Zusammenfassung Katharina Regina Winkler Hämatologisch-immunologische Verlaufsuntersuchungen bei Kühen mit Gebärparese Medizinische Tierklinik der Veterinärmedizinischen Fakultät der Universität Leipzig Eingereicht im September 2014 100 Seiten, 41 Abbildungen, 13 Tabellen, 282 Literaturangaben, 17 Seiten Anhang Schlüsselwörter: Gebärparese, Stoffwechsel, Glucocorticoide, Endotoxin, Blutbild Problemstellung: Der Mineralstoffwechsel unterliegt immunologischen Einflüssen. Vitamin-D3 ist essentiell für die Antigen- und Zytokinsynthesen in den Blutzellen. Die Osteoblastenreifung wird durch Zytokine beeinflusst. Das tangiert die Gebärparese (GP) und erschließt potentiell prophylaktische sowie therapeutische Ansätze. Zielstellung: Es wurde geprüft, ob a) es Mineralstoffunterschiede bei der GP-Diagnose und im Verlauf zu früheren Studien gibt, b) die Parameter Endotoxin (ET), anti-Lipid A-IgG-Titer (ALA-IgG-Titer) und Haptoglobin (Hp) sowie Leuko- und Erythrogramme gesicherte Beziehungen zur GP sowie zu Mineralstoffen und immunologischen Parametern haben, c) die Therapie bei GP durch Glucocorticoide verbessert werden kann und d) Jungkühe mehr Geburtsstress und Belastungen des Ca-Pi-K-Stoffwechsels haben. Versuchsanordnung: Untersucht wurden 111 HF-Kühe bzw. Jungkühe: 21 GP-Kühe mit Grundbehandlung, 22 GP-Kühe mit zusätzlicher Dexamethason-21-iso-ni-cotinat-Therapie (Dexa-IN), 40 gesunde Kontrollkühe (KG) und 28 gesunde Jungkühe. Laborkontrollen erfolgten bei den GP-Kühen vor der Therapie, bei den KG 1 - 3 Tage post partum (d p. p.) sowie 1 d und 14 d nach dem Therapiedatum. Analysiert wurden neben Stoffwechselparametern Endotoxin (LAL-Test), ALA-IgG-Titer, Haptoglobin sowie das Leuko- und Erythrogramm. Ergebnisse: Die Erstbehandlung war bei 47 % ohne und 67 % mit Dexa-IN-Therapie erfolgreich; die Heilungsrate betrug 74 bzw. 82 %, d. h., die Dexa-IN-Therapie verbesserte das Behandlungsergebnis bei GP ohne Nebenwirkungen. 69,8 % der GP-Kühe hatten eine kombinierte Hypokalz- und Hypophosphatämie. 24 Stunden nach Beginn der Therapie waren beide Mineralstoffe in den GP-Gruppen wieder physiologisch. 11,6 % der GP-Kühe und 10,7 % der Jungkühe hatten eine Hypophosphatämie. Das ist offensichtlich eine Folge des Kalbestresses in diesen Gruppen. Die Mg-, Na- und Cl-Konzentrationen waren in allen Gruppen physiologisch. Mg korrelierte negativ mit Ca und Pi (p<0,01). Die K-Konzentrationen waren in den GP-Gruppen einen d p. p. signifikant niedriger als in den KG. Sie korrelierten mit Ca- und Pi in den GP-Gruppen mit 0,42 bis 0,48 (p<0,01). Auf stärkere Stresseinflüsse auf K wiesen Korrelationen zu Glucose, Bilirubin, eosinophile und basophile Granulozyten sowie Lymphozyten hin. Die Fe-Konzentrationen der GP- und KG-Kühe waren physiologisch. Fe korrelierte mit ALA-IgG-Titer gesichert negativ. Die ET-Konzentrationen ließen nur schwache Beziehungen zur GP erkennen, wie rET:Ca=-0,17 (p<0,05). ET korrelierte mit den ALA-IgG-Titern gesichert positiv (Dexa-IN-Gruppe). Die ALA-IgG-Titer differierten bei den Kühen nicht gesichert, sie korrelierten nicht mit Ca, aber mit Pi und mit der Mehrzahl der klinisch-chemischen und hämatologischen Parameter. Das zeigt die Entzündungseinflüsse auf den Pi-Stoffwechsel mit der Förderung von Hypophosphatämien. Die Hp-Konzentrationen streuten stark und waren in allen Gruppen am Diagnose- und noch mehr am Folgetag erhöht (p>0,05). Bei Jungkühen wies der höhere Anstieg auf stärkeren Kalbestress hin. Die Leukozytenzahl war am GP-Diagnosetag erhöht (Leukozytose; p>0,05) und sank zum Folgetag in den Normbereich ab. In der Dexa-IN-Gruppe war der Abfall am stärksten (p<0,05). Die