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B12
Kinds of B12 Terms modified by B12 Selected AbstractsEtiology, pathogenesis and prevention of neural tube defectsCONGENITAL ANOMALIES, Issue 2 2006Rengasamy Padmanabhan ABSTRACT Spina bifida, anencephaly, and encephalocele are commonly grouped together and termed neural tube defects (NTD). Failure of closure of the neural tube during development results in anencephaly or spina bifida aperta but encephaloceles are possibly post-closure defects. NTD are associated with a number of other central nervous system (CNS) and non-neural malformations. Racial, geographic and seasonal variations seem to affect their incidence. Etiology of NTD is unknown. Most of the non-syndromic NTD are of multifactorial origin. Recent in vitro and in vivo studies have highlighted the molecular mechanisms of neurulation in vertebrates but the morphologic development of human neural tube is poorly understood. A multisite closure theory, extrapolated directly from mouse experiments highlighted the clinical relevance of closure mechanisms to human NTD. Animal models, such as circle tail, curly tail, loop tail, shrm and numerous knockouts provide some insight into the mechanisms of NTD. Also available in the literature are a plethora of chemically induced preclosure and a few post-closure models of NTD, which highlight the fact that CNS malformations are of hetergeneitic nature. No Mendelian pattern of inheritance has been reported. Association with single gene defects, enhanced recurrence risk among siblings, and a higher frequency in twins than in singletons indicate the presence of a strong genetic contribution to the etiology of NTD. Non-availability of families with a significant number of NTD cases makes research into genetic causation of NTD difficult. Case reports and epidemiologic studies have implicated a number of chemicals, widely differing therapeutic drugs, environmental contaminants, pollutants, infectious agents, and solvents. Maternal hyperthermia, use of valproate by epileptic women during pregnancy, deficiency and excess of certain nutrients and chronic maternal diseases (e.g. diabetes mellitus) are reported to cause a manifold increase in the incidence of NTD. A host of suspected teratogens are also available in the literature. The UK and Hungarian studies showed that periconceptional supplementation of women with folate (FA) reduces significantly both the first occurrence and recurrence of NTD in the offspring. This led to mandatory periconceptional FA supplementation in a number of countries. Encouraged by the results of clinical studies, numerous laboratory investigations focused on the genes involved in the FA, vitamin B12 and homocysteine metabolism during neural tube development. As of today no clinical or experimental study has provided unequivocal evidence for a definitive role for any of these genes in the causation of NTD suggesting that a multitude of genes, growth factors and receptors interact in controlling neural tube development by yet unknown mechanisms. Future studies must address issues of gene-gene, gene-nutrient and gene,environment interactions in the pathogenesis of NTD. [source] Protein methylation in full length Chlamydomonas flagellaCYTOSKELETON, Issue 8 2009Roger D. Sloboda Abstract Post-translational protein modification occurs extensively in eukaryotic flagella. Here we examine protein methylation, a protein modification that has only recently been reported to occur in flagella [Schneider MJ, Ulland M, Sloboda RD.2008. Mol Biol Cell 19(10):4319,4327.]. The cobalamin (vitamin B12) independent form of the enzyme methionine synthase (MetE), which catalyzes the final step in methionine production, is localized to flagella. Here we demonstrate, using immunogold scanning electron microscopy, that MetE is bound to the outer doublets of the flagellum. Methionine can be converted to S-adenosyl methionine, which then serves as the methyl donor for protein methylation reactions. Using antibodies that recognize symmetrically or asymmetrically methylated arginine residues, we identify three highly methylated proteins in intact flagella: two symmetrically methylated proteins of about 30 and 40 kDa, and one asymmetrically methylated protein of about 75 kDa. Several other relatively less methylated proteins could also be detected. Fractionation and immunoblot analysis shows that these proteins are components of the flagellar axoneme. Immunogold thin section electron microscopy indicates that the symmetrically methylated proteins are located in the central region of the axoneme, perhaps as components of the central pair complex and the radial spokes, while the asymmetrically methylated proteins are associated with the outer doublets. Cell Motil. Cytoskeleton 2009. © 2009 Wiley-Liss, Inc. [source] Production of paramylon, a ,-1,3-glucan, by heterotrophic cultivation of Euglena gracilis on potato liquorENGINEERING IN LIFE SCIENCES (ELECTRONIC), Issue 2 2010Bozidar, antek Abstract Euglena gracilis is shown to be able to grow on potato liquor as the main medium component leading to an interesting biotechnological product represented by paramylon , a ,-1,3-glucan , and, at the same time, revaluating an otherwise annoying waste stream of the potato-starch industry. Paramylon mass fractions of about 75% are obtained for biomass concentrations of 15,g/L during simple batch cultivation under heterotrophic conditions. Supplementation of the growth medium with glucose and the vitamins B1 and B12 are shown to improve growth rate as well as paramylon content. E. gracilis grows best at about 27.5°C without requiring pH control. [source] Hyperhomocysteinemia in epileptic patients on new antiepileptic drugsEPILEPSIA, Issue 2 2010Vincenzo Belcastro Summary Purpose:, Older enzyme-inducing antiepileptic drugs (AEDs) may induce supraphysiologic plasma concentrations of total (t) homocysteine (Hcy). The aim of the present study was to investigate the effect of new AEDs on plasma tHcy levels. Methods:, Patients 18,50 years of age, on AEDs monotherapy, with no other known cause of hyper-tHcy were enrolled. Plasma tHcy, folate, vitamin B12, and AEDs levels were determined by standard high-performance liquid chromatography (HPLC) methods. Methylenetetrahydrofolate-reductase (MTHFR) polymorphisms were checked using Puregene genomic DNA purification system (Gentra, Celbio, Italy). A group of healthy volunteers matched for age and sex was taken as control. Results:, Two