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Biomedical subjects

M I Levene

Publications and source records attributed to M I Levene.

At least 19 recordsLinked to original sources
PubMed1998

Impaired regeneration of monoglutamyl tetrahydrofolate leads to cellular folate depletion in mothers affected by a spina bifida pregnancy.

Periconceptional folate prevents neural tube defects (NTD) by a mechanism which is unclear. The present study found significant changes in the equilibrium of the homocysteine remethylation cycle in NTD affected mothers, possibly involving B12-dependent methionine synthase or 5,10-methylenetetrahydrofolate reductase. Data were consistent with impaired Hcy remethylation leading to poor regeneration of H4PteGlu1, the main intracellular precursor of all folates. This lesion leads to cellular folate deficiency indicated by a significantly lower radioassay RBC folate and 5CH3H4PteGlu4 in affected mothers. The drop in this tetraglutamate is associated with an increase in the abundance of longer chain oligo-gamma-glutamyl folate, again reflecting the underlying folate deficiency. This effect may compromise purine, DNA-thymine, and methionine production, particularly during embryogenesis when folate demand is high. At this time serine hydroxymethyltransferase may play a critical role in conserving H4PteGlu1 for purine synthesis. Many of these depletion effects were corrected with folate supplementation for 1 month.

Female↗
PubMed1998

Primary autosomal recessive microcephaly (MCPH1) maps to chromosome 8p22-pter.

Primary (or "true") microcephaly is inherited as an autosomal recessive trait and is thought to be genetically heterogeneous. Using autozygosity mapping, we have identified a genetic locus (MCPH1) for primary microcephaly, at chromosome 8p22-pter, in two consanguineous families of Pakistani origin. Our results indicate that the gene lies within a 13-cM region between the markers D8S1824 and D8S1825 (maximum multipoint LOD score of 8.1 at D8S277). In addition, we have demonstrated the genetic heterogeneity of this condition by analyzing a total of nine consanguineous families with primary microcephaly.

Chromosome Mapping↗
PubMed1998

Randomised double blind trial of morphine versus diamorphine for sedation of preterm neonates.

AIMS: To compare the safety and effectiveness of morphine and diamorphine for the sedation of ventilated preterm neonates in a double blind, randomised trial. METHODS: Eighty eight babies were allocated to receive either morphine (n = 44) or diamorphine (n = 44) by bolus infusion (200 or 120 mcg/kg, respectively, over two hours), followed by maintenance infusion (25 or 15 mcg/kg/h, respectively) during the initial phase of their respiratory disease. Serial monitoring of physiological, behavioural, and biochemical variables over the first 24 hours of the infusions was performed. Longer term outcomes were also monitored. RESULTS: Morphine, but not diamorphine, was associated with a mean (SEM) decrease in mean arterial blood pressure of 2.2 (1.0) mm Hg (p = 0.05) over the initial loading infusion. Physiological (blood pressure variability) and behavioural measures of sedation (clinical assessment and sedation scoring) indicated that the two drug regimens were equally effective after 24 hours, but the sedative effects of diamorphine were evident more quickly than those of morphine. Both regimens significantly reduced plasma adrenaline concentrations over the first 24 hours of the infusions. No significant differences in mortality, ventilator days, chronic lung disease or intracranial lesions were noted. CONCLUSIONS: Both drug regimens reduce the stress response to ventilation in preterm neonates. However, diamorphine's more rapid onset of sedation and morphine's hypotensive tendency suggest that diamorphine is preferable for the sedation of mechanically ventilated preterm neonates.

Anesthesia↗
PubMed1998

Magnetic resonance of the neonatal brain.

We discuss the advantages of magnetic resonance (MR) technique in the study of the neonatal brain. Major results have been obtained concerning the understanding of the normal appearance of the developing brain. Bands of cells migrating to the cortex have been identified in the frontal periventricular white matter up to late gestation. MR can also identify the disappearance of the subependymal germinal matrix with increasing gestational age. With respect to the lesions of prematurity, subependymal germinal matrix hemorrhages were for the first time identified by MR underneath the posterior horns of the lateral ventricles. Subtle ischemic lesions of the periventricular white matter, not detected by brain ultrasound scan, are also described. Analysis of the lesions of the term neonates showed the role of MR in defining a more precise prognosis of infants who have sustained "birth asphyxia". The lesions can affect the basal ganglia, watershed areas of the white matter, and cortex. MR scans performed in the second week of life seem to show a stronger association with the outcome. Brain ischemic areas of the term neonates presenting with focal or multifocal seizures can also be detected by MR. These infarcted zones are usually located in the perfusion territory of the middle cerebral artery, more often in the left hemisphere. The timing of the scan is an important factor as the conventional MR can be negative in the first two-three days after the seizures. The diffusion-weighted imaging (DWI) is a new MR technique very sensitive to acute ischemic injury, and it may solve the problem of the scan timing.

