ISSN:0361-8609    

DOI:10.1002/ajh.2830340202

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractCobalamin derivatives serve as coenzymes for the body's two cobalamin‐dependent enzymes—adenosylcobalamin‐dependent methylmalonyl CoA mutase, and methylcobalamin‐dependent methionine methyltransferase.This essay reviews, in brief form and in personal terms, the history, beginning in the mid‐1950s, of how these enzymes and coenzymes were discovered and what has been learned of their reaction mechanisms. It is clear that because of the fragility of the unique carbon‐cobalt bond in Cobalamin coenzymes, they serve primarily as free radical formers. This accounts for their efficiency in abstracting hydrogen from substrate molecules and for a subsequent chain of events that results in the isomerization of methylmalonyl CoA, the transfer of methyl groups, and (in certain bacteria) the reduction of ribonucleotides. Some thoughts are offered on the possible evolutionary significance of

ISSN:0361-8609    

DOI:10.1002/ajh.2830340203

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractThe serum cobalamin assay is the primary diagnostic test for cobalamin deficiency. It appears to be an excellent screening test since most patients with clinically confirmed cobalamin deficiency have low levels. Recent studies indicate that the clinical picture of cobalamin deficiency is much more diverse than previously believed. It is also apparent that many patients with low serum cobalamin concentrations are not cobalamin deficient. Thus, there is a need for additional diagnostic tests to further distinguish patients with low serum cobalamin levels who are actually cobalamin deficient and will benefit from lifetime treatment from those who are not deficient and will not benefit. Serum levels of methylmalonic acid and total homocysteine have been shown to be markedly elevated in most patients with cobalamin deficiency, and total homocysteine concentrations are markedly elevated in most patients with folate deficiency. The levels of these metabolites fall to normal if these patients are treated with the appropriate vitamin but remain essentially unchanged if the wrong vitamin is administered. These observations demonstrate that serum methylmalonic acid and total homocysteine levels are useful in diagnosing patients with cobalamin and folate deficiency and in distinguishing between these two vitamin deficiencies.

ISSN:0361-8609    

DOI:10.1002/ajh.2830340204

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractThe serum cobalamin level has been generally considered to be essentially 100% sensitive in the detection of the clinical disorders caused by cobalamin deficiency. We tested this hypothesis in two groups of patients. In patients with pernicious anemia or previous gastrectomy who received less than monthly maintenance therapy, early hematologic relapse was associated with elevation of the serum methylmalonic acid, total homocysteine, or both metabolites in 95% of instances, although the serum cobalamin was low in only 69%. In the absence of hematologic relapse, the methylmalonic acid was abnormal more than twice as frequently as the serum cobalamin. We also reviewed the records of 419 consecutive patients with recognized clinically significant cobalamin deficiency. Twelve patients were identified in whom deficiency was clearly present although the serum cobalamin was greater than 200 pg/ml. Anemia was usually absent or mild, but 5 had prominent neurological involvement that subsequently responded to cobalamin. Both the serum methylmalonic acid and total homocysteine were increased in each patient. The serum cobalamin was normal in 9 (5.2%) of 173 patients with recognized cobalamin deficiency seen in the last 5 years. Antibiotic treatment lowered the serum methylmalonic acid but not the total homocysteine level in two cobalamin‐deficient patients, suggesting that propionic acid generated by the anaerobic gut flora may be a precursor of methylmalonic acid in deficient patients. We conclude that the serum cobalamin is normal in a significant minority of patients with cobalamin deficiency and that the measurement of serum metabolite concentrations facilitates the identification of such patient

