Sistemi sa kontrolisanim otpuštanjem lekova zasnovani na mezoporoznoj silici i eritrocitnim membranama.

The main aim of this study is the development of two controlled drug delivery systems based on ordered mesoporous silica and erythrocyte membranes (in further text - ghosts) for two widely used drugs: fenofibrate and sodium diclofenac. In the first part of the study, in vitro and in vivo performance of ordered mesoporous silica (OMS) as a carrier for the poorly water soluble compound fenofibrate was evaluated. Fenofibrate was loaded into OMS via incipient wetness impregnation to obtain a 29% drug load and formulated into capsules. Two capsule dosage forms (containing 33.5 mg and 16.75 mg fenofibrate) were compared to the commercially available forms - Lipanthyl® (fenofibrate microcrystals) and Tricor® (fenofibrate nanocrystals). In vitro dissolution tests showed that the amount of fenofibrate released from Lipanthyl® and Tricor® was approximately 30%, whereas ca. 66 and 60% of the drug was released from OMS capsules containing 33.5 and 16.75 mg of fenofibrate, respectively. The in vivo study in dogs confirmed satisfying level of safety and tolerability of fenofibrate-OMS formulation (eq. 33.5 mg) with the potential to improve the absorption of fenofibrate. Though some variability in the data, this formulation was promising to be further investigated in a clinical trial setting. Subsequent clinical trial was conducted to assess the bioavailability-enhancing potential of ordered mesoporous silica in man. In this open-label, randomized, two-way cross-over study, 12 overnight fasted healthy volunteers received a single dose of fenofibrate formulated with ordered mesoporous silica or a marketed product based on micronized fenofibrate. Plasma concentrations of fenofibric acid, the pharmacologically active metabolite of fenofibrate, were monitored up to 96 hours post-dose. The rate (Cmax/dose increased by 77%; tmax reduced by 0.75 h) and extent of absorption (AUC0-24h/dose increased by 54%) of fenofibrate were significantly enhanced following administration of the ordered mesoporous silica based formulation. In the second part of the study controlled drug delivery system based on erythrocyte ghosts for amphiphilic compound sodium diclofenac was developed considering the differences between erythrocytes derived from two readily available materials - porcine slaughterhouse and outdated transfusion human blood. Starting erythrocytes, empty erythrocyte ghosts and diclofenac loaded ghosts were compared in terms of the encapsulation efficiency, drug releasing profiles, size distribution, surface charge, conductivity, surface roughness and morphology. The encapsulation of sodium diclofenac was performed by an osmosis based process - gradual hemolysis. During this process sodium diclofenac exerted mild and delayed antihemolytic effect and increased potassium efflux in porcine but not in outdated human erythrocytes. FTIR spectra revealed lack of any membrane lipid disorder and chemical reaction with sodium diclofenac in encapsulated ghosts. Localization in the suspension and spatial distribution (i. e. mapping) of residual hemoglobin in erythrocyte ghosts has been resolved by two photon excitation fluorescence microscopy. Outdated human erythrocyte ghosts with detected nanoscale damages and reduced ability to shrink had encapsulation efficiency of only 8%. On the other hand, porcine erythrocyte ghosts had encapsulation efficiency of 37% and relatively slow drug release rate. More preserved structure and functional properties of porcine erythrocytes related to their superior encapsulation and release performances, define them as more appropriate for the