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R Hickman

Publications and source records attributed to R Hickman.

At least 19 recordsLinked to original sources
PubMed1992

New rapid technique for renal transplantation in the rat.

Present techniques for renal transplantation in the rat include a period of 20-25 minutes warm ischemia. Our method combines a recently described sleeve anastomotic technique for the renal artery, conventional end-to-end anastomosis of the renal vein, and implantation of the ureter into the bladder. This has resulted in a reproducible ischemic interval of 12-14 minutes. Plasma creatinine and histological features in animals sacrificed from 10 to 30 days after transplantation were within normal limits with no evidence of ischemic damage. A further advantage of the technique is that kidneys can be exchanged between the donor and recipient. It is recommended that this procedure, which reduces the ischemic interval by up to 50%, should be learned and employed in studies of renal transplantation in the rat, especially if such studies include the prior administration of cyclosporine, which may aggravate the effects of ischemia.

Anastomosis, Surgical↗
PubMed1992

Relationship between DNA damage, DNA repair, metabolic state and cell lethality.

Induction of unrepairable DNA damage, accumulation of misrepaired DNA damage, and generation of imbalances in competing biochemical and/or metabolic processes have been proposed to explain the relationship between radiation-induced DNA damage and cell lethality. Theoretically, the temperature dependence of the critical DNA repair process(es) should be 1) either independent of or identical to the temperature dependence of cell killing if the first two hypotheses are correct, and 2) different if the third hypothesis is correct. To test this, exponentially growing rat 9L brain tumor cells were left at 37 degrees C or equilibrated for 3-14 h at 20 degrees C before irradiation. Cells were irradiated and allowed to repair at either 20 degrees C or 37 degrees C. Alternatively, the cells were irradiated at one of these temperatures and immediately shifted to the other temperature for repair. DNA damage was assessed by the alkaline elution technique; cell kill was assessed by a clonogenic assay. 9L cells maintained at 20 degrees C or 37 degrees C sustained the same amount of DNA damage as measured by alkaline elution. DNA repair instantaneously assumed the rate characteristic of the postirradiation temperature. For 9L cells equilibrated, irradiated, and repaired at 20 degrees C, the half-time of the fast phase of the DNA repair decreased by a factor of approximately 2 and the half-time of the slow phase decreased by a factor of approximately 5 over that measured in cells incubated, irradiated and repaired at 37 degrees C. Although the rate of DNA repair decreased substantially at 20 degrees C, the survival of 9L cells that were equilibrated and irradiated at 20 degrees C was greater (p less than 10(-4)) than those incubated and irradiated at 37 degrees C, when assayed by an immediate plating protocol. In addition, the survival of 9L cells equilibrated and irradiated at 20 degrees C and then shifted to 37 degrees C immediately after irradiation was greater (p less than 10(-2)) than that obtained with any other delayed plating protocol. Thus, the temperature dependence of the DNA repair processes measured by alkaline elution was different from the temperature dependence of cell killing measured either by an immediate or delayed plating protocol. These data support the hypothesis that many irradiated 9L tumor cells die because of imbalances in sets of competing biochemical and/or metabolic processes.

Animals↗
PubMed1992

Disturbance of plasma thyroid hormone levels after experimental liver transplantation. Is there an association with primary graft nonfunction?

It has been suggested recently that preoperative plasma thyroid hormone levels may be used to predict the success of liver transplantation in prospective recipients and also perhaps that postoperative levels may be used to identify rejection. In the present study of unimmunosuppressed porcine recipients of liver allografts, two groups of animals were identified--those that died within five days postoperatively and the other group that were longer survivors. On the first postoperative day plasma levels of total and free T4 and total and free T3 declined and of total rT3 increased. In survivors these levels returned towards normal within three days, while they persisted in nonsurvivors. As there was no obvious cause of graft failure in nonsurvivors, the state might be considered to represent primary graft nonfunction in pigs, and the changes in plasma thyroid hormone levels may be predictive of this condition; a study in patients may confirm this.

Animals↗
PubMed1992

Effect of total hepatectomy on coagulation and glucose homeostasis in the pig.

