Loading of itraconazole into porous silica and silicon microparticles: characterization and dissolution tests

Most new drug molecules discovered today suffer from poor bioavailability. Poor oral bioavailability results mainly from poor dissolution properties of hydrophobic drug molecules, because the drug dissolution is often the rate-limiting event of the drug’s absorption through the intestinal wall into the systemic circulation. During the last few years, the use of mesoporous silica and silicon particles as oral drug delivery vehicles has been widely studied, and there have been promising results of their suitability to enhance the physicochemical properties of poorly soluble drug molecules. Mesoporous silica and silicon particles can be used to enhance the solubility and dissolution rate of a drug by incorporating the drug inside the pores, which are only a few times larger than the drug molecules, and thus, breaking the crystalline structure into a disordered, amorphous form with better dissolution properties. Also, the high surface area of the mesoporous particles improves the dissolution rate of the incorporated drug. In addition, the mesoporous materials can also enhance the permeability of large, hydrophilic drug substances across biological barriers. T he loading process of drugs into silica and silicon mesopores is mainly based on the adsorption of drug molecules from a loading solution into the silica or silicon pore walls. There are several factors that affect the loading process: the surface area, the pore size, the total pore volume, the pore geometry and surface chemistry of the mesoporous material, as well as the chemical nature of the drugs and the solvents. Furthermore, both the pore and the surface structure of the particles also affect the drug release kinetics. In this study, the loading of itraconazole into mesoporous silica (Syloid AL-1 and Syloid 244) and silicon (TOPSi and TCPSi) microparticles was studied, as well as the release of itraconazole from the microparticles and its stability after loading. Itraconazole was selected for this study because of its highly hydrophobic and poorly soluble nature. Different mesoporous materials with different surface structures, pore volumes and surface areas were selected in order to evaluate the structural effect of the particles on the loading degree and dissolution behaviour of the drug using different loading parameters. The loaded particles were characterized with various analytical methods, and the drug release from the particles was assessed by in vitro dissolution tests. The results showed that the loaded drug was apparently in amorphous form after loading, and that the loading process did not alter the chemical structure of the silica or silicon surface. Both the mesoporous silica and silicon microparticles enhanced the solubility and dissolution rate of itraconazole. Moreover, the physicochemical properties of the particles and the loading procedure were shown to have an effect on the drug loading efficiency and drug release kinetics. Finally, the mesoporous silicon particles loaded with itraconazole were found to be unstable under stressed conditions (at 38 qC and 70 % relative humidity).

