Biomedical subjects
Publications and source records attributed to B J Potter.
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An experimental colitis in rabbits is described, following the intravenous injection of preformed immune complexes of human serum albumin (HSA) and anti-HSA into non-sensitised rabbits. Tissue damage was localised to the colon by the Auer technique of inducing local non-specific inflammation, by the rectal instillation of dilute formalin. Formalin alone gave transient changes that reverted to normal within 24 hours. In rabbits given intravenous immune complexes formed in antigen-excess, a severe colitis was initiated, with histological features including mucosal ulceration, mixed inflammatory cell infiltration in the lamina propria, and crypt abscess formation. It is possible that immune-complex damage may be one of the pathogenic mechanisms involved in human ulcerative colitis.
CH50 and the concentrations of C3, C4, C1 INH and factor B have been measured in sera from 34 control subjects and 178 patients with various hepatobiliary diseases, including primary biliary cirrhosis (PBC), chronic active hepatitis (CAH), cryptogenic cirrhosis (CC), alcoholic liver disease (ALD), Wilson's disease (WD), large duct biliary obstruction (LDBO) and viral hepatitis (VH). CH50 was decreased in CAH and CC. C3 was increased in PBC, LDBO and VH and decreased in CAH and CC. C4 was decreased in PBC, CAH, ALD and WD. C1 INH was increased in PBC, CAH, ALD, LDBO and VH. Factor B was increased in LDBO and VH and decreased in CC. In none of the patient groups was the mean C4 level increased or the mean C1 INH level decreased. All 5 indices of serum complement were lower in ascitic than nonascitic patients. Data on serum complement were similar in HBsAg positive and negative VH. Discriminant analysis facilitated separation of all the patient groups on the basis of complement data, except PBC and VA. Analysis of data using a within-group correlation matrix revealed a significant negative correlation between C4, the most discriminating variable of serum complement in CAH, and gamma-globulin concentration in CAH. The possible contribution of factors such as activation of complement, impaired hepatic synthesis of complement components, an acute phase response and cholestasis to altered serum complement profiles in different hepatobiliary diseases is discussed.
Large immune complexes are present in the circulation of patients with primary biliary cirrhosis and result in the activation of complement by the classical pathway. Such large complexes are capable of producing tissue damage. The granulomatous lesions surrounding the small bile-ducts within the liver of patients with primary biliary cirrhosis and the vasculitis, rheumatoid arthritis, and associated lesions are all compatible with immune complex injury. It is postulated that such large complexes could be formed in the vicinity of the bile-ducts by an antigen absorbed from the bile or biliary epithelium. Complexes reaching the systemic circulation might be responsible for the associated extra-hepatic diseases.
Serum levels of complement components Clq, C4, C3, and Properdin factor B, from the classical and alternative pathways of complement activation, have been estimated in patients with ulcerative colitis and Crohn's disease. C3, factor B, and to some extent C4 concentrations all increased when the disease was active. In remission the levels of these components did not differ from hospital control patients. There was no evidence for the preferential consumption of the proteins of either pathway of activation, even in those patients with evidence of circulating immune complexes.
The metabolism of the third component of complement (C3) has been investigated in four patients with ulcerative colitis, three patients with Crohn's disease and seven control subjects, using radioiodinated C3 prepared from fresh human plasma. Both the fractional catabolic rate and synthesis rate of C3 were increased in the patients with inflammatory bowel disease, although the serum-C3 levels were normal or raised. The results suggest that complement activation may play a role in the pathogenesis of mucosal inflammation in these diseases.
Sera from 156 patients with ulcerative colitis and Crohn's disease were tested for the presence of immune complexes, by the detection of anti-complementary activity and 125I-labelled Clq precipitation. Using aggregated IgG, a comparison between the two tests indicated that the anti-complementary test was most sensitive to aggregates of 11S in size, while the 125I-labelled Clq test detected aggregates over 20S in size. Excess anti-complementary activity was common in patients with active bowel disease, and in those with extra-intestinal manifestations, particularly acute arthritis, ankylosing spondylitis and liver disease. Large complexes were only common in patients with liver disease. Immune complexes in the gut mucosa may play a role in the pathogenesis of these diseases, and the deposition of circulatory immune complexes may explain at least some of the extra-intestinal manifestations.
1. A low-magnesium diet was fed to four sheep, each of which had been surgically prepared with a rumen fistula, a tube into the cranial one-third of the omasum, a tube to the cranial one-third of the abomasum and a re-entrant duodenal cannula. Mg, as gluconate or acate or acetate, was continuously infused for 12-14 d in turn into (1) the caudal duodenal cannula, (2) the abomasum, (3) the omasum, (4) the rumen. A continuous infusion of the chromium-ethylenediaminetetraacetic acid complex (CrEDTA) was maintained to the rumen. The abomasal effluent which flowed through the cranial duodenal cannula was continually sampled and the flow of Mg calculated from the concentrations of Mg and CrEDTA. Blood and rumen fluid samples were taken and urine and faeces collected during each period of Mg infusion. 2. The Mg infused to either the abomasum or omasum was completely recovered at the duodenum, indicating a lack of net absorption of Mg from these stomach compartments. In contrast, 13-7-18-7 mmol (36-61%) of the Mg infused to the rumen was not recovered at the duodenum which suggested that a substantial net absorption of the infused Mg occurred from the reticulo-rumen. Absorption of Mg caudal to the pylorus was not related to the site of Mg infusion and averaged 3-28 +/- 0-56 (SEM) mmol/d. 3. Compared with the intraruminal infusion, the post-ruminal infusion of Mg was associated with decreased plasma and rumen fluid Mg concentrations, decreased urinary Mg exretion, decreased Mg balance and increased faecal Mg excretion. 4. It is concluded that no significant absorption of Mg occurs from either the omasum or abomasum in sheep and that the reticulo-rumen is the principal site of Mg absorption before the pylorus. Absorption of Mg post-ruminally is insufficient to maintain normal Mg status in the animal.