It has been suggested recently that patients with fulminant liver failure should be prepared for transplantation by early hepatectomy, yet the acute effects of removal of the liver upon the coagulation profile and certain hormones are not known. This study was conducted on totally hepatectomized pigs that survived up to 27 hr. Measurements were made of serum insulin, plasma glucagon (IRG and GLI), glucose, catecholamines, and the coagulation profile. The increase in serum insulin was directly related to levels of plasma glucose--there was a 100-fold increase in animals with plasma glucose levels greater than 400 mg/100 ml and none when blood glucose was less than 100 mg/100 ml. Plasma glucagon showed a sharp transient increase within 1 hr of hepatectomy and a slow rise thereafter with levels apparently unrelated to serum insulin or plasma glucose. There was a transient increase in plasma adrenaline but a sharp continuous increase in plasma norepinephrine. No changes of note occurred in the coagulation profile--even levels of fibrinogen only declined by 20% in 27 hr. The study has shown that early total hepatectomy is safe as far as changes in coagulation are concerned but changes in serum insulin and especially plasma norepinephrine may be of more significance.

Animals↗
PubMed1992

How rapidly do hyperinsulinaemia and hyperglucagonaemia develop after portacaval shunting?

Elevation of serum insulin and plasma glucagon have been reported during and immediately after clinical and experimental liver transplantation and in patients with cirrhosis and surgically created or spontaneous portacaval shunts. There is controversy about the relative roles of portal diversion and impaired liver function in the genesis of these elevated levels of pancreatic hormones. End-to-side portacaval shunt was made in normal pigs which were fitted with catheters which allowed transhepatic sampling during and for 4 hr after the operation. Within 5 min of opening the shunt, there was a sixfold increase in portal venous insulin concentrations but hepatic clearance of insulin and the arterial concentration were unaltered. The increase in insulin was sustained for 2 hr. A twofold increase occurred within 1 hr in portal venous glucagon concentration which appeared to be predominantly of pancreatic origin and which continued for the 4 hr of the study. Hepatic glucose uptake did not occur after portacaval shunting despite levels of glucose elevated two-fold by iv infusion. There were no changes in aspartate aminotransferase, hepatic tissue energy charge, or total adenine nucleotides, suggesting that hepatic function was intact. It is concluded that portal diversion results in an increase in insulin and glucagon secretion and in the absence of hepatic uptake of glucose. This is a novel observation with relevance especially in liver transplantation when portal diversion for at least 1 hr forms part of the procedure.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Energy charge as an indication of liver viability. A comparison of changes in livers that remained intact with those subjected to autografting.

As efforts to assess the viability of liver grafts continue, the recent description of noninvasive measurement by fluorimetry or magnetic resonance spectrometry of adenine nucleotides has brought energy charge into focus again as an index of viability. Many previous studies have been conducted in human donor livers that have clinical relevance but which cannot be standardized, or in rats in which the hepatic artery is not anastomosed. In the present study, pig livers were definitively rendered ischemic for 1 or 2 hr. In one group the livers were then revascularized (intact) while in the other, the livers were removed during the final 20-30 min of the ischemic period and were subjected to autograft. There was a marked difference in survival between the intact and the autograft groups. One hour of ischemia in the intact group was associated with survival comparable to that of autograft controls (8-100 days); 2 hr of ischemia caused shortened survival, ranging from 2 to 18 days. In the recipients of autografts, survival after 1 hr of ischemia ranged from 3 to 16 days; after 2 hr of ischemia no autograft recipient survived overnight. The energy charge returned to the preoperative level after 2 hr of ischemia in both intact and autograft groups. The concentrations remained depressed after 2 hr of ischemia in autografted animals, thus being associated with survival. However, the patterns of total adenine nucleotide and adenosine triphosphate were not always similar to those of energy charge. The concentrations of aspartate aminotransferase were similarly elevated in all ischemic groups irrespective of duration or subsequent survival. There was, however, a close association between euglobulin lysis times (ELT) and survival. In the autograft recipients of livers subjected to 2 hr of ischemia that did not survive overnight the ELT remained significantly shortened. It is concluded that adenine nucleotide metabolism is important as an index of viability, but that concentrations of total and individual adenine nucleotides and the energy change all need to be computed. There does, however, appear to be an absolute relationship between survival and euglobulin lysis time that would be clinically useful in patients undergoing liver transplantation or hepatic vascular exclusion.

