Orientador: Maria Luiza Cotrim Sartor de Oliveira / Banca: Carlos Márcio Nóbrega de Jesus / Banca: Heidge Fukumasu / Não disponível / Abstract: Diuron [3-(3,4-dichlorophenyl)-1,1-dimethylurea] is a herbicide that in a previous longterm study with Wistar rats fed at 2,500 ppm concentration showed high incidence of urothelial tumors in both genders. Accordingly, USEPA categorized Diuron as a "known/likely" human carcinogen. The accepted non-genotoxic mode of action (MOA) of Diuron encompasses urothelial necrosis induced by direct cytotoxicity, followed by regenerative cell proliferation and sustained urothelial hyperplasia that may favor neoplasia development. Scanning electron microscopy (SEM), light microscopy and labeling index are essentials tools for identification and classification of cytotoxic and proliferative changes in the bladder. The present study evaluated the dose-response of Diuron regarding urothelial lesions. Sixty male Wistar rats were fed Diuron for 20 weeks mixed in the diet at 0, 60, 125, 500, 1,250, or 2,500 ppm. Simple hyperplasia was significantly increased in the Diuron 1,250 and 2,500 ppm groups, and the cell proliferation at 2,500 ppm group. By SEM, the incidences and severity of lesions were significantly greater in the 500 and 1,250 ppm. Although numerically increased, the incidence of lesions in the 2,500 ppm group did not differ significantly from the control. The present study documented a doseresponse influence of Diuron on the rat urothelium, with a no observed effect level (NOEL) of 125 ppm. / Mestre

Recentemente, tem sido constatadas falhas no controle da planta daninha capim-branco (Chloris polydactyla) pelo herbicida glyphosate em áreas de culturas anuais e perenes no Brasil. Suspeita-se que estas falhas sejam decorrentes da seleção de populações resistentes desta planta daninha ao glyphosate. No entanto, até o momento, poucos relatos estão disponíveis na literatura caracterizando estas falhas. Esta pesquisa teve como objetivo a caracterização dos níveis de suscetibilidade de populações que apresentaram falha de controle, assim como estudar seus mecanismos de resistência. Também foi objetivo do trabalho analisar comparativamente o crescimento das populações suscetíveis e as supostamente resistentes ao glyphosate e avaliar a eficácia de herbicidas considerados alternativos ao glyphosate. Na primeira etapa, foram estudadas 87 populações do capim-branco vinda de diferentes regiões do Brasil, das quais duas sobreviveram ao experimento designado \"screening\". Esses dois biótipos, 59 e 69, juntamente com outras 15 populações suscetíveis, foram submetidos a experimentos de dose-resposta para a caracterização de suas suscetibilidades e determinação da dose eficiente de controle, da qual foi calculada em 705,41 g e.a. ha-1 de glyphosate. Em seguida, os biótipos supostamente resistentes foram comparados a um biótipo suscetível (34) para o cálculo do fator de resistência, que variou entre 3,92 e 7,95, confirmando a resistência dos biótipos. Não foi possível inferir claramente que existem diferenças de crescimento entre os biótipos resistente e suscetível que implicaria em custo adaptativo do biótipo resistente. No entanto, fica evidente que nas fases iniciais de crescimento, o biótipo 34S foi ou superior ou estatisticamente igual ao biótipo 69R. Não foi possível estabelecer uma relação entre diferenças de suscetibilidade entre os biótipos, portanto, a resistência do biótipo 69R ao glyphosate não alterou sua suscetibilidade aos herbicidas alternativos ao glyphosate aqui estudados. Na pós-emergência, clethodim e fenoxaprop-P-ethyl foram eficientes para controlar os biótipos 34S e 69R, enquanto que em pré-emergência, todos os herbicidas testados foram eficientes. O biótipo 69R absorveu menor quantidade de 14glyphosate em relação ao biótipo 34S em todos os tratamentos, do qual foi estatisticamente inferior àqueles contendo 14glyphosate + surfactante não-iônico (0,25%), 14glyphosate + sulfato de amônio (3kg ha-1) e 14glyphosate isolado. O tratamento que proporcionou maior absorção para ambos os biótipos foi o 14glyphosate + surfactante não-iônico. O biótipo 69R teve absorção máxima (Amax) 17% inferior ao biótipo 34S e maior retenção de 14glyphosate na folha tratada. O acúmulo de ácido chiquímico no biótipo 34S foi 2,56 vezes maior que no biótipo 69R. Mutações no gene que codificam a EPSPs dos biótipos 34S e 69R não foram observadas. Por fim, baseando-se nos dados aqui obtidos, é possível afirmar que a absorção reduzida, bem como a maior retenção do 14glyphosate nas folhas do biótipo 69R, possuem papel importante na resistência desse biótipo ao glyphosate. / It has been recently observed failures in controlling Tall windmill grass (Chloris polydactyla) by glyphosate in agricultural areas in Brazil. It is suspected that these failures are due to selection of resistant biotypes to glyphosate. However, to date, few reports are available in the literature characterizing these failures. Therefore, this study aimed to characterize the levels of susceptibility of differents populations of Chloris polydactyla, and to study the possible mechanisms of resistance to glyphosate. It was also an objective of this study to build a comparative growth analysis between populations, as well as evaluating the effectiveness of alternatives herbicides to glyphosate. In the first step, 87 populations from different regions of Brazil were studied, of which two survived the experiment called \"screening\". These two biotypes, 59 and 69, along with 15 other susceptible populations were subjected to a dose- response experiment for the characterization and determination of their susceptibility to glyphosate and a baseline herbicide sensitivity was obteined, which was calculated in 705.41 g ae ha-1 of glyphosate. Then the supposedly resistant biotypes (59R and 69R) were compared to a susceptible population (34S) for calculate the resistance factor, which ranged from 3.92 to 7.95, confirming the resistance of the biotypes. It was impossible to infer accurately that there are differences in growth between the resistant and susceptible biotypes of Tall windmill grass, which would imply in fitness penalty for the resistant biotype. However, it is evident that in the early growth stages, in most of the variables analyzed, the 34S was biotype or higher or statistically equal to biotype 69R. It was not possible to establish a statistical difference in susceptibility among biotypes, therefore the resistance of 69R biotype to glyphosate did not alter its susceptibility to alternative herbicides. At post-emergence, clethodin and fenoxaprop-P-ethyl were efficient to control biotypes 34S and 69R. On the other hand, at pre-emergence, all herbicides were efficient to control both biotypes. The biotype 69R absorbed smaller amount of 14glyphosate relative to 34S biotype in all treatments, which was statistically inferior to those containing 14glyphosate + non-ionic surfactant (0.25%), 14glyphosate + ammonium sulfate (3 kg ha-1) and 14glyphosate alone. The treatment providing greater absorption for both biotypes was 14glyphosate + non-ionic surfactant. Biotype 69R absorbed 17% less than the biotype 34S and had higher treated leaf retention. The shikimic acid accumulation assay in the biotype 34S was 2.56 times higher than in biotype 69R. Mutations in the gene encoding EPSPs were not observed. Finally, based on data obtained here, it is clear that the reduced absorption and treated leaf retention of 14glyphosate in biotype 69R, have an important role in the resistance of this biotype to glyphosate.

