Biomedical subjects

B D Moore

Publications and source records attributed to B D Moore.

At least 19 recordsLinked to original sources

PubMed2002

Enzymatic synthesis of beta-lactam antibiotics via direct condensation.

In this paper, the feasibility of precipitation driven synthesis of acidic and zwitterionic beta-lactam antibiotics is studied. As an example of the first type, penicillin G was produced in good yield (160 mmol kg(-1)) directly from the free acid and amine aqueous substrate suspension, where the synthesis product precipitated. Such a precipitation driven synthesis via direct reversal of the hydrolytic reaction is thermodynamically unfavourable for zwitterionic beta-lactam antibiotics, such as amoxicillin. In this paper, a novel method is suggested to help favour precipitation of (poorly soluble) product salts by deliberate addition of certain counter-ions. After screening a number of different counter-ions, it was found that the amoxicillin anion forms a poorly soluble salt with Zn(2+). Despite increased beta-lactam degradation due to the presence of zinc ions, in a synthetic reaction with 0.1 M ZnSO(4) present the synthetic yield could be increased at least 30-fold.

Amoxicillin↗

PubMed2001

Phage derived peptides for targeting of doxorubicin conjugates to solid tumours.

Barriers are frequently hampering targeting of drugs and toxins to solid tumours and their microenvironment. Nano-conjugates are low molecular weight conjugates of a small drug or toxin and a targeting ligand coupled through a cleavable linker group. They offer potential advantages for tumour specific delivery in diffusion-limited situations. We have exploited fd phage-derived peptides for the targeting of low molecular weight drug conjugates to solid tumours. As a model we have chosen doxorubicin conjugates targeted to the transferrin receptor (TfR). A library of phage expressing a cyclic nona-peptide was panned against TfR. The apparent affinity of phages determined by surface plasmon resonance (SPR) increased with each cycle of the panning procedure. After five rounds approximately 80% of phages expressed the same peptide, which mediated a 30-50-fold increased receptor specific cellular uptake of the phages. The corresponding peptide was synthesised using solid phase peptide chemistry on a sulfonamide based safety catch resin. Crude mixtures of the peptide, as well as transferrin itself, were able to inhibit the phage uptake significantly. The doxorubicin conjugate of the peptide containing a cleavable linker was prepared and endosomal uptake confirmed by fluorescence microscopy.

Antibiotics, Antineoplastic↗

PubMed2001

Predicting when precipitation-driven synthesis is feasible: application to biocatalysis.

Precipitation-driven synthesis offers the possibility of obtaining high reaction yields using very low volume reactors and is finding increasing applications in biocatalysis. Here, a model that allows straightforward prediction of when such a precipitation-driven reaction will be thermodynamically feasible is presented. This requires comparison of the equilibrium constant, Keq, with the saturated mass action ratio, Zsat, defined as the ratio of product solubilities to reactant solubilities. A hypothetical thermodynamic cycle that can be used to accurately predict Zsat, in water is described. The cycle involves three main processes: fusion of a solid to a supercooled liquid, ideal mixing of the liquid with octanol, and partitioning from octanol to water. To obtain the saturated mass action ratio using this cycle, only the melting points of the reactants and products, and in certain cases the pKa of ionisable groups, are required as input parameters. The model was tested on a range of enzyme-catalysed peptide syntheses from the literature and found to predict accurately when precipitation-driven reaction was possible. The methodology employed is quite general and the model is therefore expected to be applicable to a wide range of other (bio)-catalysed reactions.

Amides↗

PubMed2001

Cycloplegic refractions in healthy children aged 1 through 48 months.

OBJECTIVES: To provide a description of refractive errors in healthy, term-born children, aged 1 through 48 months, and to test the hypotheses that spherical equivalent becomes significantly less hyperopic and less variable with increasing age. METHODS: Following a prospective, cross-sectional design, cycloplegic retinoscopy was used to measure the refractive error in both eyes of 514 healthy, term-born children in 12 age groups. Three hundred were aged 12 months or younger. Spherical equivalent and cylindrical power and axis were analyzed as a function of age. Prediction limits for spherical equivalent were calculated. RESULTS: Spherical equivalents of right and left eyes did not differ at any age. Hyperopia declined significantly with increasing age. The variability in spherical equivalent also decreased significantly with age. Cylindrical error of 1 diopter or more was found in 25% of the children; the proportion with astigmatism was highest in infancy and then waned. Myopia and anisometropia were rare, occurring in 3% and 1% of the sample, respectively. CONCLUSIONS: Significant declines in hyperopia and variability of spherical equivalent appear to be features of emmetropization. The normal prediction limits provide guidelines against which data from individual patients can be compared.

