse-phase evaporation method in multilamellar liposomes composed of 15 mg egg phosphatidylcholine and 35 mg cholesterol. Phagocytic and killing activity of neutrophils were determined by fluorescent microscopic technique. Liposome-encapsulated enrofloxacin significantly enhanced the intraphagocytic killing of bacteria in neutrophils compared to free drug. Phagocytic activity of neutrophils was not significantly different among groups. The results obtained in the present study show that use of enrofloxacin encapsulated in liposomes may improve the antibacterial efficacy of the antibiotic.Öğe Encapsulation of enrofloxacin in liposomes I: Preparation and in vitro characterization of LUV(INFORMA HEALTHCARE, 2004) Sezer, Ali Demir; Baş, Ahmet Levent; Akbuğa, JulideLiposomes are effectively used in the treatment of microbial infections. Higher cellular uptake has been reported when antibiotics are encapsulated in liposomes. In this study, enrofloxacin (ENF) was encapsulated in large unilamellar vesicles (LUVs) and the effects of formulation variables on the liposome characteristics were investigated. Liposomes were prepared using dry lipid film method. A number of variables such as molar ratios of phospholipid (DPPC; DL-alpha-phosphatidylcholine dipalmitoyl), cholesterol, ENF and amount of alpha-tocopherol and the volumes of internal (chloroform) and external phases [phosphate buffered saline PBS (pH 7.4)] were studied. In vitro characterization of the liposomes including the encapsulation capacity, size and drug release properties were carried out. Using of this method, spherical LUV liposomes with high drug content could be produced. Particle size of liposomes changed between 3.12 and 4.95 mum. The molar ratios of DPPC, cholesterol and ENF affected the size of the liposome (p < 0.05). The drug encapsulation capacities were high and changed between 37.1% and 79.5%. The highest ENF encapsulation was obtained with the highest cholesterol content. An increase in the drug encapsulation capacity of the liposome was found with increasing molar ratios of DPPC, cholesterol and ENF (p < 0.05). Furthermore, the release of ENF from the liposomes decreased as the molar ratios of DPPC, cholesterol and ENF increased (p < 0.05). In conclusion, a convenient colloidal carrier for the controlled release of ENF can be prepared by changing the formulation parameters of LUVs.Öğe Evaluation of fucoidan-chitosan hydrogels on superficial dermal burn healing in rabbit: An in vivo study(ELSEVIER SCIENCE BV, 2005) Sezer, Ali Demir; Hatipoğlu, Fatih; Oğurtan, Zeki; Baş, Ahmet Levent; Akbuğa, Julide[Abstract not Available]Öğe Evaluation of the hypocholesterolemic efficacy of lyophilized Nerium oleander(Selçuk Üniversitesi, 2022) Kızılay, Harun; Baş, Ahmet Levent; Yazıhan, NurayAim: The purpose of this study was to assess the effect of administering Nerium oleander distillate on hypercholesterolemic rats' serum biochemical parameters. Materials and Methods: Three equal groups of 30 male Sprague-Dawley rats were formed. No application was made for the control group. The second group received a high cholesterol diet, while the third group received a high cholesterol diet in addition to lyophilized Nerium oleander distillate by oral gavage once daily. After three months, blood was drawn after sedation and they were euthanized. Serum fasting blood glucose, triglyceride, highdensity lipoprotein, total cholesterol, low-density lipoprotein, alanine aminotransferase, aspartate aminotransferase, albumin, and total protein levels, as well as alkaline phosphatase, lactate dehydrogenase, creatinine, and urea levels, were determined using an autoanalyzer. Results: Alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, cholesterol, glucose, low-density lipoprotein, and triglyceride levels increased (p < 0.05) in the group fed a high cholesterol diet compared to the control group, but Nerium oleander treatment decreased the elevated aspartate aminotransferase, cholesterol, low-density lipoprotein, and triglyceride (p < 0.05). Conclusion: To summarize, it can be stated that Nerium oleander distillate has antihypercholesterolemic and liver-protective properties.