usage in sodium diclofenac encapsulation process.Glavni cilj ovog rada je razvoj dva sistema sa kontrolisanim otpuštanjem lekova zasnovanih na uređenoj mezoporoznoj silici i eritrocitnim membranama (u daljem tekstu duhovima) za dva leka u širokoj upotrebi: fenofibrat i natrijum diklofenak. U prvom delu ove studije ispitivane su in vitro i in vivo performase uređene mezoporozne silike kao nosača za slabo rastvorni lek fenofibrat. Mezoporozna silika je punjena fenofibratom metodom vlažne impregnacije incipijenta dok sadržaj leka ne dostigne 29%, a potom finalno formulisana kao kapusla. Dve vrste kapsula (koje sadrže 33.5 mg i 16.75 mg fenofibrata) poređene su sa komercijalno dostupnim oblicima - Lipantil® (fenofibrat mikrokristali) i Trikor® (fenofibrat nanokristali). In vitro testovi rastvorljivosti pokazali su da je količina fenofibrata oslobođenog iz Lipantila® i Trikora® aproksimativno iznosila 30% dok je oko 66 i 60% leka oslobođeno iz kapsula sa mezoporoznom silikom koje su sadržale 33.5 i 16.75 mg fenofibrata, respektivno. In vivo studija na psima potvrdila je zadovoljavajući nivo bezbednosti i tolerantnosti formulacija sa mezoporoznom silikom i fenofibratom (33.5 mg) kao i potencijal za poboljšanje apsorpcije fenofibrata. Uprkos variabilnosti dobijenih podataka, ova formulacija je bila obećavajuća za buduća klinička ispitivanja. Sledstvena klinička studija izvedena je sa ciljem da se proceni potencijal uređene mezoporozne silike da poboljša bioraspoloživost fenofibrata kod čoveka. U ovoj otvorenoj, randomizovanoj, dvostruko ukrštenoj studiji, 12 zdravih volontera je primilo pojedinačnu dozu fenofibrata formulisanog sa uređenom mezoporoznom silikom kao i komercijalni proizvod baziran na mikroniziranom fenofibratu. Plazma koncentracije fenofibrinske kiseline, farmakološki aktivnog metabolita fenofibrata bile su praćene 96 sati nakon uzete doze. Stepen (odnos Cmax/doza bio je povećan 77%, a tmax redukovano za 0,75 h) i obim apsorpcije (PIK0-24 h je bila uvećana za 54%) fenofibrata su bili značajno povećani nakon administracije formulacije zasnovane na uređenoj mezoporoznoj silici. U drugom delu studije razvijen je sistem sa kontrolisanim otpuštanjem za amfifilni lek natrijum diklofenak uz razmatranje razlika između eritrocita izolovanih iz dva lako dostupna materijala – svinjske otpadne klanične i prestarele humane krvi. Polazni eritrociti, prazni eritrocitni duhovi kao i inkapsulirani duhovi bili su poređeni u smislu efikasnosti inkapsulacije, profila oslobađanja leka, raspodele veličine, površinskog naelektrisanja, provodljivosti, hrapavosti površine i morfologije. Inkapsulacija natrijum diklofena izvedena je procesom zasnovanim na osmozi – gradualnom hemolizom. Tokom ovog procesa natrijum diklofenak ispoljio je blag i odložen antihemolitički efekat kao i povećan efluks kalijuma kod svinjskih ali ne i kod prestarelih humanih eritrocita. FTIR spektri su otkrili odsustvo narušavanja strukture membranskih lipida kao i hemijske reakcije između natrijum diklofena i inkapsuliranih duhova. Lokalizacija rezidualnog hemoglobina u suspenziji eritrocitinih duhova i njegova prostorna distribucija određeni su primenom dvofotonske fluorescentne mikroskopije. Prestareli humani eritrocitni duhovi sa detektovanim oštećenjma na površini i smanjenom sposobnošću da se skupljaju imali su efikasnost inkapsulacije od samo 8%. Sa druge strane, svinjski eritrocitni duhovi su imali efikasnost inkapsulacije od 37% i relativno nisku brzinu oslobađanja leka. Viši stepen očuvanosti strukture i funkcije svinjskih eritrocita posmatran kroz superiornije performanse inkapsulacije i oslobađanja leka, definiše ih kao pogodniji materijal za inkapsulaciju natrijum diklofena