Age Distribution↗

PubMed2001

Characterization of equine E-selectin.

Expression of E-selectin on activated endothelium is a critical initial step that leads to extravasation of leucocytes during inflammation, yet E-selectin is largely uncharacterized in several animal species including the horse. We have sequenced and compared E-selectin genes derived from activated cultures of purified equine (horse), cervid (black-tailed deer) and ovine (sheep) pulmonary artery endothelial cells (ECs). Phylogenetic and amino acid sequence comparisons indicate that bovine, cervid and ovine E-selectin are similar, whereas human and equine E-selectin are more closely related to each other than to the ruminant molecules. Human E- and P-selectin-specific monoclonal antibodies that also recognize equine E-selectin were identified and used to characterize its expression. Expression of E-selectin was more readily induced by lipopolysaccharide treatment in equine ECs than in human ECs and supported adhesion and activation of neutrophils, consistent with the extreme sensitivity of horses to endotoxaemia and septic shock.

Amino Acid Sequence↗

PubMed2001

The role of surgery in children with neurofibromatosis.

BACKGROUND/PURPOSE: Neurofibromatosis frequently is complicated by the development of symptomatic lesions such as optic gliomas and plexiform neurofibromas that require operative resection. Although characteristically benign, these neoplasms have often devastating functional and cosmetic effects and must be monitored for malignant transformation. The purpose of this study is to identify and describe the surgical considerations in the care of children with neurofibromatosis. METHODS: The authors reviewed the charts of all children (<21) at our institution with neurofibromatosis who underwent an operative procedure from 1979 to 1999. Patient demographics, symptomatic lesions, malignant transformation, form of surgical intervention, type of anesthesia, and outcome were collected. RESULTS: A total of 249 patients with either neurofibromatosis 1 or 2 were identified. Of these, 50 (20%) underwent a total of 93 operations. The average age at operation was 9.4 years (1.2 to 21 years). There were 40 soft tissue procedures, 21 intracranial, and 32 miscellaneous. The soft tissue masses typically were treated with wide local excision, and in 8 of these procedures multiple resections were performed. Fourteen of the 50 patients had malignancies. Five of the tumors were soft tissue sarcomas, and 9 were intracranial malignancies. Three patients died, 2 from malignancy and 1 from acute, obstructive hydrocephalus after operation. There were 3 patients alive with malignancy and 8 others living with varying levels of disability. CONCLUSIONS: Neurofibromatosis in the pediatric patient frequently requires surgical intervention, often because of symptoms such as pain or cosmetic deformity, or for malignancy. Children should be watched carefully for signs of malignant transformation and undergo biopsy for neurofibromas that exhibit rapid growth. Management of sarcomas should be aggressive with consideration given to re-excision, placement of brachytherapy catheters, metastectomy, and limb salvage with adjuvant therapy when possible. Preoperatively, children should receive clinical and radiographic (computed tomography or magnetic resonance imaging) evaluation for hydrocephalus.

Adolescent↗

PubMed2000

Measuring enzyme motility in organic media using novel H-D exchange methodology.

A novel deuterium ((2)H) NMR technique as developed for measuring the total number of deuterons exchanged by lyophilised protein samples following hydrogen-deuterium (H-D) exchange. Using this methodology differences in the H-D exchange behaviour of the proteolytic enzyme subtilisin Carlsberg hydrated either in air or an organic solvent were probed as a function of hydration. At low thermodynamic water activity (a(w)), the degree of H-D exchange increased rapidly with hydration (from anhydrous to a(w) 0.22). At a(w) 0.22, subtilisin powders hydrated in air were found to have reached an H-D exchange level comparable to that found upon aqueous dissolution and in agreement with previous studies using lysozyme. Lyophilised subtilisin hydrated in either dichloromethane (DCM) or diisopropyl ether (DIPE) showed a pattern of exchange (vs. a(w)) comparable to that found for powders hydrated in air. However, subtilisin hydrated in n-hexane showed a significant reduction in H-D exchange at all a(w) studied. Control experiments demonstrated that the reduction in H-D exchange observed for subtilisin in n-hexane was not a kinetic effect. This lower level of exchange in n-hexane implies that hydrated subtilisin Carlsberg has a lower conformational motility and more rigid protein matrix.

