INTRODUÇÃO: A administração de aciclovir por via sistêmica é o tratamento de escolha para a necrose aguda de retina. Entretanto, por ser uma doença rapidamente progressiva, a injeção intravítrea de aciclovir ao diagnóstico pode ser utilizada como terapia adjuvante, enquanto o aciclovir sistêmico ainda não alcançou níveis terapêuticos na retina. Os objetivos deste estudo experimental foram determinar a meia-vida do aciclovir no vítreo após injeção intravítrea e determinar os efeitos funcionais e morfológicos do aciclovir na retina de coelhos saudáveis após injeção intravítrea do medicamento em diferentes doses. MÉTODOS: Foram utilizados 32 coelhos albinos da raça New Zealand (estudo farmacológico) e 86 coelhos pigmentados da raça Dutch Belted (30 no estudo eletrofisiológico, 36 no estudo morfológico com microscopia de luz e 20 no estudo morfológico com imuno-histoquímica). Para a determinação da meia-vida do aciclovir no vítreo, os 32 coelhos albinos receberam injeção intravítrea de aciclovir 1 mg e foram sacrificados nos dias 2, 9, 14 e 28. Para a avaliação funcional e microscopia de luz, os 66 coelhos pigmentados receberam três doses intravítreas de aciclovir (0,1; 1 ou 10 mg) no olho direito e soro fisiológico no olho esquerdo. Destes, 30 animais foram submetidos ao eletrorretinograma (ERG) antes da injeção e nos dias 2, 7 e 15 após a injeção. Para a análise histológica (microscopia de luz), 36 animais foram sacrificados 2, 7 e 15 dias após a injeção. Para imuno-histoquímica (apoptose, GFAP, DAPI e vimentina), os 20 coelhos pigmentados receberam injeção intravítrea de 1 e 10 mg de aciclovir e foram sacrificados após cinco dias. RESULTADOS: No estudo da meia-vida do aciclovir no vítreo, as concentrações médias de aciclovir no vítreo foram 0,25, 0,09, 0,06 e 0,08 ?g/ml, respectivamente 2, 9, 14 e 28 dias depois da injeção. Nos estudos eletrofisiológico e de microscopia de luz, os olhos que receberam injeção intravítrea de 0,1 mg de aciclovir não apresentaram alterações funcionais ou histológicas. Os olhos injetados com 1 mg de aciclovir apresentaram redução significativa da amplitude das ondas a e b no ERG e desalinhamento dos fotorreceptores na microscopia de luz. Estes achados regrediram no 15º dia. Os olhos que receberam injeção intravítrea de 10 mg de aciclovir apresentaram as mesmas alterações funcionais, mas que não regrediram após o 15º dia. À microscopia de luz, esses olhos apresentaram destruição da camada de fotorreceptores e desorganização de toda a retina. Na camada de células ganglionares houve áreas com ausência de células da retina interna. A imuno-histoquímica mostrou lesão das células de Müller e apoptose de fotorreceptores apenas nos animais injetados com 10 mg. CONCLUSÕES: A meia-vida do aciclovir no vítreo após injeção intravítrea é muito curta para a sua detecção em dias. Os resultados funcionais e morfológicos sugerem que a injeção intravítrea de aciclovir em coelhos causa alterações tóxicas dose e tempo dependentes nos fotorreceptores e nos neurônios pós-receptorais da retina. A dose de 0,1 mg de aciclovir parece ser segura para injeção intravítrea em coelhos e pode ser utilizada em modelos experimentais de uveíte ou retinite viral / OBJECTIVE: The gold standard for the treatment of acute retinal necrosis is the use of systemic intravenous acyclovir. Nevertheless, as a rapidly progressive disease, use of intravitreal acyclovir injection at the time of diagnosis may be a second therapy until the systemic acyclovir reaches therapeutic levels in the retina. The aim of this experimental study was to determine pharmacological levels of the drug in the vitreous within days and to determine the functional and morphologic effects of acyclovir in the retina of healthy rabbits, after intravitreal injections in different dosages. METHODS: We have used 32 albino New Zealand rabbits for the pharmacologic experiments and 86 pigmented Dutch Belted animals for electrophysiology, immunochemistry and morphology. Thirty rabbits were used for the electrophysiological study, 36 were used for the light microscopy morphology and 20 animals were used for immunochemistry morphology. For the half-life study, the 32 albino rabbits received a 1mg acyclovir intravitreal injection and they were euthanized at 2, 9, 14 and 28 days. For functional and morphologic evaluations, the 66 pigmented animals received one of 3 intravitreal dosages of acyclovir (0,1; 1 or 10 mg) in the right eye and saline in the left eye. For the functional evaluation, 30 pigmented animals underwent electroretinography before the injection and on days 2, 7 and 15 after the procedure. For the histology with light microscopy, 36 animals were euthanized on days 2, 7 and 15 after the injection. Twenty rabbits that received 1 and 10mg of acyclovir were euthanized on day 5 were used for the immunohistochemistry to evaluate apoptosis, with GFAP, DAPI and vimentin. RESULTS: For the pharmacology study, the mean acyclovir concentrations when 1?g/ml was injected into the vitreous were respectively 0,25; 0,09; 0,06 e 0,08?g/ml on days 2, 9, 14 and 28 after injected. The eyes that received 0,1 mg acyclovir showed no functional or histological alterations. The eyes injected with 1 mg acyclovir had significant reduction on a and b waves amplitude and photoreceptor misalignment, which regressed on day 15. The 10mg injected eyes, showed the same electrophysiology changes. The retinas of those animals had photoreceptor layer destruction and total retina disorganization. In the ganglion cell layer, there were areas of absence of internal retinal cells. The immunohistochemistry showed Müller cells lesion and photoreceptor apoptosis in the 10mg animals. CONCLUSIONS: Acyclovir half-life is too short for its detection within days. The functional and morphological results suggest that the intravitreal acyclovir injection in rabbits cause toxic changes that are dose and time dependent on photoreceptors and post-receptor neurons in the retina. The 0,1 mg acyclovir dosage seems to be safe for intravitreal use in rabbits and may be studied in experimental models of viral uveitis or retinitis

