Woodchucks are the preferred animal model to study chronic viral hepatitis and the development of hepatocellular carcinoma (HCC), which occurs as a result of infection with woodchuck hepatitis virus. Significant elevations in the phosphomonoester peak in 31P-MRS spectrum correlated to the presence of HCC. Ex vivo 31P-NMR determined that HCC tissue had significantly elevated concentrations of PC compared to uninfected control tissues, confirming that PME is specific to the tumour’s growth. Finally, a recombinant vaccinia virus was constructed to stimulate the immune systems of infected woodchucks against cells expressing core antigens. Despite reductions in surface antigen expression and viral load, elevations in serum GGT and the PME in 31P-MRS indicated that there was tumour growth in treated woodchucks. In conclusion, the PME peak represents a potential biomarker of cancerous growth when used in conjunction with serological tests to detect HCC in the liver due to chronic hepatitis virus infection. / May 2009

Woodchucks are the preferred animal model to study chronic viral hepatitis and the development of hepatocellular carcinoma (HCC), which occurs as a result of infection with woodchuck hepatitis virus. Significant elevations in the phosphomonoester peak in 31P-MRS spectrum correlated to the presence of HCC. Ex vivo 31P-NMR determined that HCC tissue had significantly elevated concentrations of PC compared to uninfected control tissues, confirming that PME is specific to the tumour’s growth. Finally, a recombinant vaccinia virus was constructed to stimulate the immune systems of infected woodchucks against cells expressing core antigens. Despite reductions in surface antigen expression and viral load, elevations in serum GGT and the PME in 31P-MRS indicated that there was tumour growth in treated woodchucks. In conclusion, the PME peak represents a potential biomarker of cancerous growth when used in conjunction with serological tests to detect HCC in the liver due to chronic hepatitis virus infection.

Woodchucks are the preferred animal model to study chronic viral hepatitis and the development of hepatocellular carcinoma (HCC), which occurs as a result of infection with woodchuck hepatitis virus. Significant elevations in the phosphomonoester peak in 31P-MRS spectrum correlated to the presence of HCC. Ex vivo 31P-NMR determined that HCC tissue had significantly elevated concentrations of PC compared to uninfected control tissues, confirming that PME is specific to the tumour’s growth. Finally, a recombinant vaccinia virus was constructed to stimulate the immune systems of infected woodchucks against cells expressing core antigens. Despite reductions in surface antigen expression and viral load, elevations in serum GGT and the PME in 31P-MRS indicated that there was tumour growth in treated woodchucks. In conclusion, the PME peak represents a potential biomarker of cancerous growth when used in conjunction with serological tests to detect HCC in the liver due to chronic hepatitis virus infection.

INTRODUCTION: The detection of a second inorganic phosphate (Pi) resonance, a possible marker of mitochondrial content in vivo, using phosphorus magnetic resonance spectroscopy (31P- MRS) at 3T is technically challenging, which may prevent its reproducible quantification. PURPOSE: To determine the reproducibility of resting alkaline inorganic phosphate (Pialk) measurement using 31P-MRS in human skeletal muscle at 3 tesla (T). METHODS: Resting 31P- MRS of the quadriceps muscles was acquired on two separate visits, within seven days, in 13 healthy, sedentary to moderately active young adults using a whole-body 3T MR system. Measurement variability related to coil position, shimming procedure, and spectral analysis were also quantified. 31P-MRS data were acquired with a 31P/1H dual-tuned surface coil positioned on the quadriceps using a pulse-acquire sequence. Test-retest absolute and relative reproducibility were analyzed using coefficient of variation (CV) and intra-class correlation coefficients (ICC), respectively. RESULTS: Pialk demonstrated a within-subject reproducibility marginally greater then the 10% cutoff (CV: 10.6 ± 5.4%; ICC: 0.80), but still appropriate given its small concentration in relation to other 31P metabolites. Proximo-distal change in coil positioning along the length of the quadriceps induced large variability in Pialk quantification (CV: 21.1%). In contrast, measurement variability due to repeated shims on consecutive scans from the same muscle sample (CV: 6.6%), and the automated spectral processing procedure, were minor (CV: 2.3%). Both metrics of absolute and relative reproducibility of Pialk were of similar magnitude to other well-resolved metabolites (e.g., phosphocreatine, Pi, and phosphodiester). CONCLUSION: Using multiple metrics, the present study established the high reproducibility of Pialk quantification by 31P-MRS using a surface coil on the quadriceps muscle at 3T. However, large variability in Pialk quantification can originate from positioning the coil on the most distal part of the quadriceps, which should be avoided due to shimming inhomogeneity.

