Biomedical subjects
Publications and source records attributed to H Larsson.
A wheelchair ergometer has been developed for the study of wheelchair work. At each propulsion the peak torque can be examined, and there is an opportunity to directly study angular amplitude, power output, work etc. The physical capacity of the subject as well as the importance of chair adjustments upon performance can be evaluated.
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The interaction between calf spleen profilin and actin depends critically on the status of the C-terminus of the actin, and in the case of profilin, the C-terminus is of great importance for the physiochemical behaviour of the protein. Both proteins easily lose their C-terminal amino acids during the preparation, and special care has to be taken to ensure the isolation of the proteins in the intact form. Another factor that may seriously influence the study of the interaction of profilin with actin is the presence of varying amounts of an activity that causes an apparent stabilization of the complex even at later stages of its purification. We have found conditions for the isolation of intact profilin and actin, and studied the interaction between the two proteins, including the determination of the Kdiss for the complex formed under various ionic conditions. The complex formed between profilin and actin from calf spleen was found to be significantly stronger (Kdiss less than or equal to 10(-8) M in 50 mM KCl, and Kdiss = 4.10(-7) M in 50 mM KCl, 1 mM MgCl2) than that formed between profilin and muscle alpha-actin (Kdiss = 10(-6) M in 50 mM KCl, +/- 1 mM MgCl2). The profilactin complex formed in the mammalian system was stronger than the complex formed between Acanthamoeba actin and the profilin-like protein isolated from this organism. Analysis of the formation of the calf spleen complex in the presence of varying concentrations of divalent cations gave evidence for the presence of a high-affinity divalent-cation-binding site on the spleen actin (beta, gamma) which appears to regulate the interaction with profilin.
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In intact rats plasma gastrin levels were increased during a 20-wk treatment course with either omeprazole or ranitidine. Although plasma gastrin levels were the same during treatment, the enterochromaffinlike (ECL) cell density increased approximately linearly with time at a rate correlated to the plasma gastrin level. Antrectomy prevented the ECL cell hyperplasia seen in omeprazole-treated rats, suggesting that it was not caused by omeprazole per se. Changes in ECL cell density roughly paralleled changes in oxyntic mucosal histidine carboxylase activity and histamine concentration. Treatment with omeprazole also raised stomach weight and antral gastrin and gastrin cell density, reduced antral somatostatin cell density, but did not affect enterochromaffin cell density. Within 19 days of cessation of a 10-wk treatment course, plasma gastrin levels, oxyntic mucosal histidine decarboxylase activity, and antral gastrin and somatostatin cell densities had returned to control levels. The stomach weight was normal within 5-10 wk, antral gastrin concentration within 10 wk, and oxyntic mucosal ECL cell density and histamine concentration within 20 wk. After renewed treatment with omeprazole for 10 wk starting 10 wk after completion of the first omeprazole treatment period, changes in all parameters were of similar magnitude in animals previously treated with omeprazole and those previously treated with vehicle. The results suggest that the effects described are reversible and that gastrin cells turn over more rapidly than ECL cells.
Blood and plasma viscosity was measured in eight patients with typical effort-induced angina pectoris who did not have coronary artery stenosis at angiography. The same variables were studied in 14 patients with angina pectoris and verified coronary artery disease that in most cases was extensive. Both groups of patients had significantly higher viscosity values in whole blood, at natural hematocrit as well as standardized hematocrit (45%), than 25 healthy subjects serving as a reference group. Plasma viscosity was also significantly elevated in both patient groups. The patients without coronary artery stenosis had as high blood and plasma viscosity values as had the stenosis group. It is concluded that increased blood and plasma viscosity should be added to the list of pathological findings in patients with angina pectoris in the absence of organic coronary artery stenosis.
