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J G Waggoner

Publications and source records attributed to J G Waggoner.

At least 55 records · Page 3Linked to original sources
PubMed1981

Effect of splenectomy of hepatic bilirubin clearance in patients with hereditary spherocytosis. Implications for the diagnosis of Gilbert's syndrome.

BRT and CBR were determined from studies of radiobilirubin kinetics in 14 patients undergoing splenectomy for hereditary spherocytosis. Studies were conducted both before and after the operation in order to assess the effects of the postsplenectomy fall in BRT on CBR. Splenectomy led to a doubling of the RBC-t1/2 from 13.0 +/- 1.7 (S.E.) days to 26.1 +/- 1.5 and a fall in BRT from 15.9 +/- 4.4 mg/kg/day to 4.3 +/- 0.9. In seven patients (group A) initially normal values for CBR were unaltered by surgery. In the remaining seven (group B), low preoperative values for CBR, suggestive of Gilbert's syndrome, uniformly improved after splenectomy, becoming normal in five patients. Nevertheless, family studies and reduced values for UDPGT activity supported the initial impression of concomitant Gilbert's syndrome in group B. These studies suggest the existence of a latent state for Gilbert's syndrome that, in some patients, may be unmasked by a hemolytic stress. As such, they have important implications for both pedigree analysis and incidence studies of this condition.

Adolescent↗
PubMed1980

Deficiency of the autologous mixed lymphocyte reaction in patients with primary biliary cirrhosis.

In this study we show that patients with primary biliary cirrhosis (PCB) have a marked deficiency in the ability to generate an autologous mixed lymphocyte reaction (AMLR) but have a normal ability to generate an allogeneic mixed lymphocyte reaction (MLR). This deficiency is not due to differences in the time-course of the proliferative response or to an altered response to variable numbers of stimulator cells. The deficiency was consistently found irrespective of the methods used to isolate autologous stimulator cells. Both responder cells and stimulator cells obtained from patients with PBC were similar to normal cells in their ability to generate an MLR in allogeneic normal human serum. In addition, serum from patients with PBC inhibited the ability of normal lymphocytes to generate both the AMLR and MLR to a similar degree, suggesting that the defect of the AMLR in PBC is not due to a serum factor. It has been shown that the responder cell population in the AMLR contains a subpopulation of cells that mediate suppression. Therefore, it is possible that the deficiency of the AMLR may be related to previously described abnormalities of suppressor function in patients with PBC.

Adult↗
PubMed1980

Attachment to collagen by isolated hepatocytes from rats with induced hepatic fibrosis.

The attachment to and synthesis of collagen by hepatocytes isolated from rats with and without hepatic fibrosis were studied. Attachment of normal hepatocytes was enhanced fourfold in the presence of serum, whereas attachment of hepatocytes from CCl4-treated rats with severely fibrotic livers was enhanced only twofold by serum. Fibronectin promoted hepatocyte attachment to collagen to the same degree as serum, whereas serum from which the fibronectin had been removed did not. Thus hepatocytes adhere to collagen via fibronectin, a known adhesion protein for fibroblasts. In the absence of serum or fibronectin, hepatocytes attached best to basement membrane collagen (type IV). This enhanced attachment was abolished by periodate oxidation of the collagen, an observation which suggested that carbohydrate residues are involved in hepatocyte attachment to this collagen. Collagen synthesis was determined after hepatocytes were cultured for 24 hr. No difference was found in the amount of collagen synthesized by cultures of hepatocytes derived from control rats and from rats with hepatic fibrosis. By immunofluorescence, the cell responsible for the synthesis of collagen appeared to have a fibroblastic morphology.

Animals↗
PubMed1978

Hepatic accumulation and intracellular binding of conjugated bilirubin.

