O presente estudo foi subdividido em duas partes: análises genéticas e análises econômicas. A primeira teve por objetivos definir modelos de avaliação genética para as características de desempenho e carcaça em uma linhagem comercial de frangos e estimar os parâmetros genéticos e fenotípicos para essas características. A segunda parte teve por objetivos derivar os ponderadores econômicos para essas características de acordo com dois segmentos de mercado de carne de frango e propor índices econômicos de seleção para esses segmentos. As características avaliadas foram: taxa de conversão alimentar (CA), peso corporal à seleção juvenil (PC), pesos de carcaça (PCAR), carne de peito (PPEI) e pernas (PPER), rendimentos de carcaça (RCAR), carne de peito (RPEI) e pernas (RPER). As estimativas dos componentes de (co)variância foram obtidas pelo método de máxima verossimilhança restrita utilizando os programas MTDFREML e VCE-6. O teste de razão de verossimilhança foi utilizado para verificar qual o modelo mais adequado à avaliação genética para cada característica. Para a obtenção dos ponderadores econômicos foi desenvolvido um modelo bioeconômico determinístico e a análise econômica foi simulada para uma cadeia de produção de frangos integrada. Foi proposto um índice de seleção para o segmento de mercado frango inteiro e outro para cortes de frango. Foram obtidas estimativas de correlação por postos de Spearman entre os valores preditos pelos dois índices para três intensidades de seleção. Os efeitos de ambiente permanente materno e genético aditivo materno foram significativos (P<0,01) para todas as características. As estimativas de herdabilidade direta e materna foram 0,29 e 0,02 para CA, 0,45 e 0,05 para PC, 0,17 e 0,04 para PCAR, 0,26 e 0,06 para PPEI, 0,22 e 0,02 para PPER, 0,31 e 0,02 para RCAR, 0,53 e 0,04 para RPEI, e 0,44 e 0,02 para RPER, respectivamente. Os ponderadores econômicos foram -1,1783 R$/ponto para CA, 0,007 e 0,006 R$/g para PC respectivamente para o segmento de mercado frango inteiro e cortes de frango, 0,0552, 0,0758 e 0,0629 R$/% para RCAR, RPEI e RPER, respectivamente. Os resultados sugerem que todas as características podem ser selecionadas esperando progresso genético na população estudada. Os efeitos maternos foram importantes, mesmo de pequena magnitude (0,02 a 0,06), e devem ser considerados nos modelos de avaliação genética a fim de obter maior acurácia da predição dos valores genéticos individuais. A CA representou relevante impacto econômico para os dois segmentos de mercado. Para o segmento de mercado cortes de frango, as características de carcaça foram quase tão importantes quanto às de desempenho. A classificação das aves gerada pelos dois índices foi alterada à medida que diminuiu a proporção de aves selecionadas. Portanto, índices de seleção distintos devem ser considerados nos programas de melhoramento de frangos enquanto segmentos diferentes de mercado de carne de frango na proposta de maior eficiência econômica da utilização do mérito genético predito. / The present research was subdivided in two parts: genetic analyses and economic analyses. The first part was conducted to determine models for genetic evaluation of performance and carcass traits in a commercial broiler line and to estimate genetic and phenotypic parameters for these traits. The second part was conducted to derive economic weights for these traits according to two market segments of broiler meat and to propose economic selection indexes for these segments. The traits analyzed were: feed conversion ratio (CA), body weight at juvenile selection (PC), carcass (PCAR), breast meat (PPEI) and leg (PPER) weights, and carcass (RCAR), breast meat (RPEI) and leg (RPER) yields. Estimates of the (co)variance components were obtained by the restricted maximum likelihood method by the software MTDFREML and VCE-6. The likelihood ratio test was applied in order to verify which model was more adapted to the genetic evaluation for each trait. A deterministic bioeconomic model was developed for the derivation of economic weights and the economic analysis was simulated for an integrated broiler production system. It was proposed a selection index for the market segment of whole carcass and another for cuts. Spearman correlation estimates among predicted values from the two indexes were obtained for three selection intensities. For all traits, the maternal genetic and permanent environmental effects were significant (P<0.01). The estimates of direct and maternal heritability were 0.29 and 0.02 for CA, 0.45 and 0.05 for PC, 0.17 and 0.04 for PCAR, 0.26 and 0.06 for PPEI, 0.22 and 0.02 for PPER, 0.31 and 0.02 for RCAR, 0.53 and 0.04 for RPEI, and 0.44 and 0.02 for RPER, respectively. The economic weights were -1.1783 R$/point for CA, 0.007 and 0.006 R$/g for PC respectively for the market segment of whole carcass and cuts, 0.0552, 0.0758 and 0.0629 R$/% for RCAR, RPEI and RPER, respectively. The results suggest that traits analyzed can be selected and genetic progress will be expected. Maternal effects were important, even of small magnitude (0.02 to 0.06), and should be considered in genetic evaluation models in order to obtain accurate prediction of the breeding values of the individuals. The CA represented significant economic impact for the two market segments. For the market segment of cuts, carcass traits were almost as important as the performance traits. The classification of chickens generated by the two selection indexes was changed as the proportion of selected chickens decreased. Therefore, different selection indexes should be considered in broiler breeding programs while different segments of broiler meat market in the proposal for greater economic efficiency in the use of predicted genetic merit.