hundred fifty-nine patients (151 on newer and 108 on older AEDs) and 231 controls were enrolled. Plasma tHcy levels were significantly higher [mean values, standard error (SE) 16.8, 0.4 vs. 9.1, 0.2 ,m; physiologic range 5,13 ,m] and folate lower (6.3, 0.1 vs. 9.3, 0.1 nm; normal > 6.8 nm) in patients compared to controls. Patients treated with oxcarbazepine, topiramate, carbamazepine, and phenobarbital exhibited mean plasma tHcy levels above the physiologic range [mean values (SE) 16 (0.8), 19.1 (0.8), 20.5 (1.0), and 18.5 (1.5) ,m, respectively]. Conversely, normal tHcy concentrations were observed in the lamotrigine and levetiracetam groups [both 11.1 (0.5) ,m]. Discussion:, Oxcarbazepine and topiramate might cause hyper-tHcy, most likely because of the capacity of these agents to induce the hepatic enzymes. Because literature data suggest that hyper-tHcy may contribute to the development of cerebrovascular diseases and brain atrophy, a supplement of folate can be considered in these patients to normalize plasma tHcy. [source] Severe vitamin B12 deficiency resulting in pancytopenia, splenomegaly and leukoerythroblastosisEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 5 2008Thorvardur R. Halfdanarson Abstract Deficiency of vitamin B12 is a well known cause of megaloblastic anemia and pancytopenia. Splenomegaly and leukoerythroblastosis are much less well known manifestations of B12 deficiency. We report a B12 deficient female with severe pancytopenia including normocytic anemia who also had enlarged spleen and circulating nucleated red blood cells as well as circulating immature myeloid cells. Although these findings are reported in the earlier literature, more modern reviews of the subject often fail to mention this association. We review the literature on these unusual manifestations of B12 deficiency and remind clinicians that splenomegaly and erythroblastosis can serve as diagnostic clues in cases of severe megaloblastic anemia secondary to B12 deficiency. [source] Steroid-responsive functional B12 deficiency in association with transcobalamin II polymorphism 776C,GEUROPEAN JOURNAL OF HAEMATOLOGY, Issue 1 2006Daniel P. Gale Abstract:, We present a case of intracellular vitamin B12 deficiency presenting with confusion, subacute combined degeneration of the cord, megaloblastic anaemia and intrinsic factor antibodies in the serum. Diagnosis was delayed by a normal serum B12 level and was confirmed by a grossly elevated serum homocysteine. There was a dramatic response to steroids. The patient was heterozygous for the transcobalamin (TC) II polymorphism 776C,G. This case demonstrates the importance of functional assessment of intracellular B12 activity (e.g. serum homocysteine) in excluding B12 deficiency, the role of steroids in pernicious anaemia and a possible clinical correlation of a TCII polymorphism. [source] Mechanism-Based Inactivation of Coenzyme B12 -Dependent 2-Methyleneglutarate Mutase by (Z)-Glutaconate and Buta-1,3-diene-2,3-dicarboxylateEUROPEAN JOURNAL OF INORGANIC CHEMISTRY, Issue 18 2006Wolfgang Buckel Abstract In the presence of holo 2-methyleneglutarate mutase, buta-1,3-diene-2,3-dicarboxylate and (Z)-glutaconate [(Z)-pent-2-ene-1,5-dicarboxylate], but not (E)-glutaconate, each induced homolysis of the Co,C bond of coenzyme B12 to afford cob(II)alamin and the 5,-deoxyadenosyl radical. The latter probably added to the double bond in (Z)-glutaconate and one of the double bonds in buta-1,3-diene-2,3-dicarboxylate to afford a corresponding "radical adduct". The formation of new radicals and cob(II)alamin was diagnosed by UV/Visible and EPR spectroscopy. (Z)-Glutaconate rapidly inactivated the mutase with formation of aquocobalamin, which was possibly derived by electron transfer from cob(II)alamin to the radical adduct. In contrast, buta-1,3-diene-2,3-dicarboxylate was a much slower inactivator. In this case, the spectroscopic data revealed a relatively stable complex of the radical adduct with cob(II)alamin in the active site of the enzyme. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2006) [source] Roles of adenine anchoring and ion pairing at the coenzyme B12 -binding site in diol dehydratase catalysisFEBS JOURNAL, Issue 24 2008Ken-ichi Ogura The X-ray structure of the diol dehydratase,adeninylpentylcobalamin complex revealed that the adenine moiety of adenosylcobalamin is anchored in the adenine-binding pocket of the enzyme by hydrogen bonding of N3 with the side chain OH group of Ser,224, and of 6-NH2, N1 and N7 with main chain amide groups of other residues. A salt bridge is formed between the ,-NH2 group of Lys,135 and the phosphate group of cobalamin. To assess the importance of adenine anchoring and ion pairing, Ser,224 and Lys,135 mutants of diol dehydratase were prepared, and their catalytic properties investigated. The S,224A, S,224N and K,135E mutants were 19,2% as active as the wild-type enzyme, whereas the K,135A, K,135Q and K,135R mutants retained 58,76% of the wild-type activity. The presence of a positive charge at the ,135 residue increased the affinity for cobalamins but was not essential for catalysis, and the introduction of a negative charge there prevented the enzyme,cobalamin interaction. The S,224A and S,224N mutants showed a kcat/kinact value that was less than 2% that of the wild-type, whereas for Lys,135 mutants this value was in the range 25,75%, except for the K,135E mutant (7%). Unlike the wild-type holoenzyme, the S,224N and S,224A holoenzymes showed very low susceptibility to oxygen in the absence of substrate. These findings suggest that Ser,224 is important for cobalt,carbon bond activation and for preventing the enzyme from being inactivated. Upon inactivation of the S,224A holoenzyme during catalysis, cob(II)alamin accumulated, and a trace of doublet signal due to an organic radical disappeared in EPR. 5,-Deoxyadenosine was formed from the adenosyl group, and the apoenzyme itself was not damaged. This inactivation was thus considered to be a mechanism-based one. [source] Crystal structures of CbiL, a methyltransferase involved in anaerobic vitamin B12 biosynthesis, and CbiL in complex with S -adenosylhomocysteine , implications for the reaction mechanismFEBS JOURNAL, Issue 2 2007Kei Wada During anaerobic cobalamin (vitamin B12) biosynthesis, CbiL catalyzes methylation at the C-20 position of a cyclic tetrapyrrole ring using S -adenosylmethionine as a methyl group source. This methylation is a key modification for the ring contraction