Human-sized magnetic particle imaging for brain applications.

Determining the brain perfusion is an important task for diagnosis of vascular diseases such as occlusions and intracerebral haemorrhage. Even after successful diagnosis, there is a high risk of restenosis or rebleeding such that patients need intense attention in the days after treatment. Within this work, we present a diagnostic tomographic imager that allows access to brain perfusion quantitatively in short intervals. The device is based on the magnetic particle imaging technology and is designed for human scale. It is highly sensitive and allows the detection of an iron concentration of 263 pmolFe ml-1, which is one of the lowest iron concentrations imaged by MPI so far. The imager is self-shielded and can be used in unshielded environments such as intensive care units. In combination with the low technical requirements this opens up a variety of medical applications and would allow monitoring of stroke on intensive care units.

Hypertension is related to cognitive impairment: a 20-year follow-up of 999 men.

Recent findings of a linkage between high blood pressure (BP) and later development of dementia have given new prospects on cerebral target-organ damage in hypertension and have added substance to the concept of "preventable senility." The aim of this study was to analyze the impact of hypertension, circadian BP profile, and disturbed glucose metabolism on cognitive function. The study population consisted of 999 seventy-year-old men from a population-based cohort study in Uppsala, Sweden, followed with respect to cardiovascular risk factors since the age of 50 years. At the age of 70, 24-hour ambulatory BP was monitored together with measurements of insulin sensitivity, glucose tolerance, serum lipids, and lipoproteins. Cognitive function was assessed by the Mini-Mental State Examination and the Trail-Making Test. High diastolic BP at baseline predicted later impaired cognitive performance, even after excluding men with a previous stroke (n = 70). Cross-sectional measurements at age 70 showed that high 24-hour BP, nondipping, insulin resistance, and diabetes all were related to low cognitive function. The relationships between hypertension and cognitive impairment were strongest in untreated men. These data from a general population of healthy elderly men indicate that hypertension and associated metabolic disturbances might be susceptibility factors for cognitive disorders. The findings add support to possibilities of intervention in early stages in cognitive decline, ie, before manifest dementia.

Fatty acid composition in total phospholipids of human coronary arteries in sudden cardiac death.

A study was made of the fatty acid composition of the total phospholipid fraction of human coronary arteries in 30 cases of sudden cardiac death due to ischaemic heart disease (aged 40 +/- 5 years, mean +/- S.D.) and in 29 controls (mostly traffic accident victims, aged 45 +/- 6 years). The coronary arteries from cases of sudden cardiac death showed more atherosclerotic lesions than those of controls (P < 0.001). The percentages of palmitic acid (16:0) and linoleic acid (18:2(n-6)) were significantly higher and the percentage of arachidonic acid (20:4(n-6)) and of all the other major polyunsaturated fatty acids, both n-6 and n-3, was significantly lower in cases of sudden cardiac death than in controls. In conclusion, this study showed increased percentages of saturated and reduced percentages of polyunsaturated fatty acids, except linoleic acid, in total phospholipids of human coronary arteries in cases of sudden cardiac death. The results suggest an impaired metabolism of linoleic acid, possibly due to a decreased delta-6-desaturase activity in the coronary artery wall in cases of sudden cardiac death.

Fatty acid composition of platelets and of plasma lipid esters in relation to platelet function in patients with ischaemic heart disease.

