Robert W. Stout

Particulate air pollution and the blood

BACKGROUND Particulate air pollution has been associated with excess deaths from, and increases in hospital admissions for, cardiovascular disease among older people. A study was undertaken to determine whether this may be a consequence of alterations in the blood, secondary to pulmonary inflammation caused by the action of fine particles on alveolar cells, by repeatedly measuring haematological factors in older people and relating them to measurements of exposure to airborne particles. METHODS One hundred and twelve individuals aged 60+ years in two UK cities provided repeated blood samples over 18 months, 108 providing the maximum of 12 samples. Estimates of individual exposure to particles of less than 10 μm diameter (PM10), derived from a mathematical model based on activity diaries and comparative measurements of PM10 at multiple sites and during a variety of activities, were made for each three day period prior to blood sampling. The relationships between blood values and estimates of both personal exposure and city centre measurements of PM10 were investigated by analysis of covariance, adjusting for city, season, temperature, and repeated individual measurements. RESULTS Estimated personal exposure to PM10 over the previous three days showed negative correlations with haemoglobin concentration, packed cell volume (PCV), and red blood cell count (p<0.001), and with platelets and factor VII levels (p<0.05). The changes in red cell indices persisted after adjustment for plasma albumin in a sample of 60 of the subjects. City centre PM10 measurements over three days also showed negative correlations with haemoglobin and red cell count (p<0.001) and with PCV and fibrinogen (p<0.05), the relationship with haemoglobin persisting after adjustment for albumin. C reactive protein levels showed a positive association with city centre measurements of PM10 (p<0.01). Based on a linear relationship, the estimated change in haemoglobin associated with an alteration in particle concentration of 100 μg/m3 is estimated to have been 0.44 g/dl (95% CI 0.62 to 0.26) for personal PM10 and 0.73 g/dl (95% CI 1.11 to 0.36) for city centre PM10 measurements. CONCLUSIONS This investigation is the first to estimate personal exposures to PM10 and to demonstrate associations between haematological indices and air pollution. The changes in haemoglobin adjusted for albumin suggest that inhalation of some component of PM10may cause sequestration of red cells in the circulation. We propose that an action of such particles either on lung endothelial cells or on erythrocytes themselves may be responsible for changing red cell adhesiveness. Peripheral sequestration of red cells offers an explanation for the observed cardiovascular effects of particulate air pollution.

Insulin and atheroma.

New information on carbohydrate and lipid metabolism has resulted in reappraisal of ideas of the underlying abnormalities in diabetes and atherosclerosis. It is noted that the incidence of diabetic arteriopathy has increased in spite of control of hyperglycemia and ketosis by insulin and that many nondiabetic persons with coronary artery disease have abnormalities or carbohydrate and lipid metabolism similar to those found in diabetics. Some patients secrete abnormally large amounts of insulin in response to dietary carbohydrate; these people have a particularly high incidence of vascular disease. Physicial excercise lowers insulin requirements. Synalbumin increased serum lipids in the forms of cholesterol triglycerides and the endogenous type of hyperlipidemia induced by dietary carbohydrate have been related to the incidence of coronary artery disease. The insulin response produced by the carbohydrate diet is related to the hepatic-triglyceride-secretion rate and is considered to be the primary cause of elevated serum-triglyceride. A similar mechanism is assumed for serum-cholesterol regulation. Hyperinsulinism is found in obesity in patients with hypertension and in some women who have been taking oral contraceptives for more than 1 year. These women also show elevated triglycerides and pre-beta-lipoprotein levels. It has been reported that these women also have an increased risk of vascular diseas e. The evidence incriminating insulin and carbohydrate is considered strong and would link atherosclerosis with diabetes obesity hyperlipidemia lack of physical exercise and possibly hypertention and use of contraceptive drugs.

