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Biomedical subjects

S P Stabler

Publications and source records attributed to S P Stabler.

At least 19 recordsLinked to original sources
PubMed2001

Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening systemic illness of abrupt onset and unknown cause. Proteolysis of the blood-clotting protein von Willebrand factor (VWF) observed in normal plasma is decreased in TTP patients. However, the identity of the responsible protease and its role in the pathophysiology of TTP remain unknown. We performed genome-wide linkage analysis in four pedigrees of humans with congenital TTP and mapped the responsible genetic locus to chromosome 9q34. A predicted gene in the identified interval corresponds to a segment of a much larger transcript, identifying a new member of the ADAMTS family of zinc metalloproteinase genes (ADAMTS13). Analysis of patients' genomic DNA identified 12 mutations in the ADAMTS13 gene, accounting for 14 of the 15 disease alleles studied. We show that deficiency of ADAMTS13 is the molecular mechanism responsible for TTP, and suggest that physiologic proteolysis of VWF and/or other ADAMTS13 substrates is required for normal vascular homeostasis.

Chromosome Mapping↗
PubMed2001

Glycine N-methyltransferase deficiency: a novel inborn error causing persistent isolated hypermethioninaemia.

This paper reports clinical and metabolic studies of two Italian siblings with a novel form of persistent isolated hypermethioninaemia, i.e. abnormally elevated plasma methionine that lasted beyond the first months of life and is not due to cystathionine beta-synthase deficiency, tyrosinaemia I or liver disease. Abnormal elevations of their plasma S-adenosylmethionine (AdoMet) concentrations proved they do not have deficient activity of methionine adenosyltransferase I/III. A variety of studies provided evidence that the elevations of methionine and AdoMet are not caused by defects in the methionine transamination pathway, deficient activity of methionine adenosyltransferase II, a mutation in methylenetetrahydrofolate reductase rendering this activity resistant to inhibition by AdoMet, or deficient activity of guanidinoacetate methyltransferase. Plasma sarcosine (N-methylglycine) is elevated, together with elevated plasma AdoMet in normal subjects following oral methionine loads and in association with increased plasma levels of both methionine and AdoMet in cystathionine beta-synthase-deficient individuals. However, plasma sarcosine is not elevated in these siblings. The latter result provides evidence they are deficient in activity of glycine N-methyltransferase (GNMT). The only clinical abnormalities in these siblings are mild hepatomegaly and chronic elevation of serum transaminases not attributable to conventional causes of liver disease. A possible causative connection between GNMT deficiency and these hepatitis-like manifestations is discussed. Further studies are required to evaluate whether dietary methionine restriction will be useful in this situation.

Alanine Transaminase↗
PubMed2001

Decrease of elevated N,N-dimethylglycine and N-methylglycine in human immunodeficiency virus infection during short-term highly active antiretroviral therapy.

This study investigates fasting serum levels of methionine and related metabolites, vitamin B6, and folate during highly active antiretroviral therapy in therapy-naive human immunodeficiency virus (HIV)-1-infected outpatients. The research design consisted of before and during therapy measurements with a median treatment period of 100 days (range, 50 to 188) in frozen samples. The subjects included 17 consecutive HIV-1-infected outpatients (15 men and 2 women; 25 to 65-years-old). Controls were 42 healthy individuals (28 men and 14 women; 24- to 82-years-old) without serologic evidence of HIV and/or hepatitis C infection and normal clinical chemistry. Subjects received treatment with the reverse transcriptase inhibitors, azidothymidine (AZT) or stavudine (D4T) plus lamivudine (3TC) and either the protease inhibitors, indinavir (IND), nelfinavir (NELF), ritonavir (RITV), or saquinavir (SAQ) at the standard dosage. Serum concentrations of methionine, total homocysteine (tHcy), cystathionine (CYSTA), N,N-dimethylglycine (DMG), N-methylglycine (MG), methylmalonic acid (MMA), and total cysteine, as well as vitamin B6, folate, and soluble tumor necrosis factor receptor p75 were taken at baseline and during highly active antiretroviral therapy. Baseline, serum tHcy, MMA, CYSTA, vitamin B6 concentrations were not significantly different from healthy controls. There was, however, a trend towards lower folate serum concentrations at baseline in HIV-infected patients as compared with healthy controls (P =.06). There were no significant correlations between tHcy and vitamin B6, folate, or MMA. Elevated baseline levels of DMG and MG decreased significantly during antiretroviral therapy (P =.0019 and.04, respectively), whereas no significant changes in serum concentrations of CYSTA, MMA, or methionine were detected. tHcy increased in 12 of 17 patients (P =.09). HIV-infected patients displayed significant alterations (elevated DMG and MG serum concentrations) in metabolite levels of the betaine pathway in methionine metabolism, which might be positively influenced by newly initiated antiretroviral combination therapy.

