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Biomedical subjects

Robert H Allen

Publications and source records attributed to Robert H Allen.

At least 37 records · Page 2Linked to original sources
PubMed2004

Vitamin B12 deficiency as a worldwide problem.

Pernicious anemia is a common cause of megaloblastic anemia throughout the world and especially in persons of European or African descent. Dietary deficiency of vitamin B12 due to vegetarianism is increasing and causes hyperhomocysteinemia. The breast-fed infant of a vitamin B12-deficient mother is at risk for severe developmental abnormalities, growth failure, and anemia. Elevated methylmalonic acid and/or total homocysteine are sensitive indicators of vitamin B12-deficient diets and correlate with clinical abnormalities. Dietary vitamin B12 deficiency is a severe problem in the Indian subcontinent, Mexico, Central and South America, and selected areas in Africa. Dietary vitamin B12 deficiency is not prevalent in Asia, except in vegetarians. Areas for research include intermittent vitamin B12 supplement dosing and better measurements of the bioavailability of B12 in fermented vegetarian foods and algae.

Anemia, Megaloblastic↗
PubMed2003

Quantification of serum and urinary S-adenosylmethionine and S-adenosylhomocysteine by stable-isotope-dilution liquid chromatography-mass spectrometry.

BACKGROUND: We have developed an assay that uses stable-isotope-dilution liquid chromatography-mass spectrometry to assess S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) in body fluids to investigate the relationship of these metabolites to hyperhomocysteinemia. METHODS: Commercially obtained SAM (D(3) methyl) and (13)C(5)-SAH uniformly labeled in the adenosyl moiety, which was synthesized using S-adenosylhomocysteine hydrolase, were added to samples followed by perchloric acid protein precipitation, C(18) chromatography, and analysis by liquid chromatography-mass spectrometry with quantification by comparison of the areas of internal standard and endogenous peaks. RESULTS: Estimates of intraassay imprecision (CV) were 5% and 17% for SAM and SAH, respectively (n = 10). SAM decreased and SAH increased in serum and plasma samples at both 4 degrees C and room temperature over 80 h. SAM and SAH were unstable in samples stored longer than 2 years at -20 degrees C. In 48 volunteers, the estimated reference intervals [from mean (2 SD) of log-transformed data] for serum SAM and SAH were 71-168 and 8-26 nmol/L, respectively. Fractional excretion of SAM was higher than that of SAH, and the urinary SAM:SAH ratio was much higher than the serum or erythrocyte SAM:SAH ratios. CONCLUSIONS: Stable-isotope-dilution liquid chromatography-mass spectrometry can be used to quantify SAM and SAH in biological fluids and tissues. Sample handling and storage must be stringently controlled for any epidemiologic or clinical use of such assays.

Adult↗
PubMed2003

Prioritizing posterior arm delivery during severe shoulder dystocia.

BACKGROUND: Delivery of the posterior arm, or the Barnum maneuver, is at times used late in shoulder dystocia management algorithms, and is not often a first- or second-line management protocol. CASE: A multiparous, diabetic patient, who was morbidly obese and had a residual obstetric brachial plexus injury, experienced a precipitous second stage of labor and severe shoulder dystocia. Attempts at the McRoberts maneuver with traction failed to deliver the fetus. In lieu of alternative maneuvers or continued attempts at traction, the posterior arm was delivered and the fetal trunk followed easily. CONCLUSION: A geometric analysis reveals that using posterior arm delivery reduces the obstruction by more than a factor of two, relative to the McRoberts maneuver. We recommend earlier use of this maneuver during shoulder dystocia management.

Birth Injuries↗
PubMed2003

Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake: a diagnostic trap.

Studies were carried out to identify the cause of combined severe hypermethioninemia and moderate hyperhomocysteinemia in a cluster of 10 infants ascertained between 1999 and early 2001. Although several were thought initially to have cystathionine beta-synthase (CBS) deficiency and treated accordingly, CBS deficiency and other known genetic causes of hypermethioninemia were ruled out by assay of CBS activity in fibroblasts of four patients and by assays of plasma cystathionine and S-adenosylmethionine. Retrospective data on dietary methionine intakes and plasma concentrations of methionine and related metabolites established that the hypermethioninemia in nine of the 10 babies was related to ingestion of an infant protein hydrolysate formula, the methionine content of which had been increased from May 1998 to February 2001. The formula in question has now been reformulated and is no longer available. The 10th infant manifested similar metabolic abnormalities while receiving TPN containing excessive methionine. Brain MRI abnormalities indicative of cerebral edema, most marked in the cerebral cortex and posterior brainstem, occurred in two patients near times of extreme hypermethioninemia. Metabolic and MRI abnormalities resolved when the methionine intake decreased. A third infant had a normal MRI 1 day after the formula was changed. The possible relationship between extreme hypermethioninemia and cerebral edema is discussed and a working hypothesis offered to explain the relative sensitivity of the inferior colliculi, based upon the facts that this is the region most active in glucose utilization and that Na(+),K(+)-ATPase is inhibited by methionine and related metabolites.

