Showing papers in "Clinical Science in 1991"
TL;DR: The vasovagal response is the development of inappropriate cardiac slowing and arteriolar dilatation that reflects autonomic neural changes: bradycardia results from sudden augmentation of efferent vagal activity, and hypotensionresults from sudden reduction or cessation of sympathetic activity and relaxation of arterial resistance vessels.
Abstract: The vasovagal response is the development of inappropriate cardiac slowing and arteriolar dilatation. Vasovagal responses reflect autonomic neural changes: bradycardia results from sudden augmentation of efferent vagal activity, and hypotension results from sudden reduction or cessation of sympathetic activity and relaxation of arterial resistance vessels. Two different neural pathways are thought to be involved, one originating in the hypothalamus, the other in the heart. Direct hypothalamic activation of the medullary cardiovascular centres triggered by emotional stress or pain causes a vasovagal response (central type). The combination of a reduced central blood volume secondary to venous pooling or blood loss, and an increased inotropic state of the heart, may stimulate ventricular mechanoreceptors and provoke vasodilatation and bradycardia (peripheral type). Cardiovascular afferents originating from stretch receptors in various parts of the vascular tree sometimes induce opposite reflexes when compared with those from ventricular afferents. The depressor reflex involved in the peripheral type of vasovagal response originates in the heart itself and overrides normal baroreflex circulatory control; an antagonism between the control of volume and pressure on the filling side of the heart and the control system of arterial pressure becomes apparent. Vasovagal responses are not necessarily abnormal; the neural pathways involved in the vasovagal response are probably present in all healthy subjects who individually mainly differ in susceptibility.
320 citations
TL;DR: Correlations were sought between antioxidants in blood and (1) weekly training distance and (2) maximum oxygen uptake and erythrocyte activities of the antioxidant enzymes, glutathione peroxidase and catalase, were significantly and positively correlated with the weekly trainingdistance.
Abstract: 1. Blood antioxidants were measured in venous blood samples from 20 runners and six sedentary individuals. All subjects were male, between 20 and 40 years old, and in steady state with respect to body weight and physical activity patterns. Dietary analysis was undertaken using a 7-day weighed food intake. Correlations were sought between antioxidants in blood and (1) weekly training distance and (2) maximum oxygen uptake. In addition, 12 runners could be classified into two groups undertaking either low (range 16-43 km, n = 6) or high (80-147 km, n = 6) weekly training. 2. Body weight (range 55.3-90.0 kg) and percentage body fat (range 7-19%) both showed negative correlations with the weekly training distance (both P less than 0.001). Energy intake and maximum oxygen uptake were both correlated with the weekly training distance (both P less than 0.001). 3. Plasma creatine kinase activity, an indicator of muscle damage, was significantly correlated with the weekly training distance (P less than 0.01), whereas the plasma concentration of thiobarbituric acid-reactive substances, an indicator of free-radical-mediated lipid peroxidation, decreased with increased maximum oxygen uptake (P less than 0.01). 4. Erythrocyte alpha-tocopherol content was greater in the two running groups (P less than 0.05) compared with the sedentary group, and lymphocyte ascorbic acid concentration was significantly elevated in the high-training group (P less than 0.01) compared with the low-training group. 5. Erythrocyte activities of the antioxidant enzymes, glutathione peroxidase and catalase, were significantly and positively correlated with the weekly training distance (P less than 0.01 and P less than 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
261 citations
TL;DR: The results show that in the assessment of muscle constituents, age and sex must be taken into account.
Abstract: 1. A method is described enabling the determination of fat, water, electrolytes, protein, DNA, RNA and total creatine in a single sample of human muscle obtained by the percutaneous needle-biopsy technique. The amino acid content can also be analysed in the same muscle sample. 2. Fifty healthy subjects were studied: 29 between 19 and 40 years of age, 11 between 41 and 60 years of age, and 10 between 61 and 85 years of age. The two groups aged less than 60 years showed only marginal differences in muscle composition, whereas the highest age group showed increases in muscle fat content in relation to tissue weight and decreases in alkali-soluble protein content in relation to both tissue weight and tissue DNA content. Also, potassium, magnesium, total creatine and RNA contents were decreased in this age group when related to tissue DNA content. When alkali-soluble protein was used as a reference base, only magnesium content was decreased. 3. A comparison was also made between female (n = 23) and male (n = 18) subjects in the age groups below 60 years. Differences observed included a higher fat content in female muscle, and an increase in total creatine content in relation to tissue weight. The alkalisoluble protein content was lower per muscle cell in the females when calculated on the basis of DNA content. 4. The results show that in the assessment of muscle constituents, age and sex must be taken into account.
255 citations
TL;DR: This study demonstrates the complete absence of any activity for this enzyme in the brain of the three species examined, and demonstrates that the enzyme exists only in the cytoplasm of rat liver cells.
Abstract: 1. Conflicting reports exist as to the organ distribution of betaine-homocysteine methyltransferase (EC 2.1.1.5). It is important to establish its presence or absence in brain, since its substrate, betaine, has recently become established in the treatment of certain diseases involving this organ. 2. It remains unclear whether the reported success of this treatment results from the use of betaine to methylate homocysteine and produce methionine in situ in neural tissue, or whether the effect is secondary to these same reductions happening in other organs, such as the liver. The former would require the presence of betaine-homocysteine methyltransferase in neural tissue. 3. This study demonstrates the complete absence of any activity for this enzyme in the brain of the three species examined. The enzyme was found to be present in both the liver and kidney of man and pig, but only in the liver of the rat. 4. The only source of betaine in cells is via the oxidation of choline. Since the enzymes involved in this conversion have never been shown to exist anywhere other than the mitochondria, it has been assumed that the methyltransferase is also mitochondrial. In this study, it is demonstrated that the enzyme exists only in the cytoplasm of rat liver cells.