Adult↗
PubMed2001

Association of folate intake and serum homocysteine in elderly persons according to vitamin supplementation and alcohol use.

BACKGROUND: The serum total homocysteine concentration (tHcy), an indicator of folate status and a possible risk factor for vascular disease, is elevated with impaired renal function and poor vitamin B-12 status, which are common in the elderly. OBJECTIVE: Our objective was to determine the association between tHcy, folate intake, alcohol consumption, and other lifestyle factors in elderly persons. DESIGN: This cross-sectional study used linear regression to model changes in tHcy. Subjects were 278 men and women aged 66-94 y studied in 1993. RESULTS: Total folate intake was negatively associated with tHcy in models adjusted for age, sex, serum creatinine, and serum albumin. We found an interaction between food folate intake and supplement use. Food folate intake had an inverse dose-response relation with tHcy that was limited to nonusers of supplements. Predicted tHcy was 1.5 micromol/L lower in users of supplements containing folate and vitamin B-12 than in nonusers and was independent of food folate intake. We found a positive dose-response relation of coffee and tea intake with tHcy, a positive association for alcohol intake of > or = 60 drinks/mo compared with low intake, and an interaction of alcohol use with folate intake and supplement use. Compared with alcohol users, nonusers had higher predicted tHcy and a lower inverse dose-response relation of food folate intake with tHcy. CONCLUSIONS: The inverse association between folate intake and tHcy was strongest among nonusers of supplements and among alcohol drinkers. Identifying modifiable factors related to tHcy, a possible risk factor for vascular disease, is especially important in elderly persons.

Age Factors↗
PubMed2000

Parallel decrease in neurotoxin quinolinic acid and soluble tumor necrosis factor receptor p75 in serum during highly active antiretroviral therapy of HIV type 1 disease.

The chronic immune activation state in HIV disease leads to increased activity of the rate-limiting tryptophan-kynurenine pathway enzyme indoleamine 2,3-dioxygenase (2,3-IDO), thereby increasing the formation of neurotoxic tryptophan metabolites such as kynurenine and quinolinic acid. We investigated whether highly active antiretroviral therapy (HAART) (median duration, 100 days; range, 50-188 days) lowers serum levels of these metabolites in HIV-infected individuals and if so, whether this was paralleled by changes in a surrogate marker for immune activation, i.e., soluble tumor necrosis factor receptor p75 (sTNFR p75) concentrations. Baseline quinolinic acid (848 nM, 95% CI 567-1130 vs. 303 nM, 95% CI 267.1-339.5) and kynurenine (4.1 microM, 95% CI 3.3-4.9 vs. 2.7 microM, 95% CI 2.4-2.9) concentrations as well as the mean kynurenine-to-tryptophan ratio (108.2, 95% CI 76.1-140.4 vs. 51.4, 95% CI 47.6-55.3) in 17 HIV-1-infected outpatients (7 with AIDS) were significantly higher than those in 55 healthy age-matched controls (p < 0.01), respectively. Serum quinolinic acid concentrations in 14 of 17 patients decreased (mean, -44.4%) during HAART in comparison with baseline (471.2 nM, 95% CI 288-654.3; p = 0. 022). Thirteen of these 14 patients also had decreases in sTNFR p75 concentrations. Overall, the mean sTNFR p75 concentration decreased by 36.3% (13.5 ng/ml, 95% CI 9.3-17.8 vs. 8.6 ng/ml, 95% CI 5.9-11. 4; p = 0.01, n = 17). Reduction in viral load through HAART and subsequent mitigation of the pathological immune activation state in HIV disease may have reduced 2,3-IDO over activation. This eventually led to a decrease in quinolinic acid formation. The parallel reduction of the immune activation marker sTNFR p75 supports this hypothesis.