Brain↗
PubMed1998

MR features of developing periventricular white matter in preterm infants: evidence of glial cell migration.

PURPOSE: MR imaging of the brain is increasingly used in the investigation of the newborn, but little information is available on the normal appearance of the developing brain. We scanned a series of newborn infants in an attempt to define the normal appearance of developing periventricular white matter and to assess how pathologic conditions may modify this appearance. METHODS: Sixty-eight newborn infants, median postmenstrual age (PMA) 34 weeks (range, 24 to 42 weeks), were subdivided into two groups: group A (n = 33), which included those with normal clinical and sonographic examinations, and group B (n = 35), which contained those with evidence of neuroabnormality detected prior to the MR study, either clinically or by cerebral sonography. Images were acquired in two planes on a 1.5-T imager using turbo spin-echo pulse sequences. RESULTS: Symmetric periventricular bands of reduced signal intensity were noted in the frontal periventricular white matter on T2-weighted images in 98% of group A infants and in 97% of group B infants. The number of bands was inversely related to PMA. The reduction in number of bands with increasing PMA was delayed in group B infants. CONCLUSION: The uniform appearance of periventricular bands in a population of healthy infants and their relationship to the infants' maturity is consistent with the results of previous histologic studies. These studies demonstrate the presence of migrating glial cells within the periventricular white matter of infants beyond 20 weeks' gestation, when neuronal migration to the cortex is complete. We postulate that the bands seen on T2-weighted images represent groups of migrating glial cells, providing a further marker of cerebral maturation.

Brain↗
PubMed1997

Risk of neural tube defect-affected pregnancy is associated with a block in maternal one-carbon metabolism at the level of N-5-methyltetrahydrofolate:homocysteine methyltransferase.

The disposition of whole blood mono-to hexaglutamyl methylfolate and plasma homocysteine (HCY) was used to evaluate potential lesion sites in one-carbon metabolism which could be responsible for neural tube defect(NTD)-affected pregnancies. An isocratic high-performance liquid chromatographic system (HPLC) with photodiode array detection was used to quantify and speciate whole-blood methylfolate into mono-, di-, tri-, tetra-, penta-, and hexaglutamate forms. This technique was also used with off-line radioassay to identify nonmethyl whole-blood folates. Isocratic HPLC with fluorescence detection was used to quantify SBDF derivatized homocysteine in plasma. The study investigated blood from 11 women who had experienced a previous NTD-affected pregnancy and 11 controls of similar age and social class. No subjects were pregnant. HCY levels were significantly higher in NTD subjects (P = 0.0486, 95% CI-2.799,0.001 using the Mann-Whitney test), as was the ratio of known intracellular (tri-to hexaglutamyl) methylfolate compared to extracellular (mono- and diglutamyl) methylfolate (P = 0.0062 95% CI-0.543, 3.862 using the Mann-Whitney test). Vitamin B12, red cell folate, circulating total methylfolate, and circulating mono-to hexaglutamyl methylfolates showed no difference between population groups. The disposition between individual and cumulative glutamate chain lengths of methylfolate showed significant trends which differed between population groups: (i) total blood methylfolate (Glu1-6) appears to be utilized by N-5-methyltetrahydrofolate:homocysteine methyltransferase (MS) in control blood but not NTD blood, where it appears to accumulate following a 45-min incubation; (ii) whole-blood hexaglutamyl methylfolate (5CH3-H4PteGlus) becomes a larger proportion of the total blood methylfolate in NTD than in control populations; and (iii) the intermediate glutamate chains of methylfolate (Glu1-5) remain relatively constant as 5CH3-H4PteGlu6 accumulates in NTD but appear to increase linearly with 5CH3-H4PteGlu6 in controls. The significant elevation of HCY in the NTD population is associated with the increasing proportion of 5CH3-H4PteGlu6 relative to the total methylfolate, since, when corrected for HCY level, the proportion of 5CH3-H4PteGlus to total methylfolate is similar in NTD and control populations. These trends are consistent with a defect at the level of vitamin B12 dependent MS which "traps" folate at the 5CH3-H4PteGlus level.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1997

Student feedback: influencing the quality of teaching in a paediatric module.