Brain Edema↗
PubMed2003

Intrapartum risk factors for permanent brachial plexus injury.

OBJECTIVE: The purpose of this study was to compare maternal, neonatal, and second stage of labor characteristics in shoulder dystocia deliveries that result in permanent brachial plexus injury with shoulder dystocia deliveries that result in no injury. STUDY DESIGN: Our cases were culled from a database of deliveries that resulted in permanent brachial plexus injuries and matched to control cases that were taken from a database of consecutive shoulder dystocia deliveries from one hospital. Deliveries that resulted in injury were excluded from the control cases; those cases with no recorded shoulder dystocia were excluded from the cases. Matching was for birth weight (+/-250 g), parity, and diabetic status. Rates of precipitous and prolonged second stage, operative delivery, neonatal depression, and average number of shoulder dystocia maneuvers used were compared between the two groups with chi(2) test, Fisher exact test, and the Student t test; a probability value of <.05 was considered significant. RESULTS: There were 80 matched patients, of which 26 patients were nulliparous and 11 patients were diabetic. Mothers of the uninjured group were younger than those of the injured group (23.7+/-6.2 years vs 27.4+/-5.1 years, P<.001). The injured group had a significantly higher rate of 5-minute Apgar scores of <7 (13.9% vs 3.8%, P=.04). Differences in maternal weight, body mass index, height, race, gestational age, average number of maneuvers, head-to-body delivery interval, operative delivery rate, prolonged second stage rate, precipitous second stage rate, and sex were not significant between groups. The rates of precipitous second stage for both groups (28.0% injured and 35.0% uninjured) were more than triple the rates of prolonged second stage (9.5% injured and 11.3% uninjured). CONCLUSION: No characteristic of second-stage of labor predicts permanent brachial plexus injury. Precipitous second stage is the most prevalent labor abnormality that is associated with shoulder dystocia.

Adult↗
PubMed2003

The descent curve of the grand multiparous woman.

OBJECTIVE: The purpose of this study was to compare the descent curves and second-stage length among grand multiparous, nulliparous, and lower parity multiparous women. STUDY DESIGN: Retrospective cohorts of spontaneously laboring, vertex-presenting, term, grand multiparous women (parity >or=5) from two medical centers over 5.5 years were matched randomly to nulliparous women and lower parity multiparous women controlled for age, hospital, and year of delivery. Descent curves were modeled from serial cervical examination data by the estimation of the probability of a given station occurring at a given time before delivery with the use of ordinal logistic regression. Curves were compared by Wald tests and adjusted for possible confounders. Second-stage lengths were compared by a Cox proportional hazards model. A probability value of <.05 was considered significant. RESULTS: Grand multiparous women and lower parity multiparous women maintain a high station up to 1.5 hour before delivery and then rapidly transition to delivery. Nulliparous women transition to lower stations at a more gradual rate throughout the first and second stages. Descent curves differ among parity groups, with grand multiparous women maintaining a higher station for a longer time compared with either lower parity multiparous women or nulliparous women (P<.001). Once full dilation is reached, the median length of the second stage is 0.75, 0.85, and 1.75 hours for grand multiparous women, lower parity multiparous women, and nulliparous women, respectively (hazard ratios were 0.39 for nulliparous women vs grand multiparous women and 0.9 for lower parity multiparous women vs grand multiparous women). CONCLUSIONS: Compared with lower parity multiparous women or nulliparous women, grand multiparous women maintain a higher station for a longer time before delivery but transition rapidly to delivery once full dilation is reached.

Adult↗
PubMed2003

Hyperhomocysteinemia and vitamin B-12 deficiency in elderly using Title IIIc nutrition services.

