Search PubMed⌕ Search

Biomedical subjects

Robin Fraser

Publications and source records attributed to Robin Fraser.

At least 19 recordsLinked to original sources
PubMed2007

Caloric restriction reduces age-related pseudocapillarization of the hepatic sinusoid.

Age-related changes in the hepatic sinusoid, called pseudocapillarization, may contribute to the pathogenesis of dyslipidemia. Caloric restriction (CR) is a powerful model for the study of aging because it extends lifespan. We assessed the effects of CR on the hepatic sinusoid to determine whether pseudocapillarization is preventable and hence a target for the prevention of age-related dyslipidemia. Livers from young (6 months) and old (24 months) CR and ad libitum fed (AL) F344 rats were examined using electron microscopy and immunohistochemistry. In old age, there was increased thickness of the liver sinusoidal endothelium and reduced endothelial fenestration porosity. In old CR rats, endothelial thickness was less and fenestration porosity was greater than in old AL rats. Immunohistochemistry showed that CR prevented age-related decrease in caveolin-1 expression and increase in peri-sinusoidal collagen IV staining, but did not alter the age-related increase of von Willebrand's factor. CR reduces age-related pseudocapillarization of the hepatic sinusoid and correlates with changes in caveolin-1 expression.

Aging↗
PubMed2006

Dimethylthetin treatment causes diffuse alveolar lung damage: a pilot study in a sheep model of Continuous Ambulatory Peritoneal Dialysis (CAPD).

Total plasma homocysteine (Hcy) concentration correlates with risk of vascular disease. Over 80% of chronic renal failure patients have elevated plasma Hcy and a 10-20 times higher incidence of vascular disease. Glycine betaine lowers plasma Hcy through methylation catalysed by betaine-homocysteine methyltransferase (BHMT). Dimethylthetin (DMT), a synthetic glycine betaine analogue, is a more effective BHMT substrate. DMT is therefore a potential therapeutic agent for reducing plasma Hcy in humans and may be particularly useful in renal failure patients receiving dialysis because of chronic betaine depletion as a result of treatment. We aimed to determine whether the addition of DMT to dialysis fluid lowered plasma Hcy concentrations in a Continuous Ambulatory Peritoneal Dialysis sheep model using animals that were either in acute renal failure (n=3) or had normal renal function (n=1). Sub-acute exposure to DMT was toxic to all four animals, which died with total lung consolidation and collapse and Diffuse Alveolar Damage within 48 h of beginning treatment. Adverse side effects were observed after 4-8 doses. DMT was not detected in pre-dialysis plasma samples and the final concentration at death was 0.5-7.8 mmol/L, depending on the number of doses each animal was exposed to. Abnormalities were not observed in animals supplied standard dialysis fluid, or fluid with added glycine betaine. Toxicity associated with DMT treatment raises concerns for its use in further studies. However, sub-acute administration of DMT to sheep may provide a useful model of acute alveolar damage.

Animals↗
PubMed2006

What's happening - Scotblood 2006 advances in immunetolerance, information technology, microarrays and pathogen inactivation in transfusion medicine.

This commentary on Scotblood meeting aimed to provide a highlight on four areas of new development in blood transfusion medicine, based on the abstracts provided by the invited speakers. Dr. Jerard Seghatchian would like to express his sincere thanks to Prof. Robin Fraser, Chairman of the Scotblood Organising Committee, and Dr. Hagop Bessos, chairman of the Scotblood Programme Sub-Committee, for inviting him to attend this event and providing him with the essential material for this report.

Blood Transfusion↗
PubMed2006

Marked changes of the hepatic sinusoid in a transgenic mouse model of acute immune-mediated hepatitis.