SEASONAL VARIATIONS IN FIBRINOGEN CONCENTRATIONS AMONG ELDERLY PEOPLE

Mortality and morbidity in elderly people are higher in winter than in summer months, with seasonal variations in rates of both fatal and non-fatal myocardial infarction and stroke. To identify factors that might contribute to the excess winter frequency of cardiovascular disease in the elderly, we studied 100 subjects aged 75 and over who lived in either their own homes or in sheltered or residential accommodation. Each person was visited each month for one year, body and environmental temperatures were noted, and cardiovascular risk factors were measured. 32 subjects withdrew from the study. Significant seasonal effects were found for fibrinogen, plasma viscosity, and HDL cholesterol (p less than 0.003, Bonferroni adjustment). Plasma fibrinogen concentrations showed the greatest seasonal change and were 23% higher in the coldest six months compared with summer months. Fibrinogen was significantly (p less than 0.05) and negatively related to core body temperature and all measures of environmental temperature. Those living in institutions had greater changes in plasma fibrinogen than those living in the community. The seasonal variation in plasma fibrinogen concentration is large enough to increase the risk of both myocardial infarction and stroke in winter.

Albert's test : A neglected test of perceptual neglect

Disorders of perception are thought to be important in predicting the outcome from stroke, but their exact significance is difficult to define because of lack of standardised terminology and diagnostic methods. In a prospective study of 205 unselected stroke patients, perceptual neglect, assessed by a standardised test battery, was found in 49% of patients with lesions of the non-dominant hemisphere and in 25% with lesions of the dominant hemisphere. One component of the test battery was a simple test described by Albert in which patients cross out lines ruled in a standard fashion on a sheet of paper; this was easy to administer and related closely to neglect diagnosed by the test battery as a whole. Results of Alberts test were a significant predictor of both mortality and functional activity six months after the stroke, independent of the influence of other clinical, neurological, laboratory, and social factors. The full test battery for perceptual neglect was of no significant additional predictive value.

Overview of the Association Between Insulin and Atherosclerosis

The suggestion that insulin is associated with atherosclerosis is based on clinical, epidemiologic, and experimental evidence. In general, atherosclerosis of the coronary, cerebral, and peripheral arteries is associated with abnormally high insulin responses to oral glucose. This hyperinsulinemia is not related to acute injury or to tissue necrosis, does not occur in response to intravenous glucose or tolbutamide, and is independent of other cardiovascular risk factors. Populations who are at high risk for cardiovascular disease have higher insulin responses to oral glucose than those at lower risk. Prospective studies carried out in Australia, Finland, and France have shown that elevated insulin levels, either fasting or in response to oral glucose, have a predictive role in the development of cardiovascular disease. This association is independent of the effects of other cardiovascular risk factors. In experimental animals, insulin deficiency retards the development of diet-induced arterial disease, whereas administration of insulin promotes lesion development and prevents lesion regression. Insulin stimulates lipid synthesis in isolated arteries and stimulates proliferation and lipid accumulation in cultured arterial smooth muscle cells. The evidence linking insulin with atherosclerosis has been gathered from nondiabetic subjects; this evidence is unavailable in diabetics. As it is clear that hyperinsulinemia is often present in diabetes, either in relation to mild glucose intolerance or obesity (in noninsulin-dependent diabetes mellitus) or because of insulin therapy (in insulin-dependent diabetes mellitus), it is essential that further consideration should be given to the possibility that hyperinsulinemia may have harmful effects on the arterial wall.

The relationship of abnormal circulating insulin levels to atherosclerosis

The evidence linking insulin with atherosclerosis can be divided into two parts. First, there is evidence that a proportion of subjects who have atherosclerosis or who are at risk of developing atherosclerosis hav elevated circulating insulin levels. The high insulin levels may be associated with another metabolic abnormality such as obesity, hypertriglyceridaemia, uraemia or consumption of oral contraceptives, may be inappropriate to the blood sugar levels as in mild diabetes, or may be of exogenous origin as in insulin-treated diabetics. The tissues of these subjects are exposed to high concentrations of insulin, and it seems reasonable to suggest that elevated insulin levels may have pathological effects on these tissues. Secondly, there is increasing evidence that the arterial wall is an insulin sensitive tissue. Exposure of arterial tissue to insulin results in proliferation of smooth muscle cells, inhibition of lipolysis, and synthesis of cholesterol, phospholipid and triglyceride. Chronic exposure to high concentrations of insulin results in the development of lipid filled lesions similar to those of early atherosclerosis. Thus, insulin has the ability to promote changes in the artery which, in the long term, may progress to atherosclerosis. The two lines of evidence together suggest that high levels of circulating insulin may have a role in the development of atherosclerosis.

