Biomedical subjects
Publications and source records attributed to R Shields.
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Correct location by 201TI imaging of 48 parathyroids in 35 patients was related to size; 25 out of 26 parathyroids of mass greater than 1.0 g were correctly located, none of ten parathyroids less than 0.3 g was correctly located. In seven patients previously imaged, 108 microCi (4.0 MBq) of 201TI was injected when the thyroid was first exposed surgically. Subsequently weighed and histologically confirmed samples of parathyroid, thyroid, and skeletal muscle were counted against a standard in a well counter. Thallium-201 uptake, as %/g, did not differ between hyperplastic and adenomatous parathyroids. Mean parathyroid uptake was 0.018%/g, thyroid 0.01%/g, muscle 0.0026%/g of administered dose. Lower limits for correct location lay between 0.006-0.0149% of administered dose and between 0.25-0.8 g. Studies using a 201TI phantom containing small aliquots of 201TI at higher concentrations suggested approximately 0.0075% of the usual patient imaging dose as a lower limit for correct location.
Twenty two patients were entered into a randomised controlled clinical trial comparing the efficacy of somatostatin and vasopressin in controlling acute variceal haemorrhage. Somatostatin was significantly more successful in controlling acute variceal haemorrhage than vasopressin (p = 0.003). Furthermore, no complications were observed during treatment with somatostatin.
The effects of systemic and intraportal administration of propranolol on hepatic haemodynamics were studied in cirrhotic and non-cirrhotic rats. In the non-cirrhotic rat systemic infusion of 4 micrograms (kg body wt)-1 min-1 propranolol significantly decreased portal pressure, wedged hepatic venous pressure, portal venous flow and liver blood flow without affecting heart rate. Similar changes were observed in the cirrhotic rat following an infusion of 2 micrograms (kg body wt)-1 min-1 propranolol. Higher rates of propranolol infusion produced greater reductions in portal pressure, wedged hepatic venous pressure, portal venous flow and liver blood flow in cirrhotic and non-cirrhotic rats but these changes were accompanied by a bradycardia. The reduction in portal pressure effected by propranolol was accompanied by an increased splanchnic vascular resistance. Intraportal injection of propranolol resulted in a rapid but transient fall in portal pressure. The decrease in portal pressure was sustained if propranolol was infused intraportally. The results indicate that propranolol effects a reduction in portal pressure via a combination of increased splanchnic vascular resistance, increased hepatic arterial resistance and reduced cardiac output. The observation that propranolol can significantly reduce portal pressure without affecting heart rate may be clinically important in the long-term management of portal hypertension. Furthermore, the rapid reduction in portal pressure following intravenous administration suggests that propranolol may be of value in the acute control of variceal haemorrhage.
The effects of somatostatin (SRIF) and its long-acting analogue, SMS 201-995 on the prevention and treatment of acute pancreatitis were studied in rats. Acute pancreatitis was established by ligating the bile duct at the point of entry into the duodenum, thereby allowing reflux of bile into the pancreas. Administration of SRIF (4 micrograms kg-1 body wt IV followed by a 12 h infusion of 4 micrograms kg-1 body wt h-1) or SMS 201-995 (2 micrograms kg-1 body wt SC) at the time of bile duct ligation prevented the increase in the serum concentrations of amylase and lipase observed in control rats 12 h after bile duct ligation. Moreover, SRIF and SMS 201-995 administration prevented development of the histological changes consistent with acute pancreatitis observed in control animals. These results suggest that SRIF or SMS 201-995 may be of value in preventing acute pancreatitis following ERCP or after surgery on the pancreas. In rats with established pancreatitis, SRIF (IV bolus of 4 micrograms kg-1 body wt followed by a 24 h continuous infusion of 4 micrograms kg-1 body wt h-1) or SMS 201-995 (2 micrograms kg-1 body wt SC followed by a similar dose 12 h later): (1) significantly improved survival; (2) produced histological changes in the pancreas consistent with organization and healing; (3) prevented the accumulation of ascitic fluid; (4) reduced the serum levels of amylase and lipase. These results suggest that SRIF and SMS 201-995 may prove valuable in the treatment of established acute pancreatitis in man.