Female rats were treated orally for 3 mo with omeprazole (40 and 400 mumol/kg). Both doses caused total inhibition of gastric acid secretion and recovery was parallel to that of H+-K+-ATPase activity (30-50 and 60-80% inhibition 24 h after doses, respectively). The H+-K+-ATPase activity returned to control levels within 1 wk after the last dose. Plasma gastrin levels were dose-dependently increased during treatment but reversed to control levels within 9 days after the last dose. Parallel with a general increase in corpus mucosal mass, both pepsinogen and H+-K+-ATPase total content increased. However, their tissue concentrations did not differ from control values, suggesting that neither parietal nor chief cell density are changed by omeprazole treatment and also that their growth is parallel to the general hyperplasia. In contrast, the oxyntic mucosal histamine concentration was increased, indicating an increase in the enterochromaffin-like (ECL) cell density. Maximal capacity of the mucosa to secrete acid increased in parallel with the increase in mucosal mass and total H+-K+-ATPase content. However, basal acid secretion did not differ between treatment groups. Increased capacity slowly declined toward control levels over the 70-day recovery period after withdrawal of omeprazole. These results suggest that hypergastrinemia, induced in the rat by pharmacological inhibition of gastric acid secretion, causes a hyperplasia of oxyntic mucosal cells, ECL cells growing faster than the others. The hyperplastic mucosa has an increased capacity to produce acid and is functionally normal.
The H+,K+-ATPase inhibitor omeprazole is a highly effective gastric antisecretory agent, both in animals and man, with a long duration of action. These properties are shared by a number of recently described histamine H2-receptor antagonists. In life-long oncogenicity studies of these H2-receptor antagonists, as well as with the H+,K+-ATPase inhibitor omeprazole, gastric enterochromaffin-like cell (ECL cell) hyperplasia and carcinoids have been found. The purpose of this paper is to summarize available evidence for the "Gastrin Hypothesis" to explain the development of ECL-cell hyperplasia. The hypothesis may be outlined as follows: 1) Inhibition of gastric acid secretion leads to elevated antral pH and, secondarily, to release of gastrin from the antral gastrin cells into the blood stream. 2) Gastrin causes both general hypertrophy of the oxyntic mucosa and hyperplasia of the ECL cells in the oxyntic mucosa. That this sequence of events occurs not only with omeprazole but also with other effective gastric antisecretory agents has been verified in the rat by giving the H2-receptor antagonist ranitidine as a continuous infusion. Ranitidine caused a hypergastrinemia of a similar magnitude as that seen after omeprazole, provided that the acid secretion was inhibited to a similar degree. At similar gastrin levels, ECL-cell hyperplasia of the same magnitude developed during both ranitidine and omeprazole treatment. Antrectomy prevented the development of ECL-cell hyperplasia during omeprazole treatment, indicating that the hyperplasia was not due to the drug treatment per se, but rather to the hypergastrinemia. Both the hypergastrinemia and the ECL-cell hyperplasia were found to be reversible.(ABSTRACT TRUNCATED AT 250 WORDS)
We report three cases of ataxic hemiparesis, studied by MRI. The lesions were all contralateral and located in three different sites: the posterior limb of the internal capsule, the midpons, and the red nucleus. None of the CTs demonstrated the lesions.
Two series of experiments have been performed in gastric fistula dogs to test the antisecretory effect of two different oral dosage forms of omeprazole: 2 mumol x kg-1 x day-1 as a methylcellulose suspension for 8 weeks and 0.5 mumol x kg-1 x day-1 in enteric-coated granules (ECG) for 3 weeks. There was an increasing inhibitory effect during the first days of repeated administration of omeprazole, which is in accordance with its long duration of action. The steady-state inhibitory level was reached after five doses. During the 8-week treatment with the omeprazole suspension (2 mumol x kg-1) the mean maximal inhibitory level (3 h after dose) was 82%, and the mean minimal inhibitory level (24 h after dose) was 35%. With omeprazole in ECG (0.5 mumol x kg-1) the steady-state maximal inhibition (4th h) was 60%, whereas 40% inhibition remained after 24 h. Thus, a more even inhibitory level over day and night seems to be obtained with the ECG formulation than with the suspension. Basal and food-stimulated plasma gastrin levels were not significantly affected by the treatment with 0.5 mumol x kg-1, whereas food-stimulated gastrin levels were slightly increased during treatment with 2 mumol x kg-1. Control levels of acid secretion were reached within 4 days of stopping treatment. In the present studies, in which the inhibition of acid secretion varied over 24 h between approximately 80% and 35% (maximum and minimum), no rebound effects could be detected as measured up to 1 month after cessation of treatment.