Excimer laser refractive surgery : corneal wound healing and clinical results

Although the first procedure in a seeing human eye using excimer laser was reported in 1988 (McDonald et al. 1989, O'Connor et al. 2006) just three studies (Kymionis et al. 2007, O'Connor et al. 2006, Rajan et al. 2004) with a follow-up over ten years had been published when this thesis was started. The present thesis aims to investigate 1) the long-term outcomes of excimer laser refractive surgery performed for myopia and/or astigmatism by photorefractive keratectomy (PRK) and laser-in situ- keratomileusis (LASIK), 2) the possible differences in postoperative outcomes and complications when moderate-to-high astigmatism is treated with PRK or LASIK, 3) the presence of irregular astigmatism that depend exclusively on the corneal epithelium, and 4) the role of corneal nerve recovery in corneal wound healing in PRK enhancement. Our results revealed that in long-term the number of eyes that achieved uncorrected visual acuity (UCVA)≤0.0 and ≤0.5 (logMAR) was higher after PRK than after LASIK. Postoperative stability was slightly better after PRK than after LASIK. In LASIK treated eyes the incidence of myopic regression was more pronounced when the intended correction was over >6.0 D and in patients aged <30 years.Yet the intended corrections in our study were higher for LASIK than for PRK eyes. No differences were found in percentages of eyes with best corrected visual acuity (BCVA) or loss of two or more lines of visual acuity between PRK and LASIK in the long-term. The postoperative long-term outcomes of PRK with two different delivery systems broad beam and scanning laser were compared and revealed no differences. Postoperative outcomes of moderate-to-high astigmatism yielded better results in terms of UCVA and less compromise or loss of two more lines of BCVA after LASIK that after PRK.Similar stability for both procedures was revealed. Vector analysis showed that LASIK outcomes tended to be more accurate than PRK outcomes, yet no statistically differences were found. Irregular astigmatism secondary to recurrent corneal erosion due to map-dot-fingerprint was successfully treated with phototherapeutic keratectomy (PTK). Preoperative videokeratographies (VK) showed irregular astigmatism. However, postoperatively, all eyes showed a regular pattern. No correlation was found between pre- and postoperative VK patterns. Postoperative outcomes of late PRK in eyes originally subjected to LASIK showed that all (7/7) eyes achieved UCVA ≤0.5 at last follow-up (range 3 — 11 months), and no eye lost lines of BCVA. Postoperatively all eyes developed and initial mild haze (0.5 — 1) into the first month. Yet, at last follow-up 5/7 eyes showed a haze of 0.5 and this was no longer evident in 2/7 eyes. Based on these results, we demonstrated that the long-term outcomes after PRK and LASIK were safe and efficient, with similar stability for both procedures. The PRK outcomes were similar when treated by broad-beam or scanning slit laser. LASIK was better than PRK to correct moderate-to-high astigmatism, yet both procedures showed a tendency of undercorrection. Irregular astigmatism was proven to be able to depend exclusively from the corneal epithelium. If this kind of astigmatism is present in the cornea and a customized PRK/LASIK correction is done based on wavefront measurements an irregular astigmatism may be produced rather than treated. Corneal sensory nerve recovery should have an important role in the modulation of the corneal wound healing and post-operative anterior stromal scarring. PRK enhancement may be an option in eyes with previous LASIK after a sufficient time interval that in at least 2 years.

Examining effectiveness of an immigrant labor market integration intervention. The role of acculturation, discrimination, self-efficacy, outcome expectances, action and coping planning.

The designing of effective intervention tools to improve immigrants’ labor market integration remains an important topic in contemporary Western societies. This study examines whether and how a new intervention tool, Working Life Certificate (WLC), helps unemployed immigrants to find employment and strengthen their belief of their vocational skills. The study is based on quantitative longitudinal survey data from 174 unemployed immigrants of various origins who participated in the pilot phase of WLC examinations in 2009. Surveys were administered in three waves: before the test, right after it, and three months later. Although it is often argued that the unemployment among immigrants is due either to their lack of skills and cultural differences or to discrimination in recruitment, scholars within social psychology of behavior change argue that the best way of helping people to achieve their goals (e.g. finding employment) is to build up their sense of self-efficacy, alter their outcome expectances in a more positive direction or to help them to construct more detailed action and coping plans. This study aims to shed light on the role of these concepts in immigrants’ labor market integration. The results support the theories of behavior change moderately. Having positive expectances regarding the outcomes of various job search behaviors was found to predict employment in the future. Together with action and coping planning it also predicted increase in job search behavior. The intervention, WLC, was able to affect participants’ self-efficacy, but contrary to expectations, self-efficacy was found not to be related to either job search behavior or future labor market status. Also, perceived discrimination did not explain problems in finding employment, but hints of subtle or structural discrimination were found. Adoption of Finnish work culture together with strong family culture was found to predict future employment. Hence, in this thesis I argue that awarding people diplomas should be preferred in immigrant integration training as it strengthens people’s sense of self-efficacy. Instead of teaching new information, more attention should be directed at changing people’s outcome expectances in a more positive direction and helping them to construct detailed plans on how to achieve their goals.

Total risk rating and stability analysis of embankment dams in the Kachchh Region, Gujarat, India

A method for total risk analysis of embankment dams under earthquake conditions is discussed and applied to the selected embankment dams, i.e., Chang, Tapar, Rudramata, and Kaswati located in the Kachchh region of Gujarat, India, to obtain the seismic hazard rating of the dam site and the risk rating of the structures. Based on the results of the total risk analysis of the dams, coupled non-linear dynamic numerical analyses of the dam sections are performed using acceleration time history record of the Bhuj (India) earthquake as well as five other major earthquakes recorded worldwide. The objective of doing so is to perform the numerical analysis of the dams for the range of amplitude, frequency content and time duration of input motions. The deformations calculated from the numerical analyses are also compared with other approaches available in literature, viz, Makdisi and Seed (1978) approach, Jansen's approach (1990), Swaisgood's method (1995), Bureau's method (1997). Singh et al. approach (2007), and Saygili and Rathje approach (2008) and the results are utilized to foresee the stability of dams in future earthquake scenario. (C) 2010 Elsevier B.V. All rights reserved.