<p>Silicon diodes compared to other types of dosimeters have several attractive properties, such as an excellent spatial resolution, a high sensitivity, and clinically practical to use. These properties make silicon diodes a preferred dosimeter for relative dosimetry for several types of measurements in small field dosimetry, e.g., stereotactic treatments and intensity modulated radiotherapy (IMRT). Silicon diodes are, however, limited by an energy dependent response variation in photon beams, resulting in that the diode readout per dose to the phantom medium varies with photon spectral changes, thereby introducing a significant uncertainty in the measured data. The traditional solution for the energy dependent over-response caused by low-energy photons is to use diodes with a shielding filter of high atomic number. These shielded diodes, however, show an incorrect readout for small fields due to electrons scattered from the shielding (Griessbach <em>et al</em>. 2005). In regions with degraded lateral electron equilibrium (LEE) shielded diodes over-respond due to an increased degree of LEE, as a consequence of the high density shielding (Lee <em>et al</em>. 2002).</p><p>In this work a prototype software that corrects for the energy dependent response of a silicon diode is developed and validated for small field sizes. The developed software is based on the novel concept of Monte Carlo (MC) simulated fluence pencil beam kernels to calculate spectra (Eklund and Ahnesjö 2008), and the spectra based silicon diode response model proposed by Eklund and Ahnesjö (2009). The software was also extended to include correction of ionization chambers, for the energy dependent Spencer-Attix water/air stopping power ratio (<em>s</em>_w,air). The calculated <em>s</em>_w,air are shown to be in excellent agreement with published values to better than 0.1% for most values, the maximum deviation being 0.3%.</p><p>Measured relative depth doses, relative profiles, and output factors in water, for small square field sizes, for 6 MV and 15 MV clinical photon beams are presented in this work. The results show that the unshielded Scanditronix-Wellhöfer EFD^3G silicon diode response, corrected by the developed software, is in excellent agreement with reference ionization chamber measurements (corrected for change in <em>s</em>_w,air), the maximum deviation being 0.4%.</p><p>Measurements with two types of shielded diodes, namely Scanditronix-Wellhöfer PFD silicon diodes (FP1990 and FP2730), are also included in this work. The shielded diodes are shown to have an over-response as large as 2-3.5% for field sizes smaller than 5 cm x 5 cm. The presented results also suggest a difference in accuracy as large as 0.5-1% between the two types of shielded diodes, where the spectral composition at the measurement position dictates which type of diode is more accurate.</p><p>The fast correction of silicon diodes provided by the developed software is more accurate than shielded diodes for small field sizes, and can in radiotherapeutic clinical practice increase the dosimetric accuracy of silicon diodes.</p>