Adult↗
PubMed2000

Inhibition of vitamin B12 metabolism by OH-cobalamin c-lactam in rat oligodendrocytes in culture: a model for studying neuropathy due to vitamin B12 deficiency.

Vitamin B12 is implicated in methylation processes. Myelin basic protein is methylated on one arginine group. A defect in methylation could produce an unstable protein, leading to neurological disorders. In order to study myelin basic protein, we have developed the cultures of newborn rat oligodendrocytes in vitamin B12-depleted medium. As these cells do not grow without serum, vitamin B12 is always present. We overcame this problem by using OH-cobalamin c-lactam, an antagonist of B12. To ensure that the system was vitamin B12 deficient, we measured the concentrations of homocysteine and methylmalonic acid whose accumulations reflect a vitamin B12 deficiency. Methylmalonic acid was measured by mass spectrometry and homocysteine by HPLC. We obtained a powerful model for studying the influence of B12 deficiency on the synthesis of myelin compounds.

Animals↗
PubMed2000

Is the increase in serum cystathionine levels in patients with liver cirrhosis a consequence of impaired homocysteine transsulfuration at the level of gamma-cystathionase?

BACKGROUND: It has been suggested that the major metabolic block in the methionine catabolic pathway in cirrhotics exists at the level of the enzyme S-adenosylmethionine synthetase because in previous studies using conventional amino-acid analyzers, no intermediates of transmethylation/transsulfuration were found to accumulate in plasma downstream of S-adenosylmethionine synthesis. We therefore measured serum concentration intermediates of methionine transmethylation/transsulfuration using an improved gas chromatography/mass spectrometry technique. METHODS: Serum concentrations of methionine, homocysteine, cystathionine, N,N-dimethylglycine, N-methylglycine, methylmalonic acid, 2-methylcitric acid and alpha-aminobutyric acid were determined by gas chromatography/mass spectrometry in 108 consecutive patients with liver cirrhosis at Child stages A (mild cirrhosis, n = 27) and B/C (severe cirrhosis, n = 81), 18 outpatients with non-cirrhotic liver disease, and 55 healthy individuals. RESULTS: Serum levels of methionine, N,N-dimethylglycine, N-methylglycine, cystathionine, and homocysteine were significantly higher in patients at Child stages B/C compared with those of healthy controls (P < 0.01), and they were also significantly higher than in patients with non-cirrhotic liver disease (P < 0.01 and P < 0.05 for homocysteine, respectively). They also correlated with the Child-Pugh score (P < 0.01). Homocysteine, cystathionine, N,N-dimethylglycine, N-methylglycine, methylmalonic acid, and 2-methylcitric acid correlated with serum creatinine. The mean cystathionine concentration was significantly higher in patients with creatinine > or = 1.4 mg/dl than in patients with normal creatinine values (P < 0.01). However, the differences between cirrhotics and healthy controls were still significant after correcting for creatinine. CONCLUSIONS: Our data provides indirect evidence for two hitherto unrecognized alterations of methionine metabolism in cirrhotics, i.e. impairment of the transsulfuration of homocysteine at the level of cystathionine degradation and a shift in remethylation of homocysteine towards the betaine-homocysteine-methyltransferase reaction.

Adolescent↗
PubMed2000

Effects of parenteral cysteine and glutathione feeding in a baboon model of severe prematurity.