Öğe In vitro efficacy of azithromycin and roxithromycin against Toxoplasma gondii(SCIENTIFIC TECHNICAL RESEARCH COUNCIL TURKEY-TUBITAK, 2005) Tanyüksel, Mehmet; Baş, Ahmet Levent; Araz, Engin; Özyurt, Mustafa; Albay, Ali; Babür, CahitToxoplasmosis is a common problem, accounting for significant morbidity in developing countries. Conventional treatments are associated with frequent relapses and with additional problems including undesirable side effects. Better-tolerated and more effective drugs are clearly needed. The aim of this study is to evaluate the in vitro efficacy of azithromycin and roxithromycin against Toxoplasma gondii using acridine orange in the fluorescence microscopic assay. It was found that azithromycin and roxithromycin had significant microbicidal activity (P < 0.05). In conclusion, this observation should be assessed carefully in future clinical trials involving a large number of cases with toxoplasmosis.Öğe In vitro evaluation of enrofloxacin-loaded MLV Liposomes(INFORMA HEALTHCARE, 2007) Sezer, Ali Demir; Akbuğa, Julide; Baş, Ahmet LeventFluoroquinolones are broad-spectrum antimicrobial agents that seem to reach their intracellular target site ( DNA gyrase) in Escherichia coli by means of an uptake process through the outer and inner membranes. Delivery of quinolones with liposomes has many advantages than the free form of the drug. Liposomes may represent an excellent device for improving the selective transport of antibiotics in these respects. In this study, enrofloxacin-loaded multilamellar vesicles (MLVs) were prepared and the effects of formulation variables on the liposome characteristics were investigated. Liposomes were prepared by using the dry lipid film method. A number of variables, such as phospholipid (DL-alpha-phosphatidylcholine dipalmitoyl), cholesterol, enrofloxacin (ENF), stearylamine, and dicetyl phosphate molar ratios and alpha-tocopherol amounts, were studied. The liposome size, encapsulation capacity, drug release, stability, and electrophoretic mobility of ENF-loaded liposomes were determined. Using this method, spherical MLVs with high drug content could be produced. Particle size of liposomes changed between 1.63 and 3.31 mu m and liposome size was affected by all formulation variables ( p < 0.05) except molar ratio of ENF. MLVs can be used as a carrier system for the controlled release of ENF. The highest encapsulation of ENF amount can be obtained using positively charged SA in the formulation and changing the formulation parameters can vary drug release patterns.Öğe Investigation of Biochemical and Haematological Side-Effects of Cefquinome in Healthy Dogs(Royal Netherlands Veterinary Assoc, 2001) Maden, Mehmet; Traş, Bünyamin; Baş, Ahmet Levent; Elmas, Muammer; Yazar, Enver; Birdane, Fatih Mehmetin the present study, the effects of cefquinome, a 4(th) generation cephalosporin, on clinical, biochemical, haematological, and blood gas variables were investigated. Five healthy dogs were injected with cefquinome (1 mg/kg body weight, IM, daily) for 14 days. Negative effects of cefquinome on clinical, biochemical, and haematological variables were not observed, but it did change some blood gas variables.Öğe Investigation of Haematological and Biochemical Side Effects of Tilmicosin in Healthy New Zealand Rabbits(WILEY-BLACKWELL, 2002) Altunok, Vahdettin; Yazar, Enver; Elmas, Muammer; Traş, Bünyamin; Baş, Ahmet Levent; Çöl, RamazanIn this study, the effects of tilmicosin on some haematological and biochemical variables were investigated. Ten male New Zealand rabbits were used as material. The tilmicosin was injected (25 mg kg body weight. subcutaneously as a single injection), and the rabbits were monitored for 4 days. No negative effects of tilmicosin on haematological and biochemical variables were observed, but it did cause a temporary decrease in red and white blood cell counts.Öğe Kloramfenikol' ün sığır polimorfnükleer lökosit (PMNL) fonksiyonları üzerindeki etkilerinin in vitro ve in vivo araştırılması(2003) Baş, Ahmet Levent; Demet, ÖmerBu çalışmada kloramfenikolün polimorfnükleer lökosit (PMNL)'lerin fagositoz ve hücre içi öldürme aktiviteleri üzerindeki etkisi araştırıldı. Çalışma, in vitro ve in vivo koşullarda gerçekleştirildi. İn vivo aşamada, 08-13 aylık 9 adet Holstein-Fresian sığır kullanıldı. İn vitro bölümde ise kloramfenikol uygulanmamış hayvanlardan alınan kan örneklerinden izole edilen nötrofiller'in 10, 1-000 ve 4000 mug/ml kloramfenikol ihtiva eden inkübasyon ortamlarında fagositoz ve hücre içi öldürme aktiviteleri belirlendi. Buna göre; 10 ve 1000 mug/ml'de PMNL fonksiyonlarında bir değişiklik görülmezken, 1000 ug/ml'de nötrofil başına düşen fagositik canlı C. albicans sayısında artma, 4000 mug/ml'de ise fonksiyonlarda önemli derecede azalma saptandı. İn vivo çalışmada, 10 mg/kg 12 saat ara ile günde iki kez, beş gün süre ile kloramfenikol uygulandı. Kan örnekleri, sabah uygulamasından 2.5 saat sonra alınarak, plazma kloramfenikol ölçümü ve PMNL izolasyonu yapıldı. PMNL fonksiyonlarında, ilk günden itibaren önemli derecede azalma kaydedildi.