After the intravenous injection of unconjugated [(3)H]bilirubin into normal Sprague-Dawley and Wistar R rats, radiolabeled bile pigments rapidly accumulated in the liver. By 1.5 min after injection, an average of 36% of the injected isotope was present in liver homogenates. Between 3 and 15 min, 37-64% of the total intrahepatic radiolabeled bilirubin was conjugated, as demonstrated by extraction of label into the polar phase of a solvent partition system. This indicates both rapid conjugation, and accumulation of conjugated bilirubin within the liver cell. Fluorometric determination of the dissociation constants of purified bilirubin and its mono- and diglucuronides for homogeneous preparations of two human and four rat glutathione S-transferases, including ligandin, revealed avid binding of all three bile pigments to this class of proteins. Hence, the observation that the intrahepatic bile pigment pool contains substantial amounts of conjugated bilirubin can be attributed to the high binding affinities observed. Thin-layer chromatographic analysis of the (3)H-pigments produced by p-iodoaniline diazotization of homogenates and cytosol demonstrated that the intrahepatic pool of conjugated bilirubin was almost exclusively monoglucuronide. Examination of radiolabeled bilirubin conjugates excreted in bile during the first 20 min after injection of [(3)H]bilirubin showed no preferential excretion of diglucuronide. These studies indicate that (a) both bilirubin and its monoglucuronide accumulate within the liver cell as ligands with the glutathione S-transferase; and (b) bilirubin diglucuronide does not significantly accumulate within the general intrahepatocellular pool of protein-bound bile pigments. The latter observation is compatible with the formation and excretion of bilirubin diglucuronide directly from the canalicular pool of the liver cell.

Animals↗
PubMed1978

A model of fulminant hepatic failure in the rabbit.

A highly reproducible model of fulminant hepatic failure was developed by administering intravenously the selective hepatotoxin galactosamine hydrochloride (4.25 mmoles per kg) to genetically uniform rabbits. The great majority of rabbits died between 21 and 44 hr after injection following a period of coma which lasted 2.6 hr on average. Serum biochemical tests and liver histology reflected massive hepatic injury. Changes in plasma ammonia and amino acid concentrations, in coagulation parameters, and in the electroencephalogram were similar to those found in human fulminant hepatic failure. This model appears promising for future studies of the pathogenesis and treatment of fulminant hepatic failure.

Alkaline Phosphatase↗
PubMed1978

Studies of the kinetics of purified conjugated bilirubin-3H in the rat.

Radio-labeled conjugated bilirubin was purified from rat bile by affinity chromatography. Following the intravenous injection of tracer doses of this material, the initial fractional plasma disappearance rate of conjugated bilirubin-3H in the normal Sprague-Dawley rat was found to be approximately 50% faster than that for unconjugated bilirubin-3H (0.51 +/- 0.94 [SE] vs. 0.35 +/- 0.02 min.-1; P less than .001). Hepatic recovery studies in the rat indicated that, over the first four minutes after injection, disappearance of cholephilic anions from plasma is accounted for almost entirely by hepatic uptake. Hence, these studies demonstrate that hepatic uptake of conjugated bilirubin is substantially faster than that of unconjugated bilirubin. Net hepatic clearance of conjugated bilirubin in normal rats was three-fold greater than that of unconjugated bilirubin (0.94 +/- 0.16 vs. 0.30 +/- 0.03 ml./min./100 gm. body weight; P less than .001), presumably reflecting both the more rapid hepatic uptake and the ability of the former pigment to by-pass the conjugation step. Hepatic uptake of conjugated bilirubin was shown to be inhibited by unconjugated bilirubin, sulfobromophthalein and indocyanine green but not by glycocholate. These observations cannot be explained by simple diffusion and suggest that the hepatic uptake mechanism for conjugated bilirubin is the same as that for the unconjugated pigment.

Animals↗
PubMed1976

The effect of repeated phlebotomy on bilirubin turnover, bilirubin clearance and unconjugated hyperbilirubinaemia in the Crigler-Najjar syndrome and the jaundiced Gunn rat: application of computers to experimental design.