process, by which a porphyrin-type tetrapyrrole ring is converted to a corrin ring through elimination of the modified C-20 and direct bonding of C-1 to C-19. We have determined the crystal structures of Chlorobium tepidum CbiL and CbiL in complex with S -adenosylhomocysteine (the S -demethyl form of S -adenosylmethionine). CbiL forms a dimer in the crystal, and each subunit consists of N-terminal and C-terminal domains. S -Adenosylhomocysteine binds to a cleft between the two domains, where it is specifically recognized by extensive hydrogen bonding and van der Waals interactions. The orientation of the cobalt-factor II substrate was modeled by simulation, and the predicted model suggests that the hydroxy group of Tyr226 is located in close proximity to the C-20 atom as well as the C-1 and C-19 atoms of the tetrapyrrole ring. These configurations allow us to propose a catalytic mechanism: the conserved Tyr226 residue in CbiL catalyzes the direct transfer of a methyl group from S -adenosylmethionine to the substrate through an SN2-like mechanism. Furthermore, the structural model of CbiL binding to its substrate suggests the axial residue coordinated to the central cobalt of cobalt-factor II. [source] Factors controlling the carbon isotope fractionation of tetra- and trichloroethene during reductive dechlorination by Sulfurospirillum ssp. and Desulfitobacterium sp. strain PCE-SFEMS MICROBIOLOGY ECOLOGY, Issue 1 2007Danuta Cichocka Abstract Carbon stable isotope fractionation of tetrachloroethene (PCE) and trichloroethene (TCE) was investigated during reductive dechlorination. Growing cells of Sulfurospirillum multivorans, Sulfurospirillum halorespirans, or Desulfitobacterium sp. strain PCE-S, the respective crude extracts and the abiotic reaction with cyanocobalamin (vitamin B12) were used. Fractionation of TCE (,C=1.0132,1.0187) by S. multivorans was more than one order of magnitude higher than values previously observed for tetrachloroethene (PCE) (,C=1.00042,1.0017). Similar differences in fractionation were observed during reductive dehalogenation by the close relative S. halorespirans with ,C=1.0046,1.032 and ,C=1.0187,1.0229 for PCE and TCE respectively. TCE carbon isotope fractionation (,C=1.0150) by the purified PCE-reductive dehalogenase from S. multivorans was more than one order of magnitude higher than fractionation of PCE (,C=1.0017). Carbon isotope fractionation of TCE by Desulfitobacterium sp. strain PCE-S (,C=1.0109,1.0122) as well as during the abiotic reaction with cyanocobalamin (,C=1.0154) was in a similar range to previously reported values for fractionation by mixed microbial cultures. In contrast with previous results with PCE, no effects due to rate limitations, uptake or transport of the substrate to the reactive site could be observed during TCE dechlorination. Our results show that prior to a mechanistic interpretation of stable isotope fractionation factors it has to be carefully verified how other factors such as uptake or transport affect the isotope fractionation during degradation experiments with microbial cultures. [source] Temperature-Sensitive Nanocapsules for Controlled Drug Release Caused by Magnetically Triggered Structural DisruptionADVANCED FUNCTIONAL MATERIALS, Issue 4 2009Ting-Yu Liu Abstract Self-assembled nanocapsules containing a hydrophilic core and a crosslinked yet thermosensitive shell are successfully prepared using poly(ethylene-oxide)-poly(propylene-oxide)-poly(ethylene-oxide) block copolymers, 4-nitrophenyl chloroformate, gelatin, and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide. The core is further rendered magnetic by incorporating iron oxide nanoparticles via internal precipitation to enable externally controlled actuation under magnetic induction. The spherical nanocapsules exhibit a hydrophilic-to-hydrophobic transition at a characteristic but tunable temperature reaching 40,°C, triggering a size contraction and shrinkage of the core. The core content experiences very little leakage at 25,°C, has a half life about 5,h at 45,°C, but bursts out within a few minutes under magnetic heating due to iron oxide coarsening and core/shell disruption. Such burst-like response may be utilized for controlled drug release as illustrated here using a model drug Vitamin B12. [source] Helicobacter pylori Infection and Gastric Autoimmune Diseases: Is There a Link?HELICOBACTER, Issue 6 2003Fabio Presotto ABSTRACT Background.,Helicobacter pylori is thought to be involved in atrophic body gastritis. We explored the prevalence of H. pylori infection in asymptomatic subjects with gastric parietal cell antibodies, as well as in patients with pernicious anemia, to evaluate a possible role of H. pylori gastric infection in gastric autoimmunity. Patients and Methods., We studied 79 consecutive asymptomatic subjects with parietal cell antibodies, 24 patients with pernicious anemia, and 66 parietal cell antibody-negative controls. All patients underwent gastric biopsies for histology and detection of H. pylori. Red blood cell count and volume, serum levels of gastrin, pepsinogen I, iron, folic acid, vitamin B12, and circulating antibodies to H. pylori and to intrinsic factor were also determined. Results., We found an atrophic body gastritis in 14 of the 79 asymptomatic subjects with parietal cell antibodies (18%) and in 2 of the 66 controls (3%) (p = .01). Mean levels of gastrin were increased (p < .0001), while those of pepsinogen were reduced (p < .001) compared with controls. H. pylori was identified at the gastric level and/or circulating anti- H. pylori antibodies were detected in 46 parietal cell antibody-positive subjects (58%) compared with 26 controls (39%) (p = .03). In patients with pernicious anemia we found an atrophic body gastritis in 18 of 24 cases (75%) (p < .001 vs. controls). Mean levels of gastrin were markedly increased (p < .0001) and those of pepsinogen I decreased (p < .0001) relative to controls. Only five of these patients (21%) had evidence of H. pylori infection compared with 46 of the parietal cell antibody-positive subjects (58%) (p = .003) and 26 of the controls (39%). Considering all patients with gastric autoimmunity (i.e. with parietal cell antibodies and/or with pernicious anemia), H. pylori was found in 44 of 72 of those without atrophy (61%) but in 6 of 31 with gastric body atrophy (19%) (p < .001), indicating that H. pylori infection is greatly reduced when gastric acid secretion decreases. Conclusions., The frequent detection