BACKGROUND: The availability of cysteine for glutathione synthesis is low in premature infants with respiratory distress. OBJECTIVE: The effects of gestational age, oxygen delivery, and cysteine infusion or glutathione infusion, or both, on plasma total cysteine and other methionine metabolites were studied in a baboon model of severe premature birth with respiratory distress. DESIGN: Premature baboons were studied as part of the multiinvestigator National Institutes of Health Collaborative Project on Bronchopulmonary Dysplasia. Premature baboons, 125 d (69% of term) or 140 d (78% of term) of gestational age, were maintained in neonatal intensive care units for </=14 d. Parenteral feeding with or without supplemental cysteine and glutathione infusions was given. Plasma total cysteine, methionine, N:-methylglycine, cystathionine, and the other methionine metabolites were monitored by capillary gas chromatography-mass spectrometry. RESULTS: Cord blood plasma total cysteine was the lowest in the 125-d-old premature baboons. Plasma total cysteine decreased in the first 3 d after delivery in the 125-d-old (but not in the 140-d-old) premature baboons even when cysteine was infused. Supplementation with glutathione from the first day of life raised plasma total cysteine markedly. Plasma cystathionine increased in all animals after birth but increased 4-fold in 125-d-old animals with glutathione infusion. At 6 and 10 d postdelivery, the arterial-alveolar oxygen gradient was significantly higher in the 125-d-old animals that received glutathione infusions. CONCLUSIONS: Glutathione, but not supplemental cysteine, infusions prevented the postdelivery decline in plasma cysteine concentrations in premature baboons. Glutathione infusions resulted in marked elevations of plasma cystathionine concentration.

Animals↗
PubMed2000

Etiology and diagnostic evaluation of macrocytosis.

BACKGROUND: Elevation of mean cell volume (MCV) is a common clinical problem, but the etiologic spectrum and optimal diagnostic evaluation of macrocytosis are not well defined. METHODS: We studied 300 consecutive hospitalized adult patients with MCV values > or = 100 fL. Assessment included complete blood counts, morphologic review, liver function tests, and levels of serum cobalamin (Cbl), methylmalonic acid, and total homocysteine. RESULTS: The most common cause of macrocytosis was drug therapy, followed by alcohol, liver disease, and reticulocytosis. Megaloblastic hematopoiesis accounted for less than 10% of cases. MCV values > 120 fL were usually caused by Cbl deficiency. Anisocytosis, macro-ovalocytosis, and teardrop erythrocytes were most prominent in megaloblastic hematopoiesis. Elevated levels of serum methylmalonic acid and total homocysteine were useful in the diagnosis of Cbl deficiency. CONCLUSIONS: Drugs and alcohol are the most common causes of macrocytosis in hospitalized patients in a New York City teaching hospital. We have formulated tentative guidelines for the evaluation of high MCV values in this setting.

Adult↗
PubMed2000

Vitamin B(12) deficiency and depression in physically disabled older women: epidemiologic evidence from the Women's Health and Aging Study.

OBJECTIVE: It has been hypothesized that adequate concentrations of vitamin B(12) and folate are essential to maintain the integrity of the neurological systems involved in mood regulation, but epidemiologic evidence for such a link in the general population is unavailable. This study examined whether community-dwelling older women with metabolically significant vitamin B(12) or folate deficiency are particularly prone to depression. METHOD: Serum levels of vitamin B(12), folate, methylmalonic acid, and total homocysteine were assayed in 700 disabled, nondemented women aged 65 years and over living in the community. Depressive symptoms were measured by means of the Geriatric Depression Scale and categorized as no depression, mild depression, and severe depression. RESULTS: Serum homocysteine levels, serum folate levels, and the prevalences of folate deficiency and anemia were not associated with depression status. The depressed subjects, especially those with severe depression, had a significantly higher serum methylmalonic acid level and a nonsignificantly lower serum vitamin B(12) level than the nondepressed subjects. Metabolically significant vitamin B(12) deficiency was present in 14.9% of the 478 nondepressed subjects, 17. 0% of the 100 mildly depressed subjects, and 27.0% of the 122 severely depressed women. After adjustment for sociodemographic characteristics and health status, the subjects with vitamin B(12) deficiency were 2.05 times as likely to be severely depressed as were nondeficient subjects. CONCLUSIONS: In community-dwelling older women, metabolically significant vitamin B(12)deficiency is associated with a twofold risk of severe depression.