The effects of a selective beta 2-blocker (ICI 118,551) on hepatic haemodynamics were studied in cirrhotic and non-cirrhotic rats. Infusions of 10 and 20 microgram (kg body wt)-1 min-1 beta 2-blocker (in cirrhotic and non-cirrhotic rats) significantly reduced portal pressure, portal venous flow and liver blood flow without altering heart rate. Splanchnic vascular resistance was significantly increased following infusions of 10 and 20 micrograms (kg body wt)-1 min-1 beta 2-blocker. An intraportal injection of beta 2-blocker (10 micrograms body wt)-1 or hepatic artery ligation lowered portal pressure by approximately the same magnitude. Intraportal injection of beta 2-blocker after hepatic artery ligation did not further reduce portal pressure. The results indicate that a selective beta 2-blocker reduces portal pressure by a combination of increased splanchnic vascular resistance and hepatic arterial resistance. It is concluded that a selective beta 2-blocker may be of clinical value in the long-term managements of portal hypertension.
The effects of a somatostatin analogue, SMS 201-995 on hepatic haemodynamics were studied in rats with dimethylnitrosamine-induced cirrhosis. An intravenous infusion of 1, 2 or 4 micrograms kg-1 body wt h-1 SMS 201-995 produced a rapid and sustained decrease in portal pressure, portal venous flow and liver blood flow without significantly altering arterial blood pressure or pulse. The reductions in portal pressure, portal venous flow and liver blood were accompanied by an increase in splanchnic vascular resistance. Portal venous resistance was not affected. Subcutaneous injection of 2 micrograms kg-1 body wt SMS 201-995 produced a gradual decrease in portal pressure, the maximum reduction occurring 18 min after administration. This reduction in portal pressure was sustained for a further 20 min. The results suggest that SMS 201-995 may be of value in the control of bleeding oesophageal varices. Furthermore, the prolonged duration of action of SMS 201-995 following its subcutaneous administration suggests that the analogue may be useful in the long-term management of portal hypertension in patients with cirrhosis.
The effects of a long acting somatostatin analogue, SMS 201-995, on reticulo-endothelial system (RES) activity were studied in rats. Administration of 2 micrograms SMS 201-995 subcutaneously twice a day for 7 days significantly increased the splenic and hepatic uptake of 99mTc-sulphur colloid and damaged 51mCr-red blood cells. Furthermore, SMS 201-995 administration significantly increased the plasma clearance of colloidal carbon as indicated by a lower area under the curve and an increased elimination constant. SMS 201-995 administration also significantly improved survival after intraperitoneal injection of Escherichia coli endotoxin. These results suggest that SMS 201-995 stimulates RES activity in rats. It is suggested that SMS 201-995 may be of value in stimulating RES activity in patients with cirrhosis and portal hypertension.
The effects of a somatostatin analogue, SMS 201-995, on hepatic haemodynamics in the pig and on intravariceal pressure in man were studied. An infusion of 250 micrograms/h SMS 201-995 significantly reduced portal pressure, portal venous flow and hepatic artery flow in the pig. These changes in hepatic haemodynamics were accompanied by a reduction in cardiac output, a reflex slowing of the heart and an increase in arterial blood pressure. Splanchnic vascular resistance was increased following SMS 201-995 administration but hepatic vascular resistance remained unchanged. Administration of 50 micrograms SMS 201-995 reduced the intravariceal pressure from 27.4 +/- 2.5 to 15.8 +/- 2.1 mmHg in 9 patients with cirrhosis and portal hypertension. Administration of 50 micrograms SMS 201-995 also reduced portal pressure from 29 to 22 mmHg in a patient undergoing an elective portacaval shunt. These results suggest that SMS 201-995 may be of value in the control of bleeding oesophageal varices. Furthermore, because of its prolonged duration of action SMS 201-995 may be useful in the long term management of portal hypertension in patients with cirrhosis.
