Slow-release devices retained in the rumen, are a simple method for continuous administration of bioactives to ruminant animals. To satisfy regulatory requirements and avoid waste of bioactive due to under- or over-dosing, it is advantageous to have a constant and predictable release rate. Existing intraruminal controlled-release technologies cannot easily be adapted for different bioactives or rates of release and can be influenced by the variable physiological environment in the rumen. Some existing commercial products use the pressure generated by a hydrogen gas-producing cell to extrude fluids from a syringe-like device. This technology may provide advantages for ruminal controlled-release as the gas production rate is unaffected by environment in the rumen and can be easily adjusted using electrical resistance applied to the gas cell. This technology was adapted for use in the rumen in these studies. Initial experiments identified the need for greater understanding of the rate that hydrogen is produced by the gas cell and the rate that gas diffuses through the barrel walls. Gas production rate was found to be inversely proportional to the resistance applied to the gas-producing cell. Factors affecting gas diffusion rate from the device were studied and a polymer was identified that reduced hydrogen diffusion to 5% of that for the initial components used. A relationship was developed to predict the release profile of a device. Controlled-release devices were constructed from selected materials. They released blank formulation at in vitro at a constant rate, which was within experimental variation of predicted values. Release rates from the devices used in vivo were slightly higher than predicted. The presence of rumen gases inside in vivo devices suggested that the difference may be due to inward diffusion of these gases; these may be eliminated by further study of barrel materials. Recommendations on the redesign of this technology for use as a generic intraruminal delivery system are given.

本研究主要目的在探討證券管理委員會所強制編製之財務預測報告是否具有資訊內涵。在美國，證券交易委員會對財務預測資訊之揭露，係採鼓勵但不強制的態度。財務預測資訊由市場供需所產生，且有司法體系監督著，對於散佈不實消息包括財務預測，影響市場運作者都會受到應當懲處。故其財務預測資訊相對而言準確性較高。反觀我國預測制度，證管會基於保護投資人的立場，達到資訊充分公開，強制公開財務預測資訊。但在目前的規範體系下，後續監督能力可能較弱，市場機制未能充分發揮，是以強制公開並不能保証其合理性。 　　依據「證券發行人財務報告編製準則」第15條，及「發行人募集與發行有價證券處理準則上第18條、第25條規定，上市公司如有現金增資或公開發行公司申請上市、募集與發行可轉換公司債時，需強制性揭露財務預測，上市公司亦可自願性地揭露財務預測。當編製財務預測所依據之關鍵因素或基本假設發生變動，致營業毛利（修正前為營業損益）或稅前損益變動達百分之二十以上（修正前為百分之十以上），且影響金額達一千萬以上，公司需更新及申告公告財務預測。 　　在財務預測相關規定下，根據資訊不對稱經濟學(Economics of Informational Asymmetry)，本研究以為資訊提供者會評估其相關成本效益來決定資訊品質。由於國內相關法規對劣質財務預測資訊並無足夠罰則，且資訊環境的效率性存疑，因此，本研究大膽假設國內財務預測資訊不存在資訊內涵。另外，根據國外實證研究，公司會傾向提早公佈好消息，延遲壞消息之公佈。本研究另一實證研究，係探討財務預測更新資訊型態與公告時間性之關連性。 　　實證結果彙總如下： 　　1.我國財務預測（原始預測）之公告不具資訊內涵。 　　2.財務預測更新資訊為正向更新者，不具資訊內涵。但若財務預測為負向更新之資訊揭露，在事件期會產生負的異常報酬。此實證結果意味著，負向財務預測更新代表公司原始預測過份樂觀，亦可能公司預計營運能力的衰退。所以，市場會有負向的反應。 　　3.時間性實證研究結果顯示，公司會延遲公告負向財務預測更新。

