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Biomedical subjects

D W Jacobsen

Publications and source records attributed to D W Jacobsen.

At least 37 records · Page 2Linked to original sources
PubMed1999

Prevalence and determinants of hyperhomocysteinemia in hemodialysis and peritoneal dialysis.

BACKGROUND: Hyperhomocysteinemia is an independent risk factor for atherosclerotic complications in patients with end-stage renal disease, although the mechanisms remain unclear. The major determinants of plasma homocysteine concentration are usually folate, vitamin B12, pyridoxal 5'-phosphate (vitamin B6), and glomerular filtration rate. METHODS: We measured factors, including plasma folate, vitamin B12, vitamin B6, creatinine, as well as the dose and duration of dialysis, that might affect plasma homocysteine concentrations in 130 patients on hemodialysis (HD) and compared these observations with those in 46 patients on peritoneal dialysis (PD). Independent determinants of total homocysteine were identified using a multiple logistical regression analysis. RESULTS: Total homocysteine values averaged 29.8 mumol/liter in HD patients, significantly higher than the mean value of 19.9 mumol/liter observed in patients on PD (P < 0.001). The prevalence of hyperhomocysteinemia was 90.8% among HD patients, significantly higher than the prevalence of 67.4% among PD patients. Folate values in HD patients averaged 45.5 nmol/liter and were significantly lower than in PD patients (104.2 nmol/liter, P < 0.001). For patients on HD, the only determinant of total homocysteine concentration was plasma folate (r = -0.31, P < 0.001). In contrast, for PD patients, total homocysteine did not correlate with plasma folate, vitamin B12, or vitamin B6. CONCLUSIONS: Hyperhomocysteinemia is more prevalent and intense in HD patients compared with those on PD. The homocysteine response may become refractory to excess folate supplementation in PD patients.

Creatinine↗
PubMed1999

Serum cobalamin, homocysteine, and methylmalonic acid concentrations in a multiethnic elderly population: ethnic and sex differences in cobalamin and metabolite abnormalities.

BACKGROUND: Low cobalamin concentrations and mild hyperhomocysteinemia are common in the elderly but ethnic differences have not been defined. OBJECTIVE: Our objective was to determine the demographic characteristics of cobalamin deficiency in the elderly and its role in their hyperhomocysteinemia. DESIGN: We measured serum cobalamin, total homocysteine (Hcys), and methylmalonic acid (MMA) concentrations in 725 subjects >60 y old, and folate concentrations in 520 subjects. RESULTS: After exclusion of subjects taking cobalamin supplements or with renal insufficiency, high prevalences of low cobalamin (11.8%), high MMA (16.6%), and high Hcys (26.1%) concentrations were seen. Most cobalamin concentrations <140 pmol/L appeared to reflect deficiency because 78. 3% of them were accompanied by abnormal metabolites. Subjects with cobalamin concentrations of 140-258 pmol/L had significantly fewer metabolic abnormalities. A low cobalamin concentration and renal insufficiency were the strongest predictors of abnormal Hcys concentrations. Elderly men had higher Hcys concentrations than did women (P = 0.0001). Whites and Latin Americans had lower cobalamin concentrations than did blacks and Asian Americans (P < 0.005). Whites also had higher Hcys concentrations than all the other groups (P < 0.05). When included in the analysis, renal insufficiency in subjects was associated with 23.8% of all high Hcys and 25.5% of all high MMA concentrations; most with renal insufficiency were Asian American and black men. CONCLUSIONS: Mild cobalamin deficiency is most common in elderly white men and least common in black and Asian American women. Hyperhomocysteinemia, which is most strongly associated with low cobalamin concentrations, is also most common in elderly whites, whereas that associated with renal insufficiency is more common in blacks and Asian Americans. Ethnic differences in cobalamin deficiency and the Hcys patterns associated with it or with renal insufficiency warrant consideration in supplementation strategies. Extending suspicion of deficiency to persons with cobalamin concentrations of 140-258 pmol/L appears to provide more disadvantages than advantages.

Aged↗
PubMed1998

High homocysteine, low folate, and low vitamin B6 concentrations: prevalent risk factors for vascular disease in heart transplant recipients.