Air↗

PubMed2000

Brain volume in children with neurofibromatosis type 1: relation to neuropsychological status.

OBJECTIVE: To determine characteristics of brain morphology in children and adolescents with neurofibromatosis type 1 and relate these characteristics to neuropsychological functioning. BACKGROUND: Neurofibromatosis type 1 is associated with numerous CNS abnormalities and cognitive impairment. Abnormal high signal intensity visible on brain MRI, brain tumors, and macrocephaly are common. Research into links between neuroanatomic and cognitive features has been inconclusive. METHODS: Fifty-two children and adolescents with neurofibromatosis type 1 were compared with 19 control subjects on several quantitative neuroanatomic and neuropsychological measures. RESULTS: Total brain volume, especially gray matter, was significantly greater for neurofibromatosis type 1 subjects than the control subjects. Group differences in the ratio of gray matter to white matter were more prominent in younger than in older subjects. Volume of gray matter in the subjects with neurofibromatosis type 1 was related to their degree of learning disability. Corpus callosum size was significantly larger for subjects in the neurofibromatosis type 1 group, and diminished performance on measures of academic achievement and visual-spatial and motor skills were associated with greater regional corpus callosum size. CONCLUSIONS: Neuroanatomic morphology and the developmental pattern of gray matter and white matter in subjects with neurofibromatosis type 1 differed from in control subjects. Some of these differences are related to the neuropsychological status of the neurofibromatosis type 1 group. We propose that delayed developmental apoptosis results in macrocephaly and a delay in the development of appropriate neuronal connections in children with neurofibromatosis type 1. We further propose that these morphologic delays are related to the cognitive profile of neurofibromatosis type 1.

Adolescent↗

PubMed2000

Behavioral phenotype of neurofibromatosis, type 1.

Neurofibromatosis, type 1 (NF1) is a very common inherited disorder that was first described in the late 19th century. NF1 is associated with a myriad of behavioral manifestations in addition to its frequent and often severe medical and physical complications. Learning disability, cognitive impairment, emotional and psychosocial difficulties have been reported so frequently in neurofibromatosis that these are often considered hallmarks. This report briefly introduces the medical and physical characteristics of NF1. We then detail the behavioral manifestations of NF1 with additional discussion of possible etiologies for the high incidence of these behavioral difficulties. MRDD Research Reviews 2000;6:117-124.

Attention Deficit Disorder with Hyperactivity↗

PubMed2000

Quantitative morphology of the corpus callosum in children with neurofibromatosis and attention-deficit hyperactivity disorder.

Neurofibromatosis-1 is a common autosomal-dominant genetic disorder associated with numerous physical anomalies and an increased incidence of attention-deficit hyperactivity disorder (ADHD). Studies of children with idiopathic ADHD have suggested a link between corpus callosum size and symptom severity. This study examines the contribution of corpus callosum morphology to symptoms of ADHD in children with neurofibromatosis. Eighteen control subjects and 36 children with neurofibromatosis underwent magnetic resonance imaging of the brain. Twelve subjects with neurofibromatosis had evidence of ADHD and 24 did not. Subjects with neurofibromatosis had significantly larger total corpus callosum area and significantly larger regional measurements in three of seven areas. However, there were no differences between the neurofibromatosis alone and neurofibromatosis plus ADHD groups. Increased severity of attention problems was associated with smaller total callosal areas. These results suggest that some features of ADHD in children with neurofibromatosis could be linked to quantifiable differences in brain morphology, but the nature of the genetic mutation in neurofibromatosis suggests that neurochemical effects also could be important.

Adolescent↗

PubMed1999

Brain tumors in children with neurofibromatosis: additional neuropsychological morbidity?

