Cerebrovascular accumulation of Aβ (β-amyloid) occurs in aging and AD (Alzheimer's disease). Hypercholesterolaemia, which is associated with raised plasma LDL (low-density lipoprotein), may predispose to AD. Soluble Aβ is found in the circulation and enhances vasoconstriction. Under conditions that may favour the formation of short Aβ oligomers, as opposed to more severe polymerization leading to Aβ fibrillogenesis, we investigated the influence of LDLs on the vasoactive actions of soluble Aβ. Thus the actions of Aβ40 and Aβ42 in combination with native or oxidized LDL on vasoconstriction to NA (noradrenaline) and vasodilatation to ACh (acetylcholine) were examined in rat aortic rings. LDL, particularly when oxidized, potentiated NA-induced constriction when combined with soluble Aβ40 and, especially, Aβ42. Soluble Aβ40 reduced relaxation induced by ACh, but Aβ42 was ineffective. Native and oxidized LDL also attenuated relaxation. Synergism occurred between oxidized LDL and Aβ with respect to ACh-induced relaxation, but not between native LDL and Aβ. We have shown for the first time that, under conditions that may result in Aβ oligomer formation, LDL, particularly when oxidized, modulates the vascular actions of soluble Aβ to extents greater than those reported previously for fibrillar Aβ preparations. Mechanisms whereby a treatable condition, namely hypercholesterolaemia, might contribute to the development of the cerebrovascular component of AD are indicated.

1. In view of the importance of 5-hydroxytryptamine in coronary thrombosis, we wanted to know whether a potentially protective decrease in platelet 5-hydroxytryptamine could be achieved by treatment with an inhibitor of 5-hydroxytryptamine uptake, fluoxetine. 2. We studied 15 patients treated for psychiatric indications with fluoxetine, and compared the findings with those obtained with blood from 18 patients treated with amitriptyline and 13 controls previously treated for affective disorders. 3. Platelet-rich plasma 5-hydroxytryptamine levels were significantly decreased in the fluoxetine group ( P > 0.005) but not in the amitriptyline group compared with the control group. 4. Collagen-induced aggregation in whole blood anti-coagulated with hirudin was measured by sequential single platelet counting. The contribution of 5-hydroxytryptamine was assessed from the effect of adding the 5-hydroxytryptamine specific antagonist ICI 170809. This contribution was significantly decreased in the fluoxetine group but not in the amitriptyline group compared with the control group. 5. It is concluded that platelet 5-hydroxytryptamine is indeed decreased by fluoxetine, and we would predict a protective effect of fluoxetine against coronary thrombosis.

1. A new tracer method is described for the noninvasive measurement of bone formation in the proximal femur. The method is based on our previously described whole-body method using 85 Sr as the tracer (Reeve, J., Hesp, R. & Wootton, R. Calcif. Tissue Res. 1976; 22, 191–206). It allows correction to be made for long-term exchange processes within the skeleton. 2. The method has been applied in a study of regional and whole-body bone formation in 12 rehabilitated patients who had previously suffered a fracture of the proximal femur. Twelve healthy control subjects were studied, who were selected for their good health and continued physical activity. The aim was to explore the relationship between bone formation and physical activity. 3. Bone formation was similar in the two groups, both regionally and in the whole body. Based on analyses of four cadaver specimens, bone formation in the proximal femur was about one and two-thirds times that in the whole skeleton when related to mass of calcium in the region of interest. 4. Whole-body bone resorption, estimated from five measurements per subject of hydroxyproline excretion in relation to creatinine excretion, was significantly higher in the fracture patients ( P <0.01, Wilcoxon's test). 5. Estimates of current physical activity (and immediate pre-fracture physical activity) were made with a newly devised questionnaire. Historical levels of physical activity (at ages 15–45 years) were determined with Astrom's questionnaire. No bone formation index correlated with any index of physical activity. Urinary hydroxyproline excretion correlated inversely both with current physical activity and historical physical activity (for both regression coefficients P <0.01). 6. The results are discussed in the light of our current understanding of the control of bone remodelling by the discrete basic multicellular units of bone. The opportunity to study regional bone resorption by the additional use of serial dual X-ray absorptiometry of the same region will in future allow the direct monitoring of the effects of therapeutic interventions which have been designed to prevent contralateral hip fracture.

