Structural characterization of submerged granular packings.

We consider the impact of the effective gravitational acceleration on microstructural properties of granular packings through experimental studies of spherical granular materials saturated within fluids of varying density. We characterize the local organization of spheres in terms of contact connectivity, distribution of the Delaunay free volumes, and the shape factor (parameter of nonsphericity) of the Voronoï polygons. The shape factor gives a clear physical picture of the competition between less and more ordered domains of particles in experimentally obtained packings. As the effective gravity increases, the probability distribution of the shape factor becomes narrower and more localized around the lowest values of the shape factor corresponding to regular hexagon. It is found that curves of the pore distributions are asymmetric with a long tail on the right-hand side, which progressively reduces while the effective gravity gets stronger for lower densities of interstitial fluid. We show that the distribution of local areas (Voronoï cells) broadens with decreasing value of the effective gravity due to the formation of lose structures such as large pores and chainlike structures (arches or bridges). Our results should be particularly helpful in testing the newly developed simulation techniques involving liquid-related forces associated with immersed granular particles.

Optimization of the monolayer growth in adsorption-desorption processes.

Kinetics of the deposition process of dimers in the presence of desorption is studied by Monte Carlo method on a one-dimensional lattice. The aim of this work is to investigate how do various temporal dependencies of the desorption rate hasten or slow down the deposition process. The growth of the coverage θ(t) above the jamming limit to its steady-state value θ(∞) is analyzed when the desorption probability P(des) decreases both stepwise and linearly (continuously) over a certain time domain. We report a numerical evidence that the time needed for a system to reach the given coverage θ can be significantly reduced if P(des) decreases in time. Finally, a self-consistent optimization procedure, when the probability P(des) depends on the current coverage density θ(t), is formulated and tested. The present model reproduces qualitatively the densification kinetics and the memory effects of vibrated granular materials. Our results suggest that the process of vibratory compaction of granular materials can be optimized by using a time dependent intensity of external excitations.

Adsorption, desorption, and diffusion of k-mers on a one-dimensional lattice.

Kinetics of the deposition process of k -mers in the presence of desorption or/and diffusional relaxation of particles is studied by Monte Carlo method on a one-dimensional lattice. For reversible deposition of k-mers, we find that after the initial "jamming," a stretched exponential growth of the coverage theta(t) toward the steady-state value theta(eq) occurs, i.e., theta(eq)-theta(t) is proportional to exp[-(t/tau)(beta)]. The characteristic time scale tau is found to decrease with desorption probability P(des) according to a power law, tau is proportional to P(des)(-gamma), with the same exponent gamma=1.22+/-0.04 for all k-mers. For irreversible deposition with diffusional relaxation, the growth of the coverage theta(t) above the jamming limit to the closest packing limit (CPL) theta(CPL) is described by the pattern theta(CPL)-theta(t) is proportional to E(beta)[-(t/tau)(beta)], where E(beta) denotes the Mittag-Leffler function of order beta(0,1) . Similarly to the reversible case, we found that the dependence of the relaxation time tau on the diffusion probability P(dif) is consistent again with a simple power-law, i.e., tau is proportional to P(dif)(-delta). When adsorption, desorption, and diffusion occur simultaneously, coverage always reaches an equilibrium value theta(eq), which depends only on the desorption/adsorption probability ratio. The presence of diffusion only hastens the approach to the equilibrium state, so that the stretched exponential function gives a very accurate description of the deposition kinetics of these processes in the whole range above the jamming limit.

Kinetic model of drug distribution in the urinary bladder wall following intravesical instillation.

Intravesical administration of cytotoxic agents is commonly used in urological practice for treatment of superficial bladder cancer. The leading motive is optimisation of drug delivery near the site of action and reduction of systemic toxicity. Bladder pharmacokinetics is complicated by several mechanisms. The objectives of this work were to develop a kinetic model of drug distribution in the bladder wall following intravesical instillation and to study the effect of various parameters on tissue and systemic drug exposure and explore the potential benefits of permeability enhancing effects of chitosan (CH) and polycarbophil (PC) through simulation. Key elements of the model are variable urinary drug concentration due to urine formation and voiding, biphasic diffusion in the bladder tissue and systemic absorption. Model parameters were estimated from bladder-tissue concentration profiles obtained in previous in vitro experiments with pipemidic acid (PPA) as a model drug. The results support further investigations on application of CH and PC in intravesical drug delivery. Both polymers increase permeability of the bladder wall by diffusion enhancement in the urothelium and presumably by improving the contact with the bladder surface. The developed mathematical model could serve for optimisation of intravesical drug delivery and future development of intravesical drug delivery systems.