BACKGROUND: The effect of the folate food fortification program on the prevalence of hyperhomocysteinemia in the older population with coexisting vitamin B-12 deficiency is not known. OBJECTIVE: The objective was to determine the prevalence of hyperhomocysteinemia and vitamin B-12 deficiency in elderly who were using Title IIIc nutrition services, after folate food fortification in the United States. DESIGN: Demographic, nutritional, cognitive, routine diagnostic, and serum methylmalonic acid (MMA) and total homocysteine (tHcy) tests were performed in a convenience sample of 103 elderly enrolled in nutrition service programs in rural northeast Georgia. A subgroup (n = 27) was treated with vitamin B-12, 2.5 mg, and a multivitamin with 400 micro g folic acid, 2 mg vitamin B-6, and 27 mg ferrous fumarate. RESULTS: The total cohort included 103 participants (+/- SD age: 76.4 +/- 8.1; 80% female; 68% white, 32% African American). Vitamin B-12 deficiency (serum vitamin B-12 < 258 pmol/L and MMA > 271 nmol/L) was present in 23%. Mean serum folate was high, 39.3 nmol/L, and no subject had serum folate < 6.8 nmol/L. Mean tHcy was 17.6 +/- 7.2 micro mol/L in vitamin B-12-deficient subjects and 10.8 +/- 3.6 micro mol/L in those who were nondeficient. Determinants of high tHcy were vitamin B-12 deficiency, high serum creatinine, and low red blood cell folate. Those with vitamin B-12 deficiency were more likely to have poor cognition (58% compared with 20%, P < 0.001) and anemia (38% compared with 18%, P = 0.042). High-dose oral B-12 therapy lowered mean MMA and tHcy by 49% and 32%, respectively. CONCLUSION: Vitamin B-12 deficiency was prevalent and was associated with poor cognition, anemia, and hyperhomocysteinemia.

Activities of Daily Living↗
PubMed2003

Effect of operative vaginal delivery on the outcome of permanent brachial plexus injury.

OBJECTIVE: To evaluate whether operative vaginal delivery worsens the extent and/or degree of permanent brachial plexus injury. STUDY DESIGN: We utilized a dataset (n = 104) of vaginal deliveries resulting in permanent brachial plexus injury that ultimately underwent litigation. We excluded patients on whom neonatal injury information was incomplete (n = 5). Patients who had an operative vaginal delivery (n = 33) were compared with those who did not (n = 66) in regard to neonatal outcome and the location and extent of neurologic injury. RESULTS: The 2 classes were similar in demographic and obstetric variables. There were no differences in rates of 5-minute Apgar scores < 7 (17.9%, or 5/28, vs. 5.2%, or 3/57, P = .1), complete neurologic injury to the brachial plexus (C5-T1) (39%, or 13/33, vs. 38%, or 25/66; P = 1.0) or avulsion of the nerve roots (44%, or 12/27, vs. 36%, or 18/50; P = .5) between those with operative or spontaneous vaginal delivery. CONCLUSION: Operative vaginal delivery did not increase the severity of impairment in a dataset of deliveries resulting in permanent brachial plexus injury.

Adult↗
PubMed2002

Adverse event associated with methionine loading test: a case report.

The death of a control subject after an oral load of methionine for a study of the possible relationship between homocysteine and Alzheimer's disease is reported. The subject developed postload plasma concentrations of methionine far beyond those reported previously in humans given the usual oral loading dose of methionine (100 mg/kg body wt). Her preload plasma metabolite values rule out known genetic diseases that might predispose one to unusually high methionine concentrations. The most likely explanation for these events is that the subject received a substantial overdose of methionine. The possibility that extremely high methionine concentrations may lead to severe cerebral effects is discussed, and it is recommended that any move to increase the sensitivity of the usual methionine loading test by increasing the dose of methionine either not be undertaken or be taken only with extreme care.

Administration, Oral↗
PubMed2002

Progressive cerebral edema associated with high methionine levels and betaine therapy in a patient with cystathionine beta-synthase (CBS) deficiency.

Cystathionine beta-synthase (CBS) deficiency, the most common form of homocystinuria, is an autosomal recessive inborn error of homocysteine metabolism. Treatment of B6-nonresponsive patients centers on lowering homocysteine and its disulfide derivatives (tHcy) by adherence to a methionine-restricted diet. However, lifelong dietary control is difficult. Betaine supplementation is used extensively in CBS-deficient patients to lower plasma tHcy. With betaine therapy, methionine levels increase over baseline, but usually remain below 1,500 micromol/L, and these levels have not been associated with adverse affects. We report a child with B6-nonresponsive CBS deficiency and dietary noncompliance whose methionine levels reached 3,000 micromol/L on betaine, and who subsequently developed massive cerebral edema without evidence of thrombosis. We investigated the etiology by determining methionine and betaine metabolites in our patient, and several possible mechanisms for her unusual response to betaine are discussed. We conclude that the cerebral edema was most likely precipitated by the betaine therapy, although the exact mechanism is uncertain. This case cautions physicians to monitor methionine levels in CBS-deficient patients on betaine and to consider betaine as an adjunct, not an alternative, to dietary control.