Placental function is central for normal pregnancy and in many of the major pregnancy disorders. We used magnetic resonance imaging techniques to investigate placental function in normal pregnancy, in early and late preeclampsia and in intrauterine growth restriction. We also investigated maternal body mass index and height, as risk factors for preeclampsia. A high body mass index and a short maternal stature increase the risk of preeclampsia, of all severities. The association seems especially strong between short stature and early preeclampsia, and a high body mass index and late preeclampsia. (Study I) Using diffusion-weighted magnetic resonance imaging, we found that the placental perfusion fraction decreases with increasing gestational age in normal pregnancy. Also, the placental perfusion fraction is smaller in early preeclampsia, and larger in late preeclampsia, compared with normal pregnancies. That these differences are in opposite directions, suggests that there are differences in the underlying pathophysiology of early and late preeclampsia. (Study II) Using magnetic resonance spectroscopy, we found that the phosphodiester spectral intensity fraction and the phosphodiester/phosphomonoester spectral intensity ratio increases with increasing gestational age. Also, we found that the phosphodiester spectral intensity fraction and the phosphodiester/phosphomonoester spectral intensity ratio are higher in early preeclampsia, compared with early normal pregnancy. These findings indicate increased apoptosis with increasing gestational age in normal pregnancy, and increased apoptosis in early preeclampsia. (Study III) The placental perfusion fraction is smaller in intrauterine growth restriction than in normal pregnancy. Fetal growth, Doppler blood flow in maternal and fetal vessels, infant birth weight and plasma markers of placental function are all correlated to the placental perfusion fraction. The placental perfusion fraction examination seems therefore to offer a fast, direct estimate of the degree of placental dysfunction. (Study IV) In conclusion: Our findings in studies I-III all support the hypothesis of partly different pathophysiology between early and late preeclampsia, and suggest a strong link between early preeclampsia and placental dysfunction. Study IV shows that the placental perfusion fraction has potential to contribute to the clinical assessment of placental dysfunction.

Introduction: There have been few well controlled altitude and hypoxic training studies to date. This thesis investigated the effects of altitude and (sham controlled) intermittent hypoxic training (IHT) on exercise capacity, and the associated physiological adaptations. Methods: Chapter 3 investigated how living and training at 2320 m or at sea level affected total haemoglobin mass (tHb) and race performance in highly trained swimmers. Chapter 4 investigated how IHT or normoxic training affected cardiopulmonary variables and the incremental exercise limit of tolerance (T-Lim), in highly trained runners. Chapter 5 investigated how single-legged IHT or normoxic training affected phosphorus-31 nuclear magnetic resonance spectroscopy assessed muscle energetics. Results: In Chapter 3, tHb increased significantly more after altitude (+0.6 ± 0.4 g•kg-1, or +4.4 ± 3.2%) than after sea level (+0.03 ± 0.1 g•kg-1, or +0.3 ± 1.0%), but the changes in swimming performances were not different between groups, and there were no correlations between tHb and performance changes. In Chapter 4, submaximal heart rate in normoxia decreased significantly more after IHT than after normoxic training (-5 ± 5 vs. -1 ± 5 b∙min-1), and submaximal "V" ̇O2 in hypoxia significantly decreased, only after IHT. T-Lim in hypoxia significantly increased post-IHT, but there were no between group differences. In Chapter 5, the phosphocreatine recovery time constant was speeded significantly more in the IHT compared to the normoxic trained leg, when tested in hypoxia (-25 ± 8% vs. -13 ± 6%), but not in normoxia (-16 ± 15% vs. -9 ± 10%). Conclusions: Altitude training likely increases tHb, but this is not necessarily associated with improved athletic performance. IHT may induce other non-haematological adaptations; potentially an enhanced skeletal muscle oxidative capacity, but evidence for exercise capacity gains is lacking. The precise underlying causes for these adaptations require further investigation, as does any translation to athletic performance.