A Doença de Chagas é um dos maiores problemas de saúde pública na América do Sul causando um elevado prejuízo à população. A despeito dos inúmeros esforços para o seu controle, a doença não tem cura e apresenta problemas científicos ainda não esclarecidos. Considerando-se que vários pesquisadores têm usado a radiação ionizante para modificar protozoários ou propriedades imunológicas de biomoléculas, neste trabalho foram estudados aspectos da resposta imunológica induzida em camundongos, resistentes e suscetíveis ao T. cruzi, utilizando formas irradiadas deste parasita. Doses baixas de radiação preservaram a capacidade reprodutiva e de invasão celular. Animais resistentes e suscetíveis, imunizados com os parasitas tratados por radiação, produziram anticorpos específicos. Após o desafio, os animais apresentaram baixa parasitemia, com exceção dos grupos imunizados com parasitas que receberam apenas altas doses de radiação. A seleção de formas tripomastigotas foi obtida irradiando-se os parasitas com baixas doses, o que promoveu aprimoramento da qualidade da resposta imune, a exemplo do que se observa quando da utilização de complemento. Estes dados evidenciam a importância da seleção das formas tripomastigotas para a imunização contra o T. cruzi e apontam a radiação ionizante como alternativa para este fim, uma vez que quando a seleção é feita utilizando-se complemento, depara-se com a dificuldade de sua remoção, colocando em risco o processo de imunização por introduzir substancias estranhas ao organismo. / Chagas\'s disease is one of the major public health problems in South America, promoting high prejudice to the local population. Despite the massive efforts to control it, this disease has no cure and presents puzzling unsolved questions. Considering that many researchers have used ionizing radiation to modify protozoans or biomolecules, we investigated the immunological response aspects of susceptible and resistant mice using irradiated parasites. Low radiation doses preserved the reproductive and invasive capacities of the parasite. Both susceptible and resistant animals, after immunization with irradiated parasites produced specific antibodies. After a challenge, the animals presented low parasitaemia, excepting those immunized with the antigen irradiated with higher doses. Using low radiation doses, we were able to selectively isolate trypomastigotes, leading to an improvement in the quality of the immune response, as previously reported when performing complement system assays. These data highlight the importance of selecting trypomastigote forms for immunization against T. cruz; and point towards ionizing radiation as an alternative to achieve this selection, since when this procedure is performed using complement, the subsequent steps are impaired by the difficulties to remove this component from the system.

Investigations of DNA damage response (DDR) mechanisms in normal tissues have implications for both cancer prevention and treatments. The accumulating knowledge about protein function and molecular markers makes it possible to directly trace and interpret cellular DDR in a tissue context. Using immunohistochemical techniques and digital image analysis, we have examined several principal DDR events in epidermis from patients undergoing fractionated radiotherapy. Acquiring biopsies from different regions of the skin provides the possibility to determine in vivo dose response at clinically relevant dose levels throughout the treatment. A crucial event in cellular DDR is the repair of DNA double strand breaks (DSBs). These serious lesions can be directly visualised in cells by detecting foci forming markers such as γH2AX and 53BP1. Our results reveal that DSB-signalling foci can be detected and quantified in paraffin-embedded tissues. More importantly, epidermal DSB foci dose response reveals hypersensitivity, detected as elevated foci levels per dose unit, for doses below ~0.3Gy. The low-dose hypersensitive dose response is observed throughout the treatment course and also in between fractions: at 30 minutes, 3 hours and 24 hours following delivered fractions. The dose response at 24 hours further reveals that foci levels do not return to background levels between fractions. Furthermore, a low-dose hypersensitive dose response is also observed for these persistent foci. Investigations of end points further downstream in the DDR pathways confirmed that the low-dose hypersensitivity was preserved for: the checkpoint regulating p21 kinase inhibitor; mitosis suppression; apoptosis induction and basal keratinocyte reduction. Our results reveal preserved low-dose hypersensitivity both early and late in the DDR pathways. A possible link between the dose-response relationships is therefore suggested. The preserved low-dose hypersensitivity is a cause for re-evaluation of the risks associated with low-dose exposure and has implications for cancer treatments, diagnostics and radiation protection.

