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Every doctor should be able to make a probable diagnosis of congestive heart failure by clinical examination. The most revealing clinical sign is an elevated jugular venous pressure. The measurement of this pressure was introduced by Lewis in 1930 and refined and standardised by Borst and Molhuysen in 1952. Still, this method has fallen into disuse and is thought to be not very sensitive for diagnosing congestive heart failure. A study of the methods described in the literature reveals that variations in technique are responsible for great differences in normal values. It is argued that smaller elevations of jugular venous pressure can only be measured reliably by adhering strictly to the conditions put forward by Borst and Molhuysen. In this way the sensitivity will improve considerably. A plea is made for an intensive training in this method for doctors and medical students.

A comparison has been made of insulin absorption rate and its variability in healthy subjects (n = 12), matched Type 1 diabetic patients (n = 12), and brittle Type 1 diabetic patients (n = 13) after subcutaneous injection with a standardized injection technique. In each individual 8 U of iodinated neutral human soluble insulin were injected twice, at the fat-muscle boundary. Disappearance of radioactivity was measured for 8 h. Differences in absorption rate could not be demonstrated (T50 207 +/- 30 (+/- SD), 224 +/- 73 and 217 +/- 80 min in the three groups, respectively). Intra-individual variance was similar in the three groups (intra-individual SD of T50 14 +/- 9, 10 +/- 6 and 12 +/- 10%, respectively). Injection with the skinfold technique each patient usually employed, did not alter mean absorption rate or its variability significantly (T50 179 +/- 52 min; intra-individual SD 12 +/- 8%). In a group of Type 1 diabetic patients (n = 26) the absorption rate after deep injection was compared with that after superficial injection. No differences were found (T50 207 +/- 66 vs 236 +/- 66 min). In some of these patients (n = 10) plasma free insulin and glucose concentrations were measured. The increase in free insulin concentrations was significantly different only at some time-points, but insulin curves and plasma glucose concentrations did not differ significantly. Thus neither insulin absorption nor its variability differ between healthy subjects and diabetic patients, between deep and superficial subcutaneous injection, or between stable and brittle diabetic patients.

Recently it has been claimed that the active potassium influx in erythrocytes of patients with essential hypertension would be increased. In view of the diagnostic and possibly therapeutic potential of this claim, we have determined the Na+-K+ activated ATPase activity and the affinity of the enzyme for Na+, K+, and ATP in membranes isolated from erythrocytes of hypertensive (with and without medication) and normotensive subjects. Subsequently, the active (ouabain-sensitive) sodium and potassium fluxes and their ratios have been determined after treatment of intact erythrocytes either with cold or with p-chloromercuribenzene-sulfonate (PCMBS). Finally, in view of a subsequent claim that the furosemide-sensitive, ouabain-insensitive cation fluxes would be greatly reduced in erythrocytes of patients with essential hypertension, we have determined these fluxes in choline chloride medium containing ouabain with and without furosemide. For none of these parameters has any significant difference between hypertensive and normotensive subjects been found except for a decrease in the ouabain-sensitive K+ influx after cold treatment in hypertensives. This is also true for the hypertensive subjects who had a known hypertensive parent. It is concluded that the results do not support a role of Na+-K+ activated ATPase or the furosemide-sensitive cation carrier in the pathogenesis of essential hypertension, and that ouabain-sensitive and furosemide-sensitive cation flux determinations in erythrocytes do not seem to be useful for the diagnosis of this condition.

The efficacy of semisynthetic human insulin (HI) and monocomponent porcine insulin (PI) in treatment of diabetic ketoacidosis (DKA) was compared in 10 (PI) and 11 (HI) patients in a double-blind randomized study. Insulin (8 U/h i.v.), fluid replacement (0.65% NaCl and 5% glucose), and KCl supplements were administered according to a fixed protocol. Glucose, potassium, sodium, creatinine, calcium, phosphate, and free-insulin concentrations were never significantly different during the study. At the start, mean +/- SD of pH was 7.10 +/- 0.14 in the HI group and 7.10 +/- 0.12 in the PI group. The time to reach arbitrary values for pH, bicarbonate, base excess, and beta-hydroxybutyrate was shorter during HI treatment, but the differences were not statistically significant. During HI treatment, the arbitrary value of 1.0 mM of acetoacetate was reached faster than during PI treatment (5.2 +/- 2.6 and 8.4 +/- 0.9 h, respectively; P less than .05). The concentration of acetoacetate was significantly different between the two groups after 6 and 7 h of insulin treatment (6 h: HI 0.82 +/- 0.50 mM and PI 2.19 +/- 1.65 mM, P less than .05; 7 h: HI 0.51 +/- 0.40 mM and PI 1.74 +/- 1.54 mM, P = .05). We conclude that recovery from DKA during treatment with HI might be slightly faster than during treatment with PI. If this difference is real, it does not seem clinically important.