BACKGROUND: A high plasma homocysteine concentration is a risk factor for atherosclerosis and thrombosis, which are major causes of morbidity and mortality in heart transplant patients. High homocysteine concentrations may be caused by lower folate and vitamin B6 levels. We hypothesized that these patients might have high homocysteine concentrations and low levels of folate and vitamin B6, which could contribute to the development of vascular complications. METHODS: Total fasting plasma homocysteine was measured in 189 cardiac transplant recipients and in healthy controls, as were concentrations of folate, vitamin B12, vitamin B6, and creatinine. RESULTS: Homocysteine concentrations were higher in recipients than controls (19.1+/-13.0 vs. 11.0+/-3.0 micromol/L, P<0.01), and hyperhomocysteinemia (>90th percentile for controls, 14.6 micromol/L) was seen in 68% of recipients (P<0.01). Folate and vitamin B6 concentrations were lower (5.9+/-4.2 vs. 7.9+/-4.2 pmol/L and 40+/-25 vs. 84+/-77 nmol/L, respectively; P<0.01 for both). Folate and vitamin B6 deficiencies were seen in 10.8% and 17.91% of recipients, respectively (P<0.01). Hyperhomocysteinemia was more frequent in patients with vascular complications after transplantation than in those without (79.2% vs. 63.8%, P<0.05). CONCLUSIONS: Elevated plasma homocysteine and deficiencies of folate and vitamin B6 are common in transplant recipients. A high homocysteine concentration was more common in patients with vascular complications. Prospective studies are now required to evaluate the role of these abnormalities as risk factors for the atherothrombotic complications of transplantation.

Arteriosclerosis↗
PubMed1998

Prospective study of hyperhomocysteinemia as an adverse cardiovascular risk factor in end-stage renal disease.

BACKGROUND: Retrospective and case-control studies show that hyperhomocysteinemia is an independent risk factor for atherosclerosis in patients with end-stage renal disease. We studied prospectively the association between total homocysteine and cardiovascular outcomes. METHODS AND RESULTS: In all, 167 patients (93 men, 74 women; mean age, 56.3+/-14.7 years) were followed for a mean duration of 17.4+/-6.4 months. Cardiovascular events and causes of mortality were related to total homocysteine values and other cardiovascular risk factors. Cox regression analysis was used to identify the independent predictors for cardiovascular events and mortality. Fifty-five patients (33%) developed cardiovascular events and 31 (19%) died, 12 (8%) of cardiovascular causes. Total plasma homocysteine values ranged between 7.9 and 315.0 micromol/L. Levels were higher in patients who had cardiovascular events or died of cardiovascular causes (43.0+/-48.6 versus 26.9+/-14.9 micromol/L, P=.02). The relative risk (RR) for cardiovascular events, including death, increased 1% per micromol/L increase in total homocysteine concentration (RR, 1.01; CI, 1.00 to 1.01; P=.01). CONCLUSIONS: These prospective observations confirm that hyperhomocysteinemia is an independent risk factor for cardiovascular morbidity and mortality in end-stage renal disease, with an increased RR of 1% per micromol/L increase in total homocysteine concentration. Interventional studies are needed to evaluate the possible effects of modifying this risk factor in these patients.

Adult↗
PubMed1998

Heteronuclear NMR studies of cobalt corrinoids. 20. 31P chemical shift anisotropy of aquacobalamin and its complex with a haptocorrin from chicken serum.

Static light scattering measurements have been used to determine the molecular mass (65.3 kDa) and second virial coefficient (3.66 x 10(-4) mol mL g-2) for the complex between chicken serum haptocorrin (HC) and aquacobalamin (H2OCbl). Dynamic light scattering measurements have also been used to determine the translational diffusion coefficient of the H2OCbl-HC complex as a function of concentration. From the diffusion coefficient at infinite dilution (4.71 x 10(-7) cm2 s-1), the hydrodynamic radius (45.5 A) and rotational correlation time (85.4 ns) have been calculated. Using the latter, and measured values of the 31P NMR linewidths of the H2OCbl-HC complex at several field strengths, a detailed analysis of the 31P nuclear relaxation is possible. The chemical shift anisotropy term from the transverse relaxation equation is determined to be 95.7 ppm, and the average phosphorus-proton internuclear distance is 2.05 A. For comparison to protein-free H2OCbl, the chemical shift anisotropy of the phosphorus atom was studied by solid state NMR spectroscopy and the 31P relaxation by solution T1 measurements. These studies give values of 110.3 ppm for the chemical shift anisotropy term and 2.45 A for the average phosphorus-proton internuclear distance. The results are consistent with a significant change in the conformation of the H2OCbl phosphodiester upon binding to haptocorrin which could be due to a shortening of the axial Co-N bond.

