Diversity of risk factors for stroke: the putative roles and mechanisms of depression and air pollution.

Several conventional risk factors for stroke and cerebrovascular disease, such as hypertension, smoking, and atrial fibrillation, are widely recognized. Correct management of these modifiable factors significantly reduces stroke risk. We review the research evidence that depressive symptoms and increased atmospheric pollution are associated with an increased risk of stroke, and outline putative mechanisms that may account for these associations. The data on depression and stroke risk strongly indicate the need for treatment intervention studies. The design and implementation of intervention studies related to air pollution requires better understanding of the pathophysiologic mechanisms linking exposures to the onset of stroke.

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.

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.

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.

Fenitrothion: toxicokinetics and toxicologic evaluation in human volunteers.

An unblinded crossover study of fenitrothion 0.18 mg/kg/day [36 times the acceptable daily intake (ADI)] and 0.36 mg/kg/day (72 X ADI) administered as two daily divided doses for 4 days in 12 human volunteers was designed and undertaken after results from a pilot study. On days 1 and 4, blood and urine samples were collected for analysis of fenitrothion and its major metabolites, as well as plasma and red blood cell cholinesterase activities, and biochemistry and hematology examination. Pharmacokinetic parameters could only be determined at the higher dosage, as there were insufficient measurable fenitrothion blood levels at the lower dosage and the fenitrooxone metabolite could not be measured. There was a wide range of interindividual variability in blood levels, with peak levels achieved between 1 and 4 hr and a half-life for fenitrothion of 0.8-4.5 hr. Although based on the half-life, steady-state levels should have been achieved; the area under the curve (AUC)(0-12 hr) to AUC(0-(infinity) )ratio of 1:3 suggested accumulation of fenitrothion. There was no significant change in plasma or red blood cell cholinesterase activity with repeated dosing at either dosage level of fenitrothion, and there were no significant abnormalities detected on biochemical or hematologic monitoring.

Age-environment and gene-environment interactions in the pathogenesis of Parkinson's disease.

Parkinson's disease (PD) is a common neurodegenerative disease characterized by dopaminergic cell death and deposition of Lewy bodies within the substantia nigra of the midbrain. Although the major risk factors for PD are aging and environmental factors, there is an important genetic component. An age-related change in xenobiotic metabolism alters the metabolism of and net exposure to, environmental neurotoxins. Genetic variability in xenobiotic metabolism may similarly increase the susceptibility to PD by altering the metabolism of neurotoxins. Genetic studies of rare familial cases of PD indicate a central mechanistic role for the aggregation of alpha-synuclein, a protein found in Lewy bodies. Environmental factors like pesticides and heavy metals can also influence alpha-synuclein aggregation. Common final pathways for aging, environmental, and genetic mechanisms can thus exist, involving both direct neurotoxicity and alpha-synuclein aggregation.

Ultrastructural changes in hepatic sinusoidal endothelial cells acutely exposed to colloidal iron.

Hepatic sinusoidal endothelial cells form an important interface between the vascular system, represented by the sinusoids, and the space of Disse that surrounds the hepatocyte microvilli. This study aimed to assess the light microscopic and ultrastructural effects of acute exposure of hepatic sinusoidal endothelial cells to colloidal iron by injection of rats with iron polymaltose. Eight minutes after a single intravenous injection of iron polymaltose sinusoidal endothelial cells showed defenestration, and thickening and layering as assessed by transmission electron microscopy. Kupffer cells and stellate cells appeared activated. These changes were not observed in control animals, experiments using equivalent doses of maltose, or experiments using colloidal carbon except for Kupffer cell activation due to colloidal carbon. No significant light microscopic changes were seen in study or control animals. The findings indicate that acute exposure to colloidal iron causes changes in hepatic sinusoidal endothelial cells, stellate cells and Kupffer cells. This may be the result of a direct toxic effect of iron or increased production of reactive oxygen species. These observations suggest a possible mechanism for defenestration of sinusoidal endothelial cells in ageing and in disease states.