Both spinal pain and temporomandibular disorders (TMD) commonly occur in the general population. Previous studies demonstrate neurophysiologic and biomechanical couplings between the trigeminal and cervical regions. This investigation tested the null hypothesis of no relationship between spinal pain (neck, shoulder and/or low back) and TMD, by using questionnaires and clinical examinations of the jaw function. In an age- and sex-matched case-control study, the specific aim was to compare the prevalence of signs and symptoms of TMD among cases with long-term spinal pain and controls without spinal pain. The results showed that subjects with spinal pain had signs and symptoms of TMD significantly more often than did controls. The associations remained after excluding all participants with jaw pain. Furthermore, the comorbidity pattern was similar, regardless of location of spinal pain. In a cross-sectional study, the specific aim was to test whether there is a reciprocal cross-sectional dose-response-like relationship between spinal pain and TMD. Two different designs were used, one with frequency/severity of spinal pain as independent variable, and the other, with frequency/severity of TMD symptoms as independent variable. The analysis showed increasing odds for presence of TMD symptoms with increasing frequency/severity of spinal pain, and increasing odds for presence of spinal pain with increasing frequency/severity of TMD symptoms. In a case-control study within a 2-year prospective cohort, the specific aim was to test whether there is a reciprocal temporal relationship between signs and symptoms in trigeminally, and symptoms in spinally, innervated areas. Incidence of symptoms in these areas was analyzed in relation to presence of spinal pain, headaches, and signs and symptoms of TMD at baseline. The main findings were that presence of signs of TMD at baseline increased the onset of spinal pain and symptoms in the trigeminal area, and that spinal pain increased the onset of symptoms in the trigeminal area. An augmentation effect between the significant baseline variables was observed for the incidence of headaches and jaw pain. In conclusion, the investigation demonstrated a cross-sectional and temporal relationship between spinal pain and TMD; thus, the null hypothesis was rejected. The results indicate common pathophysiological mechanisms in the development of spinal pain and TMD. The comorbidity and reciprocal influence that were found call for an integrated and multidimensional approach in the management of individuals with long-term spinal pain and TMD.

Italian ryegrass (Lolium perenne spp. multiflorum) is a common weed management problem in turfgrasses, cereals and non-crop areas in the United States. In Oregon, the number of populations with multiple-resistance continues to increase. To manage these resistant populations, the resistance patterns must be determined. In this study, five Italian ryegrass populations (CT, R1, R2, R3 and R4) from two cropping systems were studied for resistance patterns and mechanisms. The CT population is from a Christmas tree plantation and was resistant to at least six herbicides with four different mechanisms of action: atrazine, diuron (2.4-fold), glyphosate (7.4-fold), hexazinone (3.1-fold), imazapyr (1.8-fold), and sulfometuron. The resistant indices (RI) for sulfometuron and atrazine could not be calculated because 50% growth reduction for the CT population was not reached even with the highest rates applied, 17.6 kg ai ha⁻¹and 16 kg ai ha⁻¹, respectively, which are 16 times the recommended field application rates for this two herbicides. The CT population accumulated less shikimate than the S population. There were two mutations in the CT population, Trp591 to Leu in the ALS gene and Ser264 to Gly in the psbA gene, which explain the ALS and PII cross resistance, respectively. R1, R2, R3 and R4 were collected from annual cropping systems. All four populations were resistant to flufenacet. RIs for two populations, R2 and R4, were 8.4 and 5.9, respectively. R2 and R4 also were resistant to mesosulfuron-methyl, pinoxaden, quizalofop and clethodim. R4 was resistant to diuron, but R2 was not. An Asp-2078-Gly substitution in the ACCase gene was found in both R2 and R4 populations, while another Ile-2041-Asn substitution in the ACCase gene was found in the R4 population. These mutations explain the ACCase cross resistance in the R2 and R4 populations. The mechanisms for the glyphosate resistance in the CT population and the flufenacet resistance in R1, R2, R3 and R4 populations were not identified in this study. None of the five populations were resistant to the herbicide pyroxasulfone. / Graduation date: 2013