Animals↗
PubMed1998

Dietary intake of cobalamin in elderly people who have abnormal serum cobalamin, methylmalonic acid and homocysteine levels.

OBJECTIVE: To determine if poor dietary intake can explain the cobalamin-related abnormalities often seen in the elderly. DESIGN: Prospective laboratory survey with a follow-up dietary assessment. SETTING: Social centers for the elderly and an outpatient clinic. SUBJECTS: Ninety-five free-living subjects >60y old with abnormal or suspicious findings in cobalamin-related tests and 78 subjects >60y old with normal results. INTERVENTIONS: Serum cobalamin, methylmalonic acid and homocysteine determinations to assess cobalamin status and a one year food-frequency questionnaire to assess cobalamin intake. RESULTS: Only three of the 173 subjects (1.7%), one of whom had normal cobalamin status, ingested <2 microg cobalamin/d, the Recommended Daily Allowance. Sixty-nine subjects (39.9%) ingested <6 microg/d, but they did not have more abnormal serum cobalamin or metabolite values than those ingesting >6 microg. Ordering all subjects by quintiles according to cobalamin intake revealed no significant trends or differences in any of the serum values either. Moreover, arranging subjects by results of tests of cobalamin status showed that the subjects with abnormal cobalamin status did not differ in cobalamin intake from those with normal cobalamin status, although they did differ in use of supplements. Finally, cobalamin intake, with or without supplements, did not correlate with serum cobalamin or metabolite levels. The absence of any association between cobalamin status and intake contrasts sharply with the significant correlation between folate intake and folate status (P = 0.0001). CONCLUSIONS: The high frequency of mildly abnormal cobalamin status in the elderly cannot be attributed to poor intake of cobalamin. Nondietary explanations, such as malabsorption and other phenomena, must always be sought to explain mild cobalamin deficiency in the elderly.

Aged↗
PubMed1998

Homocysteine and vitamins in cardiovascular disease.

On the basis of recent retrospective and prospective studies, it is now widely accepted that increased total plasma homocysteine is a risk factor for cardiovascular disease. Impaired enzyme function as a result of genetic mutation or deficiency of the essential B vitamins folic acid, B12, and B6 can lead to hyperhomocysteinemia. Oxidized forms of homocysteine account for 98-99% of total plasma homocysteine. Although there is uncertainty as to whether increased homocysteine is causal or merely a proxy for cardiovascular disease, several lines of evidence suggest that it may play a role in atherothrombotic disease. Homocysteine appears to alter the anticoagulant properties of endothelial cells to a procoagulant phenotype. Mildly increased homocysteine causes dysfunction of the vascular endothelium. Folic acid effectively lowers homocysteine concentration in the plasma. Intervention studies are urgently needed to determine if lowering homocysteine is effective in decreasing the morbidity and mortality of cardiovascular disease.

Blood Vessels↗
PubMed1996

Hyperhomocysteinemia confers an independent increased risk of atherosclerosis in end-stage renal disease and is closely linked to plasma folate and pyridoxine concentrations.