Neurofibromatosis type 1 is a common autosomal dominant genetic disorder associated with numerous physical anomalies and an increased incidence of neuropsychological impairment. Tumors of the CNS occur in approximately 15% of children with neurofibromatosis, presenting additional risk for cognitive impairment. This study examines the impact of an additional diagnosis of brain tumor on the cognitive profile of children with neurofibromatosis. A comprehensive battery of neuropsychological tests was administered to 149 children with neurofibromatosis. Thirty-six of these children had a codiagnosis of brain tumor. A subset of 36 children with neurofibromatosis alone was matched with the group of children diagnosed with neurofibromatosis and brain tumor. Although mean scores of the neurofibromatosis plus brain tumor group were, in general, lower than those of the neurofibromatosis alone group, these differences were not statistically significant. Children in the neurofibromatosis plus brain tumor group who received cranial irradiation (n = 9) demonstrated weaker academic abilities than did children with brain tumor who had not received that treatment. These results suggest that neurofibromatosis is associated with impairments in cognitive functioning, but the severity of the problems is not significantly exacerbated by the codiagnosis of a brain tumor unless treatment includes cranial irradiation.

Adolescent↗

PubMed1999

Neurocognitive development of children after a cerebellar tumor in infancy: A longitudinal study.

PURPOSE: To assess the long-term neuropsychologic effects experienced by children who have tumors in the cerebellum that are diagnosed and treated during infancy. PATIENTS AND METHODS: Twenty-seven children with posterior fossa tumors diagnosed at less than 36 months of age were assessed prospectively with a comprehensive set of age-appropriate tests. Group means and SDs are reported for assessments conducted at diagnosis (analysis 1) and at the most recent follow-up appointment (analysis 2). Cognitive developmental growth curves were derived from the prospective data (analysis 3) using mixed model regression analyses and controlling for age at diagnosis and socioeconomic status. RESULTS: In the first analysis, eight of 11 infants at diagnosis scored within normal limits on all neuropsychologic domains, except for motor skills, which were impaired. In the second analysis, mean scores at the most recent follow-up of 21 of 27 patients were mostly in the normal range; however, group comparisons between those who had (n = 7) and had not (n = 14) been treated with cranial radiation therapy (CRT) showed that patients in the irradiated (CRT) group scored significantly lower than those in the nonirradiated (No-CRT) group on verbal intelligence quotient (IQ) and in the motor domain. In the third analysis (growth curves of CRT and No-CRT groups), statistically significant differences in slope were found on verbal IQ, performance IQ, perceptual-motor skills, language, and attention/executive skills. Slopes on the fine-motor domain were similar; both groups declined at approximately the same rate. CONCLUSION: Neurocognitive development and outcome of children with cerebellar tumors diagnosed in infancy is very positive among those who were treated with surgery and chemotherapy. Declines in performance across time were minimal, and scores tended to remain within normal limits. By itself, a cerebellar tumor in infancy does not seem to have a significant impact on children. However, those who received CRT as part of their treatment are likely to have neurocognitive and psychosocial deficits that require remediational interventions.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1998

Activity and mobility of subtilisin in low water organic media: hydration is more important than solvent dielectric.

The relationship between hydration, catalytic activity and protein dynamics was investigated for subtilisin Carlsberg in organic solvents with low water content. The organic media were cyclohexane, dichloromethane or acetonitrile, with controlled thermodynamic water activity (aw). Catalytic rate profiles showed the same dependence on aw for the three different solvents. The structural mobility of the enzyme in air and organic media was probed by proton solid-state NMR relaxation measurements. Both spin-lattice relaxation time (T1 ) and line width at half height (apparent spin-spin relaxation time (T2)) were determined for protein which was exchanged and hydrated with D2O. We found NMR relaxation was much more dependent on aw than medium identity (despite very different dielectrics) showing that enzyme hydration is the primary determinant of mobility. Results suggest that initial hydration up to aw 0.22 causes rigidification of part of the protein structure. As aw is increased further, enzyme mobility is found to increase. Above aw 0.44, a large increase in the proportion of more mobile protons coincides with a steep rise in catalytic activity for the enzyme in each of the solvents studied.

Deuterium Oxide↗

PubMed1997

Influence of secondary structure on the decay kinetics of fluorescent donor-acceptor labelled peptides.

