Uptake of NO-releasing drugs by the P2 nucleoside transporter in trypanosomes

Nitric oxide (NO·) has been identified as a principal regulatory molecule of the immune system and the major cytotoxic mediator of activated immune cells. NO· can also react rapidly with a variety of biological species, particularly with the superoxide radical anion O2·- at almost diffusion-limited rates to form peroxynitrite anion (ONOO-). ONOO- and its proton-catalyzed decomposition products are capable of oxidizing a great diversity of biomolecules and can act as a source of toxic hydroxyl radicals. As a consequence, a strategy for the development of molecules with potential trypanocidal activities could be developed to increase the concentration of nitric oxide in the parasites through NO·-releasing compounds. In this way, the rate of formation of peroxynitrite from NO· and O2·- would be faster than the rate of dismutation of superoxide radicals by superoxide dismutases which constitute the primary antioxidant enzymatic defense system in trypanosomes. The adenosine transport systems of parasitic protozoa, which are also in certain cases implicated in the selective uptake of active drugs such as melarsoprol or pentamidine, could be exploited to specifically target these NO·-releasing compounds inside the parasites. In this work, we present the synthesis, characterization and biological evaluation of a series of molecules that contain both a group which would specifically target these drugs inside the parasites via the purine transporter, and an NO·-donor group that would exert a specific pharmacological effect by increasing NO level, and thus the peroxynitrite concentration inside the parasite.

e-Business and collaboration: A case study of pulp supply chain

This thesis studies how the case company could digitalize its supply chain and what kind of advantages this would create in the light of supply chain efficiency. The case company manufactures several pulp products that are used for paper, fabrics and packaging products by customers worldwide. The paper and pulp industry has been paying more and more attention to increasing supply chain efficiency with new operating and service models made possible by today’s information technology. The main focus of this study is on the supply chain between the case company and its key customers and the goal is to find ways to make the operations between them as efficient as possible. The study relays heavily on collaboration techniques and digitalization technologies. In addition to a theoretical framework, the study includes several empirical studies that offer real-life examples of how these theories and technologies are applied in operating environments similar to the case company. A plan with strategic and operational levels is created according to the findings of the previous sections to support the case company’s future operations. The plan is based on an RFID-supported collaboration model that aims to advance information sharing between the supply chain partners. The time for an RFID-investment is sought to be very optimal and the benefits of such system to be noteworthy, but challenging to measure in monetary terms.

Chronic effect of antidopaminergic drugs or estrogen on male Wistar rat lactotrophs and somatotrophs

The aim of the present study was to evaluate the effect of antidopaminergic agents on the somatotrophs in the presence of hyperprolactinemia. Adult male Wistar rats were divided into 6 groups: a control group and five groups chronically treated (60 days) with haloperidol, fluphenazine, sulpiride, metoclopramide or estrogen. Somatotrophs and lactotrophs were identified by immunohistochemistry and the data are reported as percent of total anterior pituitary cells counted. The drugs significantly increased the percentage of lactotrophs: control (mean ± SD) 21.3 ± 4.4, haloperidol 27.8 ± 2.2, fluphenazine 34.5 ± 3.6, sulpiride 32.7 ± 3.5, metoclopramide 33.4 ± 5.5 and estrogen 42.4 ± 2.8. A significant reduction in somatotrophs was observed in animals treated with haloperidol (23.1 ± 3.0), fluphenazine (22.1 ± 1.1) and metoclopramide (24.2 ± 3.0) compared to control (27.3 ± 3.8), whereas no difference was observed in the groups treated with sulpiride (25.0 ± 2.2) and estrogen (27.1 ± 2.8). In the groups in which a reduction occurred, this may have simply been due to dilution, secondary to lactotroph hyperplasia. In view of the duplication of the percentage of prolactin-secreting cells, when estrogen was applied, the absence of a reduction in the percent of somatotrophs suggests a replication effect on this cell population. These data provide additional information about the direct or indirect effect of drugs which, in addition to interfering with the dopaminergic system, may act on other pituitary cells as well as on the lactotrophs.

