Combinative effects of β-Lapachone and APO866 on pancreatic cancer cell death through reactive oxygen species production and PARP-1 activation.

UNLABELLED: Pancreatic cancer (PC) is one of the most lethal human malignancies and a major health problem. Patients diagnosed with PC and treated with conventional approaches have an overall 5-year survival rate of less than 5%. Novel strategies are needed to treat this disease. Herein, we propose a combinatorial strategy that targets two unrelated metabolic enzymes overexpressed in PC cells: NAD(P)H: quinone oxidoreductase-1 (NQO1) and nicotinamide phosphoribosyl transferase (NAMPT) using β-lapachone (BL) and APO866, respectively. We show that BL tremendously enhances the antitumor activity of APO866 on various PC cell lines without affecting normal cells, in a PARP-1 dependent manner. The chemopotentiation of APO866 with BL was characterized by the following: (i) nicotinamide adenine dinucleotide (NAD) depletion; (ii) catalase (CAT) degradation; (iii) excessive H2O2 production; (iv) dramatic drop of mitochondrial membrane potential (MMP); and finally (v) autophagic-associated cell death. H2O2 production, loss of MMP and cell death (but not NAD depletion) were abrogated by exogenous supplementation with CAT or pharmacological or genetic inhibition of PARP-1. Our data demonstrates that the combination of a non-lethal dose of BL and low dose of APO866 optimizes significantly cell death on various PC lines over both compounds given separately and open new and promising combination in PC therapy.

Development, physical-chemical stability and release studies of four alcohol-free spironolactone suspensions for use in pediatrics

Dissolution studies have become of great significance because, in most cases, drug dissolution is the rate-limiting step in the absorption process. As occurs with solid oral dosage forms, heterogeneous disperse systems (suspensions) could also have some problems with their in vitro dissolution. The objective of this study was to evaluate influence of the excipients on the release of spironolactone from four alcohol free suspensions (pharmaceutical compounding) of spironolactone 5 mg/mL suitable for pediatric use. Also the comparison of the physical and chemical stability of the suspensions stored at 4, 25 and 40 ºC over a 60- day period has been studied. Rheological behavior, particle size, a prediction of long-term physical stability, pH and assay of spironolactone by HPLC were assessed at prefixed times. The dissolution profile of each suspension was determined and compared with that of the commercial tablets. A microbiological study of the best formula was also performed. Chemically, the four spironolactone suspensions were stable for 60 days stored at three temperatures; Suspension IV had optimum pH values and the highest recovery percentage. In terms of physical stability, sedimentation occurred in Suspension IV and flotation of spironolactone in Suspensions I, II and III. Suspension III had the highest viscosity and the slowest drug release. Suspension IV was also microbiologically stable for 60 days. In conclusion, Suspension IV had the best properties and the least suitable form was Suspension III, as its high viscosity made it difficult to achieve homogeneous redispersion, and it had the slowest dissolution profile.

Expertise and decision making among clinicians in investigations of alleged child sexual abuse