Macrophages in regressed and progressed uveal melanoma

Uveal melanoma (UM) is the most common primary ocular malignancy in adults. In Finland, approximately 50 new cases are diagnosed yearly. Up to 50% of UM metastasize, mostly to the liver, although other organs are also affected. Despite improvements in the management of the primary tumour, the survival rates of patients with metastatic UM are poor. Until the 1970s, UMs were treated by enucleation i.e. removal of the eye. Currently, UM is usually treated by brachytherapy, which is known to influence tumour cells and blood vessels. UMs enucleated both primarily and secondarily after brachytherapy contain tumour-infiltrating macrophages, and a high number of macrophages in primary UM is associated with a shorter survival and a higher microvascular density (MVD) within the tumour tissue. The latter is independently associated with a shorter time to metastatic death. Macrophages have several diverse roles depending on their response to variable signals from the surrounding microenvironment. They function as scavengers, as producers of angiogenic and growth factors as well as proteases, which modulate extracellular matrix. Thus, tumour invasiveness and the risk for metastasis increase with increasing macrophage density. The aim of this study was to evaluate the effects of regression and progression of UM on macrophage numbers and microcirculation factors. Tumour regression is induced by primary brachytherapy, and tumour progression is evidenced by the development of metastases. Understanding the biological behaviour of UMs in the both states may help us in finding new treatment modalities against this disease. To achieve these aims case-control analyses of irradiated UMs and primarily-enucleated eyes (34 matched pairs) were performed. UMs were stained immunohistochemically to detect macrophages, extravascular matrix (EVM) loops and networks, and MVD. Following brachytherapy, a lower MVD was observed. The average number of macrophages remained unchanged. Considering that irradiated melanomas may still contain proliferating tumour cells, a clinically-relevant consequence of my study would be the reassurance that the risk for metastasis is likely to be reduced, given that the low MVD in untreated UMs indicates a favourable prognosis. The effect of progression on macrophages was studied in a paired analysis of primarily-enucleated UM and their corresponding hepatic metastases (48 pairs). A cross-sectional histopathological analysis of these pairs was carried out by staining both specimens in a similar way to the first study. MVD was greater in hepatic metastases than in corresponding primary tumours, and the survival of the patient tended to be shorter if hepatic metastases had a higher MVD. Hepatic metastases had also more dendritic macrophages than the primary UMs. Thus, the progression to metastasis seems to alter the inflammatory status within the tumour. Furthermore, determining MVD of biopsied hepatic metastases may serve as a supplementary tool in estimating the prognosis of patients with metastatic uveal melanoma. After irradiation, the majority of treated eyes have been clinically observed to have pigmented episcleral deposits. A noncomparative clinical case series of 211 irradiated UM eyes were studied by recording the number and location of pigmented episcleral deposits during follow-up visits after brachytherapy. For the first time, the study described pigmented episcleral deposits, which are found in the most UM eyes after brachytherapy, and proved them to consist of macrophages full with engulfed melanin particles. This knowledge may save patients from unnecessary enucleation, because episcleral pigmented deposits might be mistaken for extrascleral tumour growth. The presence of pigmented macrophage-related episcleral deposits was associated with plaque size and isotope rather than with tumour size, suggesting that, in addition to tumour regression, radiation atrophy of retinal pigment epithelium and choroid contributes to the formation of the deposits. In the paired (the same 34 pairs as in the first study) cross-sectional study of irradiated and non-irradiated UMs, clinically-visible episcleral deposits and migrating macrophages in other extratumoral tissues were studied histopathologically. Resident macrophages were present in extratumoral tissues in eyes with both irradiated and non-irradiated UM. Irradiation increased both the number of CD68+ macrophages in the sclera beneath the tumour and the number of clinically-observed episcleral macrophages aggregates. Brachytherapy seemed to alter the route of migration of macrophages: after irradiation, macrophages migrated preferentially through the sclera while in non-irradiated UMs they seemed to migrate more along the choroid. In order to understand the influence of these routes on tumour progression and regression in the future, labelling and tracking of activated macrophages in vivo is required.

