ABSTRACT
OBJECTIVES: To evaluate postpartum contraception experiences of mothers with premature infants in the neonatal intensive care unit (NICU), their knowledge of risk factors for preterm delivery and their interest in a family planning clinic located near the NICU. STUDY DESIGN: This is a cross-sectional survey of English or Spanish-speaking women 18 or older whose premature neonate had been in the NICU for 5 days or more in a current stable condition. RESULTS: A total of 95 women were interviewed at a median of 2.7 weeks postpartum (range 0.6-12.9). Approximately 75% of women were currently using or planning to use contraception, with 33% using less effective methods. Half of women reported they would obtain contraception at a family planning clinic near the NICU. Only 32% identified a short interpregnancy interval as a risk factor for preterm delivery. CONCLUSION: Lack of knowledge of short interpregnancy interval as a risk factor for a future preterm delivery highlights the need to address postpartum contraception education and provision in this high-risk population.
Subject(s)
Contraception/methods , Health Knowledge, Attitudes, Practice , Infant, Premature , Intensive Care Units, Neonatal/organization & administration , Mothers/education , Adolescent , Adult , Birth Intervals , Cross-Sectional Studies , Female , Humans , Infant , Infant, Newborn , Postpartum Period , Pregnancy , Risk Factors , Young AdultABSTRACT
Cobalamin (CBL), the biologically active form of vitamin B12, and its analogs, are produced by bacteria only if cobalt supply is adequate. The analogs differ generally by the nucleotide moiety of the molecule. In CBL, 5,6-dimethylbenzimidazole (5,6-DMB) is the base in the nucleotide moiety. The present study aimed to determine if a supplement of 5,6-DMB could increase utilization of dietary cobalt for synthesis of CBL and change ruminal fermentation, nutrient digestibility, omasal flow of nutrients and ruminal protozoa counts. Eight ruminally cannulated multiparous Holstein cows (mean±standard deviation=238±21 days in milk and 736±47 kg of BW) were used in a crossover design. Cows were randomly assigned to a daily supplement of a gelatin capsule containing 1.5 g of 5,6-DMB via the rumen cannula or no supplement. Each period lasted 29 days and consisted of 21 days for treatment adaptation and 8 days for data and samples collection. Five corrinoids, CBL and four cobamides were detected in the total mixed ration and the omasal digesta from both treatments. The dietary supplement of 5,6-DMB increased (P=0.02) apparent ruminal synthesis of CBL from 14.6 to 19.6 (s.e.m. 0.8) mg/day but had no effect (P>0.1) on apparent ruminal synthesis of the four analogs. The supplement of 5,6-DMB had no effect (P>0.1) on milk production and composition, or on protozoal count, ruminal pH and concentrations of volatile fatty acids and ammonia nitrogen in rumen content. The supplement had also no effect (P>0.1) on intake, omasal flow and apparent ruminal digestibility of dry matter, organic matter, NDF, ADF and nitrogenous fractions. Plasma concentration of CBL was not affected by treatments (P=0.98). Providing a preformed part of the CBL molecule, that is, 5,6-DMB, increased by 34% the apparent ruminal synthesis of CBL by ruminal bacteria but had no effect on ruminal fermentation or protozoa count and it was not sufficient to increase plasma concentrations of the vitamin. Even though the efficiency of cobalt utilization for apparent synthesis of CBL was increased from 2.0% to 2.7% by the 5,6-DMB supplement, this improved efficiency was still very low. Further research is needed to identify the factors affecting efficiency of utilization of cobalt for synthesis of CBL by the bacterial populations in rumen.
Subject(s)
Benzimidazoles/pharmacology , Cattle/metabolism , Dietary Supplements , Milk/metabolism , Rumen/drug effects , Vitamin B 12/metabolism , Animals , Benzimidazoles/administration & dosage , Benzimidazoles/metabolism , Cattle/microbiology , Cobalt/metabolism , Cross-Over Studies , Female , Fermentation , Lactation , Milk/chemistry , Omasum/metabolism , Rumen/metabolism , Rumen/microbiologyABSTRACT
The purpose of this prospective cohort study was to compare pain during IUD insertion between women with a history of vaginal delivery and women without a history of vaginal delivery. First-time IUD users chose either the CuT380A or the levonorgestrel IUS. We enrolled 49 women with previous vaginal delivery and 49 women with no history of vaginal delivery (either only caesarean deliveries or nulliparous). The mean pain score on a 0-100 mm visual analog scale during insertion in the vaginal delivery group was 34.7 (SD 31.6) compared with 51.2 (SD 29.2) in the group without previous vaginal delivery (p = 0.009). In multivariable analysis controlling for age, breast-feeding, expected pain, baseline anxiety, insertion timing (6-12 weeks postpartum, 2-4 weeks post-abortion or interval), and insertion difficulty, history of vaginal delivery was associated with a 15.5 point reduction in pain (95% CI, -27.4, -3.7). Other significant predictors of pain were 'expected pain' and 'insertion difficulty'.
