Cardiovascular effects of aprindine, a new antiarrhythmic drug. The effects of aprinidine (AC 1802), a new antiarrhythmic drug, were studied in 9 anesthetized pigs. Aprindine was administered intravenously in cumulative doses until serum levels larger than or equal to 8 mug/ml were obtained, which is more than three times the therapeutic level in man (+/- 2.5 mug/ml). Doses less than 1.75 mg/kg (serum levels 3.4 mug/ml) had no effect on the pump function of the heart, as preload, afterload, and the contractile state of the heart were not significantly altered. However, at these levels, electrocardiographic changes were significant as QRS increased to 132 +/- 14% of control (P less than 0.005). At the highest serum levels (8.7 mug/ml), cardiac output had decreased to 78 +/- 15% of control. This appears to be the result of negative inotropic properties of the drug, as preload remained unchanged and afterload actually decreased. Most striking at these levels were the electrocardiographic changes, as P-Q length increased to 281 +/- 93% of control and QRS width to 341 +/- 85%. The changes in the width of the QRS complex, prove to be the earliest indicator of aprindine activity and may serve as a warning of intoxication.


Quantitative estimation of valvular incompetence. The regurgitant flow (Qreg) through incompetent valves can be assessed by subtracting effective cardiac output (Qeff) from total left ventricular output (Qtot). Qeff was determined with the thermodilution method. A new correction factor for true injected quantity of indicator was developed and a procedure for rapid estimation of (see article) deltaT(t)dt was tested. Qtot was determined with the aid of quantitative left ventriculography. In 10 patients without incompetent valves no significant difference between Qeff and Qtot could be demonstrated. Qreg in 11 patients with mitral incompetence ranged from 0.5 till 4.7 1-min-1 m-2 and in 12 patients with aortic incompetence from 0.9 till 11.2 1-min-1 m-2. The relation of left ventricular enddiastolic volume (Ved in ml-m-2) and Qreg (in 1-min-m-2) is expressed by the regression equation: Ved = 21.7 Qreg + 59.2 (correlation coefficient 0.91), demonstrating a good relationship of regurgitant flow and volume load fo the left ventricle. Follow-up of these patients is important to detect guidelines for operation indications base on quantitative measurements of Ved and Qreg.


Tricuspid atresia. An anatomical study of 17 cases. This is a report on the anatomical characteristics of 17 cases of tricuspid atresia. Three of these cases had a discrepancy between the type of bulboventricular loop (dextro) and the position of the great arteries (the aorta being to the left of the pulmonary artery). In these a characteristic type of ventricular septal defect, located just beneath the tissue of the semilunar valves was found. In 3 cases with cardiac dextroversion and juxtaposition of the atrial appendages the great arteries were on the same frontal plane and there was a separation between the semilunar and the anterior mitral leaflet. One case was associated with a double outlet left ventricle, a D-malposition of the great arteries, and a bilateral subaortic and subpulmonary conus. Among the 6 cases with transposition of the great arteries, the ventricular septal defect was large in 2 (34.4%) only. In the analysis of the 13 cases with intact ventricular septa (2 cases) or restrictive (small and medium-sized) ventricular septal defects (11 cases) obstructive anomalies of the vessel arising from the right ventricle were found in 12 (92.3%). These anomalies involved the aorta in 4 cases. (34.4%) and the pulmonary artery in 8 (66.6%). In the study of the 4 cases with a large ventricular septal defect, obstructive anomalies in the vessel arising from the right ventricle were present in 2 cases (50%), and were located in the aorta in 1 case (25%) and in the pulmonary artery in the other case (25%). The 2 cases with intact ventricular septum were associated with a hypertrophy of this septum and an absent pulmonary valve. In 1 of these cases, a third ventricular chamber was disclosed within the ventricular septum. This chamber communicated with the right ventricle through a very small opening. In 82.3% of the cases, the projection of the dimple, the rest of the tricuspid orifice, was located either on the ventricular septum or over the left ventricle. In the 3 cases with juxtaposition of the atrial appendages there was a positive transillumination of the floor of the right atrium, which corresponded, to the rest of the tricuspid valve in one case and to the atrioventricular portion of the membranous septum in the other 2.


Cardiac tamponade. A study of 50 hearts. Fifty hearts with a rupture of the free wall were studied. From a correlation between gross and microscopic features and the clinical history, several interesting features evolved. Firstly, the gross aspect of the rupture enabled a distinction of three types. Type I, characterized by an abrupt, slit-like tear, which correlated clinically with a recent infarct, mostly of less than 24 hours previously. Type II which showed an 'erosion' of the infarcted myocardium, indicative of a slowly progressing tear. This type correlated with a somewhat larger time interval between onset of symptoms and tamponade. Type III, characterized by early aneurysm formation, which correlated clinically with older infarcts. Furthermore, occasionally, marked discrepancies were found between the histological and clinical dating. This lends support to the concept that in some patients the onset of symptoms may be secondary to the onset of rupture, in the setting of an otherwise silent infarction. Clinically, the acute episode is diagnosed as the onset of infarction. The term 'concealed rupture' is proposed for this phenomenon.