Serum lipoproteins, fatty acids in plasma lipid esters and in platelet phospholipids were assessed in 64 patients with ischaemic heart disease (IHD) and in 67 controls. Hyperlipoproteinemia (HLP) (VLDL triglycerides greater than 1.4 mmol/l and/or LDL cholesterol greater than 5.2 mmol/l) was found in 64% of the patients. In the plasma lipid esters the relative concentrations of saturated and monounsaturated fatty acids as well as dihomo-gammalinolenic acid were higher in the IHD patients whereas the linoleic acid concentrations were lower. The altered fatty acid pattern was apparent both in patients with and without HLP. In the platelet phospholipids there was a relative increase of oleic acid and a decrease of stearic acid. The relative content of eicosapentaenoic acid was slightly reduced whereas the linoleic acid concentrations were unchanged compared to the controls. Platelet aggregation induced by ADP and collagen was enhanced in the IHD patients. The lowest threshold value for ADP-induced aggregation was found in the normolipidemic patients. Since there were almost no differences in the relative contents of the long-chain polyunsaturated fatty acids in the platelet phospholipids between patients and controls it is concluded that mechanisms other than the prostaglandin-mediated pathway may contribute to the increased platelet aggregation in IHD patients.

The effect of treatment with clofibrate on hepatic triglyceride and lipoprotein lipase activities of post heparin plasma in male patients with hyperlipoproteinemia.

Twelve male patients with hyperlipoproteinemia were treated with clofibrate, 1 g twice daily. Serum triglyceride concentration decreased on the average 28 +/- 6%. No significant change of serum cholesterol concentration occurred. Post heparin plasma lipoprotein lipase activity isolated and partially purified by heparin Sepharose affinity chromatography was determined quantitatively. During the clofibrate treatment this enzyme activity increased 48 +/- 9%. The post heparin hepatic triglyceride lipase did not change significantly. The possibility that the serum triglyceride-lowering effect of clofibrate might partly be explained by an increased removal rate of triglyceride rich lipoproteins through increased lipoprotein lipase activity is discussed.

Preclinical review of cerivastatin sodium--a step forward in HMG-CoA reductase inhibition.

Epidemiological studies have established that elevated concentrations of plasma cholesterol, particularly the low density lipoprotein (LDL) cholesterol, is one of the major risk factors for the development of arteriosclerosis and ischemic heart disease. Treatment with HMG-CoA reductase inhibitors (vastatins) has become the most successful drug treatment in lowering total plasma and LDL cholesterol concentrations in the last years. The vastatins already available for treatment are therapeutically used in a dose-range between 10 and 80 mg/day. The new enantiomerically pure pyridine derivative cerivastatin sodium has demonstrated its efficacy in significantly lower doses in the microgram-range, not only in preclinical but also in clinical studies with daily doses of only 0.1-0.3 mg. The differences in the therapeutic doses are reflected by the Ki- and IC50-values from enzyme inhibition tests in comparison with various HMG-CoA reductase inhibitors. Cerivastatin sodium exhibits much higher enzyme affinity with factors between 70 and almost 200. The Ki-value for cerivastatin sodium was 1.3 x 10(-9) M in comparison to 150 x 10(-9) M for lovastatin. The extremely high enzyme affinity of cerivastatin sodium was also reflected in its high activity in vivo. In acute in vivo studies cerivastatin sodium inhibited the hepatic [14C]cholesterol synthesis from [14C]acetate in both rats and dogs by 50% after oral administration at doses of 0.002 mg/kg body weight (ED50-values). This dose was comparable to 0.3 mg/kg of lovastatin. In subchronic dog studies a dose of 0.03 mg/kg lowered the serum LDL cholesterol concentration by 35% which is comparable with doses of 8-10 mg lovastatin/kg. Interesting results were observed in cholestyramine-primed dogs when 0.1 mg cerivastatin sodium/kg p.o. markedly decreased the serum triglycerides up to 70%. Cerivastatin shows a favourable pharmacokinetic profile with high liver selectivity. Rat studies have shown almost complete absorption and rapid hepatic clearance. Cerivastatin was highly bound to plasma proteins of rats, dogs and humans (>98%). Cerivastatin metabolites were excreted mainly via feces. The metabolism of cerivastatin sodium in man follows two metabolic pathways, demethylation to metabolite M1 and stereospecific hydroxylation to M23. The three major metabolites M1, M23 and the hydroxylated and demethylated metabolite M24 are highly active inhibitors not only in vitro but also in vivo. The human specific metabolites M23 and M24 inhibited the HMG-CoA reductase isolated from rat liver with the same potency as the parent compound cerivastatin sodium (IC50: 1.0-1.2 x 10(-9) M). M1 was slightly less active. Corresponding pharmacological activity was observed in vivo. M23 and M24 inhibited [14C]cholesterol synthesis from [14C]acetate in rat liver with ED50)-values between 0.001 and 0.002 mg/kg body weight which is similar to cerivastatin sodium and M1 exhibited an ED50-value of <0.006 mg/kg The strong inhibitory activity of these metabolites, in addition to cerivastatin's high enzyme affinity may explain the extraordinary pharmacological activity of cerivastatin and its ultra-low dose in man and demonstrates cerivastatin to be the most active HMG-CoA reductase inhibitor amongst all vastatins.