Global Spare Parts Supply Chain Analysis

In today’s global industrial service business, markets are dynamic and finding new ways of value creation towards customers has become more and more challenging. Customer orientation is needed because of the demanding after-sales business which is both quickly changing and stochastic in nature. In after-sales business customers require fast and reliable service for their spare part needs. This thesis objective is to clarify this challenging after-sales business environment and find ways to increase customer satisfaction via balanced measurement system which will help to find possible targets to reduce order cycle times in a large metal and mineral company Outotec (Filters)’ Spare Part Supply business line. In case study, internal documents and data and numerical calculations together with qualitative interviews with different persons in key roles of Spare Part Supply organizations are used to analyze the performance of different processes from the spare parts delivery function. The chosen performance measurement tool is Balanced Scorecard which is slightly modified to suit the lead time study from customer’s perspective better. Findings show that many different processes in spare parts supply are facing different kind of challenges in achieving the lead time levels wanted and that these processes’ problems seem to accumulate. Findings also show that putting effort in supply side challenges and information flows visibility should give the best results.

The radio frequency identification technology in the supply chain management: a case of a big logistics company

Nowadays global business trends force the adoption of innovative ICTs into the supply chain management (SCM). Particularly, the RFID technology is on high demand among SCM professionals due to its business advantages such as improving of accuracy and veloc-ity of SCM processes which lead to decrease of operational costs. Nevertheless, a question of the RFID technology impact on the efficiency of warehouse processes in the SCM re-mains open. The goal of the present study is to experiment the possibility of improvement order picking velocity in a warehouse of a big logistics company with the use of the RFID technology. In order to achieve this goal the following objectives have been developed: 1) Defining the scope of the RFID technology applications in the SCM; 2) Justification of the RFID technology impact on the SCM processes; 3) Defining a place of the warehouse order picking process in the SCM; 4) Identification and systematization of existing meth-ods of order picking velocity improvement; 5) Choosing of the study object and gathering of the empirical data about number of orders, number of hours spent per each order line daily during 5 months; 6) Processing and analysis of the empirical data; 7) Conclusion about the impact of the RFID technology on the speed of order picking process. As a result of the research it has been found that the speed of the order picking processes has not been changed as time has gone after the RFID adoption. It has been concluded that in order to achieve a positive effect in the speed of order picking process with the use of the RFID technology it is necessary to simultaneously implement changes in logistics and organizational management in 3PL logistics companies. Practical recommendations have been forwarded to the management of the company for further investigation and procedure.

Hepatic capillariasis in rats: a new model for testing antifibrotic drugs

Rats infected with the helminth Capillaria hepatica regularly develop septal hepatic fibrosis that may progress to cirrhosis in a relatively short time. Because of such characteristics, this experimental model was selected for testing drugs exhibiting antifibrosis potential, such as pentoxifylline, gadolinium chloride and vitamin A. Hepatic fibrosis was qualitatively and quantitatively evaluated in liver samples obtained by partial hepatectomy and at autopsy. The material was submitted to histological, biochemical and morphometric methods. A statistically significant reduction of fibrosis was obtained with pentoxifylline when administered intraperitoneally rather than intravenously. Gadolinium chloride showed moderate activity when administered prophylactically (before fibrosis had started), but showed a poor effect when fibrosis was well advanced. No modification of fibrosis was seen after vitamin A administration. Hydroxyproline content was correlated with morphometric measurements. The model appears to be adequate, since few animals die of the infection, fibrosis develops regularly in all animals, and the effects of different antifibrotic drugs and administration protocols can be easily detected.

Development of new heparin-like compounds and other antithrombotic drugs and their interaction with vascular endothelial cells

The anticlotting and antithrombotic activities of heparin, heparan sulfate, low molecular weight heparins, heparin and heparin-like compounds from various sources used in clinical practice or under development are briefly reviewed. Heparin isolated from shrimp mimics the pharmacological activities of low molecular weight heparins. A heparan sulfate from Artemia franciscana and a dermatan sulfate from tuna fish show a potent heparin cofactor II activity. A heparan sulfate derived from bovine pancreas has a potent antithrombotic activity in an arterial and venous thrombosis model with a negligible activity upon the serine proteases of the coagulation cascade. It is suggested that the antithrombotic activity of heparin and other antithrombotic agents is due at least in part to their action on endothelial cells stimulating the synthesis of an antithrombotic heparan sulfate.

