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[The significance of an elevated cobalamin concentration in the blood].

Elevated levels of serum cobalamin may be a sign of a serious, even life-threatening, disease. Diseases such as chronic myeloid leukaemia, promyelocytic leukaemia, polycythaemia vera and hypereosinophilic syndrome are often accompanied by markedly elevated levels of cobalamin in the blood. A rise in the serum cobalamin concentration is one of the diagnostic criteria for polycythaemia vera and hypereosinophilic syndrome. In haematological disorders, the increase in circulating cobalamin levels is predominantly caused by enhanced production of haptocorrin. Several liver diseases such as acute hepatitis, cirrhosis of the liver, hepatocellular carcinoma and metastatic liver disease can also be accompanied by an increase in circulating cobalamin. In liver diseases, the increase in cobalamin is predominantly caused by cobalamin release during hepatic cytolysis and/or through decreased clearance of circulating cobalamin by the affected liver. Liver disorders are not an indication for determining the serum cobalamin concentration. However, a coincidentally observed elevated serum cobalamin concentration is reason for further investigation.

Hematologic Diseases↗

Longitudinal concentrations of vitamin B(12) and vitamin B(12)-binding proteins during uncomplicated pregnancy.

BACKGROUND: Because reference values for vitamin B(12) concentrations and vitamin B(12)-binding capacities for pregnant women have not been established, the reference values for nonpregnant women are often applied to assess vitamin B(12) status. The aim of the present study was to describe ranges of biochemical indices of vitamin B(12) status, including red blood cell (RBC) vitamin B(12), saturated and unsaturated cobalamin-binding proteins, and binding capacities in all trimesters of uncomplicated pregnancy. METHODS: A total of 39 healthy pregnant women with long-term daily intake of vitamin B(12) >2.6 microg/day and uncomplicated pregnancies participated in the study throughout their pregnancies. RBCs and serum vitamin B(12), holo-haptocorrin, unsaturated cobalamin-binding proteins, unsaturated and total vitamin B(12)-binding capacities, total homocysteine (tHcy), and RBC count were assessed in weeks 9-12, 20-22, and 36-38 of gestation. RESULTS: Significant changes in vitamin B(12) status occurred in the course of pregnancy. Serum vitamin B(12) concentrations and percentage of saturation of vitamin B(12)-binding proteins decreased steadily throughout pregnancy. In the third trimester, 35% of the participants had serum vitamin B(12) concentrations <150 pmol/L and 68.6% had <15% saturation of total vitamin B(12)-binding capacities, but no women had RBC vitamin B(12) concentrations <148 pmol/L. However, the decrease in these indices was not associated with reduced hemoglobin concentrations or RBC count or with increased tHcy concentrations. CONCLUSIONS: Our findings suggest that the reference values for vitamin B(12) status in nonpregnant women may not be applicable to pregnant women.

Diet↗

[The intraluminal transport of vitamin B12].

Since the existence of vitamin B12 was suggested by Castle in the first few decades of this century, vitamin B12 has been the subject of many studies which have proved the high complexity of its assimilation by the organism. Over the last few years the marked progress in functional digestive exploration methods and the physical and the chemical characteristics of biological molecules have revived the established idea of the vitamin's intraluminal transit. Our recent studies have been concentrated on the bilio-duodenopancreatic stage of the vitamin B12 transport. In nature, vitamin B12 is only exceptionally met in its free form, it is always associated with a binder. Like a ball being passed from one player to another it moves between binders. Alimentary vitamin B12 released from its protein complexes by culinary preparation and gastric secretions, is combined with haptocorrin. In the duodenum the transfer of B12 on intrinsic factor is due to partial degradation of haptocorrin by pancreatic enzymes and intraluminal pH balance. Then combined with intrinsic factor the vitamin can be caught by the ileal receptor. The partial degradation haptocorrin joins vitamin B12 analogs from excreted bile or synthesized by the intestinal microorganisms.

Biological Transport↗

Signal transduction mechanisms of C1q-mediated superoxide production. Evidence for the involvement of temporally distinct staurosporine-insensitive and sensitive pathways.

C1q, a plasma glycoprotein and the recognition component of the classical complement pathway, interacts with specific cells of the immune system resulting in the enhancement of cell function. For example, interaction of C1q with its cell-surface receptor on neutrophils induces the activation of the respiratory burst, a finding previously documented using a chemiluminescent assay to detect oxygen radical formation. In an alternative approach we have now used a modified cytochrome c reduction assay to characterize C1q-mediated production of superoxide anion (O2-) in more detail. C1q coated to microtiter wells induced O2- release, which occurred microtiter wells induced O2- release, which occurred after a lag period of 10 to 20 min, and was then sustained over approximately 1 h. O2- production could be triggered by the purified pepsin-resistant, collagen-like fragment of C1q, but not by mannose-binding protein and pulmonary surfactant protein A, proteins that also contain collagen-like domains. Concentrations of C1q which promoted a vigorous O2- generation did not induce release of neutrophil primary granules and caused little or no secondary granule release. Investigation of the biochemical events mediating C1q stimulated O2- production by neutrophils revealed that the response invoked two biochemical pathways with distinct sensitivities to previously described inhibitors. A role for Ca2+ in initiation of the response was suggested by the inhibitory effect of EGTA, the calmodulin antagonist W7, and the intracellular Ca2+ chelator BAPTA. The protein kinase inhibitor staurosporine did not inhibit the induction of the response, but did block that component of the response occurring after approximately 30 min. Neither phase of C1q-mediated O2- production was inhibited by pertussis toxin, a strong inhibitor of the G-protein-coupled FMLP-mediated response. In summary, C1q-triggered O2- production is relatively unique both in terms of the kinetics of the response and the biochemical pathways evoked. These data support the hypothesis that more than one biochemical pathway induced by ligand-receptor interaction can activate the neutrophil NADPH oxidase.

