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Biomedical subjects

A M Mackinnon

Publications and source records attributed to A M Mackinnon.

At least 19 recordsLinked to original sources
PubMed1996

Relation between oesophageal acid exposure and healing of oesophagitis with omeprazole in patients with severe reflux oesophagitis.

BACKGROUND/AIMS: Reducing oesophageal acid exposure by suppressing acid secretion with omeprazole is highly effective in healing reflux oesophagitis. Some patients with severe oesophagitis, fail to heal and whether this results from inadequate acid suppression or other factors is unclear. The aim of this study, was to investigate the relation between oesophageal acid exposure and healing in patients with severe reflux oesophagitis treated with omeprazole. METHODS: Sixty one patients with grade 3 or 4 ulcerative oesophagitis were treated for eight weeks with omeprazole 20 mg every morning. Those patients unhealed at eight weeks were treated with 40 mg every morning for a further eight weeks. Endoscopy and 24 hour oesophageal pH monitoring were performed before treatment and at the end of each treatment phase while receiving treatment. RESULTS: Thirty per cent of patients failed to heal with the 20 mg dose. Unhealed patients had greater total 24 hour oesophageal acid exposure before treatment, and while receiving treatment also had greater acid exposure and a smaller reduction in acid exposure than did patients who healed. Forty seven per cent of the unhealed patients also failed to heal with the 40 mg dose. These patients had similar levels of acid exposure before treatment to those who healed, but had greater acid exposure while receiving treatment, particularly at night when supine. CONCLUSIONS: Patients with severe ulcerative oesophagitis who are refractory to omeprazole have greater oesophageal acid exposure while receiving treatment than responding patients. This is due to a reduced responsiveness to acid suppression, and is likely to be an important factor underlying the failure of the oesophagitis to heal.

Adult↗
PubMed1989

Bile acid synthesis by cultured rabbit hepatocytes: stimulation by three lipoprotein fractions.

Bile acid and cholesterol synthesis were measured in monolayer cultures of rabbit hepatocytes maintained in a defined culture medium. In the absence of lipoproteins, bile acid synthesis and secretion were correlated with cholesterol synthesis and were increased 245% by mevalonolactone (10 mM) and inhibited 45% by lovastatin (50 micrograms/ml) over 24 h. When included in the culture medium, normal rabbit plasma low-density and high-density lipoproteins increased bile acid synthesis and secretion by up to 140% of values obtained without lipoproteins in hepatocytes from normal or cholestyramine-fed rabbits. Three cholesterol-rich lipoprotein fractions (beta-very low density, low density and high density) also were isolated from rabbits fed 1% cholesterol for 14 days. When added to rabbit hepatocyte cultures, each fraction markedly increased hepatocellular cholesterol content, stimulated bile acid synthesis and secretion in a dose-dependent manner, and inhibited cholesterol synthesis from radioactive acetate. These data indicate that three different lipoprotein fractions can provide cholesterol for uptake and subsequent breakdown to bile acids by cultured rabbit hepatocytes.

Animals↗
PubMed1989

Bile acid synthesis and secretion by rabbit hepatocytes in primary monolayer culture: comparison with rat hepatocytes.

Rabbit hepatocytes isolated after liver perfusion with collagenase were maintained in primary monolayer culture for periods up to 96 h. Bile acid synthesis and secretion was measured by capillary gas-liquid chromatography and by a rapid enzymatic-bioluminescence assay. As expected from the bile acid profile of rabbit gallbladder bile, cholic acid was the only bile acid synthesized in detectable amounts and was produced at a linear rate of 170 pmol/h per mg cell protein from 24 to 96 h in culture. Ketoconazole (20 microM) inhibited cholic acid synthesis and secretion by 78%, whereas the bile acids chenodeoxycholic acid (100 microM), deoxycholic acid (100 microM) or lithocholic acid (2 microM) had no effect. When rat hepatocytes were cultured under identical conditions, the rate of bile acid synthesis was found to be only 12 pmol/h per mg cell protein, a value in agreement with previous work. The large difference in rates of bile acid synthesis between rabbit and rat hepatocytes may be due to rapid loss of cytochrome P-450 from rat hepatocytes when placed in monolayer culture. Although reportedly active in cholesterol 7 alpha-hydroxylation, form 4 cytochrome P-450 levels in rabbit hepatocytes did not correlate with rates of bile acid synthesis.

Animals↗
PubMed1988

Development of an automated Lowry protein assay for the Cobas-Bio centrifugal analyzer.

The Lowry protein assay was directly adapted for use on the Cobas-Bio centrifugal analyzer resulting in a 50% reduction of the coefficients of variation of the manual method. It was also demonstrated that the reaction need not be pursued to its endpoint and that absorbance readings taken immediately after the addition of the Folin reagent were directly related to the protein concentration. Thus the total assay time could be reduced from 30 to 3 min with no loss of accuracy or reproducibility.

Autoanalysis↗
PubMed1988

High density lipoprotein particle size distribution in subjects with obstructive jaundice.