of H. pylori infection in subjects with early gastric autoimmunity, indicated by the presence of parietal cell antibodies, suggests that H. pylori could have a crucial role in the induction and/or the maintenance of autoimmunity at the gastric level. [source] Impact of Helicobacter pylori on the Development of Vitamin B12 Deficiency in the Absence of Gastric AtrophyHELICOBACTER, Issue 6 2002Ender Serin Abstract Background. Cobalamin (vitamin B12) deficiency is associated with Helicobacter pylori infection. This study examined how serum vitamin B12 levels relate to gastric mucosa H. pylori density and histology, and to hematological findings in patients with minimal or no gastric atrophy. A second aim was to confirm that H. pylori eradication therapy increases serum B12. Materials and Methods. Biopsies of the gastric mucosa from a population of dyspeptic patients were graded for level of chronic inflammation, neutrophil activity, atrophy, and H. pylori density. A total of 145 H. pylori -infected patients with minimal or no atrophy were included in the study. Serum cobalamin level, hemoglobin level, and mean corpuscular volume were measured in the 145 patients before eradication therapy, and in 65 of the subjects after treatment. The hematologic findings before and after eradication therapy and correlations between serum vitamin B12 level and histologic parameters, hematologic findings, and patient age were statistically analyzed. Results. There was no significant correlation between serum cobalamin level and patient age. Before treatment all the histopathological scores were inversely correlated with serum vitamin B12 level (p < .01) on univariate analysis. Only H. pylori density was significantly associated with B12 level on multivariate analysis. Serum hemoglobin and cobalamin levels were significantly increased after treatment, regardless of H. pylori eradication status (p < .001). Conclusion. The findings provide strong evidence that H. pylori infection is associated with cobalamin deficiency, and show that this is true even in patients with nonulcer dyspepsia and minimal or no gastric atrophy. [source] Effect of packing density of hollow fibers on solute removal performances of dialyzersHEMODIALYSIS INTERNATIONAL, Issue 2009Akihiro C. YAMASHITA Abstract Solute removal performances of dialyzers are dependent not only on the solute permeabilities of the membrane but also on the module design. We have investigated how the packing density of hollow fiber (PDF) affects the solute removal performances. A series of 4 polyester polymer alloy membrane test dialyzers were assembled with varying PDFs of 29.6%, 35.3%, 44.1%, and 53.1%. Clearances (CL) were measured in vitro for creatinine (MW113), vitamin B12 (MW1355), and chymotrypsin (MW25300) with various QB=100 to 400 and QD=350 to 650 mL/min in the absence of net ultrafiltration. When QB was ,300 mL/min, no significant changes were found in creatinine CL with the increase of PDF up to 35.3%. A slightly greater increase was found in CL when QB=400 mL/min. Clearances for vitamin B12, however, increased with the increase of PDF in the range of 29.6% to 35.3%. The effects of PDF on CL were greater with larger QB. More importantly, an abrupt increase of CL was found when PDF was increased from 44.1% to 53.1%. According to a rigorous mathematical model, this may be caused by the internal filtration, which is reverse ultrafiltration occurring in a dialyzer at any given time. No significant increase was found in chymotrypsin CL when the PDF was ,35.3%, which suggested that CL for large molecules was strongly dependent on the solute permeability rather than the conditions of flow patterns. A very steep increase was also found in CL for chymotrypsin when the PDF was >44.1%, which was also considered to be due to the internal filtration. Packing density of hollow fiber can be optimized in terms of solute removal performances when the target solute and therapeutic conditions are specified. [source] Genetic and cellular studies of oxidative stress in methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC),HUMAN MUTATION, Issue 11 2009Eva Richard Abstract Methylmalonic aciduria (MMA) cobalamin deficiency type C (cblC) with homocystinuria (MMACHC) is the most frequent genetic disorder of vitamin B12 metabolism. The aim of this work was to identify the mutational spectrum in a cohort of cblC -affected patients and the analysis of the cellular oxidative stress and apoptosis processes, in the presence or absence of vitamin B12. The mutational spectrum includes nine previously described mutations: c.3G>A (p.M1L), c.217C>T (p.R73X), c.271dupA (p.R91KfsX14), c.331C>T (p.R111X), c.394C>T (p.R132X), c.457C>T (p.R153X), c.481C>T (p.R161X), c.565C>A (p.R189S), and c.615C>G (p.Y205X), and two novel changes, c.90G>A (p.W30X) and c.81+2T>G (IVS1+2T>G). The most frequent change was the known c.271dupA mutation, which accounts for 85% of the mutant alleles characterized in this cohort of patients. Owing to its high frequency, a real-time PCR and subsequent high-resolution melting (HRM) analysis for this mutation has been established for diagnostic purposes. All cell lines studied presented a significant increase of intracellular reactive oxygen species (ROS) content, and also a high rate of apoptosis, suggesting that elevated ROS levels might induce apoptosis in cblC patients. In addition, ROS levels decreased in hydroxocobalamin-incubated cells, indicating that cobalamin might either directly or indirectly act as a scavenger of ROS. ROS production might be considered as a phenotypic modifier in cblC patients, and cobalamin supplementation or additional antioxidant drugs might suppress apoptosis and prevent cellular damage in these patients. Hum Mutat 30:1,9, 2009. © 2009 Wiley-Liss, Inc. [source] Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype,phenotype correlations,HUMAN MUTATION, Issue 7 2009Jordan P. Lerner-Ellis Abstract Methylmalonic aciduria and homocystinuria, cblC type, is a rare disorder of intracellular vitamin B12 (cobalamin [Cbl]) metabolism caused by mutations in the MMACHC gene. MMACHC was sequenced from the gDNA of 118 cblC individuals. Eleven novel mutations were identified, as well as 23 mutations that were observed previously. Six sequence variants capture haplotype diversity in individuals across the MMACHC interval. Genotype,phenotype correlations of common mutations were apparent; individuals with c.394C>T tend to present with late-onset disease whereas