A multicenter, case-control study of the effects of antihypertensive therapy on orthostatic hypotension, postprandial hypotension, and falls in octo- and nonagenarians in residential care facilities.

BACKGROUND: Orthostatic hypotension, postprandial hypotension, and falls are considered to be adverse drug reactions of antihypertensive therapy in older people with comorbidities. Concerns regarding these adverse events may limit the use of antihypertensive agents in this group of people. OBJECTIVE: The aim of this study was to determine the relationship between antihypertensive therapy in octo- and nonagenarians and the risk for orthostatic hypotension, postprandial hypotension, and falls. METHODS: This was a case-control study of octo- and nonagenarians living in residential care facilities who were receiving antihypertensive therapy and a control group who were not receiving antihypertensive therapy. RESULTS: A total of 119 patients, 77 who were receiving regular antihypertensive therapy and 42 who were not taking any antihypertensive agents, were enrolled in the study. The prevalence of antihypertensive use, orthostatic hypotension, postprandial hypotension, and falls was high (65%, 29%, 57%, and 45%, respectively). There were no associations between antihypertensive therapy and orthostatic hypotension, postprandial hypotension, and falls. When individual classes of antihypertensive agents were examined, the only observed association was a negative association (ie, a protective effect) between potassium-sparing diuretics and falls (odds ratio, 0.2; 95% CI, 0.04-1.0). CONCLUSION: Antihypertensive therapy was not associated with an increased risk for orthostatic hypotension, postprandial hypotension, or falls in this case-control study of octo- and nonagenarians living in residential care facilities.

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 biology and geriatric clinical pharmacology.

Population aging evokes doomsday economic and sociological prognostication, despite a minority of older people suffering significant dependency and the potential for advances in therapeutics of age-related disease and primary aging. Biological aging processes are linked mechanistically to altered drug handling, altered physiological reserve, and pharmacodynamic responses. Parenteral loading doses need only be adjusted for body weight as volumes of distribution are little changed, whereas oral loading doses in some cases may require reduction to account for age-related increases in bioavailability. Age-related reduction of hepatic blood flow and hepatocyte mass and primary aging changes in hepatic sinusoidal endothelium with effects on drug transfer and oxygen delivery reduce hepatic drug clearance. Primary renal aging is evident, although renal clearance reduction in older people is predominantly disease-related and is poorly estimated by standard methods. The geriatric dosing axiom, "start low and go slow" is based on pharmacokinetic considerations and concern for adverse drug reactions, not from clinical trial data. In the absence of generalizable dosage guidelines, individualization via effect titration is required. Altered pharmacodynamics are well documented in the cardiovascular system, with changes in the autonomic system, autacoid receptors, drug receptors, and endothelial function to modify baseline cardiovascular tone and responses to stimuli such as postural change and feeding. Adverse drug reactions and polypharmacy represent major linkages to avoidable morbidity and mortality. This, combined with a deficient therapeutic evidence base, suggests that extrapolation of risk-benefit ratios from younger adults to geriatric populations is not necessarily valid. Even so, therapeutic advances generally may convert healthy longevity from an asset of fortunate individuals into a general social benefit.

Hepatic pseudocapillarisation and atherosclerosis in ageing.

Cardiovascular disease secondary to atherosclerosis is the main cause of death and disability in industrialised countries, and ageing is the foremost risk factor for atherosclerosis. We present a hypothesis linking age-specific structural change in the liver with accepted pathogenic mechanisms leading to atherosclerosis. Ageing in the liver is associated with pseudocapillarisation of the sinusoidal endothelium, which is characterised by thickening of endothelium, basement membrane formation, and defenestration (loss of pores). Fenestrations (pores) normally form a liver sieve that allows passage of chylomicron remnants for subsequent uptake and metabolism by hepatocytes. Ageing is associated with impaired clearance of chylomicron remnants, postprandial hypertriglyceridaemia, and hence, atherosclerosis, which we propose is linked directly to loss of permeability of the liver sieve because of defenestration associated with pseudocapillarisation. Development of methods to maintain fenestrations of sinusoidal endothelium or to facilitate refenestration might be a new therapeutic strategy for management of cardiovascular disease in old people.