Education, lifestyle factors and mortality from cardiovascular disease and cancer. A 25-year follow-up of Swedish 50-year-old men.

BACKGROUND: There is a well-established inverse relation between education and mortality from cardiovascular disease and cancer. The reasons for this are still in part unclear. We aimed to investigate whether differences in traditional vascular risk factors, adult height, physical activity, and biomarkers of fatty acid and antioxidant intake, could explain this association. METHODS: In all, 2301 50-year-old men in Uppsala, Sweden (82% of the background population) were examined with regard to educational level, blood pressure, blood glucose, body mass index, serum lipids, smoking, body height, physical activity, serum beta carotene, alpha tocopherol, selenium, and serum fatty acids in cholesterol esters. Cause-specific mortality was registered 25 years later. RESULTS: Low education was associated with a higher rate of mortality from cardiovascular disease (crude relative risk [RR] = 1.67, 95% CI : 1.17-2.39), and from cancer (crude RR = 1.94, 95% CI : 1.21-3.10), compared to high educational attainment. Men with high education had an overall more beneficial risk factor profile concerning traditional cardiovascular risk factors, physical activity, and biomarkers of dietary intake of antioxidants and fat. After adjustment for all examined risk factors, the inverse gradient between education and cardiovascular mortality disappeared (RR in low education = 1.01. 95% CI : 0.67-1.52). Controlling for smoking, physical activity and dietary biomarkers explained less than half of the excess cancer mortality in the lower educational groups. Smoking (adjusted RR = 1.89, 95% CI : 1.37-2.61), and high proportions of palmitoleic acid in serum cholesterol esters (adjusted RR per 1 SD = 1.39, 95% CI : 1.07-1.82) predicted cancer mortality, independently of all other factors. There were no independent relations between serum antioxidants and mortality. CONCLUSIONS: These data indicate that modifiable lifestyle factors mediate the inverse gradient between education and death from cerebro- and cardiovascular disease. Smoking, physical activity and dietary factors explained half of the excess cancer mortality in lower educated groups. Further studies are needed to explore the proposed association between palmitoleic acid, a marker of high intake of animal and dairy fat, and cancer.

Desaturation and elongation of Fatty acids and insulin action.

Insulin resistance is characterized by specific changes of the composition of fatty acids in the serum lipids and in the skeletal muscle membranes. Impaired insulin sensitivity is associated with high proportions of palmitic (16:0) acid and low levels of linoleic (18:2 n-6) acid in serum. In addition, there are apparent changes of the fatty acid desaturase activities, suggesting an increased activity of the Delta9 and Delta6 desaturases and a decreased activity of the Delta5 desaturase. The activity of the fatty acid desaturases is regulated by long-chain polyunsaturated fatty acids and insulin and is probably also dependent on the degree of physical activity. A high ratio between arachidonic (20:4 n-6) and dihomo-gamma linolenic (20:3 n-6) acid, as a measure of Delta5 desaturase activity, in the skeletal muscle phospholipids has been related to good insulin sensitivity. Available knowledge seems to indicate that the degree of saturation of the body lipids, and especially the proportion of palmitic acid in the lipid membranes, may be critical for insulin sensitivity. The strong relationships between the Delta5 desaturase activity, a high content of long-chain polyunsaturated fatty acids in the skeletal muscle, and insulin sensitivity may be due to parallel effects of diet and/or physical activity on the fatty acid composition and on insulin sensitivity.