207 citations
TL;DR: The secretion of gelatinase by inflammatory cells at the intima of diseased aorta could have a pathological role in establishing atherosclerotic plaques and medial thinning, and secretion of collagenase, gelatinase and stromelysin from the adventitia could accelerate connective tissue degradation in the media of aneurysmal aortA.
Abstract: 1. Atherosclerosis and aneurysm of the abdominal aorta are associated with thinning of the medial connective tissue. We have investigated the presence of the connective-tissue-degrading metalloproteinases in homogenates prepared from atherosclerotic, aneurysmal and control aortic media. 2. Gelatinase activity was much increased in homogenates from atherosclerotic and aneurysmal aorta [10.9 +/- 1.8 and 13.3 +/- 3.3 micrograms of gelatin hydrolysed h-1 (mg of protein)-1 respectively]. This gelatinase activity was highest at the luminal aspect of the aortic media, where the activity increased three- to five-fold after the destruction of alpha 2-macroglobulin. Zymograms demonstrated the principal gelatinase in atherosclerotic aorta to have a molecular mass of about 92 kDa, whereas in aneurysmal aorta there was a spectrum of gelatinase activity from 92 to 55 kDa. 3. Collagenase and stromelysin (proteoglycanase) could be detected by immunoblotting in homogenates of aneurysmal aorta, but rarely in atherosclerotic aorta and never in control aorta. Collagenase and stromelysin activities were low, but increased two- to three-fold after the destruction of tissue inhibitor of metalloproteinases. Collagenase and stromelysin activities were highest at the adventitial aspect of aneurysmal media. 4. The secretion of gelatinase by inflammatory cells at the intima of diseased aorta could have a pathological role in establishing atherosclerotic plaques and medial thinning. Secretion of collagenase, gelatinase and stromelysin from the adventitia could accelerate connective tissue degradation in the media of aneurysmal aorta.
201 citations
TL;DR: The data indicate that diet-induced weight loss is associated with rapid bone loss, subsequent weight gain being accompanied by increases in bone mass, and further studies are required to establish the clinical significance of these findings.
Abstract: 1. Total body areal bone mineral density was measured by dual-energy X-ray absorptiometry in eight women before and 10 weeks after a very-low-calorie diet [405 kcal (1701 kJ)/day]. 2. The mean weight loss of 15.6 kg was accompanied by a statistically significant reduction in total body bone mineral density from 1.205 +/- 0.056 to 1.175 +/- 0.058 g/cm2 (mean +/- SD, P less than 0.005). 3. After cessation of the diet, weight gradually increased and by 10 months was similar to baseline values. Total body bone mineral density also increased after stopping the diet and mean values obtained 10 months after the diet did not differ significantly from initial values. Throughout the study total body bone mineral density values in all subjects were well within the range reported for normal subjects. 4. These data indicate that diet-induced weight loss is associated with rapid bone loss, subsequent weight gain being accompanied by increases in bone mass. Further studies are required to establish the clinical significance of these findings and, in particular, the skeletal distribution of bone loss.
185 citations
TL;DR: Treatment with recombinant human growth hormone in adults with growth hormone deficiency resulted in small increases in left ventricular pre-load, due to the sodium-retaining action of growth hormone, and activation of the renin-aldosterone system was involved in such changes.
Abstract: 1. In adult humans with growth hormone deficiency, treatment with growth hormone has recently been shown to have major anabolic effects and to improve exercise performance. The cardiovascular effects of growth hormone in adults with growth hormone deficiency were examined in 24 patients treated with recombinant human growth hormone (0.07 units/kg at night) in a double-blind, placebo-controlled trial lasting 6 months. 2. Compared with placebo, resting M-mode echocardiography showed increases in left ventricular end-diastolic dimension and stroke volume in the group treated with recombinant human growth hormone. No differences were noted between the groups with respect to left ventricular end-systolic dimension, fractional shortening, wall thicknesses or mean arterial blood pressure. Left ventricular myocardial mass increased in the group given recombinant human growth hormone. 3. The supine plasma renin activity was increased and remained elevated over the 6 months, whereas the plasma aldosterone concentration was unchanged, after treatment with recombinant human growth hormone. Clinical signs of sodium retention were evident during the first 3 months of treatment with recombinant human growth hormone. 4. We conclude that treatment with recombinant human growth hormone in adults with growth hormone deficiency resulted in small increases in left ventricular pre-load, due to the sodium-retaining action of growth hormone. Activation of the renin-aldosterone system was involved in such changes. Myocardial hypertrophy was observed without changes in mean arterial pressure, reflecting the anabolic action of growth hormone.
151 citations
TL;DR: The data suggest that anti-oxidants might have a dilatatory effect and that an imbalance of the nitric oxide-free radical interaction might facilitate the development of hypertension in humans.
Abstract: 1. In this study an acute anti-hypertensive effect of three anti-oxidant agents (vitamin C, thiopronine and glutathione) in hypertensive subjects and in both hypertensive and non-hypertensive diabetic patients is reported. 2. The anti-oxidants had no effect on blood pressure in healthy normal subjects at a dose of 6 mmol, but thiopronine and glutathione produced a significant hypotensive effect at a dose of 12 mmol. 3. These data suggest that anti-oxidants might have a dilatatory effect and that an imbalance of the nitric oxide-free radical interaction might facilitate the development of hypertension in humans.
149 citations
TL;DR: It is concluded that the metabolic sequelae of sustained exercise are similar, but not analogous, to the acute-phase response, and interleukin-1 probably plays a significant role in linking the haematological and immunological changes observed after sustained strenuous exercise.