Alkaloids↗

Correlation of messenger RNA levels with protein defects in specific granule deficiency.

Neutrophil specific granule deficiency (SGD) is a rare congenital disorder of unknown cause associated with an impaired inflammatory response and an absence of neutrophil secondary granules. Reduced levels of several neutrophil proteins have led to the suggestion that the defect may lie at the level of transcription, a hypothesis that is supported by abnormally low levels of lactoferrin message in the bone marrow of two SGD patients. We have examined the level of seven granule protein RNAs in one SGD patient and have compared them with reported protein levels. We have found the RNA levels for all of these genes to be reduced in proportion to the decreased levels of their respective proteins. These data further support the hypothesis that the reduced protein levels reflect a defect in transcriptional control.

Blood Proteins↗

[R proteins as a reflection of disorders in the cellular reception mechanisms in kidney diseases].

As many as 47 patients with amyloidosis and 31 with chronic glomerulonephritis (CGN) were examined for the blood serum content of R proteins, chemotactic activity of blood leukocytes and the degree of the inhibitory influence of the autologous serum on chemotaxis. Amyloidosis and CGN were marked by an increase of the level of receptor proteins. A reverse correlation was established between the rise of the content of R proteins and the chemotactic properties of leukocytes. In CGN, the rate of demonstration of the high titers of R proteins and the magnitude of the chemotaxis decline depended on the disease phase (the degree of activity) whereas in amyloidosis, these reactions differed insignificantly in patients with various clinical patterns and stages of renal amyloidosis.

Adolescent↗

[Generation of superoxide anion and lipid peroxidation in serum of gout patients].

Alterations in content of lipid peroxidation products, reactions of generation/interception of superoxide anion radicals, content of R-proteins and uric acid were studied in blood serum of 83 patients with gout depending on the disease activity. Rates of lipid peroxidation, estimated by content of thiobarbituric acid-positive products, and of superoxide anion generation as well as content of R-proteins correlated distinctly with activity of the inflammation. At the same time, content of uric acid in blood serum of these patients correlated reversely with content of the lipid peroxidation products at the disease preexacerbation period, while concentration of these products depended on content of total iron.

Anions↗

The reduction of cytochrome b558 and the activity of the respiratory burst oxidase from human neutrophils.

It is known that in respiratory burst oxidase preparations engaged in O2- production, cytochrome b558, a characteristic oxidase component, is partly reduced. This result has been interpreted in terms of a mechanism in which cytochrome b558 functions as an electron-carrying component of the respiratory burst oxidase, its level of reduction reflecting a steady-state partitioning of the cytochrome between reduced and oxidized forms as it ferries electrons from NADPH to oxygen. Kinetic arguments based on this interpretation have supported the proposal that the cytochrome is reduced at a rate sufficient to account for the rate of O2- production by activated neutrophils. We have confirmed the partial reduction of cytochrome b558 in neutrophil cytoplasts and in oxidase preparations exposed to NADPH, but have found that the reduction of the cytochrome bears no apparent relation to the activity of the oxidase, and can occur when NADPH is added to neutrophil membrane preparations that are unable to manufacture O2-. We therefore conclude that the NADPH-dependent reduction of cytochrome b558 seen in these preparations is unlikely to be a reflection of a catalysis-related steady state and that inferences drawn from such observations regarding the kinetic competence of the cytochrome may need to be reconsidered.

Alkaline Phosphatase↗

[Vitamin B12 in the adult: of metabolism and deficiencies].

PURPOSE: Update on cobalamin deficiencies in adults. CURRENT KNOWLEDGE AND KEY POINTS: More precise definitions establish real cobalamin deficiency and determine epidemiological features. Current data on cobalamin metabolism suggest the concept of non-dissociation of vitamin B12 from its carrier proteins (NDB12), a generalization of the food-cobalamin malabsorption concept. The new features of cobalamin deficiency include neurological, gynecological and vascular manifestations. Current treatment modalities include nasal and oral administration of cobalamin. PROSPECTS AND PROJECTS: Validate the concept of NDB12 and the usefulness of oral cobalamin therapy, establish the relevance of the new clinical manifestations.

Adult↗

The limited value of methylmalonic acid, homocysteine and holotranscobalamin in the diagnosis of early B12 deficiency.

Treatment of B12 deficiency is important to prevent progressive neurological and/or hematologic disease but requires a secure diagnosis. The aim of this study was to evaluate second line tests of B12 status as prognostic indicators of a hematologic response to vitamin B12 therapy. Forty-nine patients referred with low, serum vitamin B12 concentrations were treated with intramuscular B12 and re-assessed after 3 months. Methylmalonic acid, homocysteine, holotranscobalamin and neutrophil hypersegmentation index were measured before and after treatment. Before treatment 27/49 patients were anemic or macrocytic of whom 15 had a clear hematologic response. All the tests had a similar prognostic accuracy. Symptomatic improvement did not correlate with hematologic response. Supplementary tests of vitamin B12 status were not significantly better than total serum B12 concentration as predictors of a hematologic response to vitamin B12 therapy.

Diagnosis↗