Subject(s)
Delivery, Obstetric , Intrauterine Devices, Medicated/adverse effects , Pain/etiology , Adult , Female , Humans , Pain Measurement , Prospective Studies , Young AdultABSTRACT
In an effort to share best practices in undergraduate engineering design education, we describe the origin, evolution and the current status of the undergraduate biomedical engineering design team program at Johns Hopkins University. Specifically, we describe the program and judge the quality of the pedagogy by relating it to sponsor feedback, project outcomes, external recognition and student satisfaction. The general pedagogic practices, some of which are unique to Hopkins, that have worked best include: (1) having a hierarchical team structure, selecting team leaders the Spring semester prior to the academic year, and empowering them to develop and manage their teams, (2) incorporating a longitudinal component that incudes freshmen as part of the team, (3) having each team choose from among pre-screened clinical problems, (4) developing relationships and fostering medical faculty, industry and government to allow students access to engineers, clinicians and clinical environments as needed, (5) providing didactic sessions on topics related to requirements for the next presentation, (6) employing judges from engineering, medicine, industry and government to evaluate designs and provide constructive criticisms approximately once every 3-4 weeks and (7) requiring students to test the efficacy of their designs. Institutional support and resources are crucial for the design program to flourish. Most importantly, our willingness and flexibility to change the program each year based on feedback from students, sponsors, outcomes and judges provides a mechanism for us to test new approaches and continue or modify those that work well, and eliminate those that did not.
Subject(s)
Biomedical Engineering/education , Education, Graduate/methods , Education, Graduate/organization & administration , Education, Graduate/standards , Education, Graduate/trends , Biomedical Engineering/methods , Biomedical Engineering/organization & administration , Biomedical Engineering/trends , HumansABSTRACT
OBJECTIVE: To determine the overall folate status of a population-based multi-ethnic sample of octogenarians and centenarians and the specific dietary, demographic and physiological factors associated with observed abnormalities. DESIGN: Population-based multiethnic sample of adults aged 80 to 89 and 98 and above. SETTING: Northern Georgia, USA. PARTICIPANTS: Men and women aged 80 to 89 (octogenarians, n = 77) and 98 and older (centenarians, n = 199). ANALYSES: Wilcoxon rank sum tests, and Chi square and logistic regression analyses were used to examine associations of low and high folate status with hematological indicators and other variables of interest. RESULTS: The prevalence of low red blood cell (RBC) folate was low overall, but tended to be higher in centenarians than in octogenarians (6.5% vs. 1.3%, p = 0.058; defined as RBC folate < 317 nmol/L). The risk of having lower RBC folate (< 25th vs. > 25th percentile for RBC folate for 60yr+ in NHANES 1999-2000) was greater in association with vitamin B12 deficiency (OR = 5.36; 95%CI: 2.87-10.01), African American race (OR = 4.29; 95%CI: 2.08-8.83), and residence in a skilled nursing facility (OR = 3.25; 95%CI: 1.56-6.78) but was not influenced by age, gender, B-vitamin supplement use, high/low food score or presence of atrophic gastritis. Combined high plasma folate and low vitamin B12 status was present in some individuals (n=11), but was not associated with increased prevalence of anemia or cognitive impairment in this study. CONCLUSIONS: Low RBC folate status (< 317 nmol/L) was rare in this post folic acid fortification sample of octogenarians and centenarians. RBC folate status (< 25th percentile) was strongly associated with 1) vitamin B12 deficiency, which has strong implications for vitamin treatment, and 2) with being African American, suggesting racial disparities exist even in the oldest old.