BACKGROUND/AIMS: The liver sinusoidal endothelial cell (LSEC) is increasingly recognized as having an important role in hepatic immunity. However, the responses of LSECs and the hepatic sinusoid in immune-mediated hepatitis are poorly described. METHODS: We studied a transgenic mouse model of acute immune-mediated hepatitis: Met-Kb mice injected with T cells from Des-TCR mice. RESULTS: Hepatitis was characterized by lymphocyte infiltrates causing severe but transient liver damage. There were marked changes in the ultrastructure of the LSEC five days after injection of the T cells that coincided with the peak of the hepatitis. The porosity of fenestrations in the LSEC decreased and the endothelium became thickened. LSECs appeared to be markedly activated. These changes were associated with narrowing of the space of Disse, loss of hepatocellular microvilli and deposition of basal lamina. Lymphocytes were seen passing through fenestrations. Loss of fenestration in the LSEC prevented hepatitis induced by a second injection of lymphocytes on day 5. CONCLUSIONS: Structural changes in the LSEC occur during the peak of a mouse model of immune-mediated hepatitis. These changes were associated with attenuation of subsequent liver damage, suggesting that they may influence immunological responses mediated by LSECs or the passage of lymphocytes through LSEC fenestrations.

Acute Disease↗
PubMed2006

Hyperlipidemia and surfactants: the liver sieve is a link.

Poloxamer 407 is a ubiquitous synthetic surfactant that causes massive hyperlipidemia and atherosclerosis in the rodent. The initial step in hepatic metabolism of lipoproteins is their transfer through 100-200 nm pores (fenestrations) in the liver sinusoidal endothelial cell, prior to receptor-mediated uptake. The 'liver sieve hypothesis' emphasizes the role of these fenestrations in the regulation of lipoprotein disposition. Here we show that P407 causes dramatic defenestration of the liver sinusoidal endothelium in vivo. By 24h after intraperitoneal administration in mice, fenestrations were reduced by approximately 80% coincident with a 10-fold increase in plasma lipids. Moreover impulse-response experiments in the perfused rat liver showed that P407 prevented the passage of small chylomicrons across the liver sinusoidal endothelium. Defenestration was also induced acutely with P407 in isolated liver sinusoidal endothelial cells, indicating this is a direct effect of P407 on fenestrations. The results establish the role of the porosity of the liver sinusoidal endothelial cell as a pivotal yet relatively unrecognised mechanism for hyperlipidemia. Furthermore, the results establish an intriguing mechanism for surfactant-induced hyperlipidemia. Thus the liver sieve is a new and untapped target for the treatment and prevention of hyperlipidemia.

Animals↗
PubMed2006

T lymphocytes interact with hepatocytes through fenestrations in murine liver sinusoidal endothelial cells.

The liver has an established ability to induce tolerance. Recent evidence indicates that this unique property might be related to its distinctive architecture allowing T cells to be activated in situ independently of lymphoid tissues. Unlike lymph node-activated T cells, liver-activated T cells are short-lived, a mechanism that might contribute to the "liver tolerance effect." Although the potential role of hepatocytes as tolerogenic antigen-presenting cells has been demonstrated, the question as to whether these cells are able to interact with CD8(+) T cells in physiological settings remains controversial. Contradicting the immunological dogma stating that naïve T lymphocytes are prevented from interacting with parenchymal cells within non-lymphoid organs by an impenetrable endothelial barrier, we show here that the unique morphology of the liver sinusoidal endothelial cell (LSEC) permits interactions between lymphocytes and hepatocytes. Using electron microscopy, we demonstrate that liver resident lymphocytes as well as circulating naïve CD8(+) T cells make direct contact with hepatocytes through cytoplasmic extensions penetrating the endothelial fenestrations that perforate the LSECs. Furthermore, the expression of molecules required for primary T cell activation, MHC class I and ICAM-1, is polarized on hepatocytes to the perisinusoidal cell membrane, thus maximizing the opportunity for interactions with circulating lymphocytes. In conclusion, this study has identified, at the ultrastructural level, a unique type of interaction between naïve T lymphocytes and liver parenchymal cells in vivo. These results hold implications for the pathogenesis of viral hepatitis in which hepatocytes may represent the main antigen-presenting cell, and for the development of immune tolerance as lymphocytes pass through the liver.

Animals↗
PubMed2005

Hepatic pseudocapillarization in aged mice.

Age-related changes in the hepatic sinusoid of the rat, human and baboons called pseudocapillarization have been discovered and are important because they are considered to be implicated in the pathogenesis of some age-related diseases. In this study, we investigated whether similar changes occur in the livers of old mice. Livers of young (3-4 months) and old (20-24 months) mice were perfusion-fixed and studied using electron microscopy and immunohistochemistry. The thickness of the sinusoidal endothelium was increased in old mice (154+/-4 versus 244+/-8 nm, P<0.001). There was a reduction in fenestrations within the endothelium (porosity decreased from 4.1+/-0.3 to 2.2+/-0.2%, P<0.001). There was perisinusoidal staining with Sirius red in old mice, however, expression of laminin and von Willebrands factor was similar in young and old mice. Novel perisinusoidal fat-engorged stellate cells were found extensively in the old mice. This study confirmed that pseudocapillarization is a widespread aging change in the liver, now documented in several species including the mouse. Mice are an appropriate animal model for studying aging and the hepatic sinusoid.