The purpose of the present thesis was to explore different aspects of decision making and expertise in investigations of child sexual abuse (CSA) and subsequently shed some light on the reasons for shortcomings in the investigation processes. Clinicians’ subjective attitudes as well as scientifically based knowledge concerning CSA, CSA investigation and interviewing were explored. Furthermore the clinicians’ own view on their expertise and what enhances this expertise was investigated. Also, the effects of scientific knowledge, experience and attitudes on the decision making in a case of CSA were explored. Finally, the effects of different kinds of feedback as well as experience on the ability to evaluate CSA in the light of children’s behavior and base rates were investigated. Both explorative and experimental methods were used. The purpose of Study I was to investigate whether clinicians investigating child sexual abuse (CSA) rely more on scientific knowledge or on clinical experience when evaluating their own expertise. Another goal was to check what kind of beliefs the clinicians held. The connections between these different factors were investigated. A questionnaire covering items concerning demographic data, experience, knowledge about CSA, selfevaluated expertise and beliefs about CSA was given to social workers, child psychiatrists and psychologists working with children. The results showed that the clinicians relied more on their clinical experience than on scientific knowledge when evaluating their expertise as investigators of CSA. Furthermore, social workers possessed stronger attitudes in favor of children than the other groups, while child psychiatrists had more negative attitudes towards the criminal justice system. Male participants held less strong beliefs than female participants. The findings indicate that the education of CSA investigators should focus more on theoretical knowledge and decision making processes as well as the role of beliefs In Study II school and family counseling psychologists completed a Child Sexual Abuse Attitude and Belief Scale. Four CSA related attitude and belief subscales were identified: 1. The Disclosure subscale reflecting favoring a disclosure at any cost, 2. The Pro-Child subscale reflecting unconditional belief in children's reports, 3. The Intuition subscale reflecting favoring an intuitive approach to CSA investigations, and 4. The Anti Criminal Justice System subscale reflecting negative attitudes towards the legal system. Beliefs that were erroneous according to empirical research were analyzed separately. The results suggest that some psychologists hold extreme attitudes and many erroneous beliefs related to CSA. Some misconceptions are common. Female participants tended to hold stronger attitudes than male participants. The more training in interviewing children the participants have, the more erroneous beliefs and stronger attitudes they hold. Experience did not affect attitudes and beliefs. In Study III mental health professionals’ sensitivity to suggestive interviewing in CSA cases was explored. Furthermore, the effects of attitudes and beliefs related to CSA and experience with CSA investigations on the sensitivity to suggestive influences in the interview were investigated. Also, the effect of base rate estimates of CSA on decisions was examined. A questionnaire covering items concerning demographic data, different aspects of clinical experience, self-evaluated expertise, beliefs and knowledge about CSA and a set of ambiguous material based on real trial documents concerning an alleged CSA case was given to child mental health professionals. The experiment was based on a 2 x 2 x 2 x 2 (leading questions: yes vs no) x (stereotype induction: yes vs no) x (emotional tone: pressure to respond vs no pressure to respond) x (threats and rewards: yes vs no) between-subjects factorial design, in which the suggestiveness of the methods with which the responses of the child were obtained were varied. There was an additional condition in which the material did not contain any interview transcripts. The results showed that clinicians are sensitive only to the presence of leading questions but not to the presence of other suggestive techniques. Furthermore, the clinicians were not sensitive to the possibility that suggestive techniques could have been used when no interview transcripts had been included in the trial material. Experience had an effect on the sensitivity of the clinicians only regarding leading questions. Strong beliefs related to CSA lessened the sensitivity to leading questions. Those showing strong beliefs on the belief scales used in this study were even more prone to prosecute than other participants when other suggestive influences than leading questions were present. Controversy exists regarding effects of experience and feedback on clinical decision making. In Study IV the impact of the number of handled cases and of feedback on the decisions in cases of alleged CSA was investigated. One-hundred vignettes describing cases of suspected CSA were given to students with no experience with investigating CSA. The vignettes were based on statistical data about symptoms and prevalence of CSA. According to the theoretical likelihood of CSA the children described were categorized as abused or not abused. The participants were asked to decide whether abuse had occurred. They were divided into 4 groups: one received feedback on whether their decision was right or wrong, one received information about cognitive processes involved in decision making, one received both, and one did not receive feedback at all. The results showed that participants who received feedback on their performance made more correct positive decisions and participants who got information about decision making processes made more correct negative decisions. Feedback and information combined decreased the number of correct positive decisions but increased the number of correct negative decisions. The number of read cases had in itself a positive effect on correct positive decision.