Subject(s)
Black or African American , Erythrocytes/chemistry , Folic Acid/blood , Nutritional Status , Vitamin B Complex/blood , White People , Aged, 80 and over , Anemia/epidemiology , Anemia/etiology , Cohort Studies , Dietary Supplements , Female , Folic Acid/administration & dosage , Folic Acid Deficiency/complications , Folic Acid Deficiency/epidemiology , Georgia/epidemiology , Health Status Disparities , Humans , Male , Nutrition Surveys , Prevalence , Surveys and Questionnaires , Vitamin B 12/administration & dosage , Vitamin B 12/blood , Vitamin B 12 Deficiency/complications , Vitamin B 12 Deficiency/epidemiology , Vitamin B Complex/administration & dosageABSTRACT
OBJECTIVE: To investigate the nature and extent of neurosurgically treated obstetric plexus lesions with obstetric and neonatal precedents. DESIGN: Retrospective analysis of prospectively collected data. SETTING: Leiden, the Netherlands. POPULATION: A 9-year cohort of infants (n = 206) neurosurgically treated for obstetric brachial plexus lesion at a tertiary referral centre for nerve lesions. METHOD: Obstetric and neonatal data (parity, diabetic status, pregnancy gestation, mode of cephalic delivery and birthweight) were collected using a standardised protocol and correlated to neurological severity of the brachial plexus lesion. MAIN OUTCOME MEASURE: Neurological severity of the brachial plexus lesion. RESULTS: Nulliparous women delivered significantly lower birthweight newborns (P = 0.016), injuries in those infants were associated with the least severe injury classification. The most prominent association in ordinal logistic regression was between neurological injury severity and larger birthweight (P < 0.001). CONCLUSIONS: Birthweight is correlated with neurological severity of the injury in a group of infants experiencing brachial plexus injury resulting from cephalic vaginal delivery.
Subject(s)
Birth Injuries/epidemiology , Birth Weight , Brachial Plexus/injuries , Injury Severity Score , Birth Injuries/surgery , Brachial Plexus/surgery , Brachial Plexus Neuropathies/epidemiology , Brachial Plexus Neuropathies/surgery , Cohort Studies , Female , Humans , Infant , Infant, Newborn , Logistic Models , Male , Netherlands/epidemiology , Neurologic Examination , Parity , Pregnancy , Retrospective StudiesABSTRACT
OBJECTIVE: Test the hypotheses that vitamin B12 deficiency would be prevalent in octogenarians and centenarians and associated with age, gender, race/ethnicity, living arrangements (community or skilled nursing facility), animal food intake, B-vitamin supplement use, atrophic gastritis, folate status, and hematological indicators. DESIGN: Population-based multi-ethnic sample of adults aged 80 to 89 and 98 and above. SETTING: Northern Georgia in the United States. PARTICIPANTS: Men and women aged 80 to 89 (octogenarians, n = 80) and 98 and older (centenarians, n = 231). MEASUREMENTS: Wilcoxon signed-rank tests, Fisher's exact tests, and logistic regression analysis was used to examine the associations of vitamin B12 status with the variables of interest. RESULTS: After excluding participants receiving vitamin B12 injections (n = 17), the prevalence of vitamin B12 deficiency was higher in centenarians than in octogenarians (35.3% vs. 22.8%, p < 0.05, defined as plasma vitamin B12 < 258 pmol/L and serum methylmalonic acid > 271 nmol/L and methylmalonic acid > serum 2-methylcitrate) and in both age groups was correlated with significantly higher homocysteine (p < 0.05) and lower plasma and red cell folate (p < 0.01), but was not related to hemoglobin, anemia, mean cell volume, or macrocytosis. In logistic regression analysis, the probability of being vitamin B12-deficient was significantly increased by being a centenarian vs. octogenarian (p < 0.03), by being white vs. African American (p < 0.02), by increasing severity of atrophic gastritis (p < 0.001), and by not taking oral B-vitamin supplements (p < 0.01), but was not related to gender, living arrangements, or animal food intake. CONCLUSIONS: Centenarians and octogenarians are at high risk for vitamin B12 deficiency for many of the same reasons identified in other older adult populations. Given the numerous potential adverse consequences of poor vitamin B12 status, efforts are needed to ensure vitamin B12 adequacy in these older adults.
