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Biomedical subjects

C H Halsted

Publications and source records attributed to C H Halsted.

At least 55 records · Page 3Linked to original sources
PubMed1989

Folate absorption in alcoholic pigs: in vitro hydrolysis and transport at the intestinal brush border membrane.

We used the miniature pig to evaluate the effect of ethanol ingestion on the hydrolysis of pteroylpolyglutamate and on the uptake of pteroylmonoglutamate (PteGlu) by the intestinal brush border membrane, processes that are required for folate absorption. After feeding ethanol or sucrose at 60% of calories for 11 mo, the uptake of PteGlu by jejunal brush-border-membrane vesicles was similar in both groups of animals. Jejunal brush border pteroylpolyglutamate hydrolase was decreased by one-half in the ethanol-fed group. Jejunal brush-border-membrane fluidity, measured by fluorescence polarization, was similar in both groups. Acute exposure of the jejunal vesicles to ethanol increased membrane fluidity and decreased hydrolase activity but had no effect on PteGlu transport. Inhibition of jejunal folate hydrolase by chronic exposure to ethanol may be an early effect in the pathogenesis of folate malabsorption and deficiency in chronic alcoholism.

Alcoholism↗
PubMed1987

Increased methionine synthetase activity in zinc-deficient rat liver.

To study the effect of zinc deficiency on folate metabolism, three groups of male Sprague-Dawley rats (zinc deficient (ZD), restricted-fed (RF + Zn), and ad libitum-fed control (control] were given a semipurified 25% egg white protein diet. The ZD group received less than 10.3 nmol zinc/g of diet, while the RF + Zn and control groups were given 1620 nmol zinc/g of diet. After 6-7 weeks of feeding, severe zinc deficiency developed in ZD rats. Hepatic methionine synthetase activity was increased in the ZD group compared to both the RF + Zn and control groups, but hepatic 5,10-CH2-H4folate reductase activity was similar in all groups. This increased methionine synthetase activity found in zinc-deficient rats might induce secondary alterations in folate metabolism. These changes include significantly lowered plasma folate levels, decreased 5-CH3-H4folate in liver, and increased rates of histidine and formate oxidation. The latter two findings suggest that the available non-5-CH3-H4folate is increased in zinc deficiency.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1986

Intracellular pteroylpolyglutamate hydrolase from human jejunal mucosa. Isolation and characterization.

Human jejunal intracellular pteroylpolyglutamate hydrolase was purified 30-fold from intestinal mucosa. The apparent molecular weight of the enzyme was 75,000 by Sephadex G-200 gel filtration, and the isoelectric point was at pH 8.0. The enzyme was maximally active at pH 4.5 and was unstable at increasing temperatures. Intracellular pteroylpolyglutamate hydrolase cleaved both terminal and internal gamma-glutamate linkages. In contrast, brush-border pteroylpolyglutamate hydrolase catalyzed the hydrolysis of only terminal gamma-glutamate linkages. The intracellular enzyme showed greatest affinity for the complete folic acid molecule with longer glutamate chains. Subcellular fractionation studies showed the intracellular enzyme was localized in lysosomes. These data show that the properties of human jejunal intracellular pteroylpolyglutamate hydrolase are distinct from those of the brush-border enzyme but are similar to the properties of intracellular pteroylpolyglutamate hydrolase described in other tissues.

Carboxypeptidases↗
PubMed1986

Pteroylpolyglutamate hydrolase from human jejunal brush borders. Purification and characterization.

Pteroylpolyglutamate hydrolase was solubilized with Triton X-100 from human jejunal mucosal brush borders and purified approximately 5,000-fold using organomercurial affinity chromatography, DEAE-cellulose chromatography, and gel filtration. The apparent molecular weight of the purified enzyme in the Triton micelle was estimated as 700,000 using Bio-Gel A-1.5m gel filtration. Sodium dodecyl sulfate/urea-polyacrylamide gel electrophoresis followed by Coomassie stain demonstrated two polypeptide bands at 145,000 and 115,000 daltons. The purified enzyme had an isoelectric point of 7.2, was maximally active at pH 5.5, and was stable above pH 6.5 and at temperatures up to 65 degrees C for at least 90 min. Human jejunal brush-border pteroylpolyglutamate hydrolase is an exopeptidase which liberated [14C]Glu as the sole labeled product of PteGlu2[14C]Glue (where PteGlun represents pteroylpolyglutamate), failed to liberate a radioactive product from PteGlu2[14C]GluLeu2, and released all possible labeled PteGlun products during incubation with Pte[14C]GluGlu6 with the accumulation of Pte[14C]Glu. PteGlu2, PteGlu3, and PteGlu7 were substrates, each with Km = 0.6 microM, whereas PteGlu was a weak inhibitor of the hydrolysis of PteGlu3 with Ki = 20 microM. Components of the pteroyl moiety, Glu, and short chain Glun in alpha or gamma linkages were not inhibitory. The enzyme was activated by Zn2+ or Co2+. The properties of brush-border pteroylpolyglutamate hydrolase are different from those described for the soluble intracellular pteroylpolyglutamate hydrolase in other species and in human mucosa, yet are consistent with previous data on the process of hydrolysis of PteGlun in the intact human intestine.

