Experimental copper and Heliotropium europaeum intoxication in sheep: clinical syndromes and trace element concentrations

Merino wethers were used to determine the effects of copper (Cu) and heliotrope (Heliotropium europeaum), given together or separately, on the development of toxicity and trace element concentration in liver and kidney. The 14 sheep fed both Cu and heliotrope were given Cu and heliotrope concurrently (9 sheep) or heliotrope alone for 12 weeks, and then Cu starting 8 weeks after heliotrope consumption ceased (5 sheep). Clinically and biochemically, there was no significant difference between these two regimes. Thirteen developed clinical signs. Of those, three developed haemolysis, eight became jaundiced and two became weak without jaundice. Of the eleven given Cu alone, three developed haemolysis but no jaundice, while there was neither haemolysis nor jaundice in the ten fed heliotrope only, although one died. Throughout the experiments a similar concentration of Cu was found in liver of control and heliotrope groups. The concentration of Cu in the liver of animals fed Cu alone increased to twice, and in groups fed Cu and heliotrope it increased to three times that found in the control groups. In animals which developed haemolysis, the concentration of Cu in the blood rose prior to the onset of haemolysis. It also rose in some animals which became jaundiced, but did not develop clinical haemolysis. Feeding heliotrope alone induced the histologic changes reported in pyrrolizidine alkaloid intoxication, but was not associated with an excessive accumulation of Cu nor the development of clinical illness. However, such sheep were made more susceptible to effects of a second toxin, for in animals given Cu and heliotrope, toxicity of the two substances was markedly enhanced and excessive accumulation of Cu occurred in liver

Changes in plasma bile acids, plasma amino acids, and hepatic enzyme pools as indices of functional impairment in liver-damaged sheep

Plasma bile acids, plasma amino acids, and the total hepatic pools of aspartate aminotransferase, gamma glutamyltransferase, glutamate dehydrogenase, and sorbitol dehydrogenase were compared in control sheep (Group 1), sheep with subclinical pyrrolizidine alkaloid toxicosis (Group 2), and in sheep with acute hepatocellular necrosis associated with the hemolytic phase of chronic copper poisoning (Group 3). Subclinical pyrrolizidine alkaloid toxicosis was not associated with any changes in bile acid or amino acid status but was associated with a significant decline in the hepatic pools of sorbitol dehydrogenase and aspartate aminotransferase. This observation could not be explained in terms of enzyme leakage from damaged hepatocytes and suggested that pyrrolizidine alkaloids might specifically inhibit hepatocellular enzyme synthesis. Group 3 sheep also had reduced hepatic enzyme pools which were at least partly referable to enzyme leakage from damaged hepatocytes. In these sheep, increases in plasma bile acids were a more sensitive index of hepatic function than were either increased aromatic amino acid concentration or the ratio between branched chain and aromatic amino acids

Effect of the ingestion of heliotrope and copper on the concentration of zinc, selenium and molybdenum in the liver of sheep

Merino wethers were used to examine the effect of feeding heliotrope, with and without additional copper (Cu), on the development of clinical signs, lesions in the liver and concentration in the liver of Cu, zinc (Zn), selenium (Se) and molybdenum (Mo). The feeding of heliotrope reduced liver concentrations of Zn (P < 0·05) and Mo (P < 0·01), but Cu ingestion had no effect on these parameters. The concentration of Se in the liver was only increased when heliotrope was given with copper (P < 0·01); it had previously been shown that Cu and heliotrope ingestion is followed by an interaction which results in a marked increase in the concentration of Cu and the production of extensive lesions in the liver, The increase in liver Se may therefore have represented a passive or active response to liver necrosis, whereas effects on Zn and Mo represented specific metabolic disturbances attributable to heliotrope feeding

The effect of copper and heliotrope on the composition of bile in sheep

The effects of interrupting the enterohepatic circulation (ehc) of bile salts for seven hours and of feeding copper and heliotrope alone and combined for 13 weeks, on bile flow and excretion of copper, zinc, iron and α-mannosidase were studied in sheep. Interruption of ehc reduced bile flow rate and increased the concentration of copper, zinc, iron and bile acids while α-mannosidase's activity remained stable. Changes in concentration were related to changes in bile volume for copper and zinc only. Total output per hour was not changed. Biliary concentration of copper correlated with α-mannosidase's activity in control sheep and those given copper or heliotrope, supporting the hypothesis that lysosomes are involved in biliary secretion of copper in sheep. Increasing the intake of copper increased the rate of excretion of copper in bile. Copper output was lower when heliotrope was fed alone

Experimental copper and heliotrope intoxication in sheep: morphological changes

Young Merino wethers were used to determine the effects of copper and heliotrope, fed together or separately, on the development of toxicity and the concentration of trace elements in the liver and kidney. In one experiment copper and heliotrope were given concurrently, in a second experiment heliotrope was fed for 12 weeks and copper administration commenced 8 weeks later. The 10 sheep fed heliotrope alone did not show signs of clinical illness but one died and was found to have severe liver damage. Eleven sheep were given copper alone and three developed the clinical signs and lesions of haemolysis. Fourteen sheep were given copper and heliotrope and 13 became ill. Of these, three developed haemolysis, eight became jaundiced and two became weak without developing jaundice. The concentrations of copper in the livers of control and heliotrope-treated sheep, were comparable. In the animals given copper alone, the concentration of copper in the liver was twice as high as that in controls and in those given heliotrope and copper, it was three times as high as in the liver of control sheep. Feeding heliotrope alone induced the histological changes of pyrrolizidine alkaloid toxicity in the liver, but this was not associated with an excessive accumulation of copper or the development of clinical illness. However, it did predispose the animals to the effects of a second toxin since giving heliotrope and copper concurrently, or giving copper subsequent to feeding heliotrope, markedly enhanced the toxicity of the two substances and caused an excessive accumulation of copper in the liver