Leukozytenzahl korrelierte gesichert negativ mit den ALA-IgG-Titer sowie in den GP-Gruppen mit den Pi- sowie Ca-Konzentrationen, ebenso die neutrophilen Granulozyten. Eosinophile, basophile Granulozyten sowie Lymphozyten sanken p. p. ab (p<0,05) und korrelierten gesichert mit Ca und Pi. Die GP-Kühe hatten am Diagnosetag eine Monozytose (p<0,05). Die Monozyten korrelierten mit den ALA-IgG-Titern, mit dem Pi und dem Ca gesichert negativ. Sie hatten die engsten Beziehungen zum Entzündungsgeschehen sowie den Pi- und Ca-Konzentrationen. Die CK-Aktivitäten waren am Diagnose- und am Folgetag gegenüber der KG signifikant erhöht. Mit Ca korrelierte die CK in allen Kuh-Gruppen gesichert negativ, mit Pi nur in der GP-Gruppe ohne Dexa-IN. Die CK stand in enger gesicherter Beziehung zu Entzündungsindikatoren. Hämoglobin war in den GP-Gruppen am Diagnosetag signifikant, der Hämatokrit und die Erythrozytenzahlen tendenziell gesteigert. Schlussfolgerungen: Die Studie zeigt bei GP-Kühen vielfältige Beziehungen des Ca-Pi-K-Stoffwechsels zu Entzündungsindikatoren und legt ursächliche Einflüsse nahe, besonders zu ALA-IgG-Titern und Monozyten. Sie können Ursachen für Hypophosphat- und Hypokalämie sein. Zusätzliche Dexa-IN-Therapie verbessert das Behandlungsergebnis.

People who endure horrific, life-threatening experiences are at risk for developing post-traumatic stress disorder (PTSD). However, only about 25% of all individuals who experience trauma develop PTSD. Recent research indicates that the presence of certain physiological conditions, such as reduced cortisol and parasympathetic inhibition, during trauma may increase one's susceptibility to developing PTSD. Thus, I attempted to develop a novel animal model of PTSD and test the hypothesis that reduced adrenal and parasympathetic activity during stress would exacerbate its long-term effects on behavior.In Experiment One, adult male rats were exposed to two stress sessions, each involving one hour of immobilization plus cat exposure. Before each session, rats were injected with vehicle, metyrapone, AF-DX 116, or both drugs. The second session occurred 10 days after the first and served to model a traumatic flashback. Stressed rats endured unstable housing conditions throughout t he experiment to add an element of daily anxiety. Three weeks after the second session, all rats underwent a battery of tests to examine the lasting effects of stress on physiology and behavior. The results indicated that stressed rats exhibited heightened anxiety on the elevated plus maze, an exaggerated startle response, and greater blood pressure, relative to controls. Moreover, metyrapone, when combined with stress, led to significant short- and long-term spatial memory impairments. Experiment Two assessed the effects of the same stress paradigm on rats' sensitivity to yohimbine, an alpha-2 adrenergic receptor antagonist. Yohimbine induces flashbacks and panic attacks in patients with PTSD; thus, I hypothesized that stressed rats would react abnormally to this agent. Stressed and unstressed rats were administered vehicle or yohimbine (1 mg/kg) 30 min prior to behavioral testing. The results indicated that stressed rats were hyperresponsive to yohimbine, as evidenced by a greater su ppression of rearing, greater avoidance of the center of the open field, and a greater suppression of activity on the elevated plus maze, relative to controls. Collectively, the findings of these studies indicate that uncontrollable and unpredictable psychological stress produces lasting changes in the physiology and behavior of rats that resemble symptoms commonly observed in people with PTSD.