A avaliação ecotoxicológica dos sedimentos dos reservatórios de Barra Bonita e Salto Grande foi realizada através de testes de toxicidade aguda e crônica com o sedimento total e o solubilizado, com os organismos-teste Chironomus xanthus, Daphnia similis, Ceriodaphnia dubia, Vibrio fisheri e Spirillum volutans, além de análises físicas (pH, EH e \'O IND.2\') e químicas (fósforo, nitrogênio, carbono orgânico total, sulfetos e amônia e metais potencialmente disponíveis). A concentrações médias de matéria orgânica e fósforo obtidas para os sedimentos dos reservatórios de Barra Bonita e Salto Grande foram elevadas, e condizentes com a carga de matéria orgânica e com as baixas concentrações de oxigênio dissolvido e de potencial redox. Em relação aos metais, os resultados revelaram que, para o reservatório de Barra Bonita, eles podem estar influenciando a toxicidade detectada através dos testes de toxicidade. Em Salto Grande, os resultados indicaram que os sulfetos estão atuando como fase controladora dos metais, mantendo-os indisponíveis nos sedimentos. Para esse reservatório a principal causa da toxicidade foi a acidez. O estudo de Avaliação e Identificação da Toxicidade realizado com as amostras de sedimento dos reservatórios de Barra Bonita, Salto Grande e Rasgão mostrou que os possíveis compostos tóxicos responsáveis pela toxicidade são metais (Barra Bonita); amônia (Salto Grande e Rasgão); compostos ácidos voláteis e compostos orgânicos não iônicos (Rasgão). O tratamento com a resina zeolita foi eficiente na remoção da amônia e redução da toxicidade do sedimento do reservatório de Rasgão, confirmando dessa forma, a amônia como o principal composto tóxico. O estudo de Avaliação e Identificação da Toxicidade deve ser incorporado nos programas de controle, monitoramento e gestão dos recursos hídricos, devido a importância da identificação dos compostos responsáveis pela toxicidade. / An ecotoxicological evaluation of the sediments of Barra Bonita and Salto Grande reservoirs was performed by carrying out acute and chronic toxicity tests with both the total sediment and elutriate using Chironomus xanthus, Daphnia similis, Ceriodaphnia dubia, Vibrio fisheri and Spirillum volutans as test-organisms, as well as physical (pH, EH e \'O IND.2\') and chemical analysis (phosphorus, nitrogen, total organic carbon, sulphide, ammonium and potentially available metals). The mean concentrations of organic matter and phosphorus obtained for the sediments of Barra Bonita and Salto Grande reservoirs were high and in agreement with the organic matter loading, low dissolved oxygen concentrations and redox potential. In relation to metals, the results revealed that in Barra Bonita reservoir they might be responsible for the toxicity detected. For Salto Grande, the results indicated that sulphides act as metal controlling phase keeping them unavailable in the sediments. The main cause of the toxicity in this reservoir was acidity. The Toxicity Identification and Evaluation (TIE) carried out with the sediments of Barra Bonita, Salto Grande and Rasgão have shown that the probable toxic compounds responsible for toxicity are metals (Barra Bonita); ammonium (Salto Grande and Rasgão); volatile acid compounds and non-ionic compounds (Rasgão). The treatment with zeolite was efficient in removing ammonium and reducing toxicity in the sediment of Rasgão reservoir, thus confirming ammonium as the main toxic compound. The Toxicity Identification and Evaluation approach must be incorporated in the control, monitoring and management of water resources, due to the relevance of identifying the compounds responsible by the toxicity.