1. Plasma and platelet free catecholamine concentrations were measured in 22 normal subjects and in 10 treated and 11 untreated patients with heterozygous familial hypercholesterolaemia. 2. Plasma noradrenaline concentrations were significantly higher in both treated and untreated hypercholesterolaemic patients than in normal subjects. Adrenaline concentrations did not differ. 3. Platelet noradrenaline levels were higher in untreated hypercholesterolaemic patients than in normal subjects. 4. Positive correlations between the plasma noradrenaline concentration and the platelet noradrenaline concentration were observed in both normal subjects and hypercholesterolaemic patients. 5. Combining the data for normal subjects and hypercholesterolaemic patients revealed that the plasma noradrenaline concentration correlated positively with the plasma cholesterol concentration. The platelet noradrenaline concentration was also found to correlate with the plasma cholesterol concentration. 6. Our results suggest that an increased plasma cholesterol concentration may be associated with increased sympathetic nervous system activity as indicated by elevated plasma and platelet noradrenaline levels. Increases in circulating catecholamines may contribute to the platelet hyperaggregability seen in familial hypercholesterolaemia.

1. Energy expenditure, plasma glucose and palmitate kinetics and leg glycerol release were determined simultaneously both before and during adrenaline infusion in lean and obese human subjects. Seven lean subjects (mean 96.5% of ideal body weight) were studied in the post-absorptive state and also during mixed nutrient liquid feeding, eight obese subjects (mean 165% of ideal body weight) were studied in the post-absorptive state and six obese subjects (mean 174% of ideal body weight) were studied during feeding. 2. Resting energy expenditure was higher in the obese subjects, but the thermic response to adrenaline, both in absolute and percentage terms, was similar in lean and obese subjects. Plasma adrenaline concentrations attained (3 nmol/l) were comparable in all groups and the infusion had no differential effects on the plasma insulin concentration. Before adrenaline infusion the plasma glucose flux was higher in the obese than in the lean subjects in the fed state only (45.8 ± 3.8 versus 36.6 ± 1.0 mmol/h, P <0.05); it increased to the same extent in both groups with the adrenaline infusion. 3. Before the adrenaline infusion plasma palmitate flux was higher in the obese than in the lean subjects (by 51%, P <0.01, in the post-absorptive state and by 78%, P <0.05, in the fed state). However, there was no significant change during adrenaline infusion in the obese subjects (from 13.5 ± 1.00 to 15.0 ± 1.84 mmol/h, not significant, in the post-absorptive state and from 14.4 ± 2.13 to 15.7 ± 1.74 mmol/h, not significant, in the fed state), whereas there were increases in the lean subjects (from 8.93 ± 1.10 to 11.2 ± 1.19 mmol/h, P <0.05, in the post-absorptive state, and from 8.06 ± 1.19 to 9.86 ± 0.93 mmol/h, P <0.05, in the fed state). 4. Before adrenaline infusion the palmitate oxidation rate was also higher in the obese than in the lean subjects (1.86 ± 0.14 versus 1.22 ± .09 mmol/h, P <0.01, in the post-absorptive state and 1,73 ± 0.25 versus 1.12 ± 0.12 mmol/h, P <0.05, in the fed state). However, in response to adrenaline the fractional oxidation rate (% of flux) increased less in the obese than in the lean subjects, especially in the post-absorptive state (from 13.8 ± 1.02 to 14.9 ± 1.39%, not significant, versus from 13.7 ± 0.98 to 19.3 ± 1.92%, P <0.05). These effects were independent of feeding. Leg glycerol release increased more in the lean subjects with adrenaline infusion, although increases in the plasma glycerol concentration did not differ between the groups. 5. These results suggest that in obese subjects plasma inter-organ transport of fatty acids and the subsequent fractional oxidation responses favour storage of triacylglycerol. These factors may be important determinants for the development and maintenance of the obese state.

1. Endogenous noradrenaline release from washed platelets incubated under resting conditions and in the presence of thrombin was examined in 14 normal subjects and 10 subjects with type 1 (insulin-dependent) diabetes. 2. Irreversible aggregation of platelets from both normal and diabetic subjects was induced by thrombin (0.3 unit/ml). Platelets from diabetic subjects were more sensitive than platelets from normal subjects, extents of aggregation being 89% and 76%, respectively ( P < 0.002). 3. Stimulation with thrombin (0.3 unit/ml) elicited marked platelet release of noradrenaline to the incubation medium in both normal and diabetic subjects. Supernatant noradrenaline concentrations obtained under thrombin-stimulated conditions did not significantly differ between normal and diabetic subjects. However, under resting conditions noradrenaline levels were significantly greater (+ 93%, P < 0.02) for diabetic than normal subjects. 4. Measurement of platelet noradrenaline contents after thrombin stimulation revealed no difference between normal and diabetic subjects. Under resting conditions, however, platelet noradrenaline levels were significantly lower (−46%, P < 0.02) for diabetic than normal subjects. Thus, in the diabetic subjects increased resting platelet efflux of noradrenaline is mirrored by a decreased platelet noradrenaline content. 5. A consequence of increases in resting catecholamine efflux may be enhanced platelet activity resulting in increased platelet aggregation.

