Spontaneous foetal loss is the most common complication of pregnancy, affecting up to 20% of recognized pregnancies and recurring in 1-3% of cases. Abnormal maternal inflammation and systemic maternal coagulopathies are associated with foetal loss; however, the causal role of inflammation in the development of obstetric coagulopathies has not been determined. Further, questions remain as to whether maternal systemic coagulopathies are associated with placental haemostatic alterations and what role these local alterations play in foetal outcome. We hypothesized that abnormal maternal inflammation during pregnancy is causally linked to maternal coagulopathies and that these coagulopathies are associated with impaired utero-placental blood flow preceding foetal death. To induce inflammation-mediated fetal death, we administered lipopolysaccharide (LPS; 100-µg/kg) to Wistar rats on gestational day 14.5 and characterized the systemic maternal coagulation status 1hr post LPS administration using thromboelastograpy. Utero-placental haemostatic alterations were analyzed by periodic acid Schiff staining (PAS) and immunohistochemistry for fibrin/fibrinogen. Spiral arteriole peak flow velocity was determined by Doppler ultrasound. To determine causality between abnormal maternal inflammation, coagulopathies, and placental hemodynamics, the TNF -inhibitor etanercept (Enbrel®) was administered six hours prior to LPS administration. Systemic maternal coagulopathies were evident in 82% of LPS-treated dams and were associated with specific placental haemostatic alterations as well as reduced utero-placental blood flow. Etanercept administration prevented the development of systemic coagulopathies and placental haemostatic alterations. Furthermore, etanercept maintained normal spiral arteriole peak flow velocity. This study demonstrated that abnormal maternal inflammation is causally linked to systemic coagulopathies specific to pregnancy. Moreover, we showed that inflammation-induced systemic coagulopathies are associated with placental haemostatic alterations and reduced utero-placental blood flow preceding foetal death. Modulation of maternal inflammation may thus be useful in the prevention of coagulopathies associated with complications of pregnancy. / Thesis (Master, Anatomy & Cell Biology) -- Queen's University, 2011-08-01 14:29:12.489

Seventeen wk old male obese Zucker rats were given 0.4% (w/w) conjugated linoleic acid (CLA) isomers for 8 wk to determine effects of specific isomers on multiple eicosanoids in obesity. Liquid-chromatography-mass spectrometry analysis showed that compared to controls, those given t10,c12 CLA had increased liver leukotriene B4 levels, while immunoblotting revealed that rats given either t10,c12 or c9,t11 CLA had lower liver cyclooxygenase-2. In kidney, compared to c9,t11 CLA or controls, t10,c12 CLA increased cyclooxygenase-1, 6-keto-prostaglandin F2α and thromboxane B2 and inhibited the in vitro production of 13-hydroxyoctadecadienoic acid and 5-, 8-, 12- and 15-hydroxyeicosatetraenoic acid. In lean compared to fa/fa rats, endogenous levels and in vitro production of liver and kidney 9- and 13-hydroxyoctadecadienoic acid were elevated. Previous investigations on these tissues revealed that t10,c12 CLA reduced hepatic steatosis, but increased renal damage. How these changes in eicosanoids in response to t10,c12 CLA relate to the previous findings remains to be elucidated.

Children and adolescents are regular consumers of caffeine, and their consumption is increasing. Caffeine has been shown to affect the later behaviour of rats and mice when exposed to the drug daily before birth and during the lactational period of development. However, to date, little research has investigated the effects caffeine consumption may have on adolescent brain development, and the behavioural consequences of this. The present study, therefore, investigated the effects of repeated caffeine exposure on adolescent rats on behavioural measures of anxiety. During middle and later adulthood, the rats’ activity and emotional reactivity were assessed by means of frequencies of rearing, ambulation, immobility, defaecation and urination recorded in an open field, as well as their occupancy of corners and centre squares of the field, and their partial emergence and latencies to fully emerge from a small darkened chamber into a brightly lit arena. The results showed that those rats treated with caffeine were probably more emotionally reactive than untreated controls, as suggested by more immobility, defaecation and urination. There were also effects on rearing and ambulation that might have arisen from increased impulsivity. Overall, the results suggest that exposure to caffeine during adolescence produces some small but significant increases in emotionality in adulthood. This study may have clinical implications, as it is possible that people exposed to caffeine as adolescents, may show increased anxiety later in life.

No description available.