Subject(s)
Aging/blood , Black or African American , Vitamin B 12 Deficiency/ethnology , Vitamin B 12/blood , White People , Age Factors , Aged, 80 and over , Erythrocytes/chemistry , Female , Folic Acid/metabolism , Georgia/epidemiology , Homocysteine/blood , Humans , Male , Sex Factors , Vitamin B 12 Deficiency/bloodABSTRACT
OBJECTIVE: This project was designed to follow-up prior evidence that demonstrated a significant association between vitamin B12 transport and metabolism and the frailty syndrome in community-dwelling older women. The cross-sectional relationship between genetic variants within six candidate genes along this pathway with serum methylmalonic acid (MMA) levels and frailty was evaluated in this same population of older women. METHODS: Baseline measures were collected prior to folate fortification from 326 women in the Women's Health and Aging Studies I and II. Odds ratios and statistical tests were estimated for single SNP and haplotype via linear regression models for serum MMA, a marker for available vitamin B12, and in logistic regression models for frailty. RESULTS: Fifty-six SNPs from CBS, MTHFR, MTR, MTRR, TCN1 and TCN2 genes were genotyped. Several SNPs in MTHFR, MTR and MTRR demonstrated a modest association to elevated MMA, while SNPs in TCN2 showed significant association to the frailty syndrome. TCN2 polymorphisms, particularly one SNP reported to be in perfect LD with functional variant Pro259Arg, were significantly associated with increased odds of frailty, after adjustment for age, presence of cardiovascular disease and elevated MMA (OR = 2.25, p-value = 0.009). CONCLUSIONS: Using MMA as a marker for vitamin B12, these results suggest that TCN2 gene variants may lead to decreased vitamin B12 availability, leading to reduced energy metabolism, ultimately contributing to frailty pathology. Further studies to determine the biological role of functional TCN2 polymorphisms in frailty are needed.
Subject(s)
Frail Elderly , Genetic Variation , Methylmalonic Acid/blood , Polymorphism, Single Nucleotide , Transcobalamins/genetics , Vitamin B 12/metabolism , Aged , Biological Availability , Biomarkers/blood , Carbon/metabolism , Cohort Studies , Cross-Sectional Studies , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Female , Ferredoxin-NADP Reductase/genetics , Ferredoxin-NADP Reductase/metabolism , Folic Acid/administration & dosage , Folic Acid/metabolism , Food, Fortified , Haplotypes , Humans , Linear Models , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Methylenetetrahydrofolate Reductase (NADPH2)/metabolism , Saccharomyces cerevisiae Proteins/genetics , Saccharomyces cerevisiae Proteins/metabolism , Transcobalamins/metabolism , Transcription Factors/genetics , Transcription Factors/metabolism , Vitamin B 12/blood , Women's HealthABSTRACT
SUMMARY: Inadequate vitamin B12 status in a pregnant woman increases the risk for adverse maternal and fetal outcomes. The use of serum vitamin B12 concentration alone to assess vitamin B12 status in pregnant women is unreliable because of the decrease in serum vitamin B12 levels in normal pregnancy. The combination of serum vitamin B12 and methylmalonic acid (MMA) concentrations may provide a better estimate of vitamin B12 status. We obtained blood samples from 98 pregnant women in the third trimester at an antenatal clinic in Jos, Nigeria. All subjects were taking iron and folate supplements. Twelve of the subjects had a serum vitamin B12 concentration <148 pmol/l and 18 subjects had a serum MMA level >271 nmol/l. Using a combination of low serum vitamin B12 and elevated MMA concentrations, eight subjects were classified as having subclinical vitamin B12 deficiency. Because of the potential harmful consequences of vitamin B12 deficiency in pregnant women, it would be advisable to add vitamin B12 supplements to the existing regimen of folate and iron supplements currently provided to pregnant women in Nigeria.
Subject(s)
Pregnancy Complications/blood , Pregnancy Complications/diagnosis , Vitamin B 12 Deficiency/blood , Vitamin B 12 Deficiency/diagnosis , Vitamin B 12/blood , Adult , Ambulatory Care Facilities , Female , Folic Acid/blood , Hemoglobins/metabolism , Homocysteine/blood , Humans , Methylmalonic Acid/blood , Nigeria , Pregnancy , Prenatal Care , Young AdultABSTRACT
The aim of the project was to calculate the apparent synthesis or destruction of cobalamin (vitamin B(12)) and its analogs in the rumen as well as their apparent intestinal disappearance in dairy cows. Four lactating cows were fed a diet supplemented with cobalt alone (0.76 mg/kg of DM; control) or with cobalt and vitamin B(12) (cyanocobalamin, 500 mg/d; treated). In addition to cobalamin, the only biologically active molecule for the cow, 7 analogs were identified in duodenal and ileal digesta: cobinamide, which lacks the base, ribose, and phosphate groups; and 6 other molecules in which the base, 5,6-dimethylbenzimidazole, is replaced by cresol, 2-CH(3)-adenine, adenine, 2-CH(3)-S-adenine, or 5-OH-benzimidazole, or an unidentified cobamine. Small amounts of cobalamin and cobinamide were detected in the total mixed ration, but apparent synthesis of all forms took place in rumen. During the control period, cobalamin represented 38% of the total amounts of corrinoids produced in rumen. Approximately 11% of the average daily intake of cobalt was used for apparent ruminal synthesis of corrinoids, of which only 4% was incorporated into cobalamin. Only 20% of the supplement of cyanocobalamin was recovered at the duodenal level; cobinamide appeared to be the major product of degradation of supplementary cyanocobalamin in the rumen. During the control and treatment periods, there was an apparent intestinal disappearance of cobalamin and 5-OH-benzimidazole cobamide only; only the apparent intestinal disappearance of cobalamin differed between the 2 periods. Although cobalamin was not the major form synthesized by ruminal microflora and, even if supplementary cyanocobalamin was extensively destroyed by ruminal microflora, based on calculations of apparent intestinal disappearance, cobalamin seems to be the major form absorbed in the small intestine.