<p>The general aim of the studies presented in this thesis is to investigate the possibility of using clinical data to measure outcomes in psychiatric outpatient services. The specific aims are to investigate whether routine clinical assessments and ratings are reliable and have adequate validity, and then to use these data to calculate treatment outcomes and explore factors that affect these outcomes.</p><p>The main result shows that ratings of global mental health made by clinicians in routine clinical work can be used to evaluate treatment outcomes in outpatient settings. The clinicians responsible for diagnosing and assessing patients used the GAF scale with satisfactory reliability (ICC1,1 = 0.81) and fair interrater reliability (overall kappa = 0.53) when categorizing main diagnostic groups of the DSM-IV axis I. The GAF scale can thus be used to assess global mental health and to monitor outcomes in clinical settings. However, a GAF culture bias was observed. This bias can probably be corrected with feedback and training.</p><p>Psychiatric treatment in outpatient settings had a generally positive effect on patients’ global mental heath (ES = 0.65). The overall result when clinical significance methodology was used showed that 28.1% of the patients had recovered and a further 6.6% showed reliable improvement. Patients being treated with psychotherapeutically influenced methods showed a considerably better effect (ES = 1.00). There is a dose of sessions effect that is particularly marked for short treatment episodes. Thirteen sessions are required for 50% of the patients to show reliable improvement. The strongest influence on treatment outcome was whether the termination of a patient’s treatment was planned or unplanned.</p><p>In conclusion: Clinical databases can be used to study the outcome of psychiatric services provided they a) include a large number of subjects representing an intention-to-treat perspective; b) the instruments used are clinically relevant and reliable; c) the raters contributing to the data base are motivated to decrease attrition; d) the database includes extensive data to allow for control of confounding factors; and e) data are collected at critical occasions in treatment, such as at the start of treatment and at discharge from treatment, making it possible to focus on effects. Psychiatric outpatient treatment has a positive effect, but considerable improvements may be possible with more stringent use of psychotherapeutic methods, sufficient doses of sessions, and planned terminations. However, the progress of treatment is also affected by such factors as pre-treatment severity and diagnoses.</p>

Many studies addressing the toxicity of silver nanomaterials have found that smaller sized silver nanoparticles are usually more toxic to organisms and in cell culture than particles of larger sizes yet it is not entirely clear why. We investigated the size dependent toxicity of silver nanoparticles by measuring the response of embryonic zebrafish (Danio rerio) following exposure to a library of thirteen distinct silver nanoparticle size distributions with mean diameters between 8.9 nm and 112.6 nm. Data analysis using dose���response modeling revealed that silver nanoparticles (AgNP) induced embryo toxicity that is dependent on the total surface area and not on the mass or particle number in solution. Included in this study is a comparison between embryo toxicity induced by silver nitrate (AgNO���) and AgNPs for cardiovascular endpoints, as well as an investigation into the influence of the chorion on AgNP toxicity. This study demonstrates the importance of using alternative dose metrics in nanotoxicology, and highlights the value of using the embryonic zebrafish to explore nanomaterial structure activity relationships. / Graduation date: 2013