Qualitative and quantitative ultrastructural observations have been made on myelinated fibres in the tibial and medial plantar nerves of genetically diabetic C57/BL/Ks(db/db) and age-matched nondiabetic (m/m) control mice at 9 and 15 months of age. The cross sectional area of myelinated fibres and their axons in both nerves was found to be significantly less in diabetic mice when compared with age-matched controls. No age related decrease in axon or fibre size was noted in the diabetic at either site. The number of myelin lamellae was found to be proportionate for axon size in the tibial nerve. In the medial plantar nerve regenerated and remyelinated fibres were frequently encountered in both diabetic and age-matched controls, but were more numerous in some fascicles of diabetic animals. The morphometric data from this site was more complex, plottings of myelin area against axonal area showed a greater scatter in the 15 months diabetic group, reflecting the heterogeneity of the fibre population at this site. Plotting g ratio against axon diameter provided a rather neat way of breaking the fibre population into its component parts. The index of circularity of myelinated axons did not differ between diabetic and control animals at 15 months in the tibial nerve. However, in the plantar nerve mean axonal index of circularity was found to be significantly less in diabetic mice when compared with age-matched controls at 9 and 15 months. Axonal glycogenosomes, polyglucosan bodies, axonal compartmentalisation by Schwann cell processes and Pi granules of Reich were assessed for diabetic and control mice at both sites. Only axonal glycogenosomes were significantly more numerous in the diabetic groups. The absence of a selective reduction of axonal size in the tibial nerve in the diabetic mice did not favour a primary axonopathy. As growth in tibial bone length was reduced in these mice the reduction in fibre calibre may be due to a maturational deficit; ultrastructural abnormalities in the medial plantar nerve may suggest a pressure type neuropathy. Male Sprague Dawley rats aged 20 - 21 weeks were made diabetic with streptozotocin and maintained for 2, 4 and 6 months. Myelinated fibre area increased significantly in the tibial nerve of controls over the period of study. Fibre area in the diabetic animals was significantly less than age-matched controls at 4 and 6 months but not less than onset. Axonal perimeter was found to be significantly less in diabetic animals at 2 and 6 months when compared with age-matched controls. No significant difference was detected in the cross sectional area of axons between diabetic and age-matched controls at 2 and 4 months but was significantly less in the diabetic animals at 6 months as compared with age-matched controls (P 0.05). There was no significant difference in axonal index of circularity between diabetic and age-matched controls at 4 and 6 months, mean axonal index of circularity was significantly greater in the diabetic nerves at 2 months when compared with age-matched controls. With regard to myelin sheath thickness, the number of myelin lamellae was related in various ways to axonal dimensions. The highest correlation was found when cross sectional axonal area was related to myelin area, which was estimated from number of myelin lamellae and periodicity. Regression analysis revealed that the slope for control nerves was significantly steeper than diabetics at 4 and 6 months, suggesting a greater effect on myelin area. Myelin area estimates were significantly less in diabetic at 2, 4 and 6 months when compared with age-matched controls, but not less than onset. There was no significant difference in the incidence of the various organelles between diabetic and age-matched controls at any survival period. However, there was a border line increase in axonal glycogenosomes in the diabetics at 6 months. This study may suggest that there is a maturational deficit in nerve fibre size and myelination in streptozotocin induced diabetes in the rat.

It has been reported that the presence of Fc receptor blocking antibodies is associated with normal pregnancy and improved cadaver donor renal transplant survival. The demonstration of the development of such antibody activity in the animal model during one or more pregnancies and the effect of these pregnancies on the survival of a subsequent renal allograft form the major aims of the studies presented in this thesis.A microsurgical laboratory was therefore established at Aberdeen University and the rat renal transplant model developed. Fc receptor blocking activity was assessed using the EA inhibition assay.The results indicate that:I Fc receptor blocking activity was not found in the sera of virgin rats.2 Significant levels of these antibodies were only found after two pregnancies and they occurred in 50% of such cases3 Primiparous animals and those multiparous animals which did not develop EA inhibiting activity rejected renal allografts from the paternal strain in the same time as virgin animals.4 Only multiparous rats sharing over 30% EA inhibition failed to reject transplants carrying paternal specificities. Those animals were capable of rejecting grafts from third party donors suggesting that the Fc receptor blocking antibodies were directed towards paternal antigens.It is therefore suggested that Fc receptor blocking activity occurring as a result of pregnancy in the rat renal transplant model may enhance a renal allograft from the paternal strain. These antibodies may therefore represent a form of donor specific immunosuppression.

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Seventeen wk old male obese Zucker rats were given 0.4% (w/w) conjugated linoleic acid (CLA) isomers for 8 wk to determine effects of specific isomers on multiple eicosanoids in obesity. Liquid-chromatography-mass spectrometry analysis showed that compared to controls, those given t10,c12 CLA had increased liver leukotriene B4 levels, while immunoblotting revealed that rats given either t10,c12 or c9,t11 CLA had lower liver cyclooxygenase-2. In kidney, compared to c9,t11 CLA or controls, t10,c12 CLA increased cyclooxygenase-1, 6-keto-prostaglandin F2α and thromboxane B2 and inhibited the in vitro production of 13-hydroxyoctadecadienoic acid and 5-, 8-, 12- and 15-hydroxyeicosatetraenoic acid. In lean compared to fa/fa rats, endogenous levels and in vitro production of liver and kidney 9- and 13-hydroxyoctadecadienoic acid were elevated. Previous investigations on these tissues revealed that t10,c12 CLA reduced hepatic steatosis, but increased renal damage. How these changes in eicosanoids in response to t10,c12 CLA relate to the previous findings remains to be elucidated.