1. We have used high-performance liquid chromatography with electrochemical detection to measure plasma and platelet catecholamines in 24 normal subjects. 2. In the same subjects platelet function was assessed by measuring platelet aggregation in response to adenosine 5′-pyrophosphate, thrombin, adrenaline and collagen. Platelet sensitivity to prostacyclin was also examined. 3. Platelet noradrenaline showed a positive correlation with extent of aggregation induced by ‘low-dose’ collagen (1 μg/ml). No correlation was seen at the higher collagen concentration. 4. Platelet noradrenaline content also correlated with sensitivity of platelets to prostacyclin. High platelet noradrenaline concentrations appeared to result in decreased sensitivity to prostacyclin. 5. No other correlations were observed. 6. These data suggest that platelet noradrenaline rather than plasma levels may be involved in modifying platelet function in vivo. Local release of platelet catecholamines may affect the platelet/vessel wall interaction, the primary physiological step in platelet activation.

1. Using high-performance liquid chromatography with electrochemical detection, we have studied the release of endogenous catecholamines from washed platelets induced to aggregate by ADP and thrombin. 2. Washed platelets exhibit irreversible aggregation with 10 μmol/l ADP and 0.3 unit of thrombin/ml, extents of aggregation being 27% and 76% respectively. 3. ADP (10μmol/l) increased noradrenaline release to the medium by 20% and adrenaline by 28%. As observed with aggregation, 0.3 unit of thrombin/ml produced a more marked effect on release than ADP, noradrenaline and adrenaline being increased by 570% and 169% respectively. 4. Values for platelet noradrenaline content were found to mirror those for the release from platelets induced by thrombin. 5. A correlation was observed between catecholamine release and the concentration of thrombin present in incubations. These data reflect the changes observed with platelet aggregation. 6. This is the first study to determine catecholamine release from platelets by direct measurement. Local catecholamine release after platelet aggregation in vivo may have important consequences for tissue perfusion.

1. We have used high-performance liquid chromatography with electrochemical detection to measure content of adrenaline and noradrenaline in platelets in 13 normal subjects at rest. 2. Subjects were exercised to raise plasma catecholamine levels and promote the platelet release reaction. 3. There was a significant positive correlation between plasma noradrenaline concentrations and platelet noradrenaline content. 4. Platelet/plasma concentration ratios were 1855 for noradrenaline and 268 for adrenaline at rest and 473 and 152 respectively after exercise. 5. Plasma noradrenaline levels positively correlated with age. 6. Determination of platelet factors released to the plasma showed increases of β-thromboglobulin and platelet factor 4 with exercise, whereas thromboxane B 2 remained unchanged. No change in platelet catecholamine levels occurred with exercise and no correlations were observed between platelet catecholamines and released platelet factors. 7. These data suggest that plasma catecholamine levels influence platelet content and that noradrenaline and adrenaline are concentrated in platelets.

1. Total body potassium ( 40 K method) and total body water and exchangeable sodium (both by isotope dilution) were determined in 26 boys, aged 5-17 years, with muscular dystrophy. Total body potassium values were compared with measurements in a large series of normal boys on the basis of height. 2. Total body potassium was reduced even in the youngest patients and was only slightly higher in the older boys, despite their considerably greater height. Exchangeable sodium increased with increasing height in a way similar to that of normal boys. Total body water was also reduced but increased with growth, although to a lesser extent than expected for normal boys. The total body water measurements indicated that many of the affected boys were very obese, despite an apparently normal body weight. 3. An intravenous bolus of 22 Na distributed at a similar rate in boys with muscular dystrophy to that in normal males. 4. In relation to the predicted values, total body potassium and 24 h urinary creatinine excretion of the affected boys both declined at a rate of 4% per year.