The fatty-acid spectrum in plasma and adipose tissue in patients with psoriasis.

The long-chained fatty acids, which are precursors of prostaglandins and leukotrienes, were examined in plasma lipid esters and adipose tissue obtained from 20 male psoriatic patients and 36 matched controls. The fatty-acid composition of the plasma lipid esters (cholesterol esters, triglycerides and phospholipids) and adipose tissue was assayed using thin-layer and gas chromatography. In comparison with healthy controls, the patients' plasma lipid esters contained significantly lower levels of linoleic acid (18:2 omega 6) and alpha-linolenic acid (18:3 omega 3), and higher levels of dihomo-gamma-linolenic acid (20:3 omega 6). In the adipose tissue of the patients, the amount of alpha-linolenic acid was significantly decreased, while that of arachidonic acid (20:4 omega 6) was increased. The observed changes were more pronounced in patients with severe psoriasis than in those with a milder form of the disease. Our results suggest that psoriatic patients differ from healthy controls with regard to the distribution of several of the essential long-chained fatty acids involved in the biosynthesis of prostaglandins and leukotrienes. The relevance of these findings to the development of psoriasis remains to be established.

Hepatic triglyceride and lipoprotein lipase activities of post-heparin plasma in normals and hypertriglyceridemics.

Post-heparin plasma hepatic triglyceride lipase (H-TGL) and lipoprotein lipase (LPL) activities were 8-34 and 3.5-21 (range) mu mol/ml/hr respectively in males with normal serum lipid concentrations. In females the corresponding values were 4-25 and 4-16 mu mol/ml/hr. No significant differences were observed between ages or between the two sexes. Male patients with hypertriglyceridaemia had similar activities of H-TGL but significantly lower values for LPL activities than the control males. Significant linear correlations were found between serum triglyceride concentrations and LPL activities both for males (coefficient of correlation = r = -0.64) and for females (r = -0.62).

Failure of the biguanide moroxydine chloride to stimulate plasma fibrinolytic activity.

Eleven patients with recurrent venous thrombosis or thrombophlebitis and a decreased fibrinolytic activity after venous occlusion were given a phenformin-like substance, moroxydine chloride, for 6 months. No sustained increase in the fibrinolytic activity was observed after moroxydine treatment.

Dietary supplementation with n-3 fatty acids may impair glucose homeostasis in patients with non-insulin-dependent diabetes mellitus.

The effects on lipoprotein and glucose metabolism of addition of n-3 fatty acids were studied in 14 non-insulin-dependent diabetic patients who were given 10 g of MaxEPA (3 g n-3 fatty acids) or placebo (olive oil) per day in a randomized double-blind cross-over study during two consecutive 8-week periods. After MaxEPA treatment, there was a marked increase in long-chain polyunsaturated fatty acids of the n-3 series in the plasma lipid esters and in the platelet phospholipids, while the n-6 fatty acid content decreased. The very low density lipoprotein (VLDL) triglyceride concentrations decreased significantly (by 22%) on MaxEPA treatment. However, these changes were not significantly different from those observed during the placebo period. The blood glucose concentration tended to increase during MaxEPA treatment, and to decrease during the placebo period, the changes under the two regimes being significantly different (P less than 0.01). In addition, the rate constant for glucose disappearance (k value) for the intravenous insulin-tolerance test, which reflected the peripheral insulin sensitivity, tended to decrease during MaxEPA treatment and increase during administration of the placebo, there being a significant difference (P less than 0.03) between the changes during the two treatments. The reason for the observed changes in blood glucose concentration and peripheral insulin sensitivity is still unclear.