patients with c.331C>T and c.271dupA tend to present in infancy. Other missense variants were also associated with late- or early-onset disease. Allelic expression analysis was carried out on human cblC fibroblasts compound heterozygous for different combinations of mutations including c.271dupA, c.331C>T, c.394C>T, and c.482G>A. The early-onset c.271dupA mutation was consistently underexpressed when compared to control alleles and the late-onset c.394C>T and c.482G>A mutations. The early-onset c.331C>T mutation was also underexpressed when compared to control alleles and the c.394C>T mutation. Levels of MMACHC mRNA transcript in cell lines homozygous for c.271dupA, c.331C>T, and c.394C>T were assessed using quantitative real-time RT-PCR. Cell lines homozygous for the late onset c.394C>T mutation had significantly higher levels of transcript when compared to cell lines homozygous for the early-onset mutations. Differential or preferential MMACHC transcript levels may provide a clue as to why individuals carrying c.394C>T generally present later in life. Hum Mutat 30:1,10, 2009. © 2009 Wiley-Liss, Inc. [source] Association of hyperhomocysteinemia and folate deficiency with colon tumors in patients with inflammatory bowel diseaseINFLAMMATORY BOWEL DISEASES, Issue 2 2008Jean Marc Phelip Abstract Background: Folate deficiency associated with hyperhomocysteinemia might increase the risk of developing colorectal cancer. The aim of this study was to evaluate factors associated with colonic carcinogenesis, in particular, folate and homocysteinemia levels, in a cross-sectional study of patients with inflammatory bowel disease (IBD). Methods: IBD patients with carcinogenic lesions discovered during colonoscopy [dysplasia-associated lesion or masses (DALM), colorectal cancer] were included and compared with the whole population of IBD patients with a normal colonoscopy performed during the same period. The following parameters were collected at the time of colonoscopy: age, sex, type, duration, activity, and extent of the disease, treatment, smoking status, and vitamin B12, folate, and homocysteinemia levels. Univariate and multivariate analyses were performed after adjusting for the main parameters. Results: One hundred and fourteen patients [41 with ulcerative colitis (UC), 73 with Crohn's disease (CD)] were included. Twenty-six carcinogenic lesions were isolated: 18 DALM (7 high-grade and 11 low-grade dysplasia) and 8 colorectal cancers. In univariate analysis, the factors associated with carcinogenesis were: active smoking (P = 0.03), folate level < 145 pmol/L (P = 0.02), hyperhomocysteinemia > 15 ,mol/L (P = 0.003), duration of disease > 10 years (P = 0.006), and UC (P = 0.02). In multivariate analysis, patients with hyperhomocysteinemia associated with folate deficiency had 17 times as many carcinogenic lesions as patients with normal homocysteinemia whatever the folate status and duration of the disease (P = 0.01). Patients with hyperhomocysteinemia without folate deficiency had 2.5 times as many carcinogenic lesions as patients with normal homocysteinemia (P = 0.08). Conclusions: Our data suggest that in IBD patients with normal homocysteinemia, the increase in carcinogenic risk is negligible. Conversely, in patients with hyperhomocysteinemia, folate deficiency may be associated with increased colorectal carcinogenesis in IBD patients. (Inflamm Bowel Dis 2007) [source] The role of diet and nutrition in cervical carcinogenesis: A review of recent evidenceINTERNATIONAL JOURNAL OF CANCER, Issue 4 2005Reina García-Closas Abstract Our objective was to provide an update on recent epidemiologic evidence about the role of diet and nutrition on the risk of human papillomavirus (HPV) persistence and cervical neoplasia, taking HPV into account. We conducted a systematic review and qualitative classification of all observational studies controlling for HPV infection published between March 1995 and November 2003 and of all randomized clinical trials published between January 1991 and November 2003. Scientific evidence was classified as convincing, probable, possible or insufficient, as used in a previous study on diet and cancer. Thirty-three studies were eligible for this review (10 clinical trials, 8 observational prospective studies and 15 case-control studies). The few studies on HPV persistence showed a possible protective effect of fruits, vegetables, vitamins C and E, beta- and alpha-carotene, lycopene, luterin/zeaxanthin and cryptoxanthin. Evidence for a protective effect of cervical neoplasia was probable for folate, retinol and vitamin E and possible for vegetables, vitamins C and B12, alpha-carotene, beta-carotene, lycopene, lutein/zeaxanthin and cryptoxanthin. Evidence for an increased risk of cervical neoplasia associated with high blood homocysteine was probable. Results did not differ between studies looking at preneoplastic and invasive lesions or between retrospective and prospective studies. The available evidence for an association between diet and nutritional status and cervical carcinogenesis taking HPV infection into account is not yet convincing. Large cohort studies are needed to adequately assess the role of foods and nutrients in cervical HPV carcinogenesis. © 2005 Wiley-Liss, Inc. [source] Juvenile psoriatic arthritis with nail psoriasis in the absence of cutaneous lesionsINTERNATIONAL JOURNAL OF DERMATOLOGY, Issue 1 2000Carola Duran-McKinster MD A 4-year-old white boy without a significant family history had morning stiffness and painful swelling of his left knee and ankle, right elbow, and dorsolumbar region of 2 months' evolution. The following laboratory studies were within normal limits: complete blood cell count, C-reactive protein (CRP), latex, antistreptolysin, and antinuclear antibodies. Rheumatoid factor was negative and an increase in the erythrocyte sedimentation rate (ESR) was detected (56 mm/h). The pediatric department made an initial diagnosis of juvenile rheumatoid arthritis, and treatment with acetylsalicylic acid at 100 mg/kg/day and naproxen at 10 mg/kg/day was started. A thick, yellowish toenail was diagnosed as onychomycosis. No mycologic investigations were performed. Intermittent episodes of painful arthritis of different joints were present. The radiographic features of the peripheral joints included: narrow joint spaces, articular erosions, soft tissue swelling, and diffuse bony demineralization. Characteristic bilateral sacroiliitis and a swollen tendon sheath on