BACKGROUND: A high level of total plasma homocysteine is a risk factor for atherosclerosis, which is an important cause of death in renal failure. We evaluated the role of this as a risk factor for vascular complications of end-stage renal disease. METHODS AND RESULTS: Total fasting plasma homocysteine and other risk factors were documented in 176 dialysis patients (97 men, 79 women; mean age, 56.3 +/- 14.8 years). Folate, vitamin B12, and pyridoxal phosphate concentrations were also determined. The prevalence of high total homocysteine values was determined by comparison with a normal reference population, and the risk of associated vascular complications was estimated by multiple logistic regression. Total homocysteine concentration was higher in patients than in the normal population (26.6 +/- 1.5 versus 10.1 +/- 1.7 mumol/L; P < .01). Abnormally high concentrations (> 95th percentile for control subjects, 16.3 mumol/L) were seen in 149 patients (85%) with end-stage renal disease (P < .001). Patients with a homocysteine concentration in the upper two quintiles (> 27.8 mumol/L) had an independent odds ratio of 2.9 (CI, 1.4 to 5.8; P = .007) of vascular complications. B vitamin levels were lower in patients with vascular complications than in those without. Vitamin B6 deficiency was more frequent in patients than in the normal reference population (18% versus 2%; P < .01). CONCLUSIONS: A high total plasma homocysteine concentration is an independent risk factor for atherosclerotic complications of end-stage renal disease. Such patients may benefit from higher doses of B vitamins than those currently recommended.

Aged↗
PubMed1996

Homocysteine and coronary atherosclerosis.

Homocysteine is increasingly recognized as a risk factor for coronary artery disease. An understanding of its metabolism and of the importance of vitamins B6 and B12 and folate as well as enzyme levels in its regulation will aid the development of therapeutic strategies that, by lowering circulating concentrations, may also lower risk. Possible mechanisms by which elevated homocysteine levels lead to the development and progression of vascular disease include effects on platelets, clotting factors and endothelium. This review presents the clinical and basic scientific evidence supporting the risk and mechanisms of vascular disease associated with elevated homocysteine concentrations as well as the results of preliminary therapeutic trials.

Coronary Artery Disease↗
PubMed1996

Lipoprotein (a), homocysteine, and hypercoagulable states in young men with premature peripheral atherosclerosis: a prospective, controlled analysis.

PURPOSE: Elevated lipoprotein (a) (Lp[a]) lipoprotein, total homocysteine, and hypercoagulable states (HCS) have all been implicated as risk factors for premature-onset atherosclerosis. This study was performed to determine the prevalence of these abnormalities in young men with chronic lower extremity ischemia (peripheral vascular disease [PVD]) and to determine their relative strengths as risk factors for premature peripheral atherosclerosis. METHODS: We analyzed 50 young white men (aged 45 years or younger at onset of symptoms) and compared them with 45 age-matched white male control subjects. RESULTS: Atherosclerotic risk factors were similar in both groups. The mean (+/- SEM) Lp(a) lipoprotein level was 36 +/- 6 mg/dl among the study patients, compared with 14 +/- 2 mg/dl among control subjects (p = 0.02, Mann-Whitney). Twenty (40%) study patients and seven (16%) control subjects had Lp(a) lipoprotein levels of 30 mg/dl or greater (atherosclerotic risk threshold) (p = 0.01, odds ratio = 3.62, confidence interval (CI) 1.4 to 9.5). Positive HCS panels (antiphospholipid antibodies or deficiencies in antithrombin III, protein C, or protein S) were nearly twice as prevalent in study patients (n = 15, 30%) as in controls (n = 8, 18%), but this difference did not achieve statistical significance. The mean total plasma homocysteine level among the study patients was 15.9 +/- 0.9 mumol/L, which was not significantly different from the mean control value of 14.7 +/- 0.7 mumol/L. Lp(a) lipoprotein was related to risk of premature PVD through a linear logistic relationship (p = 0.003, odds ratio per each 1 mg/dl Lp(a) change was 1.03, CI 1.0 to 1.1). Multivariate analysis with stepwise logistic regression selected two variables: Lp(a) lipoprotein > or = 30 mg/dl (p = 0.01, odds ratio = 3.6, CI 1.3 to 9.9) and family history (p = 0.07, odds ratio = 2.2, CI 0.9 to 5.3). Tests of interaction demonstrated no effect between Lp(a) lipoprotein, HCS, and homocysteine. CONCLUSIONS: Lp(a) lipoprotein of 30 mg/dl or greater is an independent risk factor for premature peripheral atherosclerosis in men. None of the other examined variables exhibited a significant association with premature PVD.