Protective effects of centrally acting sympathomodulatory drugs on myocardial ischemia induced by sympathetic overactivity in rabbits

It is recognized that an imbalance of the autonomic nervous system is involved in the genesis of ventricular arrhythmia and sudden death during myocardial ischemia. In the present study we investigated the effects of clonidine and rilmenidine, two centrally acting sympathomodulatory drugs, on an experimental model of centrally induced sympathetic hyperactivity in pentobarbital-anesthetized New Zealand albino rabbits of either sex (2-3 kg, N = 89). We also compared the effects of clonidine and rilmenidine with those of propranolol, a ß-blocker, known to induce protective cardiovascular effects in patients with ischemic heart disease. Central sympathetic stimulation was achieved by intracerebroventricular injection of the excitatory amino acid L-glutamate (10 µmol), associated with inhibition of nitric oxide synthesis with L-NAME (40 mg/kg, iv). Glutamate triggered ventricular arrhythmia and persistent ST-segment shifts in the ECG, indicating myocardial ischemia. The intracisternal administration of clonidine (1 µg/kg) and rilmenidine (30 µg/kg) or of a nonhypotensive dose of rilmenidine (3 µg/kg) decreased the incidence of myocardial ischemia (25, 14 and 25%, respectively, versus 60% in controls) and reduced the mortality rate from 40% to 0.0, 0.0 and 12%, respectively. The total number of ventricular premature beats per minute fell from 30 ± 9 in the control group to 7 ± 3, 6 ± 3 and 2 ± 2, respectively. Intravenous administration of clonidine (10 µg/kg), rilmenidine (300 µg/kg) or propranolol (500 µg/kg) elicited similar protective effects. We conclude that clonidine and rilmenidine present cardioprotective effects of central origin, which can be reproduced by propranolol, a lipophilic ß-blocking agent.

The demand-supply balancing process in supply chain management - case mining & metals industry equipment

The aim of this thesis is to search how to match the demand and supply effectively in industrial and project-oriented business environment. The demand-supply balancing process is searched through three different phases: the demand planning and forecasting, synchronization of demand and supply and measurement of the results. The thesis contains a single case study that has been implemented in a company called Outotec. In the case study the demand is planned and forecasted with qualitative (judgmental) forecasting method. The quantitative forecasting methods are searched further to support the demand forecast and long term planning. The sales and operations planning process is used in the synchronization of the demand and supply. The demand forecast is applied in the management of a supply chain of critical unit of elemental analyzer. Different meters on operational and strategic level are proposed for the measurement of performance.

Vascular supply of the central nervous system of the land snail Megalobulimus oblongus (Gastropoda, Pulmonata)

The vascularization of the central nervous system of the snail Megalobulimus oblongus was studied by injection of carmine-gelatin solution into the arterial system and using a histochemical technique for the detection of alkaline phosphatase. The central nervous system of M. oblongus is irrigated by the anterior aorta, from which a series of small branches emerge that supply the subesophageal nervous ganglia. In turn, these branches give rise to a series of smaller vessels that irrigate the buccal bulb, the anterior portion of the foot, the cerebral ganglia, the dorsal body gland, and the anterior portion of the reproductive system. No hemolymph vessels were detected within nervous tissue although such vessels were found in the periganglionic connective sheath. This connective sheath contains vascular loops and had a series of overlaps and projections that follow the contour of the nervous ganglia. This arrangement permits a larger area of interaction between the surface of the nervous tissue and the hemolymph and reduces the distance between the deepest portion of a given ganglion and the hemolymph vessels.