Evolution and Stellar Content of AGN Host Galaxies

In this dissertation, Active Galactic Nuclei (AGN) and their host galaxies are discussed. Together with transitional events, such as supernovae and gamma-ray bursts, AGN are the most energetic phenomena in the Universe. The dominant fraction of their luminosity originates from the center of a galaxy, where accreting gas falls into a supermassive black hole, converting gravitational energy to radiation. AGN have a wide range of observed properties: e.g. in their emission lines, radio emission, and variability. Most likely, these properties depend significantly on their orientation to our line-of-sight, and to unify AGN into physical classes it is crucial to observe their orientation-independent properties, such as the host galaxies. Furthermore, host galaxy studies are essential to understand the formation and co-evolution of galactic bulges and supermassive black holes. In this thesis, the main focus is on observationally characterizing AGN host galaxies using optical and near-infrared imaging and spectroscopy. BL Lac objects are a class of AGN characterized by rapidly variable and polarized continuum emission across the electromagnetic spectrum, and coredominated radio emission. The near-infrared properties of intermediate redshift BL Lac host galaxies are studied in Paper I. They are found to be large elliptical galaxies that are more luminous than their low redshift counterparts suggesting a strong luminosity evolution, and a contribution from a recent star formation episode. To analyze the stellar content of galaxies in more detail multicolor data, especially observations at blue wavelengths, are essential. In Paper III, optical - near-infrared colors and color gradients are derived for low redshift BL Lac host galaxies. They show bluer colors and steeper color gradients than inactive ellipticals which, most likely, are caused by a relatively young stellar population indicating a different evolutionary stage between AGN hosts and inactive ellipticals. In Paper II, near-infrared imaging of intermediate redshift radio-quiet quasar hosts is used to study their luminosity evolution. The hosts are large elliptical galaxies, but they are systematically fainter than the hosts of radio-loud quasars at similar redshifts, suggesting a link between the luminosity of the host galaxies and the radio properties of AGN. In Paper IV, the characteristics of near-infrared stellar absorption features of low redshift radio galaxies are compared with those of inactive early-type galaxies. The comparison suggests that early-type galaxies with AGN are in a different evolutionary stage than their inactive counterparts. Moreover, radio galaxies are found to contain stellar populations containing both old and intermediate age components.

Balancing effluent quality, economic cost and greenhouse gas emissions during the evaluation of (plant-wide) control/operational strategies in WWTPs

The objective of this paper was to show the potential additional insight that result from adding greenhouse gas (GHG) emissions to plant performance evaluation criteria, such as effluent quality (EQI) and operational cost (OCI) indices, when evaluating (plant-wide) control/operational strategies in wastewater treatment plants (WWTPs). The proposed GHG evaluation is based on a set of comprehensive dynamic models that estimate the most significant potential on-site and off-site sources of CO2, CH4 and N2O. The study calculates and discusses the changes in EQI, OCI and the emission of GHGs as a consequence of varying the following four process variables: (i) the set point of aeration control in the activated sludge section; (ii) the removal efficiency of total suspended solids (TSS) in the primary clarifier; (iii) the temperature in the anaerobic digester; and (iv) the control of the flow of anaerobic digester supernatants coming from sludge treatment. Based upon the assumptions built into the model structures, simulation results highlight the potential undesirable effects of increased GHG production when carrying out local energy optimization of the aeration system in the activated sludge section and energy recovery from the AD. Although off-site CO2 emissions may decrease, the effect is counterbalanced by increased N2O emissions, especially since N2O has a 300-fold stronger greenhouse effect than CO2. The reported results emphasize the importance and usefulness of using multiple evaluation criteria to compare and evaluate (plant-wide) control strategies in a WWTP for more informed operational decision making