ISSN:0361-8609    

DOI:10.1002/ajh.2830340205

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractEvidence for cobalamin (vitamin B12) deficiency usually involves some combination of low serum cobalamin levels, clinical abnormalities (classically, megaloblastic anemia and neurologic defects), metabolic abnormalities, and response to therapy. However, cobalamin deficiency may often display few of the expected clinical findings. Identification of the underlying cause is also important in the diagnosis of deficiency, and its value may be particularly great when the expression of deficiency is subtle. The cause of cobalamin deficiency is usually malabsorptive, but may sometimes be limited to malabsorption of food cobalamin while free cobalamin is absorbed normally. Nongastroenterologic entities may sometimes also be found. All of these considerations allow the proposal of four patterns of cobalamin deficiency. The first type is classical deficiency; typical megaloblastic anemia with or without neurologic dysfunction occurs because of classical cobalamin malabsorption such as lack of intrinsic factor (pernicious anemia). The second type consists of classical cobalamin malabsorption in which the cobalamin deficiency is expressed subtly rather than in classical fashion. There is no megaloblastic anemia and sometimes the only evidence of deficiency may be metabolic. In the third type, cobalamin deficiency is expressed classically but is attributable to a subtle or atypical cause, such as food‐cobalamin malabsorption. In the fourth type, deficiency is both expressed subtly and arises from subtle or atypical causes. Such presentations require further investigation but are a challenging expansion of our understanding and recognition of cobalamin deficienc

ISSN:0361-8609    

DOI:10.1002/ajh.2830340206

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractA child with methylmalonic aciduria due to failure to accumulate adocbl in mitochondria has a phenotype similar to cblA disease. Deficient utilization of labeled propionate by his fibroblasts is corrected by their fusion with those from cblA patients, indicating that he belongs to a different complementation class and probably is deficient in a different gene product. The defect appears not to be due to reduced affinity of enzymes for adocbl, or for ATP, and the minimal thiol required for adocbl synthesis is not different from that of extracts of normal cells.

ISSN:0361-8609    

DOI:10.1002/ajh.2830340207

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractThe 13 cases of methylcobalamin (MeCbl) deficiency presenting in early infancy have all been developmentally delayed, and the majority have had seizures, hypotonia, lethargy, and microcephaly. The CNS injury appears to occur during the first 6 months of postnatal life. The same symptoms are seen in acquired cobalamin (Cbl) deficiency in the same age group. MRI performed at age 18–19 months and after 13–14 months of large amounts of Cbl, in two cases showed delayed myelination, most pronounced in the cerebrum. Isolated MeCbl deficiency is the consequence of cblE and G mutations where the lesion is of a single Cbl‐dependent enzyme, the methyltransferase. One effect of a deficiency of MeCbl, and of the associated failure of the methionine synthase reaction, is, therefore, an impairment of myelination of the brain of the newborn. The slow, but usually incomplete, improvement in psychomotor status after years of treatment with Cbl may be related to the eventual myelination. However, the hypotonia, lethargy, and impaired responsiveness react to treatment with Cbl within 24–48 hours, which suggests an expression of MeCbl deficiency on the CNS distinct from the delayed myelination. Although there is much to be learned, it is now clear that a normally functioning Cbl‐dependent methyl transferase is required for development and function of the hu

ISSN:0361-8609    

DOI:10.1002/ajh.2830340208

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractMyelo‐cytotoxicity of extended nitrous oxide (N2O) inhalation was described almost forty years ago and then incidentally applied already with temporary success for suppressing leukemia. In 1948 the accompanying megaloblastic maturation arrest was explained by inactivation of the methylcobalamin coenzyme and subsequent folate deficiency. We studied the anti‐leukemic effect of N2O on a transplantable acute leukemia in B(rown) N(orway) rats. Progression of this B,N,M(yelocytic)L(eukemia) was measured as spleen and liver weights, and leukemic blood cell counts. The deoxyuridine (dU)‐suppression test provided in vitro indication of the functional folate activity of leukemic cells. Breathing of N2O‐oxygen considerably reduced but did not eradicate, BNML‐proliferation. Addition of anti‐metabolites, interfering with some enzyme in the folate metabolism beyond the methylcobalamin co‐enzyme dependent methionine synthase step, acted at least synergistically. The anti‐leukemic effect of cycloleucine, which reduces S‐adenosyl‐methionine synthesis by inactivation of methionine adenosyltransferase, was moderate but became much stronger with N2O inhalation. Methotrexate, a potent anti‐leukemic agent by inhibiting tetrahydrofolate (THF) generation through inactivation of di‐HF reductase, became highly anti‐BNML, even in low dosage when combined with or preceded by N2O. 5‐Fluorouracil, which inhibits methylene‐THF dependent thymidilate synthase, itself was surprisingly anti‐BNML, but also became much more potent with previous or concomittant N2O exposure. Preliminary dU‐suppression test results with human acute leukemia cells, exposed to N2O and/or folate antagonists in vitro, correlated well with the in vivo BNML‐experiments. Combining the anticobalamin activity of N2O with an anti‐folate therefore seems to be