No description available.

Colon cancer is one of the most commonly diagnosed cancers in the US, yet small intestine cancer is a rare event. While there are many similarities between these two tissues, inherent differences such as redox status, may contribute to the variation in cancer occurrence. We examined the difference in reactive oxygen species (ROS) generation, antioxidant enzyme activity and oxidative DNA damage in the small and large intestine of rats under normal conditions and following exposure to exogenous oxidative stress. Basal ROS and antioxidant enzyme activities were greater in the colon than the small intestine, and the balance of ROS to antioxidant enzymes in the colon was more pro-oxidant than in the small intestine. During oxidative stress, ROS and oxidative DNA damage were greater in the colon than the small intestine. Thus the colon responds to oxidative stress less effectively than the small intestine, possibly contributing to increased cancer incidence at this site. We next wanted to understand how diets containing a combination of fish or corn oil and pectin or cellulose may alter the redox environment of the colon. ROS, oxidative DNA damage, antioxidant enzyme activity and apoptosis were measured in colonocytes of rats fed one of four diets containing either corn oil or fish oil and cellulose or pectin. Measurements were madein rats untreated with carcinogen and rats exposed to a chemical carcinogen and radiation. In rats not treated with a carcinogen, fish oil enhanced ROS, and fish oil/pectin suppressed antioxidant enzymes as compared to corn oil/cellulose. Oxidative DNA damage was inversely related to ROS in the fish oil/pectin diet and apoptosis was enhanced relative to other diets. In carcinogen treated and irradiated rats, a similar protective effect was seen with fish oil/pectin as evidenced by a reduction in oxidative DNA damage and enhancement of apoptosis. This suggests that a diet containing fish oil/pectin may protect against colon carcinogenesis by modulation of the redox environment to promote apoptosis and minimize oxidative DNA damage.

In chronic inflammatory diseases like asthma or rheumatoid arthritis, erroneous and exaggerated accumulation of leukocytes in a tissue inadvertently causes the body harm. Several efficient anti-inflammatory drugs exist, for example corticosteroids and cyclo-oxygenase inhibitors. However, these drugs have potent and diverse effects and often act by inhibiting events subsequent to initiation of the inflammatory response, leading to more or less severe side-effects, especially when used in high doses for long periods of time. For this reason, strategies aimed at early inhibition of recruitment and activation of leukocytes have been suggested as safer and more specific approaches to reduce inflammation. Leukocyte adhesion to activated endothelium is a prerequisite to the following activation and extravasation, and takes place in the initial phase of inflammation. By using a model that allows leukocytes to adhere to tumour necrosis factor (TNF)-activated endothelial cells, thus mimicking aspects of an inflammatory reaction, we found that uridine, 4-thiouridine and isomaltitol could all reduce adhesion. This suggested that they may have anti-inflammatory potential. We therefore tried the three substances in a Sephadex-induced lung inflammation model and found that uridine and 4-thiouridine have several anti-inflammatory effects, such as being able to reduce leukocyte accumulation, decrease TNF protein levels and partly inhibit the oedema induced by Sephadex. Isomaltitol turned out to have immunomodulating, rather than anti-inflammatory, effects, which could be of interest in diseases where inadequate inflammatory responses are a problem.