Subject(s)
Cattle/metabolism , Intestinal Mucosa/metabolism , Rumen/metabolism , Vitamin B 12/analogs & derivatives , Vitamin B 12/metabolism , Animals , Dairying , FemaleABSTRACT
OBJECTIVE: To evaluate the association between markers of vitamins B12, B6 and folate deficiency and the geriatric syndrome of frailty. DESIGN: Cross-sectional study of baseline measures from the combined Women's Health and Aging Studies. SETTING: Baltimore, Maryland. PARTICIPANTS: Seven hundred three community-dwelling women, aged 70-79. MEASUREMENTS: Frailty was defined by five-component screening criteria that include weight, grip strength, endurance, physical activity and walking speed measurements and modeled as binary and 3-level polytomous outcomes. Independent variables serum vitamin B6, vitamin B12, methylmalonic acid, total homocysteine, cystathionine and folate were modeled continuously and as abnormal versus normal. RESULTS: Serum biomarker levels varied significantly by race. All analyses were race-stratified and results are reported only for Caucasian women due to small African American sample size. In polytomous logistic regression models of 3-level frailty, Caucasian women with increasing MMA, defined either continuously or using a predefined threshold, had 40-60% greater odds of being prefrail (p-values < 0.07) and 1.66-2.33 times greater odds of being frail (p-values < 0.02) compared to nonfrails after adjustment for age, education, low serum carotenoids, alcohol intake, cardiovascular disease and renal impairment. Both binary and polytomous frailty models evaluating vitamin B12 as the main exposure estimated odds ratios that were similar in trend yet slightly less significant than the MMA results. CONCLUSIONS: These results suggest that vitamin B12 deficiency may contribute to the frailty syndrome in community-dwelling older women. Future studies are needed to explore these relationships longitudinally.
Subject(s)
Frail Elderly , Malnutrition/blood , Vitamin B Complex/blood , Vitamin B Deficiency/epidemiology , Black or African American , Aged , Biomarkers/blood , Cohort Studies , Cross-Sectional Studies , Female , Humans , Malnutrition/epidemiology , Nutritional Status , Prevalence , Risk Factors , White People , Women's HealthABSTRACT
OBJECTIVES: To examine the association between methylenetetrahydrofolate reductase (MTHFR) (C677T and A1298C), methionine synthase (MTR) A2756G and methionine synthase reductase (MTRR) A66G gene polymorphisms and total homocysteine (tHcy), methylmalonic acid (MMA) and S-adenosylmethionine/S-adenosylhomocysteine (SAM/SAH) levels; and to evaluate the potential interactions with folate or cobalamin (Cbl) status. SUBJECTS/METHODS: Two hundred seventy-five healthy women at labor who delivered full-term normal babies. Cbl, folate, tHcy, MMA, SAM and SAH were measured in serum specimens. The genotypes for polymorphisms were determined by PCR-restriction fragment length polymorphism (RFLP). RESULTS: Serum folate, MTHFR 677T allele and MTR 2756AA genotypes were the predictors of tHcy levels in pregnant women. Serum Cbl and creatinine were the predictors of SAM/SAH ratio and MMA levels, respectively. The gene polymorphisms were not determinants for MMA levels and SAM/SAH ratios. Low levels of serum folate were associated with elevated tHcy in pregnant women, independently of the gene polymorphisms. In pregnant women carrying MTHFR 677T allele, or MTHFR 1298AA or MTRR 66AA genotypes, lower Cbl levels were associated with higher levels of tHcy. Lower SAM/SAH ratio was found in MTHFR 677CC or MTRR A2756AA genotypes carriers when Cbl levels were lower than 142 pmol/l. CONCLUSIONS: Serum folate and MTHFR C677T and MTR A2576G gene polymorphisms were the determinants for tHcy levels. The interaction between low levels of serum Cbl and MTHFR (C677T or A1298C) or MTRR A66G gene polymorphisms was associated with increased tHcy.