Conservation Genetics of Exploited Finnish Salmonid Fishes

Genetic diversity is one of the levels of biodiversity that the World Conservation Union (IUCN) has recognized as being important to preserve. This is because genetic diversity is fundamental to the future evolution and to the adaptive flexibility of a species to respond to the inherently dynamic nature of the natural world. Therefore, the key to maintaining biodiversity and healthy ecosystems is to identify, monitor and maintain locally-adapted populations, along with their unique gene pools, upon which future adaptation depends. Thus, conservation genetics deals with the genetic factors that affect extinction risk and the genetic management regimes required to minimize the risk. The conservation of exploited species, such as salmonid fishes, is particularly challenging due to the conflicts between different interest groups. In this thesis, I conduct a series of conservation genetic studies on primarily Finnish populations of two salmonid fish species (European grayling, Thymallus thymallus, and lake-run brown trout, Salmo trutta) which are popular recreational game fishes in Finland. The general aim of these studies was to apply and develop population genetic approaches to assist conservation and sustainable harvest of these populations. The approaches applied included: i) the characterization of population genetic structure at national and local scales; ii) the identification of management units and the prioritization of populations for conservation based on evolutionary forces shaping indigenous gene pools; iii) the detection of population declines and the testing of the assumptions underlying these tests; and iv) the evaluation of the contribution of natural populations to a mixed stock fishery. Based on microsatellite analyses, clear genetic structuring of exploited Finnish grayling and brown trout populations was detected at both national and local scales. Finnish grayling were clustered into three genetically distinct groups, corresponding to northern, Baltic and south-eastern geographic areas of Finland. The genetic differentiation among and within population groups of grayling ranged from moderate to high levels. Such strong genetic structuring combined with low genetic diversity strongly indicates that genetic drift plays a major role in the evolution of grayling populations. Further analyses of European grayling covering the majority of the species’ distribution range indicated a strong global footprint of population decline. Using a coalescent approach the beginning of population reduction was dated back to 1 000-10 000 years ago (ca. 200-2 000 generations). Forward simulations demonstrated that the bottleneck footprints measured using the M ratio can persist within small populations much longer than previously anticipated in the face of low levels of gene flow. In contrast to the M ratio, two alternative methods for genetic bottleneck detection identified recent bottlenecks in six grayling populations that warrant future monitoring. Consistent with the predominant role of random genetic drift, the effective population size (N_e) estimates of all grayling populations were very low with the majority of N_e estimates below 50. Taken together, highly structured local populations, limited gene flow and the small N_e of grayling populations indicates that grayling populations are vulnerable to overexploitation and, hence, monitoring and careful management using the precautionary principles is required not only in Finland but throughout Europe. Population genetic analyses of lake-run brown trout populations in the Inari basin (northernmost Finland) revealed hierarchical population structure where individual populations were clustered into three population groups largely corresponding to different geographic regions of the basin. Similar to my earlier work with European grayling, the genetic differentiation among and within population groups of lake-run brown trout was relatively high. Such strong differentiation indicated that the power to determine the relative contribution of populations in mixed fisheries should be relatively high. Consistent with these expectations, high accuracy and precision in mixed stock analysis (MSA) simulations were observed. Application of MSA to indigenous fish caught in the Inari basin identified altogether twelve populations that contributed significantly to mixed stock fisheries with the Ivalojoki river system being the major contributor (70%) to the total catch. When the contribution of wild trout populations to the fisheries was evaluated regionally, geographically nearby populations were the main contributors to the local catches. MSA also revealed a clear separation between the lower and upper reaches of Ivalojoki river system – in contrast to lower reaches of the Ivalojoki river that contributed considerably to the catch, populations from the upper reaches of the Ivalojoki river system (>140 km from the river mouth) did not contribute significantly to the fishery. This could be related to the available habitat size but also associated with a resident type life history and increased cost of migration. The studies in my thesis highlight the importance of dense sampling and wide population coverage at the scale being studied and also demonstrate the importance of critical evaluation of the underlying assumptions of the population genetic models and methods used. These results have important implications for conservation and sustainable fisheries management of Finnish populations of European grayling and brown trout in the Inari basin.