[Chemical and pharmacological research on derivatives of 1H-naphto/2,1-b/pyran. IV. Substituted 1-oxo-3-dialkylamino-1H-naphto/2,1-b/pyrans]. Reaction of N,N-dialkylethoxycarbonylacetamides with substituted beta-naphthols in 3 or 6 or 7 positions with halogen, alkyl, methoxycarbonyl, methoxyl, ethoxyl in the presence of phosphorus oxychloride, led to the formation of 1-oxo-3-dialkylamino-1H-naphtho[2,1-b]pyrans bearing substituents in 5 or 8 or 9 positions, respectively. Moreover, on account of the chemical nature of such substituents, suitable chemical transformations of these compounds afforded some other 1H-naphtho[2,1-b]pyran derivatives. Pharmacological tests showed that anticonvulsant activity was improved by introduction of methoxy or ethoxy group in 9 position of several 1-oxo-3-dialkylamino-1H-naphtho[2,1-b]pyrans.


[Some pharmacological actions of furazan hydrazides and of 2 correspondent furoxan derivatives]. A study has been made of the acute toxicity, action on the guinea pig ileum, on the ventricle edge, on frog spinal reflex, and on the respiratory and cardiac activity and pulse of the following compounds: 3-methyl-4-furazancarbohydrazide (I); 3-methyl-4-furoxancarbohydrazide (II); 4-methyl-3-furoxancarbohydrazide (III). The compounds had no action on guinea pig ileum or ventricle edge. Compound (I) showed depressant activity on frog spinal reflex whereas compound (II) showed excitation and compound (III) had no direct spinal action. The compounds tested affected respiration and ECG only at the highest doses used. The pulse rate was raised by substance (I) in all cases whereas substances (II) and (III) raised pulse rate only at low doses.


Mass spectrometric identification of 10,11-dihydro-10,11-dihydroxyprotriptyline in rat urine after administration of protriptyline. 10,11-Dihydro-10,11-dihydroxyprotriptyline was identified in rat urine following administration of protriptyline 40 mg kg-1 i.p. Gas chromatographic-mass spectrometric characterization confirmed the structure of this stable metabolite, and its identity with a synthetic sample.


The search for new drugs in the group of xanthine derivatives. XXXIX - Reaction of 1,2-epoxycyclohexane with theophylline and 8-halotheophyllines. Reaction of 1,2-epoxycyclohexane with theophylline and 8-halotheophyllines in n-butanol n-propanol DMF medium brought up a good yield of the corresponding trans-diequatorial-DL-7-(2'-hydroxycyclohexyl-1')-derivatives (I - III). The products (VII - IX), (XII), (XIII) were formed by nucleophilic displacement of the halogen of (II) or (III) by alkoxides or cyclamines. Acid hydrolysis of the alkoxy derivatives (VII -IX) gave the same compound:  1,3-dimethyl-trans-diequatorial-DL-7-(2'-hydroxycyclohexyl-1')-uric acid (X). The structures of these products were confirmed by U.V., I.R. and N.M.R. spectroscopy.


[Research on nitrogen heterocyclic compounds. IX. Synthesis of 5-hydroxy-2,4-dicarbethoxypyrroles]. Reaction between diethyl ethoxymethylenemalonate and N-substituted diethylaminomalonates in the presence of sodium ethoxide gives 5-hydroxy-2,4-dicarbethoxypyrroles. By treating these compounds with acetic anhydride we shall get the corresponding 5-acethoxy-2,4-dicarbethoxypyrroles and, by catalytic reduction, the corresponding 2,4-dicarbethoxy-5-pyrrolidinones, which in turn are hydrolyzed to the well known corresponding pyroglutamic acids. The I.R. and N.M.R. spectral data are in agreement with the proposed structures.


Structure-activity relationships for anticholinergic morpholinium derivatives. The anticholinergic activity of a series of morpholinium derivatives was studied by means of the Free-Wilson method. The importance of steric and lipophilic effects is pointed out.


Somatic cell genetic analysis of the interferon system. Current advances in the use of somatic cell hybrid systems have enhanced the value of these systems for studying eukaryotic cell functions. We have reviewed the use of somatic cells to investigate the human interferon system. It has been shown that interspecific heterokaryons and hybrid cells can produce interferon(s) of both parental types and may be protected from viral challenge by interferon(s) from either parent. Using mouse-human hybrid cells we have assigned a human gene(s) responsible for regulating interferon to chromosome 21 and genes involved in the production of human interferon to chromosomes 2 and 5. Our data also suggest possible assignment of a locus involved in control of interferon production to chromosome 16. Suggested further uses of the somatic cell system for interferon studies include study of the subunit structure of interferons and the development of hybrid lines that produce human interferon at high levels (interferon/somatic cell hybrids/human gene assignment.