Subject(s)
5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase/genetics , Ferredoxin-NADP Reductase/genetics , Homocysteine/blood , Methylenetetrahydrofolate Reductase (NADPH2)/genetics , Polymorphism, Restriction Fragment Length , Pregnancy/blood , Adolescent , Adult , Alleles , Analysis of Variance , Female , Folic Acid/blood , Gene Frequency , Genotype , Humans , Methylmalonic Acid/blood , Polymerase Chain Reaction , Pregnancy/genetics , S-Adenosylhomocysteine/blood , S-Adenosylmethionine/blood , Vitamin B 12/blood , Young AdultABSTRACT
BACKGROUND: While folic acid (FA) reduces plasma homocysteine (Hcy), whether the simultaneous improvement in endothelial function is dependent on Hcy lowering per se is questionable. In the present study the relationship between FA dose, Hcy lowering and endothelial function in patients with coronary artery disease (CAD) was investigated. MATERIALS AND METHODS: Eighty-four patients with CAD received either 400 microg FA or 5 mg placebo daily for a 6-week treatment period. A further 44 patients with CAD received either 100 mg kg(-1) day(-1) of betaine or placebo for a 6-week treatment period. Flow-mediated dilatation (FMD), a measure of endothelial function, was assessed before and after the 6-week periods. Isometric tension and Western blotting were used to investigate the effect of FA on endothelial function and endothelial nitric oxide synthase (eNOS) dimerization in isolated rabbit aortic rings and cultured porcine aortic endothelial cells (PAEC), respectively. RESULTS: Both 400 micro g day(-1) and 5 mg day(-1) FA significantly increased plasma folate and decreased plasma Hcy. The FMD improved significantly after 6 weeks' treatment of 5 mg day(-1) FA but did not correlate with the reduction in Hcy. There was no change in FMD in either the 400 micro g FA or placebo group. In a subgroup analysis of 11 patients in the betaine group, despite a reduced Hcy, a significant impairment in FMD was observed. In the in vitro studies FA, but not betaine, reversed methionine-induced endothelial dysfunction. Moreover, the FA promoted eNOS dimerization in cultured PAEC. CONCLUSIONS: These data suggest that FA dose-dependently improves endothelial function in CAD via a mechanism independently of Hcy lowering. It may involve promotion of eNOS dimerization.
Subject(s)
Betaine/therapeutic use , Cardiotonic Agents/therapeutic use , Coronary Artery Disease/drug therapy , Endothelium, Vascular/drug effects , Folic Acid/administration & dosage , Hematinics/administration & dosage , Aged , Betaine/blood , Dose-Response Relationship, Drug , Double-Blind Method , Endothelium, Vascular/metabolism , Female , Folic Acid/blood , Hematinics/blood , Humans , Male , Middle AgedABSTRACT
This paper reports the third proven human case of deficient S-adenosylhomocysteine (AdoHcy) hydrolase activity. The patient is similar to the only two previously reported cases with this disorder in having severe myopathy, developmental delay, elevated serum creatine kinase (CK) concentrations, and hypermethioninaemia. Although he has been followed from infancy, the basic enzyme deficiency was established only at age 26 years. The diagnosis was based on markedly elevated plasma concentrations of both AdoHcy and S-adenosylmethionine, some 20% of the mean control activity of AdoHcy hydrolase activity in haemolysates of his red-blood cells, and two missense mutations in his gene encoding AdoHcy hydrolase. He had low values of erythrocyte phosphatidylcholine and plasma free choline and marginally elevated excretion of guanidinoacetate, suggesting that the elevated AdoHcy may have been inhibiting methylation of phosphatidylethanolamine and guanidinoacetate. His leukocyte DNA was globally more methylated than the DNA's of his parents or the mean extent of methylation measured in age-matched control subjects.