Postprandial systolic blood pressure responses of older people in residential care: association with risk of falling.

BACKGROUND: The association between postprandial blood pressure, falls and medications is controversial. OBJECTIVE: To investigate cardiovascular responses to meals in elderly people together with clinical associations and therapeutic issues. METHODS: A cross-sectional observational study of 179 semi-independent older people (age 83.2 +/- 7.0 years) in residential care facilities was undertaken. Data on the frequency of falls, medical and medication history and measurement of blood pressure before and after a breakfast meal, and then after standing and walking after the meal were documented. RESULTS: Postprandial hypotension (>/=20 mm Hg fall in systolic blood pressure (SBP)) and low absolute SBP (

Age-related alteration in hepatic disposition of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and pesticides.

Idiopathic Parkinson's disease may be caused by environmental neurotoxins such as pesticides, however the major risk factor is old age. We postulated that the high incidence of Parkinson's disease in older people is secondary to age-related impairment of the hepatic detoxification of xenobiotics. Previously, we have shown that there are significant differences between the hepatic disposition of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and pesticides. Here, we investigated whether there are age-related differences in the hepatic disposition of MPTP and pesticides, putatively associated with the pathogenesis of Parkinson's disease. We measured the hepatic disposition of paraquat, dichlorodiphenyltrichloroethane (DDT), malathion and MPTP using the multiple indicator dilution technique in the perfused livers of Fischer F344 rats aged 3 and 18 months. The recoveries of MPTP, DDT and malathion were increased from the livers of the older rats (by 258%, 253% and 134% compared with young rats, respectively). The hepatic transport of DDT and malathion into hepatocytes was reduced with age suggesting that part of the impaired uptake of neurotoxins may be secondary to an age-related barrier to influx. Ageing may increase risk of Parkinson's disease by altering hepatic detoxification and increasing systemic bioavailability of neurotoxins.

Entacapone-induced hepatotoxicity and hepatic dysfunction.

We describe 2 patients with Parkinson's disease who developed hepatotoxicity associated with the use of entacapone, a novel, mainly peripheral acting inhibitor of catechol-D-methyltransferase. Hepatotoxicity resolved rapidly with discontinuation of the drug. Analysis of causality in a further case initially linked to entacapone exposure was confounded by conflicting serial adverse reaction reports.

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.

Age-related pseudocapillarization of the human liver.

Age-related changes in liver function are important because they may promote susceptibility to adverse drug reactions, neurotoxicity, atherosclerosis, and other important diseases in older people. Age-related changes in the rat hepatic sinusoidal endothelium, termed pseudocapillarization, have been described recently and these may contribute to hepatic impairment. The present study has examined surgical and post-mortem specimens with immunohistochemistry and transmission electron microscopy to determine whether pseudocapillarization also occurs in older humans. The age of the subject, independent of systemic disease or hepatic pathology in surgical and post-mortem samples of human liver, was associated with increased peri-sinusoidal expression of von Willebrand's factor, collagen I, collagen IV, and staining with Masson's trichrome. Electron microscopy revealed significant age-related thickening of the sinusoidal endothelium (young 165 +/- 17 nm, middle age 222 +/- 11 nm, older 289 +/- 9 nm, p < 0.001) with loss of fenestrations (young 7.7 +/- 0.7 per 10 micro m, middle age 3.6 +/- 0.5 per 10 micro m, older 1.5 +/- 0.4 per 10 micro m, p < 0.001), and age-related deposition of basal lamina and collagen. In conclusion, ageing in humans is associated with morphological changes in the sinusoidal endothelium and space of Disse which are presumptively related to the ageing process and potentially represent an important link between the ageing process and disease susceptibility.