Abstract: 1. It has been suggested that the physiological consequences of strenuous exercise are analogous to those of the acute-phase response. 2. In 70 male and 20 female competitive distance runners, a marked, but transient, neutrophil leucocytosis occurred immediately after these athletes completed a standard (42 km) marathon race. Concomitant significant increases were noted in the plasma cortisol levels, creatine kinase activity, C-reactive protein level, total protein level and albumin level (P less than 0.01). 3. The plasma fibrinogen, C-reactive protein and total protein concentrations were markedly increased both 24 h and 48 h after exercise (P less than 0.01). The serum haptoglobin level was significantly decreased after exercise (P less than 0.01), and increased 48 h later (P less than 0.05). There was no change in the serum iron level, total iron-binding capacity, per cent saturation of transferrin and serum ferritin level. 4. A significant increase in interleukin-1-type activity was demonstrated immediately and 24 h after exercise (P less than 0.01). 5. It is concluded that the metabolic sequelae of sustained exercise are similar, but not analogous, to the acute-phase response, and interleukin-1, probably plays a significant role in linking the haematological and immunological changes observed after sustained strenuous exercise.
147 citations
TL;DR: Stable-isotope usage in human metabolic studies has been without documented significant adverse effect, and should perturbation of the delicate homoeostatic characteristic of living organisms occur with use of stable isotopes, it is almost undoubtedly at some level of administration greatly in excess of those administered currently in biomedical research.
Abstract: Approaching half a century of stable-isotope usage in human metabolic studies has been without documented significant adverse effect. Side-effects with acute D dosing are transitory with no demonstrated evidence of permanent deleterious action. The threshold of D toxicity has been defined in animals and is far in excess of concentrations conceivably used in human studies. The possibility that D may have additional beneficial pharmacological applications cannot be excluded. For isotopes other than D, evidence of observed toxicity remains to be produced even at dosages far in excess of the range used in metabolic studies. Absence of adverse effect may be attributable to small mass differences and the similar properties of tracer and predominantly abundant isotope. Absolute determination of stable isotope toxicity in humans is rendered impossible by ethical considerations. Also, the precision of extrapolating toxicity thresholds from animal studies remains unknown. However, should perturbation of the delicate homoeostatic characteristic of living organisms occur with use of stable isotopes, it is almost undoubtedly at some level of administration greatly in excess of those administered currently in biomedical research.
138 citations
TL;DR: The Borg scale provides a reliable technique for studying the sensation of breathlessness over extended time periods and was highly reproducible both after 1 week and after 40 weeks of the study.
Abstract: 1. The intensity of breathlessness in normal subjects during exercise was measured on seven occasions over a 40-week study period to assess the long-term repeatability of Borg scale estimates of breathlessness. 2. In all subjects there was a significant correlation (P = 0.0001) between breathlessness and minute ventilation. Minute ventilation measured at each work rate did not differ between the seven exercise tests (P greater than 0.05). 3. There was no significant difference between the mean Borg scores (measured with respect to a given level of ventilation) in 5 of the 7 test weeks (P greater than 0.05). The slope of the relationship Borg score/minute ventilation did not differ between the seven exercise tests (P greater than 0.05). 4. Breathlessness estimation was highly reproducible both after 1 week and after 40 weeks of the study (both P greater than 0.05). 5. The duration without testing between consecutive tests did not affect reproducibility: the mean Borg score was as equally reproducible after an interval of 22 weeks without testing as after an interval of 1 week (P greater than 0.05). 6. The Borg scale provides a reliable technique for studying the sensation of breathlessness over extended time periods.
TL;DR: It is concluded that release of atrial natriuretic peptide decreases with continuous positive airway pressure treatment in those patients with obstructive sleep apnoea who have increased release ofAtrial nativity peptide before treatment.
Abstract: 1. Patients with obstructive sleep apnoea have increased diuresis during sleep, which decreases with nasal continuous positive airway pressure treatment. These changes have been attributed to an increased release of atrial natriuretic peptide in obstructive sleep apnoea, and its decrease with continuous positive airway pressure treatment. 2. In order to clarify the change in plasma atrial natriuretic peptide level and to investigate the underlying mechanisms, blood samples were taken at 10 min intervals from nine patients with obstructive sleep apnoea during two nights when the patients were either untreated or treated with continuous positive airway pressure. Polysomnographic monitoring, including transcutaneous oximetry, and measurement of oesophageal pressure were performed simultaneously. Plasma arginine vasopressin was also measured. 3. The plasma level of arginine vasopressin did not change. The level of atrial natriuretic peptide was high and exhibited secretion bursts in six out of the nine patients; it drastically decreased with continuous positive airway pressure treatment. 4. Across the patients, the mean plasma levels of atrial natriuretic peptide was correlated with the degree of hypoxaemia and the degree of oesophageal pressure swings during the sleep apnoeas. 5. Within the patients, cross-correlation studies suggested that the atrial natriuretic peptide secretory bursts were related either to the oesophageal pressure swings or to the apnoea-related hypoxaemia. 6. We conclude that release of atrial natriuretic peptide decreases with continuous positive airway pressure treatment in those patients with obstructive sleep apnoea who have increased release of atrial natriuretic peptide before treatment. 7. The results are in agreement with the hypothesis that the haemodynamic changes induced by the increased swings in intra-thoracic pressure during ineffective respiratory efforts or by the hypoxia-induced vasoconstriction play a role in these changes.
TL;DR: Blood pressure was higher at the onset of menstruation than at most other phases of the cycle, and changes in plasma 17 beta-oestradiol and progesterone concentrations were also similar in the two groups.