Simulation study of granular compaction dynamics under vertical tapping.

We study, by numerical simulation, the compaction dynamics of frictional hard disks in two dimensions, subjected to vertical shaking. Shaking is modeled by a series of vertical expansion of the disk packing, followed by dynamical recompression of the assembly under the action of gravity. The second phase of the shake cycle is based on an efficient event-driven molecular-dynamics algorithm. We analyze the compaction dynamics for various values of friction coefficient and coefficient of normal restitution. We find that the time evolution of the density is described by rho(t)=rho{infinity}-DeltarhoE{alpha}[-(ttau){alpha}], where E{alpha} denotes the Mittag-Leffler function of order 0

Predicting the anti-hypertensive effect of nitrendipine from plasma concentration profiles using artificial neural networks.

Nitrendipine is an effective and safe calcium-channel blocker for the treatment of mild to moderate hypertension. The aim of this study is to show that an artificial neural network (ANN) model of the relationship between nitrendipine plasma levels and pharmacodynamic effects can be built and used for pressure-drop prediction after oral administration of the drug in spite of the poor correlation between plasma concentrations and the effect. To achieve the goal, the following steps were taken: evaluation of the quality of the database for training the ANN, definition of the optimal input set for the ANN, and prediction of the diastolic pressure drop using the ANN. The possible consequences of successful ANN modelling are an optimisation of the drug administration regimen, to achieve the best possible effect, as well as optimal drug formulation for drugs with complicated pharmacokinetic/pharmacodynamic relationships.

Asymptotic properties of path integral ideals.

We introduce and analyze an interesting quantity, the path integral ideal, governing the flow of generic discrete theories to the continuum limit and greatly increasing their convergence. The said flow is classified according to the degree of divergence of the potential at spatial infinity. Studying the asymptotic behavior of path integral ideals we isolate the dominant terms in the effective potential that determine the behavior of a generic theory for large discrete time steps.

Systematically accelerated convergence of path integrals.

We present a new analytical method that systematically improves the convergence of path integrals of a generic N-fold discretized theory. Using it we calculate the effective actions S(p) for p< or =9, which lead to the same continuum amplitudes as the starting action, but that converge to that continuum limit as 1/N(p). We checked this derived speedup in convergence by performing Monte Carlo simulations on several different models.

Pathways of paracetamol absorption from layered excipient suppositories: artificial intelligence approach.

When studying paracetamol availability after rectal administration, the differences between slower and faster release suppositories were discovered. Approach with modelling and simulation of compartment-based models was used to explore the differences. A study of paracetamol from layered excipient suppositories shows that many different mechanisms are involved in the drug pharmacokinetics. There is also a large number of articles, each dealing with only one or with a few of the mechanisms. However, there is little information available on how the mechanisms interact in the organism and thus govern the pharmacokinetics of the drug, which means that systemic view in the expert knowledge is missing. In the case of paracetamol rectal availability the use of partially fuzzyfied model allowed systemic combination of all described mechanisms found in the literature and measured data. In spite of non-identifiability, the model showed that patterns that explained differences in bioavailabilities of the two formulations of suppositories could be found. Results of modelling and simulation show that "in vivo" there is practically no difference in cumulative release profiles between the two formulations. However, due to higher content of mono-di-glycerides in a slower release formulation, the extent of absorption is augmented both by absorption-enhancing effect of mono-di-glycerides and the liver bypass mechanism via diminished viscosity.

Transport theory of granular swarms.

The transport of trace granular gas (swarm) in a carrier granular fluid is studied by means of the Boltzmann-Lorentz kinetic equation. Time-dependent perturbation theory is used to follow the evolution of the granular swarm from an arbitrary initial distribution. A nonhydrodynamic extension of the diffusion equation is derived, with transport coefficients that are time dependent and implicitly depend on the wave vector. Transport coefficients of any order are obtained as velocity moments of the solutions of the corresponding kinetic equations derived from the Boltzmann-Lorentz equation. For the special case of the initial distribution of swarm particles, transport coefficients are identified as time derivatives of the moments of the number density. Finally the granular particle transport theory is extended by the introduction of the concept of non-particle-conserving collisions.