Turnover of plasma oleic acid measured by radio-gas chromatography. Gas-liquid chromatography with radioactivity detection (Radio-GLC) was investigated as an analytical means of determining the fractional turnover rates of plasma free fatty acids. For this purpose normal dogs were infused with 1.838 muCi/min of [1-14C]oleic acid complexed with albumin and plasma samples were taken at 0 to 110 minutes. The plasma free fatty acids were isolated by a modified Dole extraction and the methyl esters, prepared by diazomethylation, were identified and quantitated by GLC and radio-GLC using radioactive methyl heptadecanoate as internal standard. The study demonstrates that physiologically feasible infusion rates and loads of radioactive acids can be found which permit accurate analyses of plasma free fatty acids by radio-GLC. During a 2-hour infusion no labeled acid other than oleic appeared in plasma indicating that the method could be used to study the turnover of a mixture of fatty acids simultaneously. These results also indicate that conventional methods of determination of radioactivity in purified extracts can be employed without concern for recycling of label among the fatty acids, at least over short periods of time. The radio-GLC technique described yields approximately 20% higher fractional turnover times for oleic acid than do standard methods.


Application of tracers in studying free fatty acid metabolism of various organs in vivo. A few selected examples are given of the application of radio-labeled fatty acids in studying substrate utilization under in vivo conditions. The flux of free fatty acids (FFA) may be calculated by the constant infusion technique of Armstrong et al. using either labeled palmitic or oleic acid. Utilization of FFA by the myocardium is conveniently studied by the constant infusion of 14C-labeled palmitate or oleate. The extraction ratio of these two fatty acids is very similar both in the case of myocardium and of several other tissues investigated. Using this technique not only the removal and oxidation of FFA may be calculated but also competition between the major substrates (FFA, lactate, ketone bodies) can be studied. Arterial FFA concentration, rate of coronary blood flow, and myocardial work are mentioned as some of the important factors influencing the rate of myocardial FFA utilization. The study of skeletal muscle metabolism employing labeled fatty acids is of great importance since release as well as uptake of FFA takes place across most muscle beds and thus net arteriovenous differences may be misleading. A somewhat similar situation also exists in the splanchnic region. Labeled fatty acids have also been utilized to investigate both the oxidation of FFA and their incorporation into brain lipids. Both the uptake and release of FFA may be followed in the adipose tissue by the use of labeled palmitate or oleate.


Turnover of individual free fatty acids in man. The use of tracer fatty acids in the study of free fatty acid (FFA) metabolism in man is reviewed in light of the present knowledge of the metabolism of individual FFA. The fractional turnovers of palmitic, stearic and oleic acids are very similar and close to the values reported for the total plasma FFA. The fractional turnover of the polyunsaturated arachidonic acid is higher and there is also a sex difference, women showing 70% higher values than men. Splanchnic fractional uptake differs considerably among the individual FFA, while muscle uptake is virtually independent of the chemical structure of the fatty acid. It is concluded that labeled oleic or palmitic acid can be used as tracers for the total FFA fraction when studying the whole body turnover in the postabsorptive state. In other situations, conclusions from result  of tracer experiments should be limited to the particular fatty acid studied. For measurements of splanchnic FFA metabolism, no single fatty acid seems to be adequate as a tracer for the total FFA fraction.


Induction by PGF2a of 20alpha-hydroxysteroid dehydrogenase in first generation corpora lutea of the rat. 20alpha-Hydroxysteroid dehydrogenase (20alpha-OH-SDH) activity was determined in the first generation corpora lutea from prepubertal rats injected with 10 I.U. of pregnant mare's serum gonadotrophin (PMSG) on day 30. The enzyme was not detectable in 1-9-day-old corpora lutea but a significant activity was seen on day 10. Enzyme activity increased during day 11 and day 12. In vivo administration of prostaglandin F2a (PGF2a) induced the enzyme in rats with corpora lutea older than 3 days. When prolactin was given concurrently with PGF2a, the corpus luteum activity of 20alpha-OH-SDH was lower than when PGF2a was given alone. It is concluded that the present "corpus luteum model" is suitable for further analysis of the cellular mechanisms of the luteolytic effect of prostaglandins (PGs) as well as of the role of gonadotrophins in the luteolytic process.


Cataracts in beagle dogs given diazoxide. In two studies for toxicity, cataracts occurred in beagle dogs given diazoxide daily in high doses. Two of eighteen dogs given diazoxide intravenously at doses of 30.0 mg. per kilogram twice a day for fourteen days had reversible lenticular changes. These changes were not observed in dogs given 22.5 or 10.0 mg. per kilogram twice a day. By fifty-eight days after the last treatment, the cataracts had regressed or disappeared completely. In a study of diazoxide given orally for a maximum of seventy-eight weeks, cataracts developed in six of forty-two dogs given doses ranging from 50 to 200 mg. per kilogram daily, but none occurred in dogs receiving 15 or 30 mg. per kilogram daily. Hyperglycemia was observed at doses of 50 mg. per kilogram or higher. In five of the six dogs that had cataracts and hyperglycemia, vacuolation or absence of islet cells was seen on histologic examination of pancreatic tissue at necropsy. Ocular changes were attributed to the hyperglycemic effect of high doses of diazoxide given daily for prolonged periods. The daily doses given dogs in which cataracts developed were from ten to forty times that suggested in man (5 mg./kg.).