Betaine↗
PubMed2002

High homocysteine and thrombosis without connective tissue disorders are associated with a novel class of cystathionine beta-synthase (CBS) mutations.

Cystathionine beta-synthase (CBS) is a crucial regulator of plasma levels of the thrombogenic amino acid homocysteine (Hcy). Homocystinuria due to CBS deficiency confers a dramatically increased risk of thrombosis. Early diagnosis usually occurs after the observation of ectopia lentis, mental retardation, or characteristic skeletal abnormalities. Homocystinurics with this phenotype typically carry mutations in the catalytic region of the protein that abolish CBS activity. We describe a novel class of missense mutations consisting of I435T, P422L, and S466L that are located in the non-catalytic C-terminal region of CBS that yield enzymes that are catalytically active but deficient in their response to S-adenosylmethionine (AdoMet). The P422L and S466L mutations were found in patients suffering premature thrombosis and homocystinuric levels of Hcy but lacking any of the connective tissue disorders typical of homocystinuria due to CBS deficiency. The P422L and S466L mutants demonstrated a level of CBS activity comparable to that of the AdoMet stimulated wild-type CBS but could not be further induced by the addition of AdoMet. In terms of temperature stability, oligomeric organization, and heme saturation the I435T, P422L, and S466L mutants are indistinguishable from wild-type CBS. Our findings illustrate the importance of AdoMet for the regulation of Hcy metabolism and are consistent with the possibility that the characteristic connective tissue disturbances observed in homocystinuria due to CBS deficiency may not be due to elevated Hcy.

Adult↗
PubMed2002

Cystathionine beta-synthase is coordinately regulated with proliferation through a redox-sensitive mechanism in cultured human cells and Saccharomyces cerevisiae.

Cystathionine beta-synthase (CBS) catalyzes the condensation of serine with homocysteine to form cystathionine and occupies a crucial regulatory position between the methionine cycle and the biosynthesis of cysteine by transsulfuration. Analysis of CBS activity under a variety of growth conditions indicated that CBS is coordinately regulated with proliferation in both yeast and human cells. In batch cultures of Saccharomyces cerevisiae, maximal CBS activities were observed in the exponential phase of cells grown on glucose, while growth-arrested cultures or those growing non-fermentatively on ethanol or glycerol had approximately 3-fold less activity. CBS activity assays and Western blotting indicated that growth-specific regulation of CBS is evolutionarily conserved in a range of human cell lines. CBS activity was found to be maximal during proliferation and was reduced two- to five-fold when cells became quiescent at confluence. In cultured HepG2 cells, the human CBS gene is induced by serum and basic fibroblast growth factor and is downregulated, but not abolished, by contact inhibition, serum-starvation, nutrient depletion, or the induction of differentiation. Consequently, for certain cell types, CBS may represent a novel marker of both differentiation and proliferation. The intracellular level of the CBS regulator compound, S-adenosylmethionine, was found to reflect the proliferation status of both yeast and human cells, and as such, constitutes an additional mechanism for proliferation-specific regulation of human CBS. Our data indicates that screening compounds for the ability to affect transsulfuration in cultured cell models must take proliferation status into account to avoid masking regulatory interactions that may be of significance in vivo.

Blood Physiological Phenomena↗
PubMed2002

Response of elevated methylmalonic acid to three dose levels of oral cobalamin in older adults.