The general aim of the studies presented in this thesis is to investigate the possibility of using clinical data to measure outcomes in psychiatric outpatient services. The specific aims are to investigate whether routine clinical assessments and ratings are reliable and have adequate validity, and then to use these data to calculate treatment outcomes and explore factors that affect these outcomes. The main result shows that ratings of global mental health made by clinicians in routine clinical work can be used to evaluate treatment outcomes in outpatient settings. The clinicians responsible for diagnosing and assessing patients used the GAF scale with satisfactory reliability (ICC1,1 = 0.81) and fair interrater reliability (overall kappa = 0.53) when categorizing main diagnostic groups of the DSM-IV axis I. The GAF scale can thus be used to assess global mental health and to monitor outcomes in clinical settings. However, a GAF culture bias was observed. This bias can probably be corrected with feedback and training. Psychiatric treatment in outpatient settings had a generally positive effect on patients’ global mental heath (ES = 0.65). The overall result when clinical significance methodology was used showed that 28.1% of the patients had recovered and a further 6.6% showed reliable improvement. Patients being treated with psychotherapeutically influenced methods showed a considerably better effect (ES = 1.00). There is a dose of sessions effect that is particularly marked for short treatment episodes. Thirteen sessions are required for 50% of the patients to show reliable improvement. The strongest influence on treatment outcome was whether the termination of a patient’s treatment was planned or unplanned. In conclusion: Clinical databases can be used to study the outcome of psychiatric services provided they a) include a large number of subjects representing an intention-to-treat perspective; b) the instruments used are clinically relevant and reliable; c) the raters contributing to the data base are motivated to decrease attrition; d) the database includes extensive data to allow for control of confounding factors; and e) data are collected at critical occasions in treatment, such as at the start of treatment and at discharge from treatment, making it possible to focus on effects. Psychiatric outpatient treatment has a positive effect, but considerable improvements may be possible with more stringent use of psychotherapeutic methods, sufficient doses of sessions, and planned terminations. However, the progress of treatment is also affected by such factors as pre-treatment severity and diagnoses.

Silicon diodes compared to other types of dosimeters have several attractive properties, such as an excellent spatial resolution, a high sensitivity, and clinically practical to use. These properties make silicon diodes a preferred dosimeter for relative dosimetry for several types of measurements in small field dosimetry, e.g., stereotactic treatments and intensity modulated radiotherapy (IMRT). Silicon diodes are, however, limited by an energy dependent response variation in photon beams, resulting in that the diode readout per dose to the phantom medium varies with photon spectral changes, thereby introducing a significant uncertainty in the measured data. The traditional solution for the energy dependent over-response caused by low-energy photons is to use diodes with a shielding filter of high atomic number. These shielded diodes, however, show an incorrect readout for small fields due to electrons scattered from the shielding (Griessbach et al. 2005). In regions with degraded lateral electron equilibrium (LEE) shielded diodes over-respond due to an increased degree of LEE, as a consequence of the high density shielding (Lee et al. 2002). In this work a prototype software that corrects for the energy dependent response of a silicon diode is developed and validated for small field sizes. The developed software is based on the novel concept of Monte Carlo (MC) simulated fluence pencil beam kernels to calculate spectra (Eklund and Ahnesjö 2008), and the spectra based silicon diode response model proposed by Eklund and Ahnesjö (2009). The software was also extended to include correction of ionization chambers, for the energy dependent Spencer-Attix water/air stopping power ratio (sw,air). The calculated sw,air are shown to be in excellent agreement with published values to better than 0.1% for most values, the maximum deviation being 0.3%. Measured relative depth doses, relative profiles, and output factors in water, for small square field sizes, for 6 MV and 15 MV clinical photon beams are presented in this work. The results show that the unshielded Scanditronix-Wellhöfer EFD3G silicon diode response, corrected by the developed software, is in excellent agreement with reference ionization chamber measurements (corrected for change in sw,air), the maximum deviation being 0.4%. Measurements with two types of shielded diodes, namely Scanditronix-Wellhöfer PFD silicon diodes (FP1990 and FP2730), are also included in this work. The shielded diodes are shown to have an over-response as large as 2-3.5% for field sizes smaller than 5 cm x 5 cm. The presented results also suggest a difference in accuracy as large as 0.5-1% between the two types of shielded diodes, where the spectral composition at the measurement position dictates which type of diode is more accurate. The fast correction of silicon diodes provided by the developed software is more accurate than shielded diodes for small field sizes, and can in radiotherapeutic clinical practice increase the dosimetric accuracy of silicon diodes.