One-lung ventilation (OLV) as an established procedure during thoracic surgery may be injurious in terms of increased mechanical stress characterised by alveolar cell stretch and overdistension, increased cyclic tidal recruitment of alveolar units, compression of alveolar vessels and increased pulmonary vascular resistance. This may result in ventilation-induced lung injury with pro-inflammatory cytokine production, leukocyte recruitment and neutrophil-dependent tissue destruction. Despite the consequences of delivering the whole tidal volume (VT) to only a single lung, relatively high VT are used during OLV to maintain arterial oxygenation and carbon dioxide elimination. However, this may increase mechanical stress in the dependent lung and may aggravate alveolar injury. There is a lack of data on the alveolar immune consequences of OLV. Therefore, the present studies investigate the epithelial damage and pro-inflammatory response induced by mechanical ventilation and OLV. OLV induced pulmonary injury, but alveolar damage in the ventilated lung decreased by reduction of the tidal volume in patients scheduled for thoracic surgery (study I). The use of the volatile anaesthetic desflurane in OLV patients attenuated the OLV-induced alveolar immune response (study II). Furthermore, an experimental model of thoracic surgery was established to investigate the systemic and pulmonary consequences of OLV and thoracic surgery in comparison with the effects of conventional two-lung ventilation and spontaneous breathing. The experimental data indicate that beside the pulmonary immune response volatile anaesthetics have also modulated the plasma concentrations of cytokines during and after OLV (study III). In contrast, OLV and thoracic surgery increased the expression of pro-inflammatory mRNA in BAL cells and lung tissue samples. General anaesthesia did not affect this response (study 4). The results of the present studies indicate that OLV and thoracic surgery may be injurious to the lung tissue to a similar degree. The recruitment and activation of alveolar granulocytes characterise the alveolar damage. The administration of different anaesthetics modulates the activation of alveolar cells, specified by decreased inflammatory mediator release in subjects that receive desflurane anaesthesia, which does not affect the expression of cytokine mRNA in alveolar cells and lung tissue samples.

Sepsis-induced organ failure is associated with high morbidity and mortality rates. The onset of an exaggerated host response to microbial invasion and/or trauma, is believed to be the primary cause of excessive inflammation and the subsequent tissue hypoperfusion observed in patients with severe sepsis. In our mouse model of sepsis induced by cecal ligation and perforation (CLP), symptoms indicative of the disease, including diarrhea, increased ventilation and persistent hypothermia, are present at six hours after the surgery (T6). In the untreated CLP mice, mortality occurs starting at T15. As induced hypothermia has shown to exert immunomodulatory effects, this study is aimed at assessing its potential in attenuating inflammation and improving survival in experimental sepsis. Our data has shown that deep hypothermia initiated at T6, by means of cold chamber-induced cooling, prolongs survival. Plasma cytokine quantification by enzyme-linked immunosorbent assays (ELISA) also reveals that induced deep hypothermia reduces tumour necrosis factor(TNF)-α and interleukin (IL)-6 production in untreated CLP mice. In contrast, induced moderate hypothermia does not have such effect. Antibiotic (cefotaxime) and saline resuscitation initiated immediately following CLP ensures survival. However, when these supportive treatments are initiated at T6, >50% mortality is observed in the CLP mice with or without induced hypothermia. In summary, this preliminary study provides proof for a downregulated inflammatory response mediated by external cooling. However, to achieve a survival benefit, treatment strategies in addition to cooling and antibiotics may be required.

Sepsis-induced organ failure is associated with high morbidity and mortality rates. The onset of an exaggerated host response to microbial invasion and/or trauma, is believed to be the primary cause of excessive inflammation and the subsequent tissue hypoperfusion observed in patients with severe sepsis. In our mouse model of sepsis induced by cecal ligation and perforation (CLP), symptoms indicative of the disease, including diarrhea, increased ventilation and persistent hypothermia, are present at six hours after the surgery (T6). In the untreated CLP mice, mortality occurs starting at T15. As induced hypothermia has shown to exert immunomodulatory effects, this study is aimed at assessing its potential in attenuating inflammation and improving survival in experimental sepsis. Our data has shown that deep hypothermia initiated at T6, by means of cold chamber-induced cooling, prolongs survival. Plasma cytokine quantification by enzyme-linked immunosorbent assays (ELISA) also reveals that induced deep hypothermia reduces tumour necrosis factor(TNF)-α and interleukin (IL)-6 production in untreated CLP mice. In contrast, induced moderate hypothermia does not have such effect. Antibiotic (cefotaxime) and saline resuscitation initiated immediately following CLP ensures survival. However, when these supportive treatments are initiated at T6, >50% mortality is observed in the CLP mice with or without induced hypothermia. In summary, this preliminary study provides proof for a downregulated inflammatory response mediated by external cooling. However, to achieve a survival benefit, treatment strategies in addition to cooling and antibiotics may be required.