Adult↗
PubMed1996

Comparison of the deoxyuridine suppression test with serum levels of methylmalonic acid and homocysteine in mild cobalamin deficiency.

Both the deoxyuridine suppression test (dUST) and the cobalamin-dependent metabolites, methylmalonic acid (MMA) and homocysteine, are valuable tools for identifying clinical cobalamin deficiency. Examination of these metabolic changes in mild or marginal deficiency can provide useful comparisons of diagnostic frequencies and sensitivities and help define the sequence of metabolic changes in early deficiency. These tests were therefore compared directly with each other in 50 patients with low cobalamin levels and few or no obvious signs of deficiency. Serum homocysteine (P=0.0003) and MMA levels (P=0.0004) correlated with dUST results. However, the dUST results were abnormal significantly more often (38/50 patients) when matched against levels of homocysteine (25 abnormal results of 50; P=0.007) or MMA (20/50; P=0.008). Abnormalities of one or both serum metabolite levels (30/50 patients) occurred almost as often as dUST abnormalities (P=0.059). Metabolite levels, even when originally 'normal', fell with cobalamin therapy in many cases. The results indicate that both the dUST and serum metabolite levels become abnormal before macrocytic anaemia develops in mild cobalamin deficiency. The dUST appears to be most frequently abnormal of the tests; metabolite levels appear to rise almost concurrently but they do not become diagnostically abnormal as soon.

Bone Marrow↗
PubMed1996

Accumulation of methylmalonic acid caused by vitamin B12-deficiency disrupts normal cellular metabolism in rat liver.

To clarify the relationship between intracellular concentrations of methylmalonic acid and metabolic and growth inhibition in vitamin B12-deficient rats, hepatic methylmalonic acid levels were assayed and inhibition of glucose and glutamic acid metabolism by methylmalonic acid was studied in isolated hepatocytes. Vitamin B12-deficient rats (14 weeks old) excreted more urinary methylmalonic acid and had lower body weights than the control rats. Hepatic methylmalonic acid levels (3.6(SD 1.30)-5.3 (SD 0.51) mumol/g tissue; 7.9 (SD 2.90)-11.8 (SD 1.14) mM) were increased and correlated with the extent of the growth retardation during vitamin B12-deficiency. Isolated hepatocytes and mitochondria from normally fed rats were labelled with [14C(U)]glucose and [14C(U)]glutamic acid respectively, in the presence or absence of 5 mM-methylmalonic acid. Although methylmalonic acid did not affect the incorporation of 14C into protein and organic acid fractions in the hepatocytes, it inhibited 14CO2 formation (an index of glucose oxidation by the Krebs cycle) by 25% and incorporation of 14C into the amino acid fraction by 30%. In the mitochondria, methylmalonic acid inhibited 14CO2 formation (indicating glutamic acid oxidation by the Krebs cycle) by 70%, but not the incorporation of 14C into the protein fraction. The incorporation of 14C into the organic acid fraction was significantly stimulated by the addition of methylmalonic acid. These results indicate that the unusual accumulation of methylmalonic acid caused by vitamin B12-deficiency disrupts normal glucose and glutamic acid metabolism in rat liver, probably by inhibiting the Krebs cycle.

Animals↗
PubMed1996

Hormone replacement therapy and cobalamin status in elderly women.

Serum cobalamin concentrations are frequently low in the elderly but the cause is often not apparent. Because oral contraceptives have been associated with low cobalamin concentrations in young women, we compared hormone use with cobalamin status in elderly women to determine whether it could account for their unexplained low cobalamin concentrations. Thirty-eight of the 111 women had abnormal cobalamin status (defined by low cobalamin, elevated methylmalonic acid, and/or elevated homocysteine concentrations) and 73 had normal status. There was no difference in hormone use between the two groups: 7 (18.4%) of the 38 cobalamin-deficient subjects used estrogens compared with 20 (27.4%) of the 73 control subjects. No differences in hormone use were apparent either when analysis was confined to abnormal serum cobalamin concentrations alone. Similarly, the 27 women taking hormones and the 84 women not taking hormones did not have significantly different serum cobalamin or serum total homocysteine concentrations. Indeed, hormone users had slightly, though not significantly, higher cobalamin concentrations and lower homocysteine concentrations than nonusers; furthermore, hormone users also had significantly lower serum methylmalonic acid concentrations. Thus, neither cobalamin concentrations nor cobalamin metabolic status were significantly worse in elderly women taking estrogen than in those not taking it (and, if anything, may have been slightly better). Hormone use does not appear to be a significant contributor to the low cobalamin concentrations or the mild metabolic evidence of cobalamin deficiency so often seen in the elderly.