Liver blood flow (xenon-133 clearance method) and portal venous flow were measured in cirrhotic and non cirrhotic rats following the infusion of vasopressin at varying rates. At low rates of infusion, vasopressin had no significant effect on portal venous flow or liver blood flow in cirrhotic or non-cirrhotic rats. Infusion of vasopressin at a rate of 0.08 microU/g body wt/min in non-cirrhotic rats and 0.04 and 0.08 microU/g body wt/min in cirrhotic rats decreased portal venous flow and increased liver blood flow. At higher rates of infusion (0.2 microU/g body wt/min in non-cirrhotic rats and 0.16 microU/g body wt/min in cirrhotic rats) these effects were reversed. Furthermore, an infusion of 0.08 microU/g body wt/min vasopressin significantly reduced portal pressure in the cirrhotic rat. However, portal pressure was not significantly altered following an infusion of 0.16 microU/g body wt vasopressin. The implications of these findings in relation to the possible deleterious effects of high rates of vasopressin infusion in the management of portal hypertension and bleeding oesophageal varices is discussed.
By separating large and small 3T3 cells we show here that cell growth (in volume) after stimulation from quiescence is not 'autocatalytic'. Rather, large cells grow significantly more slowly, in relative terms, than small cells. It follows that 3T3 cells do not require a size control mechanism operating at the level of division timing in order to achieve cell size homeostasis.
A method of producing cirrhosis consistently in rats by the administration of dimethylnitrosamine (DMNA) is described. Two weeks following the cessation of DMNA treatment there was distortion of the lobular architecture of the liver and some focal nodule formation. This 'pre-cirrhotic' state was accompanied by portal hypertension, biochemical abnormalities and the development of ascites. The mortality 2 weeks after cessation of DMNA was 42%. Twenty-four weeks after DMNA treatment cirrhosis had developed with diffuse nodularity and fibrosis, marked portal hypertension, and accumulation of ascites. There was also a deterioration in liver function, with hypoproteinaemia and jaundice. The overall mortality 24 weeks after the cessation of DMNA treatment had risen to 52%. This model of cirrhosis in the rat may be useful in evaluating the efficacy of drugs in the long-term management of portal hypertension in man.
Portal venous flow, total hepatic blood-flow and hepatic artery flow were measured in healthy dogs by electromagnetic flowmetry and a double indicator dilution technique. Functional liver blood-flow was measured by the double indicator dilution technique. Functional hepatic blood-flow did not correlate with portal venous flow, total hepatic blood-flow or hepatic artery flow, measured by either electromagnetic flowmetry or a double indicator dilution technique. There was a good correlation (r = 0.83, P less than 0.001) between functional hepatic blood-flow and liver blood-flow, measured by the clearance of Xenon-133 injected directly into the liver parenchyma. It is concluded that the clearance of Xenon-133, injected directly into the liver parenchyma, is a rapid and simple method for measuring functional hepatic blood-flow.
Very little is known about the normal temporal and quantitative relationships between gastric emptying and gall bladder emptying. Using a non-invasive double isotope technique these relationships were investigated in 22 normal healthy adults. 99Tcm EHIDA was used as the biliary tracer and 113Inm labelled bran as the gastric content tracer. Gastric emptying was monoexponential with a t1/2 of 45 +/- 3 minutes (mean +/- SEM). In 15 subjects the gall bladder emptied in relation to eating according to a double exponential function. In these subjects 15.0 +/- 1.6% of gall bladder contents emptied before gastric emptying began. They could be further divided into two clear cut types (p less than 0.001), according to the ejection fraction at 10 minutes and the t1/2 of the first exponential. Emptying of the gall bladder was faster and more of its contents were ejected in subjects with a type I response (n = 9) than in subjects with a type II response (n = 6). In the remaining seven subjects the gall bladder began to empty spontaneously, unrelated to eating. These observations suggest that gall bladder emptying: (a) may have a cephalic phase, (b) can be expressed as a double exponential function, (c) may occur unrelated to eating, (d) which occurs only in relation to eating would appear to be either fast (type I) or slow (type II).