A method for the introduction of chemically reactive groups onto polymeric surfaces, suitable for immunoassays, is described. The method, referred to as grafting, uses gamma irradiation from a 60Co source to initiate the free radical reaction. Polystyrene and polyvinyl chloride surfaces were grafted with crotonic acid and characterized with ESCA. 2 nmol/cm2 of carboxylic groups were added during the method. Increased hydrophilic properties of the carboxylated surfaces were recorded by contact angle measurements. The grafting reaction did not impair the optical quality of the polymers studied. Various proteins were covalently linked to the modified surfaces of microtiter plates and tubes by means of a water-soluble carbodiimide. A significantly enhanced total capacity and strength of binding to grafted surfaces was demonstrated as compared to passive adsorption of the proteins to untreated surfaces.
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An open circuit tracer gas washout method for measurement of lung volume in patients during anesthesia and intensive care is described and tested. The method employs a device for dispensing the tracer gas, sulfur hexafluoride (SF6), a fast SF6 analyzer, a pneumotachograph, and a computer. The dispensing device delivers SF6 into the airway in proportion to instantaneous inspiratory flow so that inspiratory SF6 concentration is held constant, usually at about 0.5%, regardless of the inspiratory flow pattern. The amount of SF6 present in the lungs at the end of a washin is calculated during washout from signals representing expired SF6 concentration and expired flow. From this, lung volume is derived. Accurate and reproducible results were obtained in lung model tests during ventilation with air, N2O in O2, and halothane in O2. Functional residual capacity (FRC) was measured both with SF6 washout and nitrogen washout in five mechanically ventilated patients. This gave the regression equation: FRCSF6 = 10 ml + 1.04 x FRCN2, r = 0.99. A similar close agreement was observed for total lung capacity (TLC) and residual volume (RV) measurements in eight healthy, spontaneously breathing subjects: TLCSF6 = 91 ml + 1.01 x TLCN2, r = 0.99; RVSF6 = -32 ml + 0.97 x RVN2, r = 0.95. Comparison with body plethysmography in eight healthy, sitting subjects gave the regression equation: FRCSF6 = 180 ml + 0.96 x FRCbox, r = 0.99. The median (range) for the coefficient of variation at duplicate determinations in 10 anesthetized, paralyzed, and mechanically ventilated adults was 3.0% (0.2-6.6%).(ABSTRACT TRUNCATED AT 250 WORDS)
Regional blood flow in the gastrointestinal tract (forestomach, corpus, antrum, duodenum, jejunum, and colon) was determined in the conscious rat by means of the microsphere technique. The effects on blood flow were determined after omeprazole (orally and intravenously) and cimetidine (intravenously) during both basal and pentagastrin-stimulated gastric acid secretion. Under basal conditions neither omeprazole nor cimetidine decreased the blood flow in the gastrointestinal tract in spite of pronounced inhibition of acid secretion. On the contrary, there was a tendency towards an increased blood flow in the mucosal layer of the corpus after the oral (80 mumol/kg) and the high intravenous (10 mumol/kg) dose of omeprazole. When omeprazole was given intravenously to rats during pentagastrin-stimulated acid secretion, blood flow in the gastric mucosa was unaffected in spite of complete or almost complete inhibition of acid secretion. In contrast, cimetidine decreased the mucosal blood flow, indicating that the pentagastrin-induced increase in blood flow to some extent is mediated by H2 receptors.
The gastric acid secretion in response to graded doses of gastrin, histamine, impromidine (a selective H2-receptor agonist), and the muscarinic-1 agonist McN-A-343 was studied in the totally isolated, vascularly perfused rat stomach. Combinations of stimulants at doses giving maximal acid secretion for each secretatogue were thereafter tested. All stimulants increased the gastric acid output significantly compared with the base-line output (7.2 +/- 2.0 mu eq/h). Gastrin induced significant increases in acid outputs at very low and physiologically relevant concentrations with a threshold concentration of 65 pM. Nevertheless, maximal gastrin-stimulated acid secretion represented only 55% of the maximal histamine-stimulated acid output of 154.8 +/- 10.0 mu eq/h. Impromidine and McN-A-343 induced a maximum 59% and 34% of maximal histamine-stimulated acid output, respectively. Adding gastrin to the maximal histamine of impromidine-stimulated stomachs did not increase the acid secretion further. Histamine and McN-A-343 in combination, however, induced a more than additive increase in the gastric acid output (232.0 +/- 14.7 mu eq/h) than did histamine and McN-A-343 separately (154.8 +/- 10.0 and 53.0 +/- 6.7 mu eq/h, respectively). The results indicate that in the rat, gastrin stimulates the parietal cell indirectly via histamine release, whereas muscarinic agents (cholinergic stimulation) act directly via a separate receptor.