Abstract: 1. Changes in blood pressure during the normal menstrual cycle are not well documented, and previous studies have given conflicting results. 2. Thirty normotensive women and ten mildly hypertensive women measured their blood pressure at home each morning for 6 weeks, under standardized conditions, using a UA-751 semi-automatic sphygmomanometer. All had normal menstrual cycles and subjects entered the study at different phases of the cycle. 3. Blood pressure was higher at the onset of menstruation than at most other phases of the cycle (systolic blood pressure, P less than 0.05; diastolic blood pressure, P less than 0.001). Adjusted diastolic blood pressure was higher in the follicular than in the luteal phase (mean difference 1.23 mmHg, P less than 0.001). Similarly, blood pressure was lower during days 17-26 than during the remainder of the cycle (adjusted mean difference in systolic blood pressure -0.65 mmHg, P = 0.07; adjusted mean difference in diastolic blood pressure -1.19 mmHg, P less than 0.001). 4. Similar patterns were seen in normotensive and hypertensive subjects, and changes in plasma 17 beta-oestradiol and progesterone concentrations were also similar in the two groups.
TL;DR: It is concluded that the demonstrated increase in erythrocyte turnover may be sufficient to precipitate an iron deficiency in endurance athletes when dietary intake or absorption does not meet the accelerated erythropoietic demands.
Abstract: 1. Exercise-induced haemolysis has been implicated in the sub-optimal iron status of endurance-trained athletes. Accordingly, erythrocyte survival studies using 51Cr were performed on male and female distance runners (n = 20) and sedentary control subjects (n = 10) in order to determine whether the rate of erythrocyte destruction was altered as a consequence of repetitive exercise training. 2. The chromium half-disappearance time of the male (25.4 +/- 3.6 days, mean +/- SD) but not the female (28.3 +/- 4.6 days) athletes was significantly lower than that of the male (33.1 +/- 4.5 days) and female (32.3 +/- 2.6 days) control subjects (P less than 0.01). The mean erythrocyte lifespan of the male and female distance runners (67.2 +/- 22.2 and 72.4 +/- 26.0 days, respectively) was significantly shorter than that of the non-exercising male and female subjects (113.4 +/- 31.0 and 114.1 +/- 29.0 days, respectively) (P less than 0.01). 3. There was no correlation between the mean erythrocyte lifespan and the haemoglobin concentration, serum ferritin levels, body mass, weekly training distance, number of years running or daily protein intake. The mean cell volume and reticulocyte count measured in the same athletes before and after completing a standard 42 km marathon race were within the normal range, whereas the plasma haemoglobin levels were elevated (77.0 +/- 50.5 mg/l) and the serum haptoglobin levels were decreased (0.89 +/- 0.4 g/l) at rest, with a further significant decrease after running (0.69 +/- 0.4 g/l) in the latter measurement (P less than 0.05). 4. It is concluded that the demonstrated increase in erythrocyte turnover may be sufficient to precipitate an iron deficiency in endurance athletes when dietary intake or absorption does not meet the accelerated erythropoietic demands.
TL;DR: The data suggest that there are at least two major sources of acetate in man, an endogenous source and the colon which probably becomes more important when fermentation of carbohydrate is occurring.
Abstract: 1. To test the hypothesis that the colon contributes significantly to venous plasma acetate concentrations, experiments were carried out in healthy volunteers and ileostomy patients. 2. Fasting plasma acetate levels were measured in 10 ileostomy patients and compared with those in 21 control subjects. Values in ileostomy patients (21.3 +/- 0.8 mumol/l) were significantly lower than in control subjects (48.0 +/- 4.2 mumol/l). 3. Plasma acetate concentration was estimated in eight healthy volunteers during 108 h of continuous fasting. Acetate concentrations rose significantly from 12 h (43.9 +/- 4.4 mumol/l) to 108 h of starvation (114.0 +/- 15.6 mumol/l) and fell back to normal fasting values on refeeding and another 12 h fast (44.3 +/- 4.7 mumol/l). 4. When colonic fermentation was stimulated after oral ingestion of 10 g of lactulose, the plasma acetate concentration increased significantly (from 44.0 +/- 7.4 to 114.4 +/- 16.2 mumol/l) in seven healthy control subjects. This rise was not affected by concomitant dosage of metronidazole. 5. These data suggest that there are at least two major sources of acetate in man, an endogenous source and the colon which probably becomes more important when fermentation of carbohydrate is occurring.
TL;DR: Exercise of monoclonal antibody 7F7 and immunoperoxidase staining and expression of intercellular adhesion molecule-1 found on the majority (59%) of infiltrating mononuclear cells in all forms of glomerulonephritis revealed no change in expression.
Abstract: 1. Expression of intercellular adhesion molecule-1 was investigated in five normal kidneys and 47 renal biopsies with the use of monoclonal antibody 7F7 and immunoperoxidase staining. 2. In the normal kidney, intercellular adhesion molecule-1 was expressed on endothelial cells of glomerular and peritubular capillaries, on Bowman's capsule, on some interstitial cells and weakly in the mesangium. 3. Increased glomerular staining was detected in early cases of rapidly progressing glomerulonephritis (5/8) and in some cases of non-IgA mesangioproliferative glomerulonephritis (5/9), IgA nephropathy (3/5), Henoch-Schoenlein purpura (2/2), lupus nephritis (5/6) and focal segmental glomerulosclerosis (1/3). A decrease in intercellular adhesion molecule-1 expression was noted in advanced rapidly progressive glomerulonephritis (3/8), two cases of membraneous nephropathy, one severe mesangioproliferative glomerulonephritis biopsy, the two membranoproliferative glomerulonephritis biopsies and in sclerotic loops in focal segmental glomerulosclerosis. 4. Expression de novo on tubular epithelial cells occurred in rapidly progressive glomerulonephritis, in membranoproliferative glomerulonephritis, and to a lesser extent in some cases of membraneous nephropathy, minimal change disease, IgA nephropathy, focal segmental glomerulosclerosis, a severe case of mesangioproliferative glomerulonephritis and in the mixed essential cryoglobulinaemia case. In 63% of positive tubuli, intraluminal cells which expressed CD18, the common beta-chain of leucocyte-function-associated antigen-1, Mac-1 and p150,95, were present. 5. Intercellular adhesion molecule-1 was also found on the majority (59%) of infiltrating mononuclear cells in all forms of glomerulonephritis.
