Accelerated long-term forgetting in presymptomatic autosomal dominant Alzheimer's disease: a cross-sectional study.

Tests sensitive to presymptomatic changes in Alzheimer's disease could be valuable for clinical trials. Accelerated long-term forgetting-during which memory impairment becomes apparent over longer periods than usually assessed, despite normal performance on standard cognitive testing-has been identified in other temporal lobe disorders. We assessed whether accelerated long-term forgetting is a feature of presymptomatic autosomal dominant (familial) Alzheimer's disease, and whether there is an association between accelerated long-term forgetting and early subjective memory changes.This article is available via Open Access. Click on the Additional Link above to access the full-text via the publisher's site

The interaction of Cyclosporin A with Lipoproteins

The success of transplantation has been largely attributed to the introduction of the immunosuppressant, Cyclosporin A (CsA). However, patients receiving CsA frequently become dyslipidemic and this is thought to augment the nephrotoxic and hepatotoxic effects by interfering with the distribution and pharmacokinetics of CsA in plasma. In addition, CsA alone can cause hypercholesterolemia, which is believed to contribute to the pathogenesis of post-transplant atherosclerosis and coronary artery disease. The mechanism of CsA-induced hypercholesterolemia is unknown but it has been suggested that CsA affects the uptake of LDL at the level of the LDL-receptor. The objectives of this thesis were two-fold: 1) to test the hypothesis that CsA contributes to dyslipidemia by decreasing the cellular uptake of LDL via the LDL-receptor and 2) to determine how lipoproteins affect the binding and distribution of CsA in human plasma. To investigate the effect(s) of CsA on LDL uptake via the LDL-receptor, the binding, internalization, and degradation of ¹²⁵I-LDL In vitro was measured in human skin fibroblasts. The results show that CsA does not decrease LDL binding. Further, CsA did not decrease the Bm a x or Kd of the LDL for its receptor, nor did it decrease LDL-receptor mRNA levels. Contrary to my expectations, CsA significantly increased LDL degradation. To determine whether the association of CsA with LDL had any effect on the binding of LDL to its receptor, CsA was equilibrated with ¹²⁵I-LDL prior to its incubation with human skin fibroblasts. These results demonstrate that the association of CsA with LDL did not affect the binding or Kd of LDL to its receptor. Collectively, these data show that CsA does not reduce L D L uptake by decreasing the binding, internalization, or degradation of L D L and this suggests that decreasing LDL uptake via the LDL-receptor is not a mechanism by which CsA contributes to hyperlipidemia in patients receiving this drug. To investigate CsA's distribution in dyslipidemic plasma, CsA was added to plasma from the following groups: normolipidentic, hypercholesterolemic, hypertriglyceridemic, hypoalphalipoproteinemic, and a combination of hypercholesterolemic and hypertriglyceridemic. By using the phosphotungstic acid precipitation method to fractionate plasma, it was shown that the distribution of CsA in all of the dyslipidemic groups was significantly different from the normolipidentic control. In addition, the amount of CsA associated with the VLDL/LDL and HDL fractions was quite variable between the groups but the amount with the LPDP fraction remained relatively constant. These data suggest that factors other than the amount of lipid, such as the composition of the lipoprotein, play a role in the distribution of CsA.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat

Quantitative changes in Factor II messenger RNA levels during ischemic/reperfusion injury in porcine liver

When organs are harvested, stored and transplanted they are subjected to a period of ischemia followed by reperfusion. This process results in significant damage to the organ and the success of transplantation is frequently dictated by the magnitude of this insult. It is for this reason that a high priority has been given to studying the pathological mechanisms underlying this type of ischemic and reperfusion injury. Ischemic/reperfusion injury to the liver significantly decreases the ability of the organ to synthesize proteins. In liver transplant recipients a decrease from pre-operative values is seen in the levels of all plasma protein clotting factors. In particular, Factor II levels decrease to 36% of their pre-operative level. Studies in ischemic rat liver have indicated that during post-ischemic recovery, the translatable levels of mRNA that code for albumin are qualitatively altered. It is not known whether these changes are quantitative. For these reasons, we elected to quantitate the levels of Factor II mRNA in tissue and compare them with plasma levels of Factor II in a porcine model of warm hepatic ischemic/reperfusion injury. In the model we employed, hepatic ischemia was achieved by diverting the portal blood through a shunt to the right external jugular vein and by clamping the hepatic and gastroduodenal arteries. Reperfusion was initiated following 90 minutes of ischemia by removal of the shunt and clamps. Blood and tissue biopsy samples were collected prior to ischemia, following ischemia and at 90 minutes, 270 minutes, 1 day and 2 days of reperfusion. Tissue mRNA was extracted and quantitated relative to the total DNA content. The extraction efficiencies were monitored and corrected for by means of a synthesized internal standard developed for this study. The effect of ischemic/reperfusion injury on Factor II mRNA was assessed using a Factor II cDNA probe and "dot-blot" hybridization techniques. A quantitative method for the determination of porcine Factor II in plasma during ischemic/reperfusion injury was established using a synthetic chromogenic substrate. In addition, routine plasma measurements of liver function and Indocyanine Green clearance tests were performed. The changes seen in the routine plasma measurements performed were found to be similar to those of other investigators. Plasma AST (aspartate aminotransferase) levels rose significantly during the reperfusion phase indicating that hepatocellular damage had occured. Plasma glucose and lactate levels increased significantly during ischemia and returned to normal by 90 minutes of reperfusion. Plasma K⁺ levels decreased significantly during the early stages of reperfusion (15 minutes) and returned to normal by 90 minutes of reperfusion. In contrast to the changing plasma levels of lactate, AST, glucose and K⁺, bilirubin values did not vary throughout the operative procedure. The clearance of ICG decreased significantly during ischemia due to the decrease of blood flow to the liver. During reperfusion, the clearance of ICG was also decreased significantly, and it was concluded that this reduction was due to some degree of hepatocellular injury although differences in hepatic blood flow and perfusion cannot be ruled out. At one and two days of reperfusion, the ICG clearances returned to normal. Plasma Factor II levels decreased significantly during the ischemic phase. Concomitant with the decrease in plasma levels was trend in which there was an increase in the tissue levels of Factor II mRNA. However, during reperfusion, the tissue levels of Factor II mRNA decreased to control biopsy values. The decrease in the levels of Factor II mRNA may have occurred as the result of damage inflicted during the reperfusion phase, specifically the production of oxygen radicals. With continued reperfusion (two days postoperatively), the Factor II mRNA levels remained low in some of the animals studied; in others, the levels started to rise again. The plasma Factor II levels, however, remained low throughout. It is anticipated that these findings will further our understanding of the pathological mechanisms underlying ischemic/reperfusion injury.Medicine, Faculty ofPathology and Laboratory Medicine, Department ofGraduat