[Hematologic characteristics of leishmaniasis]. / Hematoloske karakteristike lajsmanijaze.

INTRODUCTION: Leishmaniasis is a chronic infectious disease from the group of anthropozoonoses. It is caused by protozoa in the genus leishmania flagellate. There are five major foci of this disease in the world: India, Mediterranean countries, East Africa, South China and South America. Endemic regions in the Balkans are as follows: Montenegro, Macedonia, Herzegovina and the Morava's valley (1,2). Reservoirs of infection are infected humans and animals (dogs and rodents). Infection is transmitted by insects the most significant representative of which is a sandfly. The course of the disease may be acute, subacute and chronic and several forms are differentiated such as visceral, cutaneous and mucocutaneous. Signs of disease are elevated temperature, gastrointestinal disorders, splenomegaly and hepatomegaly and rarely generalized lymphadenomegaly. Laboratory findings point to pancytopenia. The diagnosis is established on the basis of parasitological findings in macrophages of the bone marrow and is confirmed by serologic tests (4,5). However, mortality is decreased to 5% after the application of 5-valent antimony and amphotericin B (6,7). CASE REPORT: A female patient aged 19 year from Novi Sad was admitted at the Clinic of Hematology due to unclear febrile state lasting 3 months accompanied by pancytopenia and enlarged spleen. The first discomforts were experienced in the second half of August in 1997 upon the patient's return from Sutomore. The disease started gradually with uncharacteristic manifestations. Firstly, discomforts developed in the region of the gastrointestinal tract and were characterized by loss of appetite, nausea, and vomiting in addition to drastic weight loss. Secondly, fatigue occurred during effort, later on at rest as well, accompanied by increased body temperature. Temperature increased twice a day and was followed by shuddering, fever, shivering and very often by nocturnal sweating. Antibiotics and antipyretics were used, but without fall of temperature. Subjective discomforts were increasingly pronounced, so that due to unclear febrile state and in addition to the present pancytopenia the patient was referred to hospital treatment and was therefore admitted at the Clinic of Hematology. Febrile state, tachycardia, a striking paleness of the skin and visible mucosa as well as splenomegaly were confirmed. Basic laboratory findings (Table 1) pointed to pancytopenia. Apart from anemia and mild thrombocytopenia, leukopenia with neutropenia, lymphocytosis and monocytosis were pronounced. Sternal puncture was the most significant diagnostic procedure on the basis of which the diagnosis was established. In hypocellular bone marrow in macrophages, both intra- and extracellular, protozoa were found in smaller and greater groups which resembled leishmaniasis (Figure 1). The diagnosis was confirmed by serologic tests to leishmaniasis, antibody titre was > 1:32. In order to exclude other infections and hematologic diseases, other diagnostic tests were performed (Table 1) and the findings were normal. After the establishment of diagnosis the patient was transferred to the Clinic of Infectious Diseases where the causal therapy with 5-valent antimony was introduced, parenterally. As early as the first week of therapy, the patient was afebrile, subjective discomforts disappeared, she regained appetite and put on weight. Also, the decrease of the spleen was observed as well as improvement in hematological findings. DISCUSSION AND CONCLUSION: This paper predominantly deals with hematological findings which are characteristic for leishmaniasis on the basis of which the diagnosis of this disease has been quickly established (1,2). Hematological findings were the key of diagnosis being confirmed by serologic and other tests. The disease is very rare in this region, so that there is a difficulty in recognizing it. In our case, the diagnosis was made on the basis of sternal puncture survey, because protozoa were found in hy

Interdependence of histamine and methylhistamine kinetics: modelling and simulation approach.

In the article a model of histamine kinetics is described. A motivation of this project was to investigate the hypothesis that methylhistamine may be a marker of histamine appearance in plasma. A model has been made to support the hypothesis. Since metabolic and transport pathways of histamine and methylhistamine are complex and not very well known, the relationship between histamine and methylhistamine should be elucidated by mathematical modelling. From experimental data and the information in the literature, a nonlinear and time-varying four-compartment model is proposed. Extensive release of histamine from mast cells when methylhistamine is injected, is modelled as histamine to methylhistamine ratio control loop.