Aging↗
PubMed2005

Age-related changes in the hepatic sinusoidal endothelium impede lipoprotein transfer in the rat.

The mechanisms for the association of old age with post-prandial hyperlipidemia and atherosclerosis are not well understood. Post-prandial hyperlipidemia has emerged as a significant risk for atherosclerosis. The liver is the central organ for lipoprotein metabolism. The initial step in the hepatic uptake of post-prandial lipoproteins is their transfer from the hepatic sinusoidal capillary lumen across the hepatic sinusoidal endothelium into the space of Disse. Here, they access hepatocytes for receptor-mediated uptake. We proposed that fenestrations (pores) within the hepatic sinusoidal endothelium filter lipoproteins on the basis of size. Recently we discovered age-related changes in the sinusoidal endothelium (pseudocapillarization), including reduction in the porosity of the endothelium. Using the impulse response technique in perfused rat livers, we found that aging is associated with impaired hepatic transendothelial transfer of chylomicrons with diameters smaller than those of fenestrations. In conclusion, age-related pseudocapillarization of the hepatic sinusoidal endothelium provides a novel mechanism for the association of old age with impaired hepatic lipoprotein metabolism and with atherosclerosis.

Aging↗
PubMed2005

The hepatic sinusoid in aging and cirrhosis: effects on hepatic substrate disposition and drug clearance.

The fenestrated sinusoidal endothelium ('liver sieve') and space of Disse in the healthy liver do not impede the transfer of most substrates, including drugs and oxygen, from the sinusoidal lumen to the hepatocyte. Plasma components transfer freely in both directions through the endothelial fenestrations and into the space of Disse. The endothelium is attenuated, there is no basement membrane and there is minimum collagen in the space of Disse, thus minimising any barriers to substrate diffusion. Both cirrhosis and aging are associated with marked structural changes in the sinusoidal endothelium and space of Disse that are likely to influence bulk plasma transfer into the space of Disse, and diffusion through the endothelium and space of Disse. These changes, termed capillarisation and pseudocapillarisation in cirrhosis and aging, respectively, impede the transfer of various substrates. Capillarisation is associated with exclusion of albumin, protein-bound drugs and macromolecules from the space of Disse, and the progressive transformation of flow-limited to barrier-limited distribution of some substrates. There is evidence that the sinusoidal changes in cirrhosis and aging contribute to hepatocyte hypoxia, thus providing a mechanism for the apparent differential reduction of oxygen-dependent phase I metabolic pathways in these conditions. Structural change and subsequent dysfunction of the liver sieve warrant consideration as a significant factor in the impairment of overall substrate handling and hepatic drug metabolism in cirrhosis and aging.

Aging↗
PubMed2004

The effects of oxidative stress on the liver sieve.

BACKGROUND/AIMS: Oxidative stress is implicated in the pathogenesis of age-related and disease-associated changes in the hepatic sinusoid. We studied the effects of oxidative stress on the morphology of the liver, focusing specifically on the hepatic sinusoidal endothelium (the 'liver sieve'). METHODS: The effects of tert-butyl hydroperoxide on the intact liver and isolated sinusoidal endothelial cells were assessed by electron microscopy, immunohistochemistry and biochemical analysis. RESULTS: Immunohistochemistry revealed a dose-dependent increase in peri-sinusoidal 3-nitrotyrosine staining, particularly in the regions adjacent to the portal triads. Electron microscopy showed dose-dependent formation of large intracellular gaps in the sinusoidal endothelium with reduction in the diameter of the remaining endothelial fenestrations. Activated Kupffer cells extending processes through the fenestrations to contact hepatocytes were noted. Biochemical analysis of total liver tissue showed no significant changes in malondialdehyde content but a decrease in the ratio of GSH to GSSG. tert-Butyl hydroperoxide administered directly onto isolated liver sinusoidal endothelial cells was associated with similar gap formation, indicating a direct effect on the endothelial cells by tert-butyl hydroperoxide. CONCLUSIONS: Oxidative stress selectively damages hepatic sinusoidal endothelial cells. This has implications for those processes associated with changes in the sinusoidal endothelium such as ageing, cirrhosis and exposure to hepatotoxins.