Reporting of Green Supply Chain Management and Industrial Symbiosis

The purpose of this thesis is to examine how the reporting of operations related to green supply chain management and industrial symbiosis has evolved in UPM, Fortum and Kemira within the last ten years. The focus is on the improved operations, which are studied based on annual reports of these companies. The study provides a deeper understanding of the nature of green supply chain management and industrial symbiosis as well as the possibilites that their combination offers. The research is part of the DemaNET research project The study indicates that the environmental regulations and reporting standards have forced the studied companies to report their operations related to green supply chain management and industrial symbiosis more in detail during the last ten years. The operations related to green supply chain management in the studied companies are more common compared to operations related to industrial symbiosis. Often these two operations were also partially integrated, indicating a hybrid model. Even though firms often used hybrid models they still focused mainly on greening the internal operations rather than finding alternative ways for symbiosis outside the organization. The integration of green supply chain management and industrial symbiosis is most likely to occur when mutually beneficial relationships align the interests of all parties, thus resulting in the co-creation of value. The findings suggest that identifying mutual benefits and the flow of by-products are the ones that companies should give more attention to.

Supply base development for life-cycle business

Yritysten liiketoimintamallit ovat jatkuvan kehityksen kohteena. Viimeisinä vuosina valmistavien yhtiöiden kiinnostus huolehtia asiakkaistaan koko tuotteen elinkaaren aikana ja tarjota erilaisia palveluita asiakkailleen on kasvanut. Tämän palvelujen laajentumisen myötä myös vaateet yrityksen omaa toimittajakenttää kohtaan ovat muuttuneet. Yritykset eivät kykene tuottamaan kaikkia tuotteistamiaan palveluja itse, jolloin yrityksen toimittajakenttä ja sen kyvykkyydet tuottaa tarvittavia palveluita ovat avainasemassa yrityksen menestystekijänä. Tämän työn teoriaosuudessa on esitelty toimittajakentän hallinnan perusteorioita. Kirjallisuus osuuden lisäksi työssä on hyödynnetty toimintatutkimusta kohdeyrityksessä. Tässä diplomityössä on tutkittu mahdollisia keinoja kehittää organisaation omaa toimintaa ja sekä yrityksen toimittajakenttää niin, että se tukee liiketoimintamallin kehitystä koneenrakennusyrityksestä kohti elinkaariliiketoimintaa. Työssä esitetyt keinot voidaan ottaa käyttöön, joko yksitellen tai kokonaisuutena.

Cardiac and vascular effects of diltiazem, dobutamine and amrinone, drugs used after myocardial revascularization

Hemodynamic care during postoperative management of myocardial revascularization should include vasorelaxing drugs to insure adequate graft and coronary flow, and stimulation of stroke volume to maintain vascular perfusion pressure. We tested the cardiac (inotropic and lusitropic) and vascular (relaxant) effects of diltiazem (0.1 nM to 0.1 mM), dobutamine (10 µM to 10 mM) and amrinone (10 µM to 1 mM) on isolated rat atria and thoracic aorta, and also on isolated human saphenous vein (HSV) and human mammary artery (HMA). Dobutamine produced a maximal positive inotropic effect (+dF/dt max = 29 ± 7%) at its ED50 for aortic relaxation (88 ± 7 µM). Conversely, at their ED50 for aortic relaxation diltiazem depressed myocardial contractility and amrinone did not exhibit myocardial effects. In HSV and HMA contracted with 80 mM potassium, diltiazem and dobutamine (but not amrinone) had a vasorelaxant activity similar to that in rat aorta. Norepinephrine-contracted human vessels were significantly more sensitive than potassium-contracted vessels to the relaxant effect of amrinone (ED50 HMA = 15 ± 5 µM, ED50 HSV = 72 ± 31 µM, P < 0.05). We conclude that at concentrations still devoid of myocardial effects dobutamine and amrinone are effective dilators in graft segment vessels and rat aorta contracted by membrane depolarization. If the difference between aortic and myocardial tissue still holds in human tissues, at the appropriate concentrations these drugs should be expected to improve cardiac performance while still contributing to the maintenance of graft patency.