High density lipoproteins (HDL) from 14 patients with obstructive jaundice were examined by gradient gel electrophoresis to determine the effect of obstruction on particle size distribution. HDL from 7 of these patients were fractionated by gel permeation chromatography and further characterized by electron microscopy, SDS gel electrophoresis, apolipoprotein A-I and apolipoprotein A-II immunoturbidimetry, and analysis of chemical composition. In addition, lecithin:cholesterol acyltransferase (LCAT) activity was measured and correlated with plasma apolipoprotein A-I concentration and particle size distribution. HDL were abnormal in all patients regardless of severity, cause, or duration of obstruction. The major HDL subfraction in normal subjects, HDL3a (radius 4.1-4.3 nm) was either absent or considerably diminished, and HDL2b (radius 5.3 nm) was also frequently absent. Very small particles comparable in size to normal HDL3c (radius 3.8 nm) were prominent. In patients with a bilirubin concentration greater than 250 mumol/l, normal HDL had totally disappeared and were replaced by large discoidal particles of radius 8.5 nm and small spherical particles of radius 3.6-3.7 nm. Both populations of particles were markedly depleted of cholesteryl ester and enriched in free cholesterol and phospholipid. The discoidal particles were rich in apolipoproteins E, A-I, A-II, and C, while the small spherical particles contained predominantly apolipoprotein A-I. LCAT activity was diminished in all subjects to 8-54% of normal, and was strongly positively correlated (r = 0.91 P less than 0.05) with plasma apolipoprotein A-I levels.

Adult↗
PubMed1987

Regulation of bile acid synthesis in cultured rat hepatocytes: stimulation by apoE-rich high density lipoproteins.

Cultured rat hepatocytes obtained by liver perfusion with collagenase in the presence of soybean trypsin inhibitor were used to examine the role of high density lipoproteins (HDL) in supplying cholesterol to the hepatocyte for bile acid synthesis. Within 6 hr of adding HDL (d 1.07-1.21 g/ml) obtained from rat serum there was a significant stimulation of bile acid synthesis and secretion that reached 2-fold after 24 hr. The stimulation by HDL occurred at normal plasma concentrations (i.e., 500 micrograms/ml) and showed further stimulation in a dose-dependent manner reaching a maximum stimulation of 2- to 2.5-fold. The stimulation of bile acid synthesis was dependent on the cholesteryl ester content of the HDL. Several lines of evidence show that the HDL is taken up by a receptor-mediated process dependent on apoE. These include: 1) at the same concentration (500 micrograms/ml) apoE-poor HDL (not retained by heparin affinity chromatography of HDL isolated from the plasma of rats fasted for 72 hr stimulated bile acid synthesis by 48%, whereas apoE-rich HDL stimulated bile acid synthesis by 110%; 2) reductive methylation totally blocked the stimulation of bile acid synthesis by HDL; 3) HDLC, which contained apoE as its major protein component, also maximally stimulated bile acid synthesis; and 4) human HDL, which contained no detectable apoE, failed to stimulate bile acid synthesis. Additional studies showed that apoE-enriched HDL and HDLC both inhibited cholesterol synthesis (determined by the incorporation of 3H2O) and caused a net accumulation of cholesteryl esters in hepatocytes.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Effects of serum amyloid A protein (SAA) on composition, size, and density of high density lipoproteins in subjects with myocardial infarction.

The acute phase reactant serum amyloid A protein (SAA) circulates in plasma as a constituent of high density lipoproteins (HDL). Advantage has been taken of the induction of SAA in human subjects with myocardial infarction to study the effect of SAA on the physical and chemical properties of HDL. HDL were isolated by sequential ultracentrifugation and assayed for chemical composition. Apolipoprotein composition was assessed by SDS polyacrylamide gel electrophoresis. Size distribution of HDL was determined by gradient gel electrophoresis and density distribution by density gradient ultracentrifugation. In studies of 18 subjects with myocardial infarction, SAA accounted for 8-87% (median 52%) of the HDL apolipoprotein. These SAA-enriched HDL had a density comparable to that of normal HDL subfraction-3 (HDL3). Their chemical composition differed from normal HDL3, however, with a reduced phospholipid (17% vs 24%) and an increased triglyceride (7.7% vs 1.6%) value. When separated by gradient gel electrophoresis, the SAA-enriched HDL were much larger than normal HDL3, having a radius of 4.5-5.3 nm that extended well into the size range of HDL2; particle size correlated with SAA content. This disassociation between particle density and particle size was also observed with the SAA-enriched HDL isolated from a subject with secondary amyloidosis and also with normal HDL that had been enriched with SAA during incubation in vitro. Thus, the presence of high levels of SAA has been found to be associated with phospholipid-depleted particles of a density comparable to HDL3 but a size larger than normal HDL3.

Adult↗
PubMed1984

Appearance of serum amyloid protein in high-density lipoproteins of rabbits subjected to relatively mild stimuli.