The introduction of Mormonism to Finnish society, 1840-1900

This study examines the place of The Church of Jesus Christ of Latter-day Saints (commonly known as the Mormon church) in the Russian Grand Duchy of Finland between the years 1840 and 1900. Attention is put on both the internal workings of the movement and the reactions of society. Theoretical insight is gained through the concepts of social construction and religious economies. Mormon image formation in Finland began by 1840 through newspaper reports on activities abroad and through essays on the faith’s history and doctrine. Mormons are mentioned almost 3,500 times in Finnish newspapers between 1840 and 1900, and at least twelve unique book titles sold in the country were explicitly devoted to discussing Mormonism. Most of the publicity was derived from foreign sources. Discourse analysis of this textual corpus shows a hegemonic discourse that combined themes such as fraud, deception, and theocracy in explaining the Mormon movement. Accompanied by plural marriage, these themes contributed to the construction of a strongly negative image of Mormonism already before the first missionaries arrived in 1875. In a society with a stringently regulated religious economy, this image contributed to a high level of resistance by civil authorities and Lutheran clergy. Twenty-five Mormon missionaries worked in Finland between 1875 and 1900, with a concentrated effort taking place between 1875 and 1889. At least 78 persons converted, mostly in the coastal areas among the Swedish-speaking minority population. Nine percent emigrated to Utah, 36% were excommunicated, others fell into oblivion, while still others clung to their new faith. The work was led from Sweden, with no stable church organization emerging among the isolated pockets of converts. Mormonism’s presence was thus characterized by private or small-group religiosity rather than a vibrant movement. The lack of religious community, conversation, and secondary socialization eventually caused the nineteenth-century manifestation of Finnish Mormonism to die out. Only one group of converts was perpetuated past World War II, after which large-scale proselytizing began.

Multifrequency VLBI Observations of Selected Active Galactic Nuclei

In this dissertation, active galactic nuclei (AGN) are discussed, as they are seen with the high-resolution radio-astronomical technique called Very Long Baseline Interferometry (VLBI). This observational technique provides very high angular resolution (_ 10−300 = 1 milliarcsecond). VLBI observations, performed at different radio frequencies (multi-frequency VLBI), allow to penetrate deep into the core of an AGN to reveal an otherwise obscured inner part of the jet and the vicinity of the AGN’s central engine. Multi-frequency VLBI data are used to scrutinize the structure and evolution of the jet, as well as the distribution of the polarized emission. These data can help to derive the properties of the plasma and the magnetic field, and to provide constraints to the jet composition and the parameters of emission mechanisms. Also VLBI data can be used for testing the possible physical processes in the jet by comparing observational results with results of numerical simulations. The work presented in this thesis contributes to different aspects of AGN physics studies, as well as to the methodology of VLBI data reduction. In particular, Paper I reports evidence of optical and radio emission of AGN coming from the same region in the inner jet. This result was obtained via simultaneous observations of linear polarization in the optical and in radio using VLBI technique of a sample of AGN. Papers II and III describe, in detail, the jet kinematics of the blazar 0716+714, based on multi-frequency data, and reveal a peculiar kinematic pattern: plasma in the inner jet appears to move substantially faster that that in the large-scale jet. This peculiarity is explained by the jet bending, in Paper III. Also, Paper III presents a test of the new imaging technique for VLBI data, the Generalized Maximum Entropy Method (GMEM), with the observed (not simulated) data and compares its results with the conventional imaging. Papers IV and V report the results of observations of the circularly polarized (CP) emission in AGN at small spatial scales. In particular, Paper IV presents values of the core CP for 41 AGN at 15, 22 and 43 GHz, obtained with the help of the standard Gain transfer (GT) method, which was previously developed by D. Homan and J.Wardle for the calibration of multi-source VLBI observations. This method was developed for long multi-source observations, when many AGN are observed in a single VLBI run. In contrast, in Paper V, an attempt is made to apply the GT method to single-source VLBI observations. In such observations, the object list would include only a few sources: a target source and two or three calibrators, and it lasts much shorter than the multi-source experiment. For the CP calibration of a single-source observation, it is necessary to have a source with zero or known CP as one of the calibrators. If the archival observations included such a source to the list of calibrators, the GT could also be used for the archival data, increasing a list of known AGN with the CP at small spatial scale. Paper V contains also calculation of contributions of different sourced of errors to the uncertainty of the final result, and presents the first results for the blazar 0716+714.