A double-blind cross-over trial of the non-selective beta-blocker propranolol and the beta1-selective blocker metoprolol was carried out in 8 hypertensive patients. At the end of each 4-week period of treatment haemodynamic and respiratory indices and perceived exertion were studied during moderate exercise. Both beta-blockers resulted in reduced heart rate, cardiac output, and blood pressure, whereas the stroke volume increased. Total peripheral resistance did not change. During exercise the expiratory peak flow rate equally increased in every period. However, the peak flow rate at rest, as well as during exercise, was reduced by propranolol, while metoprolol had no such influence. Neither of the beta-blockers changed O2 consumption, CO2 production, tidal volume, or respiratory rate. Moreover, they did not influence perceived exertion. These results suggest that the arteriolar and bronchiolar beta2-receptors do not play a major role in the alteration of circulation and ventilation during exercise. As far as their practical use as antihypertensive agents is concerned, this study shows no advantage in the use of either of these beta-blockers.

We studied polyethylene glycol 6000 precipitation of lipoproteins other than high-density lipoproteins, before cholesterol is estimated in the supernate. Other lipoproteins in the supernatant fractions were detected by using rocket immunoelectrophoresis. A polyethylene glycol concentration of 75 g/L in the final mixture appeared to be optimal, and results agreed with those obtained by ultracentrifugation. Differences in serum pH, use of polyethylene glycol from different suppliers, or the presence of ethylenediaminetetraacetate resulted in values that differed significantly (by 40 to 60 mumol/L) from the reference values. Polyethylene glycol did not interfere in four different methods for determination of cholesterol. In combination with an enzymic cholesterol method, the polyethylene glycol method appeared to be very precise, even when lipemic sera (triglycerides up to 5.5 mmol/L) were analyzed that had diminished high-density lipoprotein cholesterol values. We consider this method a method of choice, especially when lipemic sera are tested and enzymic cholesterol analysis is used.

Two low-density lipoprotein subfractions, LDL-1 and LDL-2, with density ranges of respectively 1.023-1.034 and 1.036-1.041 g/ml, were isolated by aspiration after density gradient ultracentrifugation of human pooled serum. In vitro interactions of both LDL subfractions with the LDL receptor of human cultured fibroblasts, human hepatoma cell line Hep G2 and human hepatocytes were compared. No difference in association (binding and internalization) nor in degradation between LDL-1 and LDL-2 by these cells was found. However, kinetic studies in guinea pigs showed that LDL-2 disappeared faster from the circulation and accumulated to a greater extent in the liver, compared to LDL-1. Thus, we were unable to show a difference in the LDL receptor-mediated uptake of both LDL subfractions by various cells in vitro. The results obtained in vivo suggest that LDL-1 is more atherogenic than LDL-2, because its longer half-life renders the particle more susceptible to uptake by the scavenger LDL receptor on macrophages.

In a double blind placebo-controlled cross-over trial of 24 weeks 31 patients with Raynaud's syndrome were treated with the alpha-blocker phenoxybenzamine (10-20 mg daily) and with the combination of the alpha-blocker phenoxybenzamine (10-20 mg daily) and the beta-blocker sotalol (40-80 mg daily). A favourable effect on recovery of finger temperature after finger cooling was demonstrated after alpha-blockade as com pared to the before treatment situation. This favourable effect was not different when the group received the combined alpha- and beta-blockade. The blood pressure was not influenced by either of the 2 medications. Fluid retention appeared with alpha-blockade and was absent with combined alpha- and beta-blockade. Decrease of heart rate oc curred with alpha- plus beta-blockade and was absent with alpha-blockade alone. Clinical symptoms of Raynaud's syndrome equally were alleviated by the two medica tions. Common, and equally frequent side effects of the two medications were nasal congestion, disturbed ejaculation and potence, dry mouth, exercise-induced and ortho- static dizziness. We conclude that alpha-blockade is beneficial in Raynaud's syndrome and that additional beta-blockade counteracts the alpha-blocker side-effect fluid retention, re duces the heart rate and thus may prevent alpha-blocker induced tachycardia, and that it does not cause hypotension.

