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PubMedDate not supplied

Gastric intrinsic factor hypersecretion stimulated by pentagastrin in cystic fibrosis.

The gastric pentagastrin-stimulated secretions of acid (peak acid output) and of unsaturated intrinsic factor in eight cystic fibrosis patients (1.4 +/- 0.5 mEq/kg/h and 0.27 +/- 0.12 nmol/kg/h, respectively) were significantly enhanced (p less than 0.05) when compared with six normal controls (0.27 +/- 0.16 mEq/kg/h and 0.10 +/- 0.02 nmol/kg/h, respectively). Despite the gastric hypersecretion of intrinsic factor, no significant physicochemical modification of this glycoprotein was observed in cystic fibrosis when using gel filtration and isoelectrofocusing. Haptocorrin (a cobalamin glycoproteic binder that does not promote the assimilation of cobalamin) also increased in gastric juice after stimulation. Since the sequestration of cobalamin to haptocorrin is pH dependent, the gastric acid hypersecretion observed in cystic fibrosis may explain that the malabsorption of crystalline cobalamin is much more frequent in cystic fibrosis than in chronic pancreatitis.

Adolescent↗
PubMed1990

Physicochemical characterization and biological activity of intrinsic factor in cystic fibrosis.

Absorption of crystalline labeled cobalamin is strongly decreased in cases of cystic fibrosis. In order to determine if this is due to an alteration or a lack of activation of intrinsic factor by proteases, the physicochemical properties and biological activity of intrinsic factor have been studied. Intrinsic factor was purified 800-fold from stimulated gastric juice of cystic fibrosis patients with a yield of 64.2%. Cystic fibrosis intrinsic factor had an estimated Mr of 57,000 in SDS-polyacrylamide gel electrophoresis. Its carbohydrate content resembled that of normal human intrinsic factor, except that the ratio fucose/sialic acid was higher (6.1 and 1.6, respectively) and that the content in N-acetylgalactosamine was decreased. The same alterations in carbohydrate composition were observed for Hc purified from cystic fibrosis saliva. Purified intrinsic factor from cystic fibrosis gastric juice was biologically active in vitro in the presence of ileal solubilized receptor as well as in vivo (Schilling test). The fate of iodinated cystic fibrosis intrinsic factor in guinea pig ileum studied by high-resolution radioautography was similar to that of normal intrinsic factor. In conclusion, despite modifications of the carbohydrate content of the molecule, the biological activity of intrinsic factor is not altered in cases of cystic fibrosis. The malassimilation of crystalline cobalamin observed in cystic fibrosis is due to a mechanism independent from intrinsic factor secretion.

Animals↗
PubMed2002

Mechanisms of vitamin B(12) absorption in breast-fed infants.

OBJECTIVES: The mechanisms of vitamin B(12) absorption in infants are unknown. We investigated whether haptocorrin (HC), a vitamin B(12) -binding protein in human milk, facilitates vitamin B(12) absorption during the neonatal period or if it occurs by a process similar to that in adults involving another vitamin B(12) -binding protein, intrinsic factor (IF). METHODS: To determine whether HC or IF can deliver vitamin B(12) to the enterocyte, binding studies using Caco-2 intestinal cells in culture and purified human milk HC-[ (57)Co]vitamin B(12) or [(125)I]IF-vitamin B(12) were performed. Determination of IF secretion by infant stomach was investigated by a competitive ELISA on fecal extracts from breast-fed infants. Determination of receptors specific for IF-vitamin B(12) or HC-vitamin B(12) in infant intestine was achieved by ligand blot analysis using isolated brush border membrane vesicles (BBMV) from fetal and adult intestine and Caco-2 cells. PCR was performed to identify the IF receptor gene transcript in Caco-2 cells and fetal intestine. RESULTS: Limited binding of both HC and IF to Caco-2 cells was observed; however, HC displayed affinity to low molecular weight proteins in BBMV from fetal intestine and Caco-2 cells while IF showed affinity for a 240 kDa protein in BBMV from fetal intestine and Caco-2 cells. IF receptor gene transcript was identified in fetal intestine and Caco-2 cells. An increase in IF excretion from breast-fed infants throughout early life was observed. CONCLUSIONS: An IF-dependent vitamin B(12) absorption mechanism appears to be in place in breast-fed infants. However, IF levels may be too low in early life to participate in vitamin B(12) absorption; therefore, haptocorrin may mediate vitamin B(12) absorption until the absorption function can be taken over by a more mature IF system.

Asialoglycoprotein Receptor↗
PubMed2003

Predictors of cobalamin deficiency in Guatemalan school children: diet, Helicobacter pylori, or bacterial overgrowth?

