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Biomedical subjects

C H Halsted

Publications and source records attributed to C H Halsted.

At least 19 recordsLinked to original sources
PubMed1997

Efficacy of enzyme supplementation after surgery for chronic pancreatitis.

Although surgical procedures that improve pancreatic drainage alleviate abdominal pain in the vast majority of patients with chronic pancreatitis, postoperative absorption and nutritional status are less predictable. The present study was designed to determine the efficacy of pancreatic enzyme supplementation in maintaining postoperative digestion and nutrition in patients who had received the local resection-longitudinal pancreaticojejunostomy (LR-LPJ) procedure for chronic pancreatitis. We evaluated nutritional status and intestinal absorption in 11 patients who had undergone LR-LPJ. The efficacy of postoperative pancreatic enzyme supplementation was studied by measurements of intestinal absorption and nutritional status at baseline, after 4 weeks of individualized daily dosage of pancreatin (Creon), and after an additional 4 weeks of randomization to receive another 4 weeks of pancreatin or placebo. All patients demonstrated abnormal digestion of fat, protein, and total energy at baseline 3 weeks after surgery. Pancreatin supplementation significantly improved the coefficients of absorption of dietary fat and total energy over the next 4 weeks. Between 4 and 8 weeks, pancreatin significantly improved protein absorption and nitrogen balance, whereas placebo substitution worsened the absorption of dietary fat and total energy. Nutritional status was not significantly altered over the 8-week study period, although four patients receiving pancreatin gained more than 3.6 kg body weight. The data suggest that long-term postoperative pancreatic enzyme supplementation is both efficacious and necessary in chronic pancreatitis patients after LR-LPJ.

Adult↗
PubMed1996

Folate binding protein: molecular characterization and transcript distribution in pig liver, kidney and jejunum.

Folate-binding protein (FBP) was identified and characterized in a pig liver cDNA library by screening with a 0.6 kb fragment from the cDNA of FBP from a human KB cell cancer line. The cDNA of pig liver FBP included 1230 bp containing 759 bp in the open reading frame with 80% similarity to the human placenta FBP. The deduced 253 amino acid sequence showed 67-73% similarity to previous sequences and contained 16 conserved cysteine residues, 11 tryptophan potential folate-binding sites, three sites for N-linked glycosylation and 14 hydrophobic C-terminal residues. Northern analysis and reverse transcriptase PCR identified transcripts in pig liver and kidney, but not in jejunal mucosa. Although defining the molecular structure of pig liver FBP, these studies suggest that this protein participates in the regulation of folate uptake by liver and kidney membranes but is not involved in folate absorption.

Amino Acid Sequence↗
PubMed1996

Ethanol feeding of micropigs alters methionine metabolism and increases hepatocellular apoptosis and proliferation.

Chronic alcoholism is associated with increased cancer risk that may be related to ethanol-induced alterations in methionine and deoxynucleotide metabolism. These metabolic relationships were studied in micropigs fed diets for 12 months that contained 40% ethanol or cornstarch control with adequate folate. Ethanol feeding altered methionine metabolism without changing mean terminal liver folate levels. After initial equilibration to diet, ethanol feeding significantly increased monthly serum homocysteine levels while reducing serum methionine levels over the time course of the experiment. After 12 months, hepatic methionine synthase activity and the ratio of S-adenosylmethionine (SAM) to S-adenosylhomocysteine (SAH) were significantly reduced in ethanol-fed animals, whereas the ratio of liver deoxyuridine triphosphate (dUTP) to deoxythymidine triphosphate (dTTP) was increased and correlated inversely with methionine synthase activity. These findings were associated with increased frequency of hepatocytes with apoptotic bodies and positivity for proliferating cell nuclear antigen (PCNA) in livers from ethanol-fed minipigs. These studies suggest that chronic ethanol feeding perturbs methionine metabolism by impairment of methionine synthase activity, resulting in deoxynucleoside triphosphate (dNTP) imbalance, increased apoptosis, and regenerative proliferation. These biochemical alterations may provide a promoting environment for carcinogenesis during long-term ethanol exposure.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1995

Sequential acetaldehyde production, lipid peroxidation, and fibrogenesis in micropig model of alcohol-induced liver disease.