<p>Syftet med detta examensarbete är att analysera packinspektionsflödet samt att presentera förbättringsförslag för att effektivisera transportpackningsprocessen och reducera platsbristen på packytan. Arbetet är utfört på Siemens Industrial Turbomachinery AB (SIT) i Finspång under sommaren och hösten 2009.</p><p> </p><p>SIT är en del av det tyskägda företaget Siemens AG och är ett världsledande företag inom tillverkning av gas- och ångturbiner. Ett påtagligt problem är den platsbrist som råder och företaget har inga egna möjligheter att lagra ytterligare produkter, vare sig kortidslagring eller långtidslagring. Vidare är tillverkningskedjan ursprungligen utformad för att klara av ett fåtal kontinuerliga beställningar. I nuläget befinner sig företaget i en situation där de tillverkar fler turbiner än någonsin, vilket medför att både maskiner och personal utsätts för en högre belastning och tillverkningsprojekten måste bedrivas parallellt utan störningar för att kunna produceras i tid. En störning som företaget vill begränsa är den som uppstår vid packinspektioner. Under leveransfasen transportpackas leveransen och i ett fåtal av projekten kräver kunden en packinspektion innan leverans sker.</p><p> </p><p>För att kartlägga packinspektionsmomentet har en nulägesbeskrivning av befintlig process konstruerats. Därifrån konstaterades att den störning som en packinspektion medför är en dominoeffekt som påverkar flera avdelningar i företaget såsom, spedition, transportpackning samt kvalitetsavdelningen. Nulägesbeskrivningen har sedan utgjort underlag för att ta fram de förbättringsförslag som presenteras för att reducera platsbristen på packytan. Majoriteten av förbättringsförslagen baseras på Lean-konceptet, där huvudsyftet har varit att minimera påverkan av packinspektionerna i verksamheten för att få ett bättre flöde, hålla hög kundservice samt minimera ytan som en packinspektion upptar. Ett exempel på detta kan vara att strukturera befintlig packinspektionsprocess.</p><p> </p><p>Resultatet av de förbättringsförslag som redovisats i analysdelen påvisar att det går att få ett bättre flöde genom packinspektionsmomentet samtidigt som packytan inte blir lika belastad vid en packinspektion. I framtiden kommer de förbättringsförslag som behandlas att kunna tillämpas på andra avdelningar och företag som tillämpar packinspektioner. </p>

<p>Communication between neuronal and non-neuronal is called volume transmission when the released neurotransmitter (NT) acts via diffusion and affects several target cells. Both the neurosecretory and postsynaptic cell responses are linked to [Ca²⁺]_i elevations. </p><p>In the present thesis the role of pre-and postsynaptic Ca²⁺ elevations has been investigated in the reconstituted "synapse" model comprised of NGF-differentiated PC12 and HEL cells as well as in SH-SY5Y neuroblastoma cells. In PC12 cells, both 70mM K⁺ and nicotine triggered NT release, which could be detected as a secondary [Ca²⁺]_i increase in surrounding HEL cells. Both secretagogues shared the same voltage-dependent Ca²⁺ influx pathway as judged from the pharmacological profile blockers of voltage-gated Ca²⁺ channels. The coupling of electrical responses to the activation of Ca²⁺ signaling via muscarinic receptors in SH-SY5Y cells was also studied. These data revealed that depolarization caused a considerable potentiation of the muscarinic Ca²⁺ response. The potentiated Ca²⁺ increase was mainly dependent on the enhanced Ca²⁺ influx and to a lesser extent on [Ca²⁺]_i release from intracellular stores. A phospholipase C (PLC) activator, m-3M3FBS was used to further study the role of G-protein coupled receptor (GPCR)-coupled Ca²⁺ signaling. However, it was found that m-3M3FBS instead triggered [Ca²⁺]_i elevations independently of PLC activation. </p><p>In conclusion, the results indicate that the magnitude of NT release from PC12 cells is sufficient to cause a robust activation of neighboring target cells. Postsynaptic muscarinic signaling is amplified due to integration of electrical excitation and GPCR signaling. The PLC activator, m-3M3FBS is not suitable for studies of PLC-mediated signals in intact cells.</p>