Adenine Nucleotides↗
PubMed1992

Ex vivo versus in situ resection of segmental liver grafts in pigs--a comparison in immediate and four-hour-stored grafts.

This study compared the function of reduced grafts prepared in situ or ex vivo and transplanted immediately or after 4 hr of cold storage. Measurements of acid/base balance, plasma electrolytes, albumin, and urea showed no differences between groups. There was no difference between the increase and decline of plasma AST in recipients of grafts transplanted immediately after either ex vivo or in situ reduction; the increase in plasma AST of recipients of stored grafts was up to 10-fold and persisted until the end of the study at 7 days, with some decline. Plasma fibrinogen decreased intraoperatively but levels were restored within 24 hr in all groups; plasma prothrombin and partial thromboplastin times were not significantly disturbed. The patterns of decline and return of tissue adenine nucleotides were similar in all groups. While the regenerative response measured by tissue thymidine kinase and mitotic figures was not different between the groups, comparison with results from a group of partially hepatectomized animals showed a 3-4-fold depression in response in reduced liver grafts. The contributions of the effects of ischemia, flushing, and preservation to the depressed regenerative response of reduced liver grafts need to be determined. The present studies suggest however, that with regard to functional assessment, results are not affected either by ex vivo or in situ reduction of the graft, or by cold storage for 4 hr.

Adenine Nucleotides↗
PubMed1992

Plasma fibronectin levels during acute rejection and acute tubular necrosis in renal transplant patients.

Fibronectin (Fn), an acute phase glycoprotein synthesized by the liver, has an important immunomodulatory role. We have investigated the changes in plasma Fn in patients after renal transplantation in order to determine whether these changes predict graft injury or rejection episodes. Besides normal healthy controls, healthy pregnant controls, and a trauma control group, we used two groups of chronic renal failure patients as controls: group I, patients with end-stage renal failure (ESRF) on peritoneal dialysis; group II, patients with ESRF on hemodialysis. These were compared with two groups of renal transplant patients: group III, patients 3 months after successful renal transplantation; group IV, patients studied sequentially 10 days immediately posttransplantation. The renal transplant patients were treated with low-dose cyclosporine, azathioprine, and steroids. Citrated plasma samples were collected for Fn assay by a sandwich-type ELISA and for SDS-PAGE analysis and Western blotting. The mean plasma Fn levels were as follows: healthy controls 311.6 SEM, 13.5 micrograms/ml; healthy pregnant controls 357 SEM, 5.9 micrograms/ml; trauma controls 262.3 SEM 31.7, micrograms/ml; group I 169 SEM, 25.1 micrograms/ml; group II 199 SEM, 27.2 micrograms/ml; group III 272 SEM, 21.7 micrograms/ml; group IV 212 SEM, 27.4 micrograms/ml (day 3 postop). There was a significant difference in the plasma Fn levels on day 3 posttransplant between the patients with delayed and immediate renal function (P less than 0.03) (group IV). A significant decrease in plasma Fn levels occurred immediately after steroid therapy was stopped (P less than 0.03) in patients treated for acute rejection. Plasma Fn levels were significantly decreased in the presence of delayed graft function but did not predict rejection.

Fibronectins↗
PubMed1992

Presentations to the Surgical Research Society of Southern Africa--the second 10 years (1982-1991).

Over the 10-year period 1982-1991, 594 papers were read at the annual meetings of the Surgical Research Society of Southern Africa. One hundred and thirty-five (23%) reported work performed on experimental animals with a trend to an increase from this base; 152 (26%) were presentations from surgeons-in-training, also with a trend to increase over the decade. The distribution by subspecialty was: upper gastro-intestinal tract 28%; hepatobiliary 12%; vascular 16%; immunology/transplantation 9%; further subspecialties 9%; and miscellaneous 26%. Major observations are that the number of papers has doubled since the first decade, probably due to establishment of the poster session, and that presentations by surgeons-in-training remain in the minority at the Society.