Gastric inhibitory polypeptide. Its physiologic release and insulinotropic action in the dog. Studies were carried out in conscious dogs in which the immunoreactive gastric inhibitory polypeptide (IR-GIP) response to graded doses of oral fat (triglycerides) and glucose was investigated. The IR-GIP response to the doses of triglycerides used was greater and more prolonged than the response to the glucose loads employed. In addition, the relative insulinotropic potencies of exogenous porcine GIP and IR-GIP released by fat as against those released by oral glucose were assessed. When glucose was administered by the oral route, the immunoreactive insulin (IRI) response was magnified above the IRI response to a comparable intravenous glucose load. The serum IRI response to oral glucose was accompanied by a concomitant rise in serum IR-GIP levels, suggesting a causal relationship. IR-GIP released by oral fat was shown to augment the IRI response to an intravenous glucose load, resulting in an improvement of glucose tolerance. Fat-released IR-GIP augmented IRI levels to a lessor degree than either oral glucose or an infusion of porcine GIP.


Quantification of collagen in renal glomeruli isolated from human nondiabetic and diabetic kidneys. Previous studies of diabetic renovascular complications have measured morphologic changes in relatively few glomerular vessels by electron microscopy. The present study samples 20,000 to 80,000 glomeruli from each of ten nondiabetic and ten diabetic age- and sex-matched subjects. Glomeruli were isolated and fractionated by size with a sieving method. Three samples of glomeruli from each subject were analyzed for size, mass, and hydroxyproline content as an index of basement membrane collagen. Approximately 40 per cent of the glomeruli in each sample were isolated. Glomeruli comprised 94 per cent of the tissue elements present, and 92 per cent of the isolated glomeruli were intact. Diabetic glomeruli are larger than nondiabetic glomeruli (mean diameter +/- S.E.M. = 258 +/- 10 mu versus 196 +/- 6 mu) and heavier (499 +/- 63 ng. versus 232 +/- 16 ng.). Diabetic glomeruli have greater hydroxyproline content than nondiabetic glomeruli when content is expressed per glomerulus (21.9 +/- 3.3 ng. versus 7.1 +/- 0.5 ng.) and when expressed per milligram dry weight of glomeruli (44.0 +/- 2.4 mug. versus 31.6 +/- 1.9 mug.). Glomeruli from diabetics of longest duration show the greatest increases in mass and hydroxyproline values. A pathologist's semiquantitative estimation of diffuse glomerulosclerosis revealed a high correlation between hydroxyproline values and histologic determination  of the extent of the renal lesion. These measurements allow quantification of basement membrane collagen and may be used to follow development of diabetic vascular complications.


Relationship between insulin response to oral glucose load and creatinine clearance. In order to investigate the relationship between insulin response to oral glucose load and renal function, a 100-gm. oral glucose tolerance test was performed in twenty-two patients with chronic glomerulonephritis, whose creatinine clearances ranged form 5 to 96 ml. per minute. Glucose areas during oral glucose load were little affected by the creatinine clearance in this study. Insulin area during oral glucose load increased in proportion to the decrease in creatinine clearance. The ratio of insulin area to glucose area correlated closely with creatinine clearance and a linear relationship was obtained (y = 1.46 - 0.01x, r = -0.82, p less than 0.001). There were also significant correlations with serum creatinine, blood urea nitrogen, and PSP (r = 0.6, 0.63, and -0.62, respectively). These results show that the impaired renal function has a significant influence on the plasma insulin levels, and it seems likely that such influence becomes manifest below approximately 60 ml. per minute of creatinine clearance.


Influence of antecedent carbohydrate intake on the biphasic insulin response to intravenous glucose. The insulin secretory response to a sudden and sustained intravenous glycemic stimulus was measured in three groups of dogs whose antecedent carbohydrate intake ranged from zero to 300 or more grams daily. Insulin outflow rate from the pancreaticoduodenal vein was measured every minute for ten minutes, then at increasing intervals through sixty minutes. It was found that starvation erased the first phase of the biphasic insulin response shown by dogs on ordinary carbohydrate intake and that high-carbohydrate intake abolished the trough between the two phases. The data suggest that, during truly physiologic stimulation of insulin secretion, the latter represents the final stage of a continuum of hormonal synthesis, storage, and release, rather than emanating from one of two separate pools of fast-versus-slow insulin secretion.


Insulin sensitivity of the large human adipocyte in vitro. Adipose tissue from twelve normal-weight and ten obese subjects on weight-maintaining diets and nine obese subjects on hypocaloric diets was removed at surgery and incubated in vitro. Basal glucose oxidation correlated significantly (r = 0.68, p less than 0.005) with fat-cell diameter in subjects on weight-maintaining diets. This relationship was significantly altered (p less than 0.02) in subjects on calorie-restricted diets. In tissue from subjects on weight-maintaining diets, physiologic concentrations of insulin (25 muU./ml.) significantly increased glucose incorporation into carbon dioxide (p less than 0.005) and glycogen (p less than 0.001). Maximum insulin-stimulated glucose oxidation (increase over basal) was significantly enhanced (p less than 0.05) in tissue from obese subjects, whereas insulin-mediated glucose incorporation into glycogen was similar in controls and obese subjects on weight-maintaining diets. Insulin-stimulated glucose oxidation was imparied in tissue from subjects on hypocaloric diets although fat-cell diameter was similar to those of obese subjects on weight-maintaining diets. The effect of insulin on glucose incorporation into glycogen in isolated adipocytes was also studied. There was no correlation between insulin-stimulated glycogen synthesis and cell diameter. When cells from the same individual were separated into small and large adipocytes by differential flotation, the insulin effect was similar whether expressed as absolute or per cent increase over basal. These results indicate that in vitro glucose oxidation by adipose tissue, in both the absence and the presence of insulin, is largely determined by dietary factors. This may also be true for insulin-stimulated glycogen synthesis. No evidence is provided for the concept that the enlarged human fat cell of obesity is insensitive to insulin in vitro.