OBJECTIVES: Because the effects of lower-dose oral cobalamin (Cbl) supplements on older people with cobalamin deficiency are not known, we determined whether oral Cbl supplements at three different dose levels would normalize elevated serum methylmalonic acid (MMA) and total homocysteine (tHcy) concentrations. DESIGN: Sequential nonrandomized intervention study of three dose levels. SETTINGS: Two university-based senior care clinics. PARTICIPANTS: Twenty-three older adults (aged >/=65) with serum Cbl levels of 221 pmol/L (300 pg/mL) or lower and serum MMA greater than 271 nmol/L who had been enrolled in a previous screening study for Cbl deficiency (mean age 79 +/- 9; 17 male, 6 female; 17 white, 6 other). INTERVENTION: Sequential daily treatment with 25 microg oral cobalamin, followed by 100 microg and 1,000 microg cobalamin each for a 6-week period. MEASUREMENTS: Serum MMA, tHcy, and other metabolites at baseline and after each 6-week dosing interval. RESULTS: Treatment with 25 microg and 100 microg lowered but did not normalize MMA levels in most subjects. A dose of 1,000 microg/day proved to be the most effective in lowering MMA levels to within normal limits. Serum tHcy was normalized in six of 11 subjects who had elevated tHcy pretreatment with oral Cbl alone and in one subject in combination with a multivitamin. CONCLUSIONS: Most Cbl-deficient older people require more than 100 microg of oral Cbl to normalize serum MMA, which is a larger dose than is available in most standard multivitamins and Cbl supplements.

Administration, Oral↗
PubMed2002

Elevated plasma total homocysteine in severe methionine adenosyltransferase I/III deficiency.

Abnormal elevation of plasma methionine may result from several different genetic abnormalities, including deficiency of cystathionine beta-synthase (CBS) or of the isoenzymes of methionine adenosyltransferase (MAT) I and III expressed solely in nonfetal liver (MAT I/III deficiency). Classically, these conditions have been distinguished most readily by the presence or absence, respectively, of elevated plasma free homocystine, detected by amino acid chromatography in the former condition, but absent in the latter. During the present work, we have assayed methionine, S-adenosylmethionine, S-adenosylhomocysteine, total homocysteine (tHcy), cystathionine, N-methylglycine (sarcosine), and total cysteine (tCys) in groups of both MAT I/III- and CBS-deficient patients to provide more evidence as to their metabolite patterns. Unexpectedly, we found that MAT I/III-deficient patients with the most markedly elevated levels of plasma methionine also had elevations of plasma tHcy and often mildly elevated plasma cystathionine. Evidence is presented that methionine does not inhibit cystathionine beta-synthase, but does inhibit cystathionine gamma-lyase. Mechanisms that may possibly underlie the elevations of plasma tHcy and cystathionine are discussed. The combination of elevated methionine plus elevated tHcy may lead to the mistaken conclusion that an MAT I/III-deficient patient is instead CBS-deficient. Less than optimal management is then a real possibility. Measurements of plasma cystathionine, S-adenosylmethionine, and sarcosine should permit ready distinction between the 2 conditions in question, as well as be useful in several other situations involving abnormalities of methionine and/or homocysteine derivatives.

Adolescent↗
PubMed2002

Correlating head-to-body delivery intervals with neonatal depression in vaginal births that result in permanent brachial plexus injury.

OBJECTIVE: The purpose of this study was to evaluate which variables predict neonatal depression in vaginal deliveries that result in permanent brachial plexus injury. STUDY DESIGN: With the use of a data set of litigated vaginal deliveries (n = 103 deliveries) from 1978 through 1999 that resulted in permanent brachial plexus injury, detailed delivery and neonatal and pediatric information was obtained by chart review. Neonatal depression was defined as a 5-minute Apgar score of <7. Data that were extrapolated from neonates with low Apgar scores at 5 minutes were compared with neonates with Apgar scores of > or =7 with the use of the Fisher exact test, chi(2) test, or one-way analysis of variance; a two-tailed probability value of <.05 was considered significant. RESULTS: Nine of 89 neonates (10%) had low 5-minute Apgar scores. Head-to-body delivery intervals (available for 36 deliveries) were significantly longer in neonates with 5-minute Apgar scores of <7 vs > or =7 (294 +/- 68 seconds vs 147 +/- 82 seconds, P <.001). Differences in other clinical variables (ie, maternal weight, gestational age, diabetes mellitus, parity, birth weight, and sex) were not significant. None of the infants in this data set, which includes those infants with neonatal depression) died or had long-term asphyxia-related sequelae in the form of speech impediments, seizures, cerebral palsy, coma, or organ dysfunction. CONCLUSION: The head-to-body delivery interval was the only significant factor in the prediction of 5-minute Apgar score of <7 in a data set of deliveries that resulted in permanent brachial plexus injury. Despite extended times (< or =6 minutes) on the perineum that resulted in a higher reduced Apgar score rate, there was no asphyxia-related morbidity.

Apgar Score↗