General Surgery↗
PubMed1992

Orthotopic liver transplantation at Groote Schuur Hospital.

We present data on 10 patients (5 men and 5 women, aged 21-56 yrs) with end-stage liver disease or tumour who underwent orthotopic liver transplantation at Groote Schuur Hospital between October 1988 and June 1991. Standard surgical techniques were used for procuring the donor liver, the recipient hepatectomy and the implantation of the liver. The venovenous bypass method was used in all but 2 patients. Postoperative immunosuppression was usually achieved with cyclosporin, azathioprine and low-dose steroids. Six patients were treated with prophylactic OKT3. Rejection episodes were treated with bolus doses of intravenous steroids. The indications for liver transplantation included chronic active hepatitis progressing to cirrhosis (5), biliary cirrhosis in association with inflammatory bowel disease (1), sclerosing cholangitis (2), alpha 1-antitrypsin deficiency (1), and tumour (1). All patients with chronic liver disease had experienced at least one complication, examples of which included encephalopathy, bacterial peritonitis, ascites, variceal bleeding and septicaemia. Serious postoperative complications included acute rejection of the transplanted liver, renal and liver failure that responded to intensive care support and medical management. One patient died on the 11th postoperative day with complications of bleeding oesophageal ulcer, shock and fungaemia. The remaining patients are alive and well 1-31 months after transplantation.

Adult↗
PubMed1991

Administration of sucralfate prolongs survival of animals with experimental peptic ulceration.

Ligation of the pig bile duct (BDL) results in 100% incidence of pars esophageal ulceration within 48 hours of the procedure. Usually such ulceration is uniformly fatal unless a highly selective vagotomy is performed simultaneously with the BDL. The administration of sucralfate to pigs with BDL prolonged their survival for up to 7 days, with evidence of healing of the ulcer on macroscopic and histologic observations. An increase in cell proliferation in the squamous epithelium of the ulcerated area was also seen in this sucralfate group. These features were not seen in controls, pigs with BDL only, or pigs with BDL and with magaldrate (Riopone), colloidal bismuth subcitrate (DeNol), or carbenoxolone. Analysis by Sepharose 2B gel filtration showed that there was no significant difference in the amounts of polymeric mucin in any group, with a wide scatter of the data seen especially for pigs in the untreated BDL-only group. This study suggests that sucralfate may enhance healing in this experimental pig ulcer model via a mechanism independent of the stimulation of mucus secretion. We propose that coating the mucosa with sucralfate provides a temporary substitute barrier that creates a microenvironment conducive to wound repair by mucosal proliferation.

Aluminum Hydroxide↗
PubMed1991

Animal models of fulminant hepatic failure.

The six requirements for a satisfactory animal model of fulminant hepatic failure are reversibility, reproducibility, death from liver failure, a therapeutic window, a large animal model, and minimal hazard to personnel. Different models may be required to evaluate the various types of liver failure seen in man. The available models include surgical anheptic and devascularization procedures, as well as hepatotoxic drug administration using agents such as carbon tetrachloride, acetaminophen, or galactosamine. Currently combined surgical and drug models appear to provide the best model but the search for the ideal models continues.

Acetaminophen↗
PubMed1991

Six-hour porcine liver storage without flushing or perfusion.

Livers from normal porcine donors were preserved by surface cooling only, without flushing or perfusion, for periods up to 24 hr. All recipients of livers stored for 6 hr survived until sacrifice at 7 days. In a separate, similar group, survival up to 21 days was noted. Only 2 of 6 recipients survived after 9-hr liver storage, but one of these lived for greater than 120 days. No animals survived longer than 2 days after transplantation of livers stored for 12 or 24 hr. The changes in plasma levels of aspartate aminotransferase of recipients of 6-hr surface-cooled livers were not significantly different from AST levels of recipients of livers stored in University of Wisconsin or Euro-Collins solution as observed in previous studies in this laboratory. At sacrifice after 7 days, there was no histologic evidence of damage after surface cooling. In the light of recent reports of evidence of endothelial and reticuloendothelial damage caused by flushing solutions, it is suggested that surface cooling of the liver may provide adequate preservation for 6 hr in appropriate circumstances. Further studies will be needed to confirm that this method of preservation is applicable to livers removed from brain-dead donors and that it does not cause endothelial damage.