The pathogenesis of alcohol-induced liver disease involves the adverse effects of ethanol metabolites and oxidative tissue injury. Previous studies indicated that covalent protein adducts with reactive aldehydes may be formed in alcohol consumers. To study the role of such protein adducts in the development of liver injury, we examined the sequential appearances of adducts of the ethanol metabolite acetaldehyde (AA) and of two products of lipid peroxidation, malondialdehyde (MDA) and 4-hydroxynonenol (HNE), in ethanol-fed micropigs. Immunohistochemical stainings using specific antibodies that recognize epitopes of each adduct were performed from liver biopsy specimens obtained at 1, 5, and 12 months from micropigs fed either control diet (n = 5) or ethanol-containing diets (n = 5). After 1 month on the ethanol diet, AA and MDA adducts were observed primarily in the perivenous regions co-localizing with each other and coinciding with increased concentrations of serum aminotransferase markers of liver injury. HNE adducts were usually less intense and more diffuse, and were also seen in some biopsy specimens from control animals. Although the most intense staining reactions at 5 months remained in zone 3, a more widespread distribution was usually seen together with increased evidence of steatonecrosis and focal inflammation. In terminal biopsies at 12 months, perivenous fibrosis was present in three of five biopsy specimens. More extensive pericentral and intralobular fibrosis was noted in one micropig fed ethanol for 21 months. These studies demonstrate that covalent adducts of proteins with reactive aldehydes are formed in early phases of alcohol-induced liver disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetaldehyde↗
PubMed1994

Development of malabsorption and nutritional complications in simian immunodeficiency virus-infected rhesus macaques.

OBJECTIVE: To assess the development and cause of malabsorption in rhesus macaques following experimental simian immunodeficiency virus (SIV) infection and to evaluate its impact on nutritional status. DESIGN: Clinical malabsorption tests and serial jejunal aspirates and biopsies were obtained from nine SIV-infected and three uninfected animals prior to infection and at 1, 2, 4, 8, 12, 24, 40 and 52 weeks postinoculation. METHODS: Malabsorption was measured by sucrose breath hydrogen (H2) analysis and blood assay of D-xylose. Digestive enzyme activity was determined in jejunal mucosal homogenates. Bacterial and protozoal flora were determined in jejunal aspirates. Nutritional assessment was evaluated using specific blood micronutrient values. Cellular targets of SIV in the jejunum were determined by combined in situ hybridization and immunohistochemistry. RESULTS: Eight out of nine SIV-infected monkeys, including asymptomatic animals, exhibited malabsorption by either increased breath H2 and/or decreased blood D-xylose. All animals that died of AIDS had diarrhea, D-xylose malabsorption and decreased sucrase activity. Significant changes in nutritional status were associated with malabsorption. Bacterial overgrowth was not considered to be a cause of malabsorption. Histopathological biopsy findings included dilated villus lacteals, excessive cellular debris, lymphoplasmocytic infiltrates and cytoplasmic vacuoles in crypt epithelial cells. SIV-infected T cells and macrophages were detected as early as 1 week postinoculation. CONCLUSIONS: SIV-associated malabsorption can occur prior to clinical complications of disease. Severe intestinal complications are associated with malabsorption and malnutrition in the terminal stages of AIDS. The high proportion of macaques experiencing malabsorption without detectable pathogens, suggests an enteropathogenic role for SIV.

Animals↗
PubMed1994

Selective reduction of delta 6 and delta 5 desaturase activities but not delta 9 desaturase in micropigs chronically fed ethanol.