The influence of gamma inulin and Algammulin on the immune response in sheep to a recombinant antigen of Taenia ovis

Gamma inulin and Algammulin, two new adjuvants, were examined and compared with alum and Freund's Complete/Incomplete Adjuvant (FCA/FIA), for potentiation of cell-mediated immunity (CMI) and humoral immunity in sheep to a recombinant Taenia ovis antigen. The ability to protect sheep when challenged with live T. ovis eggs was also assessed The results showed that gamma inulin and Algammulin induced a CMI response which was comparable to the FCA/FIA and alum groups and significantly higher than the control saline group. While gamma inulin, Algammulin and alum performed similarly and induced a significantly higher humoral immune response than the saline group, FCA/FIA elicited a much higher humoral immune response. Algammulin did not show the synergistic effect seen in mice and performed similarly to gamma inulin and alum alone. All the adjuvant groups induced significantly higher IgG1 and IgG2 levels than the saline group and they all favoured IgG1 production. When the sheep were challenged with live T. ovis eggs, at 25 weeks after primary immunization, the only group to show significant protection was the one which received FCA/FIA

Safety and efficacy of non-steroidal anti-inflammatory drugs to reduce ileus after colorectal surgery

Background: Ileus is common after elective colorectal surgery, and is associated with increased adverse events and prolonged hospital stay. The aim was to assess the role of non-steroidal anti-inflammatory drugs (NSAIDs) for reducing ileus after surgery. Methods: A prospective multicentre cohort study was delivered by an international, student- and trainee-led collaborative group. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The primary outcome was time to gastrointestinal recovery, measured using a composite measure of bowel function and tolerance to oral intake. The impact of NSAIDs was explored using Cox regression analyses, including the results of a centre-specific survey of compliance to enhanced recovery principles. Secondary safety outcomes included anastomotic leak rate and acute kidney injury. Results: A total of 4164 patients were included, with a median age of 68 (i.q.r. 57\u201375) years (54\ub79 per cent men). Some 1153 (27\ub77 per cent) received NSAIDs on postoperative days 1\u20133, of whom 1061 (92\ub70 per cent) received non-selective cyclo-oxygenase inhibitors. After adjustment for baseline differences, the mean time to gastrointestinal recovery did not differ significantly between patients who received NSAIDs and those who did not (4\ub76 versus 4\ub78 days; hazard ratio 1\ub704, 95 per cent c.i. 0\ub796 to 1\ub712; P = 0\ub7360). There were no significant differences in anastomotic leak rate (5\ub74 versus 4\ub76 per cent; P = 0\ub7349) or acute kidney injury (14\ub73 versus 13\ub78 per cent; P = 0\ub7666) between the groups. Significantly fewer patients receiving NSAIDs required strong opioid analgesia (35\ub73 versus 56\ub77 per cent; P &lt; 0\ub7001). Conclusion: NSAIDs did not reduce the time for gastrointestinal recovery after colorectal surgery, but they were safe and associated with reduced postoperative opioid requirement

Safety of hospital discharge before return of bowel function after elective colorectal surgery

Background: Ileus is common after colorectal surgery and is associated with an increased risk of postoperative complications. Identifying features of normal bowel recovery and the appropriateness for hospital discharge is challenging. This study explored the safety of hospital discharge before the return of bowel function. Methods: A prospective, multicentre cohort study was undertaken across an international collaborative network. Adult patients undergoing elective colorectal resection between January and April 2018 were included. The main outcome of interest was readmission to hospital within 30 days of surgery. The impact of discharge timing according to the return of bowel function was explored using multivariable regression analysis. Other outcomes were postoperative complications within 30 days of surgery, measured using the Clavien\u2013Dindo classification system. Results: A total of 3288 patients were included in the analysis, of whom 301 (9\ub72 per cent) were discharged before the return of bowel function. The median duration of hospital stay for patients discharged before and after return of bowel function was 5 (i.q.r. 4\u20137) and 7 (6\u20138) days respectively (P &lt; 0\ub7001). There were no significant differences in rates of readmission between these groups (6\ub76 versus 8\ub70 per cent; P = 0\ub7499), and this remained the case after multivariable adjustment for baseline differences (odds ratio 0\ub790, 95 per cent c.i. 0\ub755 to 1\ub746; P = 0\ub7659). Rates of postoperative complications were also similar in those discharged before versus after return of bowel function (minor: 34\ub77 versus 39\ub75 per cent; major 3\ub73 versus 3\ub74 per cent; P = 0\ub7110). Conclusion: Discharge before return of bowel function after elective colorectal surgery appears to be safe in appropriately selected patients