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The possibliity that the disturbed immunity associated with primary biliary cirrhosis (PBC) includes abnormal metabolism of the complement system has been investigated by conducting simultaneous studies of the turnover of highly purified, hemolytically active, 125-i-labeled C3 (third component of complement) and 131i-albumin in seven control subjects and nine patients with PBC. Aliquots of each 125i-C3 preparation were injected, together with 131i-albumin, into one or two normal subjects and one to three patients with PBC and plasma and urine radioactivity data were analyzed. In all patients with PBC disappearance of 125i from plasma was much more rapid than in controls. In five of these patients no terminal monexponential decline of 125i occurred. The mean fractional catabolic rate (FCR) of C3 was higher in PBC (4.23 +/- 0.32 [S.E.M.] per cent IV pool per hour) than in controls (2.02 +/- 0.08% IV pool per hour, p less than 0.0005). In contrast, the mean FCR of albumin was similar in PBC (11.4 +/- 1.29 per cent IV pool per day) and controls (11.5 +/- 0.76 per cent IV pool per day), suggesting that the increased FCR of C3 in PBC was not due to a nonspecific process. There was no correlation between values for the FCR of C3 and indices of cholestasis. The mean synthetic rate of C3 was higher in PBC (2.94 +/- 0.48 MG. PER KILOGRAM PER HOUR) THAN IN CONTROls (1.03 +/- 0.11 mg. per kilogram per hour, p less than 0.0025). In five patients relatively more C3 was extravascular than in controls. The results are consistent with PBC being associated with chronic activation of the complement system and increased tissue attachement of C3, phenomena which could be related to a process of pathogenic significance in this disease.
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Total serum haemolytic complement activity (CH(50)) and the serum concentrations of both the third and fourth components of the complement system (C3 and C4) have been measured in 29 control subjects, 92 patients with chronic hepatocellular disease, and eight patients with large duct biliary tract obstruction. The mean C4 concentration was reduced in all types of chronic liver disease studied. However, the mean CH(50) and C3 values were increased in compensated primary biliary cirrhosis, were relatively normal in non-cirrhotic chronic active hepatitis, and were decreased in cryptogenic cirrhosis, particularly when ascites was present. There was a significant correlation between CH(50) and C3 in patients with chronic liver disease but no correlation between CH(50) and C4 or between C3 and C4. Raised values for CH(50) and C3 in primary biliary cirrhosis may be due at least in part to concomitant cholestasis since these values tend to be raised in patients with large duct biliary tract obstruction. Although primary biliary cirrhosis, chronic active hepatitis, and cryptogenic cirrhosis are considered to be part of a spectrum of chronic liver disease associated with disturbed immunity, the results of this study emphasize that there are clearly definable differences between these diseases in terms of the pattern of changes in serum complement.
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1. Sheep, which had access to a solution containing 1.3% sodium chloride as their sole source of drinking water for 6 months or more, were infused with a hypertonic solution (10%) of sodium chloride, and their ability to tolerate this salt load was compared with that of a similar group of sheep which drank only rain water.2. The sheep which drank the rain water were often affected by the infusion and exhibited signs resembling potassium deficit. No such signs were apparent in the animals which consumed saline water.3. Glomerular filtration rates were increased in all sheep by the hypertonic saline infusion, the increases being greater in the sheep which were maintained on the saline water. Effective renal plasma flow rates, though extremely variable, behaved in a similar manner.4. Plasma values for sodium and chloride were increased in all sheep, but remained at a higher level for a longer period in the sheep which consumed rain water. The diuresis produced by hypertonic saline appeared to persist for a longer period in the sheep which drank rain water, while the excretion of sodium and chloride tended to be greater in the sheep maintained on saline water.5. Plasma potassium was reduced in all sheep and urinary excretion of potassium increased. The latter response was more pronounced in the sheep which drank the rain water.6. Filtered loads of sodium, chloride and potassium were greater in the sheep which were accustomed to drinking saline water. However, the amounts of potassium excreted were greater than those filtered in the rain water sheep and less than those filtered in the sheep which drank saline water. It therefore seems that secretion of potassium into the kidney tubules predominated in the former group and reabsorption prevailed in the latter.7. Reabsorption of free water in excess of solute was greater in the kidney tubules of the sheep which drank saline water.8. Increased blood volume and greater dilution of plasma proteins occurred in the sheep which drank rain water.