The effect of inhibiting acid secretion by pharmacologic agents on the gastric content of regulatory peptides has been determined by radioimmunoassay and immunocytochemistry. Plasma, antral, and fundic concentrations of gastrin were elevated in rats rendered virtually achlorhydric by treatment with high-dose omeprazole (400 mumol/kg daily for 10 wk). This was associated with an increase in the number and staining intensity of gastrin immunoreactive cells. A clear reciprocal relationship was observed between antral gastrin and somatostatin as assessed by both quantitative and qualitative methods. These changes had disappeared 10 wk after treatment was stopped. No alteration was found in the concentrations of other regulatory peptides proposed as important in control of acid secretion. Plasma and antral gastrin concentrations were elevated in rats treated with high-dose ranitidine (700 mumol/kg daily), but to a lesser extent than during omeprazole therapy, and somatostatin concentrations were unchanged.
Unoperated female rats were subjected to daily oral treatment with omeprazole (10 or 400 mumol/kg body wt), ranitidine (175 + 175 + 350 mumol/kg body wt), or vehicle and antrectomized rats were treated with omeprazole (400 mumol/kg body wt) or vehicle. After 10 wk of treatment, plasma gastrin levels were high in unoperated rats treated with the high omeprazole dose and with ranitidine, and low in antrectomized controls. Plasma gastrin levels were slightly higher in the low-dose omeprazole group than in the intact controls. In antrectomized rats treated with the high dose of omeprazole, the plasma gastrin level was in the same range as in intact control rats. A close correlation (r = 0.89, p less than 0.0001) was found between the plasma gastrin level and the oxyntic mucosal enterochromaffinlike cell density (as well as the tissue levels of histidine decarboxylase and histamine in the oxyntic mucosa) in all groups. The somatostatin cell density in the oxyntic mucosa was not altered by the various treatments. During a recovery period of 10 wk after the 10-wk treatment, the enterochromaffinlike cell density and histamine concentration decreased by 30%-40% in the rats treated with the high dose of omeprazole, whereas the corresponding values increased by 50% and 40%, respectively, in the control rats. The difference between the two groups, however, was still statistically significant. Plasma gastrin levels and gastric histidine decarboxylase activity returned to control values during recovery. The results suggest that the observed changes in enterochromaffinlike cell density are related to the plasma gastrin levels and that they are reversible. it is concluded that neither omeprazole nor ranitidine per se is likely to induce proliferation of enterochromaffinlike cells.
Hypo- or anacidity, caused by antisecretagogues, stimulates gastrin release and leads to hypergastrinaemia. If drug treatment is maintained over a period of time, the hypergastrinaemia can be expected to give rise to trophic effects. We examined the trophic consequences of the very marked hypergastrinaemia produced by long-term treatment (16-20 weeks) of rats with large doses of the substituted benzimidazole, omeprazole, a potent and long-acting blocker of acid secretion. The weight of the stomach and the oxyntic mucosal thickness were increased, whereas the weight of the pancreas and the intestines and the thickness of the mucosa of the antrum and small and large intestine were unaffected. The number of exocrine cells (parietal, zymogen and mucous cells) were uniformly increased by 25-30%. The density of parietal and zymogen cells, expressed as number of cell nuclei per mm2 epithelium, was unchanged. The volume density of parietal cells, expressed as % of epithelial volume, was also unchanged, implying that the volume of the individual parietal cell had not increased. The density of endocrine ECL cells in the stomach increased 5-fold. Thus, the findings demonstrate a growth-promoting effect of the hypergastrinaemia on the oxyntic mucosa, the ECL cells in particular, and the lack of such an effect on the antrum, pancreas and intestines.