Skin temperature of one finger was measured before and after immersion of the gloved fingers of both hands in 16 degrees C water for 5 min [room temperature (Ta) 24 or 20 degrees C]. At Ta 24 degrees C, 23 of 25 normal nonsmokers (92%) had finger rewarming to above 24 degrees C in 12 min after cold immersion, at Ta 20 degrees C, only 1 of 12 (8%) had similar rewarming. Among 12 habitual smokers only 4 (33%) rewarmed above 24 degrees C (Ta 24 degrees C) following a 1-h abstinence from smoking, but 8 (67%) did so after a 24-h abstinence. Only 2 of these 8, however, did so in a retest 10 min after smoking a cigarette. The smokers were not tested at Ta 20 degrees C. We conclude that air temperature and cigarette smoking are important determinants of finger rewarming following a finger-cooling test.

We evaluated the density-gradient ultracentrifugation method in a swinging-bucket rotor (Anal Biochem 111, 149-157, 1981) in a slightly modified version for isolation and determination of high-density lipoprotein (HDL) subfractions. We prestained the serum with Coomassie Brilliant Blue R, which did not change the hydrated densities of the lipoproteins, and after only 2.2 X 10(8) gav . min obtained an equilibrium distribution of the lipoproteins along the gradient. The density distribution of the HDL of 120 sera obtained from apparently healthy persons and from patients with different types of hyperlipoproteinemia was bimodal. The HDL2 could be isolated in the density range 1.072-1.098 kg/L and the HDL3 at 1.100-1.176 kg/L, the latter fraction being more heterogeneous. At a solvent density of 1.100 we obtained similar results for HDL2-and HDL3-cholesterol by ultracentrifugation in two different fixed-angle rotors with tube angles of 15 degrees or 35 degrees. Independent of the rotor and the ultracentrifugation technique, subfractionation at d = 1.100 resulted in more distinct stained entities than ultracentrifugation at d = 1.125. In the swinging-bucket rotor procedure, interference by sinking pre-beta-lipoproteins was minimized because, having hydrated densities between 1.058 and 1.075, they could be removed without aspirating the HDL2. The method is both accurate and precise. For HDL2- and HDL3-cholesterol determined in a thawed frozen serum pool, CVs were 8.8 and 6.3%, respectively (n = 18).

Twenty patients with primary and 11 with secondary Raynaud's syndrome were treated with the alpha-adrenoceptor blocker phenoxybenzamine (10-20 mg daily). In the secondary group mean age and mean duration of symptoms as well as presence of positive ANA and positive Clq blinding test were signifi cantly higher than in the primary group. In both groups a beneficial effect of the medication on finger temperature 12 min after finger cooling and on clinical symptoms was established. Secondary Raynaud's syndrome reacted at least as well as primary syndrome.

The role of the apo E polymorphism in the removal of remnants of very low density lipoproteins and chylomicrons was studied after a carbohydrate-rich diet in 10 healthy normolipidemic volunteers with different apo E phenotypes during 7 days. The cholesterol concentration in the heparin-sepharose bound part of the VLDL + IDL fraction (d < 1.019 g/ml) was taken as an estimate of the remnant concentration. Before and after carbohydrate-rich diet retinyl palmitate, mixed with cream, was consumed by each subject the evening before the fasting venepuncture to quantify the removal of chylomicron remnants. After the diet there was a comparable mean rise in the three groups in serum and in very low density lipoprotein triglycerides of about 30% and 50%, respectively. The concentration of remnants of very low density lipoproteins increased slightly in all subjects. The concentration of retinyl palmitate in the d < 1.019 g/ml fraction was 20% lower than before this diet in the E-2 homozygous subjects. In the other two groups, however, 25 to 80% higher retinyl palmitate levels were found. It is concluded, that after a carbohydrate-rich diet there is only a slight increase of very low density lipoprotein remnants, independent of the apo E polymorphism. The removal of chylomicron remnants, however, seems to be facilitated in E-2 homozygous subjects, in contrast to a slower removal in the groups with other apo E phenotypes.