This study investigated the mechanism by which chronic ethanol feeding reduces arachidonate and other highly unsaturated fatty acids in pig liver phospholipids. Five micropigs were fed a diet providing 89 kcal/kg body wt for 12 mo, with ethanol and fat as 40 and 34% of energy, respectively. Five control pigs were pairfed corn starch instead of ethanol. The activities of delta 6 and delta 5 desaturases (expressed as microsomal conversion of precursor to product) in liver from ethanol-fed pigs were reduced to less than half that of controls, whereas the activity of delta 9 desaturase was unaffected in the ethanol group. delta 5 Desaturase activity showed positive correlation with the abundance of its products in liver total phospholipids and microsomes in the ethanol group, but not in the controls. Correlation between delta 6 desaturase activity and its products showed similar pattern to that of delta 5 desaturase, but did not reach statistical significance. No difference was observed between the two groups in coenzyme A concentration in the liver. These results suggest that the selective reduction of delta 6 and delta 5 desaturase activities, not the microsomal electron transport system, are directly responsible for the altered profile of liver phospholipids.

Alcoholism↗
PubMed1994

Effects of ethanol feeding on liver, kidney and jejunal membranes of micropigs.

The micropig model of chronic alcoholism was used to study the relationship of lipid composition and physical properties in three different tissue membranes from the same animals. Ethanol feeding reduced membrane anisotropy, as measured with the diphenylhexatriene probe, in liver plasma and kidney brush-border membranes but not in jejunal brush-border membranes. Preincubation with ethanol reduced anisotropy in each of the three control membranes, whereas all three membranes from the ethanol-fed group were relatively tolerant to the acute effect of ethanol. In liver and kidney membranes, ethanol feeding increased levels of linoleic (18:2 omega 6) acid and decreased levels of arachidonic (20:4 omega 6) and docosahexaenoic (22:6 omega 3) acids and their specific double-bond positions, consistent with reduced activities of delta 6 and delta 5 fatty acid desaturases. In liver and kidney membranes, anisotropy parameters and the acute effect of ethanol correlated inversely with levels of linoleic acid and directly with levels of arachidonic and docosahexaenoic acids and their specific double bonds. Levels of docosahexaenoic acid correlated with the acute effect of ethanol in all three membranes. Phospholipid fatty acid profiles were similar in jejunal brush-border membranes and terminal bile samples, suggesting that the effects of ethanol on jejunal fatty acids and physical properties are modulated by intraluminal biliary phospholipids. The effect of ethanol on anisotropy could not be attributed to changes in membrane cholesterol/phospholipid ratios. These studies affirm the value of this new animal model of chronic alcoholism and provide comprehensive evidence for the central role of fatty acid desaturation in the membrane-associated effects of ethanol exposure.

Administration, Oral↗
PubMed1993

Centrilobular distribution of acetaldehyde and collagen in the ethanol-fed micropig.

We established a new animal model of alcoholic liver disease in the micropig, a species that consumes ethanol voluntarily in the diet. Ten micropigs were pair-fed diets containing 40% of calories as ethanol or cornstarch with identical amounts of fat, protein and micronutrients for 12 mo. Liver histopathology in the ethanol-fed pigs included steatonecrosis in all five and interstitial and perivenous fibrosis in three. Electron microscopy showed Ito-cell transformation with perisinusoidal collagen accumulation. Acetaldehyde adducts were found by immunofluorescence in the centrilobular region and were focused in perivenous zone 3 of all ethanol-fed animals. Protein and triglyceride levels were increased, whereas vitamin A and iron levels were decreased in liver homogenates from ethanol-fed animals. Thus, in this new animal model of alcoholism, ethanol feeding produced the features of alcoholic liver disease concurrent with hepatic deficiency of selected nutrients. Histological and immunofluorescent studies provide in vivo evidence that perivenous collagen deposition is linked to ethanol metabolism and acetaldehyde production.

Acetaldehyde↗
PubMed1993

The body composition and lipid metabolic effects of long-term ethanol feeding during a high omega 6 polyunsaturated fatty acid diet in micropigs.