Aged↗
PubMed1996

Neutrophil nuclear segmentation in mild cobalamin deficiency: relation to metabolic tests of cobalamin status and observations on ethnic differences in neutrophil segmentation.

Neutrophil hypersegmentation is considered the most sensitive peripheral blood cell marker of cobalamin deficiency. However, its diagnostic value in the mild deficiency states that accompany most low cobalamin levels and its relation to metabolic test of cobalamin status are unknown. The authors compared neutrophil lobe averages and percent neutrophils with 5 or more lobes (%5+ lobes) in 169 subjects with their mean corpuscular volume (MCV) and serum cobalamin, methylmalonic acid (MMA), homocysteine, and folate levels and, in 65 cases, with the deoxyuridine suppression test (dUST). Only 9 subjects had hypersegmentation by lobe average and 20 subjects by %5+ lobes. They were not more often cobalamin-deficient than subjects without hypersegmentation. Moreover, only one of 34 subjects with dUST results diagnostic for cobalamin deficiency had neutrophil hypersegmentation. Both indices of neutrophil segmentation in the 169 subjects correlated significantly with homocysteine levels. They also showed weak inverse correlation with cobalamin levels, but did not correlate with MMA, folate, or MCV values. Cobalamin therapy for 6 months did not significantly change neutrophil lobe averages in 35 subjects with mild deficiency, compared with 8 nondeficient controls, and only marginally improved the %5+ lobes. A surprising, incidental observation was that blacks had significantly greater neutrophil segmentation by both criteria than did whites and others. This difference was unrelated to cobalamin or folate status. Our results indicate that dUST abnormalities precede all morphologic changes of deficiency, including hypersegmentation. Although a tendency exists for neutrophil segmentation to increase very slightly as some serum values, especially homocysteine, start to worsen in mild cobalamin deficiency, the metabolic changes precede overt hypersegmentation. Neutrophil nuclear segmentation is insufficiently sensitive in relation to metabolic evidence of deficiency to be used as a clinical tool in the diagnosis of mild cobalamin deficiency.

Asian People↗
PubMed1995

The dynamics of cobalamin utilization in L-1210 mouse leukemia cells: a model of cellular cobalamin metabolism.

The uptake and metabolism of cobalamin (Cbl) has been studied in L-1210 murine leukemia cells propagating in vitro. Extracellular Cbl (protein bound and free) and intracellular Cbl (protein bound and free) were determined after culturing L-1210 cells in the presence of [57Co]cyanocobalamin (CN-Cbl) bound to transcobalamin II (transcobalamin, TC). The intracellular pool of free [57Co]Cbl increased during the first 24 h of culture and a substantial fraction of this free pool was effluxed from the cell to the medium. Upon depletion of extracellular TC-[57Co]CN-Cbl, the intracellular concentration of free Cbl decreased as did the efflux of Cbl to the medium. Internalized [57Co]CN-Cbl was converted to hydroxocobalamin (OH-Cbl), methylcobalamin (Me-Cbl) and 5'-deoxyadenosylcobalamin. These Cbl forms were found in both soluble (cytoplasmic) and insoluble (membrane) fractions. Intracellular protein-bound [57Co]Cbl fractionated with methionine synthase (MS) and methylmalonyl-CoA mutase (MU) activity. The major form of Cbl associated with the two enzymes was OH-Cbl. Cells propagated in medium containing N5-methyltetrahydrofolate and homocysteine showed a substantial increase in MS activity which paralleled the increase in the intracellular concentration of Me-Cbl and the Cbl bound to the enzyme.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