Haemodynamic effects of a cold pressor test (foot immersion for 6 min in water at 5 degrees C) without medication and after the non-selective beta-adrenoceptor blocker propranolol and the selective beta-adrenoceptor blocker metoprolol were studied in 17 volunteers. In the control study as well as in the study with the beta-adrenoceptor blockers cold exposure caused comparable changes, namely a blood pressure rise and a reduction of forearm blood flow. The increase in heart rate during cold exposure was clearly and equally reduced by both beta-adrenoceptor blockers. Plasma noradrenaline rose significantly by 47%, plasma adrenaline did not change. It is concluded, that as to this kind of stress, beta 1-selective-adrenoceptor blockade confers no important advantage over non-selective beta-adrenoceptor blockade.

Cardiac output measurements were performed during 50 exercise tests in 16 normal subjects employing the indirect Fick principle for CO2. During sub-maximal steady state exercise the plateau CO2 tension (PplatCO2) was estimated with a rebreathing procedure. The mixed venous CO2 tension (PvCO2) was calculated by subtracting the alveolocapillary CO2 tension difference from the PplatCO2. Compared with data from the literature the most valid calculation of the cardiac output was obtained by using the PvCO2. Cardiac output values, calculated via the PplatCO2 turned out to be too low. The reproducibility was tested by repitition of 18 exercise tests at least after 5 days. The relative standard error of a single observation was 4.1% for the cardiac output, which was found to be as good as that of invasive measurements.

A double-blind randomized study was designed to investigate differences in the recovery of finger skin temperature after finger cooling during dosing with placebo or one of four β-blockers: propranolol, atenolol, pindolol, and acebutolol. In 11 normotensive nonsmoking subjects, finger skin temperature was measured with a thermocouple before and 20 minutes after immersion of one hand in a water bath at 16° C. This finger cooling test caused no significant changes in systemic hemodynamics such as arterial blood pressure, heart rate, and forearm blood flow. The recovery of finger skin temperature during propranolol dosing was better than that during pindolol and atenolol dosing. There were no differences between the recoveries of skin temperature during pindolol, atenolol, and acebutolol dosing. Thus we could demonstrate no favorable effect of intrinsic sympathomimetic activity or β1-selectivity on the recovery of finger skin temperature after finger cooling. Clinical Pharmacology and Therapeutics (1986) 39, 353–357; doi:10.1038/clpt.1986.52

We studied polyethylene glycol 6000 precipitation of lipoproteins other than high-density lipoproteins, before cholesterol is estimated in the supernate. Other lipoproteins in the supernatant fractions were detected by using rocket immunoelectrophoresis. A polyethylene glycol concentration of 75 g/L in the final mixture appeared to be optimal, and results agreed with those obtained by ultracentrifugation. Differences in serum pH, use of polyethylene glycol from different suppliers, or the presence of ethylenediaminetetraacetate resulted in values that differed significantly (by 40 to 60 mumol/L) from the reference values. Polyethylene glycol did not interfere in four different methods for determination of cholesterol. In combination with an enzymic cholesterol method, the polyethylene glycol method appeared to be very precise, even when lipemic sera (triglycerides up to 5.5 mmol/L) were analyzed that had diminished high-density lipoprotein cholesterol values. We consider this method a method of choice, especially when lipemic sera are tested and enzymic cholesterol analysis is used.

The fluctuations of serum lipid and lipoprotein concentrations within one cycle were studied both in women using and not using oral contraceptives. High-density lipoprotein cholesterol decreased significantly from 1.47 mmol/l (57 mg/100 ml) to 1.30 mmol/l (50 mg/100 ml) during one contraceptive cycle in eight women and rose again to the initial value during the pill-free days. The mean concentration of total cholesterol also fell significantly as a result of the decrease of high-density lipoprotein cholesterol and of a not significant decrease of low-density lipoprotein cholesterol. The mean serum triglyceride concentration did not change significantly. The fluctuations in the concentration of serum lipids and lipoproteins in 10 women not using oral contraceptives were smaller than in the women using oral contraceptives and no significant changes in the concentrations were found during one cycle. Thus, high-density lipoprotein cholesterol concentration decreases during each contraceptive cycle. The time of blood sampling during the cycle is, therefore, of vital importance in interpreting the effect of oral contraceptives on high-density lipoprotein cholesterol. In women not using oral contraceptives blood can be sampled on random days during the cycle.