Correlation of in vitro and in vivo paracetamol availability from layered excipient suppositories.

An in vivo investigation of paracetamol availability was carried out on eight healthy volunteers, comparing two paracetamol suppository formulations prepared using two different gliceride bases, a fast drug-releasing one and a slow drug-releasing one, i.e. Witepsol H15 and W35, respectively. The formulations were selected on the basis of a previous in vitro drug release study, which showed that, by superimposing the excipients in two layers within the same suppository, the drug release kinetics could be modulated using different ratios between the two layers. The comparison between the two different formulations in terms of plasma profiles and total amounts of drug excreted in urine revealed an increase in the extent of drug absorption from the layered excipient suppository. As the W35 has a higher monoglyceride content than the H15, this improved paracetamol availability could be ascribed to the absorption-enhancing effect of the monoglycerides. Moreover, the W35 has also a higher viscosity, which could possibly cause the suppository to be retained for a longer time in the lower part of the rectum, where the blood is drained directly to the systemic circulation. It was therefore hypothesized that the enhanced paracetamol availability could be also due to a liver bypass mechanism. For a further examination of the paracetamol absorption kinetics after rectal administration, a one-compartment model was fitted to the drug plasma concentration data. This approach allowed to draw absorption versus time profiles, which showed that a retardation actually occurred in paracetamol absorption when using suppositories containing the slow drug releasing excipient W35. These absorption data were then employed for an A level in vitro-in vivo correlation testing, and a linear relationship was found between in vitro release rate and in vivo absorption rate, both for fast releasing and for the layered excipient suppositories.

Influence of fever on the pharmacokinetics of ciprofloxacin.

The influence of fever on the pharmacokinetics of ciprofloxacin was investigated in seven patients with acute febrile diseases. Antibiotic serum concentrations were determined using high-performance liquid chromatograpy (HPLC). The analog computer and the Simulink software package were used to identify the pharmacokinetic model and Penoclin software package to obtain the secondary parameters. During fever, higher maximum serum concentrations (Cmax) of ciprofloxacin were observed in six out of seven patients. The result suggests that the influence of fever on the pharmacodynamics of ciprofloxacin is favorable.

Influence of fever on cefazolin pharmacokinetics.

The influence of fever on the pharmacokinetics of cefazolin was investigated in patients with acute febrile diseases. Nine patients were included in the study. Antibiotic serum concentrations were determined using high performance liquid chromatograpy (HPLC). An analog computer and the SIMULINK software package were used to identify the pharmacokinetic model and PCNONLIN software package to obtain the secondary parameters. In 6 patients a two-compartment pharmacokinetic model of cefazolin was observed during fever and after defervescence. In 2 patients a two-compartment model changed to a one-compartment after defervescence, and a one-compartment model was observed in one patient during both periods. Cefazolin-treated patients with a two-compartment model (6/9) had higher Cmax, mean steady state serum concentrations (Css), and area under the plasma concentration-time curve (AUC(0-->infinity)), smaller central compartment volume (V1), and lower clearance (Cl) during fever. The varying distribution of antibiotics during fever probably reflects different hemodynamic responses to fever.

[Complications in the use of blood transfusions--alloimmunization in polytransfused patients]. / Komplikacija primanja transfuzija krvi--aloimunizacija politransfundovanih bolesnika.

INTRODUCTION: The objective of this paper was to examine the frequency of red blood cell (RBC) alloantibodies in polytransfused hematologic patients. MATERIAL AND METHODS: Blood samples of 2669 polytransfused hematologic patients were examined on clinical significant alloantibodies using antibody screening and identification according to Standards of AABB Technical Manual (1). Available medical charts were reviewed for sex, age and medical history and total number of given transfusions. RESULTS: During a three year period blood samples of 2669 polytransfused hematologic patients were examined for RBC alloantibodies. Alloantibodies were detected in 48 cases with the incidence of 1.79%. 36 patients (1.35%) developed single antibody while in 12 patients (0.45%) multiple antibodies were detected. Antibodies were registered more frequently in females than in males (37:17). In patients with single antibody next specificity was detected: anti-D (38.89%), anti-K (22.22%), antibodies to antigens MNSs system (22.22%), while anti-Le, anti-Fy and anti-P specificity was detected in 13.89%. Patients with multiple antibodies had specificity to Rhesus, Kell, Duffy, MNSs, Lewis and P blood group systems. All patients received more than 10 RBC transfusions. CONCLUSION: The incidence of alloimmunization was 1.79%. Sensibilization occurred more frequently in females than in males. Usually, the discovered alloantibodies were clinically significant and made problems in pretransfusion testings and required special efforts in blood selection for transfusion. For patients with the risk of frequent transfusions we suggest to include blood transfusion charts with complete phenotyping against antigens in Rhesus, Kell, Kidd and MNSs blood group systems and the data of all received transfusions.