<p>Serum levels of eosinophil granule proteins namely ECP, EPO and EPX, which are stored in the matrix of specific granules, were shown to correlate with the course of disease in disorders involving eosinophils. The concentration of eosinophil proteins in serum is the result of their release <i>in vivo</i> and <i>ex vivo</i> during the sampling procedure. Generally, eosinophils release the content of their specific granules in three ways: exocytosis, piecemeal degranulation (PM) or cytolysis. Which of them is operating in circulating eosinophils has not yet been defined. The aim of this thesis was to study the mechanisms of granule protein release from blood eosinophils in respect of protein subcellular localization and cell ultrastructure.</p><p>In patients with bacterial infections, serum levels of ECP but not EPO increased, while in patients with viral infections both proteins remained within the range of healthy controls. G-CSF is a cytokine involved in the response mechanism to bacterial but not viral infections. Administration of G-CSF to healthy subjects induced an elevation of eosinophil numbers and a preferential increase of serum EPX and ECP in comparison to EPO.</p><p>The model of PM consists of the stepwise transportation of specific granule contents from the granules towards the plasma membrane. We observed that administration of G-CSF to healthy subjects and the allergen exposure of allergic subjects during the pollen season, caused changes in the ultrastructure of eosinophil specific granules such as loosening of the matrix, granule matrix lucency and ragged losses of their core. Similar alterations of morphology had been previously described for eosinophils undergoing PM.</p><p>ECP, EPX and EPO were localized not only in the specific granules but also in extra-granular compartments as shown both by immuno electron microscopy and subcelular fractionations, An extra-granular EPX compartment was present in healthy as well as in allergic and in hypereosinophilic subjects, and there were no significant differences in its size between the groups. The size of the extra-granular compartments of ECP and EPO was increased in allergics during the season, and these compartments were clearly separate from that of EPX. Results of this show the differential mobilization ofgranule proteins in blood stream eosinophils serum and indicates PM as its mechanism.</p>

<p>This thesis investigates the potential of using positron emission tomography (PET) to study the biosynthesis and release of serotonin (5HT) at the brain serotonergic neuron. As PET requires probe compounds with specific attributes to enable imaging and quantification of biological processes, emphasis was placed on the evaluation of these attributes. </p><p>The experiments established that the 5HT transporter radioligand [¹¹C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile, [¹¹C]DASB, is suitable for imaging and quantification of transporters in rats and rhesus monkeys. In addition, the binding of [¹¹C]DASB in brain tissue is decreased when 5HT concentrations are increased by tranylcypromine administration. The sensitivity of [¹¹C]DASB binding, under these experimental conditions, to increased endogenous 5HT concentrations demonstrates the potential of in vivo monitoring of 5HT release in rat and monkey models.</p><p>The irreversible binding of 5-hydroxy-L-[β-¹¹C]tryptophan, [¹¹C]HTP, in the monkey brain was lower in the presence of NSD1015, which was used to inhibit the decarboxylase step in 5HT synthesis. [¹¹C]HTP seems thus to have potential for tracking changes in the activity of this biosynthesis enzyme. In contrast, the accumulation of [¹¹C]HTP was unaffected by clorgyline, which was used to inhibit metabolism of the probe in the brain. This appears to indicate that elimination of the main metabolite from the brain could be negligible and thus will not alter [¹¹C]HTP quantification. The extent and distribution of the irreversible binding of a substrate for the first enzyme in 5HT formation, α-[¹¹C]methyl-L-tryptophan, [¹¹C]AMT, was different from those for [¹¹C]HTP. This suggests that the two studied probe compounds provide estimates related to the enzyme activity of different steps in the 5HT biosynthesis pathway. </p><p>A reference tissue version of the Patlak method for the analysis of data obtained by PET was also developed. This approach takes into account irreversible binding in the reference region and appears, therefore, to yield more reliable parameter estimates than the conventional reference Patlak analysis. The method is recommended for parameter estimation of [¹¹C]HTP data when no metabolite-corrected plasma curve is available. </p><p>Knowledge of altered 5HT synthesis and release in disease states and the consequences for effective pharmacotherapy can improve our knowledge of the aetiology of certain psychiatric and neurological diseases and enhance our ability to design more effective drugs.</p>