Cognitive Development of Very Low Birth Weight Children from Infancy to Pre-school Age

The survival of preterm born infants has increased but the prevalence of long-term morbidities has still remained high. Preterm born children are at an increased risk for various developmental impairments including both severe neurological deficits as well as deficits in cognitive development. According to the literature the developmental outcome perspective differs between countries, centers, and eras. Definitions of preterm infant vary between studies, and the follow-up has been carried out with diverse methods making the comparison less reliable. It is essential to offer parents upto-date information about the outcome of preterm infants born in the same area. A centralized follow-up of children at risk makes it possible to monitor the consequences of changes in the treatment practices of hospitals on developmental outcome. This thesis is part of a larger regional, prospective multidisciplinary follow-up project entitled “Development and Functioning of Very Low Birth Weight Infants from Infancy to School Age” (PIeniPAinoisten RIskilasten käyttäytyminen ja toimintakyky imeväisiästä kouluikään, PIPARI). The thesis consists of four original studies that present data of very low birth weight (VLBW) infants born between 2001 and 2006, who are followed up from the neonatal period until the age of five years. The main outcome measure was cognitive development and secondary outcomes were significant neurological deficits (cerebral palsy, CP, deafness, and blindness). In Study I, the early crying and fussing behavior of preterm infants was studied using parental diaries, and the relation of crying behavior and cognitive and motor development at the age of two years was assessed. In Study II, the developmental outcome (cognitive, CP, deafness, and blindness) at the age of two years was studied in relation to demographic, antenatal, neonatal, and brain imaging data. Development was studied in relationship to a full-term born control group born in the same hospital. In Study III, the stability of cognitive development was studied in VLBW and full-term groups by comparing the outcomes at the ages of two and five years. Finally, in Study IV the precursors of reading skills (phonological processing, rapid automatized naming, and letter knowledge) were assessed for VLBW and full-term children at the age of five years. Pre-reading skills were studied in relation to demographic, antenatal, neonatal, and brain imaging data. The main findings of the thesis were that VLBW infants who fussed or cried more in the infancy were not at greater risk for problems in their cognitive development. However, crying was associated with poorer motor development. The developmental outcome of the present population was better that has been reported earlier and this improvement covered also cognitive development. However, the difference to fullterm born peers was still significant. Major brain pathology and intestinal perforation were independent significant risk factors for adverse outcome, also when several individual risk factors were controlled for. Cognitive development at the age of two years was strongly related with development at the age of five years, stressing the importance of the early assessment, and the possibility for early interventions. Finally, VLBW children had poorer pre-reading skills compared with their full-term born peers, but the IQ was an important mediator even when children with mental retardation were excluded from the analysis. The findings suggest that counseling parents about the developmental perspectives of their preterm infant should be based on data covering the same birth hospital. Neonatal brain imaging data and neonatal morbidity are important predictors for developmental outcome. The findings of the present study stress the importance of both short-term (two years) and long-term (five years) follow-ups for the individual, and for improving the quality of care.

Effect of toxin-g from Tityus serrulatus scorpion venom on gastric emptying in rats

The effect of toxin-g from Tityus serrulatus scorpion venom on the gastric emptying of liquids was studied in 176 young adult male Wistar rats (2-3 months of age) divided into subgroups of 8 animals each. Toxin-g was injected iv at doses of 25, 37.5, 50 or 100 µg/kg and the effect on gastric emptying was assessed 30 min and 8 h later. A time-course study was also performed by injecting 50 µg of toxin-g /kg and measuring the effect on gastric emptying at times 0.25, 0.5, 1, 2, 4, 8, 24 and 48 h post-venom. Each envenomed animal was paired with its saline control and all received a saline test meal solution containing phenol red (60 µg/ml) as a marker. Ten minutes after administering the test meal by gavage the animals were sacrificed and gastric retention was determined by measuring the residual marker concentration of the test meal. A significant delay in gastric emptying, at 30 min and 8 h post-venom, was observed only after 50 and 100 µg of toxin-g /kg compared to control values. The responses to these two doses were significantly different after 8 h post-venom. Toxin-g (50 µg/kg) significantly delayed the gastric emptying of liquids at all times studied, with a peak response at 4 h after toxin administration compared to control values. These results indicate that the iv injection of toxin-g may induce a rapid, intense and sustained inhibition of gastric emptying 0.25 to 48 h after envenomation.