the left ankle were detected. At 11 years of age the nail changes had extended to five other toenails and to four fingernails, were yellow,brown in color, and showed marked subungual hyperkeratosis ( Figs 1, 2). The rest of the nails showed significant nail pitting. Trials of griseofulvin alternated with itraconazole in an irregular form for five consecutive years resulted in no clinical improvement, which prompted a consultation to our dermatology department. On three different occasions, KOH nail specimens were negative for fungus, but the presence of parakeratotic cells aroused the suspicion of psoriasis. A complete physical examination was negative for psoriatic skin lesions. A nail bed biopsy specimen was characteristic of nail psoriasis ( Fig. 3). Figure 1. Thickened nails with severe subungual hyperkeratosis in five fingernails Figure 2. Secondary deformity of nail plate. No "sausage" fingers were observed Figure 3. Light microscopic appearance of a nail biopsy specimen showing parakeratotic hyperkeratosis, elongation of interpapillary processes, and Munroe abscess (arrow) (hematoxylin and eosin stain, ×40) The following human leukocyte antigens (HLAs) were positive: A9, A10, B12, B27, Cw1, Bw4, DR6, DR7, DQ1, DQ2, and DR53. A diagnosis of juvenile psoriatic arthritis associated with nail psoriasis was made. Toenail involvement became so painful that walking became very difficult. Occlusive 40% urea in vaseline applied to the affected toenails for 48 h resulted in significant improvement. Currently, the patient is 20 years old with nail involvement, but no psoriatic skin lesions have ever been observed. [source] Methylenetetrahydrofolate reductase gene and risk of Alzheimer's disease in KoreansINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 5 2008Jae-Min Kim Abstract Background The association between methylenetetrahydrofolate reductase (MTHFR) c.677C,>,T (A222V) polymorphism and Alzheimer's disease (AD) is controversial. The objectives of the study were to investigate the association between MTHFR c.677C,>,T polymorphism and AD in Korean elders and to the extent to which it is modified by the major components of one-carbon metabolism and apolipoprotein E (APOE) genotype. Methods Seven hundred and thirty-two community residents aged 65 or over were clinically assessed for AD. Genotyping was performed for MTHFR c.677C,>,T and APOE; serum levels of folate, vitamin B12, and homocysteine were assayed. Age, gender and education were included as covariates. Results A trend of association between TT genotype of MTHFR c.677C,>,T and AD was found [adjusted OR (95% CI): 1.73 (0.80,3.74)]. The association was significant in the presence of below-median vitamin B12 level [3.66 (1.14,11.71)] and in APOE e4 non-carriers [2.97 (1.00,8.55)] with significant interaction terms, and bordered on significance in the presence of above-median homocysteine level [2.73 (0.94,7.90)]. Conclusions These findings suggest gene-environment and gene-gene interactions on the risk of AD in Koreans. Copyright © 2007 John Wiley & Sons, Ltd. [source] Dementia in primary care: the first survey of Irish general practitionersINTERNATIONAL JOURNAL OF GERIATRIC PSYCHIATRY, Issue 4 2006Suzanne Cahill Abstract Objective To investigate General Practitioners' (GPs) attitudes and practices in relation to screening, diagnosing, and disclosing a dementia diagnosis to patients. Design National postal survey. Participants A random sample of 600 GPs from a national database of 2400. Results Of the 600 GPs surveyed, 60% returned questionnaires of which 50% (300) were useable. GPs reported diagnosing on average four new cases of dementia annually. A multivariate analysis revealed that females diagnosed significantly fewer cases annually (t,=,5.532, df,=,289, p,<,0.001). A large majority of GPs reported performing thyroid function tests (77%), B12 (75%) and Folic acid tests (75%) to out rule reversible causes of cognitive impairment. The most reliable signs and symptoms of dementia identified were memory problems (58%). Main barriers to diagnosis were difficulty differentiating normal ageing from symptoms of dementia (31%), lack of confidence (30%) and the impact of the diagnosis on the patient (28%). GPs' age (,2,=,14.592, df,=,3, p,<,0.005) and gender (,2,=,11.436, df,=,3, p,<,0.01) were significantly associated with barriers to diagnosis. Only 19% claimed they often or always disclosed a diagnosis to a patient. Over one-third of GPs (38%) reported that the key factor influencing their disclosure patterns was their perceptions of the patient's level of comprehension. Most GPs (90%) had never undergone any dementia specific training and most (83%) expressed a desire for this. Conclusions GPs experience difficulty diagnosing and disclosing a diagnosis of dementia to patients. To improve dementia care in Ireland, there is an urgent need to develop an active and more systematic approach to GP training in dementia care. Copyright © 2006 John Wiley & Sons, Ltd. [source] Evaluation of reticulocyte parameters in iron deficiency, vitamin B12 deficiency and , -thalassemia minor patientsINTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY, Issue 5 2007C. CEYLAN Summary The aim of this study was to test the clinical utility of reticulocyte parameters in differential diagnosis in iron deficiency anemia (IDA), vitamin B12 deficiency (B12) and , -thalassemia minor (TM). We analyzed the percentage of reticulocyte, absolute reticulocyte count, mean content hemoglobin of reticulocyte (CHr), mean corpuscular volume of reticulocyte (MCVr), corpuscular hemoglobin concentration mean of reticulocyte (CHCMr), MCVr/MCV ratio, CHr/CH ratio and CHCMr/CHCM ratio in healthy donors (n = 34), iron deficiency (IDA) (n = 41), vitamin B12 deficiency (B12) (n = 22), and TM (n = 34). This study demonstrates that the cutoff value of CHr was 25.7 as indicative of IDA (85.4% sensitivity, 97.1% specificity). CHr and MCVr may be useful for TM (cutoff value , 24.8 for CHr) and B12 (>102.1, cutoff value for MCVr), respectively. Sensitivity and specificity of these parameters were 90.9, 86.4% and 97.1, 82.4%, respectively. CHCMr is useful to differentiate IDA and TM from B12. While CHr was low value in microcytic groups (mean 21.8 ± 3.3 for IDA, 21.0 ± 2.9 for TM), it was high in B12 (mean 32.1 ± 5.7). However, that of CHr/CH ratio was only significantly in IDA group compared with the control (P < 0.05, mean 0.98). Therefore, there are limitations regarding CHr and CHr/CH ratio