Our previous research with miniature pigs has shown that long-term ethanol feeding with a low-fat diet decreases arachidonic acid (20:4 omega 6) levels in multiple tissues, but we did not find significant liver pathology. In this study, we investigated the effect of ethanol feeding with high dietary linoleic acid (18:2 omega 6) on tissue fatty acid (FA) profiles and body composition. Five Yucatan micropigs were fed 370 kJ (89 kcal)/kg body weight of a diet containing ethanol and fat as 40% and 34% of energy, respectively; five control pigs were pair-fed corn starch in place of ethanol. Corn oil, 61% 18:2 omega 6, supplied most of the dietary fat. Liver biopsies were performed at baseline (n = 2 per group) and at three other time points (n = 5 per group). Phospholipid (PL) FA levels were measured by thin-layer and gas chromatography. Body composition was analyzed by underwater weighing of carcasses. Body composition analysis demonstrated a marked reduction of carcass fat in the ethanol group, but no significant reduction of carcass lean weight after 12 months. In liver PLs, the ethanol group showed decreased 20:4 omega 6 and docosahexaenoic acid (22:6 omega 3) after 1 month. While the decreased 20:4 omega 6 remained constant after 1 month, 22:6 omega 3 showed a progressive decrease up to 12-months, resulting in a continuous decrease of the omega 3/omega 6 FA ratio. This slowly progressive decrease in the omega 3/omega 6 ratio in liver PLs with ethanol feeding may have enhanced the inflammatory response in the liver, contributing to liver pathology. Body composition results indicate marked wasting of energy in the ethanol group.

Analysis of Variance↗
PubMed1993

Biennial survey of physician clinical-nutrition training programs.

This is the fourth survey of physician clinical-nutrition training programs. As in previous reports, current fellowship training programs were identified, descriptive information obtained, and program content surveyed. In addition, a questionnaire developed by the American Board of Nutrition Committee on Fellowship Training Programs was used to determine the degree of emphasis given to content in the areas of basic nutrition science, clinical applications, and research training. Among the 38 programs identified, uniform ratings of importance were found in all major topic areas. There was also uniformity in most subtopics, with minor exceptions. As expected, in the area of nutrition in the life cycle, pediatric training programs emphasized infancy and childhood whereas medical-surgical programs emphasized adulthood and aging. Alcoholism was emphasized in medical-surgical training programs whereas cystic fibrosis and inborn errors of metabolism were emphasized in pediatric programs. Nutrition in burn patients received minor emphasis in all programs. The overall uniformity of curricular content in training programs confirms the contention that clinical nutrition has a defined clinical scope and should be considered for establishment as a recognized subspecialty in American medicine.

Education↗
PubMed1993

Simian immunodeficiency virus infection of the gastrointestinal tract of rhesus macaques. Functional, pathological, and morphological changes.

Gastrointestinal dysfunction and wasting are frequent complications of human immunodeficiency virus (HIV) infection. Nutrient malabsorption, decreased digestive enzymes and HIV transcripts have been documented in jejunal mucosa of HIV-infected patients; however, the pathogenesis of this enteropathy is not understood. Rhesus macaques infected with simian immunodeficiency virus (SIV) also exhibit diarrhea and weight loss; therefore, we investigated the use of this animal model to study HIV-associated intestinal abnormalities. A retrospective study of intestinal tissues from 15 SIV-infected macaques was performed to determine the cellular targets of the virus and examine the effect of SIV infection on jejunal mucosal morphology and function. Pathological and morphological changes included inflammatory infiltrates, villus blunting, and crypt hyperplasia. SIV-infected cells were detected by in situ hybridization in stomach, duodenum, jejunum, ileum, cecum, and colon. Using combined immunohistochemistry and in situ hybridization, the cellular targets were identified as T lymphocytes and macrophages. The jejunum of SIV-infected animals had depressed digestive enzyme activities and abnormal morphometry, suggestive of a maturational defect in proliferating epithelial cells. Our results suggest that SIV infection of mononuclear inflammatory cells in intestinal mucosa may alter development and function of absorptive epithelial cells and lead to jejunal dysfunction.

Animals↗
PubMed1992

Reduced tissue arachidonic acid concentration with chronic ethanol feeding in miniature pigs.

The effect of ethanol feeding on the essential fatty acid content of tissues has been contradictory. To define the effect, we analyzed fatty acid profiles in various tissues from five miniature pigs fed daily 105 kJ basal diet/kg body wt and 146 kJ ethanol/kg body wt, and also five control pigs pair-fed the same amount of basal diet but with corn starch substituted for ethanol. After 12 mo, biopsy samples were taken, and tissue fatty acid profiles were analyzed. In the phospholipid fraction from the ethanol group there was a uniform decrease in arachidonic acid (AA) and an increase in oleic acid in liver, serum, and muscle. AA was consistently decreased in the triglyceride fractions of liver, serum and subcutaneous adipose of the ethanol group. Possible explanations for this general reduction in tissue AA with ethanol feeding include decreased activities of delta 6 and delta 5 desaturases, and a displacement of AA from lipid fractions by other fatty acids.