1. A multicompartmental model of erythrokinetics and bilirubin production has been developed to predict the consequences of chronic phlebotomy on daily bilirubin turnover. 2. Control values for four physiological variables including bilirubin turnover were determined in a 20-year-old woman with type I congenital nonhaemolytic jaundice (Crigler-Najjar syndrome). With these base-line data, the model predicted the following changes during phlebotomy: a 34% fall in bilirubin turnover; a 240% increase in the haemoglobin content of bone-marrow erythroid precursors; a 25% fall in the half-life of 51Cr-labelled erythrocytes; a characteristic alteration of the erythrocyte survival curve after labelling with [2-14C]glycine. 3. On the assumption, previously validated in normal volunteer subjects and patients with Gilbert's syndrome, that hepatic bilirubin clearance was independent of turnover and would therefore remain unchanged, a fall in plasma unconjugated bilirubin concentration during phlebotomy from 436 to 282 mumol/1 was expected. 4. Accordingly, the patient underwent phlebotomy 350 ml/week for 2 months, and 500 ml/week during an additional 3 months. Appropriate studies during phlebotomy confirmed each of the predictions in paragraph 2 above. In particular, turnover fell by 31%. Unexpectedly, plasma unconjugated bilirubin remained essentially unchanged. Analogous results were observed in phlebotomized jaundiced Gunn rats. 5. Kinetic studies in both the patient and the rats demonstrated that the failure of plasma unconjugated bilirubin to fall in parallel with bilirubin turnover resulted from a prolongation of the terminal half-life of radioactively labelled bilirubin and a fall in bilirubin clearance in every instance. 6. These studies indicate that (a) in congenital non-haemolytic jaundice, bilirubin clearance is uniquely influenced by bilirubin turnover and (b) compartmental modelling and kinetic studies are useful for predicting and interpreting the results of both physiological experiments and experimental therapeutic regimens.

Adult↗
PubMed1976

A new approach to quantitation of the various sources of bilrubin in man.

Studies of the "early labeling" of fecal bile pigment have been widely interpreted as indicating that 10 to 20 per cent of total bile pigment production in normal man is derived from the processes which give rise to the "early labeled" pigment peak (ELP). However, this conclusion is based on a very small number of studies with inherent experimental and analytic limitations. In the present study, a new experimental approach was employed. Plasma bilirubin turnover (BRT), total red blood cell volume (TRCV), and red cell survival were measured in 26 normal volunteers and 35 patients with various hepatic and/or hematologic disorders. The quantity of bilirubin derived from red blood cell degradation (BRRBC) was calculated from TRCV and the mean red cell life-span, and the difference between BRT and BRRBC, designated "excess bilirubin synthesis (EBS)," was considered to represent the quantity of bilirubin derived from the processes responsible for ELP. In normal volunteer subjects, EBS averaged 1.0 mg. per kilogram per day, and accounted for 25 per cent of daily bilirubin turnover. Hence, results derived by this approach exceeded the range estimated from analysis of "early labeled peak" data. Further analysis of the data in terms of a simple model of bilirubin sources was compatible with the hypothesis that EBS consists of an essentially constant component, averaging 0.8 mg. per kilogram per day, presumably derived principally from the liver, and a second component which varies with the erthropoietic rate. Hence, in normal man the liver may contribute the major fraction of EBS.

Acute Disease↗
PubMed1976

Abnormal hepatic transport of indocyanine green in Gilbert's syndrome.

The plasma fractional disappearance rate of indocyanine green (kICG, min-1) and the absolute hepatic ICG removal rate (VICG, mg per kg per min) were determined in 26 patients with Gilbert's syndrome (GS) and 19 normal control volunteers following intravenous administration of doses of 0.5, 2.0, 3.5, and 5.0 mg per kg of dye. The diagnosis of GS was based on studies of radiobilirubin kinetics in all cases and liver biopsy in 22 cases. The patients were further classified into 3 subgroups, based on patterns of sulfobromophthalein (BSP) kinetics, as follows: GS I (15 patients) had normal BSP metabolism; GS II (5 patients) had a defect in BSP metabolism beyond the stage of initial hepatic uptake; and GS III (6 patients) had a defect in the initial hepatic uptake of BSP (Gastroenterology 63:472-481, 1972). Both kICG and VICG were significantly reduced, compared to normal controls, in the GS III group with defective BSP uptake, but did not differ significantly from normal in the GS I and GS II groups. Michaelis-Menten analysis of the data indicated that VMAX for ICG uptake in the GS III group (1.2 +/- 0.6 mg per min per kg) was significantly reduced compared to the previously established normal value of 3.6 +/- 0.6 mg per min per kg; (P less than 0.01). For the total population of 26 patients with Gilbets' syndrome, there was a highly significant correlation (r= 0.77, P less than 0.01) between kICG and lambda21BSP, the fractional hepatic uptake rate for BSP. These studies confirm previous work indicating that patients with Gilbert's syndrome constitute a heterogeneous population with regard to defects in hepatic organic anion transport, some of the defects not being attributable to glucuronyl transferese deficiency. Future studies of Gilbert's syndrome must take into account the existence of these subgroups, since they may have different underlying pathogenetic mechanisms.