1. Body weight and total body potassium were measured in 23 hyperthyroid patients before and at various stages during treatment and in 19 athyreotic patients who were being treated with high-dose l-thyroxine. 2. In the hyperthyroid patients the total body potassium rose by 23 ± 2.8% (sem) within a few weeks of restoring the blood thyroid hormone levels to normal. The body potassium values after treatment were close to that expected in these individuals if they were healthy indicating that a considerable loss of body potassium is usual in hyperthyroidism. 3. The gain of total body potassium in hyperthyroidism averaged 71 ± 8 mmol for each kg of body weight gained (compared with muscle potassium concentration of about 92 mmol/kg). In contrast, weight loss produced by dietary treatment of obesity caused very little change of body potassium (maximum averaged was 14 ± 4 mmol/kg wt. loss). 4. Among the patients with hyperthyroidism, the greatest muscular weakness was present in those with the greatest body potassium loss and these patients regained a large amount of potassium relative to weight on recovery. 5. Total body potassium changes were closely related to total plasma tri-iodothyronine concentrations but unrelated to the thyroxine levels.

1. Vitamin B 12 absorption was measured in 18 patients with tropical malabsorption. 2. Absorption was particularly impaired in patients with severe mucosal lesions. 3. Sequential measurements with 57 Co- and 58 Co-labelled vitamin B 12 were made before and 48 h after the start of tetracycline therapy. A rapid improvement (on average 22% increase in absorption) occurred in four of six patients with marked mucosal lesions. Further improvement occurred in four of five patients measured after 4 weeks' tetracycline, including the two who failed to improve initially. 4. These rapid changes in vitamin B 12 absorption after antibiotics occur too early to be due to mucosal recovery and suggest that bacterial metabolism is an important factor in the malabsorption in these patients.

1. Whole-body retention and plasma values of 131 I after a test dose were measured for up to 32 days in patients previously rendered athyreotic by surgery and 131 I treatment for thyroid carcinoma, and who were without detectable functioning tissue at the time of study. 2. About 99·8% of the administered 131 I was rapidly excreted, consistent with renal iodide excretion. The remainder (about 0·2%) was eliminated slowly, with mean half-life 15 days; we call this the slow-turnover component. 3. By the sixth day after the 131 I dose, very little [ 131 I]iodide remained in the plasma. The average protein-bound 131 I was only 0·0035% of dose/l, with mean half-life 14·1 days; 90% was non-extractable in butanol. Labelled albumin accounted for about 80% of the non-extractable fraction. 4. The distribution space estimated from the slow-turnover component and protein-bound 131 I was 34 1, indicating that most of the slow-turnover component is extravascular. 5. Stable potassium iodide administration, starting 2 days after giving 131 I, had no observable effect on the variables measured. 6. Impairment of renal function delayed [ 131 I]iodide excretion and increased both slow-turnover component and plasma protein-bound 131 I. 7. A simple model describing iodine kinetics in athyreotic individuals is suggested. It predicts that the slow-turnover component contains only about 4 μg of iodine and, since this is distributed widely in body tissues, it is unlikely to be of biological significance.

1. Total body potassium was estimated by 40 K measurement with a high-sensitivity whole-body counter in normal individuals over a wide age range and in patients who were obese or were grossly wasted as a result of various conditions which restricted food intake. 2. Potassium concentration (mmol/kg body weight) fell with increasing age over 30 years in both normal males and females, but when individuals of different age groups were matched for height, a significant fall in total body potassium with increasing age was observed only in males. Total body potassium of females was about 75% that of males of similar height when young, the sex difference decreasing with ageing. In the normal population, total body potassium was significantly correlated with height and with weight; regression equations for various relationships are given. 3. Fat-free mass was estimated from total body potassium, values of 65 and 56 mmol of potassium/kg fat-free mass being used for males and females respectively. Body fat estimated by this method correlated well with skinfold measurements over a wide range of body weight but in malnourished individuals having inadequate food intake there was considerable discrepancy and present formulae for estimating fat-free mass from total body potassium appear unsatisfactory in malnutrition. Considerable differences between expected and observed values of total body potassium were found in muscular individuals and in normal individuals who were thin but whose body weight was relatively constant. 4. The patients with malnutrition were low both in body fat as estimated by skinfold thickness and in total body potassium estimated on the basis of height. Plasma potassium was, however, normal and potassium supplements did not increase the total body potassium. 5. Total body potassium of obese individuals was not significantly different from that of normal weight individuals on the basis of height. Total body potassium fell on weight reduction with a very low energy diet of 1260 kJ (300 kcal.) daily but changed little with a 3300 kJ (800 kcal.) diet over several months' observation. 6. For overweight, obese individuals, total body potassium was best predicted from the individual's height. For those whose body weight was less than expected, the use of weight gave the best prediction but the error was considerable when the weight deviation was large.