Myoblast Sheet Transplantation for Treatment of Heart Failure after Myocardial Infarction

Heart failure is a common, severe, and progressive condition associated with high mortality and morbidity. Because of population-aging in the coming decades, heart failure is estimated to reach epidemic proportions. Current medical and surgical treatments have reduced mortality, but the prognosis for patients has remained poor. Transplantation of skeletal myoblasts has raised hope of regenerating the failing heart and compensating for lost cardiac contractile tissue. In the present work, we studied epicardial transplantation of tissue-engineered myoblast sheets for treatment of heart failure. We employed a rat model of myocardial infarction-induced acute and chronic heart failure by left anterior descending coronary artery ligation. We then transplanted myoblast sheets genetically modified to resist cell death after transplantation by expressing antiapoptotic gene bcl2. In addition, we evaluated the regenerative capacity of myoblast sheets expressing the cardioprotective cytokine hepatocyte growth factor in a rat chronic heart failure model. Furthermore, we utilized in vitro cardiomyocyte and endothelial cell culture models as well as microarray gene expression analysis to elucidate molecular mechanisms mediating the therapeutic effects of myoblast sheet transplantation. Our results demonstrate that Bcl2-expression prolonged myoblast sheet survival in rat hearts after transplantation and induced secretion of cardioprotective, proangiogenic cytokines. After acute myocardial infarction, these sheets attenuated left ventricular dysfunction and myocardial damage, and they induced therapeutic angiogenesis. In the chronic heart failure model, inhibition of graft apoptosis by Bcl-2 improved cardiac function, supported survival of cardiomyocytes in the infarcted area, and induced angiogenesis in a vascular endothelial growth factor receptor 1- and 2-dependent mechanism. Hepatocyte growth factor-secreting myoblast sheets further enhanced the angiogenic efficacy of myoblast sheet therapy. Moreover, myoblast-secreted paracrine factors protected cardiomyocytes against oxidative stress in an epidermal growth factor receptor- and c-Met dependent manner. This protection was associated with induction of antioxidative genes and activation of the unfolded protein response. Our results provide evidence that inhibiting myoblast sheet apoptosis can enhance the sheets efficacy for treating heart failure after acute and chronic myocardial infarction. Furthermore, we show that myoblast sheets can serve as vehicles for delivery of growth factors, and induce therapeutic angiogenesis in the chronically ischemic heart. Finally, myoblasts induce, in a paracine manner, a cardiomyocyte-protective response against oxidative stress. Our study elucidates novel mechanisms of myoblast transplantation therapy, and suggests effective means to improve this therapy for the benefit of the heart failure patient.

A Study of The Fatigue, Impact and fracture-Toughness Characteristics of Electroslag Refined IS-7670 Alloy

The nuclear, aerospace, naval and missile industries place emphasis on materials with high structural integrity and reliable performance so as to meet certain stringent requirements in service. Strength is not the only criterion for selection. Properties such as fatigue resistance. impact toughness and fracture toughness are equally important. Electroslag refining (ESR) has been used widely and successfully over the years for improving the fatigue resistance, creep resistance, impact strength and fracture toughness of steels and alloy steels. But application of ESR to aluminium alloys is only a recent endeavour. A high-strength aircraft aluminium alloy IS: 7670 was therefore chosen for studies on the fatigue strength and the impact and fracture toughness. The results indicate that the fatigue resistance is considerably improved after refining and that the impact strength and fracture toughness of the refined alloy are comparable with that of the unrefined alloy.