Adipose Tissue↗
PubMed1991

Human immunodeficiency virus infection of enterocytes and mononuclear cells in human jejunal mucosa.

Intestinal malabsorption is a recognized cause of malnutrition in patients infected with human immunodeficiency virus. However, the relationships among human immunodeficiency virus infection, morphological changes in the intestine, and development of intestinal malabsorption are not well established. Nine patients infected with human immunodeficiency virus underwent tests of intestinal absorption and jejunal biopsies for morphometric measurements, enzyme assays, and virus detection by in situ hybridization. Steatorrhea and low lactase activities were found in more than 85% of the patients. All biopsy specimens were abnormal with reversal of the ratio of villus length to crypt depth in seven and enlarged enterocyte nuclear size in nine. Human immunodeficiency virus was detected in five jejunal biopsy specimens, within villus enterocytes of one patient who had the most severe malabsorption of the group and in four other biopsy specimens in mononuclear infiltrating cells of the lamina propria. These results suggest that human immunodeficiency virus infection of the small intestinal mucosa is an early event that is associated with altered enterocyte differentiation and function.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Functional specificity of jejunal brush-border pteroylpolyglutamate hydrolase in pig.

To determine the functional specificity of intestinal brush-border pteroylpolyglutamate hydrolase (PPH), we compared the regional location of in vivo hydrolysis of pteroyltriglutamate (PteGlu3) with the location of activity and immunoreactivity of the enzyme in the pig. After in vivo incubations, PteGlu3 hydrolytic products were recovered from intestinal segments in the jejunum but not from the ileum. Brush-border PPH activity in fractionated mucosa was 10-fold greater in the jejunum than in the ileum, whereas the activity of intracellular PPH was increased in the distal ileum. Antibodies to purified brush-border PPH identified a major protein band at 120 kDa and a minor protein band at 195 kDa in solubilized jejunal brush border. Immunohistochemistry identified the enzyme only on the brush-border surface of the jejunum, whereas an immunoblot of solubilized brush-border membranes identified brush-border PPH in the jejunum but not in the ileum. The parallel of the regional location of in vivo hydrolysis of PteGlu3 with the location of brush-border PPH activity and immunoreactivity demonstrates the functional specificity of this enzyme in folate digestion.

Animals↗
PubMed1991

Jejunal brush-border folate hydrolase. A novel enzyme.

Dietary folate, a vitamin required for DNA synthesis and cell regeneration, occurs as pteroylpolyglutamates that are hydrolyzed to pteroylglutamate during the process of intestinal absorption. Studies from our laboratory over the past 15 years have shown that jejunal brush-border folate hydrolase is essential and rate-limiting in folate absorption. Brush-border folate hydrolase activity and pteroylpolyglutamate hydrolysis are inhibited in disease and conditions associated with folate deficiency, including celiac and tropical sprue, the use of sulfasalazine to treat inflammatory bowel disease, and chronic alcoholism. Brush-border folate hydrolase is an exopeptidase located on the jejunal brush-border surface that liberates hydrolytic products of pteroylpolyglutamates in a progressive fashion, with a final release of pteroylglutamate. Subsequent steps in folate absorption include uptake by a brush-border folate-binding-protein receptor and transport across the brush-border membrane into the enterocyte. These steps are probably followed by an intracellular synthesis of pteroylglutamates for folate-dependent reactions and intracellular hydrolysis to pteroylglutamate for transport across the basolateral membrane to the portal circulation. In pigs, the active form of jejunal brush-border folate hydrolase has a molecular weight of 240 kd and is probably a homodimer of the 120-kd protein found after immunoprecipitation with specific antibody. Regulating the synthesis and expression of brush-border folate hydrolase may be critical to the availability of dietary folate.

Alcoholism↗