The aim of this study was to assess the impact of feedback on the quality of tutorials. Students completed structured feedback questionnaires on the perceived usefulness of teaching sessions. They perceived significant differences in the quality of tutorials delivered by experienced and inexperienced teachers (P < 0.01), although the differences tended to become less throughout the year. In the second year, teachers had advice from an experienced tutor in planning the sessions, in addition to receiving feedback from the students. During the second year, the students did not perceive any difference in the usefulness of these tutorials to them. The study showed that the quality of tutorials can be improved by passing structured feedback to the teacher, but that some skills training was also required to completely eliminate perceived differences.

Attitude↗
PubMed1997

Prevalence and type of cerebral palsy in a British ethnic community: the role of consanguinity.

Little is known about the prevalence of cerebral palsy (CP) within ethnic subgroups born in Britain. The Yorkshire Regional Cerebral Palsy Register has ascertained all cases of CP in children born within the Regional Health Authority boundary in 1985 to 1987 inclusive and diagnosed by 5 years of age. Birth registrations recorded by ethnic subgroups allowed us to determine the prevalence of CP within the Bradford District Health Authority (BDHA) boundaries by Asian and non-Asian ethnic subgroups. All the children with CP in BDHA were examined by one individual and careful family pedigrees recorded. We noted that BDHA had a high prevalence of CP; 3.87 to 4.16 per 1000. The prevalences in the non-Asian and Asian populations were 3.18, and between 5.48 and 6.42, per 1000, respectively. This difference was statistically significant (P = 0.03). First cousin marriages occurred in 15 of the 39 Asian families (51.7%) and nine of these families had another first or second degree family member with a similar type of CP to the index child. There was no consanguinity in the non-Asian families. These data highlight the increased need for services in some ethnic populations living in Britain and the likely genetic aetiology of a significant proportion of cases of CP in Asian families.

Cerebral Palsy↗
PubMed1997

Randomised controlled double blind study of role of recombinant erythropoietin in the prevention of chronic lung disease.

AIM: To evaluate the role of recombinant human erythropoietin (R-HuEpo) in reducing iron infusion, which may exacerbate free radical damage, leading to chronic lung disease. METHODS: A multicentre, randomised, placebo controlled, double blind study was carried out in four neonatal intensive care units in Yorkshire. Infants were randomly allocated and received either R-HuEpo (480 U/kg/wk) or placebo by twice weekly subcutaneous injection. The primary outcome measure was the number of days on respiratory support and a secondary outcome the number of blood transfusions required. RESULTS: Forty two very low birthweight (VLBW) infants were randomly allocated. There was little difference in the need for respiratory support one month after randomisation, but subsequently there was a trend towards a reduction in the proportion requiring respiratory support in the R-HuEpo group (difference at three months -0.50, 95% confidence interval -1.00, 0.17). During stay in hospital, the median number of blood transfusions was lower for infants in the R-HuEpo group (difference in medians -2, 95% CI -4, 0). The study was stopped early because of failure to recruit babies at the expected rate. CONCLUSIONS: R-HuEpo seems to reduce the number of days in oxygen for ill VLBW infants. These data could be used to construct a larger multicentre study to evaluate this effect further.

Blood Transfusion↗
PubMed1996

Folate intake in young women and their knowledge of preconceptional folate supplementation to prevent neural tube defects.

OBJECTIVES: To ascertain knowledge of periconceptional folate for prevention of neural tube defect (NTD) and to estimate folate intake in young women. STUDY DESIGN: Three hundred young women were questioned about their knowledge of folate for prevention of NTD. Their folate intake was assessed by food frequency questionnaire. RESULTS: Fourteen per cent of 16-19 year olds and 41% of undergraduates were aware of the need to increase folate intake before conception. Median folate intake was estimated to be 235 micrograms/d in 16-19 year olds and 248.5 micrograms/d in undergraduates. More than a quarter of women in both groups had folate intakes less than the reference nutrient intake (RNI) (200 micrograms/d) below which prevalence of NTD rises dramatically and these women would therefore be at increased risk of having a child with NTD should they have an unplanned pregnancy. CONCLUSIONS: Strategies are required to increase folate intake among young women and inform them of the benefit of peri-conceptional folate supplementation.

Adolescent↗
PubMed1996

Analysis and biochemistry of blood folate.