Long-Term Excess Mortality after Aneurysmal Subarachnoid Hemorrhage

Objective There is high case-fatality rate and loss of productive life-years related to aneurysmal subarachnoid hemorrhage (aSAH) but little data on long-term survival of SAH patients. We aim to evaluate long-term excess mortality and related risk factors after aSAH. Methods One year survivors (n=3080) after aSAH from Department of Neurosurgery in Helsinki between 1980 and 2007 were reviewed for this retrospective follow-up study. Follow-up started one year after SAH and continued until death or the end of 2008 (36 960 patient-years). Mortality and relative survival ratio (RSR) were compared with matched general population. Results After 20 years, survivors of aSAH showed 18% excess mortality compared to general population. Risk factors included: old age; poor preoperative clinical condition; conservative aneurysm treatment; multiple aneurysms; and unfavourable clinical outcome at 3 months. Conclusion Even after initially favourable recovery, patients with aSAH experience excess mortality in the long run. Cardiovascular and cerebrovascular diseases are prominent in this population.

Hemiorchidectomy leads to dramatic and immediate alterations in pituitary follicle-stimulating hormone secretion and the functional activity of the remaining testis in the adult male bonnet monkey (Macaca radiata)

The aim of the present study was to examine the effect of hemiorchidectomy (HO) on serum FSH, LH, testosterone (T), and inhibin (INH) concentrations as well as on the testicular volume (TV) and on changes in the kinetics of germ cell turnovers in the remaining testis of adult male bonnet monkeys. Blood samples collected at 2200 h at various times before and after HO and testicular biopsies obtained at different periods were subjected to hormone analysis and DNA flow cytometry. Though serum T levels were lowered (p < 0.05) at 12 h after HO, T levels rapidly returned to intact control concentrations by Day 5. While serum LH remained unaltered, serum FSH increased markedly within 2 days of HO and remained significantly (p < 0.05) elevated over the next 90 days. Though serum INH showed a significant decrease (p < 0.05) by 15 min of HO, it returned to approximately 80% of intact levels within one week. The TV of the remaining testis showed maximal increment by Day 30 (p < 0.05) of HO. DNA flow cytometric analysis 24 days after HO showed increases (p < 0.05) in spermatogonia (2C) and primary spermatocytes (4C). These cell types by Day 45 had transformed to round (1C) and elongate (HC) (by 38%, p < 0.001) spermatids. Overall spermatogenesis (conversion of 2C to 1C and HC) showed significant enhancement at Days 110 and 175, suggesting that the spurt in spermatogenic activity is not confined to a single spermatogenic cycle.

Phase relations and thermodynamic properties of condensed phases in the system calcium-copper-oxygen

The isothermal sections of the phase diagram for the system Ca-Cu-0 at 1073 and 1223 K have been determined. Several compositions in the ternary system were quenched after equilibration, and the phases present were identified by optical microscopy, X-ray diffraction, and electron probe microanalysis. Two ternary compounds Ca2CuO3 and Cao.8&uO1.9s were identified at 1073 K. However, only Ca2CuO3 was found to be stable at 1223 K. The thermodynamic properties of the two ternary compounds were determined using solid-state cells incorporating either an oxide or a fluoride solid electrolyte. The results for both types of cells were internally consistent. The compound C ~ O . ~ & U Ow~h.i~ch~ c, a n also be represented as Ca15Cu18035h, as been identified in an earlier investigation as Cao.828CuOz. Using a novel variation of the galvanic cell technique, in which the emf of a cell incorporating a fluoride electrolyte is measured as a function of the oxygen potential of the gas phase in equilibrium with the condensed phase electrodes, it has been confirmed that the compound Cao.828CuO1.93 (Ca15Cu18035d) oes not have significant oxygen nonstoichiometry. Phase relations have been deduced from the thermodynamic data as a function of the partial pressure of oxygen for the system Ca-Cu-0 at 873, 1073, and 1223 K.

Continuous Recording of Retardation and Intensity of Echoes from the Ionosphere

Pulse retardation method of Breit and Tuve has been modified to record continuously the equivalent height as well as the intensity of reflections from the ionosphere. Synchronized pulses are transmitted, and the received ground pulse and the reflected pulses, after amplification and suitable distortion, are applied to the focusing cylinder of a cathode ray tube the horizontal deflecting plates of which are connected to a synchronized linear time base circuit. The pattern on the screen is composed of a bright straight line corresponding to the time base with dark gaps corresponding to the received pulses. The distance between the initial points of the gaps represents retardation while the widths of the gaps correspond to the intensity of the pulses. The pattern is photographed on a vertically moving film. One of the first few records taken at Bangalore on 4 megacycles is reproduced. It shows, among other things, that the less retarded component of magneto-ionic splitting from the F layer is present most of the time. Whenever the longer retardation component does occur, it has stronger intensity than the former. Towards the late evening hours, just before disappearing, when the F layer rises and exhibits magnetoionic splitting, the intensity of the less retarded component is extremely low compared with the other component.