ISSN:0361-8609    

DOI:10.1002/ajh.2830340209

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractIn AIDS, as previously found in pernicious anemia (PA), the earliest serum marker of subnormal vitamin B12(cobalamin) absorption, and therefore of negative B12balance, is low serum holotranscobalamin II (holo‐TC II; B12‐TC II) despite normal total serum B12level, normal serum homocysteine, and normal classic (oral free radio‐B12) Schilling test. This may be accompanied by subtle and insidious damage to hematopoietic, immunologic, neuropsychiatric, nutritional and alimentary systems, confirmed by correction on therapeutic trial with B12therapy. Our studies suggest such selective B12deficiency occurs in about half of the HIV‐1 infected, in part due to frequent depression of B12absorption by HIV‐1 attack on the gastric mucosa and/or opportunistic infection attack on the small bowel, and in part due to a telescoping of the continuum of the stages of negative B12balance in relation to damage to B12delivery by the infective and/or systemic disease process. In AIDS, when total serum B12is normal despite tissue depletion of B12, if the classic Schilling test does not reveal subnormal food B12absorption, the food Schilling test does. We hypothesize that DNA‐synthesizing cells of the hematopoietic, immunologic, neurologic and other systems which have surface receptors solely for holo‐TC II, and which have low B12stores, rapidly become dysfunctional due to B12deficiency when holo‐TC II is low, while cells (such as liver cells) which also have surface receptors for holohaptocorrin (B12‐haptocorrin) remain B12‐replete. We believe this to be another example of the concept of selective nutrient deficiency in one cell l

ISSN:0361-8609    

DOI:10.1002/ajh.2830340210

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY

摘要:

AbstractFor simultaneous demonstration of cellular ultrastructure, myeloperoxidase activity, and presence of a membrane‐bound antigen in a given blood cell, we examined three different fixatives: periodate‐lysine‐paraformaldehyde (PLP) and paraformaldehyde and glutaraldehyde for their applicability to preembedding electron microscopic immunocytochemistry using monoclonal antibodies and the avidin‐biotin‐peroxidase complex (ABC) technique. This procedure was examined in samples from 3 normal volunteers and 29 patients with acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL), lymphosarcoma cell leukemia (LSCL), blastic phase of chronic myelogenous leukemia (CML‐BC), or other unclassified leukemias. PLP fixation preserved the immunoreactivity of surface glycoproteins as well as immunoglobulins to the most satisfactory extent. Leukemic cells fixed with PLP maintained their fine structural details, so that we could identify their cytoplasmic organelles, although glutaraldehyde produced the best preservation of cellular ultrastructure. In three patients with ALL, our method revealed that a significant portion of blasts possessed both lymphoid surface antigens and peroxidase‐positive cytoplasmic granules. Our method was also useful in identifying the lineage of peroxidase‐negative leukemic cells, including monoblastic leukemia and megakaryoblastic leukemia cells. Ultraimmunocytochemistry using PLP fixation and the ABC technique may be a promising strategy for determining the nature of blastic cells that remain unclear after a conventional work‐up, for characterizing leukemic cells in patients with a relatively low blast cell count in the bone marrow or peripheral blood, and for estimating the presence and frequency of leukemia with multil

ISSN:0361-8609    

DOI:10.1002/ajh.2830340211

出版商:Wiley Subscription Services, Inc., A Wiley Company    

年代:1990

数据来源: WILEY