Evaluation by blue native polyacrylamide electrophoresis colorimetric staining of the effects of physical exercise on the activities of mitochondrial complexes in rat muscle

Blue native polyacrylamide electrophoresis (BN-PAGE) is a technique developed for the analysis of membrane complexes. Combined with histochemical staining, it permits the analysis and quantification of the activities of mitochondrial oxidative phosphorylation enzymes using whole muscle homogenates, without the need to isolate muscle mitochondria. Mitochondrial complex activities were measured by emerging gels in a solution containing all specific substrates for NADH dehydrogenase and cytochrome c oxidase enzymes (complexes I and IV, respectively) and the colored bands obtained were measured by optique densitometry. The objective of the present study was the application of BN-PAGE colorimetric staining for enzymatic characterization of mitochondrial complexes I and IV in rat muscles with different morphological and biochemical properties. We also investigated these activities at different times after acute exercise of rat soleus muscle. Although having fewer mitochondria than oxidative muscles, white gastrocnemius muscle presented a significantly higher activity (26.7 ± 9.5) in terms of complex I/V ratio compared to the red gastrocnemius (3.8 ± 0.65, P < 0.05) and soleus (9.8 ± 0.9, P < 0.001) muscles. Furthermore, the complex IV/V ratio of white gastrocnemius muscle was always significantly higher when compared to the other muscles. Ninety-five minutes of exhaustive physical exercise induced a decrease in complex I/V and complex IV/V ratios after all resting times (0, 3 and 6 h) compared to control (P < 0.05), probably reflecting the oxidative damage due to increasing free radical production in mitochondria. These results demonstrate the possible and useful application of BN-PAGE-histochemical staining to physical exercise studies.

A new map of Denmark, Norway, Sweden, & Moscovy shewing their present general divisions, cheif, [!] cities or towns, rivers, mountains, &c.

[N. 1:8500000].

An improved strategy for evaluating the extent of chronic arterial baroreceptor denervation in conscious rats

There is no index or criterion of aortic barodenervation, nor can we differentiate among rats that have suffered chronic sham, aortic or sino-aortic denervation. The objective of this study was to develop a procedure to generate at least one quantitative, reproducible and validated index that precisely evaluates the extent of chronic arterial barodenervation performed in conscious rats. Data from 79 conscious male Wistar rats of about 65-70 days of age with diverse extents of chronic arterial barodenervation and used in previous experiments were reanalyzed. The mean arterial pressure (MAP) and the heart rate (HR) of all rats were measured systematically before (over 1 h) and after three consecutive iv bolus injections of phenylephrine (PHE) and sodium nitroprusside (SNP). Four expressions of the effectiveness of barodenervation (MAP lability, PHE ratio, SNP ratio, and SNP-PHE slope) were assessed with linear fixed models, three-level average variance, average separation among levels, outlier box plot analysis, and overlapping graphic analysis. The analysis indicated that a) neither MAP lability nor SNP-PHE slope was affected by the level of chronic sodium intake; b) even though the Box-Cox transformations of both MAP lability [transformed lability index (TLI)] and SNP-PHE slope [transformed general sensitivity index (TGSI), {((3-(ΔHRSNP-ΔHRPHE/ΔMAPSNP-ΔMAPPHE))-0.4-1)/-0.04597}] could be two promising indexes, TGSI proved to be the best index; c) TLI and TGSI were not freely interchangeable indexes for this purpose. TGSI ranges that permit differentiation between sham (10.09 to 11.46), aortic (8.40 to 9.94) and sino-aortic (7.68 to 8.24) barodenervated conscious rats were defined.