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Because adherence of histamine to glass is well-known, we tested for its adherence to a mechanical homogenizer commonly used in the extraction of histamine from tissue samples. During 60 sec of homogenization, 15% to 17% of the histamine originally present in the samples "disappeared," and the reason for the disappearance was reversible binding of histamine to the homogenizer. Adding trace amounts of [14C]histamine to each sample before homogenization and measuring the disappearance of radioactivity during homogenization permitted correction for binding to the homogenizer. This technique for correction was validated by the measurement of endogenous concentrations of histamine in the tracheal posterior membranes of six dogs (range of mean concentrations: 0.63 to 1.51 ng/mg wet weight) followed by the measurement of known amounts of exogenous histamine added before homogenization to tracheal tissue samples from the same dogs. In the latter samples, 96 +/- 13% (mean +/- SEM) of the histamine added was measured by our technique. We conclude that binding of histamine to mechanical homogenizers may be an important cause of inaccuracy of the enzymatic assay for the measurement of histamine concentrations in tissue but that such binding may but that such binding may be easily corrected for.
The effect of low (0.08 microU g-1 body wt min-1) and high (0.16 microU g-1 body wt min-1) rates of vasopressin infusion on blood flow to normal liver tissue and to liver metastases derived from azoxymethane induced colorectal carcinomas was studied in 36 male Wistar rats. Portal venous flow was measured by electromagnetic flowmetry and blood flow to normal and metastatic liver tissue by the clearance of xenon-133 injected directly into the liver parenchyma or metastasis. The low rate of vasopressin infusion decreased portal venous flow but increased blood flow to normal and metastatic liver tissue while at the higher rate of infusion these effects were reversed. Hepatic artery ligation (HAL) immediately following a low rate of vasopressin infusion abolished the observed increase in blood flow to both normal liver tissue and metastases. HAL immediately following the higher rate of vasopressin infusion further reduced blood flow to metastases but did not further alter blood flow to normal liver tissue. HAL prior to the infusion of the vasoactive drug significantly reduced blood flow to metastatic liver tissue, increased portal venous flow and was without effect on blood flow to normal liver tissue. Following HAL, blood flow to metastatic liver tissue was not further altered by either the low or high rates of vasopressin infusion. However, blood flow to normal liver tissue after HAL was reduced by a low rate of infusion of vasopressin and increased by the higher rate of infusion. The results of this study indicate that blood flow to normal or metastatic liver tissue can be increased or decreased by differential rates of infusion of vasopressin. These observations may have important implications in the treatment of liver metastases in man where different rates of vasopressin infusion may potentiate the effects of hepatic artery ligation or cytotoxic therapy.
Liver blood flow (xenon-133 clearance method) and portal venous flow were measured in hypophysectomised rats following the infusion of vasopressin at a range of infusion varying from 0.0125 to 0.8 microU/g b.w./min over the range 0.0125-0.1 microU/g b.w./min, portal venous flow was reduced, the reduction being linearly related to the logarithm of the dose (r = -0.88). Following the infusion of 0.8 microU/g b.w. of vasopressin, portal venous flow significantly increased above pre-infusion levels (p less than 0.05). Liver blood flow was increased significantly (p less than 0.05) when vasopressin was infused over the range 0.0125-0.2 microU/g b.w. At higher rates of infusion, liver blood flow was progressively reduced, and at 0.8 microU/g b.w./min liver blood flow was less than pre-infusion levels (p less than 0.05). These data suggest that the effects of vasopressin on hepatic haemodynamics is related to the rate of infusion with a reversal of effects at higher rates of infusion. The implications of these findings in relation to the use of vasopressin in the management of portal hypertension and bleeding oesophageal varices is discussed.