The role of pharmacokinetic modelling and computer simulation in drug formulation design.

The purpose of this study is to develop a formulation for a once-a-day peroral application with controlled release of nitrendipine. The second aim of the study is to define by the use of modelling and computer simulation those critical points in the development of the formulation, the knowledge and controlling of which brings a rationalisation in the sense of time and material.

[Agranulocytosis as a complication of acute infectious mononucleosis]. / Agranulocitoza kao komplikacija akutne infektivne mononukleoze.

INTRODUCTION: Acute infections mononucleosis is the most common clinical manifestation of primary Epstein-Barr virus (EBV) infection occurring during adolescence. It is a benign lymphoproliferative, usually self-limiting disease. Complications are relatively rare, but they may occur, especially hematological. Most common are autoimmune hematolytic anemia and thrombocytopenia, and they respond to corticoid therapy. Deuteration of white blood cells is rather rare, whereas mild neutropenia is a normal finding during the course of acute disease. On the other hand, agranulocytosis is extremely rate, and almost every case has been reported in the literature. Filgrastim--the recombinant human granulocyte colony-stimulating factor (G-CSF) stimulates the activation, proliferation and maturation of progenitor granulocyte cells. This drug is usually applied in treatment of iatrogenic neutropenia, during chemotherapy of malignancies and in some idiopathic and cyclic neutopenias. CASE REPORT: A female patient, 18 years of age, has been hospitalized at the Clinic of Infectious Diseases in Novi Sad on two occasions. First because of severe acute infectious mononucleosis with acute hepatitis and jaundice 10 days after onset of symptoms. Physical examination revealed severe intoxication, dehydration, icteric skin, mucosis and massive hepatosplenomegaly. The diagnosis was confirmed by ELISA IgM, EBV VCA positive and ELISA IgG EBV VCA and IgG EBVNA negative results. The patient was discharged from hospital after 24 days without complaints and with normal physical and laboratory findings. For several days she felt well, but gradually severe fatigue and malaise occurred and she became febrile again. That was the reason why she was hospitalized again, two weeks later. This time she was febrile, extremely intoxicated with general lymphadenopathy, catarrhal gingivostomatitis and massive splenomegaly. The first laboratory findings showed severe neutropenia (absolute count of granulocytes was 0.156 x 10/l, with only 12% segmented neutrophils). Mild anemia--3.05 x 10/l was also registered, while the platelet count was normal. Other biochemical analyses were normal, the Coombs' test negative, while the serological response was also normal. Bone marrow puncture was performed and normocellular bone marrow was registered, somewhere hypercellular due to hyperplasia of granulocyte progenitor cells from promyelocytes to normal maturated cells. Anemia showed megaloblastoid proliferation, while megakaryocytes were normal. High doses of corticosteroids were applied (dexamethasone 160 mg daily) and filgrastim 5 micrograms every other day. From the very beginning of therapy the patient felt better, whereas granulocytes responded with elevation as soon as 48 hours after initiation of therapy. On the sixth day the treatment was stopped because the level of granulocytes was normal and the patient has completely recovered. She was discharged from hospital 4 weeks later with mild meteorism, but normal physical and laboratory findings and mild splenomegaly registered only by ultrasonography. DISCUSSION: During the last 10 years only several cases of severe leukopenia with acute infectious mononucleosis had been reported in literature. In all cases it was associated with some other hematological complications and it occurred in young adults without previously registered immunodeficiency. We have no knowledge about application of filgrastim in treatment of EBV-induced agranulocytosis, but the International Association for Studying Agranulocytosis and Aplastic Anemia reported that in 4% of patients Epstein-Barr virus can cause agranulocytosis even a year after the occurrence of acute disease.

Effect of serum from thrombocytopenic patients on platelet count in blood of mice.