Carboxypeptidases↗
PubMed1986

Complications of parenteral nutrition.

All hospitalized patients except infants (a total of 1,647 patients) who received central venous TPN solutions at UCDMC from 1981 through 1985 were studied to determine the incidence of complications from the use of TPN. A complication was considered to have occurred if the patient experienced obvious morbidity, mortality, or both; an event known to be deleterious, despite a lack of demonstrable morbidity; or premature loss of the central venous catheter. Complications related to catheter placement occurred in 5.7 percent of patients, sepsis in 6.5 percent, mechanical complications in 9 percent, and metabolic complications in 7.7 percent. The incidence of induction of sepsis increased during 1984 to 1985 due to the introduction of multilumen central venous catheters. The most frequent catheter placement complications were hemorrhage and pneumothorax. Major venous thrombosis and nursing mishaps were the most common mechanical complications. Metabolic complications were infrequent and were generally not severe after adjustment of the protocol in late 1981. Four patients (0.2 percent) died from TPN-associated complications: a child on home TPN who underwent a catheter change and in whom hyperosmolar hyperglycemic coma developed, a patient with end-stage chronic obstructive pulmonary disease in whom tension pneumothorax occurred, a patient who died from complications of subclavian artery laceration, and a patient who died from Candida septicemia. Complications of TPN are frequent and may be severe. Quality assurance mechanisms for identification of these complications are necessary and should form the basis for the establishment of appropriate protocols.

Acidosis↗
PubMed1986

Folate binding and hydrolysis by pig intestinal brush-border membranes.

The intestinal absorption of dietary polyglutamyl folate involves hydrolysis, binding, and transport at the brush-border surface of the enterocyte. We studied the binding of [3H]folic acid ([3H]PteGlu) and the hydrolysis of [14C]pteroyltriglutamate ([14C]PteGlu3) by use of brush-border vesicles prepared from pig jejunal mucosa. [3H] PteGlu associated with the vesicles was not affected by increasing the osmolarity of the incubation solution, verifying that the experiments describe binding and not transport of PteGlu. The binding of [3H]PteGlu was saturable (Kd = 0.08 microM) and pH dependent with maximal binding at pH 5.2. Binding was competitively inhibited by PteGlu3 (Ki = 0.25 microM) and 5-methyltetrahydrofolate (Ki = 0.8 microM) but was not affected by components of the PteGlu molecule. ZnCl2, MgCl2, and MnCl2 enhanced the binding capacity but not the affinity of the binding component for PteGlu. We distinguished the processes of folate binding and hydrolysis by demonstrating differences in metal ion requirements and susceptibilities to various inhibitors. In addition, the binding component and the hydrolytic enzyme had distinct affinities for PteGlu (Ki = 45 microM for PteGlu3 hydrolysis). These data demonstrate pH-dependent, specific, and saturable binding of PteGlu to the intestinal brush-border membrane and suggest that the binding component is separate from the hydrolytic enzyme.

Animals↗
PubMed1986

Clinical studies of intestinal folate conjugases.

Clinical differences between the two human intestinal mucosal folate conjugases were assessed by measurement of their activities in normal individuals and in patients with chronic diarrhea of differing causes. Intracellular folate conjugase (ICFC) was 15-fold more active than brush border folate conjugase (BBFC) in jejunal mucosa from seven obese patients undergoing elective gastric bypass surgery. The activity of ICFC was similar among normal volunteers and patients with diarrhea of unknown origin (DUO), gluten-sensitive enteropathy (GSE), inflammatory bowel disease (IBD), and the short bowel syndrome (IBD-SBS). By contrast, BBFC, sucrase, and lactase were decreased significantly in GSE, and BBFC was increased in IBD-SBS. The activity of BBFC correlated with lactase and with sucrase in the normal subjects and in patients with DUO, whereas no correlations were found with the activity of ICFC in any group. Our clinical studies confirm that ICFC and BBFC are different enzymes. ICFC is not affected by intestinal disease, whereas the activity of jejunal BBFC, like that of other brush border enzymes, is decreased by mucosal injury and is also capable of adapting to distal small intestinal disease or surgical resection.