The histological classification of duodenitis in fibreoptic biopsy specimens. Recent advances in biopsy techniques using fibreoptic instruments have refocussed attention on the condition on non-specific duodenitis. Investigation of the topography of duodenitis and its relationship to possible aetiological factors and to duodenal ulcer calls for a proper histological classification. Such a classification is proposed based on the subjective appearances and a quantitative examination of 747 fibreoptic biopsy specimens in a wide range of clinical conditions.


Carcinoma of pancreas, A study based on autopsy data from 1928 to 1972 in Vienna, Austria. The analysis of autopsy data from 1928 to 1972 shows that the relative frequency of carcinoma of pancreas has undergone a threefold increase during the past 30 years. During period B (1953--1972) there has been a real increase (twofold) for the middle and higher age groups as compared with that during period A (1928-1952). Further, it seems that the frequency rises non-linearly with age and that the higher age groups are relatively more prone to a malignant change of the pancreas. The pattern of pathological manifestations has been discussed and its practical importance pointed out.


Action of intragastric ethanol on the pancreatic secretion of conscious rats. A surgical procedure has been disigned which permits injection in the stomach and the duodenum by separate catheters, collection of the pancreatic juice during the experiments, recirculation of the pancreatic juice into the duodenum between experiments, and a normal circulation of bile in rats. Experiments were performed in conscious rats given either 20% ethanol or water. In rats submitted to daily ethanol consumption for 13 months, the intragastric injection of 2 g/kg 20% ethanol considerably increased the pancreatic secretion of protein and, to a lesser extent, of water. In control non-alcoholic rats, a short period of increased secretion is followed by a major inhibition of pancreatic secretion, this reverse reaction to ethanol of pancreatic secretion according to whether or not rats are adapted to regular ethanol consumption is similar to what has been previously observed in dog. In chronic alcoholic rats, the release of secretin is probably not very different from controls.


Calcium-binding activity of rat intestinal mucosa after massive small bowel resection. Male Sprague-Dawley rats underwent resection of 50 cm of either proximal or distal small intestine or sham-operation. 6-7 weeks after operation mucosal calcium-binding activity was measured in segments of duodenum ileum and remaining 'midgut'. Similar measurements were obtained from weight and age-matched unoperated rats. There was no difference in calcium-binding activity between unoperated and sham-operated animals. After proximal resection the binding activity increased significantly in duodenum and midgut but did not change in ileum. After distal resection the binding activity decreased in duodenum but was unchanged in midgut and ileum. These studies show that mucosal calcium-binding activity undergoes changes but alteration of the binding activity in remaining gut varies with the location of the small bowel resection.


Endoscopic diagnosis of advanced gastric cancer. Factors influencing yield. Factors influencing diagnostic yield by directed endoscopic biopsy and cytology were studied in 50 patients with advanced gastric cancer using a forward-viewing panendoscope. The diagnostic yield was higher for exophytic lesions than for infiltrative tumor, and directed brush cytology alone was more productive than directed biopsy alone. The lesions that provided non-diagnostic tissue were mostly recurrent or infiltrative cancers, and were most often in the cardia, antrum, or were of the linitis plastica type. The combination of infiltrative character and location in antrum or cardia, especially if recurrent, often resulted in non-diagnostic biopsy and cytology specimens.


Serial insulin tests over a five-year period after highly selective vagotomy for duodenal ulcer. Twenty-one patients underwent serial insulin testing, approximately 1 week, 1 year, 3 years, and 5 years after highly selective vagotomy (HSV) for duodenal ulcer (DU). They were thought to be representative of the much larger number of patients who have undergone HSV for DU in Leeds. The results obtained were compared with the responses to insulin of 40 other DU patients who were tested before HSV. Before operation, all tests were positive in the 1st hr after insulin ("early-positive") by Hollander's criteria and the mean peak acid response to insulin after subtraction of basal acid output (PAO1) was 33 mEq per hr. One week after HSV, all 21 tests were negative and mean PAOI was 0.05 mEq per hr. One year after HSV, 62% OF 21 tests were Hollander-positive and PAOI had increased significantly (P less than or equal to 0.001) to a mean of 2.3 mEq per hr. Three years after HSV, 15 of 17 tests (94%) were Hollander-positive and mean PAOI was 3.1 mEq per hr (0.1 greater than or equal to P greater than or equal 0.05, compared with PAOI at 1 year). Five years after HSV, 65% of 20 tests were positive and mean PAOI was 3.5 mEq per hr, a significant increase (P less than or equal 0.05) compared with PAOI at 1 year. Only 2 patients (10%) had consistently negative insulin tests over the 5-year period and neither of them was tested 3 years after operation. Thus, HSV was found to abolish consistently the acid response to insulin soon after operation, but on serial testing 90% of the patients eventually developed positive responses to insulin by Hollander's criteria. Most of the acid responses to insulin after HSV were small and the mean reduction in PAOI 5 years after compared with PAOI before operation is approximately 90%. The positive responses to insulin in the long term after HSV could be due to vagal nerve regeneration or to other causes. After a mean period of follow-up of 5 years (range 3 1/2 to 6 1/2 years), only 1 of the first 100 patients who were treated by HSV for DU in Leeds has so far developed recurrent ulceration. The findings of a positive response to insulin by Hollander's criteria more than 1 year after HSV appears to have no prognostic significance.