Clustering of Lyman alpha emitters at z ~ 4.5

We present the clustering properties of 151 Lyman alpha emitting galaxies at z ~ 4.5 selected from the Large Area Lyman Alpha (LALA) survey. Our catalog covers an area of 36' x 36' observed with five narrowband filters. We assume that the angular correlation function w(theta) is well represented by a power law A_w = Theta^(-beta) with slope beta = 0.8, and we find A_w = 6.73 +/- 1.80. We then calculate the correlation length r_0 of the real-space two-point correlation function xi(r) = (r/r_0)^(-1.8) from A_w through the Limber transformation, assuming a flat, Lambda-dominated universe. Neglecting contamination, we find r_0 = 3.20 +/- 0.42 Mpc/h. Taking into account a possible 28% contamination by randomly distributed sources, we find r_0 = 4.61 +/- 0.6 Mpc/h. We compare these results with the expectations for the clustering of dark matter halos at this redshift in a Cold Dark Matter model, and find that the measured clustering strength can be reproduced if these objects reside in halos with a minimum mass of 1-2 times 10^11 Solar masses/h. Our estimated correlation length implies a bias of b ~ 3.7, similar to that of Lyman-break galaxies (LBG) at z ~ 3.8-4.9. However, Lyman alpha emitters are a factor of ~ 2-16 rarer than LBGs with a similar bias value and implied host halo mass. Therefore, one plausible scenario seems to be that Lyman alpha emitters occupy host halos of roughly the same mass as LBGs, but shine with a relatively low duty cycle of 6-50%.Comment: 23 pages in preprint format, 4 figures, ApJ accepte

New Examples of Systems of the Kowalevski Type

A new examples of integrable dynamical systems are constructed. An integration procedure leading to genus two theta-functions is presented. It is based on a recent notion of discriminantly separable polynomials. They have appeared in a recent reconsideration of the celebrated Kowalevski top, and their role here is analogue to the situation with the classical Kowalevski integration procedure.Comment: 17 page

PAI -1 INHIBITOR AS BIOMARKER OF CARDIORENAL DAMAGE

Plasminogen activator inhibitor 1 (PAI-1), which belongs to the family of serine protease inhibitors  is the primary regulator of plasminogen activity. PAI-1 is synthesized as a single-chain glycopeptide and is deposited in the platelets in a latent form, from which it is released upon their activation. It is spontaneously converted into stable molecules, unless it reacts with proteins from the plasma. As a powerful inhibitor of fibrinolysis, it participates in the pathogenesis of endothelial damage, processes of accelerated atherosclerosis and thromboembolism. All the diseases of the cardiovascular system which are dominated by the processes of fibrosis and thrombosis lead to an increase in PAI-1 in the circulation. In the emergence and development of atherosclerosis, it plays a role not only in the formation of intraluminal thrombus but also in neointimal proliferation. PAI-1 is not normally present in kidney tissue, but its concentration increases significantly in its acute and chronic kidney disease, thanks to the synthesis by the intrarenally localized inflammatory cells. In addition to genetic predisposition, the factors that directly influence the production of PAI-1 are the following: glycemia, insulin and various neurohumoral factors. It is not normally present in the kidney tissue, but its intrarenal concentration increases significantly in acute and chronic kidney diseases. Numerous studies have confirmed the significant role of PAI-1 in the development of diabetes complications. During the last decade there has been a growth of interest in the introduction of non-invasive methods or biomarkers that would assess the degree of fibrosis in the kidney. Many studies have confirmed association between kidney and heart disease. It is not only that these diseases share common risk factors, but many other mechanisms have been suggested. Plasminogen activator inhibitor -1 plays a role in the pathogenesis of endothelial damage, processes of fibrosis and thrombosis, development of diabetes complications and acute and chronic kidney diseases

Tunable coupling to a mechanical oscillator circuit using a coherent feedback network

We demonstrate a fully cryogenic microwave feedback network composed of modular superconducting devices connected by transmission lines and designed to control a mechanical oscillator coupled to one of the devices. The network features an electromechanical device and a tunable controller that coherently receives, processes and feeds back continuous microwave signals that modify the dynamics and readout of the mechanical state. While previous electromechanical systems represent some compromise between efficient control and efficient readout of the mechanical state, as set by the electromagnetic decay rate, the tunable controller produces a closed-loop network that can be dynamically and continuously tuned between both extremes much faster than the mechanical response time. We demonstrate that the microwave decay rate may be modulated by at least a factor of 10 at a rate greater than $10^4$ times the mechanical response rate. The system is easy to build and suggests that some useful functions may arise most naturally at the network-level of modular, quantum electromagnetic devices.Comment: 11 pages, 6 figures, final published versio