TL;DR: There was a wide intersubject variation in the magnitude of both breathlessness 'intensity' and 'distress' estimates, but the differences between subjects in these two components of the sensation did not appear to follow a common pattern.
Abstract: 1. This study was designed to examine whether normal subjects could differentiate between the 'intensity' of their breathlessness and the amount of 'distress' it evoked, by specific wording of the instructions. 2. A preliminary study showed no significant difference between 'distress' score during exercise measured on two separate occasions (P = 0.3). 3. Ten subjects each performed two identical incremental cycle-ergometer exercise tests on separate occasions during which they were asked to quantify either 'intensity' or 'distress' by using modified Borg scales. 4. In all subjects there was a significant correlation (P less than 0.001) between 'intensity' and minute ventilation. In eight subjects there was a significant correlation (P less than 0.05) between 'distress' and minute ventilation. One subject displayed no significant correlation and one registered no distress. 5. Mean 'intensity' was greater than the mean 'distress' (P = 0.0001). The slope of 'intensity'/minute ventilation was greater than the slope of 'distress'/minute ventilation (P = 0.0001). 6. Within individuals there was a significant correlation between 'intensity' and 'distress' (P less than 0.05). There was a wide scatter in the slope of this relationship between subjects and maximum 'intensity' and 'distress' did not correlate. 7. Different elements of the breathlessness sensation could be identified and selectively measured depending on the wording of the instructions given to the subject. 8. There was a wide intersubject variation in the magnitude of both breathlessness 'intensity' and 'distress' estimates, but the differences between subjects in these two components of the sensation did not appear to follow a common pattern.
TL;DR: The provision of an alternate metabolic fuel thus produced immediate changes in the neurohumoral responses to hypoglycaemia, consistent with the hypothesis that human nervous tissue can metabolize ketones acutely.
Abstract: 1. The effect of hyperketonaemia on counter-regulatory hormone responses to hypoglycaemia has been examined in six healthy subjects. 2. A controlled, step-wise reduction in blood glucose concentration was achieved by adjusting the rate of glucose infusion during a primed-continuous infusion of soluble insulin (1.5 m-units min-1 kg-1 body weight, plasma insulin concentration approximately 90 m-units/l). Simultaneous infusion of either saline or beta-hydroxybutyrate (3 mg min-1 kg-1 body weight) was administered in a single-blind fashion, in random order. Despite a need for 40% more glucose during the ketone infusion, an identical fall in blood glucose concentration was achieved in each study. 3. The glycaemic threshold for stimulating an adrenaline response of 0.41 nmol/l was reduced from 3.1 to 2.8 mmol/l (P less than 0.05) during ketone infusion, and that for stimulating a response of more than 50% of basal from 3.6 to 3.1 mmol/l (P less than 0.001). The peak adrenaline response fell from 7.97 to 2.6 nmol/l (P less than 0.04). Peak noradrenaline, cortisol and growth hormone responses were also significantly lower during ketone infusion (P = 0.04, 0.001 and 0.006, respectively). Glucagon responses alone were unaffected by hyperketonaemia. 4. The provision of an alternate metabolic fuel thus produced immediate changes in the neurohumoral responses to hypoglycaemia. This is consistent with the hypothesis that human nervous tissue can metabolize ketones acutely.
TL;DR: Results show that arginine in high dose is a vasodilator in both human resistance vessels and superficial veins in vivo.
Abstract: 1. L-Arginine is the physiological precursor for the formation of endothelium-derived nitric oxide. The synthesis of nitric oxide is stereospecific: D-arginine is not a substrate for nitric oxide synthase. It is possible that the provision of excess L-arginine substrate might increase the vascular synthesis of nitric oxide. We have examined this possibility by studying the effects of local infusion of L- and D-arginine in the forearm resistance bed and the superficial dorsal hand veins of healthy subjects. 2. Drugs were either infused locally into a vein on the back of the hand and then the vein diameter was measured using a linear displacement technique, or into the brachial artery and then the forearm blood flow was measured by venous occlusion plethysmography. 3. In the superficial hand veins, L- and D-arginine free base and L- and D-arginine hydrochloride (all four preparations at a dose of 5 mumol/min) all caused a significant increase in venous diameter. The responses of the L- and D-enantiomers did not differ significantly from one another. 4. In the forearm resistance bed, L- and D-arginine free base and L- and D-arginine hydrochloride were without effect at doses of 10 and 40 mumol/min. However, at doses of 160 mumol/min all three preparations of arginine caused a significant increase in forearm blood flow compared with control values. The responses to the three preparations of arginine did not differ significantly from one another. 5. These results show that arginine in high dose is a vasodilator in both human resistance vessels and superficial veins in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: It is concluded that an elevated basal metabolism occurs in chronic cardiac failure and resting energy expenditure was found to account for some of this difference.