A study of the relationship between serum group I pepsinogen levels and gastric acid secretion. Serum group I pepsinogen (PG I) levels, basal acid output, and peak acid output (PAO) have been determined in 120 patients, 54 with duodenal ulcer, 14 with prepyloric ulcer, 12 with gastric ulcer, and 40 without ulcer. The correlation between serum PG I and PAO was statistically significant (r = 0.736, P less than 0.001) up to a serum PG I level of 250 ng per ml. Serum PG I levels above 250 ng per ml were associated with a plateau in the PAO. Each of 8 patients with a serum PG I of less than 40 ng per ml had a PAO of less than 10 mEq per hr. Of 34 patients with a serum PG I over 200 ng per ml, 29 (85.3%) had a PAO of greater than 40 mEq per hr and all had a PAO above 34 mEq per hr. Of 51 patients with a serum PG I between 60 and 150 ng per ml, 47 (92.2%) had a PAO of between 10 and 40 mEq per hr. The results indicate that a significant relationship exists between the concentration of PG I in serum and the acid secretory capacity of the gastric mucosa.


Distribution of parietal cells in the antral mucosa of human stomachs. The distribution of parietal cells in the antral mucosa was examined in 118 stomachs obtained at necropsy from persons of both sexes and all ages in whom death resulted from a wide variety of causes, except gastric lesions. The parietal cells appeared in the antrum in 116 out of 118 cases (98.3%). The patterns of distribution of parietal cells were divided into 4 groups. The most frequent pattern (76.3%) was that in which the parietal cells were distributed in all regions of the antrum including just proximal to the gastro-duodenal junction. Parietal cells were found most frequently in the area just proximal to the junction at 20 to 40 years of age and also at 70 years of age. In 18 of the 118 stomachs the focal concentration of the parietal cells near the duodenum was greater than the other part of the antrum, reaching more than 50% of the parietal cells of the average fundic gland. The density increased in slight antral gastric and decreased in cases with moderate to severe antral gastritis. On the other hand, clustered parietal cells were present in the proximal part of the duodenum in 27 of 118 cases. Parietal cells were found also in the antrum of stomachs from newborns and infants, thus this is not metaplasia or dystopia, but is a physiological finding. Therefore the parietal cells in the antrum were considered as a usual cell component of the pyloric gland.


Ultrastructural and physiological changes in piglet oxyntic cells during histamine stimulation and metabolic inhibition. Neonatal pig gastric mucosa was studied in order to correlate electrophysiological and secretory parameters with ultrastructural changes in membrane components of oxyntic cells. The non-stimulated tissue had a transmucosal resistance of about 130omega - cm2 while the oxyntic cells were characterized by numerous cytoplasmic tubulovesicles and short microvilli extending into patent glandular and canalicular lumina. Upon histamine-stimulation, the average rate of H+ secretion was 8.1 mueq - cm2 - hr-1 and the resistance decreased to 77omega - cm2. The changes were coupled with an immense elaboration of the oxyntic cell apical and canalicular surfaces with a concomitant decrease of  tubulovesicles. Thus, the observed decrease in resistance was correlated to large increases in secretory membrane area. Anoxia inhibited H+ secretion while resistance increased to 211omega - cm2. Anoxic oxyntic cells were characterized by swollen mitochondria and occlusion of the lateral intercellular space and basal infoldings. Little change in the configuration of the secretory surfaces was noted, thereby suggesting that restriction of lateral and basal membranes might be responsible for the observed resistance increase. An electrical analogue of gastric mucosa is proposed on the basis of these morphological observations.


Intestinal uptake of macromolecules. IV.--The effect of pancreatic duct ligation on the breakdown of antigen and antigen-antibody complexes on the intestinal surface. We have previously shown a consistent decrease in antigen absorption in vitro by ileal and jejunal gut sacs from orally or parenterally immunized rats in contrast to controls. In immunized rats, antigen appeared to be retained on the surface of the intestine and to be retained on the surface of the intestine and to undergo enhanced degradation by local proteases. This study was concerned with the role of pancreatic enzymes in degradation of antigen and antigen-antibody complexes. The breakdown of [125I]bovine serum albumin (BSA) by jejunal and ileal gut sacs from BSA-immunized, pancreatic duct-ligated rats was significantly decreased in comparison to that of BSA-immunized, sham-operated controls. Treatment of the immunized, pancreatic duct-ligated rats with pancreatic extracts prior to removal of the gut sacs, led to an increase in breakdown of [125I]BSA by the gut sacs in vitro. These findings suggest that pancreatic enzymes adsorbed to the surface of the intestine contribute to the proteolysis of antigens and antigen-antibody complexes at this site.