Insulin as a mitogenic factor: Role in the pathogenesis of cardiovascular disease

Evidence has been accumulating that insulin has actions that may promote the development of atherosclerosis. Research has involved three broad areas: actions of insulin on cultured arterial cells, the effect of insulin on isolated artery preparations, and the development of lipid-containing lesions in the arteries of experimental animals. Insulin, in concentrations similar to those found in physiologic conditions, stimulates proliferation of cultured arterial smooth muscle cells from a number of species, including humans. Insulin also stimulates migration of smooth muscle cells. Cholesterol synthesis and low-density lipoprotein interaction with its receptor in smooth muscle cells are stimulated by insulin. Insulins mitogenic action appears to be mediated by the insulin-like growth factor receptor. Endothelial cells cultured from large vessels are resistant to the actions of insulin, but hyperglycemia inhibits their proliferation. Insulin deficiency protects animals from experimental atherosclerosis; this protection is lost with insulin treatment. Insulin administration results in lipid-containing lesions in chickens and rats fed a normal diet, and in increased lipid synthesis in the arteries of pigs and dogs. Isolated artery preparations from insulin-deficient or insulin-treated animals undergo lipid metabolism at a rate that correlates with the insulin concentrations in the donor animals. The biological actions of insulin (and glucose) on arterial tissue suggest that hyperglycemia and hyperinsulinemia may promote the development of atherosclerosis.

Glucose inhibits replication of cultured human endothelial cells

SummaryDiabetes is an important risk factor for atherosclerosis but the mechanism of the risk is unknown. As endothelial injury is considered to be an early event in the development of atherosclerosis, the effect of glucose on endothelial cell replication was studied. Concentrations of glucose of 11.2, 16.8 and 22.4 mmol/l inhibited DNA synthesis in cultured human umbilical venous endothelial cells by 8.1±10.8, 24.3±8.8 and 30.9±7.4%, respectively. Glucose also inhibited the proliferative response of endothelial cells to experimental wounds in the cell layer. Sorbitol (22.4 mmol/l) inhibited endothelial cell DNA synthesis by 50±13.6%, but mannitol (22.4 mmol/l) inhibited DNA synthesis by only 3±24.3%. It is suggested that in diabetic subjects, high blood glucose levels may cause endothelial injury, or inhibit its repair, and hence allow the exposure of the arterial media to plasma and its constituents.

The effect of insulin and glucose on sterol synthesis in cultured rat arterial smooth muscle cells

The smooth muscle cell plays an important role in the process of atherogenesis, proliferating in the arterial intima and becoming filled with lipid during the course of the disease. In these experiments the effect of insulin and glucose on sterol synthesis in cultured rat arterial smooth muscle cells was studied. Arterial smooth muscle cells were cultured from pieces of intima and inner media of young rat aortas. The cells were grown in Petri dishes in culture medium with foetal calf serum and when confluent were exposed to insulin or glucose for 24 hours. Insulin in concentrations of 10 micromicron-100 millimicron per ml stimulated the incorporation of sodium [2-(14)C]acetate into non-saponifiable lipids and digitonin precipitable sterols. However, insulin had no effect on the incorporation of labelled mevalonate into cell sterols. Increasing concentrations of glucose in the medium up to 140 mM had had no effect on the incorporation of isotope into sterols, but higher concentrations of glucose caused cell damage and sterol synthesis was markedly depressed. These results may have relevance to the development of atherosclerosis in diabetes and obesity.

Evaluation of four screening tests for bacteriuria in elderly people.

Four screening tests for bacteriuria were assessed at ward level in 418 elderly subjects and were compared with standard methods of bacterial culture. The tests were visual appearance; microscopy; dipstick for nitrite, leucocyte esterase, protein, and blood; and dipstick for nitrite and organisms. The sensitivity of the tests varied from 85.6% to 98.3%, and the specificity from 18.4% to 82.9%. A combination of visual appearance and dipstick testing for nitrite and leucocyte esterase gave a sensitivity of 96.1% with a specificity of 50.6%, and could have reduced by almost one-third the number of urine samples submitted to the laboratory for processing.