Colon cancer is one of the most commonly diagnosed cancers in the US, yet small intestine cancer is a rare event. While there are many similarities between these two tissues, inherent differences such as redox status, may contribute to the variation in cancer occurrence. We examined the difference in reactive oxygen species (ROS) generation, antioxidant enzyme activity and oxidative DNA damage in the small and large intestine of rats under normal conditions and following exposure to exogenous oxidative stress. Basal ROS and antioxidant enzyme activities were greater in the colon than the small intestine, and the balance of ROS to antioxidant enzymes in the colon was more pro-oxidant than in the small intestine. During oxidative stress, ROS and oxidative DNA damage were greater in the colon than the small intestine. Thus the colon responds to oxidative stress less effectively than the small intestine, possibly contributing to increased cancer incidence at this site. We next wanted to understand how diets containing a combination of fish or corn oil and pectin or cellulose may alter the redox environment of the colon. ROS, oxidative DNA damage, antioxidant enzyme activity and apoptosis were measured in colonocytes of rats fed one of four diets containing either corn oil or fish oil and cellulose or pectin. Measurements were madein rats untreated with carcinogen and rats exposed to a chemical carcinogen and radiation. In rats not treated with a carcinogen, fish oil enhanced ROS, and fish oil/pectin suppressed antioxidant enzymes as compared to corn oil/cellulose. Oxidative DNA damage was inversely related to ROS in the fish oil/pectin diet and apoptosis was enhanced relative to other diets. In carcinogen treated and irradiated rats, a similar protective effect was seen with fish oil/pectin as evidenced by a reduction in oxidative DNA damage and enhancement of apoptosis. This suggests that a diet containing fish oil/pectin may protect against colon carcinogenesis by modulation of the redox environment to promote apoptosis and minimize oxidative DNA damage.

Modification of the radiation response of oral mucosa (mouse) by inhibition of nitric oxide synthase via nitro-L-arginin-methyl-ester (L-NAME)