Gastric emptying and small intestinal mucosal injury in rats. A technique was developed to produce small intestinal mucosal injury in vivo by perfusing the mid-small intestine of rats with HCl, NaOH, FeSO4, and AgNO3. Three hours following injury, gastric emptying and small intestinal transit were measured by examining the gastrointestinal distribution of a non-absorbable radioisotope which had been placed in the stomach for 1 hour. There was a strong association between the villus injury produced by various concentrations of the injurious agents and the degree of gastric retention. Necrosis of villus tips, as produced by AgNO3, was sufficient to cause marked gastric retention. Injury to the small intestinal mucosa of one parabiotic rat did not produce gastric retention in the partner. It is concluded that injury to small intestinal villi is sufficient to induce gastric retention and that the effect is most likely nerve-mediated.


Short chain fatty acids in rats with jejunal blind loops. I. Analysis of SCFA in small intestine, cecum, feces, and plasma. The luminal and plasma levels of short chain fatty acids (SCFA), products of bacterial fermentation, were measured in rats with surgically produced, self-filling blind loops located in the proximal small intestine. High levels of acetic, propionic, and butyric acids were detected in the blind loop segment and in the distal small bowel, regions which in normal and sham-operated rats contain no SCFA. Isobutyric, isovaleric, and valeric acids were also present. Feeding or fasting made little difference in the amount or composition of luminal SCFA. Although the amount of SCFA in each animal varied, the ratio of these acids was relatively constant. The ceca of the blind loop rats had relatively less acetic acid (48% of total SCFA) than did normal rats (64%) and proportionately more isobutryic, isovaleric, and valeric acids. The concentrations of SCFA increased in the feces of blind loop rats. The acetic acid concentration was 50% higher in blind loop rat feces; propionic, isobutryic, and isovaleric acids were elevated to a greater extent. The total output of most of the SCFA was also of acetic acid (137 +/- 32 mug per ml), the rest being isovaleric (5.2 +/- 2.6 mug per ml) and isobutyric (1.4 +/- 0.7 mug per ml) acids. Blind loop animals had nearly twice the concentration of acetic acid in the plasma (240 +/- 29 mug per ml) as normal animals, while the other acids were unchanged. The present study suggests that endogenous substances may be important substrates for the production of SCFA in the intestinal lumen. The high levels of SCFA in the small intestine and in feces and the substantial increase in the concentration of acetic acid in thvergrowth syndrome if the same relationships were found in man.


Role of cholinergic mechanisms in the response to secretin of isolated canine pancreas. The effects of carbamylcholine (CCH, 100 mug per hr) and of atropine (0.25, 1.0, and 10.0 mg per hr) on the response of the exocrine pancreas to secretin (0.1, 0.5, and 5.0 clinic units per hr) were studied using the isolated canine pancreas perfused with whole heparin-treated blood. CCH induced a sharp decrease in D50 (dose of secretin which elicits half the calculated maximal response) but no increase in maximal response to secretin. Experiments performed under different haemodynamic conditions show that this potentiating effect (synergism) is partly due to vasomotor modifications and chiefly to the action of CCH on the receptor of secretin. Although this work indicates that cholinergic tone is not necessary for secretin-induced hydrelatic response to occur, it evidences that this cholinergic tone plays a major role in modulating the pancreatic response to submaximal doses of secretin. It has also been found that large doses of atropine (10 mg per hr) were necessary to achieve a complete inhibition of enzymatic response to CCH. Even at these high doses, however, enzymatic response to secretin and cholecystokinin-pancreozymin were not significantly inhibited.


Arthritis associated with chronic active hepatitis: complement activation and characterization of circulating immune complexes. Circulating immune complexes were identified in cryoproteins isolated from serial serum samples from 6 to 10 patients with chronic active hepatitis (CAH) with frank arthritis and arthralgias. These immune complexes were not detectable in patients with uncomplicated CAH. Only cryoprecipitates from CAH patients with frank arthritis contained IgG, IgM, IgA, and complement components C3, C4, and C5. Hepatitis B surface antigen was concentrated several-fold in the cryoprotein immune complexes as compared with the serum concentration. The C3 activator fragment of the properdin complex was found in fresh serum in all patients with arthritis but was undetectable in patients with arthralagias and uncomplicated CAH. Thus, the presence of circulating complement-fixing immune complexes in patients with alternate complement pathways, and suggests that they play an important role in the pathogenesis of the arthritis.


Dynamic studies on the portal hemodynamics of scintiphotosplenoportography. Streamline flow in the human portal vein. To demonstrate streamline flow in the human portal vein, the hepatic lobar distribution of splenic flow was studied in 6 patients without liver disease and 4 patients with chronic hepatitis using a new technique, scintiphotosplenoportography, followed by 198Au-colloid liver scintigraphy. In two patients, a 99mTcO4-bolus injected into the spleen drained predominantly into the left lobe of the liver. A repeat examination performed in one patient revealed that the bolus was chiefly directed to the other lobe, the right lobe. In 3 patients, the distribution of 99mTcO4- radioactivity was the same as that observed with 198Au-colloid. In the other 5 patients the predominant distribution of 99mTcO4- was observed in the right lobe. In 8 of 11 studies, splenic flow was distributed either to the right or left lobe instead of diffusely to both lobes. This result suggests that flow in the human portal vein is streamline rather than turbulent.