We evaluated the density-gradient ultracentrifugation method in a swinging-bucket rotor (Anal Biochem 111, 149-157, 1981) in a slightly modified version for isolation and determination of high-density lipoprotein (HDL) subfractions. We prestained the serum with Coomassie Brilliant Blue R, which did not change the hydrated densities of the lipoproteins, and after only 2.2 X 10(8) gav . min obtained an equilibrium distribution of the lipoproteins along the gradient. The density distribution of the HDL of 120 sera obtained from apparently healthy persons and from patients with different types of hyperlipoproteinemia was bimodal. The HDL2 could be isolated in the density range 1.072-1.098 kg/L and the HDL3 at 1.100-1.176 kg/L, the latter fraction being more heterogeneous. At a solvent density of 1.100 we obtained similar results for HDL2-and HDL3-cholesterol by ultracentrifugation in two different fixed-angle rotors with tube angles of 15 degrees or 35 degrees. Independent of the rotor and the ultracentrifugation technique, subfractionation at d = 1.100 resulted in more distinct stained entities than ultracentrifugation at d = 1.125. In the swinging-bucket rotor procedure, interference by sinking pre-beta-lipoproteins was minimized because, having hydrated densities between 1.058 and 1.075, they could be removed without aspirating the HDL2. The method is both accurate and precise. For HDL2- and HDL3-cholesterol determined in a thawed frozen serum pool, CVs were 8.8 and 6.3%, respectively (n = 18).

The underlying pathophysiological defect was studied in four siblings with familial hyperchylomicronemia. Deficiency of apolipoprotein C-II and E-3 was identified. In addition, these subjects had markedly decreased LPL activity in postheparin plasma. Addition of normal plasma to the assay as source for apoC-II enhanced LPL activity only to a limited extent. In contrast with previously reported patients with apoC-II deficiency, a far less pronouced effect of intravenous infusion of normal plasma was seen in one of the siblings, probably due to the combined deficiency of apoC-II and LPL. Plasma VLDL-TG turnover rate was not decreased in one of the siblings with apoC-II and LPL deficiency, suggesting different metabolic pathways for chylomicrons and VLDL. Family study confirmed an autosomal recessive mode of inheritance both for apoC-II and for apoE-3 deficiency. The mode of inheritance for LPL deficiency could not be established exactly.

We examined in a double blind fashion and placebo controlled the effects of some alpha and beta adrenergic receptor agonists and antagonists on the recov ery of finger skin temperature 12 min after finger cooling (5 min waterbath for both hands) in twelve patients with Raynaud's syndrome. A favourable effect was established on phenoxybenzamine 20 mg as compared to placebo. A signifi cant but rather small effect on orciprenaline 10 mg. The beta-agonists pre nalterol (10 mg) and terbutaline (5 mg) did not influence the recovery of finger skin temperature. The beneficial effect of phenoxybenzamine 20 mg was not influenced by the addition of beta-agonists (prenalterol 10 mg or terbutaline 5 mg) or a beta-blocker (propranolol 40 mg). The beta-agonists terbutaline and orciprenaline caused a fall in diastolic pressure and an increase in heart rate. These effects presumably were con nected with one collaps and three near-collapses. On alpha- and beta-blocker (phenoxybenzamine and propranolol) a decrease in systolic pressure appeared, whereas diastolic pressure did not significantly differ from the placebo value. While physical exercise is considered to exacerbate the hypotensive effect of alpha-blockers, a fall in blood pressure during physical exercise could not be established in our experiments after the addition of propranolol to the alpha- blocker phenoxybenzamine. Our results suggest that an alpha-blocker is a good choice in Raynaud's syndrome, whereas the addition of a beta-blocker may have some advantages.