Abstract: 1. Resting energy expenditure has previously been shown to be elevated in the acute phase of heart failure, but the situation in the compensated state of chronic cardiac failure is unclear. Resting energy expenditure was assessed in 14 patients with stable chronic cardiac failure and 14 matched control subjects by using indirect calorimetry. 2. Resting energy expenditure was significantly elevated in the patients with chronic cardiac failure (112.6 +/- 18.1 versus 87.1 +/- 12.2 kJ day-1 kg-1 total body weight, P less than 0.0002; mean +/- SD) as were resting O2 consumption (3.88 +/- 0.64 versus 3.00 +/- 0.43 ml min-1 kg-1, P less than 0.0002), ventilation (164 +/- 40.3 versus 104 +/- 16.2 ml min-1 kg-1, P less than 0.0001) and heart rate (85.8 +/- 16.9 versus 66.6 +/- 6.9 beats/min, P less than 0.001). Both the resting plasma concentration of noradrenaline (4.48 +/- 1.52 versus 2.28 +/- 0.96 nmol/l, P less than 0.0001) and the serum concentration of free fatty acids (0.78 +/- 0.21 versus 0.57 +/- 0.27 mmol/l, P less than 0.03) were greater in the patients with chronic cardiac failure. Analysis of covariance indicated that most of the difference in resting energy expenditure could be accounted for by the elevated ventilation in the patients with chronic cardiac failure. Arm muscle area, an index of wasting, was lower in the patients with chronic cardiac failure (39.1 +/- 13.1 versus 50.5 +/- 9.4 cm2, P less than 0.02) and resting energy expenditure was found to account for some of this difference. 3. We conclude that an elevated basal metabolism occurs in chronic cardiac failure.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Renal and cardiovascular effects of three dosages of insulin were investigated in healthy males by using a euglycaemic clamp technique and there was a positive correlation between the change in fractional sodium excretion and thechange in systolic blood pressure over control values.
Abstract: 1. Renal and cardiovascular effects of three dosages of insulin [50 (Ins I), 300 (Ins II) and 500 (Ins III) m-units h-1 kg-1] were investigated in healthy males by using a euglycaemic clamp technique. On separate days, control experiments were carried out to correct for any circadian variation in the variables studied. 2. All three insulin dosages resulted in a marked decline in fractional sodium excretion (actual experiments: basal, 0.95 +/- 0.15%, Ins I, 0.79 +/- 0.10%, Ins II, 0.80 +/- 0.12%, Ins III, 0.84 +/- 0.08%; control experiments: basal, 0.96 +/- 0.10%, Ins I, 1.20 +/- 0.12%, Ins II, 1.53 +/- 0.15%, Ins III, 1.43 +/- 0.10%; means +/- SEM, P less than 0.005, analysis of variance). With the highest insulin dosage, the reduction in fractional sodium excretion tended to be less striking. This coincided with a rise in heart rate, pulse pressure and pulse rate-systolic blood pressure product (double product). Although blood pressure itself did not change, systolic blood pressure also tended to increase (actual experiments: basal, 133 +/- 5 mmHg, Ins I, 132 +/- 5 mmHg, Ins II, 139 +/- 5 mmHg, Ins III, 143 +/- 4 mmHg; control experiments: basal, 128 +/- 3 mmHg, Ins I, 129 +/- 3 mmHg, Ins II, 130 +/- 3 mmHg, Ins III, 133 +/- 3 mmHg; means +/- SEM, P = 0.09, analysis of variance). There was a positive correlation between the change in fractional sodium excretion and the change in systolic blood pressure over control values (r = 0.696, P less than 0.028).(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Chylomicron-triacylglycerol, appearing in the plasma post-prandially, may compete with very-low-density lipoprotein- triacyl glycerol for clearance by adipose tissue lipop protein lipase, and this mechanism may explain, at least in part, the post- prandial rise in very- low- density lipop Protein-Triacyl Glycerol.
Abstract: 1. Triacylglycerol extraction by subcutaneous adipose tissue and forearm muscle was studied in nine normal subjects after an overnight fast and after the consumption of a mixed meal.
2. There was an inverse correlation between the total plasma fractional triacylglycerol extraction across the adipose tissue and the fasting arterial plasma triacylglycerol concentration. In contrast, there was no correlation between the lower fractional triacylglycerol extraction across the forearm muscle and the fasting plasma triacylglycerol concentration.
3. Chylomicron-triacylglycerol concentrations in arterial(ized) plasma increased post-prandially and peaked at 240–300 min. There was a comparable increase in the very-low-density lipoprotein-triacylglycerol concentration, peaking at 300 min.
4. Clearance of chylomicron-triacylglycerol by adipose tissue increased after the meal ( P <0.05). In contrast, the clearance of very-low-density lipoprotein-triacylglycerol by adipose tissue decreased post-prandially ( P <0.05).
5. Although there was significant uptake of chylomicron-triacylglycerol by the forearm muscle post-prandially, this was less than by the adipose tissue. Very-low-density lipoprotein-triacylglycerol was unaffected by passage through the forearm muscle at any time.
6. We conclude that the extraction of lipoprotein-triacylglycerol by human adipose tissue is important in determining the fasting plasma triacylglycerol concentration. Chylomicron-triacylglycerol, appearing in the plasma post-prandially, may compete with very-low-density lipoprotein-triacylglycerol for clearance by adipose tissue lipoprotein lipase, and this mechanism may explain, at least in part, the post-prandial rise in very-low-density lipoprotein-triacylglycerol. Forearm muscle, in contrast, appears to play a much smaller role in the extraction of plasma triacylglycerol, especially that in the very-low-density lipoprotein fraction.
TL;DR: Both normal gastric mucosa and Barrett's mucosa have potential autocrine growth regulatory mechanisms, but Barrett’s mucosa has increased expression of both of the measured ligands and of the epidermal growth factor receptor.