Animals↗
PubMed1991

Comparison of the effects of semi-occlusive polyurethane dressings and hydrocolloid dressings on dermal repair: 1. Cellular changes.

The effects on dermal repair of two wound dressings, one the semi-occlusive polyurethane sheet Opsite, the other the hydrocolloid Granuflex, were compared in full-thickness excised lesions on porcine skin during the period from 5 d to 6 months after injury. Quantitative studies were made of changes in the populations of polymorphonuclear leucocytes, macrophages, fibroblasts, and endothelial cells. The progress of repair in the wounds covered with the semi-occlusive dressing showed a decrease in the number of inflammatory cells (polymorphonuclear leukocytes and macrophages) from 5 to 60 d, whereas the number of proliferative phase cells (fibroblasts and endothelial cells) increased from 5 to 7 d. The total cellularity per unit area showed an increase between 5 and 7 d, that is, during the proliferative phase of repair, and then progressively decreased as the proliferative phase was succeeded by the remodeling phase. In contrast, the repair process in the hydrocolloid-dressed wounds was more complex. The number of inflammatory cells remained relatively high throughout and there were consistently fewer endothelial cells present throughout. Fibroblast number showed an initial fall from 5 to 14 d but then started to increase in number from 21 to 60 d. This chronic inflammatory reaction appeared to be in response to particulate matter that had been incorporated into the wound bed and hypodermis, and was still apparent 6 months after injury, when hydrocolloid particles were detectable microscopically in the hypodermis.

Animals↗
PubMed1991

Heparin as the cause of coagulopathy which may complicate grafting of the liver.

Disposal of heparin is accomplished rapidly by the normal liver, but the effects of ischemia, flushing and hypothermia during hepatic transplantation have not been investigated before. The results of the present study showed that neither laparotomy, hypothermia nor insertion of the portosystemic bypass seemed markedly to affect the coagulation profile, but autograft associated with 30 to 45 minutes of warm ischemia resulted in a twofold prolongation of the t1/2 heparin as calculated from sequential measurements of the activated clotting time. Unexpectedly, the storage of livers for four hours in EuroCollins solutions seemed to result in more rapid disappearance of heparin than in animals after laparotomy. After hepatectomy, the clearance of heparin was delayed for two hours but, thereafter, the slope of the disappearance resembled that in sham operated animals. Autograft and allograft of livers in normal pigs that did not receive transfusion were also associated with changes in fibrinolysis and declining levels of fibrinogen together with severe intraoperative bleeding problems and rapid death on the operating table in 30 per cent of the pigs. While administration of heparin alone did not appear to precipitate these changes, use of the drug after dissection, mobilization and storage of the liver may release other tissue factors that activate fibrinolysis.

Animals↗
PubMed1990

The relevance of the order of revascularization in liver grafting.

A study was conducted comparing the effects of initial arterialization vs. initial portal revascularization in unstored warm ischemic (for 30 min) livers, livers stored for 4 hr at 0 degrees C in Collins solution and livers rendered warm ischemic for 1 hr before removal and replacement as autografts. All livers that received initial arterialization showed uniform diffuse perfusion, whereas those with initial portal perfusion were patchy and well perfused only in the right lobe. In the experimental animal, initial arterialization using an end-to-end method was much easier and required less retraction. The energy charge and ATP levels dropped sharply during brief warm ischemia but returned rapidly to normal on revascularization. Although the decline in energy charge was less in stored livers, the return to normal was slower and incomplete. Plasma levels of AST indicated much greater damage in the stored livers and were lowest in recipients in unstored livers that were arterialized first. After longer warm ischemia, energy charge values declined and only completely returned to 60% of preoperative values within 2 hr of grafting. Despite this, the survival rate of these animals was very poor and only one survived overnight. Seven of the 12 survived the procedure, but in five death occurred within 30 min of full revascularization. In this group, AST levels rose sharply after revascularization to a mean level of 1,000 U.(ABSTRACT TRUNCATED AT 250 WORDS)

Acid-Base Equilibrium↗