Age Factors↗
PubMed1999

Total homocysteine is associated with nephropathy in non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) and hyperhomocysteinemia are both associated with premature vascular disease. We tested the hypothesis that homocysteine is associated with vascular disease and other diabetic complications in patients with NIDDM. The current investigation is a cross-sectional analysis of baseline variables for participants in the Appropriate Blood Pressure Control in Diabetes (ABCD) Trial. Men and women aged 40 to 74 years with NIDDM and a mean diastolic blood pressure (BP) of 80 mm Hg or higher were eligible. We measured serum levels of total homocysteine (tHcy), cystathionine, and methylmalonic acid (MMA) and correlated these values with clinical and other laboratory measures of the complications of diabetes mellitus in 452 subjects. tHcy was higher in males than in females and correlated with the duration of hypertension and systolic BP. tHcy was significantly correlated with MMA (r = .35, P < .0001) and cystathionine (r = .53, P < .0001) levels and inversely correlated with serum B12 (r = -.23, P < .0001) and folate (r = -.18, P < .0001). It was significantly correlated with serum creatinine (r = .28, P < .0001 for males and r = .39, P < .0001 for females) and inversely correlated with creatinine clearance (r = -.19, P < .005 for males and r = -.30, P < .0001 for females). tHcy was not increased in subjects with cardiovascular disease or retinopathy, but it was increased in those with neuropathy (10.3 v 9.3 micromol/L, P < .05) and macroalbuminuria (11.0 v 9.2 micromol/L, P < .005). Of these subjects, 2.2% met the criteria for vitamin B12 deficiency and 1% met the criteria for folate deficiency. We conclude that elevations of tHcy in this population appear to be the result of a combination of vitamin deficiency and decreased renal function and do not appear to be a predictor of cardiovascular disease.

Adult↗
PubMed1999

Racial differences in prevalence of cobalamin and folate deficiencies in disabled elderly women.

BACKGROUND: Many previous investigations of cobalamin and folate status were performed in white populations. OBJECTIVE: Our objective was to determine whether there are racial differences in the prevalence of cobalamin and folate deficiency. DESIGN: The study was a cross-sectional comparison of baseline serum cobalamin, folate, methylmalonic acid (MMA), total homocysteine (tHcy), and creatinine concentrations, complete blood count, and vitamin supplementation in 550 white and 212 African American subjects from a cohort of physically disabled older women. RESULTS: The mean (+/-SD) serum MMA concentration was significantly higher in whites than in African Americans: 284 +/- 229 compared with 218 +/- 158 nmol/L (P = 0.0001). tHcy concentration was higher in African Americans than in whites: 12.4 +/- 7.0 compared with 10.9 +/- 4.6 micromol/L (P = 0.001). Serum cobalamin was lower in whites (P = 0.0002). Cobalamin deficiency (serum cobalamin <258 pmol/L and MMA >271 nmol/L) was more frequent in the white women (19% compared with 8%; P < 0.0003). Folate deficiency (serum folate <11.4 nmol/L, tHcy >13.9 micromol/L, and MMA <271 nmol/L) was more prevalent in African Americans than in whites (5% compared with 2%; P = 0.01). Multivitamin use was associated with lower tHcy but not with MMA concentrations. Regression models showed that age >85 y, African American race, serum creatinine >90 micromol/L, and high MMA concentration were all significantly correlated with higher tHcy. Creatinine > 90 micromol/L, white race, and folate concentration were positively associated with MMA concentration. CONCLUSIONS: Cobalamin deficiency with elevated serum MMA concentration is more prevalent in elderly white than in African American women and elevated serum tHcy and folate deficiency are more prevalent in elderly African American than in white women.

Aged↗
PubMed1999

Pancytopenia in Zimbabwe.