Crystal Structures and Physicochemical Properties of Four New Lamotrigine Multicomponent Forms

In the present study, four new multicomponent forms of lamotrigine (LTG) with selected carboxylic acids, viz. acetic acid, propionic acid, sorbic acid, and glutaric acid, have been identified. Preliminary solid-state characterization was done by differential scanning calorimetry/thermogravimetric, infrared, and powder X-ray diffraction techniques. X-ray single-crystal structure analysis confirmed the proton transfer, stoichiometry, and the molecular composition, revealing all of these to be a new salt/salt-cocrystal/salt monosolvate monohydrate of LTG. All four compounds exhibited both the aminopyridine dimer of LTG (motif 4) and cation-anion dimers between protonated LTG and the carboxylate anion in their crystal structures. Further, these new crystal forms were subjected to solubility studies in water, powder dissolution studies in 0.1 N HCl, and stability studies under humid conditions in comparison with pure LTG base. The solubility of these compounds in water is significantly enhanced compared with that of pure base, which is attributed to the type of packing motifs present in their crystal structures as well as to the lowering of the pH by the acidic coformers. Solid residues of all forms remaining after solubility and dissolution experiments were also assessed for any transformation in water and acidic medium.

Morals in business organizations: an approach based on strategic value and strength for business management

[EN] In the last decades, the topic of business ethics has attracted great interest at the academic and professional levels. Nowadays business ethics is being increasingly implemented as a necessary discipline in universities’ study plans on business management. Moreover, its importance is also evident according to the worldwide increase of organizations and/or institutions that have implemented ethics systems. However, some approaches thoroughly do not consider the importance and the need of an ethical behaviour and are still guiding the actions and the way of thinking of many academics and professionals led to consider that the only responsibility of business is limited just to profit maximization.

Moral cleansing and moral licenses: experimental evidence

Research on moral cleansing and moral self-licensing has introduced dynamic considerations in the theory of moral behavior. Past bad actions trigger negative feelings that make people more likely to engage in future moral behavior to offset them. Symmetrically, past good deeds favor a positive self-perception that creates licensing effects, leading people to engage in behavior that is less likely to be moral. In short, a deviation from a “normal state of being” is balanced with a subsequent action that compensates the prior behavior. We model the decision of an individual trying to reach the optimal level of moral self-worth over time and show that under certain conditions the optimal sequence of actions follows a regular pattern which combines good and bad actions. We conduct an economic experiment where subjects play a sequence of giving decisions (dictator games) to explore this phenomenon. We find that donation in the previous period affects present decisions and the sign is negative: participants’ behavior in every round is negatively correlated to what they did in the past. Hence donations over time seem to be the result of a regular pattern of self-regulation: moral licensing (being selfish after altruist) and cleansing (altruistic after selfish).

Efficacy and Residue Comparisons between Two Slow-release Formulations of Fluridone

Residue profiles and efficacy of Avast and Sonar, two slow release pellet formulations of fluridone {1-methyl-3-phenyl-5- [3-(trifluoromethyl)phenly]-4(1H)-pyridinone}, were compared in outdoor tanks. Hydrilla (Hydrilla verticillata (L.f.) Royle) and southern naiad (Najas guadalupensis (Sprengel) Magnus) were treated with a split application of 6, 12, 18 and 24 μg/l a.i. fluridone and the concentrations of both formulations compared over a 134-day period. Both pellet formulations exhibited very similar residues over time for each respective treatment, resulted in peak concentrations of fluridone 40 to 50 days after application, and effectively and similarly controlled southern naiad and hydrilla at all rates tested by 92 days after initial application. (PDF contains 3 pages.)