Effects of centrally acting antihypertensive drugs on the microcirculation of spontaneously hypertensive rats

We investigated the acute effects of centrally acting antihypertensive drugs on the microcirculation of pentobarbital-anesthetized spontaneously hypertensive rats (SHR). The effects of the sympatho-inhibitory agents clonidine and rilmenidine, known to activate both alpha2-adrenoceptors and nonadrenergic I1-imidazoline binding sites (I1BS) in the central nervous system, were compared to those of dicyclopropylmethyl-(4,5-dimethyl-4,5-dihydro-3H -pyrrol-2-yl)-amine hydrochloride (LNP 509), which selectively binds to the I1BS. Terminal mesenteric arterioles were observed by intravital microscopy. Activation of the central sympathetic system with L-glutamate (125 µg, ic) induced marked vasoconstriction of the mesenteric microcirculation (27 ± 3%; N = 6, P < 0.05). In contrast, the marked hypotensive and bradycardic effects elicited by intracisternal injection of clonidine (1 µg), rilmenidine (7 µg) and LNP 509 (60 µg) were accompanied by significant increases in arteriolar diameter (12 ± 1, 25 ± 10 and 21 ± 4%, respectively; N = 6, P < 0.05). The vasodilating effects of rilmenidine and LNP 509 were two-fold higher than those of clonidine, although they induced an identical hypotensive effect. Central sympathetic inhibition elicited by baclofen (1 µg, ic), a GABA B receptor agonist, also resulted in vasodilation of the SHR microvessels. The acute administration of clonidine, rilmenidine and LNP 509 also induced a significant decrease of cardiac output, whereas a decrease in systemic vascular resistance was observed only after rilmenidine and LNP 509. We conclude that the normalization of blood pressure in SHR induced by centrally acting antihypertensive agents is paralleled by important vasodilation of the mesenteric microcirculation. This effect is more pronounced with substances acting preferentially (rilmenidine) or exclusively (LNP 509) upon I1BS than with those presenting important alpha2-adrenergic activity (clonidine).

Effect of therapeutic plasma concentrations of non-steroidal anti-inflammatory drugs on the production of reactive oxygen species by activated rat neutrophils

The release of reactive oxygen specie (ROS) by activated neutrophil is involved in both the antimicrobial and deleterious effects in chronic inflammation. The objective of the present investigation was to determine the effect of therapeutic plasma concentrations of non-steroidal anti-inflammatory drugs (NSAIDs) on the production of ROS by stimulated rat neutrophils. Diclofenac (3.6 µM), indomethacin (12 µM), naproxen (160 µM), piroxicam (13 µM), and tenoxicam (30 µM) were incubated at 37ºC in PBS (10 mM), pH 7.4, for 30 min with rat neutrophils (1 x 10(6) cells/ml) stimulated by phorbol-12-myristate-13-acetate (100 nM). The ROS production was measured by luminol and lucigenin-dependent chemiluminescence. Except for naproxen, NSAIDs reduced ROS production: 58 ± 2% diclofenac, 90 ± 2% indomethacin, 33 ± 3% piroxicam, and 45 ± 6% tenoxicam (N = 6). For the lucigenin assay, naproxen, piroxicam and tenoxicam were ineffective. For indomethacin the inhibition was 52 ± 5% and diclofenac showed amplification in the light emission of 181 ± 60% (N = 6). Using the myeloperoxidase (MPO)/H2O2/luminol system, the effects of NSAIDs on MPO activity were also screened. We found that NSAIDs inhibited both the peroxidation and chlorinating activity of MPO as follows: diclofenac (36 ± 10, 45 ± 3%), indomethacin (97 ± 2, 100 ± 1%), naproxen (56 ± 8, 76 ± 3%), piroxicam (77 ± 5, 99 ± 1%), and tenoxicam (90 ± 2, 100 ± 1%), respectively (N = 3). These results show that therapeutic levels of NSAIDs are able to suppress the oxygen-dependent antimicrobial or oxidative functions of neutrophils by inhibiting the generation of hypochlorous acid.