<p>This thesis describes results from fundamental studies of liposomes intended for drug delivery and pH or temperature triggered release. In addition, the effect of lipid composition on bilayer disc formation and a potential application of the bilayer discs were investigated.</p><p>The lower pH encountered by endocytosed liposomes can be utilized to trigger drug release. The mechanisms behind cytosolic drug delivery were investigated using two different kinds of pH-sensitive liposomes. The results indicate that incorporation of non-lamellar forming lipids into the endosome membrane may allow for drug escape into the cytosol.</p><p>Temperature-sensitive liposomes containing lysolipid (LTSL) release their content almost instantly when heated to temperatures close to the gel to liquid crystalline phase transition temperature (T<i>C</i>). Morphological changes of the liposomes in response to temperature cycling were studied. Temperature cycling induced liposome openings and disintegration of the liposomes into bilayer discs. Incubation of LTSL in the presence of multilamellar liposomes (MLVs) resulted in relocalisation of lysolipid into the MLVs, which affected the rapid release from LTSL. We propose that the presence of micelle-forming components, such as lysolipids and PEG-lipids, facilitates the formation of defects and membrane openings during the initial phase of membrane melting, resulting in the observed rapid release. Similar to added lysolipids, also hydrolysis generated lysolipids induce disc-formation upon heating through T<i>C</i> of the lipid mixture.</p><p>Two fundamentally different micelles may form in PEG-lipid/lipid mixtures. We found that discoidal structures are preferred over cylindrical micelles when the mixture contains components that reduce the spontaneous curvature, increase the monolayer bending modulus, or reduce PEG-lipid/lipid miscibility. The large discoidal micelles found at low PEG-lipid content are better described as bilayer discs. We evaluated such discs as model membranes in drug partitioning studies, and suggest that they, in some cases, produce more accurate data than liposomes.</p>

Peripheral vascular diseases such as peripheral artery disease (PAD) and critical limb ischemia (CLI) are growing at an ever-increasing rate in the Western world due to an aging population and the incidence of type II diabetes. A growing economic burden continues because these diseases are common indicators of future heart attack or stroke. Common therapies are generally limited to pharmacologic agents or endovascular therapies which have had mixed results still ending in necrosis or limb loss. Therapeutic angiogenic strategies have become welcome options for patients suffering from PAD due to the restoration of blood flow in the extremities. Capillary sprouting and a return to normoxic tissue states are also demonstrated by the use of angiogenic cytokines in conjunction with bone marrow cell populations. To this point, it has been determined that spatial and temporal controlled release of growth factors from vehicles provides a greater therapeutic and angiogenic effect than growth factors delivered intramuscularly, intravenously, or intraarterialy due to rapid metabolization of the cytokine, and non-targeted release. Furthermore, bone marrow cells have been implicated to enhance angiogenesis in numerous ischemic diseases due to their ability to secrete angiogenic cytokines and their numerous cell fractions present which are implicated to promote mature vessel formation. Use of angiogenic peptides, in conjunction with bone marrow cells, has been hypothesized in EPC mobilization from the periphery and marrow tissues to facilitate neovessel formation. For this purpose, controlled release of angiogenic peptides basic fibroblast growth factor (FGF-2) and granulocyte-colony stimulating factor (G-CSF) was performed using tunable ionic gelatin hydrogels or fibrin scaffolds with ionic albumin microspheres. The proliferation of endothelial cell culture was determined to have an enhanced effect based on altering concentrations of growth factors and method of release: co-delivery versus sequential. Scaffolds with these angiogenic peptides were implanted in young balb/c mice that underwent unilateral hindlimb ischemia by ligation and excision of the femoral artery. Endpoints for hindlimb reperfusion and angiogenesis were determined by Laser Doppler Perfusion Imaging and immunohistochemical staining for capillaries (CD-31) and smooth muscle cells (alpha-SMA). In addition to controlled release of angiogenic peptides, further studies combined the use of a fibrin co-delivery scaffold with FGF-2 and G-CSF with bone marrow stem cell transplantation to enhance vessel formation following CLI. Endpoints also included lipophilic vascular painting to evaluate the extent of angiogenesis and arteriogenesis in an ischemic hindlimb. Tissue engineering strategies utilizing bone marrow cells and angiogenic peptides demonstrate improved hindlimb blood flow compared to BM cells or cytokines alone, as well as enhanced angiogenesis based on immunohistochemical staining and vessel densities.