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Background: An important role has been suggested for tissue-specific glucocorticoid metabolism in the development of obesity and its complications. 11ß hydroxysteroid dehydrogenase 1 (11ßHSD1) is an enzyme that catalyzes the interconversion of biologically inactive cortisone to active cortisol, thereby regulating its access to glucocorticoid receptors in target tissues. Indeed, an unfavorable metabolic outcome has been associated with increased 11ßHSD1 gene expression and activity in adipose tissue and liver in humans and rodents. Cortisol is an important regulator of phosphoenolpyruvate carboxykinase (PEPCK) a key enzyme in gluconeogenesis and lipid metabolism. In rodents, overexpression of PEPCK in adipose tissue leads to adiposity and increased fatty acid re-esterification. In human obesity, PEPCK has been positively associated with body fat, total cholesterol levels, and plasma triglycerides. However, few studies have addressed the putative reversibility of peripheral cortisol levels and disturbed fatty acid homeostasis that may accompany weight loss. The aim of this thesis was to investigate alterations in peripheral glucocorticoid metabolism in the context of obesity, and putative modulations of glucocorticoid metabolism in the context of weight changes in humans and rodents. Materials &amp; Methods: 11ßHSD1 expression/activity in different adipose tissue depots and liver, the expression of genes involved in adipogenesis and fatty acid homeostasis, and serum levels of adipose tissue-derived adipokines were investigated in severely obese women before and after surgically induced weight loss. The same parameters were measured in female Sprague-Dawley rats fed on high-fat and control diets. Results: In severely obese women, 11ßHSD1 expression was higher in subcutaneous adipose tissue (SAT), while 11ßHSD1 activity and PEPCK expression were higher in the omental depot. In a multivariate analysis, SAT 11ßHSD1 activity was an independent predictor for central fat accumulation. Hepatic 11ßHSD1 activity and levels of intra-abdominal fat storage correlated negatively, while 11ßHSD1 correlated positively with PEPCK in adipose tissue and liver. Weight loss after gastric bypass surgery was followed by significant and metabolically beneficial reductions in subcutaneous 11ßHSD1 and leptin gene expression, as well as reduced circulating leptin and increased adiponectin levels. In contrast, PEPCK gene expression did not change with weight loss. In rats, a high-fat diet did not affect body weight, but was associated with increased serum leptin and decreased adiponectin levels. Short-term, high-fat diet feeding resulted in the up-regulation of SAT 11ßHSD1 expression, while chronic feeding led to its significant down-regulation (compared with the control diet and short-term, high-fat feeding). Interestingly, hepatic 11ßHSD1 expression was constantly downregulated in rats that were fed a high-fat diet. Conclusions: Severe obesity in women was accompanied by a metabolically adverse increase of 11ßHSD1 in adipose tissue, with a concomitant decrease in the liver. Subcutaneous 11ßHSD1 was an independent predictor for central fat accumulation. As weight loss was followed by significant down-regulation of subcutaneous 11ßHSD1, we suggest that up-regulation of this enzyme was a consequence, rather than a cause of obesity. In rodents, a high-fat diet induced dynamic changes in 11ßHSD1 in SAT and liver, both being down-regulated after chronic high-fat feeding without altered weight. In summary, weight changes and alterations in fat and liver glucocorticoid metabolism are closely linked. Moreover, a high-fat diet significantly influences 11ßHSD1 expression/activity in adipose tissue and liver without affecting body weight.

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Mountain caribou (Rangifer tarandus caribou) are endangered in British Columbia and motorized backcountry recreation has been identified as a potential threat to their persistence. My objective was to test if fecal glucocorticoids (GCs), indicative of physiological effects of ecological stress in wildlife, could be used as a non-invasive tool to quantify stress response in free-ranging caribou exposed to motorized recreation. I validated an enzyme-linked immunosorbent assay (ELISA) to measure concentration of fecal GCs for R. tarandus using an adrenocorticotropic hormone (ACTH) challenge experiment on captive reindeer exposed to extreme variation in winter weather. Female reindeer expressed elevated fecal GCs 9-11 hrs after ACTH injection. Males showed no detectable increase, perhaps due to underdosing. Fecal GCs varied markedly in both sexes in response to natural variation in weather. Overall, my results indicated fecal assays can be used to track biologically meaningful changes in adrenal activity in R.tarandus. I investigated the effects of motorized recreation on stress hormone production by measuring GCs in feces of mountain caribou exposed to snowmobile and heli-ski activity. Concentrations of fecal GCs in snowmobile and heli-ski areas were higher than those measured from caribou in areas where motorized recreation was not allowed. Caribou sampled up to 4km. 8km and I0 km distant from snowmobile activity showed elevated fecal GCs when compared to those sampled further from snowmobile activity areas. Other variables with a significant effect on fecal GCs included reproductive state, snow, aspect. minimum ambient temperature, and daily temperature range. My study indicates that measurement of fecal GCs provides a useful, noninvasive approach in the evaluation of physiological effects of environment, reproductive state, and human-induced stressors on free-ranging mountain caribou. Although research on many species indicates that chronically elevated GCs carry a variety of physiological costs, more study is needed to know whether GCs can be used as an index of human impact on population health or trend.

Glucocorticoids are commonly used to treat cows with clinical ketosis and fatty liver disease. This study investigated the effects of 10 mg/mL of FlucortRTM and PredefRTM 2X on the day of calving on blood metabolites, immune function and milk composition on 30 transitional Holstein cows. Sample of blood and milk were analyzed for energy metabolites (glucose, NEFA, BHB and insulin), mineral metabolites (Ca, P, Na, K, Cl and Mg), energy function parameters (antibody, lymphocyte), milk compositional parameters (protein, fat, lactose, SCC). There were no differences in glucose, Na, Cl, Mg, antibody, lymphocyte and milk fat, were observed among treatments. FlucortRTM treated cows had significantly lower NEFA on D1, higher BHB on D21 and D28, lower insulin on D14, higher Ca on D1 and lower P on D1. PredefRTM 2X treated cows had significantly higher BHB on D21, higher insulin on D7, lower Ca on D1, higher SCC on D1 and higher milk protein on D1. With respect to the significant data in this study, the use of glucocorticoids FlucortRTM and Predef RTM 2X in a single intramuscular injection on d1 for the treatment of ketosis is not warranted.