Estimation of the effect of sera obtained from patients suffering from several forms of megakaryocytic (immune) thrombocytopenia (19), and those with acute non-lymphoblastic leukemia (13), on the platelet count in the peripheral blood of mice was carried out. Several groups of mice were injected intravenously with 0.2 ml of patients' sera, and the platelet count was followed up for 10 days. A marked and highly significant decrease of platelet count in recipient mice was established even 6 hours after the application of both groups of patients' sera. In the control group of mice receiving pooled serum of healthy persons this decrease was not registered. It can be presumed with great probability that the mechanism of development of thrombocytopenia in both groups of patients is very similar: there is an extremely increased destruction of platelets in the peripheral blood in cases with immune thrombocytopenia by antibodies, and in cases with acute leukemias by antibodies and/or other cytotoxic substances. In further investigations the influence of thrombopoietin on this phenomenon will be tested.

[Clinical use of thrombopoietin (c-Mpl Ligand)]. / Klinicka upotreba trombopoetina (c-Mpl LIGANDA).

INTRODUCTION: Results in clinical use of thrombopoietin have been published later than of other hematopoietic growth factors, because until recently the research was the least understood aspect of blood cell development. Reasons for this time gap were numerous, from inconvenient methods for measurement of thrombopoietin activity, to difficulties of its chemical purification. It is claimed recently that the understanding of platelet production has been profoundly advanced by the recombinant-gene synthesis and characterization of c-Mpl ligand (Megakaryocyte Growth and Development Factor), a substance which strongly enhances the proliferation of megakaryocytic line and the production of platelets. In this paper, some historical facts and biology of thrombopoietin are briefly discussed as well as the recent of the clinical use of thrombopoietin. THE HISTORY OF RESEARCH AND PRODUCTION OF THROMBOPOIETIN: The concept that the platelet production is underlying humoral regulation was first promoted by a group of Hungarian authors and they also named that humoral regulator--thrombopoietin. Further research followed in several countries including our own, and the initial studies proved that the serum of thrombocytopenic animals induced proliferation and maturation of megakaryocytic cell line and thrombocytosis in the peripheral blood of recipient animals. Later, when in vitro techniques were developed, it was shown that this humoral regulator has also a colony stimulating activity on megakaryocytic precursors. During the following two decades, studies of megakarycytopoiesis supported the hypothesis that two types of factors are involved in platelet production: early acting--megakaryocyte colony stimulating factors (Meg-CSF), and late acting--megakaryocyte potentiators, first of all thrombopoietin (TPO). However, extensive attempts on the purification of substances that either stimulate megakaryocyte development or augment platelet production failed to yield a homogeneous protein adequate for protein sequencing and cDNA cloning, the usual route which led to the production of other hematopoietic growth factors. Furthermore, a large number of other cytokines were described that possessed activity in various assays of megakaryocyte development. In spite of great number of accumulated data, it seemed in early 1990s that the production of a distinct, clinically useful lineage specific thrombopoietin will not be soon possible to achieve. The breakthrough occurred in 1994, when four groups of investigators published simultaneously their successful results on production of c-Mpl ligand, a substance which specifically binds to the Mpl receptors on megakaryocytes and has a very potent thrombocytopoietic effect. This production is based on genetic engineering and two companies (Kirin and Amgen) are already able to produce recombinant human thrombopoietin in large amounts, for clinical use. Although this substance is not commercially available yet, it passed the preclinical and clinical trials whose results are presented here. RESULTS OF THE PRECLINICAL TRIALS OF RECOMBINANT THROMBOPOIETIN: The chemical structure of human recombinant thrombopoietin (rTPO) is well defined, it is a glycoprotein consisting of 353 amino acids and molecular weight of 30 kD. The biologic actions of this molecule are in vitro: stimulation of megakaryocyte colony forming, endoreduplication of chromosomes and megakaryocyte maturation, and in vivo: increase of the number of progenitors and of megakaryocytes in the bone marrow, and an extensive elevation of platelet count in the peripheral blood 4-7 days after its application. Also, in synergism with other pluripotent cytokines, it can stimulate the proliferation of other progenitors including CD34+ stem cells. Based on these data it is considered that c-Mpl ligand is the main physiological humoral regulator of thrombocytopoiesis, having the biological actions both of MegCSF and TPO.