Alcoholic beverages have been classified as carcinogenic to humans. As alcoholic beverages are multicomponent mixtures containing several carcinogenic compounds, a quantitative approach is necessary to compare the risks. Fifteen known and suspected human carcinogens (acetaldehyde, acrylamide, aflatoxins, arsenic, benzene, cadmium, ethanol, ethyl carbamate, formaldehyde, furan, lead, 4-methylimidazole, N-nitrosodimethylamine, ochratoxin A and safrole) occurring in alcoholic beverages were identified based on monograph reviews by the International Agency for Research on Cancer. The margin of exposure (MOE) approach was used for comparative risk assessment. MOE compares a toxicological threshold with the exposure. MOEs above 10,000 are judged as low priority for risk management action. MOEs were calculated for different drinking scenarios (low risk and heavy drinking) and different levels of contamination for four beverage groups (beer, wine, spirits and unrecorded alcohol). The lowest MOEs were found for ethanol (3.1 for low risk and 0.8 for heavy drinking). Inorganic lead and arsenic have average MOEs between 10 and 300, followed by acetaldehyde, cadmium and ethyl carbamate between 1,000 and 10,000. All other compounds had average MOEs above 10,000 independent of beverage type. Ethanol was identified as the most important carcinogen in alcoholic beverages, with clear dose response. Some other compounds (lead, arsenic, ethyl carbamate, acetaldehyde) may pose risks below thresholds normally tolerated for food contaminants, but from a cost-effectiveness point of view, the focus should be on reducing alcohol consumption in general rather than on mitigative measures for some contaminants that contribute only to a limited extent (if at all) to the total health risk.

Anemia and micronutrient deficiencies in infancy are common in low-income settings. These are partly due to maternal malnutrition and may impair child health and development. We studied the impact of maternal food and micronutrient supplementation, duration of exclusive breastfeeding (EBF), growth and infection on infant anemia and micronutrient status. In the MINIMat trial in Matlab, Bangladesh, pregnant women were randomized to Early or Usual promotion of enrolment in a food supplementation program and to one of three daily micronutrient supplements. Capsules containing 400µg folic acid and (a) 30 mg iron (Fe30Fol), (b) 60 mg iron (Fe60Fol), (c) 30 mg iron and other micronutrients (MMS) were provided from week 14 of gestation. Capsule intake was assessed with the eDEM device recording supplement container openings. Blood samples (n=2377) from women at week 14 and 30 were analyzed for hemoglobin (Hb). Duration of EBF and infant morbidity was based on monthly maternal recalls. Infants were weighed and measured monthly. Blood samples (n=1066) from 6-months-old infants were analyzed for Hb and plasma ferritin, zinc, retinol, vitamin B12 and folate. In women, Hb increase per capsule reached a plateau at 60 Fe60Fol capsules, indicating that nine weeks of daily supplementation produced maximum Hb response. Anemia was common (36%) at capsule intakes >60 indicating other causes of anemia than iron deficiency. In infants, vitamin B12 deficiency prevalence was lower in the MMS (26.1%) than in the Fe30Fol group (36.5%), (p=0.003) and zinc deficiency prevalence was lower in the Usual than in the Early group. There were no other differential effects of food or micronutrient supplementation on infant anemia or micronutrient status. Infants exclusively breast-fed for 4-6 months had a higher mean plasma zinc concentration (9.9±2.3 µmol/L) than infants exclusively breast-fed for <4 months (9.5±2.0 µmol/L), (p< 0.01). No other differences in anemia, iron or zinc status were observed between EBF categories. Infection, low birth weight and iron deficiency were independent risk factors for infant anemia. Regardless of studied interventions, prevalence of anemia (43%), deficiency of zinc (56%), vitamin B12, vitamin A (19%) and iron (22%) in infancy was high and further preventive strategies are needed. / MINIMat