Introduction: Prostate cancer is the most common type of cancer in Sweden and is often treated using antiandrogenic drug therapy. Two substances belonging to this class of pharmaceuticals are bicalutamide and flutamide. After excretion from the human body, the drug molecules enter the wastewater treatment plant (WWTP). The WWTPs are not effective enough to completely remove pharmaceutical residues, why presence of both bicalutamide and flutamide can be detected in WWTP effluent water. Previous findings: Antiandrogens have been reported to affect reproduction in adult fish, but studies regarding possible effects on the embryonic development of fish are few. Aim: The present study sought to investigate if exposure to bicalutamide or flutamide cause toxicity in the early developmental stages of zebrafish embryos, and whether negative effects occur within concentrations relevant to measured environmental levels. Method: A modified OECD FET-test was used, where additional sublethal endpoints were included and the time period for assessment extended to 144 hours post fertilization (hpf). In addition, a locomotor activity assay was performed at 144 hpf in order to observe any sub-lethal swimming behavioral effects. Results: High doses (10 mg/L) of flutamide led to 100% lethality of the zebrafish embryos but the results suggest no acute toxic effects in the high dose treatment group of bicalutamide, or of either flutamide or bicalutamide within in the low (0.1 mg/L) or intermediate (1 mg/L) treatment groups. Neither did the locomotor activity assay result in statistically significant results, although the pattern of swimming activity in the low dose groups suggests that behavioral developmental effects could be present. Conclusions: High doses of flutamide caused mortality of the embryos, but no lethal or sublethal effects were present at environmentally relevant concentrations. The modest outcome of present study however suggests that further investigation of behavioral developmental effects of antiandrogens could be of future relevance. Analysis of the expression of genes related to neuronal growth, memory and other cognitive behaviors associated with behavioral changes, would then be of interest for further studies.

No description available.