Effect of primary bile acid ingestion on bile acid metabolism and biliary lipid secretion in gallstone patients. Bile acid kinetics were measured by isotope dilution, and hourly outputs of bile acid, cholesterol, and phospholipid were quantified by duodenal perfusion over 24 hr including three liquid meals and an overnight fast in 6 gallstone patients during a pretreatment period and two randomized treatment periods with chenodeoxycholic (chenic) acid or cholic acid. During chenic acid ingestion, bile contained predominantly chenyl conjugates. During cholic acid ingestion, bile was composed of about equal amounts of cholyl and deoxycholyl conjugates; chenyl conjugates decreased markedly due in part to a 50% decrease in chenic acid synthesis. Total bile acid pool size doubled in half the patients receiving either bile acid and was not different during treatment with chenic or cholic acid. Compared to cholic acid, chenic acid caused decreased cholesterol output with no difference in bile acid or phospholipid output. Therefore, bile unsaturated with cholesterol entered the duodenum for more hours per day during chenic acid ingestion than during the cholic or pretreatment periods. There was no relationship among bile acid pool size, bile acid output, and hours per day of supersaturated bile; there was an inverse relationship between total pool size and recycling frequency such that bile acid output remained stable over a wide range of pool sizes. Fasting-state gallbladder bile was supersaturated during the cholic and pretreatment periods, but became unsaturated during chenic acid ingestion. However, hours per day of supersaturated bile could not be reliably predicted from the degree of saturation of fasting-state gallbladder bile (r = 0.62). The efficacy of chenic acid and the lack of efficacy of cholic acid for gallstone dissolution appear related to their different specific effects on biliary cholesterol secretion and not to any effect on bile acid and phospholipid secretion or bile acid pool size.


Bile-salt metabolism in the primate fetus. Fetal bile salt metabolism was assessed by the intravenous infusion of e114C]cholate into 6 monkey fetuses. The placental transfer, fetal plasma clearance, and fetal hepatic excretion of the administered radiolabeled bile salt were measured. Placental transfer averaged 30% of the injected dose, while biliary excretion averaged 36%. Of the amount excreted by the fetal liver, 78% was in the form of [14C]taurocholate. The findings suggest that bile salt metabolic and excretory mechanisms are undergoing developmental maturation at birth.


Ischemic colitis after abdominoperineal resection. Four cases of ischemic colitis occurring at intervals from 3 months to 7 years after abdominoperineal resection are described. In 3 of the 4 cases patency of the direct arterial supply to the ischemic segment was documented. The lack of collateral circulation provided by the resected colon probably increases the risk of developing ischemic colitis in the remaining colon.


Adenosquamous carcinoma of the liver.

Adenosquamous carcinoma of the liver. A rare case of adenosquamous carcinoma of the liver is reported. An 85-year-old white man presented with a 6-month history of weight loss and an enlarged liver. A biopsy demonstrated a squamous cell carcinoma which was presumed to be metastatic with an occult primary. At autopsy, the liver was partially replaced by a focally cystic tumor. Histologically, the neoplasm demonstrated both malignant squamous and glandular contradistinctionmponents as well as foci of transition between the two. This is in co to the 5 previous reported cases of primary hepatic squamous cell carcinomas or tumors containing a squamous component. It is suggested that this neoplasm arose from malignant transformation of squamous metaplasia in a pre-existing cholangiocarcinoma.


Metastatic malignant melanoma of the esophagus: a case report. This report documents the 4th case in the world literature of a malignant melanoma metastatic to the esophagus. The value of gallium scanning in the evaluation of known cancer patients is exemplified by this patient.


Evidence for the existence of definitive hepatic cholesterol precursor compartments for bile acids and biliary cholesterol in man. A bile fistula patient was administered intravenously a constant infusion of [3H]mevalonic acid for 4 hrs, and then after 2 weeks he was given a pulse of [3H]mevalonic acid. Bile and blood were collected at frequent intervals. The specific activity-time course curves did not show a precursor-product relationship between biliary cholesterol, plasma free cholesterol and bile acids. Both the constant infusion and pulse labeling data indicated that the bile acid precursor had a more rapid rate of turnover than plasma or biliary cholesterol; the biliary cholesterol precursor turned over more rapidly than plasma cholesterol. The data suggest the presence of multiple hepatic cholesterol precursor compartments. Bile acids may be derived predominantly from newly synthesized cholesterol in man.


Effect of pentagastrin and caerulein on intragastric pressure in the dog. When gastric acid was not neutralized, doses of pentagastrin as small as 1 mug kg-1 hr-1 decreased intragastric pressure in dogs. When gastric acid was neutralized the smallest effective dose of pentagastrin was 8 mug kg-1 hr-1 which is 16 times the D50 for acid secretion. Thus the decrease in intragastric pressure by small doses of pentagastrin is mediated at least in part by acid secretion. Even with gastric neutralization, a dose of caerulein as small as 63 ng kg-1 hr-1, which is the D50 for pancreatic protein secretion, decreased intragastric pressure. These findings support the view that inhibition of gastric pressure occurs with physiological doses of the cholecystokinin-like peptide caerulein but only with pharmacological doses of pentagastrin.