Subject(s)
Adenosylhomocysteinase/deficiency , Metabolism, Inborn Errors/diagnosis , Adult , Choline/metabolism , DNA Methylation , Erythrocytes/metabolism , Family Health , Humans , Magnetic Resonance Imaging , Male , Metabolism, Inborn Errors/pathology , Muscular Diseases/diagnosis , Mutation, Missense , S-Adenosylhomocysteine/blood , S-Adenosylmethionine/bloodABSTRACT
S-Adenosylhomocysteine (AdoHcy) hydrolase deficiency has been proven in a human only once, in a recently described Croatian boy. Here we report the clinical course and biochemical abnormalities of the younger brother of this proband. This younger brother has the same two mutations in the gene encoding AdoHcy hydrolase, and has been monitored since birth. We report, as well, outcomes during therapy for both patients. The information obtained suggests that the disease starts in utero and is characterized primarily by neuromuscular symptomatology (hypotonia, sluggishness, psychomotor delay, absent tendon reflexes, delayed myelination). The laboratory abnormalities are markedly increased creatine kinase and elevated aminotransferases, as well as specific amino acid aberrations that pinpoint the aetiology. The latter include, most importantly, markedly elevated plasma AdoHcy. Plasma S-adenosylmethionine (AdoMet) is also elevated, as is methionine (although the hypermethioninaemia may be absent or nonsignificant in the first weeks of life). The disease seems to be at least to some extent treatable, as shown by improved myelination and psychomotor development during dietary methionine restriction and supplementation with creatine and phosphatidylcholine.
Subject(s)
Adenosylhomocysteinase/deficiency , Adenosylhomocysteinase/genetics , Amino Acids/chemistry , Brain/pathology , Child, Preschool , Creatine Kinase/blood , Croatia , DNA Methylation , Erythrocytes/metabolism , Exons , Family Health , Humans , Infant , Magnetic Resonance Imaging , Magnetic Resonance Spectroscopy , Male , Methionine/metabolism , Mutation , Myelin Sheath/chemistry , Time Factors , Transaminases/blood , Treatment OutcomeABSTRACT
OBJECTIVE: Several studies implicate elevated homocysteine as a risk factor for dementia and cognitive decline, but most studies have involved subjects older than 55 years from homogeneous populations. The authors examined homocysteine and cognition in a tri-ethnic community sample 40 years and older. METHOD: The Northern Manhattan Study includes 3,298 stroke-free subjects. Of these 2,871 had baseline fasting total homocysteine (tHcy) levels and Mini-Mental State Examination (MMSE) scores available. The authors used multiple linear regression to examine the cross-sectional association between baseline tHcy levels and mean MMSE scores adjusting for sociodemographic and vascular risk factors. RESULTS: Homocysteine levels were related to age, renal function, and B12 deficiency. Those with B12 deficiency had tHcy levels five points higher (9.4 vs 14.4 nmol/L). Mean MMSE scores differed by age, sex, and race-ethnic group. Those with hypertension, diabetes, cardiac disease, and B12 deficiency had lower MMSE scores. In multivariate analyses, elevated tHcy was associated with lower mean MMSE scores for those older than 65 but not for those 40 to 64. Adjusting for B12 deficiency and sociodemographic factors the mean MMSE was 2.2 points lower for each unit increase in the log tHcy level (95% CI -3.6, -0.9). Adding vascular risk factors to the model did not attenuate this effect (mean MMSE -2.2 points; 95% CI -3.5, -0.9). CONCLUSIONS: Elevated homocysteine was independently associated with decreased cognition in subjects older than 65 in this tri-ethnic cohort, adjusting for sociodemographic and vascular risk factors.
Subject(s)
Cognition , Ethnicity , Homocysteine/blood , Adult , Black or African American , Age Factors , Aged , Apolipoprotein E4 , Apolipoproteins E/genetics , Cognition Disorders/blood , Cognition Disorders/ethnology , Cohort Studies , Fasting/blood , Female , Hispanic or Latino , Humans , Hyperhomocysteinemia/blood , Hyperhomocysteinemia/ethnology , Linear Models , Male , Middle Aged , New York City , Psychological Tests , Risk Factors , Socioeconomic Factors , Vitamin B 12 Deficiency/blood , Vitamin B 12 Deficiency/ethnology , White PeopleABSTRACT
Four pregnancies in a women with moderately severe deficiency of methionine adenosyltransferase I/III (MAT I/III) activity are reported. She is an apparent homozygote for a point mutation in MAT1A, the gene that encodes the catalytically active subunit of MAT I/III. This mutation reduces the activity of her expressed enzyme to some 11% of wild-type. She was the first such individual identified in the United States, and these are the first pregnancies known in anyone with this extent of MAT I/III deficiency. No adverse effects were noted in the mother. Three normal babies resulted, but fetal arrest was detected in one embryo at 10-11 weeks gestation. Plasma methionine concentrations remained virtually constant at their elevated levels of 300-350 micromol/L throughout the pregnancies. Plasma free choline was below the reference range. In view of the evidence that maternal choline delivery to the fetus is important for brain development, it was suggested the patient ingest two eggs daily from gestation week 17. Plasma choline and phosphatidylcholine tended to rise during such supplementation. Plasma cystathionine concentrations rose progressively to far above normal during these pregnancies, but not during pregnancies in control women. This may be explained by delivery of excessive methionine to the fetus, with consequent increased cystathionine synthesis by fetal tissues. Because fetal tissues lack gamma-cystathionase, presumably cystathionine accumulated abnormally in the fetus and was transferred in abnormal amounts back to the mother. Plasma and urinary concentrations of methionine transamination metabolites rose during pregnancy for reasons that remain obscure.