Adult↗
PubMed1985

Clinical and nutritional implications of radiation enteritis.

The clinical and nutritional significance of radiation enteritis was assessed in eight patients with chronic diarrhea which followed curative doses of radiotherapy for pelvic malignancies. Steatorrhea, found in seven malnourished patients, was ascribed to ileal disease or previous surgery, or to bacterial contamination of the small intestine. Lactose intolerance, assessed by breath hydrogen excretion after oral lactose and by jejunal lactase levels, was found in six patients. In a subgroup of five patients, the administration of two different defined formula liquid diets by nasoduodenal infusion decreased fecal fluid and energy losses by about one-half. Compared to Vivonex-HN, the infusion of Criticare-HN was associated with greater likelihood of intestinal gas production but a three-fold greater utilization of protein. Intestinal malabsorption and malnutrition in radiation enteritis has diverse etiologies. Whereas nutritional support by liquid diet limits fecal fluid and energy losses, these diets differ significantly in clinical tolerance and biologic value.

Adult↗
PubMed1985

Changes in hepatic superoxide dismutase activity in alcoholic monkeys.

The hepatic concentrations of copper, zinc and manganese, the activity of the mitochondrial enzyme manganese-superoxide dismutase (MnSOD), and the activity of the cytosolic enzyme copper-zinc SOD (CuZnSOD) were measured in control and ethanol-fed monkeys. In the ethanol-fed group, liver Zn levels were decreased while the Mn concentration was increased. The activity of MnSOD was higher in the ethanol-fed group while the activity of CuZnSOD tended to be lower. The finding of increased activity of MnSOD is consistent with the finding of enlarged mitochondria and increased liver Mn in the ethanol-fed group. Increased MnSOD may reflect substrate induction, since superoxide anions are generated by ethanol metabolism. On the other hand, insufficient CuZnSOD activity may contribute to increased ethanol-induced lipid peroxidation with resultant mitochondrial damage. Thus, the chronic consumption of ethanol results in altered levels of trace minerals and SOD activities in the liver which in turn may contribute to hepatic injury.

Alcoholism↗
PubMed1985

Human intestinal folate conjugase: adaptation after jejunoileal bypass.

During intestinal absorption, dietary polyglutamyl folates are hydrolyzed to monoglutamyl folates by pteroylpolyglutamate hydrolase (folate conjugase). This enzyme is present in the brush border and intracellular fractions of human jejunal mucosa. We compared the activities of brush border and intracellular folate conjugase (BBFC and ICFC), and other mucosal enzymes in the jejunum in continuity and bypassed loop in nine patients who underwent intestinal reconstitution operations 3 to 9 yr after jejunoileal bypass. Control jejunum was obtained from seven obese patients undergoing gastric bypass surgery. Jejunal morphometry showed mucosal hyperplasia with taller villi, larger crypts, and no change in cell size in the jejunum in continuity as compared to control or bypass jejunum. In brush border fractions, specific activities of sucrase and BBFC were significantly greater in the jejunum in continuity than in the control or bypass jejunum. In contrast, the specific activities of the other brush border and intracellular enzymes, including ICFC, were similar in all three segments. This is the first evidence that BBFC, like sucrase, adapts to luminal nutrition. The difference in response of BBFC and ICFC to diet and/or pancreato-biliary secretions provides evidence that these are distinct enzymes which are regulated by different mechanisms.

Adaptation, Physiological↗
PubMed1985

Comparison of folate conjugase activities in human, pig, rat and monkey intestine.

Folate conjugase, an intestinal enzyme that hydrolyzes dietary polyglutamyl folate to the absorbable monoglutamyl derivative, is present in two locations in human jejunal mucosa: one on the brush border membrane, the other soluble and intracellar. Although the brush border enzyme has not been found in the rodent, a recent study demonstrated both brush border and intracellular folate conjugases in the pig with properties similar to the human enzymes. To confirm and expand these data, we compared folate conjugase activities in intestinal brush border and 30,000 X g supernatant fractions in human, pig, rat and monkey mucosa. In both the human and pig, brush border folate conjugase was active from pH 4.5 to 8.5, and activity was significantly increased by zinc acetate. In contrast, folate conjugase activity was negligible in rat and monkey mucosal brush borders. Intracellular folate conjugase was maximally active at pH 4.5 in the human, pig and monkey, whereas this enzyme was equally active from pH 4.0 to 7.5 in the rat. In each species, supernatant activity at pH 4.5 was completely inhibited by p-hydroxymercuribenzoate. Although folate conjugase was quantitatively more active in the human than in the pig intestine, the brush border and intracellular enzymes exhibited similar properties. Sucrase, lactase and aminopeptidase activities were also similar in the two species. Our data show marked species differences in mucosal folate conjugase activities and indicate that the pig may be a suitable experimental animal for further studies of folate hydrolysis and absorption in humans.