Animals↗
PubMed2003

Hepatic sinusoidal pseudocapillarization with aging in the non-human primate.

BACKGROUND/AIMS: Age-related changes in the hepatic sinusoid termed pseudocapillarization have been reported in the rat and human and have implications for disease susceptibility in old age. In this study, we investigated whether similar changes occur in the livers of old baboons and thus represent a widespread aging change. METHODS: Liver tissue from five young baboons (5.4+/-0.5yrs) and five old baboons (21.8+/-0.7yrs) was compared by transmission electron microscopy, scanning electron microscopy and immunohistochemistry. RESULTS: The thickness of the sinusoidal endothelium was increased in old baboons (130+/-8 nm versus 186+/-9 nm, P<0.001) and the frequency of endothelial fenestrae decreased, with the porosity declining from 4.2+/-0.5% to 2.4+/-0.4% (P=0.006). The expression of laminin and von Willebrands factor was more extensive in old baboons. Novel perisinusoidal ring-shaped cells, probably fat-engorged stellate cells, were prominent in the old baboons. CONCLUSIONS: Pseudocapillarization is a significant age-related change in the baboon liver. Aging in baboons is associated with a novel aging change in the stellate cell not reported in other species. Hepatic pseudocapillarization is a widespread aging liver change found in several species including humans and other non-human primates.

Aging↗
PubMed2003

The Tn antigen-specific lectin from ground ivy is an insecticidal protein with an unusual physiology.

Leaves of ground ivy (Glechoma hederacea) contain a lectin (called Gleheda) that is structurally and evolutionary related to the classical legume lectins. Screening of a population of wild plants revealed that Gleheda accounts for more than one-third of the total leaf protein in some clones, whereas it cannot be detected in other clones growing in the same environment. Gleheda is predominantly expressed in the leaves where it accumulates during early leaf maturation. The lectin is not uniformly distributed over the leaves but exhibits a unique localization pattern characterized by an almost exclusive confinement to a single layer of palisade parenchyma cells. Insect feeding trials demonstrated that Gleheda is a potent insecticidal protein for larvae of the Colorado potato beetle (Leptinotarsa decemlineata). Because Gleheda is not cytotoxic, it is suggested that the insecticidal activity is linked to the carbohydrate-binding specificity of the lectin, which as could be demonstrated by agglutination assays with different types of polyagglutinable human erythrocytes is specifically directed against the Tn antigen structure (N-acetylgalactosamine O-linked to serine or threonine residues of proteins).

Aging↗
PubMed2003

Who needs budgets?

Budgeting, as most corporations practice it, should be abolished. That may sound radical, but doing so would further companies' long-running efforts to transform themselves into developed networks that can nimbly adjust to market conditions. Most other building blocks are in place, but companies continue to restrict themselves by relying on inflexible budget processes and the command-and-control culture that budgeting entails. A number of companies have rejected the foregone conclusions embedded in budgets, and they've given up the self-interested wrangling over what the data indicate. In the absence of budgets, alternative goals and measures--some financial, such as cost-to-income ratios, and some nonfinancial, such as time to market-move to the foreground. Companies that have rejected budgets require employees to measure themselves against the performance of competitors and against internal peer groups. Because employees don't know whether they've succeeded until they can look back on the results of a given period, they must use every ounce of energy to ensure that they beat the competition. A key feature of many companies that have rejected budgets is the use of rolling forecasts, which are created every few months and typically cover five to eight quarters. Because the forecasts are regularly revised, they allow companies to continuously adapt to market conditions. The forecasting practices of two such companies, both based in Sweden, are examined in detail: the bank Svenska Handelsbanken and the wholesaler Ahlsell. Though the first companies to reject budgets were located in Northern Europe, organizations that have gone beyond budgeting can be found in a range of countries and industries. Their practices allow them to unleash the power of today's management tools and realize the potential of a fully decentralized organization.

Budgets↗