Abstract: 1. In order to assess potential abnormalities in the control of mucosal proliferation, 30 patients with Barrett's oesophagus were studied in order to evaluate the presence and distribution of epidermal growth factor, transforming growth factor-alpha and epidermal growth factor receptor to determine the Ki-67 labelling index in the affected oesophageal mucosa. Serial sections were analysed immunohistochemically. Ten of the patients had adenocarcinoma in the Barrett's mucosa and the other 20 had differing histological types of Barrett's mucosa (10, intestinal-type; 10, fundic- or cardiac-type). 2. The expression of transforming growth factor-alpha, epidermal growth factor and epidermal growth factor receptor was increased and the Ki-67 labelling index was higher in Barrett's mucosa compared with normal gastric mucosa. The 'intestinal-type' of Barrett's mucosa had the greatest expression of transforming growth factor-alpha, epidermal growth factor receptor and the highest Ki-67 labelling index compared with the other types of Barrett's metaplasia. Five cases of 'intestinal-type' Barrett's metaplasia had especially high Ki-67 labelling indices and these patients over-expressed both transforming growth factor-alpha and epidermal growth factor receptor. The patients with adenocarcinomas in the Barrett's mucosa also over-expressed transforming growth factor-alpha and epidermal growth factor receptor, but not epidermal growth factor, compared with normal gastric mucosa. 3. In conclusion, both normal gastric mucosa and Barrett's mucosa have potential autocrine growth regulatory mechanisms, but Barrett's mucosa has increased expression of both of the measured ligands and of the epidermal growth factor receptor.
TL;DR: The mechanism of action of octreotide on splanchnic blood flow is uncertain and may be mediated via a direct vascular effect or it may act via suppression of vasoactive intestinal hormones.
Abstract: 1. The effects of the subcutaneous administration of a long-acting somatostatin analogue (octreotide) or of placebo on the splanchnic blood flow response to a mixed solid meal has been examined in eight normal subjects by using a transcutaneous Doppler ultrasound technique. Each subject was studied on two occasions more than 1 week apart. 2. On the control day, feeding had a pronounced effect on both superior mesenteric artery and portal venous blood flows, causing a peak rise of 82% in superior mesenteric artery blood flow at 15 min and of 75% in portal venous blood flow at 30 min post-prandially (P less than 0.001). Blood flows remained elevated 2 h after the meal. Pulse and blood pressure showed no significant changes from baseline. 3. Octreotide reduced fasting superior mesenteric artery blood flow by 59% (P less than 0.05) and portal venous blood flow by 49% (P less than 0.01) and blunted the normal post-prandial rise. Pulse and blood pressure did not change in response to either the injection or the ingestion of the meal. 4. Octreotide suppressed the release of insulin, glucagon and pancreatic polypeptide in response to feeding and resulted in post-prandial hyperglycaemia. 5. The mechanism of action of octreotide on splanchnic blood flow is uncertain. It may be mediated via a direct vascular effect or it may act via suppression of vasoactive intestinal hormones.
TL;DR: It is demonstrated that a wrist cuff at supra-systolic pressure is most appropriate for the exclusion of the hand circulation in order to measure the forearm blood flow correctly.
Abstract: 1. To determine whether a wrist cuff is necessary to measure the forearm blood flow correctly, we studied the effects of wrist cuff inflation to supra-venous and supra-systolic pressure values over a large range of forearm blood flow values: in the basal state, during post-occlusive hyperaemia of the hand, and during heating of the hand with warm air. Eleven healthy men participated, and the study was carried out at two different ambient temperatures of 20 and 25 degrees C. 2. In the basal state, the measured forearm blood flow was lowest with the wrist cuff at supra-systolic pressure. With the wrist cuff at supra-venous pressure the forearm blood flow was also lower than with an uninflated cuff, but only significantly so when the basal forearm blood flow was higher (at a room temperature of 25 degrees C). 3. During post-occlusive hyperaemia, inflating the wrist cuff to supra-systolic pressure produced the lowest forearm blood flow value at both room temperatures. In addition, with the wrist cuff at supra-venous pressure, forearm blood flow values were lower than with the uninflated cuff, but the supra-venous cuff pressure was clearly less efficient in excluding the hand blood flow than the supra-systolic cuff pressure. 4. During heating of the hand, both supra-systolic and supra-venous cuff pressures were effective in excluding the hand blood flow at both room temperatures. The forearm blood flow measured with the wrist cuff at supra-systolic pressure was lower than that measured with the wrist cuff at supra-venous pressure, but the difference was only significant at a room temperature of 20 degrees C. 5. In conclusion, we have demonstrated that a wrist cuff at supra-systolic pressure is most appropriate for the exclusion of the hand circulation in order to measure the forearm blood flow correctly.
TL;DR: The tryptase and histamine concentrations measured suggest that there is continuous degranulation of mast cells within the normal lung, but that this process is more pronounced in patients with bronchial carcinoma or interstitial lung disease.
Abstract: 1. Mast cell activation in the lung was investigated by measuring concentrations of mast cell tryptase and histamine in the bronchoalveolar lavage fluid from patients with bronchial carcinoma, sarcoidosis, extrinsic allergic alveolitis or cryptogenic fibrosing alveolitis and from normal subjects. 2. Histamine concentrations in bronchoalveolar lavage fluid supernatants were elevated in the bronchial carcinoma and cryptogenic fibrosing alveolitis groups, and were correlated with the histamine content of the cells recovered. 3. An avidin-biotin-enhanced antigen-capture e.l.i.s.a., using polyclonal rabbit antibody specific for tryptase, and mouse monoclonal antibody AA5, allowed the quantification of tryptase in all samples of bronchoalveolar lavage fluid. Tryptase concentrations were increased in the bronchial carcinoma and extrinsic allergic alveolitis groups and in some of the patients with sarcoidosis, and the levels correlated with mast cell numbers and also with concentrations of albumin. 4. There was no significant correlation between levels of tryptase and histamine, suggesting differences in the rates of metabolism or different cellular sources. 5. The tryptase and histamine concentrations measured suggest that there is continuous degranulation of mast cells within the normal lung, but that this process is more pronounced in patients with bronchial carcinoma or interstitial lung disease.