Subject(s)
Isoenzymes/deficiency , Methionine Adenosyltransferase/deficiency , Pregnancy Complications/metabolism , Adult , Cystathionine/blood , Female , Humans , Methionine/metabolism , Milk, Human/metabolism , Phosphatidylcholines/administration & dosage , Pregnancy , Pregnancy Complications/therapy , Pregnancy OutcomeABSTRACT
We report studies of a Greek boy of gypsy origin that show that he has severe deficiency of glycine N -methyltransferase (GNMT) activity due to apparent homozygosity for a novel mutation in the gene encoding this enzyme that changes asparagine-140 to serine. At age 2 years he was found to have mildly elevated serum liver transaminases that have persisted to his present age of 5 years. At age 4 years, hypermethioninaemia was discovered. Plasma methionine concentrations have ranged from 508 to 1049 micro mol/L. Several known causes of hypermethioninaemia were ruled out by studies of plasma metabolites: tyrosinaemia type I by a normal plasma tyrosine and urine succinylacetone; cystathionine beta-synthase deficiency by total homocysteine of 9.4-12.1 micro mol/L; methionine adenosyltransferase I/III deficiency by S -adenosylmethionine (AdoMet) levels elevated to 1643-2222 nmol/L; and S -adenosylhomocysteine (AdoHcy) hydrolase deficiency by normal AdoHcy levels. A normal plasma N -methylglycine concentration in spite of elevated AdoMet strongly suggested GNMT deficiency. Molecular genetic studies identified a missense mutation in the coding region of the boy's GNMT gene, which, upon expression, retained only barely detectable catalytic activity. The mild hepatitis-like manifestations in this boy are similar to those in the only two previously reported children with GNMT deficiency, strengthening the likelihood of a causative association. Although his deficiency of GNMT activity may well be more extreme, his metabolic abnormalities are not strikingly greater. Also discussed is the metabolic role of GNMT; several additional metabolite abnormalities found in these patients; and remaining questions about human GNMT deficiency, such as the long-term prognosis, whether other individuals with this defect are currently going undetected, and means to search for such persons.
Subject(s)
Methyltransferases/genetics , Mutation , Child, Preschool , Glycine N-Methyltransferase , Humans , Male , Methionine/metabolism , Methyltransferases/deficiencyABSTRACT
To explore the pathogenesis of cystathionine beta-synthase (CBS) deficiency and to test the efficacy of pharmacological therapy we examined a panel of metabolites in nine homocystinuric patients under treated and/or untreated conditions. Off pharmacological treatment, the biochemical phenotype was characterized by accumulation of plasma total homocysteine (median 135 micromol/L) and blood S -adenosylhomocysteine (median 246 nmol/L), and by normal levels of guanidinoacetate and creatine. In addition, enhanced remethylation was demonstrated by low serine level (median 81 micromol/L), and by increased concentration of methionine (median 76 micromol/L) and N -methylglycine (median 6.8 micromol/L). Despite the substantially blocked transsulphuration, which was evidenced by undetectable cystathionine and severely decreased total cysteine levels (median 102 micromol/L), blood glutathione was surprisingly not depleted (median 1155 micromol/L). In 5 patients in whom pharmacological treatment was withdrawn, the differences of median plasma total homocysteine levels (125 micromol/L after withdrawal versus 33 micromol/L under treatment conditions), total cysteine levels (139 versus 211 micromol/L) and plasma serine levels (53 versus 103 micromol/L) on and off treatment demonstrated the efficacy of long-term pyridoxine/betaine administration ( p <0.05). The treatment also decreased blood S -adenosylhomocysteine level (133 versus 59 nmol/L) with a borderline significance. In summary,our study shows that conventional treatment of CBS deficiency by diet and pyridoxine/betaine normalizes many but not all metabolic abnormalities associated with CBS deficiency. We propose that the finding of low plasma serine concentration in untreated CBS-deficient patients merits further exploration since supplementation with serine might be a novel and safe component of treatment of homocystinuria.