Serum levels of eosinophil granule proteins namely ECP, EPO and EPX, which are stored in the matrix of specific granules, were shown to correlate with the course of disease in disorders involving eosinophils. The concentration of eosinophil proteins in serum is the result of their release in vivo and ex vivo during the sampling procedure. Generally, eosinophils release the content of their specific granules in three ways: exocytosis, piecemeal degranulation (PM) or cytolysis. Which of them is operating in circulating eosinophils has not yet been defined. The aim of this thesis was to study the mechanisms of granule protein release from blood eosinophils in respect of protein subcellular localization and cell ultrastructure. In patients with bacterial infections, serum levels of ECP but not EPO increased, while in patients with viral infections both proteins remained within the range of healthy controls. G-CSF is a cytokine involved in the response mechanism to bacterial but not viral infections. Administration of G-CSF to healthy subjects induced an elevation of eosinophil numbers and a preferential increase of serum EPX and ECP in comparison to EPO. The model of PM consists of the stepwise transportation of specific granule contents from the granules towards the plasma membrane. We observed that administration of G-CSF to healthy subjects and the allergen exposure of allergic subjects during the pollen season, caused changes in the ultrastructure of eosinophil specific granules such as loosening of the matrix, granule matrix lucency and ragged losses of their core. Similar alterations of morphology had been previously described for eosinophils undergoing PM. ECP, EPX and EPO were localized not only in the specific granules but also in extra-granular compartments as shown both by immuno electron microscopy and subcelular fractionations, An extra-granular EPX compartment was present in healthy as well as in allergic and in hypereosinophilic subjects, and there were no significant differences in its size between the groups. The size of the extra-granular compartments of ECP and EPO was increased in allergics during the season, and these compartments were clearly separate from that of EPX. Results of this show the differential mobilization ofgranule proteins in blood stream eosinophils serum and indicates PM as its mechanism.

Communication between neuronal and non-neuronal is called volume transmission when the released neurotransmitter (NT) acts via diffusion and affects several target cells. Both the neurosecretory and postsynaptic cell responses are linked to [Ca2+]i elevations. In the present thesis the role of pre-and postsynaptic Ca2+ elevations has been investigated in the reconstituted "synapse" model comprised of NGF-differentiated PC12 and HEL cells as well as in SH-SY5Y neuroblastoma cells. In PC12 cells, both 70mM K+ and nicotine triggered NT release, which could be detected as a secondary [Ca2+]i increase in surrounding HEL cells. Both secretagogues shared the same voltage-dependent Ca2+ influx pathway as judged from the pharmacological profile blockers of voltage-gated Ca2+ channels. The coupling of electrical responses to the activation of Ca2+ signaling via muscarinic receptors in SH-SY5Y cells was also studied. These data revealed that depolarization caused a considerable potentiation of the muscarinic Ca2+ response. The potentiated Ca2+ increase was mainly dependent on the enhanced Ca2+ influx and to a lesser extent on [Ca2+]i release from intracellular stores. A phospholipase C (PLC) activator, m-3M3FBS was used to further study the role of G-protein coupled receptor (GPCR)-coupled Ca2+ signaling. However, it was found that m-3M3FBS instead triggered [Ca2+]i elevations independently of PLC activation. In conclusion, the results indicate that the magnitude of NT release from PC12 cells is sufficient to cause a robust activation of neighboring target cells. Postsynaptic muscarinic signaling is amplified due to integration of electrical excitation and GPCR signaling. The PLC activator, m-3M3FBS is not suitable for studies of PLC-mediated signals in intact cells.