Relatively mild stimuli have been found to induce an appearance of the serum amyloid protein in the high-density lipoproteins (HDL) of rabbits. Large amounts of serum amyloid protein appeared in the HDL of rabbits, following intravenous infusions of the artificial triacylglycerol emulsion, Intralipid. Lesser, but still significant amounts of serum amyloid protein also appeared in rabbit HDL after intravenous infusions of sterile saline and even in non-infused rabbits that had been subjected to no more than serial blood sampling. Given that these latter procedures are necessary components of many metabolic experiments performed in vivo, the observation that they induce an appearance of serum amyloid protein in HDL has potentially major implications in terms of the interpretation of in vivo studies of HDL metabolism.

Amyloid↗
PubMed1984

Detection of lipid transfer protein activity in rabbit liver perfusate.

Cholesteryl ester, triacylglycerol and phospholipid transfer activity was detected in rabbit liver perfusate after 2 h perfusions in situ. Lipoproteins were removed from the perfusate plasma by ultracentrifugation prior to hydrophobic interaction chromatography of the lipoprotein-free perfusate. The hydrophobic protein, eluted with water from a Phenyl-Sepharose column, facilitated the transfer of radiolabelled cholesteryl ester, triacylglycerol and phosphatidylcholine from low-density lipoprotein to high-density lipoprotein during 3 h incubations at 37 degrees C. These results suggest that rabbit plasma lipid transfer protein is produced by the liver.

Animals↗
PubMed1981

Serum lecithin: cholesterol acyltransferase activity in the bile duct-ligated rat.

Serum lipoprotein cholesterol concentration, lecithin: cholesterol acyltransferase (LCAT) activity and lipoprotein X (LP-X) were studied after acute cholestasis had been produced by ligation of the common bile duct in rats fed a liquid fat-free diet. The concentration of serum-free cholesterol, predominantly contained in the low density lipoprotein fraction, increased steadily up to 72 h after ligation. The concentration of cholesterol in the high density lipoprotein fraction did not change significantly, and similarly the serum concentration of esterified cholesterol was not altered. The activity of LCAT, expressed in molar terms as millimoles of cholesterol esterified per litre per hour, did not change during the 72-hour study period. These data indicate acute cholestasis in the rat does not result in a LCAT deficiency and suggest that the accumulation of serum-free cholesterol in this situation is independent of the serum cholesterol-esterifying mechanism.

Acute Disease↗
PubMed1976

Hepatic microsomal mixed function oxidase system response to selective biliary obstruction.

Three days after selective biliary obstruction in rats, bile output from the single unobstructed lobe was equivalent to the usual output from three hepatic lobes. There was a significant decrease in the level of the hepatic microsomal mixed function oxidase system components, cytochrome P-450 and NADPH-cytochrome c reductase. The levels observed after three days were reduced to an equivalent extent in both selectively obstructed and unobstructed lobes, and corresponded to the level seen after total biliary obstruction. Hepatic bromosulphothalein Tm was significantly reduced three days after selective obstruction, but did not differ from normal after six days. These data indicate that a factor generated in response to biliary obstruction acts to lower hepatic mixed function oxidase system components and increase bile flow in functioning hepatic tissue.

Animals↗
PubMed1976

Effect of bile duct ligation on the ultrastructural morphology of hepatocytes.

The effect of severe cholestasis produced by bile duct ligation on surface membrane ultrastructure was compared to control. Isolated well preserved hepatocytes were prepared by boric acid dissociation and examined under the scanning electron microscope. Normal sinusoidal, intratrabecular, and canalicular surface membrane topography is described. In particular the bile canalicular microvilli were observed to be derived from two locations: a "marginal ridge" whose microvilli are unaltered after bile duct obstruction, and the bile canalicular surface whose microvilli are lost in obstruction and primarily account for the appearance previously described by transmission electron microscopy. Thus, newer techniques in tissue preparation and scanning electron microscopy demonstrate that bile canalicular microvilli are derived from two anatomical sites and respond differently to bile duct ligation.

Animals↗
PubMed1975

Adaptive changes in vitamin B12 absorption in celiac disease and after proximal small-bowel resection in man.

Resection of the proximal small bowel is known to cause mucosal hyperplasia and enhanced absorption in the ileum of experimental animals, but similar adaptive changes had not previously been studied in man. Since intrinsic-factor-bound vitamin B12 (IF-B12) absorption is confined to the ileum, as an index of ileal adaptation, we measured whole-body IF-58 Co B12 absorption in 24 control subjects, in 4 patients after proximal small-bowel resection, and in 9 patients with adult celiac disease (where mucosal damage is often limited to the proximal intestine and spares the ileum). Control subjects absorbed 20.4% (+/- 1 SD 6.2%) of the administered 5-mug dose of vitamin B12, while the corresponding 7-day retention values in patients with proximal resection (mean 42.3%; range 32-61%) and in 2 of the 9 celiac patients (44.1% and 54%, respectively), were above the normal range. The increased vitamin B12 absorption in these patients suggest that functional adaptation also occurs in the ileum in man. The results also illustrate the application of a newly developed whole-body counting technique to study vitamin B12 absorption in man.

Adolescent↗