Time-resolved fluorescence decays from a series of methoxynaphthalene labelled peptides in ethyl acetate were monitored over the temperature range -40 to 60 degrees C. The quenching effect of a piperidone acceptor group placed at various positions along the peptide chain relative to the fluorescent methoxynaphthalene donor was studied. In this moderately polar solvent the mechanism of quenching is most likely electron transfer, although a Dexter exchange mechanism cannot be ruled out. Both donor and acceptor moieties were covalently attached to the side-chains of glutamic acid residues. These were either placed adjacently, in the case of a dipeptide, or separated by three and six amino acids within a 12 and 15 amino-acid oligopeptide, respectively. The presence of the piperidone group resulted in a reduction in the fluorescence lifetime and a change from a simple monoexponential decay to more complex behaviour. This was found to vary reversibly with temperature and not to be caused by impurities. Modelling of the fluorescence decays was carried out using either the sum of two exponentials or a distribution of decays. For the dipeptide the best fit was a distribution while in the case of the 12-mer two clearly distinguishable populations could be observed. The results for the 15-mer were equivocal. Importantly, regardless of the fitting method used the quenching rate was found to be fastest for the 12-mer. The slower quenching rates observed for the dipeptide compared to the oligopeptides provide strong evidence that secondary structure promotes better electronic coupling between the donor and acceptor. The biexponential fluorescence behaviour for the 12 amino-acid oligopeptide is ascribed to two slowly (> 10 ns) interconverting conformational states. Comparison with circular dichroism and infrared obtained in acetonitrile indicates these two conformers are likely to be an alpha-helix and a 3(10)-helix with electronic coupling strongest in the latter case.

Fluorescence↗

PubMed1997

Visual anomalies in young children exposed to cocaine.

PURPOSE: The number of children exposed to cocaine in utero each year is increasing. Recent reports suggest significant visual anomalies in infants prenatally exposed to cocaine. The purpose of this retrospective study was to determine if children exposed prenatally to cocaine were at a greater risk for visual abnormalities, such as strabismus and significant refractive errors. METHODS: This pilot study was conducted at two sites, an outpatient clinic and a hospital-based practice. Consecutive files from January to July, 1993, of 79 children (aged 4 months to 94 months); who were identified by case history or meconium analysis information as being exposed to cocaine in utero, were reviewed. Fifty-five children met the inclusion criteria for the study. In addition, a control group of 100 pediatric patients were randomly selected from the pediatric patients seen at the outpatient clinical site. RESULTS: Of the 30 children from the Illinois Eye Institute (IEI) and the 25 children from The Children's Hospital (TCH), spherical refractive errors in the right eye ranged from +6.50 to -12.50 D. The median refractive errors were +0.75 and +0.50 D, respectively. No statistical difference was found in spherical refractive error, astigmatism, or anisometropia between the cocaine-exposed cohorts and the control group (N = 100). Strabismus was found in 15/55 (27%) of the children in the cocaine-exposed group. There was a statistically significant difference in the prevalence of strabismus between the cocaine-exposed group and the control group. Further analysis revealed that full birthweight (> 2500 g) children prenatally exposed to cocaine were at a greater risk for strabismus as compared to the full birthweight control group. Ocular abnormalities were rare, but included optic nerve atrophy and retinopathy of prematurity. CONCLUSIONS: These data suggest cocaine exposure during pregnancy may place a child at risk for conditions that may negatively impact the visual system, specifically strabismus.

Abnormalities, Drug-Induced↗

PubMed1996

Correlation of medical and neurosurgical events with neuropsychological status in children at diagnosis of astrocytoma: utilization of a neurological severity score.

Neuropsychological studies of children who have brain tumors have yielded diverse results with respect to identifying factors that contribute to poor intellectual outcome. The purpose of this study was to evaluate the relationship between pre- and perioperative events, tumor-related factors, and the neuropsychological status of children diagnosed with astrocytoma. Events that could potentially be detrimental to neuropsychological outcome were quantified utilizing a new "neurological severity score." The Neurological Severity Score was developed as a research tool to test our hypothesis that ultimate intellectual outcome is a result of cumulative, interactive insults on the central nervous system. This study constitutes a first step in examining the predictive value of the Neurological Severity Score by evaluating its correlation with baseline neuropsychological status. Fifty-nine children who had astrocytoma (36 supratentorial and 23 infratentorial) received complete neurological and neuropsychological evaluations within 3 months of diagnosis. Each child's neurological history and examination results were scored by an independent observer using the Neurological Severity Score. Neuroimages obtained at diagnosis and at the time of neuropsychological testing were evaluated as well. For the group as a whole, memory, attention, and motor abilities were significantly below age-appropriate norms, whereas intelligence, language, and academic skills were preserved. Patterns of deficits were identified and related to tumor site. There were no significant differences in mean neuropsychological domain scores between groups based on gender, pre-versus post-operative status, ethnicity, tumor grade, or abnormalities on magnetic resonance imaging (MRI). The Neurological Severity Score was significantly inversely correlated with visual-spatial skills, memory, attention, performance IQ, and global IQ. In conclusion, among all the medical and neurological factors present at diagnosis, the neurological severity score had the highest correlation with neuropsychological scores. This instrument has promise as a research tool in investigations of the psychological effects of cancer and its treatment on children.