Future of Internet News Portals after the Case of Delfi

The thesis analyzes liability of Internet news portals for third-party defamatory comments. After the case of Delfi AS v. Estonia, decided by the Grand Chamber of the European Court of Human Rights on 16 June 2015, a portal can be held liable for user-generated unlawful comments. The thesis aims at exploring consequences of the case of Delfi for Internet news portals’ business model. The model is described as a mixture of two modes of information production: traditional industrial information economy and new networked information economy. Additionally, the model has a generative comment environment. I name this model “the Delfian model”. The thesis analyzes three possible strategies which portals will likely apply in the nearest future. I will discuss these strategies from two perspectives: first, how each strategy can affect the Delfian model and, second, how changes in the model can, in their turn, affect freedom of expression. The thesis is based on the analysis of case law, legal, and law and economics literature. I follow the law and technology approach in the vein of ideas developed by Lawrence Lessig, Yochai Benkler and Jonathan Zittrain. The Delfian model is researched as an example of a local battle between industrial and networked information economy modes. The thesis concludes that this local battle is lost because the Delfian model has to be replaced with a new walled-garden model. Such a change can seriously endanger freedom of expression.

NMR studies of the exchange reactions of CH3CN.BX3 with excess CH3CN /|nJoseph Fogelman. -- 260 St. Catharines, Ont. : [s. n.],

Exchange reactions between molecular complexes and excess acid or base are well known and have been extensively surveyed in the literature(l). Since the exchange mechanism will, in some way involve the breaking of the labile donor-acceptor bond, it follows that a discussion of the factors relating to bonding in molecular complexes will be relevant. In general, a strong Lewis base and a strong Lewis acid form a stable adduct provided that certain stereochemical requirements are met. A strong Lewis base has the following characteristics (1),(2) (i) high electron density at the donor site. (ii) a non-bonded electron pair which has a low ionization potential (iii) electron donating substituents at the donor atom site. (iv) facile approach of the site of the Lewis base to the acceptor site as dictated by the steric hindrance of the substituents. Examples of typical Lewis bases are ethers, nitriles, ketones, alcohols, amines and phosphines. For a strong Lewis acid, the following properties are important:( i) low electron density at the acceptor site. (ii) electron withdrawing substituents. (iii) substituents which do not interfere with the close approach of the Lewis base. (iv) availability of a vacant orbital capable of accepting the lone electron pair of the donor atom. Examples of Lewis acids are the group III and IV halides such (M=B, AI, Ga, In) and MX4 - (M=Si, Ge, Sn, Pb). The relative bond strengths of molecular complexes have been investigated by:- (i) (ii) (iii) (iv) (v] (vi) dipole moment measurements (3). shifts of the carbonyl peaks in the IIIR. (4) ,(5), (6) .. NMR chemical shift data (4),(7),(8),(9). D.V. and visible spectrophotometric shifts (10),(11). equilibrium constant data (12), (13). heats of dissociation and heats of reactions (l~), (16), (17), (18), (19). Many experiments have bben carried out on boron trihalides in order to determine their relative acid strengths. Using pyridine, nitrobenzene, acetonitrile and trimethylamine as reference Lewis bases, it was found that the acid strength varied in order:RBx3 > BC1 3 >BF 3 • For the acetonitrile-boron trihalide and trimethylamine boron trihalide complexes in nitrobenzene, an-NMR study (7) showed that the shift to lower field was. greatest for the BB~3 adduct ~n~ smallest for the BF 3 which is in agreement with the acid strengths. If electronegativities of the substituents were the only important effect, and since c~ Br ,one would expect the electron density at the boron nucleus to vary as BF3of back-bonding varies inversely as the bo~on halogen distance and one would therefore expect the B-F bond to exhibit greater back-bonding character than the B-Cl or B-Br bonds. Since back-bonding transfers electron density from substituent to the boron atom site, this process would be expected to weaken the Lewis acid strength. This explains the Lewis acid strength increasing in the order BF 3 BC1 3 BBr 3 . When the acetonitrile boron trihalide complex is formed, the boron atom undergoes ~_cbange of hybridization from sp2 to sp3. From a linear relationship between the heat of formation of ethyl acetate adducts and the shift in the carbonyl I.R. stretch, Drago (22) et al have proposed that the angular di~tortion of the X-B-X bonds from sp2 (12 ) to sp3 (10 hybridization is proportional to the amount of charge transferred, i.e. to the nature of the base, and they have rejected the earlier concept of reorganization energy in explaining the formation of the adduct bond (19).