Contribution to studies on white-tailed eagle (Haliaeetus albicilla Linnaeus, 1758) in Western Serbia and the Republic of Srpska

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Evaluasi dan Analisis Produktivitas dengan Menggunakan Metode Marvin E. Mundel di PT. Xyz

Persaingan diantara Perusahaan diukur dari tingkat produktivitas Perusahaan tersebut. Perusahaan banyak gagal dalam merencanakan rencana produksi sehingga produktivitas menurun. Hal tersebut terjadi pada objek penelitian yaitu PT. XYZ. Rencana produksi yang gagal menyebabkan waktu penyelasaian produk tidak tepat waktu. Umumnya keterlambatan pelaksanaan penyelesaian produk terlambat sekitar 80%-90%. Untuk memenuhi permintaan konsumen tepat waktu, Perusahaan mengambil kebijakan peningkatan jumlah jam kerja lembur hingga mencapai mencapai 15 jam/minggu dan pada akhirnya meningkatkan biaya produksi. Oleh sebab itu, sangat menarik dilakukan penelitian tentang analisis produktivitas. Produktivitas ditinjau dengan pendekatan Marvin E. Mundel. Analisis produktivitas berfokus pada nilai output yaitu nilai produk yang dihasilkan selama tahun 2011 dan 2012. Kemudian dibandingkan dengan nilai input yaitu biaya tenaga kerja, bahan, dan energi, serta depresiasi dan perawatan mesin selama tahun 2011 dan 2012. Dari hasil pengukuran produktivitas total Perusahaan pada tahun 2011 adalah 0,95 dan tahun 2012 meningkat menjadi 1,01. Produktivitas parsial tenaga kerja meningkat 4,38, produktivitas parsial bahan meningkat 0,21 dan produktivitas parsial energi meningkat 5,05. Penyebab rendahnya produktivitas Perusahaan adalah keterlambatan bahan baku. tingginya jam kerja pekerja. dan peralatan kerja yang kurang mendukung. Evaluasi produktivitas menggunakan metode Productivity Evaluation Tree (PET) menghasilkan pengurangan nilai input melalui perhitungan jumlah tenaga kerja aktual sehingga produktivitas total meningkat 0,07

Fazni prijelaz drugog reda izazvan zamrznutim nasumičnim razrjeđenjem u 3D

The effect of the quenched random dilution on the ferromagnetic transitions, in particular, the conversion from the first- to second-order transition is discussed. The new results are presented for the diluted three-dimensional three-state Potts model. The critical exponents of the disorder-induced second-order phase transition are derived by the finite-size scaling analysis of the moments of the energy and the largest cluster, obtained from the Monte Carlo simulations.Raspravlja se učinak nasumičnog, zamrznutog razrjeđenja na feromagnetske prijelaze, posebice na promjenu iz prijelaza prvog u onaj drugog reda. Prikazani su novi rezultati za razrijeđeni trodimenzijski Pottsov model s tri stanja. Kritični eksponenti faznog prijelaza drugog reda izazvanog neredom izvedeni su ljestvičnom analizom momenata energije i najvećeg grozda, dobivenih Monte Carlo simulacijama

Fazni prijelaz drugog reda izazvan zamrznutim nasumičnim razrjeđenjem u 3D

The effect of the quenched random dilution on the ferromagnetic transitions, in particular, the conversion from the first- to second-order transition is discussed. The new results are presented for the diluted three-dimensional three-state Potts model. The critical exponents of the disorder-induced second-order phase transition are derived by the finite-size scaling analysis of the moments of the energy and the largest cluster, obtained from the Monte Carlo simulations.Raspravlja se učinak nasumičnog, zamrznutog razrjeđenja na feromagnetske prijelaze, posebice na promjenu iz prijelaza prvog u onaj drugog reda. Prikazani su novi rezultati za razrijeđeni trodimenzijski Pottsov model s tri stanja. Kritični eksponenti faznog prijelaza drugog reda izazvanog neredom izvedeni su ljestvičnom analizom momenata energije i najvećeg grozda, dobivenih Monte Carlo simulacijama