BACKGROUND: There has been little systematic study of the clinical spectrum of pancytopenia, and the optimal diagnostic approach to pancytopenia remains undefined. METHODS: The authors studied 134 hospitalized pancytopenic patients in Zimbabwe in both consecutive and nonconsecutive fashion. RESULTS: The most common cause of pancytopenia was megaloblastic anemia, followed by aplastic anemia, acute leukemia, acquired immunodeficiency syndrome (AIDS), and hypersplenism. Severe pancytopenia was usually due to aplastic anemia. Patients with aplastic anemia and acute leukemia were usually children, whereas those with megaloblastic anemia were adults. Moderate to severe anemia was noted throughout the series, but was most striking in patients with megaloblastic anemia, aplastic anemia, and acute leukemia. The mean corpuscular volume (MCV) was elevated in most patients with megaloblastic hematopoiesis, aplastic anemia, and acute nonlymphocytic leukemia. Normal or low MCV values were noted in almost one third of patients with megaloblastic anemia. Anisocytosis, poikilocytosis, macroovalocytosis, microcytosis, fragmentation, and teardrop erythrocytes were more prominent on the blood films of patients with megaloblastic anemia. CONCLUSIONS: Megaloblastic anemia, aplastic anemia, and AIDS are the most common causes of pancytopenia in Zimbabwe. Aplasia is the most frequent cause of severe pancytopenia. The authors have formulated tentative guidelines for the evaluation of pancytopenic patients in this setting.

Acquired Immunodeficiency Syndrome↗
PubMed1998

Effective treatment of cobalamin deficiency with oral cobalamin.

Because cobalamin deficiency is routinely treated with parenteral cobalamin, we investigated the efficacy of oral therapy. We randomly assigned 38 newly diagnosed cobalamin deficient patients to receive cyanocobalamin as either 1 mg intramuscularly on days 1, 3, 7, 10, 14, 21, 30, 60, and 90 or 2 mg orally on a daily basis for 120 days. Therapeutic effectiveness was evaluated by measuring hematologic and neurologic improvement and changes in serum levels of cobalamin (normal, 200 to 900 pg/mL) methylmalonic acid (normal, 73 to 271 nmol/L), and homocysteine (normal, 5.1 to 13.9 micromol/L). Five patients were subsequently found to have folate deficiency, which left 18 evaluable patients in the oral group and 15 in the parenteral group. Correction of hematologic and neurologic abnormalities was prompt and indistinguishable between the 2 groups. The mean pretreatment values for serum cobalamin, methylmalonic acid, and homocysteine were, respectively, 93 pg/mL, 3,850 nmol/L, and 37. 2 micromol/L in the oral group and 95 pg/mL, 3,630 nmol/L, and 40.0 micromol/L in the parenteral therapy group. After 4 months of therapy, the respective mean values were 1,005 pg/mL, 169 nmol/L, and 10.6 micromol/L in the oral group and 325 pg/mL, 265 nmol/L, and 12.2 micromol/L in the parenteral group. The higher serum cobalamin and lower serum methylmalonic acid levels at 4 months posttreatment in the oral group versus the parenteral group were significant, with P < .0005 and P < .05, respectively. In cobalamin deficiency, 2 mg of cyanocobalamin administered orally on a daily basis was as effective as 1 mg administered intramuscularly on a monthly basis and may be superior.

Administration, Oral↗
PubMed1998

Relevance of vitamins, homocysteine and other metabolites in neuropsychiatric disorders.

Indistinguishable hematologic abnormalities are seen in most patients with cobalamin (Cbl, vitamin B12) or folate deficiency. Approximately one third of Cbl-deficient patients develop a wide variety of non-focal neuropsychiatric abnormalities that are not seen in folate deficiency. Serum levels of homocysteine are elevated to a similar degree in Cbl-deficient patients with and without neuropsychiatric abnormalities, and in folate-deficient patients. Serum levels of eight other metabolites including methylmalonic acid also fail to elucidate the biochemical basis for the neuropsychiatric abnormalities. Levels of homocysteine and methylmalonic acid are often only slightly elevated in Cbl-deficient patients who have significant neuropsychiatric defects. Moderate elevations of homocysteine and methylmalonic acid occur in 20%-30% of various elderly populations (mean age 80) and may play a role in the similar neuropsychiatric abnormalities that occur increasingly with aging. Taken together, these studies suggest that an important unknown Cbl-dependent enzyme, metabolic abnormality, environmental factor, or genetic factor may play a major role in the pathophysiology of the neuropsychiatric abnormalities caused by Cbl deficiency.

Central Nervous System Diseases↗