OBJECTIVES: The authors investigated whether low vitamin B12 intake, impaired gastric function, infection, and bacterial overgrowth were risk factors for the high prevalence of cobalamin deficiency observed in Guatemalan children. METHODS: The plasma cobalamin concentration of 556 school children was measured and classified as low, marginal, or adequate. In 60 children from each of these three groups, concentrations of serum methylmalonic acid (MMA), plasma homocysteine, and plasma holotranscobalamin II were measured, and usual dietary B12 intake was estimated. Serum gastrin and pepsinogen I concentrations were measured, and and bacterial overgrowth were diagnosed using C-urea and C-xylose breath tests, respectively. RESULTS: infection was present in 83% (144 of 174) of children, and bacterial overgrowth was found in 25% (28 of 113). Children with infection had higher serum gastrin and pepsinogen I. There were no significant differences among the plasma cobalamin groups in the prevalence of infection, bacterial overgrowth, serum gastrin, or pepsinogen I concentrations. However, there was a significant positive correlation between serum MMA and gastrin concentrations. The average daily consumption of dietary B12 was 5.5 +/- 5.2 microg/day, but intakes for 23% of children were <1.8 micro g/day. B12 intake from fortified snacks added an additional 0.3 +/- 0.2 microg/day. B12 intake was not significantly different among the plasma cobalamin groups, but it was significantly correlated with plasma cobalamin. CONCLUSIONS: The specific cause of cobalamin deficiency in this population remains unclear, but these results suggest that low dietary B12 intake is a risk factor and alterations in gastric secretions may also play a role.

Analysis of Variance↗
PubMed2004

The multiassembly problem: reconstructing multiple transcript isoforms from EST fragment mixtures.

Recent evidence of abundant transcript variation (e.g., alternative splicing, alternative initiation, alternative polyadenylation) in complex genomes indicates that cataloging the complete set of transcripts from an organism is an important project. One challenge is the fact that most high-throughput experimental methods for characterizing transcripts (such as EST sequencing) give highly detailed information about short fragments of transcripts or protein products, instead of a complete characterization of a full-length form. We analyze this "multiassembly problem"-reconstructing the most likely set of full-length isoform sequences from a mixture of EST fragment data-and present a graph-based algorithm for solving it. In a variety of tests, we demonstrate that this algorithm deals appropriately with coupling of distinct alternative splicing events, increasing fragmentation of the input data and different types of transcript variation (such as alternative splicing, initiation, polyadenylation, and intron retention). To test the method's performance on pure fragment (EST) data, we removed all mRNA sequences, and found it produced no errors in 40 cases tested. Using this algorithm, we have constructed an Alternatively Spliced Proteins database (ASP) from analysis of human expressed and genomic sequences, consisting of 13,384 protein isoforms of 4422 genes, yielding an average of 3.0 protein isoforms per gene.

Algorithms↗
PubMed1983

Enhanced release of inflammatory mediators from lithium-stimulated neutrophils in psoriasis.

We have used lithium salts to stimulate degranulation in order to assess neutrophil activity in psoriasis. Evidence is presented for significant enhancement of degranulation of beta-glucuronidase (primary granules) and vitamin B12-binding protein (secondary granules) from lithium-stimulated neutrophils in psoriatic whole blood. Basal levels of granule markers showed no significant difference between normal and psoriatic neutrophils. On the other hand, enzymes associated with neutrophil function (myeloperoxidase and catalase) were found to be markedly increased in resting psoriatic neutrophils.

Catalase↗
PubMed1982

Demonstration of vitamin B12 analogues in human sera not detected by microbiological assay.

Sera were absorbed with polyacrylamide beads to which purified human intrinsic factor was attached. This procedure removed the vitamin B12 analogues which are measured by microbiological assay with Lactobacillus leichmannii and Euglena gracilis and which are measured in an isotope dilution method using intrinsic factor. Such sera still contained B12 analogues that were assayed in an isotope dilution method using a non-intrinsic factor vitamin B12 binder. Such vitamin B12 analogues make up approximately half of the total vitamin B12 analogues in human serum.

Biological Assay↗
PubMed1983

The effects of surgery on the activity of neutrophil granule proteins.

Activities of the neutrophil granule-associated proteins beta-glucuronidase, lysozyme and vitamin B12 binding protein were measured, serially, in the cells and serum of 10 patients undergoing total abdominal hysterectomy. The neutrophil leucocytosis which followed total abdominal hysterectomy was accompanied by a fall in the intraneutrophilic activities of all three granule-associated proteins. Intraneutrophilic lysozyme activity and intraneutrophilic vitamin B12 binding capacity were maximally reduced within 4 h of surgery and fell to 62 +/- 13% (mean +/- SEM) and 63 +/- 9% of their preoperative levels, respectively. This contrasted with the activity of intraneutrophilic beta-glucuronidase which was not maximally reduced until 24 h post-surgery when a fall to 80 +/- 6% of the preoperative level was observed. By the fifth postoperative day activities of the three intraneutrophilic granule proteins were increasing and approaching those observed preoperatively. Serum lysozyme and plasma unsaturated vitamin B12 binding capacity (UBBC) rose steadily following surgery and were significantly elevated by the fifth postoperative day. It is suggested that activation and in vivo degranulation of circulating neutrophils may be responsible for these changes in activity of neutrophil granule proteins following surgery.