This study has examined the effect of 3 doses of Methylphenidate (MPH) on the speed of motor and cognitive performance in children diagnosed with ADHD. Thirty children clinically diagnosed with Attention Deficit/Hyperactivity Disorder (ADHD) aged 6-12 years were recruited through the ADHD Clinic and the Severe and Disruptive Behavior Disorders Program at the Douglas Mental Health University Institute. The three doses of MPH were administered according to a double blind randomized cross-over three day trial (0.3; 0.5 0.8 mg/kg/day in a bid schedule). An improvement across all three doses of MPH on motor, cognitive and behavioural measures was observed. The improvement is significant at low doses of MPH and an increase of dose up to 0.8 mg/kg/day does not lead to further improvement of the speed of simple motor task, but might be beneficial to specific cognitive tasks. No deterioration was observed in association with higher doses of MPH.

The overall objective of this study was to develop and characterise new normoxic polymer gel formulations for evaluation of complex 3-D treatment volumes for application in radiotherapy dosimetry. Throughout this thesis, the essential characteristics of normoxic polymer gels have been extensively investigated. Studies were performed on the chemical components of the MAGIC gel and an improved formulation was proposed. Various anti-oxidants were studied and different versions of the MAGIC gel with fewer chemicals were developed and named MAGAS and MAGAT gel dosimeters. The ascorbic acid anti-oxidant was found to have a slow oxygen scavenging rate and therefore a delay period between manufacture and irradiation of the MAGAS gel was necessary before the gel became radiation sensitive. Vacuum pumping on the MAGAS gel solution to remove dissolved oxygen was shown to initially increase the R2-dose response and sensitivity of the dosimeter, reducing the time between manufacture and irradiation. Studies of the MAGAS gel for measurement of depth dose showed that MAGAS gel has potential as a clinical radiotherapy dosimetry tool. The radiological properties of MAGIC, MAGAS and MAGAT gels were investigated. Due to their high gelatine and monomer concentration, differences with water were observed for the cross-section ratios for attenuation, energy absorption and collision stopping power coefficient ratios through the therapeutic energy range. It was determined that when using and developing normoxic polymer gels the most important consideration for radiological water equivalence are the mass and relative electron densities. A preliminary study was performed with the hypoxic PAG gel dosimeter combined with tetrakis (hydroxymethyl) phosphonium chloride anti-oxidant to form a normoxic PAG gel dosimeter named PAGAT gel. It was found PAGAT gel compared favourably with previous studies of the hypoxic PAG gel. An extensive study was subsequently undertaken in which PAGAT gel was investigated for a number of essential characteristics. The PAGAT gel formulation showed potential as a normoxic polymer gel for clinical radiotherapy dosimetry, which has a significantly reduced manufacturing time and procedure compared with the hypoxic PAG gel dosimeter. The radiological attenuation properties of the PAGAT and MAGAT gels were investigated as a feasibility study for using x-ray computerised tomography (CT) as an evaluation technique of normoxic polymer gels. CT was shown to have potential as an evaluation tool for measuring the dose response of normoxic polymer gel dosimeters. An investigation was performed on the CT diagnostic dose response of normoxic polymer gels. Normoxic polymer gels were found to have potential for use as a specialised tool in measuring computerised tomography dose index (CTDI) for acceptance testing and quality assurance of CT scanners in diagnostic radiology. These findings provide a significant contribution toward the development and successful implementation of normoxic polymer gel dosimetry to clinical radiotherapy.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2002. / Härtill 5 uppsatser.

Thesis--University of Oklahoma. / Bibliography: leaves 152-154.