Acetates↗
PubMed1984

Alcohol and the gastrointestinal tract.

The effects of acute and chronic ethanol ingestion on esophageal motility and the potential complications of these alterations are reviewed. Injury to the gastric mucosa and the small intestine and alterations in intestinal absorption can also result from alcohol abuse.

Alcoholic Intoxication↗
PubMed1984

Effect of age on poly- and monoglutamyl folacin absorption in human subjects.

Intestinal folacin absorption and mucosal conjugase activities were assessed in healthy male elderly (65-83 years) and young (20-29 years) human subjects. Luminal disappearance as measured simultaneously from the perfused jejunum of 3 mumol of both [3H]pteroylmonoglutamate [( 3H]PG-1) and pteroyl-[14C]glutamyl-hexaglutamate [( 14C]PG-7) as well as the urinary recovery of each isotope and mucosal conjugase activities were compared. Luminal disappearance of either [3H]PG-1 or [14C]PG-7 was not different for the two age groups (P greater than 0.05). The average (mean +/- SD) disappearance of [3H]PG-1 was 63 +/- 12% in the elderly and 67 +/- 6% in the young groups. In contrast, the disappearance of [14C]PG-7 averaged 51 +/- 6% in the elderly and 48 +/- 3% in the young group. Urinary recovery (percent in 48 hours) was not different for either isotope when the two age groups were compared (P greater than 0.05). The urinary recovery of 3H averaged 60 +/- 21% in the elderly and 59 +/- 13% in the young in contrast to 35 +/- 22% and 35 +/- 7% for 14C recovery in the elderly and young groups, respectively. Folacin conjugase activities measured at pH 6.5 and at pH 4.5 were not different between the groups (P greater than 0.05). The findings indicate that intestinal absorption of folacin and activity of folacin conjugases are not affected by the aging process.

Adult↗
PubMed1983

Experience with home parenteral nutrition.

Twenty-nine patients underwent courses of home parenteral nutrition therapy ranging from 1.5 to 52 months (mean 14.5 months). The primary diagnoses responsible for the requirement of home parenteral nutrition were radiation enteritis in seven patients, short bowel syndrome secondary to resection in seven, Crohn's disease in two, malabsorption states in six, and other reasons in seven. Seventeen patients (57 percent) had at least one complication. Nine patients had intravenous catheter complications and nine had metabolic complications. Nine patients have died, 11 have been successfully weaned from home parenteral nutrition, and 9 continue to receive home parenteral nutrition. Home parenteral nutrition is useful in a variety of catastrophic clinical situations, including preparation for subsequent operative therapy, temporary malabsorption, and permanent disability of the gastrointestinal tract. Complications are frequent and may be life-threatening.

Adolescent↗
PubMed1983

Folate turnover in chronically alcoholic monkeys.

To study the pathogenesis of folate deficiency in chronic alcoholism, monkeys were fed nutritionally complete liquid diets containing 50% of energy as ethanol for 4 years. The initial excretion and subsequent turnover of a tracer dose of intramuscular 3H-folic acid was measured during a 25-day period prior to autopsy. Within the first 3 days, the excretion of tritium in the urine and feces was significantly greater in the ethanol-fed monkeys than in their pair-fed controls, and most of the folate recovered in the urine of the third day was unchanged 3H-folic acid. Analysis of total body tritium retention revealed a rapid phase of elimination (0 to 3 days), in which the half-time of elimination was shorter in the ethanol-fed group, and a slow phase (4 to 25 days) with similar half-times of elimination. At autopsy, the levels and total amounts of endogenous folates in the liver were decreased in the ethanol-fed monkeys, as was the recovery of tritium. These studies suggest that folate deficiency in chronic alcoholism is caused in part by increased urinary and fecal losses and resultant decreased hepatic incorporation of exogenous folate whereas long-term folate turnover is unchanged.

Alcoholism↗