Although the analysis of low plasma concentrations of 5-methyltetrahydrofolate by several specific HPLC methods has been reported, considerably fewer routine chromatographic techniques exist for the analysis of specific folate coenzymes in the erythrocyte where a nonspecific bioassay indicates that the vitamin achieves a level 10 times higher than that in plasma. By using three separate folypolyglutamate deconjugation procedures and combining an extraction technique which adequately preserves all native folate coenzymes with an HPLC technique utilizing fluorescence, diode array, and off-line radioassay detection capable of resolving all crucial native folates in their monoglutamyl forms, we were unable to demonstrate levels of 5-methyltetrahydrofolate in whole blood hemolysate beyond what might be expected from the plasma component. While the exact nature of erythrocyte folate could not be ascertained, we provide evidence that a proportion of it may exist at the formyl level of oxidation. The complex pH and enzymatic interrelationship between folate coenzymes at the formyl oxidation level is discussed in terms of our extraction technique and findings, as well as in a broader biological context. This paper also describes a simple acid precipitation technique for measuring plasma 5-methyltetrahydrofolate, as well as providing comprehensive data on the chromatographic behavior of all the folylmonoglutamates in reversed-phase and weak anion-exchange modes, including useful spectral data for optimizing detection parameters and identifying individual coenzymes. 10-Formyltetrahydrofolate and 5-methyltetrahydrofolate are the two most important one-carbon-substituted folate coenzymes. 10-Formyltetrahydrofolate is unavailable commercially, probably due to its instability. We chart the chemical synthesis of this important coenzyme and show that it and what is thought to be 5,10-hydroxymethylenetetrahydrofolate are actually minor products compared to the parent 5,10-methenyltetrahydrofolate and the ultimate reaction product, 5-formyltetrahydrofolate. Since intraerythrocyte folate binds to a specific hemoglobin site, we ascertained the total number of binding sites on hemoglobin (Bmax) and the equilibrium dissociation constant (Kd) for 5-methyltetrahydrofolate, 5-formyltetrahydrofolate, and the antimetabolite methotrexate. Binding affinities were consistent with a low-affinity, low-capacity interaction for all three. It was demonstrated that hemoglobin has a greater affinity for 5-methyltetrahydrofolate than for the other folate derivatives (Kd = 1.2 x 10(-3) M), while rather surprisingly, methotrexate had a higher affinity for hemoglobin than did 5-formyltetrahydrofolate (Kd = 2.5 x 10(-3) and 3.7 x 10(-2) M, respectively.

Binding Sites↗
PubMed1996

The influence of dietary folate and methionine on the metabolic disposition of endotoxic homocysteine.

We have investigated the disposition of potentially endotoxic homocysteine (Hcy) and its transsulfuration metabolite cysteine (Cys) in 98 individuals (age range 20-66 years). Our study reports on the relationship between Hcy and two important dietary factors likely to influence plasma levels of this thiol: dietary folate and dietary methionine. chi2 analysis shows a low frequency of elevated plasma Hcy at high folate intake. This frequency for Hcy >10 micromol/liter with a folate intake >350 microg/day is significant (P < 0.02). The data reflect a tendency for elevated Hcy values to be associated with low dietary folate, although many subjects with a low dietary folate also had a low plasma Hcy. Intake of dietary methionine was found to be significantly higher in males than in females (P < .0001). This may account for the looser relationship between Hcy and its transsulfuration product, Cys, in females (R2 = 0.30) compared to males (R2 = 0.73), since conversion of methionine to SAM in males would activate cystathionine beta synthase and commit excess Hcy to transsulfuration. The generally lower methionine intake of females means that more Hcy is utilized in the remethylation cycle in which methionine is produced from the de novo methyl group of 5-methyltetrahydrofolate or from the preformed methyl group of betaine. Clearly a Hcy moiety locked up in remethylation would be further removed from Cys, the end product of transsulfuration. An increasing number of studies are clarifying the relationship between Hcy, folate, and other B vitamins. However, less attention seems to be given to the influence of dietary methionine on the disposition of Hcy. The present study supports biochemical theory and indicates that more focus should be given to the effect of dietary methionine on Hcy. These findings have particular significance since even moderate increases in plasma Hcy are associated with a toxic vascular effect. Consequently the relationship between dietary folate and Hcy levels should be a factor in evaluating recommended dietary allowances for this vitamin. The simplicity of our dietary folate questionnaire also raises the possibility of a screening test in which individuals can ascertain whether their folate intake is adequate to reduce Hcy levels to a benign value.

Adolescent↗
PubMed1996

Reduction of pain response in premature infants using intraoral sucrose.

The potential of sucrose to reduce the pain response in a group of healthy premature infants was investigated. Fifteen infants of 32-34 weeks postmenstrual age were tested in a blind crossover manner on two separate occasions no more than two days apart. Either 1 ml of 25% sucrose solution or sterile water was syringed into the baby's mouth 2 minutes before routine heel lancing. Response to the painful stimuli was measured by duration of cry and by facial expression (pain score). There was a significant reduction in the duration of first cry, the percentage of time spent crying in the 5 minutes after heel prick, and the pain score in the sucrose treated group. It is concluded that sucrose has analgesic effects in healthy premature infants.

Administration, Oral↗