Background: Older patients are vulnerable to chemotherapy-related toxicity (CRT). Therefore we evaluated screening tools in their power to predict CRT. Methods: Patients with cancer aged ≥65 years completed three screening questionnaires (G8, optimised G8 and Cancer and Ageing Research Group (CARG). Additionally, Comprehensive geriatric assessment (CGA) for verification of supportive care needs was undertaken on patients with impaired G8 scores. During chemotherapy treatment patients were assessed, capturing grade 0–5 CRT as defined by NCI CTCAE 4. Results: 104 patients with non-haematological cancers were included at three study sites. Median age was 73 years (range 65–85). Onco-geriatric screening detected 74% as impaired using G8 and optimised G8 questionnaires and 86% using CARG screening. Grade 3–5 toxicity affected 64.4% of all patients. G8 (OR 0.3 95% CI [0.1;1.0]) and optimised G8 (OR 0.4 95% CI [0.1; 1.5]) did not reliably predict CRT, whereas screening with CARG demonstrated a strong prediction of severe CRT: OR 4.2, 95% CI [1.1, 15.9]. CGA was undertaken on 66 patients, revealing deficiencies in nutritional (83%) and functional-status (54%) and occurrence of relevant comorbidity (53%). Conclusion: The CARG tool could be useful for predicting CRT. CGA showed clinically relevant supportive care needs in patients with a positive G8 screening.:1. Einleitung ..................................................................................................................................... - 3 - 1.1 Epidemiologie der Krebserkrankungen bei älteren Patienten .................................................. - 4 - 1.2 Herausforderungen der geriatrischen Onkologie ..................................................................... - 5 - 1.3 Status Quo ................................................................................................................................. - 7 - 1.4 Geriatrisches Assessment (GA)................................................................................................ - 11 - 1.6 Geriatrisches Screening ........................................................................................................... - 13 - 1.5 Chemotherapie assoziierte Toxizität ....................................................................................... - 15 - 2 Ableitung der Studienrationale ...................................................................................................... - 17 - 3 Publikationsmanuskript .................................................................................................................. - 18 - 4 Zusammenfassung der Arbeit ........................................................................................................ - 26 - 5 Literaturverzeichnis der Einleitung ................................................................................................ - 29 - 6 Anlagen ........................................................................................................................................... - 35 - 7 Abkürzungsverzeichnis ................................................................................................................... - 52 - 8 Erklärung über die eigenständige Abfassung der Arbeit ................................................................ - 53 - 9 Lebenslauf – David Immanuel Kotzerke ......................................................................................... - 54 - 10 Spezifizierung des eigenen Beitrages ........................................................................................... - 56 - 11 Danksagungen .............................................................................................................................. - 58 -

No description available.

The presence of toxic order ow and predatory HFT strategies in a multi-market setting are scarcely researched in the academic world. This thesis studies the toxicity levels of a set of markets by examining unconsolidated quote data and firm specific trade data. A method for deducing the markets toxicity levels is presented along with proxies for toxic order ow, namely: changes in spread and quoted volume, following a trade in a given market. We find both signs of toxicity and different toxicity levels between the markets. However, the results are lacking in statistical significance but they show that this field is of great interest for further research. Also, the methods proposed for deducing the toxicity levels are rudimentary but could serve well as a premise for further development. / Närvaron av toxic order flow och predatoriska HFT-strategier i en flermarknadsmiljö är föga studerat i den akademiska världen. Denna avhandling studerar detta på en uppsättning marknader genom att undersöka okonsoliderad quote data och firma specifika trades, och på så vis ta fram marknadernas toxicity-nivåer. En metod för att fastställa marknadernas toxicity-nivåer presenteras tillsammans med proxys för toxic order flow, mer specifikt: förändringar i spread och quotad volym, efter en handel på en given marknad. Vi finner både tecken på toxicity och olika toxicityniv åer mellan marknaderna. Resultaten saknar dock statistisk signifikans men de visar ändå på att detta område är av stort intresse för ytterligare forskning. De metoder som föreslås för att fastställa toxicity-nivåerna är rudimentära, men kan tjäna som en utgångspunkt för vidare utveckling.