On 26 April 1986 an accident occurred in the Chernobyl nuclear power plant resulting in the release of large amount of radionuclides. Almost five percent of the total released caesium-137 was deposited in Sweden. The incidence of malignancies in the most affected counties in Sweden was investigated in three epidemiological studies. In the first study the incidence of malignancies in children and adolescents was studied for the period 1978-1992. The parishes and their inhabitants were classified according to the ground deposition of caesium-137 on an analogue map provided be the Swedish Radiological Protection Authority. A continuous increase of brain tumour incidence observed during the time of the study had no clear relationship to the Chernobyl fallout. A somewhat decreased relative risk of ALL was observed in areas with increased deposition. Other malignancies showed no changes in incidence over time or with regard to the exposure of caesium-137. In study II and III we enlarged the study base by including adults. We improved the methodology by defining a cohort of subjects who lived in the same parish from 31 December 1985 to 31 December 1987. The inhabitants from seven counties were included. Parishes were classified the same way as in study I. Due to the large number of individuals six exposure categories could be created; &lt;3, 3–29, 30–39, 40–59, 60–79, and 80–120 kBq caesium-137/m2. The inhabitants of the 117 non-affected parishes (&lt;3 kBq/m2) served as reference. During the 1988-1996 followup, 22,409 malignancies were recorded. The MH-IRR in the fully adjusted model was 1.00 (reference), 1.05, 1.03, 1.08, 1.10 and 1.21, respectively. ERR was 0.11 per 100 kBq/m2 (95% CL 0.03;0.20). A more advanced method was used in Study III by ignoring the exposure classification for parishes, and instead matching the dwelling coordinate to a digital map of deposition of casesium-137. In spite of a more valid exposure classification the risk estimates were similar in study II and III. Also, the ERR during the longer follow-up of 1988-1999 was almost identical, 0.10 per 100 kBq/m2 (95% CL 0.00;0.23). The strongest dose-response relationship was seen in the first four years (1988-1991). No obvious excess for leukaemia or thyroid cancer was recognised in either study II or III. The estimated number of exposure related cases was calculated to 849 in study II and 1,278 in study III. Our interpretation is that we have shown an increased incidence of total malignancies with dose-response relationship for caesium-137, only a few years after the Chernobyl accident. In study IV we compared the two different ways of classifying the exposure in study II and III. Out of the 450 parishes 111 got a different classification. The similar risk estimates in study II and III could probably be explained by relatively homogenous exposure in the parishes making the intra-parish difference less influential, especially when included in categories. In study V we examined the urinary excretion of 8-OHdG in Belarussian children from areas with high and low fallout of caesium-137, respectively. We found significantly lower urinary 8-OHdG levels in children from rural contaminated areas compared to urban uncontaminated areas, suggesting an urban, rather than a radiation related, risk factor. Using the Hill criteria for causality there is support for a causal inference between the fallout of caesium-137 from the Chernobyl accident and the increased incidence in total malignancies in Northern Sweden.

Most breast cancer patients undergo radiation diagnostics and are also treated with radiotherapy. In addition to being an important treatment modality, ionizing radiation (IR) is a potent tumour-causing agent that has been linked to breast cancer development. However, the exact molecular etiology of IR-induced mammary gland carcinogenesis remains unknown. We set out to analyze the role of DNA methylation in mammary gland responses to low dose IR using a well-established rat model. We also studied low dose IR effects on global gene expression and microRNAome. We found that exposure to low, mammography-like dose of IR led to a significant loss of global DNA methylation in rat mammary gland tissue. Furthermore, low dose IR significantly affected rat mammary gland transcriptome and microRNAome. The datasets generated within the scope of this thesis may be used to identify novel predictive biomarkers for assessment of the magnitude of IR effects on mammary gland tissue. / xi, 120 leaves ; 29 cm

Studies on relations between number of sessions and effect of psychotherapy have usually assumed a constant rate of change across different lengths of therapy, explained by a model called the dose-effect model. This assumption has been challenged by the good-enough level (GEL) model, which makes the prediction that the rate of change will vary as a function of total number of sessions. This study aimed to compare these models. We also assessed the relationship between reliable and clinically significant change (RCSI) and total dose of therapy. Participants were drawn from two datasets in the Swedish primary care (n = 640) and adult psychiatric care (n = 249). The participants made session-wise ratings on the Clinical Outcomes in Routine Evaluation-Outcome Measure (CORE-OM). Multilevel analyses indicated a better fit using the GEL-model, with some reservations concerning RCSI and patterns of change. The results may indicate a general lawful relationship that may have implications for future research, as well as psychotherapy practice and policy making.