differential diagnosis in microcytic and macrocytic groups. CHr, MCVr, and CHCMr are not sufficiently sensitive and specific to differentiate TM from IDA. We conclude that measurement of reticulocyte count and parameters may be a very useful implement in the diagnosis of IDA and TM. [source] Low Plasma Vitamin B12 Is Associated With Lower BMD: The Framingham Osteoporosis StudyJOURNAL OF BONE AND MINERAL RESEARCH, Issue 1 2005Katherine L Tucker Abstract Vitamin B12 is important to DNA synthesis and may affect bone formation. We examined the association between this vitamin and BMD in 2576 adults. Men with plasma B12 < 148 pM had significantly lower BMD at the hip, and women at the spine, relative to those with higher B12, and trends were similar for both at all sites. Low vitamin B12 may be a risk factor for low BMD. Introduction: Vitamin B12 is important to DNA synthesis and may affect bone formation. It has been linked to osteoblastic activity in clinical studies and cell culture. Materials and Methods: We examined the relationship between plasma vitamin B12 status and BMD in 2576 adult participants in the Framingham Offspring Osteoporosis Study (1996,2001). BMD was measured by DXA at the hip and spine. Plasma vitamin B12 was measured by radioassay. Mean BMD measures were estimated for four categories of vitamin B12 concentration, based on commonly used cut-offs, using analysis of covariance, adjusted for age, BMI, physical activity score for the elderly (PASE), alcohol use, smoking status, total calcium and vitamin D intake, season of bone measurement, and for women, menopause status and current estrogen use. Further adjustment for protein intake and total homocysteine concentration was also performed. Results: Both men and women with vitamin B12 concentrations <148 pM had lower average BMD than those with vitamin B12 above this cut-off. These differences were significant (p < 0.05) for men at most hip sites and for women at the spine. Significance remained after further adjustment for protein intake and plasma homocysteine. Conclusions: Vitamin B12 deficiency may be an important modifiable risk factor for osteoporosis. [source] Transition metal,boron complexes BnM: From bowls (n = 8,14) to tires (n = 14)JOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 15 2006Si-Dian Li Abstract Transition metal,boron complexes BnM have been predicted at density functional theory level to be molecular bowls (n = 8,14) hosting a transition metal atom (M) inside or molecular tires (n = 14) centered with a transition metal atom. Small Bn clusters prove to be effective inorganic ligands to all the VB,VIIIB transition metal elements in the periodic table. Density functional evidences obtained in this work strongly suggest that bowl-shaped fullerene analogues of Bn units exist in small BnM complexes and the bowl-to-tire structural transition occur to the first-row transition metal complexes BnM (M = Mn, Fe, Co) at n = 14, a size obviously smaller than n = 20 where the 2D-3D structural transition occurs to bare Bn. The half-sandwich-type B12Cr (C3v), full sandwich-type (B12)2Cr (D3d), bowl-shaped B14Fe (C2), and tire-shaped B14Fe (D7d) and B14Fe, (C7v) are the most interesting prototypes to be targeted in future experiments. These BnM complexes may serve as building blocks to form extended boron-rich BnMm tubes or cages (m , 2) or as structural units to be placed inside carbon nanotubes with suitable diameters. © 2006 Wiley Periodicals, Inc. J Comput Chem, 2006 [source] Performance of DFT in modeling electronic and structural properties of cobalaminsJOURNAL OF COMPUTATIONAL CHEMISTRY, Issue 12 2006Jadwiga Kuta Abstract Computational modeling of the enzymatic activity of B12 -dependent enzymes requires a detailed understanding of the factors that influence the strength of the CoC bond and the limits associated with a particular level of theory. To address this issue, a systematic analysis of the electronic and structural properties of coenzyme B12 models has been performed to establish the performance of three different functionals including B3LYP, BP86, and revPBE. In particular the cobalt,carbon bond dissociation energies, axial bond lengths, and selected stretching frequencies have been analyzed in detail. Current analysis shows that widely used B3LYP functional significantly underestimates the strength of the CoC bond while the nonhybrid BP86 functional produces very consistent results in comparison to experimental data. To explain such different performance of these functionals molecular orbital analysis associated with axial bonds has been performed to show differences in axial bonding provided by hybrid and nonhybrid functionals. © 2006 Wiley Periodicals, Inc. J Comput Chem 27: 1429,1437, 2006 [source] Developmental differences in the immortalization of lung fibroblasts by telomeraseAGING CELL, Issue 5 2003Nicholas R. Forsyth Summary The role of ambient (21%) and physiological oxygen (2,5%) in the immortalization of fetal vs. adult human lung fibroblasts was examined. Growth in low oxygen and antioxidants extended the lifespan of both fetal and adult strains. As the ectopic expression of telomerase could immortalize adult lung fibroblasts cultured in ambient oxygen, the lifespan-shortening effects of 21% oxygen must have been largely limited to telomeres. By contrast, fetal lung fibroblasts could not be immortalized in ambient oxygen in spite of telomere elongation by telomerase, suggesting more widespread oxidative damage. The long-term culture requirements for the immortalization of WI-38 fetal lung fibroblasts included supplementation with N-(tert) butyl hydroxylamine, dexamethasone, zinc and vitamin B12, in addition to growth in physiological oxygen. The mechanisms regulating telomere shortening remain controversial. The present results suggest that both end-replication and oxidative damage events contribute to telomere shortening in lung fibroblasts in vitro. These observations emphasize the need for better analytical techniques to distinguish whether the correlation of short telomeres with disease and mortality in humans reflects the consequences of increased proliferation, telomere shortening as a result of oxidative damage or some combination of these processes. [source] Expression and characterization of the periplasmic cobalamin-binding protein of Photobacterium damselae subsp. piscicidaJOURNAL OF FISH DISEASES, Issue 9 2009R Boiani Abstract Cobalamin (vitamin B12) is an essential cofactor in a variety