Achievement↗

PubMed1996

Neuropsychologic effects of chemotherapy on children with cancer: a longitudinal study.

PURPOSE: A prospective study was conducted to assess the effects of chemotherapy for cancer on children's long-term neuropsychologic status. PATIENTS AND METHODS: Ninety-nine children who received no cranial radiation therapy (CRT) completed four annual neuropsychologic assessments. Fifty-one patients received intrathecal (IT) chemotherapy (ITC); 48 received no CNS treatment. These two groups were compared using repeated-measures analysis of variance on IQ, memory, language, freedom from distractibility, academic achievement, executive functions, and fine-motor, perceptual-motor, and tactile-spatial skills. In addition, 51 of the sample of 99 patients had been examined 5 to 11 years after diagnosis. Their data were analyzed to evaluate the longer-term effects of chemotherapy. The predictability of demographic and medical variables on neuropsychologic outcome at 3-year and long-term follow-up study were assessed using multiple regression techniques. RESULTS: Overall, the effects of chemotherapy in the absence of CRT appear to be slight. Patients who received ITC and intravenous (IV) methotrexate declined slightly on perceptual-motor skills, but were still well within the normal range. Both groups, regardless of treatment, declined on academic achievement tests, although not to a statistically significant degree. Age effects were found on performance IQ (PIQ) and perceptual-motor skills. Socioeconomic status (SES) correlated with a large number of variables. Sex effects were not significant. CONCLUSION: The present results are largely consistent with previous findings for nonirradiated groups. Treatment effects from ITC are slightly more apparent 5 to 11 years after diagnosis than at 3-year follow-up evaluation but this does not constitute a clinically meaningful difference. More noticeable are academic declines among all groups, regardless of treatment.

Adolescent↗

PubMed1996

Neuropsychological significance of areas of high signal intensity on brain MRIs of children with neurofibromatosis.

Of children with neurofibromatosis (NF), 40% have a cognitive or learning impairment. Approximately 60% also have anomalous areas of high signal intensity on T2-weighted brain MRIs. The association of these hyperintensities and neuropsychological status is not fully understood. We administered a battery of neuropsychological tests and a standard clinical MRI to determine the impact of hyperintensity presence, number, and location on cognitive status in 84 children (8 to 16 years) with NF type 1. These children underwent standard clinical MRI using a GE 1.5-tesla scanner (except one child who was examined with a 1.0-tesla scanner). We conducted three types of analyses: Hyperintensity presence or absence.-Scores of children with (55%) and without hyperintensities (45%) were compared using t tests. No statistically significant differences between groups in intellectual functioning or any neuropsychological variable were found. Number of hyperintensities-The number of hyperintensity locations per child ranged from one to five (mean = 2.22). Pearson correlations revealed no significant association between the number of hyperintensities and neuropsychological performance. Location of hyperintensities-In four of the five locations studied, no statistically significant differences were found between scores of children with a hyperintensity in an area and those with one elsewhere. However, mean scores for IQ, Memory, Motor, Distractibility, and Attention domains for children with hyperintensities in the thalamus were significantly lower than scores for those with hyperintensities elsewhere. These results suggest that the simple presence or absence of hyperintensities, or their total number, is not as important as their anatomic location for detecting their relationship with neuropsychological status. Taking location into account, hyperintensities in the cerebral hemispheres, basal ganglia, brainstem, or cerebellum seem to have no impact on neuropsychological functioning, whereas hyperintensities in the thalamus do.

Adolescent↗