TL;DR: The present findings suggest that the main goal in the treatment of chronic protein loss should be to sustain protein synthesis, owing to reductions in both Cs and kRNA.
Abstract: 1 Little information is currently available on protein turnover during chronic protein loss situations We have thus measured the whole-body and tissue protein fractional synthesis rates (ks), the whole-body fractional protein degradation rate (kd), the capacity for protein synthesis (Cs) and the efficiency of protein synthesis (kRNA) in vivo in fed and fasted (1, 5 and about 9 days) 400 g rats 2 One day of starvation resulted in a reduced ks and an increased kd in the whole body ks was selectively depressed in skeletal muscles, mainly owing to a reduced kRNA, and was not modified in heart, liver and skin The contribution of skin to whole-body protein synthesis increased by 39% 3 During the phase of protein sparing (5 days of fasting), kd in the whole body decreased below the control fed level ks in skeletal muscles was sustained because kRNA was restored to 82-98% of the control value 4 Rats were in a protein-wasting phase after 9 days of starvation kd in the whole body did not increase and was actually 78% of the value observed in fed animals By contrast, ks in the whole body and tissues decreased to 14-34% of the control values, owing to reductions in both Cs and kRNA Whatever the duration of the fast, the contribution of the skin to whole-body protein synthesis largely exceeded that of skeletal muscle 5 The present findings suggest that the main goal in the treatment of chronic protein loss should be to sustain protein synthesis(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: The results suggest that heparin and heparan sulphate, as components of cellular and basement membranes, are likely to have a role in protecting structural proteins, such as elastin, from the proteolytic activity of human leucocyte elastase.
Abstract: 1. Heparin and heparan sulphate strongly inhibited human leucocyte elastase activity in an automated assay using the soluble substrate, n-succinyl-(l-alanine)3-p-nitroanilide (50% inhibition of 250 μl of 10 μg of human leucocyte elastase/ml was obtained with 80 μl of 2.8 μg of heparin/ml and 8 μg of heparan sulphate/ml). Less significant inhibition at the same concentrations was seen with the other glycosaminoglycans tested: hyaluronic acid and chondroitin sulphates A–C. 2. Heparin and heparan sulphate also strongly inhibited human leucocyte elastase activity towards insoluble human lung elastin, as determined by an e.l.i.s.a. for soluble elastin-derived peptides released by elastolytic activity on the elastin. This inhibition was shown not to be due to a direct interference of the glycosaminoglycans in the e.l.i.s.a. nor to the inhibition causing a change in the size of the elastin-derived peptides. However, unlike the chromogenic assay with n-succinyl-(l-alanine)3-p-nitroanilide as substrate, where heparin was the more effective inhibitor, in this assay system heparan sulphate was the more effective inhibitor (50% inhibition of 100 μl of 50 ng of human leucocyte elastase/ml was obtained with 100 μl of 4.5 μg of heparin/ml and 0.8 μg of heparan sulphate/ml). These results suggest that heparin and heparan sulphate, as components of cellular and basement membranes, are likely to have a role in protecting structural proteins, such as elastin, from the proteolytic activity of human leucocyte elastase. 3. The degree of inhibition by heparin was independent of pH within the range of pH studied (pH 6–9) and was almost immediate in the automated chromogenic assay system where a 10 s preincubation step was used. The inhibitory effect of heparin could be prevented by the addition of protamine sulphate or by the removal of heparin by an ion-exchange resin. 4. Low Mr preparations of heparin were also found to inhibit human leucocyte elastase, although preparations with Mr of 2000 or less did not inhibit the enzyme to the same extent as commercial preparations. 5. Heparin at the same concentrations did not inhibit other leucocyte enzymes, such as cathepsin G and myeloperoxidase, nor the pancreatic enzymes, pancreatic elastase, trypsin and chymotrypsin.
TL;DR: In this paper, forearm blood flow was measured during brachial artery infusions of vasoconstrictors (angiotensin II and noradrenaline) and vasodilators (sodium nitroprusside and carbachol) in 16 healthy control subjects and in 18 patients with uncomplicated insulin-dependent diabetes mellitus.
Abstract: 1. We measured forearm blood flow during brachial artery infusions of vasoconstrictors (angiotensin II and noradrenaline) and vasodilators (sodium nitroprusside and carbachol) in 16 healthy control subjects and in 18 patients with uncomplicated insulin-dependent diabetes mellitus. Erythrocyte Na+/Li+ countertransport and platelet Na+/H+ antiport activities were also measured. 2. The mean basal forearm vascular resistance was 22% lower in diabetic patients than in control subjects. The effects of each infusion on forearm vascular resistance were similar in diabetic patients and control subjects. 3. Erythrocyte Na+/Li+ countertransport activities were similar in diabetic patients and control subjects. Platelet Na+/H+ exchange (Vmax) was approximately 40% greater in diabetic patients than in control subjects, whereas the Km for Na+ was similar. 4. In diabetic patients, but not in control subjects, the responses to sodium nitroprusside and carbachol correlated inversely with Na+/Li+ countertransport in erythrocytes (rs = -0.76, P less than 0.001, and rs = -0.66, P less than 0.005, respectively), but not with Na+/H+ exchange in platelets.