Adult↗
PubMed1987

Development of the phagocytic and cidal capacity during maturation of myeloid cells: studies on cells from patients with chronic myelogenous leukaemia.

Myeloid cells from peripheral blood of patients with chronic myelogenous leukaemia were isolated and fractionated by density gradient centrifugation using Lymphoprep gradient followed by discontinuous Percoll gradients. Six fractions were obtained, each enriched in one of the morphologically identifiable types of myeloid cells from myeloblasts to polymorphonuclear neutrophils. Each of these cell types were functionally and biochemically characterized. The development of the capacities for phagocytosis and killing of yeast cells and the ability to generate a respiratory burst of phagocytosis correlated closely with the content of cytochrome b and vitamin B12-binding protein, a marker of specific granules. These results support the notion that the specific granules provide the developing neutrophil with components which are essential for its microbicidal activity.

Blood Bactericidal Activity↗
PubMed2005

Holotranscobalamin--a first choice assay for diagnosing early vitamin B deficiency?

OBJECTIVES: The performance of holotranscobalamin (holoTC) was compared with the other markers of vitamin B12 deficiency, and the influence of age, renal function, and thyroid status was examined. DESIGN AND INTERVENTIONS: We examined 937 individuals not treated with vitamin B12 but in whom vitamin B12 deficiency was suspected because of a plasma methylmalonic acid (MMA) above 0.28 micromol L(-1) within the past 4 years. Besides laboratory tests, a structured interview and a neurological examination were performed amongst 534 individuals. Amongst these, 140 individuals qualified for a randomized trial (MMA 0.40-2.00 micromol L(-1)). They were randomized to injections with vitamin B12 or placebo and re-examined after 3 months. SETTING: One university hospital in Aarhus, Denmark. RESULTS: The ROC curves indicate that holoTC (AUC: 0.90) compared favourable with plasma vitamin B12 (AUC: 0.85) for identifying individuals likely to have vitamin B12 deficiency (MMA > or =0.75 micromol L(-1) and plasma total homocysteine (tHcy) > or =15 micromol L(-1)), and further that holoTC (AUC: 0.91) might replace combined testing with plasma vitamin B12 and the metabolites. No association was observed between the biochemical markers and symptoms and signs possibly related to vitamin B12 deficiency. HoloTC, TC saturation, plasma vitamin B12, MMA, and tHcy were significantly associated with plasma creatinine (all with P <0.001). Only tHcy was significantly associated with thyroid stimulating hormone (P=0.02). CONCLUSIONS: HoloTC shows promise as first-line tests for diagnosing early vitamin B12 deficiency.

Adult↗
PubMed1990

Mixed enzyme-linked immunosorbent assay (MELISA) for HLA class I antigen: a plasma membrane marker.

This study introduces a simple, reproducible assay for HLA class I antigen using antibodies against beta 2-microglobulin and the heavy chain on HLA. The sandwich technique was named mixed enzyme-linked immunosorbent assay (MELISA), and was designed for identification of plasma membranes in neutrophil subcellular fractions. The subcellular localization of HLA was identical to that of other plasma membrane markers, [3H]concanavalin A and detergent-independent alkaline phosphatase, and was unchanged by stimulation of cells by weak and strong secretagogues. In addition to the presence as part of the HLA complex in the plasma membrane uncomplexed beta 2-microglobulin is present in the specific granules of neutrophils. However, the release of beta 2-microglobulin from intact neutrophils stimulated with formyl-methionylleucylphenylalanine was much higher than could be explained by exocytosis of specific granules. Subcellular fractionation studies demonstrated that beta 2-microglobulin is localized in fractions characterized by latent alkaline phosphatase and released from this novel secretory compartment in response to stimulation with formyl-methionylleucylphenylalanine.

Alkaline Phosphatase↗
PubMed1990

Isolation and characterization of a cDNA encoding porcine gastric haptocorrin.

A cDNA encoding the gastric haptocorrin was isolated from a porcine gastric mucosal lambda gt11 cDNA library using oligonucleotide probes. The 1.4-kb cDNA contains a 1.25-kb open reading frame and 178 nucleotides of 3' noncoding region. Although no initiator methionine is present, primer extension analysis indicated that the transcription initiation site is only 100 bp upstream of the 5' end of this clone. Northern blot analysis showed that a single mRNA species of 1.6 kb exists in hog gastric mucosa. There was no cross-hybridization between this cDNA and the mRNA for haptocorrin in rat submaxillary gland or gastric RNA by Northern blot analysis. This lack of cross-reactivity was also seen on Southern blots, where cow, sheep and dog but neither rat nor mouse genomic DNAs showed cross-hybridizing bands. Comparison of the deduced amino acid sequence of this cDNA with that previously reported for rat intrinsic factor [Dieckgraefe, B.K. et al. (1988) Proc. Natl Acad. Sci. USA 85, 46-50] showed considerable similarity, suggesting that these cobalamin-binding proteins may have a common evolutionary origin.

Amino Acid Sequence↗