Evaluation of euglobulin clot lysis time as a screening method for determination of blood plasma fibrinolytic activity after venous occlusion.

Determination of the fibrinolytic activity should be performed in patients with recurrent thromboembolic disease. As a screening procedure we suggest the euglobulin clot lysis time test after venous occlusion. This test is sufficiently reliable and easier to perform than the fibrin plate method, especially outside coagulation laboratories.

Peripheral glucose metabolism and insulin sensitivity in Alzheimer's disease.

Twenty-four patients with Alzheimer's disease and matched controls were examined with reference to metabolic parameters such as peripheral insulin and glucose metabolism, serum lipid concentrations and blood pressure levels. Blood glucose levels and insulin response were measured during an intravenous glucose tolerance test and peripheral insulin sensitivity was estimated with the hyperinsulinemic euglycemic clamp technique. There were no differences recorded between the two groups in glucose metabolism, triglyceride, cholesterol or HDL-cholesterol levels. The patients with Alzheimer's disease had significantly lower blood pressure levels, which partly could be explained by ongoing treatment with neuroleptics and antidepressives. Previous findings of higher insulin levels in Alzheimer's disease could not be verified.

Effects of dietary supplementation with n-6 and n-3 long-chain polyunsaturated fatty acids on serum lipoproteins and platelet function in hypertriglyceridaemic patients.

Twenty-seven patients with hypertriglyceridaemia were given dietary supplementation either with evening primrose oil rich in gammalinolenic acid (GLA, 18:3 n-6) (n = 13) or a marine oil concentrate containing n-3 fatty acids (n = 14) in a double-blind cross-over design during 8 + 8 weeks with olive oil as placebo. During GLA supplementation, increases in GLA and dihomogammalinolenic acid (20:3 n-6) were found in plasma lipid esters and platelet phospholipids, whereas platelet function and serum lipoproteins were unaffected. During supplementation with n-3 fatty acids there was a significant decrease in triglycerides in all lipoprotein fractions with a slight increase in high density lipoprotein and low density lipoprotein cholesterol. A marked increase in the long-chain n-3 fatty acids was found both in plasma and platelets, mainly at the expense of the n-6 fatty acids. No pronounced effects on platelet reactivity could be demonstrated. Our results confirm a triglyceride-lowering effect of n-3 fatty acids, whereas no such effect of GLA could be demonstrated.

How do we treat, or not treat, high blood pressure in the oldest old? A practice study in Swedish geriatricians.

No clear guidelines exist for the treatment of hypertension in the oldest old (age 80+). While on the one hand the benefits of antihypertensive treatment in stroke prevention are greatest in very old people, on the other hand the adverse effects of treatment are more frequent in these frail, elderly patients. What is optimum blood pressure (BP) in healthy old patients, and in old patients with stroke or dementia? This study aimed to describe physicians opinions regarding BP treatment in geriatric patients. Of 462 Swedish geriatricians sent a postal questionnaire, 350 responded. In answer to the question what stage they would initiate treatment in a healthy, 82-year-old female patient, more than half responded that they would start treatment at higher BP levels (systolic BP >180 mmHg or diastolic BP >100 mmHg) than is recommended for younger elderly. Opinion varied on ideal BP in the case of a recent minor stroke, or dementia. Findings from epidemiological studies concerning the relations between BP and stroke and dementia are discussed. We conclude that further research is needed in this area.

High content of dietary linoleic acid does not reduce platelet reactivity in patients with hyperlipoproteinaemia.