Adolescent↗
PubMed1975

Hepatic organic anion uptake in the rat.

The hepatic uptake of bilirubin (BR), indocyanine green (ICG), and sulfobromophthalein (BSP) was studied in 350 anesthetized Sprague-Dawley rats by determining the initial plasma disappearance rate (V) of various doses of unlabeled ICG, or of tracer quantities of [3H]BR or [35S]BSP injected into the jugular vein simultaneously with varying amounts of unlabeled BR or BSP. Similar studies were also performed involving the simultaneous injection of potential inhibitors of hepatic uptake. The results indicate that: (a) hepatic uptake determined by direct tissue measurement could be accurately estimated from the plasma disappearance data; (b) saturation of hepatic uptake with increasing dose was readily demonstrated for each of these three organic anions, and in each instance a plot of V versus dose took the form of a rectangular hyperbola analyzable in terms of Michaelis-Menten kinetics; (c) for BR, the saturable uptake process showed a Vmax more than 100 times the normal net transfer rate from plasma to bile; (d) hepatic uptake of BR, BSP, and ICG showed relatively selective, mutually competitive inhibition; glycoholic acid did not inhibit hepatic uptake of any of these substances; and (e) "counter-transport" could be demonstrated for each of the three test substances. These data are compatible with the existence of a carrier-mediated transport process for hepatic uptake of each of these three organic anions and clarify the relationship of hepatic BR uptake to its overall transport from plasma to bile.

Animals↗
PubMed1974

Removing substances from blood by affinity chromatography. II. Removing bilirubin from the blood of jaundiced rats by hemoperfusion over albumin-conjugated agarose beads.

In vitro studies indicate that bilirubin and other albumin-bound substances can be efficiently removed from plasma by filtration over albumin-conjugated agarose beads. The effectiveness of this technique in vivo was investigated in rats by using a closed extracorporeal hemoperfusion system. Five Gunn rats whose endogenous bilirubin pool had been labeled with [(3)H]bilirubin and five Sprague Dawley rats with surgically created biliary obstruction were chosen as models of unconjugated and conjugated hyperbilirubinemia. Indocyanine green was injected into rats and its removal also studied. In the Gunn rats, 98% of the bilirubin was removed from plasma during the initial pass over the column as determined isotopically and chemically. Plasma bilirubin levels fell more than 70% from 8.2+/-1.6 mg/100 ml (mean+/-SD) to 2.6+/-0.5 mg/100 ml during a 1-h hemoperfusion. An average of 1,061 mug of bilirubin was recovered from the columns, representing 22.5+/-4.2% of the total exchangeable bilirubin pool and 96+/-36.4% of the plasma pool. Results were similar in the rats with biliary obstruction and in those given indocyanine green. Normal Sprague Dawley rats experience minimal changes in formed blood elements, electrolytes, and proteins as the result of hemoperfusion. When the total volume of the column did not exceed 51% of the estimated blood volume of the animal, the survival rate was 100% in 20 studies, and the procedure was without observable ill effect. Extrapolation of both in vitro and in vivo data to man suggests that extracorporeal hemoperfusion over albumin-agarose columns may be a practical means of assisting hepatic excretory function.

Animals↗