Die Mucositis enoralis ist eine häufige und dosislimitierende Nebenwirkung der Strahlentherapie von Kopf-Hals-Tumoren. Die zugrunde liegenden Pathomechanismen sind komplex und beinhalten die Reaktionen und Interaktionen von Epithelzellen, Fibroblasten, Makrophagen und Gef¨aßendothelzellen. Dies schließt die vermehrte Bildung von Stickstoff-Monoxid (NO) in Folge einer Stimulation der induzierbaren NO-Synthase (iNOS) ein. Ziele der Untersuchungen: Ziel der vorliegenden Arbeit ist es, die Wirkung von L-NAME (nitro-L-Arginin-Methyl-Ester), einem unselektiven Inhibitor der NOS, auf die Strahlenreaktion der oralen Mukosa im etablierten Tiermodell der Schleimhaut der Zungenunterseite der Maus zu untersuchen. Materialien und Methoden: Die Untersuchungen erfolgen mit Mäusen des InzuchtWildtypstammes C3H/Neu. Als Bestrahlungstechniken kommen die perkutane Schnauzenbestrahlung (200 kV Röntgenstrahlung) und/oder die lokale Bestrahlung (25 kV Röntgenstrahlung) eines 3·3 mm2 großen Testfeldes der Zungenunterseite der Maus zum Einsatz. In Fraktionierungsprotokollen werden 5x3 Gy/Woche über 1 (Tage 04) sowie 2 Wochen (Tage 0-4, 7-11) auf die gesamte Schnauze der Tiere appliziert. Anschließend erfolgt eine lokale Aufsättigungsbestrahlung mit gestaffelten Dosen (5 Dosisgruppen, je 10 Tiere) zur Generierung kompletter Dosis-Effekt-Kurven (Tag 7 bzw. 14). Einzeitbestrahlungen des lokalen Testfeldes finden ebenfalls mit gestaffelten Dosen statt. L-NAME (täglich 0,2 mg/kg i.p.) wird an den Bestrahlungstagen 30 Minuten vor der Bestrahlung appliziert. Bei Einzeitbestrahlung werden 2 verschiedene Behandlungszeiträume getestet: 3 Tage vor der Bestrahlung bis zur Erstdiagnose (-3/D) oder Ausheilung der Ulzerationen (-3/H). In Kombination mit fraktionierter Bestrahlung über 1 Woche werden 3 Zeiträume untersucht (-3/7, -3/D oder -3/H). Bei 2 Wochen fraktionierter Bestrahlung erfolgt die L-NAME-Gabe in folgenden Intervallen: -3/7, -3/D, -3/H, -3/14 oder 7/14. Als quantaler Endpunkt für Dosis-EffektAnalysen dient die Ulzeration der Schleimhaut im Testfeld. Mittels Logit-Analyse werden Dosis-Effekt-Beziehungen ermittelt. Der ED50-Wert und dessen Standardabweichung σ dienen der Charakterisierung der Dosis-Effekt-Kurven. In histologischen Untersuchungen werden maximal 10 Fraktionen zu 3 Gy über 2 Wochen appliziert, mit/ohne Gabe von L-NAME von Tag -3 bis zur Tötung. Die Zungenentnahme erfolgt bei je 5 Tieren in zweitägigen Abständen (Tag 1 bis 25). Ergebnisse: Für die alleinige Einzeitbestrahlung ergibt sich eine signifikante Dosisabhängigkeit der Ulkusinzidenz mit einer ED50 von 13,6±1,0 Gy. Die mittlere Latenzzeit beträgt 10,6±1,1 Tage, die durchschnittliche Ulkusdauer 3,5±1,0 Tage. Nach alleiniger einwöchig fraktionierter Bestrahlung beträgt die ED50 der Testbestrahlung 12,3±0,8 Gy. L-NAME von Tag -3 bis Tag 6 bzw. -3/D hat keinen signifikanten Einfluss (ED50 13,3±1,2 Gy bzw. 12,8±1,0 Gy). Lediglich für den Applikationszeitraum Tag -3/H kann eine signifikante Erhöhung der ED50 auf 14,7±1,7 Gy (p=0,0298) nachgewiesen werden. Die Testbestrahlung nach 2-wöchiger Fraktionierung ohne L-NAME ergibt eine ED50 von 13,0±0,1 Gy. L-NAME hat wiederum keinen signifikanten Einfluss auf die Strahlenempfindlichkeit der Mundschleimhaut (ED50-Werte: -3/6 - 12,9±0,1 Gy, -3/14 - 13,0±0,1 Gy, -3/H - 13,8±1,4 Gy und 7/14 - 13,1±0,8 Gy). Während alleiniger fraktionierter Bestrahlung nimmt die Zellzahl zunächst ab (Tag 11: 70 %). Im Anschluss steigt sie über das Ausgangsniveau (Tag 19: 126 %). F¨ur die L-NAME-behandelte Schleimhaut findet sich ein qualitativ vergleichbarer Verlauf; es zeigt sich lediglich eine geringfügige Erhöhung der Zellzahl in der funktionellen Schicht (150 % statt 140 %). Die Epitheldicke nimmt unter L-NAME-Behandlung in den ersten Tagen der Nachbeobachtungszeit deutlich zu. Schlußfolgerungen: Zusammenfassend erweist sich in der vorliegenden Arbeit nur die L-NAME-Applikation -3/H bei einwöchig fraktionierter Bestrahlung als wirksam, wobei der Grund f¨ur diese selektive Wirkung unklar bleibt. Offensichtlich sind NOvermittelte Prozesse ohne substanzielle Relevanz f¨ur die epitheliale Strahlenreaktion der Mundschleimhaut. Auf der Basis dieser Ergebnisse ist die Hemmung von iNOS durch L-NAME keine aussichtsreiche Strategie zur Reduktion der radiogenen Mucositis enoralis, und sollte deshalb auch nicht in klinischen Studien verfolgt werden. Die Frage, ob andere (i)NOS-Hemmstoffe ein mukoprotektives Potential besitzen, sollte in weiteren, translationalen strahlenbiologischen Studien geklärt werden.