<p>  </p> <p>Perfluoroalkyl substances (PFAS) are synthetic chemicals that are composed of fluorinated aliphatic chains and are widely used in industrial and consumer products. These chemicals are very stable and persist in the environment. Due to concerns linked with longer chain PFAS, shorter chain chemicals are being used as replacements. There are limited human health data regarding the shorter chain chemicals. In addition, these alternatives are persistent in the environment similar to the longer chain PFAS. The main objective of this dissertation was to assess developmental toxicity of the shorter chain PFAS or shorter chain PFAS with chemical modifications represented by perfluorobutanoic acid (PFBA, C4), perfluorohexanoic acid (PFHxA, C6), perfluorobutane sulfonate (PFBS, C4), and perfluoro-2-proxypropanoic acid (GenX, C6). Overall, the results showed that chain length and functional group are determinants of toxicity of PFAS. All tested PFAS induced one or more developmental adverse outcome, but the effects of each chemical are unique, warranting further studies to address the toxicity of the replacement PFAS. </p>

Since their emergence in the early 1990s, neonicotinoid use has increased exponentially to make them the world's most prevalent insecticides. Although there is considerable research concerning the lethality of neonicotinoids, their sub-lethal and developmental effects are still being explored, especially with regards to non-mammalian species. The goal of this research was to investigate the effects of the neonicotinoid imidacloprid on the morphological and physiological development of northern bobwhite quail (Colinus virginianus). Bobwhite eggs (n = 650) were injected with imidacloprid concentrations of 0 (sham), 10, 50, 100 and 150 grams per kilogram of egg mass, which was administered at day 0 (pre-incubation), 3, 6, 9, or 12 of growth. Embryos were dissected on day 19 when they were weighed, staged, and examined for any overt structural deformities. Embryonic heart, liver, lungs and kidneys were also weighed and preserved for future use. Treated embryos exhibited increased frequency of severely deformed beaks and legs, as well as larger hearts and smaller lungs at the higher dosing concentrations. Some impacts are more pronounced in specific dosing periods, implying that there may be critical windows of development when embryos are highly susceptible to neonicotinoid exposure. This investigation suggests that imidacloprid could play a significant role in chick survival and declining quail populations in treated regions of the country.

Indiana University-Purdue University Indianapolis (IUPUI) / Monomers like triethylene glycol dimethacrylate (TEGDMA) leach from dental composites and adhesives due to incomplete polymerization or polymer degradation. The release of these monomers causes a variety of reactions that can lead to cell death. This death can be either necrotic, which is characterized mainly by inflammation and injury to the surrounding tissues, or apoptotic, which elicits little inflammatory responses, if any at all. TEGDMA-induced apoptosis in human pulp has been reported recently. However, the molecular mechanisms and the apoptotic (pro and anti) proteins involved in this process remain unclear. The objective of this study was to determine the apoptotic proteins expressed or suppressed during TEGDMA-induced apoptosis. Human pulp fibroblasts (HPFs) were incubated for 24 hours with different TEGDMA concentrations (0.125-1.0 mM). Cytotoxicity was determined using the cytotoxicity Detection KitPLUS (Roche Applied Science, Mannheim, Germany). TEGDMA was shown to cause cell cytotoxicity at concentrations of 0.50 mM and up. The highest concentration with no significant cytotoxicity was used. Cells were incubated with or without 0.25 mM TEGDMA for 6 h and 24 h. Cell lysates were then prepared and the protein concentrations determined using the Bradford protein assay. A Human Apoptosis Array kit (Bio-Rad Hercules, CA ) was utilized to detect the relative levels of 43 apoptotic proteins. The results of this study showed statistically significant increases of multiple examined pro-apoptotic proteins. The anti-apoptotic proteins were also altered. Pro-apoptotic proteins involved in the intrinsic and extrinsic apoptotic pathways were increased significantly. The results indicated that TEGDMA has effects on both the extrinsic and intrinsic apoptotic pathways.