Seventeen patients with hypertriglyceridaemia were given a lipid-lowering diet with a high P/S-ratio 2.1 during a 3-week period. The very low density lipoprotein triglycerides decreased by 43%, low density lipoprotein cholesterol by 19% and high density lipoprotein cholesterol by 12%. There was a marked increase of linoleic acid (18:2 n-6) in all plasma lipid esters with a concomitant decrease of the saturated and monounsaturated fatty acids. There was a slight increase of the linoleic acid metabolites 18:3 n-6, 20:3 n-6 and 20:4 n-6 in serum triglycerides whereas the fatty acids of the n-3 series decreased in all plasma lipid esters. In the platelets a similar pattern was found with an increase of linoleic acid and its metabolite 22:4 n-6 and a decrease of 18:1 n-9 as well as of the n-3 fatty acids. No significant differences in platelet reactivity was found. However, in a few patients there was an increased platelet aggregation after the diet period. Our results suggest that this diet based on a very high content of linoleic acid may not affect platelet reactivity in a beneficial way. The reason may be an increased turnover of arachidonic acid in the platelets or an imbalance between the n-6 and n-3 series of fatty acids.

Supplementation with n-3 fatty acids reduces triglycerides but increases PAI-1 in non-insulin-dependent diabetes mellitus.

The effects of dietary supplementation with n-3 fatty acids on lipid and glucose metabolism and on fibrinolysis were evaluated in 14 non-insulin-dependent diabetic patients who were given 10 g of MaxEPA (3 g n-3 fatty acids) or placebo (olive oil) per day in a randomized double-blind cross-over study during two consecutive 8-week periods. The serum triglyceride (TG) concentrations decreased by 27% (P < 0.01) after addition of MaxEPA with a reduction of VLDL TG by 36% (P < 0.05) while LDL cholesterol increased by 6% (P = 0.05). The fasting blood sugar and HbA1c concentrations increased significantly after addition of MaxEPA but the changes were not significantly different from those during the placebo period. The highest glucose concentrations at fasting and after an i.v. glucose injection were seen after MaxEPA while the serum insulin concentrations were unchanged. The peripheral insulin sensitivity, as measured by a euglycaemic, hyperinsulinaemic clamp technique, did not change during the study. The mean plasminogen inhibitor-1 (PAI-1) activity of the patients was elevated compared with healthy controls. In spite of the reduction of the triglyceride concentrations and unchanged insulin levels, there was a significant increase of the activity of PAI-1 (+21%, P < 0.01) after MaxEPA suggesting a possible impairment of the fibrinolytic capacity. In many situations there seems to be a reduction of PAI-1 when the triglycerides are lowered. In the diabetic patients given n-3 fatty acids this was not the case.

Cognitive function, vascular risk factors and education. A cross-sectional study based on a cohort of 70-year-old men.

OBJECTIVES: A low level of education is associated with an increased risk of developing a dementia disorder, as well as with a higher risk of cardiovascular disease. The aim of this study was to investigate the association between education and cardiovascular risk factors, and to study the relation between these factors and cognitive function in elderly men. DESIGN: Cross-sectional population-based study. SETTING: Uppsala, Sweden. SUBJECTS: 504 men aged 69-74 years, participants in a longitudinal health survey concerning cardiovascular risk factors. MAIN OUTCOME MEASURE: Cognitive function as measured by a composite score of 13 standard psychometric tests. RESULTS: A low level of education was associated with poorer cognitive performance, as well as with obesity, smoking, diabetes, high concentrations of serum triglycerides and plasma fibrinogen. In the entire cohort, subjects with obesity, smoking, diabetes or hypertriglyceridaemia showed impaired cognitive test results, independent of socio-economic factors. When stroke cases were excluded, obesity and smoking were still related to impaired cognitive function. CONCLUSIONS: Smoking and obesity with associated metabolic disturbances are inversely related both to educational level and to cognitive function. Cognitive decline of vascular origin is potentially preventable by treatment of risk factors. The question of whether the increased vascular risk contributes to the higher prevalence of cognitive disorders in individuals with low socio-economic status, needs to be further evaluated in longitudinal population-based studies.