of enzymatic reactions and most prokaryotes contain transport systems to import vitamin B12. A gene coding for a periplasmic cobalamin-binding protein of Photobacterium damselae subsp. piscicida was identified by in silico analysis of sequences from a genomic library. The open reading frame was composed of 834 bp encoding a protein of 277 amino acids. The protein showed 61% identity with the vitamin B12 -binding protein precursor of P. profundum, 53% identity with the corresponding protein of Vibrio parahaemolyticus and 43% identity with the periplasmic binding protein BtuF of Escherichia coli. The expression of the native protein was investigated in P. damselae subsp. piscicida, but BtuF was weakly expressed under normal conditions. To characterize the BtuF of P. damselae subsp. piscicida, the recombinant protein was expressed with a C-terminal His6 -tag and purified; the molecular weight was estimated to be approximately 30 kDa. The protein does not contain any free thiol group, consistent with the view that the two cysteine residues are involved in a disulphide bond. The purified BtuF binds cyanocobalamin with an affinity constant of 6 ± 2 ,m. [source] A population-based intervention study on elevated serum levels of methylmalonic acid and total homocysteine in elderly people: results after 36 months of follow-upJOURNAL OF INTERNAL MEDICINE, Issue 5 2004K. Björkegren Abstract. Objectives., To study the effects of vitamin B12 and folic acid treatment on haematological measures, reported symptoms and clinical findings over a 3-year period. Design., A longitudinal two-cohort study. Setting., A mid-Swedish community. Subjects., A 20% random sample of persons 70 years or older in a defined geographical area were invited to a survey (n = 266). Sixty-nine persons who had serum cobalamin <300 pmol L,1 and serum methylmalonic acid (MMA) ,0.37 ,mol L,1 or serum total homocysteine (tHcy) ,15 ,mol L,1 and who had no vitamin B12 or folic acid substitution were selected for treatment. Main outcome measures., Serum cobalamin, folate, MMA and tHcy. Presence of gastrointestinal, neurological, psychiatric and some other symptoms, obtained by questionnaire, and Mini Mental State Examination (MMSE) score, vibration sense measurement and findings at a physical examination. Results., After combined vitamin B12,folic acid treatment, all persons normalized their serum tHcy and MMA levels and the effect remained after 3 years. The study design allowed separation of pure vitamin B12 deficiencies from folate and combined deficiencies. There was a tendency towards improvement of vibration sense, especially in the long nerve paths, and improvement of neurological symptoms and oral mucosa findings. No improvement was seen for other symptoms, reflex activity or MMSE score. Conclusions., Vitamin treatment of elderly people in the early phase of the condition may reverse damage that otherwise would become irreversible. If initiated, the treatment should be combined with vitamin B12 and folic acid. [source] Homocysteine, malondialdehyde and endothelial markers in dialysis patients during low-dose folinic acid therapyJOURNAL OF INTERNAL MEDICINE, Issue 5 2002T. Apeland Abstract. Apeland T, Mansoor MA, Seljeflot I, Brønstad I, Gøransson L, Strandjord RE (Rogaland Central Hospital, Stavanger; and Ullevål University Hospital, Oslo; Norway). Homocysteine, malondialdehyde and endothelial markers in dialysis patients during low-dose folinic acid therapy. J Intern Med 2002; 252: 456,464. Objectives. Haemodialysis patients have elevated levels of the atherogenic amino acid homocysteine. We wanted to assess the effects of small doses of intravenous folinic acid (the active form of folic acid) on some biochemical risk factors of cardiovascular disease. Design. Longitudinal and open intervention study. Setting. Two dialysis units in the County of Rogaland. Subjects. All patients on maintenance haemodialysis were invited, and 32 of 35 patients gave their informed consent. Interventions. After each dialysis session, the patients were given 1.0 mg of folinic acid intravenously thrice a week for a period of 3 months. Prior to and during the study, all patients were on maintenance supplementation with small doses of vitamins B1, B2, B3, B5, B6 and B12. Main outcome measures. Changes in the levels of (i) plasma total homocysteine (p-tHcy) and folate, (ii) circulating endothelium related proteins , markers of endothelial activation and (iii) serum malondialdehyde (S-MDA) , a marker of oxidative stress and lipid peroxidation. Results. The p-tHcy levels were reduced by 37% (P < 0.0001), whilst the serum and erythrocyte folate levels increased by 95 and 104%, respectively (P < 0.0001 for both). The circulating levels of endothelium related cellular adhesion molecules and haemostatic factors remained high and unchanged, except the thrombomodulin (TM) levels increased (P = 0.0004). The high levels of S-MDA were reduced by 26% (P = 0.003). Conclusions. Low doses of folinic acid given intravenously to dialysis patients reduced their levels of p-tHcy and S-MDA and thus improved their cardiovascular risk profile. The concurrent increment in TM levels was unexpected and of unknown clinical significance. [source] "Whippets"-Induced Cobalamin Deficiency Manifesting as Cervical MyelopathyJOURNAL OF NEUROIMAGING, Issue 3 2004Alan L. Diamond ABSTRACT Background. Nitrous oxide (N O) is inhaled in anesthesia and as a recreational drug from whipped cream dispensers. Its abuse reaches ,10% in some age groups. By inactivating cobalamin (Cbl) (vitamin B12), N O can cause neurologic and hematologic manifestations. We present a case of N O-induced Cbl deficiency presenting as cervical myelopathy. Case History. After regularly inhaling N O for many months, a 31-year-old man developed limb paresthesiae and ataxia over 3 months. Examination revealed finger pseudoathetosis, hyporeflexia, decreased sensation, and gait ataxia. Brain magnetic resonance imaging (MRI) was normal, but the posterior columns of the cervical and upper thoracic cord revealed patchy nonenhancing hyperintense lesions. Serum Cbl was 98 pg/mL (normal = 170,900 pg/mL). Cbl replacement led to recovery within 3 months.Discussion. This patient presented with the symptoms and signs of Cbl deficiency. The MRI lesions in the posterior columns aided the diagnosis. Physicians need to have a high level of suspicion in cases of unexplained Cbl deficiency and myelopathy. [source] | ||||||||||||||||||||||||||||||||||||||||